Latest Entries »

I need to close this Blog for a few Weeks because i can’t stay focused,

always the earth is shaking here in Suburbia of Tokyo and new harder  Tremors are always possible!

But i will be back, if i am still alive!

For the People who do/ need a proper research i recommend the Documents at

Drugs-Forum.com

as you can see in my Blog-list!

Stay well, stay tuned and stay informed!

Regards from Tokyo

Drogenabhängige sind gegen kostenloses Heroin“, berichtet Politiken. Wie die dänische Tageszeitung erklärt, können sich Süchtige seit zehn Monaten in öffentlichen Hilfseinrichtungen kostenlos rezeptpflichtige Heroin-Dosen verabreichen lassen. Es handelt sich um reines Heroin, dass ohne jede strafrechtliche Verfolgung konsumiert werden kann. Dennoch haben nur 80 Menschen dieses Angebot in Anspruch genommen, an das ebenfalls eine Behandlung gebunden ist. Insgesamt verfügen die Einrichtungen über 300 Plätze. „Die Behandlung schränkt den Patienten sehr ein, wird streng überwacht und kontrolliert“, erklärt der leitende Sozialmediziner der dänischen Hauptstadt. Die Drogenabhängigen müssen ein oder zwei Mal täglich in die Einrichtung kommen und jede einzelne Dosis muss unter medizinischer Aufsicht eingenommen werden. „Wenn die Junkies das vom Staat bezahlte Heroin ablehnen, ist klar, dass das Programm überarbeitet werden muss“ und die betroffenen Personen vielmehr angehört werden müssen, meint Politiken.

Bonn/Rheinbach. Dass in vielen Gefängnissen nicht nur Handys und Alkohol, sondern auch Drogen unter den Gefangenen gehandelt werden, ist ein offenes Geheimnis. In der Justizvollzugsanstalt (JVA) Rheinbach sollen sich jetzt sogar zwei Beamte mit sechs Gefangenen und zwei externen Dealern zusammengetan haben, um den Handel mit Heroin und Cannabis professionell zu organisieren.

 Foto: Saxler-SchmidtFoto: Saxler-Schmidt

Wie Oberstaatsanwalt Robin Faßbender am Mittwoch mitteilte, wurden die zehn Männer im Alter zwischen 27 und 52 Jahren jetzt wegen bandenmäßigen Drogenhandels sowie Bestechlichkeit und Bestechung im besonders schweren Fall angeklagt. Voraussichtlich müssen sie sich demnächst vor der 3. Großen Strafkammer des Bonner Landgerichts verantworten.

„Ein derartiger Fall ist im hiesigen Bereich noch nicht bekannt geworden“, so Faßbender zu der Dimension des Drogenhandels hinter Gittern. Bei 13 Taten, die in den Augen der Staatsanwaltschaft nachgewiesen werden können, sollen 635 Gramm Heroin und 800 Gramm Cannabis in das Gefängnis eingeschleust worden sein.

Der Verkauf der Drogen brachte anscheinend mehr als 100 000 Euro ein. Die Initiative soll im März 2008 von zwei Insassen der JVA ausgegangen sein: Offenbar wussten sie, dass ein 52 Jahre alter Bediensteter in finanziellen Schwierigkeiten steckte.

Der Vollzugsbeamte ließ sich schließlich laut Anklage auf den Plan der Männer ein: Von zwei Dealern bekam er die in Päckchen verpackten Drogen nach Hause in seinen Briefkasten geliefert, so der Oberstaatsanwalt. Anschließend soll er die Päckchen in die JVA geschleust haben.

Dort hatten die beteiligten Gefangenen, die allesamt mehrjährige Haftstrafen absitzen, anscheinend ein regelrechtes Handelsnetz aufgebaut: Neben den Drogen sollen auch eingeschleuste Waren wie Mobiltelefone und Sonnenbrillen an die Mithäftlinge verkauft worden sein.

Wenn Gefangene Bestellungen aufgaben, sollen sich die Bandenmitglieder bei einem mitangeklagten 36 Jahre alten Beamten – der Einblick in die Gefangenenkonten hatte – erst einmal über deren finanzielle Verhältnisse Klarheit verschafft haben.

Doch im November 2008 bekamen die Ermittler Wind von dem Treiben: Ein 43 Jahre alter Häftling, der an den Bestellungen und dem Verkauf der Drogen beteiligt gewesen sein soll, packte aus. Es folgten verdeckte Ermittlungen, bei denen vor allem etliche Handys überwacht wurden.

Im März 2009 schlugen die Fahnder der Ermittlungsgruppe „Briefkasten“ dann zu: Sie durchsuchten unter anderem bei dem 52-Jährigen und nahmen den Vollzugsbeamten in Untersuchungshaft. Nach fünf Monaten wurde er gegen Auflagen wieder auf freien Fuß gesetzt.

Dass erst jetzt Anklage erhoben wurde, lag laut Faßbender an den langwierigen Ermittlungen – insgesamt wurden Verfahren gegen mehr als 100 Personen eingeleitet – und der sich nur nach und nach entwickelnden Aussagebereitschaft der inzwischen teilgeständigen Angeklagten. Das Fall wird in Kürze am Bonner Landgericht verhandelt.

Artikel vom 10.03.2011 http://www.general-anzeiger-bonn.de/index.php?k=loka&itemid=10001&detailid=860047

DOCTORS are writing thousands of suspect prescriptions for a pharmaceutical variation of heroin, much of it destined for the black market, forcing the federal government to investigate the actions of 50 medical practitioners.

More than 580,000 taxpayer-funded scripts were approved in NSW in the past two years for OxyContin and similar opiate painkillers, such as OxyNorm and MS-Contin, dubbed “hillbilly heroin“.

For every $34 script of OxyContin, users are obtaining a box of 20, 80 milligram tablets. Each tablet can then sell on the black market for as much as $50. With further subsidies to pensioners, the box can be bought for as little as $6 – and its contents might be sold on the street for $1000.

Advertisement: Story continues below 

While the medication has revolutionised care for chronic pain sufferers, it is leaking out of the health system to such an extent that police and health experts warn it could soon surpass street heroin and ice as the needle addict’s drug of choice.

The prescription opioids are obtained unlawfully by dealers and addicts who “doctor shop“ for multiple prescriptions. One patient visited 46 doctors in three months and obtained 119 scripts, primarily for OxyContin, the government has confirmed.

Sydney doctor Alan Saunders, who has been targeted by doctor shoppers, warned: „It’s not just OxyContin – it’s valium and all the other drugs. The government is subsidising the drug trade.“

Pharmacists say they are confronted with stolen and fake scripts, while legitimate pain sufferers are obtaining the drug and then selling it.

The government acknowledges the problem. Federal Minister for Human Services Tanya Plibersek confirmed to The Sun-Herald that Medicare had identified 50 doctors for “unusually high levels of prescription writing for drugs such as OxyContin and OxyNorm“.

„The misuse of prescription narcotics is a growing problem which destroys lives and tears communities apart. Doctors suspected of making these drugs available to patients who do not require them for clinical purposes will be put on notice.“

With a slow-release formula, OxyContin capsules are designed to work through the day. Illicit users, however, discard the other binding agents and extract the drug in its purest form so, when injected, it delivers an instant hit.

According to new state government statistics released to The Sun-Herald, more than $557 million worth of illegal drugs were seized in the state last year – more than double the street value of the previous year’s tally of $260 million. The haul included $185.2 million worth of cannabis, $126 million of cocaine, $195 million of amphetamines and $28 million of MDMA/ecstasy. NSW Police Minister Michael Daley said the figures showed police were doing “a fantastic job keeping our streets safe“, adding: “It’s millions of doses of deadly substances that have been kept out of the veins of would-be drug users.“

Significantly, NSW police also seized more than $25 million worth of heroin. At the same time, a taxpayer-funded version of the drug is infiltrating the black market. The commander of the NSW drug squad, Nick Bingham, said: “We’re talking pharmaceutical-grade heroin. It’s highly sought after in the drug-using community and, unfortunately, it is finding its way [onto the streets]. To be honest, police don’t particularly want to have to target prescription opiates when there are other important things to tackle, such as organised crime.“

Inspector Bingham is part of the recently formed National Pharmaceutical Misuse Strategy Committee and said prescription opiates were “high on the agenda … One of the discussion points is educating doctors in regards to prescriptions … there needs to be tighter scrutiny.“ The director of the Alcohol and Drug Service at St Vincent’s Hospital, Alex Wodak, agrees major reforms are needed to improve the way opiates are prescribed by the medical profession: “The process needs to be far more discriminating, more realistic, more careful.

“GPs do the bulk of this work. They’re under tremendous pressure and could do with better assistance from the whole system, whether it be from medicine doctors, psychiatrists, pain doctors or better guidelines tailored to them.“

Dr Wodak also referred to the “long overdue“ national real-time database which, if implemented, could alert authorities when “runners“ try to use multiple scripts at different chemists, at different locations.

“The Commonwealth seems interested in trying to get all the states to adopt a similar live system,“ he said. “If we are serious about this issue, we have to form a national response.“

But Richard Mattick, from the National Drug and Alcohol Research Centre, fears a crackdown could hit genuine pain sufferers.

“Let’s not forget these medications are terribly important to the community,“ he said. “If you have a loved one affected by cancer or serious pain, you want them to receive the best possible care and these medications are much better, much safer than anything previously available. The community is better served and, in a way, that has allowed prescribing to be more generous.

“The danger here is that we see the bad side but don’t balance that against the need.“

Gideon Warhaft, of the NSW Users & AIDS Association, argues: “There will always be people who inject drugs and there will always be people with narcotics dependencies. The positive advantage with OxyContin is that users know exactly what they’re getting, whereas with heroin, they don’t. Many now prefer OxyContin because it’s clean and it’s safer.“

Patients ’sell drugs to help families‘

"Better than heroin" ... Stephen buys Oxycontin from people who are terminally ill.„Better than heroin“ … Stephen buys Oxycontin from people who are terminally ill. Photo: Jacky Ghossein

FORMER heroin user Stephen* has been using Oxycontin for six years but has a better alternative than doctor shopping. He buys the drug from terminally ill people who use the funds as a legacy for their families.

“I got introduced to Oxycontin by a sick friend who was being prescribed it. They were receiving roughly 30 per cent more than they needed so I took it off their hands.

“There are a lot of terminally ill people out there who get so much of this stuff, they’re selling it and making a fortune. It’s their legacy, for their kids … it’s a far better option than doctor shopping, taking risks and ending up in jail. They’re helping you and you feel as though you’re helping them.“

Advertisement: Story continues below

He said the Oxycontin rush wasn’t as intense as heroin and it wore off more quickly but the feeling was “extremely similar“ to heroin and many users preferred it.

“Heroin can be dangerous, particularly if you don’t know where it’s come from … I have overdosed twice. But with Oxycontin, you know exactly what dose you’re getting and at $30-$40 for an 80 milligram tablet, it’s far better value for money.“

He said if politicians came down on Oxycontin, users would “revert … to heroin – which can mean stealing, armed robberies and doing absolutely anything to fund it“.

source: http://www.smh.com.au/nsw/legal-heroin-sold-to-addicts-20110305-1bipy.html

More young people are becoming addicted to heroin in Burma’s northernmost Kachin state as authorities fail to clamp down on dealers, sources in several towns have warned.

Males between the ages of 17 and 40 were among the most affected,s aid a resident of Mogaung town, which lies just west of the Kachin capital, Myitkyina. Other towns suffering rising rates of addiction were Mohnyin, Myitkyina and Hpakant, he added.

“The kids are so ruined,” the man said. “Everyone, from students aged around 18 to even farmers, are addicted to heroin. They were only trying it out at the beginning but now are addicted.”

He continued that most addicts were injecting the drug, a cheaper method despite the health risks. One intra-venous hit, he said, cost around 1000 kyat ($US1), while smoking through a pipe costs up to 4000 kyat ($US4.50).

A group of heroin dealers were reportedly arrested last month in Mohnyin by the government’s Anti-Drugs Task Force (ADTF) but later released on bail. The man said they had quickly got back to dealing.

BurmaBurma

Assertions by the Burmese government that it is stamping out the country’s lucrative drugs trade have been widely doubted: the US released a report last week saying that Burma had “demonstrably failed” to halt the trade of heroin and its derivative, opium, whilst statistics showed that in-country production of methamphetamine continues to rise.

The report was followed by an announcement in the state-run New Light of Myanmar newspaper that 15,021 acres of poppy fields were destroyed in 2010-2011, 411 of which were in Kachin state. Regardless, however, criticism continues to abound.

“The government is the main culprit for this,” said the Mogaung resident. “The government is the first to blame and the dealers the second. They are openly selling drugs on a tray.”

He claimed that dealers paid monthly bribes of up to 400,000 kyat ($US450) to government officials, including the ANTF.

Two years ago the Kachin News Group released an alarming report claiming that a significant number of students at the once prestigious Myitkyina University in Kachin state had fallen victim to drug addiction, notably heroin, with dealers initially luring students in with free samples.

Until the late 1990s and the explosion in Afghan heroin, Burma had held the distinction of being the world’s leading source of the narcotic, with the ethnic United Wa State Army producing hundreds of thousands of tonnes each year.

A report released last year by the Thailand-based Shan Drug Watch claimed that junta-backed militias had taken over ethnic armies as Burma’s main drugs’ producers, with the product finding its way to neighbouring Thailand and China.

 

source:http://www.eurasiareview.com/world-news/asia/burma-heroin-use-up-as-supply-goes-unchecked-08032011/

There has been a dramatic decrease in the amount of heroin in the UK, BBC News has learned.

The Serious Organised Crime Agency claimed the drop was due to supply routes being cut off and said the street price of the drug had doubled.

Europe’s biggest drug testing company, Concateno, said the number of addicts testing positively for heroin had halved in the past six months.

However, it warned that suppliers were diluting heroin with other drugs.

If heroin purity returned to normal levels, addicts would face an increased risk of overdose.

There are an estimated 300,000 users of heroin, which comes mainly from Afghanistan and Pakistan, in the UK.

Concateno takes swabs from anyone on a court testing order or in drug treatment for heroin.

Its figures show positive tests occurring in up to 48% of cases over recent years, but last December the rate fell to 22%.

The suggestion of an interruption in the supply is backed up by police reports of shortages in several places in the UK.

Officers from the Serious Organised Crime Agency (Soca) point to both the efforts of law enforcement agencies and environmental factors such as the floods in Pakistan.

And they say exaggerated perceptions among traffickers of a poppy blight may have led dealers to hold their supplies back and create higher prices on the street.

Relationships between Soca and the Turkish police are also said to be strengthening, leading to pressure on what has been a key supply route.

The drug is now said to command £40,000 a kilo – double the price of last year.

Posted by the BBC

 

Auf angemessene Behandlung haben Schmerzpatienten einen klaren Anspruch. Ärzte befürchten jetzt, dass eine neue medizinische Leitlinie ihre Arbeit erschweren könnte.

Schlafmohn, aus dem natürlich Opioide gewonnen werden

 

Schmerzpatienten müssen geduldig sein. Oft vergehen leidvolle Jahre mit einer Odyssee von Arzt zu Arzt, bis sie endlich eine angemessene Behandlung erfahren. Aber auch die Geduld von Schmerztherapeuten wird strapaziert. Nachdem Pioniere wie Thomas Flöter in Frankfurt am Main und Dietrich Jungck in Hamburg vor fast dreißig Jahren die ersten kassenärztlichen Praxen für Schmerztherapie eröffnet hatten, war es noch ein steiniger Weg zu der Einsicht in der Ärzteschaft, dass Schmerz als eigenständige Krankheit auftreten kann.

Nun sehen Schmerztherapeuten neues Unheil heraufziehen. Anlass ist eine im vergangenen Herbst vorgelegte Leitlinie mit dem Kürzel „Lonts“, in der die Langzeit-Anwendung von Opioiden bei nicht tumorbedingten Schmerzen in Frage gestellt wird. „Über drei Monate hinausgehende Daueranwendungen opioidhaltiger Analgetika haben keine nachgewiesenen anhaltenden Schmerzlinderungen erbracht“, lautet eine der Schlussfolgerungen. Auf dem Deutschen Schmerz- und Palliativtag vergangene Woche in Frankfurt am Main sorgte dieses Papier für Empörung. Man ging mit ihm hart ins Gericht.

Artikel-Services

Schmerztherapie

Streit um Opioide

Auf angemessene Behandlung haben Schmerzpatienten einen klaren Anspruch. Ärzte befürchten jetzt, dass eine neue medizinische Leitlinie ihre Arbeit erschweren könnte.

Von Reinhard Wandtner

Schlafmohn, aus dem natürlich Opioide gewonnen werdenSchlafmohn, aus dem natürlich Opioide gewonnen werden

29. März 2010

Schmerzpatienten müssen geduldig sein. Oft vergehen leidvolle Jahre mit einer Odyssee von Arzt zu Arzt, bis sie endlich eine angemessene Behandlung erfahren. Aber auch die Geduld von Schmerztherapeuten wird strapaziert. Nachdem Pioniere wie Thomas Flöter in Frankfurt am Main und Dietrich Jungck in Hamburg vor fast dreißig Jahren die ersten kassenärztlichen Praxen für Schmerztherapie eröffnet hatten, war es noch ein steiniger Weg zu der Einsicht in der Ärzteschaft, dass Schmerz als eigenständige Krankheit auftreten kann.

Nun sehen Schmerztherapeuten neues Unheil heraufziehen. Anlass ist eine im vergangenen Herbst vorgelegte Leitlinie mit dem Kürzel „Lonts“, in der die Langzeit-Anwendung von Opioiden bei nicht tumorbedingten Schmerzen in Frage gestellt wird. „Über drei Monate hinausgehende Daueranwendungen opioidhaltiger Analgetika haben keine nachgewiesenen anhaltenden Schmerzlinderungen erbracht“, lautet eine der Schlussfolgerungen. Auf dem Deutschen Schmerz- und Palliativtag vergangene Woche in Frankfurt am Main sorgte dieses Papier für Empörung. Man ging mit ihm hart ins Gericht.

Anzeige

Vor gar nicht langer Zeit herrschte unter Ärzten noch die Ansicht vor, Schmerzen seien stets eine Begleiterscheinung von „echten“ Erkrankungen. Die Schmerzbekämpfung galt gewissermaßen als Nebentätigkeit des jeweiligen Facharztes. Rückenschmerzen etwa fielen klar in die Zuständigkeit des Orthopäden. Besondere Kenntnisse schienen nicht nötig zu sein: bei leichten Beschwerden ein leichtes Mittel wie Paracetamol, bei starken Leiden notfalls ein Opioid.

Sind die Studien tatsächlich aussagekräftig?

Unermüdlich haben Ärzte, die über Erfahrung in spezieller Schmerztherapie verfügen, mit wissenschaftlicher Unterstützung gegen dieses Schubladendenken angekämpft – mit Erfolg. Inzwischen orientieren sich informierte Therapeuten nicht mehr nur an der Stärke des Schmerzes, sondern vor allem an den von Patient zu Patient oft recht unterschiedlichen Mechanismen. So kann es angebracht sein, das Stufenschema auf den Kopf zu stellen und auch bei nicht tumorbedingten Schmerzen gleich ein Opioid anzuwenden, damit die Beschwerden nicht chronisch werden. Chronischer Schmerz kann sogar Hirnstrukturen verändern und ist schwer auszulöschen. Soeben ist in den „Proceedings“ der amerikanischen Nationalen Akademie der Wissenschaften (doi: 10.1073/pnas.1001504107) der Bericht einer finnischen Forschergruppe um Sanna Malinen erschienen, dem zufolge chronischer Schmerz auch bei ruhenden Patienten mit einem auffälligen Aktivitätsmuster im Gehirn einhergeht.

Ungezählte Patienten mit chronischen Schmerzen haben von der dauerhaften Opioidanwendung schon profitiert. Diesen Erfolg sehen viele Therapeuten durch die neue Leitlinie gefährdet, und entsprechend harsch fiel die Kritik aus. Der Psychologe Hardo Sorgatz von der Technischen Universität Darmstadt, unter dessen Leitung „Lonts“ im Auftrag der Deutschen Gesellschaft zum Studium des Schmerzes erarbeitet wurde, versuchte in Frankfurt einen verbalen Präventivschlag zur Verteidigung der Leitlinie. Diese genüge strengsten methodischen Kriterien und beruhe ausschließlich auf den Ergebnissen der wissenschaftlich aussagekräftigsten Studien. Doch Michael Überall vom Nürnberger Institut für Qualitätssicherung in Schmerztherapie und Palliativmedizin förderte hinter der Glanzfassade des Wissenschaftsgebäudes etliche Risse zutage. Er attestierte „massive methodische Schwächen bei der Analyse von wissenschaftlichen Studien“, die „zu falschen Schlussfolgerungen für die Langzeit-Therapie mit Opioiden“ führten.

Das Grundrecht auf Behandlung

Aufwendige Studien zur Wirkung von Opioiden und anderen Schmerzmitteln stammen häufig aus den Zulassungsverfahren für neue Medikamente. Diese erstrecken sich aber kaum über mehr als drei Monate, so dass man ihnen tatsächlich nichts über eine längere Anwendungsdauer entnehmen kann. Für den Präsidenten der Deutschen Gesellschaft für Schmerztherapie, Gerhard Müller-Schwefe aus Göppingen, steht der Nutzen für viele Patienten gleichwohl außer Frage. Nur lässt er sich schwer wissenschaftlich dokumentieren, denn dazu müsste man einigen Patienten die Opioide vorenthalten, was ethisch kaum zu rechtfertigen wäre.

So hilfreich Opioide sind – sie bergen auch Risiken. Das zeigt sich an der sogenannten Hyperalgesie, dem Phänomen, dass nach einiger Zeit die Schmerzempfindung sogar verstärkt werden kann. Gefördert wird dieser Effekt durch einen abrupten Entzug. Eine Gruppe um Jürgen Sandkühler von der Medizinischen Universität Wien hat herausgefunden, dass hierbei Kalzium-Ionen über bestimmte Rezeptorkanäle in die Nervenzellen der Schmerzbahn im Rückenmark strömen. Möglicherweise verursachen auch starke Schwankungen des Opioidspiegels während der Therapie eine Hyperalgesie. „Darum ist der Einsatz retardierter Darreichungsformen, die den Wirkstoff gleichmäßig über einen längeren Zeitraum abgeben, besonders wichtig“, sagte Sandkühler.

Patienten, die wegen Schmerzen in die Sprechstunde kommen, haben mehr Rechte, als sie und die Ärzte oft glauben. Darauf wies Klaus Kutzer, ehemals Vorsitzender Richter am Bundesgerichtshof, in Frankfurt hin. Er verdeutlichte, „dass es ein allgemeines Menschenrecht ist, von Schmerzen befreit zu werden und, wo dies nicht möglich ist, Schmerzlinderung zu erfahren“. Zudem gebe es hierzulande ein Grundrecht auf eine entsprechende Behandlung. Unter Bezug auf das jüngste Urteil zur Sicherung des Existenzminimums von Hartz-IV- Empfängern sagte Kutzer, die Bekämpfung schwerer Schmerzen sei „genauso ein Aspekt des menschenwürdigen Existenzminimums wie der Erhalt der zum Lebensunterhalt benötigten Geldmittel“. Unterlassene Schmerztherapie könne sogar Körperverletzung sein, denn „das Unterlassen ist dem Tun gleichzustellen, wenn die Pflicht besteht, Schmerzen zu beseitigen“.

Eine Vorreiterrolle beim konsequenten Schmerzmanagement will jetzt die Stadt Münster einnehmen. Dort wurde an diesem Dienstag ein Forschungsvorhaben der Paracelsus Medizinischen Privatuniversität Salzburg vorgestellt, das auf die umfassende Dokumentation und Verbesserung der stationären sowie ambulanten Versorgung zielt. Das Projekt „Aktionsbündnis Schmerzfreie Stadt Münster“ ist auf drei Jahre angelegt.

Text: F.A.Z.
Bildmaterial: Mark Nesbitt and Delwen Samuel, 1988

http://www.faz.net/s/Rub7F74ED2FDF2B439794CC2D664921E7FF/Doc~EF78D87D12166497697ECAB9B90BB7587~ATpl~Ecommon~Scontent.html

Die verbreitete Ansicht, dass Opioide sich nicht in ihrem Risikoprofil unterscheiden, muss möglicherweise revidiert werden. Ergebnissen einer Kohortenanalyse zufolge könnte eine länger andauernde Therapie mit Codein das kardiovaskuläre Risiko erhöhen, das Sterberisiko unter Codein und Oxycodon könnte steigen.

Immer wieder werden Ärzte aufgefordert, auch bei schweren, nicht tumorbedingten Schmerzen Opioide einzusetzen. Dabei ist, anders als bei nichtsteroidalen Antirheumatika, wenig darüber bekannt, wie die Risiken der einzelnen Opioide im Vergleich aussehen und ob die Annahme, dass sich Opioide in ihrem Risikoprofil ähneln, richtig ist. Deshalb wurden in einer amerikanischen Kohortenanalyse die Opioide Codein, Hydrocodon, Oxycodon, Propoxyphen und Tramadol im Hinblick auf ihr Risiko für Frakturen, kardiovaskuläre Ereignisse, gastrointestinale Komplikationen und die Sterblichkeit verglichen. Dazu wurden 6.275 Patienten nach dem Propensity-score-matched-Verfahren den fünf Opioid-Gruppen zugeordnet.

Kardiovaskuläre Ereignisse traten 30 Tage nach Behandlungsbeginn in allen Gruppen ähnlich häufig auf, waren jedoch nach 180 Tagen unter Codein erhöht (RR, 1,62; 95% CI, 1,27 – 2,06). Das Frakturrisiko war im Vergleich zu Hydrocodon nach 30 Tagen Einnahme von Tramadol und Propoxyphen signifikant reduziert. Keine Unterschiede wurden im Hinblick auf gastrointestinale Komplikationen gefunden. Dagegen war die Gesamtsterblichkeit im Vergleich zu Hydrocodon nach 30 Tagen Oxycodon-Therapie 2,4-fach, nach Codein-Therapie 2,05-fach erhöht. Die Autoren diskutieren, dass das erhöhte Sterberisiko in Zusammenhang mit kardiovaskulären Ereignissen stehen könnte oder aber auf weitere, nicht erfasste Confounder zurückzuführen ist. Insgesamt muss nach den Ergebnissen dieser Studie davon ausgegangen werden, dass sich Opioide in ihrem Risikoprofil unterscheiden. So ist bei Codein ein erhöhtes kardiovaskuläres Risiko bei längerer Anwendung nicht auszuschließen. Dieses Ergebnis ist überraschend und muss nach Ansicht der Autoren in weiteren Studien validiert werden.

 

Quelle: Salomon DH et al.: The Comparative Safety of Opioids for Nonmalignant Pain in Older Adults. Arch Intern Med 2010; 170(22): 1979-1986

 

Abstract

Ketamine administered intraoperatively in very small doses reduces postoperative opioid consumption. We suggest that this effect is the result of attenuation of acute tolerance to the analgesic effect of opioids. We sought to demonstrate that acute tolerance induced by alfentanil infusion can be attenuated by a dose of ketamine that is too small to produce a direct antinociceptive effect. The experiments were conducted in rats with the use of an infusion algorithm designed to maintain a constant plasma level of the opioid for 4 h. The degree of acute tolerance was determined on the basis of decline in the level of analgesia measured with a tail compression test. Ketamine (10 mg/kg) did not change the baseline pain threshold and did not increase the peak of alfentanil-induced analgesia. At the same time, it attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion. These effects were similar to those observed with dizocilpine (0.1 mg/kg). The development of acute tolerance to analgesia induced by the infusion of an opioid can be attenuated by ketamine administered in doses that are not large enough to provide a direct antinociceptive effect. Therefore, ketamine has the potential to reduce opioid consumption even in subanalgesic doses.

Abstract

Implications: Ketamine attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion.

The idea of combining an N-methyl-d-aspartate (NMDA) receptor antagonist, inhibiting pain-induced central hypersensitivity, with an opioid (1) has stirred considerable interest in analgesia research. Ketamine as a clinically available NMDA receptor antagonist has been especially attractive in this regard. The authors of a recent review summarizing studies on combined ketamine-opioid administration in postoperative pain concluded that results on the ability of ketamine to improve opioid analgesia are rather contradictory (2). Sethna et al. (3) demonstrated only simple additivity in the effects of ketamine and alfentanil on experimental pain in volunteers. The analgesic effect of ketamine in postoperative pain was observed when the drug was used in a dose range from 0.3 to 0.5 mg/kg, and the effect lasted only for 40 to 60 min (4–6).

Some of the clinical studies (7–9) revealed that ketamine administered during surgery reduced postoperative opioid consumption. These authors used small doses of ketamine (75–150 μg/kg) that could not provide analgesic concentrations in the biophase during the postoperative period. The reduction of opioid consumption was explained by the effect of ketamine on pain-induced central sensitization (7–9). An alternative explanation could be based on the ability of NMDA receptor antagonists to inhibit acute tolerance to the analgesic effect of opioids. We have reported previously (10) that the NMDA receptor antagonist dizocilpine attenuates the development of acute tolerance to analgesia induced in rats by IV infusion of alfentanil. This outcome is similar, although not identical, to the results reported in studies on chronic tolerance in which NMDA receptor antagonists (11–13) or NMDA receptor defect (14) blocked tolerance to the analgesic effect of morphine. Suppression of acute tolerance to alfentanil by dizocilpine, which does not have an analgesic effect by itself, indicates that the direct analgesic effect of ketamine and its effect on opioid-induced analgesia are not necessarily related: the opioid-induced analgesia could be enhanced by the effect of ketamine on opioid acute tolerance that reveals itself in relatively small subanalgesic doses.

Our principal purpose was to test the hypothesis that acute tolerance induced by alfentanil infusion can be attenuated by ketamine in a dose that is not large enough to provide a direct antinociceptive effect. With this aim, it will be possible to substantiate an approach to the treatment of postoperative pain that was actually used in a few clinical studies with ketamine, but the mechanism of ketamine-induced potentiation of opioid analgesia was not identified correctly. The potential of NMDA receptor antagonists to reduce acute tolerance to opioids may be a basis for a novel and important contribution to the relief of postoperative pain. An additional purpose of our study was to examine the effect of ketamine on another opioid-induced adaptive response-delayed hyperalgesia that follows the alfentanil infusion.

Methods

Experiments were performed on male Sprague-Dawley rats weighing 320–370 g. The animals were housed with a 12-h light-dark cycle, and food and water were available ad libitum. The protocol for this study was approved by the Institutional Panel on Laboratory Animal Care.

A catheter for the drug infusion was chronically implanted into the jugular vein, and its free end was exteriorized through the skin at the back of the neck. The surgical procedure for implantation was performed under pentobarbital (55 mg/kg intraperitoneally [IP]) anesthesia several days before the experiment. Alfentanil was infused with a Harvard Apparatus pump (model 55–2222; Harvard Apparatus Co., Natick, MA). Alfentanil infusion algorithm was based on the constants of one compartment model for rats derived from our previous study (15).

The responses to mechanical noxious stimulation were determined by measuring the threshold of motor response to increasing pressure applied to the tail—tail compression test (16) with the use of an Analgesy-Meter® (Ugo Basile, Milan, Italy). The rat’s tail was positioned on a Teflon platform, and the pressure plate (0.7-mm edge) attached to this device was applied to the tail while the rat was held in the experimenter’s hand. Pressure was increased at a constant rate (cutoff pressure of 2.375 kg) until coordinated struggle occurred. Three consecutive measurements were recorded, and the mean of the last two measurements was taken as the pressure threshold. For each consecutive determination of the pain threshold, the pressure plate was moved 2-mm cephalad. Measurements were made by an experimenter who was unaware of expected changes in the reaction thresholds among the treatment groups.

Animals were randomly divided into four groups: Alfentanil-Ketamine, Alfentanil-Dizocilpine, Alfentanil-Saline (bolus), and Saline (infusion)-Ketamine, each consisting of eight rats. In all groups, alfentanil was administered as described previously (15,17): a bolus dose of 50 μg/kg followed by an infusion rate of 155 μg · kg−1· h−1 for 4 h. This pattern was chosen to rapidly achieve and maintain a stable alfentanil plasma concentration. The degree of acute tolerance was determined on the basis of decline in the level of pressure threshold during the infusion period. After the alfentanil administration, the pressure threshold was measured twice: 1.5 h and 23 h after the infusion. The last measurement was made to determine the rebound hyperalgesia after the alfentanil infusion. According to preliminary experiments, the measurements made the next day revealed the maximal rebound hyperalgesia that disappeared in a few days after the infusion.

The interacting drugs were administered IV with the first injection given 60 min before the beginning of alfentanil infusion. The following doses were used: ketamine 10 mg/kg (Alfentanil Infusion-Ketamine Bolus Group); dizocilpine 0.1 mg/kg (Alfentanil Infusion-Dizocilpine Bolus Group); isotonic saline (Alfentanil Infusion-Saline Bolus Group); and ketamine 10 mg/kg (Saline Infusion-Ketamine Bolus Group).

The selection of the dose of ketamine was based on the preliminary experiments in which it was verified that 10 mg/kg was not providing an analgesic effect immediately after the drug injection. To further reduce the probability of some direct analgesic influence by ketamine, the interval between the injection of ketamine and the start of alfentanil administration was extended to 1 h. In the rat, ketamine 60 mg/kg IM provides incomplete analgesia, and only at doses of 100 to 120 mg/kg IP can it provide a complete anesthetic effect (18). A more specific NMDA receptor antagonist, dizocilpine, was used in a dose of 0.1 mg/kg.

In the above doses, neither ketamine nor dizocilpine produced behavioral effects interfering with the pressure threshold measurements. The interacting drugs were also administered 5 min after the last measurement of the pressure threshold on the day of alfentanil infusion (second administration) and on the next day, 19 h after the end of alfentanil infusion (third administration), both in the same dose as the first injection (see schedule for drug administration in Table 1).

Table 1.

Effect of Ketamine on Acute Tolerance and Rebound Hyperalgesia Induced by Alfentanil Infusion

The pressure threshold in each of the groups was determined before, and 5 min after, the administration of an interacting drug, at 30, 60, 120, 180, and 240 min after the beginning of alfentanil infusion, and at 1.5 and 23 h after the end of alfentanil infusion. Racemic ketamine hydrochloride was from Parke-Davis (Morris Plains, NJ), dizocilpine maleate (MK-801) was from Sigma Chemical Co. (St. Louis, MO), and alfentanil hydrochloride was from Taylor Pharmaceuticals (Decatur, IL).

The pressure threshold was treated as a continuous variable and was analyzed using a two-way (groups and time) analysis of variance with time treated as a repeated measures factor. Comparisons among groups at each time were performed with the use of an one-way analysis of variance. Multiple comparisons among pairs of means were made by using the Fisher’s protected least significant difference method (19). Differences were declared statistically significant if P < 0.05.

Results

Table 1 shows a summary of the data obtained in all four groups of experiments. The comparison of the pressure threshold before, and 5 min after, ketamine administration (10 mg/kg) indicates that ketamine had no significant analgesic effect. Because alfentanil administration was started 60 min after the ketamine injection, the presence of any direct analgesic effect of ketamine at that time would be even less likely. Dizocilpine also did not produce any changes in the pressure threshold measured 5 min after its injection.

The effect of ketamine on acute tolerance to alfentanil is illustrated by Figure 1, which shows a comparison of the alfentanil-induced changes in the pressure threshold. It demonstrates (A segment) that, in the Alfentanil-Saline Group, the pressure threshold before the end of alfentanil infusion was only insignificantly more than that before the start of infusion (808 ± 78 g vs 733 ± 66 g, not significant). At the same time, in the Alfentanil-Ketamine Group, the pressure threshold at the end of alfentanil infusion was much higher than that before the start of infusion (1078 ± 191 g vs 763 ± 64 g, P < 0.001); and it was higher than in the Alfentanil-Saline Group at the same time interval (1078 ± 191 g vs 808 ± 78 g, P < 0.05). The changes in the Alfentanil-Dizocilpine Group were similar to those in the Alfentanil-Ketamine Group. The Saline-Ketamine Group demonstrated a constant pressure threshold level for the whole study period.

Figure 1. The effect of ketamine on acute tolerance to continuously infused alfentanil. Alfentanil was administered as a bolus of 50 μg/kg followed by a constant-rate infusion at 155 μg · kg−1 · h−1 for 4 h. Ketamine was injected in a dose of 10 mg/kg IV 60 min before the start of alfentanil administration. A, Alf + Sal = alfentanil infusion and isotonic saline as an interacting drug; Alf + Diz = alfentanil infusion and dizocilpine 0.1 mg/kg IV 60 min before alfentanil; Alf + Ket = alfentanil infusion and ketamine 10 mg/kg IV 60 min before alfentanil; Sal + Ket = isotonic saline infusion and ketamine 10 mg/kg IV 60 min before the start of saline infusion. Each dot reflects a mean ± sd for a group of eight rats at various time intervals. *P < 0.05, +P < 0.01, both versus value at 30 min in each of the groups. B, Changes in cumulative reductions of the initial analgesic effect. Columns represent reductions in percent (mean ± sd). Cumulative reduction of the initial analgesic effect was calculated by comparing the alfentanil-induced increase in pressure threshold (from predrug baseline value) at 30 min of the infusion (initial analgesic effect) with the increases from the predrug baseline separately at 60, 120, and 240 min (gradual cumulation of the effect). *P < 0.05 versus corresponding value of Alf + Sal group.

The effects of ketamine and dizocilpine for reduction of the initial analgesic response at various time intervals during alfentanil infusion are presented in Figure 1B. Both drugs significantly (P<0.05) attenuated tolerance development at all time intervals as presented by cumulative reduction of the initial analgesic effect (explanation in the legend to Figure 1B). The effect of dizocilpine had a tendency to be more pronounced than that of ketamine, although this tendency did not reach statistical significance.

In addition to the attenuation of acute tolerance to alfentanil, ketamine inhibited the alfentanil-induced rebound hyperalgesia. After the 4-h alfentanil infusion, there was a decrease in the pressure threshold that reached its maximum the day after infusion and then gradually returned to the baseline level, usually 1–2 days later. Table 1 indicates that in the Alfentanil-Saline Group, 23 h after the end of alfentanil infusion, the pressure threshold was decreased 27% from baseline level (532 ± 65 g vs 733 ± 66 g, P < 0.001). In the Alfentanil-Ketamine Group, animals received three injections of ketamine 10 mg/kg (60 min before the start of alfentanil infusion, and 5 min and 19 h after its end). This treatment resulted in a decrease of the pressure threshold decline 23 h after the end of alfentanil infusion (539 ± 65 g in Alfentanil-Saline Group vs 692 ± 54 g in the Alfentanil-Ketamine Group, P < 0.001). Figure 2 shows a comparison of the degree of the rebound hyperalgesia with and without the NMDA receptor antagonist’s administration. Both ketamine and dizocilpine suppressed it, with dizocilpine completely suppressing it; however, statistical significance (P = 0.058) of the difference between the Dizocilpine and Ketamine Groups did not reach the accepted level of P value.

Figure 2. Effect of ketamine on rebound hyperalgesia induced by alfentanil infusion. Columns represent reductions of pressure thresholds (percent of baseline value, mean ± sd) 23 h after the end of the 4-h alfentanil infusion. Animals received three injections of interacting drugs in equal doses: 60 min before the start of alfentanil infusion, and 5 min and 19 h after its end. Ketamine was used at a dose of 10 mg/kg, and dizocilpine at a dose of 0.1 mg/kg. *P < 0.001 versus corresponding value of the alfentanil (Alf) + isotonic saline (Sal) group.

Discussion

Both alfentanil-induced adaptive changes assessed in the present study—acute tolerance and rebound hyperalgesia—were attenuated by ketamine. The development of acute tolerance to the antinociceptive effect of alfentanil was decreased by ketamine at all time-intervals of the four-hour alfentanil infusion. The ability of ketamine to attenuate chronic tolerance to morphine was reported with systematic and intrathecal drug administration in rodents (20–22).

In our experiments, ketamine 10 mg/kg was administered IV one hour before the beginning of alfentanil infusion. The baseline pressure threshold measured five minutes after ketamine was not changed (Table 1), and the peak of the alfentanil-induced antinociceptive effect with ketamine pretreatment was the same as that with the saline pretreatment (Table 1 and Figure 1A). These results indicate that the dose of ketamine we used was not large enough to provide a direct antinociceptive effect, even in combination with alfentanil. Similar results with systemic ketamine 10 mg/kg were reported in mice: ketamine did not change the response to mechanical or thermal nociceptive stimuli (23). Also, when ketamine 10 mg/kg was administered with morphine in rats, the morphine dose-response curve was not changed to any significant degree (21). With phasic pain, ketamine provides analgesia only in very large doses (24). That agrees well with the fact that, in rats, only at doses 100 to 120 mg/kg IP does it block motor nociceptive responses in minor surgical procedures (18).

The pattern of ketamine biodisposition is characterized by a very rapid redistribution from the brain to other tissue (25). In the rat, 60 minutes after an IV ketamine injection, its brain level declined 20-fold compared with the level measured immediately after the injection (26). This indicates that when attenuation of acute tolerance to alfentanil occurred (two to five hours after ketamine bolus injection), in our experiments, the ketamine biophase concentration was at least 20-fold smaller than that immediately after the injection. Thus, despite the fact that the ketamine concentration was too small to produce a direct antinociceptive effect, it effectively attenuated the development of acute tolerance to alfentanil.

Bilsky et al. (12) reported that NMDA receptor antagonists blocked chronic antinociceptive tolerance to morphine, but not however, to selective μ or δ agonists, including fentanyl. They concluded that the effect of NMDA receptor antagonists on opioid tolerance is not a general phenomenon related at all opioids. Alfentanil, used in our study, belongs to the same group of opioids as fentanyl. The difference in the results is probably related to the difference in the model of tolerance (chronic versus acute).

Rebound hyperalgesia that was present the day after the alfentanil infusion was also attenuated by ketamine. This confirms similar observations with delayed hyperalgesia induced by multiple bolus injections of fentanyl (27). The rebound hyperalgesia observed during opioid abstinence could result from reduction of a tonic inhibitory modulation that was present before opioid administration; however, the activation of modulatory neurons that facilitate nociceptive transmission could also be involved (28).

Ketamine is a nonspecific noncompetitive NMDA receptor antagonist; however, its effects on acute tolerance to alfentanil and on delayed hyperalgesia were almost the same as those of dizocilpine, a specific noncompetitive NMDA receptor antagonist. The effects of dizocilpine were only insignificantly more pronounced than those of ketamine.

The activation of NMDA receptors in the central nervous system is seen as a mechanism involved in the adaptive changes underlying both tolerance to opioids and delayed hyperalgesia. It was suggested that activation of opioid receptors leads to protein kinase C-mediated activation of NMDA receptors (29,30). The attenuation of acute tolerance and rebound hyperalgesia by the NMDA receptor antagonists is in agreement with this suggestion.

Could our results be relevant to the clinical experience with acute opioid exposure in surgery? The tolerance to analgesia during remifentanil infusion in humans is profound and develops very rapidly (31). Chia et al. (32) reported that the preoperative and intraoperative use of fentanyl in large doses (15 μg/kg plus 100 μg/h for 2–3 h) resulted in an increased postoperative fentanyl consumption via patient-controlled analgesia (up to 50%) and increased pain severity compared with preoperative administration of a small dose of fentanyl (1 μg/kg). It was also found that patients who received more morphine during the initial postoperative period had increased opioid requirements for pain relief after the initial period (33). In a recent editorial, Eisenach (34) concluded that we may be contributing to postoperative pain by the use of large doses of opioids intraoperatively. Thus, attenuation of the development of acute tolerance to opioids could be a clinically important approach for the treatment of postoperative pain, and the possible role of ketamine in this regard deserves specific attention.

The value of ketamine in the treatment of postoperative pain is a very controversial issue (2,25). To provide a direct analgesic effect, ketamine should be used in relatively large doses, which is associated with significant adverse effects. However, several authors (7–9) reported that ketamine administered during surgery in small doses (75–150 μg/kg) reduced postoperative opioid consumption. We hypothesize that this effect is the result of attenuation of acute tolerance to opioids. Figure 3 illustrates this suggestion by presenting three antinociceptive effects of ketamine that require different concentrations of the drug. Attenuation of tolerance to the analgesic effect of opioids occurs at the smallest concentration. Therefore, ketamine in subanesthetic (effect on phasic pain) or subanalgesic (effect on tonic pain) doses can still reduce opioid consumption.

Figure 3. Hypothetical dose-response relationship for the effects of ketamine related to nociception.

There is a separate pharmacologic property of ketamine that is related to the treatment of postoperative pain. NMDA receptor antagonists, including ketamine, can prevent the induction of injury-induced central sensitization and abolish hypersensitivity to pain once it is established (35). This property is a basis for the use of ketamine for preemptive analgesia (2). In a study on surgical patients, we could not demonstrate the preemptive effect of ketamine (used in a large dose of 2 mg/kg bolus + 20 μg · kg−1 · min−1 infusion during surgery) on spontaneous or movement-induced pain; however, its effect on hyperalgesia to pressure on the wound was observed even 48 hours after the surgery (36). The effect of ketamine on pain-induced central sensitization could be a factor in the decrease of postoperative pain, and consequently, in the reduction of opioid requirements (7–9). This study suggests that the ketamine-induced attenuation of acute tolerance to opioids might also be a potentially beneficial mechanism in the treatment of postoperative pain resulting in reduction of opioid requirements. It is interesting that mechanisms underlying injury-induced central sensitization and opioid-induced tolerance have close relationships. Mao et al. (30) suggested that these two seemingly unrelated phenomena may have common neural substrates that interact at the level of excitatory amino acid receptor activation and related intracellular events.

In conclusion, ketamine attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion.

Acknowledgments

Supported by National Institutes of Health Grant GM35135.

Footnotes

  • Accepted August 17, 2000.

References

  1. Chapman V, Dickenson AH. The combination of NMDA antagonism and morphine produces profound antinociception in the rat dorsal horn. Brain Res 1992; 573: 321–3.
  2. Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain 1999; 82: 111–25.
  3. Sethna NF, Liu M, Gracely R, et al. Analgesic and cognitive effects of intravenous ketamine-alfentanil combinations versus either drug alone after intradermal capsaicin in normal subjects. Anesth Analg 1998; 86: 1250–6.
  4. Sadove MS, Shulman M, Hatano S, Fevold N. Analgesic effects of ketamine administered in subdissociative doses. Anesth Analg 1971; 50: 452–7.
  5. Austin TR. Ketamine hydrochloride: a potent analgesic. Br Med J 1976; 2: 943.
  6. Maurset A, Skoglund LA, Hustveit O, Oye I. Comparison of ketamine and pethidine in experimental and postoperative pain. Pain 1989; 36: 37–41.
  7. Roytblat L, Korotkoruchko A, Katz J, et al. Postoperative pain: the effect of low-dose ketamine in addition to general anesthesia. Anesth Analg 1993; 77: 1161–5.
  8. Suzuki M, Tsueda K, Lansing P, et al. Small-dose ketamine enhances morphine-induced analgesia after outpatient surgery. Anesth Analg 1999; 89: 98–103.
  9. Menigaux C, Fletcher D, Dupont X, et al. The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg 2000; 90: 129–35.
  10. Kissin I, Bright CA, Bradley EL Jr. Acute tolerance to the analgesic effect of alfentanil: role of CCK and NMDA-NO systems. Anesth Analg 2000; 91: 110–6.
  11. Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 1991; 251: 85–7.
  12. Bilsky EJ, Inturrisi CE, Sadée W, et al. Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective μ or δ opioid agonists in mice. Pain 1995; 68: 229–37.
  13. Dunbar S, Yaksh TL. Concurrent spinal infusion of MK801 blocks spinal tolerance and dependence induced by chronic intrathecal morphine in the rat. Anesthesiology 1996; 84: 1177–88.
  14. Kolesnikov Y, Jain S, Wilson R, Pasternak GW. Lack of morphine and enkephalin tolerance in 129/SvEv mice: evidence for a NMDA receptor defect. J Pharmacol Exp Ther 1998; 284: 455–9.
  15. Kissin I, Lee SS, Arthur GR, Bradley EL Jr. Time course characteristics of acute tolerance development to continuously infused alfentanil in rats. Anesth Analg 1996; 83: 600–5.
  16. Green AF, Young PA. A comparison of heat and pressure analgesimetric methods in rats. Br J Pharmacol 1951; 6: 572–85.
  17. Kissin I, Lee SS, Arthur GR, Bradley EL. Effect of midazolam on development of acute tolerance to alfentanil: the role of pharmacokinetic interactions. Anesth Analg 1997; 85: 182–7.
  18. Green CJ. Animal anaesthesia. London: Laboratory Animals Ltd, 1982.
  19. Carmer SG, Swanson MR. An evaluation of ten pairwise multiple comparison procedure by Monte Carlo methods. J Am Stat Assoc 1973; 68: 66–74.
  20. Trujillo KA, Akil H. Inhibition of opiate tolerance by non-competitive N-methyl-d-aspartate receptor antagonists. Br Res 1994; 633: 178–88.
  21. Shimoyama N, Shimoyama M, Inturrisi C, et al. Ketamine attenuates and reverses morphine tolerance in rodents. Anesthesiology 1996; 85: 1357–66.
  22. Miyamoto H, Saito Y, Kirihara Y, et al. Spinal coadministration of ketamine reduces the development of tolerance to visceral as well as somatic antinociception during spinal morphine infusion. Anesth Analg 2000; 90: 136–41.
  23. McLeod AL, Ritchie J, Cuello AC. Transgenic mice over-expressing substance P exhibit allodynia and hyperalgesia which are reversed by substance P and N-methyl-d-aspartate receptor antagonists. Neuroscience 1999; 89: 891–9.
  24. Lakin ML, Winters WD. Behavioral correlates of naloxone inhibition of analgesia induced by various CNS excitatory drugs in the rat. Proc West Pharmacol Soc 1978; 21: 27–30.
  25. White PF, Way WL, Trevor AJ. Ketamine: its pharmacology and therapeutic uses. Anesthesiology 1982; 56: 119–36.
  26. White PF, Marietta MP, Pudwill CR, et al. Effects of halothane anesthesia on the biodisposition of ketamine in rats. J Pharmacol Exp Ther 1976; 196: 545–55.
  27. Célèrier E, Rivat C, Jun Y, et al. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology 2000; 92: 465–72.
  28. Kaplan H, Fields HL. Hyperalgesia during acute opioid abstinence: evidence for a nociceptive facilitating function of the rostral ventromedial medulla. J Neurosci 1991; 11: 1433–9.
  29. Chen L, Huang LYM. Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature 1992; 356: 521–3.
  30. Mao JR, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995; 62: 259–74.
  31. Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998; 86: 1307–11.
  32. Chia YY, Liu K, Wang JJ, et al. Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth 1999; 46: 872–7.
  33. Marshall H, Porteus C, McMillan I, et al. Relief of pain by infusion of morphine after operation: does tolerance develop? Br Med J 1985; 291: 19–21.
  34. Eisenach JC. Preemptive hyperalgesia, not analgesia? Anesthesiology 2000; 92: 308–9.
  35. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methyl-d-aspartic acid receptor activation: implications for the treatment of post-injury pain hypersensitivity states. Pain 1991; 44: 293–9.
  36. Tverskoy M, Oz Y, Isakson A, et al. Preemptive effect of fentanyl and ketamine on postoperative pain and wound hyperalgesia. Anesth Analg 1994; 78: 205–9.

source: http://www.anesthesia-analgesia.org/content/91/6/1483.full

Kidnappings, incarceration and the world’s worst heroin habit

In a country with more than two million heroin addicts, Irina Teplinskaya was one of the first. It was back in 1981, as a 14-year-old girl in the Baltic port of Kaliningrad, that she first tried the drug. She came from a prestigious family of senior Communists and was one of just a few who could afford the exciting new drug. She became addicted and suddenly, instead of a move to Moscow to study, her life began to take a very different path. She spent over a decade in prison and contracted hepatitis C, tuberculosis and HIV. right align image
During her last stay in jail, which ended in 2007, her HIV transitioned into full-blown Aids. Her life could have been very different, she says, if people had treated her drug addiction as an illness rather than a crime.
„The answer for me and for millions of others is simple,“ says Ms Teplinskaya, 44, who now works for an organisation advocating a more humane drug policy in Russia – substitution therapy. Almost every country in Europe allows treatment using methadone. Like heroin, it is an opiate, but is administered orally, meaning no risk of HIV transmission through needles.

Russia is the world’s largest heroin consumer and, to add to that, risky injecting practices have fuelled one of the world’s fastest-growing HIV epidemics. With tens of thousands of people dying every year, in a country where the population is shrinking, the twin epidemics are a catastrophe.
Campaigners say methadone would help tame both the heroin and HIV epidemics. As well as preventing HIV transmission, giving addicts methadone also brings them into the medical system, help steer them away from committing crimes to fund their habit and takes trade away from illegal dealers. Even China uses the technique to treat drug addicts. But Russian officials will have none of it. Government figures say it is perverse to treat drug addiction with other drugs and favour methods based on full withdrawal, sometimes against an addict’s will. It’s risky even to discuss methadone – advocates can be accused of „pro-drugs propaganda“ and taken to court.

„There is no logical reason behind Russia’s opposition to substitution therapy,“ says Anya Sarang, a campaigner who advocates the introduction of methadone. „I’ve been fighting this battle for 12 years and I don’t understand the mentality at all. The scientific evidence is all there to prove that it works.“

Ms Sarang and a group of Western academics published a study in the British Medical Journal last year which found that the widespread introduction of substitution therapy could cut rates of HIV transmission in Russia by up to 55 per cent. Estimates vary, but it’s thought that more than two million Russians inject heroin and the drug causes 30,000 deaths per years, as well as tens of thousands of new HIV cases. Russia is located on the transit route for drugs from Afghanistan to Europe and cheap heroin is readily available – a dose of heroin on the streets costs about 600 roubles (£12). If methadone therapy is not available, activists say programmes that offer addicts clean needles and syringes to avoid HIV transmission are essential.

The government, however, is adamant that only aggressive punitive measures can work to tackle drug use. Needle-exchange programmes funded by foreign donors have been discontinued in recent years, leading many addicts to share injecting equipment.
While there is some discussion about whether needle exchanges should be reintroduced, methadone is completely taboo. Leading Russian drugs specialists denounce substitution therapy as a failed Western imposition and see it as a „legalisation“ of drug use.

„We have no evidence from the international community that methadone is effective,“ said the Health minister, Tatyana Golikova, this week, reiterating a long-held government policy.
Others go further. Evgeny Roizman is a former Russian MP from the city of Yekaterinburg in the Ural mountains. He runs a series of clinics there where drug addicts go cold turkey, without methadone or any other drugs to ease the withdrawal symptoms.

He insists that methadone advocates are simply being disingenuous. „These people will say anything to get Western funding,“ says Mr Roizman. „I have worked with drug addicts for years, and I can tell you: methadone doesn’t work.“

He wants to bring in a range of policies, including harsher penalties for drug dealers and compulsory drugs testing in all Russian schools and colleges. „We need forced treatment for drug addicts,“ he says. „We need to force them into special institutions where there are no drugs and where they can be treated. This is the answer, not methadone.“

Last year, a disciple of Mr Roizman was sentenced to three-and-a-half years in prison for kidnapping drug addicts. Yegor Bychkov said addicts‘ parents had given him permission to „cure“ their children. „Patients were tortured, chained up to steel beds, starved,“ says Ms Sarang. „It was absolutely outrageous and when the court case against him started, we thought there would be a scandal.“

But a huge wave of support for Mr Bychkov swept through the country. Even many from Russia’s beleaguered human rights community joined with church figures and government officials to condemn his trial and in the end the court suspended his sentence and he was released. Mr Bychkov was „overenthusiastic“, said Mr Roizman, but his heart was in the right place.
Ms Teplinskaya, who is still a heroin user, travelled to Moscow last week to meet Navi Pillay, the UN High Commissioner for Human Rights, and ask her to press the Russian government on substation therapy. „I think I could have done a lot of good things for my country,“ she said. „But instead, I’ve lost my home, my health and my family. Methadone could have helped me lead a normal life.“

But her opponents are confident their views will prevail. Mr Roizman says: „They can shout as much as they want with their Western money. Methadone will never be legal in Russia.“

source:http://www.independent.co.uk/news/wo…t-2220673.html

MOSCOW, Feb 10 (Reuters) – Activists have asked the UN human rights

chief to pressure Russia to legalise the heroin substitute methadone when she visits next week amid a worsening HIV/AIDS crisis, an international health group said on Thursday.

UN High Commissioner for Human Rights Navi Pillay will meet President Dmitry Medvedev, government officials and around 60 rights campaigners during a five-day visit to Moscow.

‚This is a national health crisis and a human rights priority in Russia that must be raised at the highest levels,‘ said senior human rights analyst Damon Barrett from the London-based International Harm Reduction Association (IHRA).

The IHRA and 16 other HIV-focused rights organisations have sent a letter to Pillay asking her to push for HIV/AIDS and drug-fighting measures including the introduction of methadone, during her meetings with Russian government.

The UN’s World Health Organisation (WHO) says Russia has one of the fastest growing HIV/AIDS epidemics in the world, fueled up to three million heroin addicts, many of whom use dirty needles, local health organisations say.

Unlike most countries, Russia refuses to finance harm reduction programmes such as needle exchanges, or to legalise the replacement drug methadone.

The Health Ministry says there is no proof methadone is effective, while the country’s top doctor Gennady Onishchenko has called methadone ‚just another narcotic‘.

‚The fact that the government’s policy is so incomprehensible is what makes it so frustrating,‘ Barrett said.

The WHO says there are a million HIV-positive people in Russia, and deems methadone essential in fighting the epidemic.

Pillay will meet Russian activist Irina Teplinskaya during her visit, said the Moscow-based Andrey Rylkov Foundation, for whom Teplinskaya volunteers. HIV-positive and a heroin user, Teplinskaya has become a symbol of Russia’s drug woes.

‚Because there is no opioid substitution therapy in Russia, drug-dependent people are not able to receive treatment for HIV… they are forced to spend whole days acquiring money in a criminal way so they can buy drugs,‘ Teplinskaya said in a speech she will deliver to Pillay on Sunday.

((For a special report on Russia’s heroin and HIV/AIDS problem: ))

LONGVIEW — Amy Lynn Cowling was 33, she had three children, and her first grandchild was born a day after she died in an East Texas jail — slumped over her bed, clutching a bottle of Diet Dr Pepper, after a day of wailing and seizures.

Ms. Cowling was pulled over on Christmas Eve for speeding and arrested for outstanding warrants on minor charges. She was bipolar and methadone-dependent and took a raft of medications each day. For the five days she was in Gregg County Jail, Ms. Cowling and her family pleaded with officials to give her the medicines that sat in her purse in the jail’s storage room. They never did.

Ms. Cowling’s death is the most recent at Sheriff Maxey Cerliano’s Gregg County Jail in Longview. Since 2005, nine inmates have died there — most were attributed to health conditions like cancer, diabetes and stomach ulcers — far more than at other facilities its size. Bowie County Jail, in East Texas on the Arkansas border, reported five deaths in the same period, as did Brazoria County Jail, south of Houston on the Gulf Coast. In Williamson County in Central Texas near Austin, the jail reported just two deaths.
Interviews with prison experts and people with firsthand experience with the Gregg County lockup and its medical staff, as well as a review of scores of public documents, reveal a troubled local jail where staff turnover is high and inmates routinely complain about conditions. Criminal justice advocates say the situation in Gregg County is not unique; it is representative of systemic problems that plague local jails statewide.
Sheriff Cerliano defends the medical treatment in his jail and said he does his best to weed out bad jailers. “It’s only about doing the right thing,” he said.

Vicki Bankhead never went a day without talking to Ms. Cowling, her daughter and best friend. “I miss hearing her voice,” Ms. Bankhead said, sobbing. Ms. Cowling became a mother at age 15. She had become addicted to prescription pills and was found guilty in 2001 of possessing a fraudulent prescription. She struggled to keep a job.

Although Ms. Cowling had been clean for several years and was getting treatment at a methadone clinic, Ms. Bankhead said, her daughter had other health problems, including bipolar disorder, heart troubles and a failing kidney. “Amy needed her medication to stay alive,” she said. “That’s why I was begging them to help her repeatedly.”

Public records show that Ms. Cowling told Gregg County Jail officials that she had high blood pressure, arthritis and only one kidney. She reported that she took Seroquel to treat bipolar disorder and that she had been receiving methadone treatment for a decade — but neither of those drugs is allowed in the jail.

State standards require only that jails provide treatment according to the facility’s health care plan. Dr. Lewis A. Browne, the county health administrator and jail doctor since 1992, decides which drugs are allowed. Drugs like Seroquel and methadone, he said, are often traded among inmates for illicit favors.

Gregg County officials said that Ms. Cowling had received appropriate substitute medications.

Reports on her case submitted to the Texas attorney general’s office show that Ms. Cowling began having “seizure activity” while she was in the facility. The morning before she died, a jail nurse called Dr. Browne to report that Ms. Cowling was “hollering and uncooperative.” Dr. Browne told the nurse to give Ms. Cowling a dose of the antipsychotic drug Haldol. When a nurse called Dr. Browne later to report that Ms. Cowling was yelling again, he ordered more Haldol and put her on suicide watch. Ms. Cowling was booked on a Friday morning, and a jailer discovered her dead just after midnight on Wednesday.

Precisely what caused Ms. Cowling’s death remains unknown. A preliminary autopsy was inconclusive. Her family has retained a lawyer.

County officials contend that Ms. Cowling’s death was not their fault. She was not honest with them about all of her health problems, said Robert Davis, a lawyer for the county. “I absolutely do not believe that the jail or jail staff contributed to this inmate’s death whatsoever,” Mr. Davis said.

Sheriff Cerliano, however, concedes that not everything went according to the jail’s policies. After Ms. Cowling’s death, he conducted an investigation that he said showed that one jailer falsified observation logs that night. He fired five jailers and a sixth resigned. (Not all of the firings were related to Ms. Cowling’s death, he said, but were for conduct discovered during the investigation.) Two of the jailers were arrested for falsifying government documents.

Still, he said, the jail staff followed medical protocol in caring for Ms. Cowling. “We do everything we can to take care of inmates,” he said.
Since 2008, Gregg County inmates have filed more than 20 complaints with the Texas Commission on Jail Standards about conditions in the lockup. Most of the complaints were health-care-related; inmates said they could not get medicine and did not receive timely medical attention. An inmate who hanged himself in the jail in 2009 had complained that among many other grievances, he was not allowed medication he had been prescribed on the outside and had not been seen by a doctor.

In letters responding to nearly all the complaints, Adan Muñoz, the commission’s executive director, wrote, “The Texas Commission on Jail Standards does not question the professional opinion of medical personnel.”

Inmates have sued Sheriff Cerliano and Dr. Browne at least twice since 2005, alleging that their constitutional rights were violated by the jail’s deliberate indifference to their medical needs. In both cases, the courts found that Dr. Browne and the jail had attempted to provide adequate care.

Dr. Browne, who has his own family medical practice in Longview, is paid more than $100,000 per year to act as the jail doctor and director of the county health authority. He said that inmate health care was “the toughest medical situation to deal with.” Inmates are often uncooperative and dishonest about their health conditions, he said, and many are drug addicts. Adding to the challenge is that it is hard to retain medical staff, Dr. Browne said.

Medical staff members at the jail are not the only ones with a high turnover rate; records from the sheriff’s department show that in 2009 and 2010, more than 40 percent of the 167 jail employees either quit or were fired.

Sheriff Cerliano said the pay is low for jailers and that they have to go through months of training, pass drug screenings and work in challenging situations.

Lt. David Drosche, who works in the Brazos County Sheriff’s Office and is president of the Texas Jail Association, agreed that retaining jailers is difficult but said that a 40 percent turnover rate is “extremely high.” The higher turnover, he said, results in more inexperienced jailers.

County lockups in Texas are accountable to the Texas Commission on Jail Standards. Before Ms. Cowling’s death, the Gregg County Jail had passed every commission inspection for the last five years. Within weeks after she died, the commission, which reviews county jail deaths, decided the jail was in compliance with state standards.

But the commission does not require that jails meet specific health care criteria, only that they have medical plans on file. It also doesn’t keep track of jail staff turnover.

Diana Claitor, executive director of the Texas Jail Project, which advocates for improved jail conditions, said better health care standards and monitoring of data like staff turnover could help prevent more deaths like Ms. Cowling’s. From January 2005 to September 2009, more than 280 inmates died from illnesses in Texas county jails.

“One of the chief factors playing into mistreatment or neglect would be ill-trained, inexperienced staff,” she said. But with the state budget crunch, pressing the jail standards commission to provide additional oversight is a tough sell, Ms. Claitor said.

Sheriff Cerliano said his jailers already receive more training than is required by state standards and that the medical staff provides the best care possible. Ms. Cowling’s death was unfortunate, he said, but it does not mean that wholesale changes are needed in the way jails are regulated.
“We do have inmates that come in sick,” he said. “It’s incumbent upon us to try to do the best we can.”

source: http://www.nytimes.com/2011/02/13/us…ed=2&src=twrhp

Geld aus Drogengeschäften korrumpieren Regierungen und lösen weltweit Gewalt aus. Warum wir einen pragmatischeren Ansatz zur Bekämpfung brauchen.

Aufgrund der direkten Demokratie in der Schweiz können die Bürger dieses Landes durch das Sammeln von genügend Unterstützungsunterschriften landesweite Referenden über Regierungspolitik und Gesetze veranlassen.

To match Special Report RUSSIA/HEROIN
Foto: REUTERS Den Besitz illegaler Drogen zu entkriminalisieren, führt nicht nur zu mehr Drogenkonsumenten in Behandlung (statt im Gefängnis), sondern auch zu einem bedeutenden Rückgang der Ansteckungen von Drogenkonsumenten mit HIV

Nach einer Welle von Aids-Todesfällen in den 1980er Jahren, sahen sich die Schweizer mit einem Problem konfrontiert, das in den USA, Russland, Lateinamerika, der Europäischen Union, Südasien und anderen Regionen dieser Welt schon Millionen Menschenleben gekostet hat. Intravenös injizierende Drogenkonsumenten – vor allem Heroinabhängige – hatten öffentliche Plätze in Zürich und anderen Schweizer Städten in so genannte „Needle Parks“ verwandelt. AIDS erwies sich als Krankheit, die offenbar auch vor dem Wohlstand nicht Halt macht.

Die Schweizer reagierten auf das Problem nicht mir jener Art von Nachlässigkeit, mit der die russische Regierung bislang auf ihre Heroin- und HIV-Epidemien reagiert hat – dort gibt es über zwei Millionen Drogenkonsumenten und eine geschätzte Million Menschen mit HIV-Infektion, von denen sich über 60 Prozent durch kontaminierte Nadeln ansteckten. Ebenso wenig reagierten die Schweizer mit einem „Krieg gegen Drogen“ oder mit noch mehr Geld für mehr Polizei, mehr Gefängnisse und zwingende Haftstrafen.

Dieser Krieg ist nämlich endgültig verloren. In den USA sitzen heute mehr Menschen im Gefängnis als in jedem anderen Land und dies ist größtenteils auf die sprunghaft steigende Zahl von Verurteilungen aufgrund von Drogen zurückzuführen, wobei die Zahl afroamerikanischer und hispanoamerikanischer Insassen überproportional hoch ist.

Der Krieg gegen Drogen ermöglichte den Drogenkartellen höhere Profite als jemals zuvor und verwandelte in Lateinamerika ganze Städte in Feudalgebiete. Drogengelder korrumpieren demokratische Regierungen und Institutionen der Gesetzesvollstreckung auf der ganzen Welt. Gewalt im Zusammenhang mit Drogen hat in Afghanistan, Burma, Kolumbien, den USA und Mexiko unzählige Opfer gefordert.

Die Schweizer überprüften die Drogenpolitik ihrer Regierung mit Pragmatismus. Fachleute aus dem medizinischen Bereich übernahmen die Führung einer Kampagne, mit der die Regierung – durch die Mechanismen der direkten Demokratie – dazu gebracht werden sollte, ihren Schwerpunkt von Haft und Strafen für Drogenkonsumenten hin zu einer Gesundheitspolitik zu verlagern, die auf Grundlage wissenschaftlicher Erkenntnisse erhebt, welche Ansätze funktionieren.

Die Schweizer führten Methadonprogramme ein und um die Ansteckung mit HIV zu vermeiden, wurde der Nadelaustausch – auch in Gefängnissen – etabliert. Überdies wurden im großen Maßstab Drogenkonsumräume geschaffen. Das Schweizer Bundesamt für Gesundheit überwachte auch ein Experiment, im Zuge dessen man Heroin an Personen verschrieb, die über lange Zeit von Opiaten abhängig waren.

Die sorgfältige Auswertung dieses Ansatzes durch die Schweizer Regierung zeigte, dass eine heroingestützte Therapie sowohl machbar als auch kosteneffizient ist und dass sie für die Patienten mit signifikanten Verbesserungen der Gesundheit einhergehen kann. Außerdem wurde damit ein Beitrag zu einem erstaunlichen Rückgang der Drogenkriminalität geleistet. Die Schweizer Öffentlichkeit war von den Vorteilen der heroingestützten Therapie so überzeugt, dass die Bürger diese Politik trotz politischer Opposition im eigenen Land und Kritik des Internationalen Suchtstoffkontrollrats in zwei landesweiten Referenden unterstützten.

Die Schweiz ist ein konservatives Land. Der Handel mit Suchtstoffen bleibt weiterhin illegal. Im November 2008 wurde ein Antrag für eine Entkriminalisierung von Cannabis nach holländischem Muster abgelehnt. Und manche politischen Entscheidungsträger fragen sich, ob sich der Schweizer Ansatz in der Drogenpolitik zu sehr auf die öffentliche Gesundheit und zu wenig auf die Bekämpfung von Armut und soziale Ausgrenzung konzentriert, mit der sich die Drogenkonsumenten konfrontiert sehen.

Der pragmatische Ansatz der Schweiz hinsichtlich des Drogenmissbrauchs bietet dennoch wichtige Lehren, die auch auf die USA, Russland und viele andere, von Drogen und HIV/AIDS belastete Länder in deren Einflussbereich angewendet werden können. Ähnlich verhält es sich mit den Erfahrungen in Portugal, das vor einem Jahrzehnt die EU-Rangliste der mit Drogen in Zusammenhang stehenden HIV/AIDS-Fälle anführte.

Die Entscheidung Portugals aus dem Jahr 2001, den Besitz illegaler Drogen zu entkriminalisieren, führte nicht nur zu mehr Drogenkonsumenten in Behandlung (statt im Gefängnis), sondern auch zu einem bedeutenden Rückgang der Ansteckungen von Drogenkonsumenten mit HIV.

Eine Lehre für politische Entscheidungsträger besteht darin, dass es von zentraler Bedeutung ist, die neuen Programme auf Grundlage strenger wissenschaftlicher Überprüfung – und nicht auf Basis populistischer Rhetorik, religiösem Moralismus und Großstadtlegenden – durchzuführen.

Dies erfordert die Koordination von Polizeiarbeit und Gesundheitsprogrammen innerhalb eines einheitlichen Rahmenwerks, Investitionen in Forschung und öffentliche Aufklärung über Drogenpolitik, die Öffnung neuer Programme gegenüber unabhängiger Überprüfung und die Fähigkeit, ideologischer Kritik auf nationaler und internationaler Ebene mit wissenschaftlichen Beweisen und Pragmatismus entgegenzutreten.

Um diese und andere bedeutende Lehren zu vermitteln sowie weltweit für eine effektive, schadensmindernde Politik – sowie eine breitere öffentliche Debatte über effizientere und humanere Drogenpolitik – einzutreten, haben wir gemeinsam mit bedeutenden Persönlichkeiten die Globale Kommission zur Drogenpolitik ins Leben gerufen, die im Januar in Genf ihre Gründungsversammlung abhielt.

Unser Ziel ist zu beweisen, dass der Krieg gegen Drogen verloren ist. Die Schweiz, Portugal und andere Länder haben gezeigt, dass es einen besseren Weg gibt, indem man Pragmatismus und Wirtschaftlichkeit mit Mitgefühl und Respekt vor den Menschenrechten kombiniert.

Fernando Henrique Cardoso war von 1995 bis 2003 Präsident Brasiliens und ist nunmehr Vorsitzender der Globalen Kommission zur Drogenpolitik. Michel D. Kazatchkine ist Geschäftsführer des Globalen Fonds zur Bekämpfung von AIDS, Tuberkulose und Malaria.

Siehe auch https://exilope.wordpress.com/2011/02/04/neue-wege-in-d…-drogenpolitik/

quelle is die Welt: http://www.welt.de/debatte/die-welt-in-worten/article12462030/Der-Krieg-gegen-Drogen-ist-schon-lange-verloren.html

When Charlie Sheen finally entered rehab, it wasn’t terribly shocking news. But what most people did find surprising was that instead of checking into a swanky Malibu treatment center as he has done in the past, Sheen opted to receive in-home rehab. Immediately the media began criticizing his choice and questioning his commitment to getting sober.

There are undoubtedly certain challenges related to in-home rehab, but are you really guaranteed better care if you check into a treatment center?

Absolutely not, thanks to the lack of standardization in our current rehab system.

Each year, about three million Americans seek help from a seemingly endless list of treatment facilities. But who is ensuring these treatment centers are qualified to effectively treat them?

With a lax application process for state licensure and certification, there is little accountability placed on facilities, or their ownership, to ensure proper treatment is being offered. With more than 12,000 rehab centers in the country, the odds of finding the one that best fits your needs are next to impossible.

When treatment fails, which it often does, it is then assumed to be the addict who failed, when in reality it was often the addict who was failed by a flawed system.

This leads to a vicious cycle of relapse — a story all too familiar to families struggling with addiction, not to mention one we’ve seen repeatedly played out by Hollywood stars.

It is true that some don’t take advantage of their treatment and fail at sobriety on their own, but others simply weren’t given a chance to succeed.

This is made worse by the fact that most rehab clinics market themselves as „all inclusive“ — able to treat any type of addiction disorder — which most are certainly not. Addicts and their families are often so desperate to get help that they select a rehab clinic based on cost and availability, without understanding whether or not the care providers are properly certified in the type of addiction that affects them or are qualified to fulfill any additional needs they might have (including mental health needs).

This is especially true of first-timers (over 60 percent of those seeking addiction treatment are first-timers). They don’t know what questions to ask or even what they are looking for out of a treatment center, making it nearly impossible to find the right option for their individual needs.

We need to try and get some measure of standardization into the system so that we are able to match those looking for treatment with providers that fit their needs. Currently, there is essentially no oversight regarding the services addiction treatment providers report and their actual capabilities for providing those services.

In the place of a centralized federal or state-level vetting system, there are some private groups that provide directories. But it is not easy to tell how well these directories actually vet the treatment centers listed. It is critical for treatment candidates to know exactly what type of credentialed treatment services are provided. This should be provided by the public health departments, but until that happens, it’s basically „every man for himself.“ (At my site All About Addiction, we recently launched our own „rehab finder,“ to provide a vetting system in the meantime.)

We believe this is a crucial element for successful treatment; especially when you consider that more than 50 percent of addicts suffer from mental health issues, meaning they need special care by a trained professional. And while some may promise this, there is no verification process to ensure they are able to deliver on their promise.

In fact, a huge survey of the addiction treatment industry found that more than 20 percent of addicts entering treatment were missing crucial mental health services that they needed. (About 50 percent were missing other necessary medical services.)

Rehab is a business — a booming one, at that — and right now it is too easy to sell the idea of recovery. Because there is no model of care to follow, the system is compromised with clinics that don’t know how to do things better, some that limit their treatment due to dogma and other centers that are actually trying to „game“ the system.

The bottom line is, without some level of standardization, treatment becomes nothing more than a crapshoot. You are left at the mercy of a broken system and never know what kind of treatment you are going to receive until it is too late.

Right now, you could easily check into rehab facility and find they offer nothing more than an expensive 12-step program. This is unacceptable. We have tools, like cognitive behavioral therapy and motivational enhancement therapy, which we know are effective, we just need to ensure they are part of the treatment model being offered to patients.

Add to that some very effective, if poorly utilized, medications and it’s clear we’re handicapping our patients, pun and all.

However, there is hope, and a better way of doing things, but it will require us to adopt a more progressive model of treatment.

Our society has too readily accepted the supposed „fact“ that recidivism rates are high, and will always be high, for addicts. The fact of the matter is that the treatment process itself is deeply flawed and until we fix the model of care for recovering addicts, we will never be able to truthfully tell how many of them can recover. Addiction isn’t a death sentence. It is a treatable disease; we need to acknowledge that the way we are doing things doesn’t work and do something to change it.

After many years of trial and error, researchers and doctors have finally begun to grasp what works and what doesn’t in terms of treating addiction.

It is now our job and our responsibility to start developing a system that gets the proper treatment to the people who need it.

Any doctor will tell you, there are no guarantees with addiction. All we can do is give people the best shot at treatment, and sadly, right now, our system is failing at that.

Adi Jaffe,
AlterNet
February 11, 2011

http://www.alternet.org/story/149898/

Adi Jaffe, Ph.D. is a Los Angeles addiction psychologist and researcher. Himself a former drug addict and convicted drug dealer, Dr. Jaffe is an expert on substance abuse, especially on the neuroscience and policy issues involved. Today, he is a UCLA-affiliated researcher on addictions, founder of AllAboutAddiction.com and a columnist for Psychology Today.

© 2011 Independent Media Institute. All rights reserved.

HarmReductionLeitfadenzumrisikoarmenAbsetzenvonPsychopharmaka1EdOnline

Quelle ist: http://theicarusproject.net/alternativetreatments/harmreductionguidegermantranslation-harmreduction-leitfadenzumrisikoarmenabsetzenvonpsychopharmaka

Dies ist auf Deutsch

Die Opiat-Substitution gilt als Standardtherapie bei Opiatabhängigkeit.
Neben Methadon, einem Razemat aus den beiden Enantiomeren
Levomethadon und Dextromethadon, kommt dabei in Deutschland seit
20 Jahren auch das Enantiomer Levomethadon zum Einsatz, das in verschiedenenStudien eine bessere Wirksamkeit und Verträglichkeit gezeigt hat.
Im Rahmen der nicht-interventionellen STABIL-Studie (= Studie zur Therapie Opiat-/Opioid-Abhängiger nach Behandlungsumstellung instabiler
Methadon-Patienten auf Levomethadon-Lösung zur Substitution)
wurden opioidabhängige Patienten mit instabilem Behandlungsverlauf
unter dem Methadon-Razemat auf Levomethadon umgestellt.

Die Auswertungen hinsichtlich Verträglichkeit, Suchtdruck und Beikonsum zeigen,dass sich durch die Umstellung der Substitutionsbehandlung auf
Levomethadon bei Patienten mit einem unbefriedigenden Behandlungsverlauf
unter Methadon-Razemat eine signifikante Verbesserung
der Therapie bezüglich Wirksamkeit und Verträglichkeit sowie eine signifikante Verringerung des Suchtdrucks (craving) und des Beigebrauchs
erreichen lässt. Diese Ergebnisse sind vor allem auch deshalb positiv zu
bewerten, weil die meisten Patienten in dieser Studie einen langen
polytoxikomanen Drogenkonsum (im Median 13 Jahre), eine hohe Komorbiditätsrate
und hohen Beikonsum von Drogen, Medikamenten und
Alkohol aufwiesen.

1 EINLEITUNG

Die Opiat-Substitution hat sich, in Deutschland wie auch
weltweit, zur Standardtherapie der Opiatabhängigkeit entwickelt
(Gerlach 2002). Der überwiegende Teil der in
Deutschland gemeldeten Substitutionspatienten wird mit
Methadon behandelt. Aus stereochemischer Sicht handelt
es sich dabei um ein Gemisch (Razemat), das zu gleichen
Teilen aus den beiden Enantiomeren Levomethadon und
Dextromethadon besteht. Die beiden Enantiomere unterscheiden
sich in Bezug auf ihre physikalischen Eigenschaften
nur hinsichtlich der optischen Aktivität (Drehung des

polarisierten Lichts), jedoch sind die pharmakologischen
Unterschiede beträchtlich (Judson et al.1976). Diese Tatsache
ist bereits seit langem bekannt und wurde früh in
die klinisch-experimentelle Beobachtung einbezogen (Kleibel
1963, Ther et al. 1963, Scherbaum et al. 1998).

Das Enantiomer Levomethadon ist die wirksame Substanz,
die mit wesentlich höherer Affinität an den µ-Opiatrezeptoren
bindet und die gewünschte „Substitutionswirkung“
vermittelt. Das Enantiomer Dextromethadon ist zwar auch
pharmakologisch wirksam, wird aber vor allem für unerwünschte
Arzneimittelwirkungen mitverantwortlich gemacht.
Dazu gehören z.B. starkes Schwitzen, gastrointestinale Störungen,
Gewichtszunahme, aber auch lebensbedrohliche
Kammertachykardien und QTc-Verlängerungen.

Die pharmakokinetischen Eigenschaften der beiden Enantiomere
unterscheiden sich ebenfalls, etwa bei der Plasma-
Halbwertzeit und der Verstoffwechselung über verschiedene
P-450-Enzymsysteme (Ferrari et al. 2004, Eap et al. 2002).
Methadon-Razemat ist ausschließlich am Opiat-Rezeptor
schwächer wirksam; im Hinblick auf unerwünschte Wirkungen
und pharmakologische Wechselwirkungen aber von
großer Wichtigkeit (Soyka 2008b).

In Deutschland werden laut Substitutionsregister aktuell
etwa 72.000 Substitutionspatienten behandelt (Bundesministerium
für Gesundheit 2009); die geschätzte Gesamtzahl
aller Opiatabhängigen in Deutschland liegt bei 200.000
bis 250.000. Für die Verwendung der unterschiedlichen
Substanzen zur Substitution gibt es derzeit keine einheitlichen
Richtlinien. Unter Kostenaspekten entwickelte sich
vor Jahren eine starke Ausrichtung auf die Verordnung
von Methadon-Razemat und so ist erklärbar, dass derzeit
noch fast 60% der gemeldeten Patienten mit Methadon-
Razemat behandelt werden (Michels et al. 2009) und nur
etwas mehr als 20% mit Levomethadon (Bundesministerium
für Gesundheit, 2009). Levomethadon wird seit über
20 Jahren für die Substitutionstherapie verwendet und ist
seit 2001 als Fertigarzneimittel in Deutschland verfügbar.
Verschiedene Studien und zahlreiche klinische Befunde aus
der sucht- als auch aus der opioidpflichtigen Schmerztherapie
bescheinigen dem Präparat dabei eine bessere Wirksamkeit
und Verträglichkeit im Vergleich zum Razemat
(Kleibel 1963, Cernaj 2006, Soyka und Zingg 2009, Ulmer
1995).

Für den Einsatz von Levomethadon sprechen auch die Ergebnisse
einer Studie unter dem Gesichtspunkt von Kammertachykardien
(Eap et al. 2007). Die Daten dieser Untersuchung
zeigen, dass Dextromethadon den kardialen
Kaliumkanal um 350% stärker blockiert als Levomethadon
und so das Risiko von QTc-Intervall-Verlängerungen
durch Methadon drastisch erhöht. Dieses Risiko könnte
nach Ansicht der Autoren durch die Verwendung von
Levomethadon vermindert werden. Insbesondere hat auch
die Kombination von Methadon mit Psychopharmaka einen
QTc-verlängernden Effekt, sodass unter dieser Medikation
eine erhöhte Arrhythmiegefahr besteht (Maremmani
et al. 2005, Elsner 2005).

Für eine praxisrelevante Beurteilung der Wirksamkeit und
Verträglichkeit der Substitutionsbehandlung, besonders von
multimorbiden Opiatabhängigen, sind nicht nur die Ergebnisse
aus kontrollierten klinischen Studien wichtig, sondern
vor allem auch die Beobachtungen aus niedergelassenen
Praxen, da sie die realen Alltagsbedingungen abbilden
(Wittchen et al. 2008). So konnte anhand von Daten
einer nicht-interventionellen Beobachtungsstudie auf der
Basis von 1.552 Patienten gezeigt werden, dass während
der Substitution mit Levomethadon signifikant weniger

Beigebrauch, Suchtdruck und Entzugssymptome auftraten
als während der Vorbehandlung mit Methadon-Razemat
(Cernaj 2006).

Im Rahmen der vorliegenden Follow up-Beobachtungsstudie
wird diese Erhebung von Praxisdaten zur Substitutionsbehandlung
mit Levomethadon fortgeführt. Dabei stehen
insbesondere Patienten im Vordergrund, die unter der Vorbehandlung
mit Methadon-Razemat einen instabilen, unbefriedigenden
Behandlungsverlauf aufwiesen, z.B. solche
Patienten mit frühzeitig auftretenden Entzugssymptomen,
hohem Suchtdruck und Beigebrauch sowie verschiedenen
nicht beherrschbaren unerwünschten Arzneimittelwirkungen.
Die Studie wurde mit Unterstützung der Sanofi-
Aventis Deutschland GmbH durchgeführt.

2
MATERIAL UND METHODEN

Die vorliegende Untersuchung ist eine nicht-interventionelle
Beobachtungsstudie bei niedergelassenen Ärzten. Einschlusskriterien
waren


Mindestalter 18 Jahre,

Opiatabhängigkeit,

Substitutionstherapie mit Methadon-Razemat bis unmittelbar
vor Studienbeginn,

unbefriedigender Verlauf der Substitutionstherapie.
Zu den Kriterien für eine unbefriedigende Vorbehandlung
gehörten nicht beherrschbare Nebenwirkungen wie übermäßiges
Schwitzen und Magen-Darm-Beschwerden, aber
auch nicht tolerabler Beikonsum und psychische Symptome
wie Depressionen, Psychosen oder anhaltender Sucht-
druck. Bei diesen Patienten wurde nach einer Eingangsuntersuchung
der Verlauf der Substitutionsbehandlung mit
Levomethadon über einen Zeitraum von vier Wochen dokumentiert.

Die Dokumentationsbögen umfassten im Rahmen der Eingangsuntersuchung
neben Patientendaten Angaben zur
Dauer der Opiatabhängigkeit und Informationen zur Substitutionsbehandlung
mit Methadon-Razemat:


Beginn,

Auftreten von Entzugssymptomen,

Suchtdruck und Beigebrauch,

Verträglichkeit,

Globalbeurteilung.
Begleiterkrankungen und Begleitmedikation wurden dokumentiert
und die Gründe für die Umstellung der Substitutionsbehandlung
auf Levomethadon erfragt.

Nach zwei und vier Wochen wurde neben der Levomethadon-
Dosierung dokumentiert:


Auftreten von Entzugssymptomen,

Suchtdruck und Beigebrauch,

unerwünschte Ereignisse,

Beurteilung der Verträglichkeit der Levomethadon-Substitution.
Beim Beobachtungsende wurden darüber hinaus die Fortsetzung
der Levomethadon-Behandlung sowie die Begleittherapie
beschrieben und eine Globalbeurteilung zur bisherigen
Substitution mit Levomethadon abgegeben.

Bei der Eingangsuntersuchung und am Beobachtungsende
wurde ein Drogenscreening durchgeführt. Dazu wurden
Urinproben auf die folgenden Substanzen untersucht: Amphetamin/
Metamphetamin, Barbiturate, Benzodiazepine,
Cannabionoide (THC), Kokain, Opiate (Morphin), LSD
und Alkohol.

Die Daten der Dokumentationsbögen wurden nach Abschluss
der Datenerfassung mit Hilfe des Datenmanagement-
Systems DMSys Version 5.1 erfasst. Dabei wurden
simultane und sequenzielle Plausibilitätskontrollen durchgeführt.
Bei der Kodierung der Klartextangaben kamen
das WHO Drug Dictionary Enhanced 2006 für Begleitmedikationen
und die MedDRA Version 10.0 für Begleiterkrankungen
zum Einsatz.

Alle Daten wurden deskriptiv ausgewertet. Die Beurteilungen
zum Auftreten von Entzugssymptomen, zum Sucht-
druck, zum Beigebrauch und zur Verträglichkeit wurden
in numerische Werte transformiert: nein = 1, wenig = 2,
mäßig = 3, stark = 4, sehr stark = 5. Für diese Daten
wurden mit Hilfe von Wilcoxon-Vorzeichen-Rangtests deskriptive
p-Werte (zweiseitig) berechnet. Die Berechnungen
wurden mit dem Statistikprogrammpaket SPSS for
Windows (Release 15.0.0) durchgeführt.

3
ERGEBNISSE

3.1 PATIENTEN
Die vorliegende statistische Auswertung basiert auf den
Daten von 862 Patienten, die in 87 Zentren von März
2007 bis April 2008 dokumentiert wurden. Die Rekrutierung
der Patienten erfolgte ausschließlich durch niedergelassene
Ärzte. 66,1% (N = 570/862) der Patienten wurden
von Allgemeinmedizinern bzw. praktischen Ärzten,
19,3% (N = 166/862) von Internisten und 8,8% (N = 76/
862) von Ärzten der Fachrichtungen Psychiatrie und Psychotherapie
behandelt. Bei 50 Patienten war die Fachrichtung
des Arztes eine andere oder nicht angegeben.

66,5% (N = 573/862) der Patienten waren Männer. Das
Alter betrug bei den Männern im Median 37,0 Jahre, bei
den Frauen 33,0 Jahre. 39,2% (N = 338/862) der Patien

ten waren verheiratet oder lebten in einer eheähnlichen
Beziehung. 31,8% (N = 274/862) der Patienten hatten Kinder
und 27,0% (N = 233/862) waren berufstätig. Die Patienten
waren im Median seit 13 Jahren opiatabhängig.
Bei 56,3% (N = 485/862) der Patienten bestand die Opiatabhängigkeit
seit 5-20 Jahren (.
Abb. 1).

Abb. 1: Bisherige Dauer der Opiatabhängigkeit (kategorial)

3.1.1 BEGLEITERKRANKUNGEN UND BEGLEITMEDIKATION
Insgesamt wurden bei 78,1% (N = 673/862) der Patienten
Begleiterkrankungen dokumentiert, am häufigsten Hepatitis
C-Infektionen (55,9%; N = 482/862). Unter psychischen
Erkrankungen litten 41,5% (N = 358/862) der Patienten,
darunter 26,6% (N = 229/862) aller Patienten an Depressionen,
14,3% (N = 123/862) an Angstzuständen und
11,0% (N = 95/862) an Persönlichkeitsstörungen. 11,4%
(N = 98/862) der Patienten hatten eine Hepatitis B-Infektion
und 4,4 % (N = 38/862) eine HIV-Infektion (.
Tab. 1).

Tabelle1: Begleiterkrankungen (Mehrfachnennungen möglich)

N %
HIV-Infektion 38 4,41 %
Hepatitis B 98 11,37 %
Hepatitis C 482 55,92 %
Atemwegs- oder sonstige Infektion 62 7,19 %
Magen-Darm-Erkrankung 54 6,26 %
Herz-Kreislauf-Erkrankung 31 3,60 %
Leberinsuffizienz 36 4,18 %
Niereninsuffizienz 5 0,58 %
Psychische Erkrankung 358 41,53 %
Depression 229 26,57 %
Angstzustände 123 14,27 %
Psychose 30 3,48 %
Persönlichkeitsstörung 95 11,02 %
nicht näher spezifiziert 6 0,70 %
Sonstige 84 9,74 %
Gesamt 862 100,00 %

Suchtmed 12 (3) 2010
189

ORIGINALARBEITEN | STABIL-STUDIE: UMSTELLUNG AUF LEVOMETHADON

Trotz des hohen Anteils an Begleiterkrankungen erhielten
nur 40,3% (N = 347/862) der Patienten eine Begleitmedikation.
Dabei wurden Psychopharmaka mit Abstand am
häufigsten gegeben (27,3% der Patienten; N = 235/862).

3.2 BEHANDLUNG
3.2.1 VORTHERAPIE MIT METHADON-RAZEMAT
Die Dauer der Substitutionstherapie mit Methadon-Razemat
vor Umstellung auf Levomethadon betrug im Median
13,0 Monate. Bei 13,6% (N = 117/862) der Patienten erfolgte
die Umstellung innerhalb des ersten Monats nach
Beginn der Substitution mit Methadon-Razemat, bei 33,4%
(N = 288/862) nach mehr als einem Monat bis einem Jahr
und bei 49,8% (N = 429/862) nach mehr als einem Jahr. Bei
3,2% (N = 28/862) der Patienten fehlte hierzu die Angabe.

Die zuletzt gegebene Tagesdosis des Methadon-Razemats
lag im Mittel bei 82,3 ± 41,4 mg (Mittelwert ± Standardabweichung).
26,5% (N = 228/862) der Patienten erhielten
eine Dosierung bis 50 mg, 47,9% (N = 413/862) eine Dosierung
zwischen 50 und 100 mg und 23,8% (N = 205/862)
erhielten mehr als 100 mg Methadon. Bei 1,9% (N = 16/862)
der Patienten fehlte hierzu die Angabe.

Die häufigsten Argumente für eine Umstellung der Substitutionstherapie
von Methadon-Razemat auf Levomethadon
waren eine erwartete bessere Verträglichkeit bei 81,9%
(N = 706/862) der Patienten und eine erwartete bessere bzw.
längere Wirkdauer über 24 Stunden bei 74,2% (N = 640/
862) der Patienten.

3.2.2 LEVOMETHADON
Bei Behandlungsbeginn betrug die mittlere Tagesdosis von
Levomethadon Lösung zur Substitution 51,6 ± 47,2 mg

(Mittelwert ± Standardabweichung). 66,6% (N = 574/862)
der Patienten erhielten eine Dosierung bis 50 mg. 29,2%
(N = 252/862) eine Dosierung über 50-100 mg und 3,5%
(N = 30/862) der Patienten erhielten mehr als 100 mg
Levomethadon (bei 0,7% fehlten die Angaben hierzu). Im
Beobachtungsverlauf kam es nur zu geringfügigen Veränderungen
der Levomethadon-Tagesdosis. Der Median der
Tagesdosis lag bei allen drei Untersuchungszeitpunkten
bei 45,0 mg.

Die dokumentierte Behandlungsdauer mit Levomethadon
lag im Median bei 31,0 Tagen. Bei 94,4% (N = 814/862)
der Patienten wurde die Substitution mit Levomethadon
über das Beobachtungsende hinaus fortgesetzt. Bei 4,6%
(N = 40/862) erfolgte ein Abbruch der Behandlung und
für 0,9% (N = 8/862) lagen keine Angaben zur Weiterbehandlung
vor. Bei den 40 Patienten mit einem vorzeitigen
Ende der Behandlung waren die am häufigsten genannten
Gründe dafür „Patient nicht mehr erschienen“ (1,6% der
Patienten; N = 14/862), „ungenügende Wirksamkeit“ (1,3%;
N = 11/862) und „Patientenwunsch“ (0,8%; N = 7/862).

3.3 WIRKSAMKEIT
3.3.1 DROGENSCREENING UND BEIGEBRAUCH
Sowohl bei der Eingangsuntersuchung als auch am Beobachtungsende
wurde ein Drogenscreening für alle wichtigen
psychotropen Substanzen (Amphetamin/Metamphetamin,
Barbiturate, Benzodiazepine, Cannabinoide (THC),
Kokain, Opiate (Morphin), LSD und Alkohol) durchgeführt.

Das Drogenscreening bei der Eingangsuntersuchung spiegelt
aufgrund der Substitution mit Methadon-Razemat bis
zu diesem Zeitpunkt den Beigebrauch unter Methadon-
Razemat wieder: Bei 73,5% (N = 634/862) der Patienten
fand sich mindestens ein positiver Drogennachweis, bei
22,4% (N = 193/862) der Patienten wurden keine der unter-

Abb. 2:

Anteil positiver Drogenscreening-Befunde bei
der Eingangsuntersuchung (Methadon-Razemat)
und am Beobachtungsende (Levomethadon)

190 Suchtmed 12 (3) 2010

STABIL-STUDIE: UMSTELLUNG AUF LEVOMETHADON | ORIGINALARBEITEN

suchten Drogen nachgewiesen. Bei 4,1% (N = 35/862)
der Patienten war kein Drogenscreening angegeben.

Das Drogenscreening am Beobachtungsende spiegelt den
Beigebrauch unter der Therapie mit Levomethadon wider:
Bei 44,1% (N = 380/862) der Patienten fand sich mindestens
ein positiver Drogennachweis, bei 49,1% (N = 423/
862) der Patienten wurden keine der untersuchten Drogen
nachgewiesen und bei 6,8% (N = 59/862) der Patienten war
kein Drogenscreening angegeben.

Die Untersuchungshäufigkeit der einzelnen Drogenarten
war sehr unterschiedlich. Es wurde am häufigsten versucht,
den Beigebrauch von Opiaten, Benzodiazepinen und Kokain
nachzuweisen bzw. auszuschließen (.
Abb. 2):

Opiate wurden unter Methadon-Razemat bei 95,1% (N =
820/862) und unter Levomethadon bei 92,1% (N = 794/
862) der Patienten untersucht. Ein positiver Nachweis fand
sich bei 43,3% (N = 355/820) der untersuchten Patienten
unter Methadon-Razemat, unter Levomethadon dagegen
nur noch bei 10,3% (N = 82/794) der Patienten.

Benzodiazepine wurden unter Methadon-Razemat bei 94,9%
(N = 818/862) und unter Levomethadon bei 92,7% (N =
799/862) der Patienten untersucht. Ein positiver Nachweis
fand sich bei 45,0% (N = 368/818) der untersuchten Patienten
unter Methadon-Razemat, unter Levomethadon dagegen
nur noch bei 22,2% (N = 177/799) der Patienten.

Kokain wurde unter Methadon-Razemat bei 93,4% (N =
805/862) und unter Levomethadon bei 90,5% (N = 780/862)
der Patienten untersucht. Ein positiver Nachweis fand sich
bei 15,8% (N = 127/805) der untersuchten Patienten unter
Methadon-Razemat, unter Levomethadon dagegen nur noch
bei 4,0% (N = 31/780) der Patienten.

Zusätzlich zum erhobenen Drogenscreening wurden die
beteiligten Ärzte auch direkt nach dem Beikonsum ihrer
Patienten gefragt. Der Anteil an Patienten ohne Beikonsum
war unter der Substitutionstherapie mit Levomethadon
deutlich höher (57,0%; N = 491/862) als unter der Thera

pie mit Methadon-Razemat (17,4%; N = 150/862).

3.3.2 AUFTRETEN VON ENTZUGSSYMPTOMEN
Das Auftreten von Entzugssymptomen wurde von den behandelnden
Ärzten im Rahmen der Eingangsuntersuchung
sowie am Beobachtungsende beurteilt. Bei der Eingangsuntersuchung
wurden dabei die Entzugssymptome unter
dem Einfluss der Vortherapie mit Methadon-Razemat beurteilt.
Am Beobachtungsende sollte das Auftreten der Entzugssymptome
unmittelbar vor der nächsten Gabe von
Levomethadon eingeschätzt werden.

Das frühzeitige Auftreten von Entzugssymptomen innerhalb
der letzten 24 Stunden vor der nächsten Substitution
wurde mithilfe der Kategorien „nein“, „wenig“, „mäßig“,
„stark“ und „sehr stark“ beurteilt. Der Anteil der Patienten
ohne ein frühzeitiges Auftreten von Entzugssymptomen
erhöhte sich deutlich im Beobachtungsverlauf: Während
vor der Umstellung der Substitutionstherapie auf Levomethadon
14,4% (N = 124/862) der Patienten frei von Entzugssymptomen
waren, betrug der Anteil bei Beobachtungsende
58,6% (N = 505/862). Bezogen auf die Patienten mit
validen Angaben zur Eingangsuntersuchung und bei Beobachtungsende
(N = 751) betrug die Verbesserung im Mittel
1,45 Kategorienstufen (p < ,001).

Das Auftreten sowie die Ausprägung der Entzugssymptome
Schwitzen, innere Unruhe, Tachykardie, Unkonzentriertheit
und Angstzustände wurde ebenfalls mit Hilfe der Kategorien
„nein“, „wenig“, „mäßig“, „stark“ und „sehr stark“
beurteilt. Die folgende Tabelle 2 stellt den Anteil der Patienten
ohne diese Entzugssymptome bei der Eingangsuntersuchung
sowie am Beobachtungsende dar (.
Tab. 2).

Die Daten zeigen bei allen beurteilten Symptomen einen
höheren Anteil an Patienten, die unter dem Einfluss von
Levomethadon am Beobachtungsende frei von Entzugssymptomen
waren gegenüber der Eingangsuntersuchung.
Die Veränderungen der Beurteilungen sind für alle erfragten
Entzugssymptome statistisch signifikant (p < ,001).

Eingangsuntersuchung
(Methadon Razemat)
Beobachtungsende
(Levomethadon)
Signifikanz*
(Wilcoxon Rang-Test,
zweiseitig)
Schwitzen 9,4 % (N = 81) 40,8 % (N = 352) p <,001
Innere Unruhe 12,6 % (N = 109) 47,2 % (N = 407) p <,001
Tachykardie 38,9 % (N = 335) 72,3 % (N = 623) p <,001
Unkonzentriertheit 17,4 % (N = 150) 49,8 % (N = 429) p <,001
Angstzustände 31,9 % (N = 275) 60,4 % (N = 521) p <,001
* Bezogen auf die Veränderung der kategorialen Einschätzung
Tabelle 2: Anteil der Patienten ohne Entzugssymptome (N = 862)
Suchtmed 12 (3) 2010 191

3.3.3 SUCHTDRUCK
Der Anteil der Patienten ohne Suchtdruck (Craving) erhöhte
sich deutlich im Beobachtungsverlauf. Während vor einer
Umstellung der Substitutionstherapie auf Levomethadon
11,8% (N = 102/862) der Patienten frei von diesem Symptom
waren, betrug der Anteil bei Beobachtungsende 57,7%
(N = 497) (.
Abb. 3). Bezogen auf die Patienten mit validen
Angaben zur Eingangsuntersuchung und bei Beobachtungsende
(N = 829) betrug die Verbesserung im Mittel
1,4 Kategorienstufen (p < ,001) (.
Abb. 3).

3.4 VERTRÄGLICHKEIT
Sowohl im Rahmen der Eingangsuntersuchung als auch
am Beobachtungsende wurden von den behandelnden Ärzten
die folgenden Unverträglichkeitsreaktionen beurteilt:
Schwitzen, Kopfschmerzen, Magen-Darm-Probleme, Schlafstörungen,
Müdigkeit/Sedierung, Stimmungsstörungen/

Abb. 3:

Patienten ohne Suchtdruck
(p < ,001; zweiseitiger Wilcoxon Rang-Test)

psychische Probleme, Libidostörungen, Antriebslosigkeit
und Schmerzen. Das Auftreten sowie die Ausprägung der
Reaktionen wurde mit Hilfe der Kategorien „nein“, „wenig“,
„mäßig“, „stark“ und „sehr stark“ beurteilt.

Die Daten zeigen bei allen beurteilten Unverträglichkeitsreaktionen
einen höheren Anteil an Patienten ohne diese Reaktionen
am Beobachtungsende (d.h. unter dem Einfluss
von Levomethadon) gegenüber der Eingangsuntersuchung

(d.h. unter dem Einfluss von Methadon-Razemat). Die Veränderungen
der Beurteilungen sind für alle erfragten Reaktionen
statistisch signifikant (p < ,001).
.
Tabelle 3 stellt den Anteil der Patienten ohne diese Unverträglichkeitsreaktionen
(Einschätzung „nein“) bei der
Eingangsuntersuchung sowie am Beobachtungsende dar.
UNERWÜNSCHTE ARZNEIMITTELWIRKUNGEN

Bei sieben der 862 Patienten (0,81%) traten insgesamt 13
unerwünschte Arzneimittelwirkungen (UAW) auf. Sie be-

Eingangsuntersuchng
(Methadon-Razemat)
Beobachtungsende
(Levomethadon)
Signifikanz*
(Wilcoxon Rang Test,
zweiseitig)
Schwitzen 8,1 % (N = 70) 40,0 % (N = 345) p <,001
Kopfschmerzen 46,9 % (N = 404) 80,5 % (N = 694) p <,001
Magen-Darm-Probleme 29,6 % (N = 255) 66,0 % (N = 569) p <,001
Schlafstörungen 13,5 % (N = 116) 43,0 % (N = 371) p <,001
Müdigkeit / Sedierung 22,5 % (N = 194) 57,8 % (N = 498) p <,001
Stimmungsstörungen /
psychische Probleme
17,2 % (N = 148) 48,5 % (N = 418) p <,001
Libidostörungen 36,4 % (N = 314) 59,4 % (N = 512) p <,001
Antriebslosigkeit 20,3 % (N = 175) 55,0 % (N = 474) p <,001
Schmerzen 59,9 % (N = 516) 83,1 % (N = 716) p <,001
* Bezogen auf die Veränderung der kategorialen Einschätzung

trafen am häufigsten die MedDRA Primary System Organ
Class „Gastrointestinal disorders“ (0,46% der Patienten).
Die häufigsten Einzelnennungen gemäß MedDRA Preferred
Term waren Verstopfung (N = 2; 0,23%) sowie Ekzeme,
allergische Hautreaktionen, Schwindel, Gastritis, gastrointestinale
Blutungen, Kopfschmerzen, Schwitzen, Unwohlsein,
Übelkeit, Ödeme und Erbrechen (jeweils N = 1;
0,12%). Schwerwiegende unerwünschte Arzneimittelwirkungen
traten nicht auf. Ein Patient verstarb aufgrund eines
Leberversagens im Verlauf der Studie (0,12% aller
Patienten). Ein Kausalzusammenhang mit Levomethadon
konnte ausgeschlossen werden.

3.5 GLOBALBEURTEILUNG DER SUBSTITUTIONSTHERAPIE
Die nachfolgenden Abbildungen/Tabellen enthalten die Beurteilung
der Substitutionstherapie mit Levomethadon nach
ca. vier Wochen bzw. bei Beobachtungsende sowie – zum
Vergleich – die Beurteilung der Therapie mit einem Methadon-
Razemat bei der Eingangsuntersuchung.

3.5.1 WIRKSAMKEIT
Die Wirksamkeit der Substitutionstherapie mit Levomethadon
wurde bei 91,9% (N = 792/862) der Patienten mit
„sehr gut“ bis „gut“ und bei 5,1% (N = 44/862) mit „mäßig“
bis „unbefriedigend“ angegeben (fehlende Angaben:
3,0%) (.
Abb. 4). Die Wirksamkeit der Behandlung mit
einem Methadon-Razemat vor Therapieumstellung auf
Levomethadon wurde bei 28,0% (N = 241/862) der Patienten
mit „sehr gut“ bis „gut“ und bei 71,3% (N = 615/862)
mit „mäßig“ bis „unbefriedigend“ angegeben (fehlende
Angaben: 0,7%. Bezogen auf die Patienten mit validen
Angaben zur Eingangsuntersuchung und bei Beobachtungsende
(N = 830) betrug der Unterschied im Mittel 1,2
Kategorienstufen zu Gunsten von Levomethadon und war
statistisch signifikant (p < ,001).

Abb. 4: Globalbeurteilung der Wirksamkeit der Substitutionstherapie
mit Levomethadon

3.5.2 VERTRÄGLICHKEIT
Die Verträglichkeit der Substitutionstherapie mit Levomethadon
wurde bei 93,4% (N = 805/862) der Patienten mit
„sehr gut“ bis „gut“ und bei 3,5% (N = 30/862) mit „mäßig“
bis „unbefriedigend“ angegeben (fehlende Angaben:
3,1%). Die Verträglichkeit der Behandlung mit einem Methadon-
Razemat vor Therapieumstellung wurde bei 23,0%
(N = 198/862) der Patienten mit „sehr gut“ bis „gut“ und
bei 76,2% (N = 657/862) mit „mäßig“ bis „unbefriedigend“
angegeben (fehlende Angaben: 0,8%). Der Unterschied
betrug im Mittel 1,4 Kategorienstufen zu Gunsten
von Levomethadon und war statistisch signifikant (p < ,001;
N = 828).

3.5.3 COMPLIANCE
Die Patienten-Compliance unter der Substitutionstherapie
mit Levomethadon wurde bei 87,2% (N = 752/862) der
Patienten mit „sehr gut“ bis „gut“ und bei 9,6% (N = 83/
862) mit „mäßig“ bis „unbefriedigend“ angegeben (fehlende
Angaben: 3,1%). Die Patienten-Compliance unter der
Behandlung mit einem Methadon-Razemat vor Therapieumstellung
wurde bei 49,9% (N = 430/862) der Patienten
mit „sehr gut“ bis „gut“ und bei 49,0% (N = 422/862) mit
„mäßig“ bis „unbefriedigend“ angegeben (fehlende Angaben:
1,2%). Der Unterschied betrug dabei im Mittel 0,80
Kategorienstufen zugunsten von Levomethadon und war
statistisch signifikant (p < ,001; N = 825) (.
Tab. 4).

Tabelle 4: Globalbeurteilung zur Compliance der Patienten

Eingangs Beobachtungsuntersuchung
ende
(Methadon(
Levo-
Razemat) methadon)
N % N %
sehr gut 76 8,8 % 331 38,4 %
gut 354 41,1 % 421 48,8 %
mäßig 323 37,5 % 74 8,6 %
unbefriedigend 99 11,5 % 9 1,0 %
keine Angabe 10 1,2 % 27 3,1 %
Total 862 100 % 862 100 %

3.5.4 BEFINDLICHKEIT
Die Befindlichkeit des Patienten wurde unter der Substitutionstherapie
mit Levomethadon bei 88,4% (N = 762/862)
der Patienten mit „sehr gut“ bis „gut“ und bei 8,5% (N =
73/862) mit „mäßig“ bis „unbefriedigend“ angegeben (feh-

lende Angaben: 3,1%). Die Befindlichkeit des Patienten un-862) der Patienten als „gleich“ und bei 0,9% (N = 8/862)
ter der Behandlung mit einem Methadon-Razemat vor The-der Patienten als „schlechter“ bzw. „viel schlechter“ berapieumstellung
wurde bei 18,2% (N = 157/862) der Patien-wertet (bei 2,9% fehlte diese Angabe) (.
Abb. 6).

ten mit „sehr gut“ bis „gut“ und bei 80,9% (N = 697/862)
mit „mäßig“ bis „unbefriedigend“ angegeben (fehlende
Angaben: 0,9%). Der Unterschied betrug dabei im Mittel
1,25 Kategorienstufen zu Gunsten von Levomethadon und
war statistisch signifikant (p < ,001; N = 827) (.
Tab. 5).

Eingangs
untersuchung
(Methadon-
Razemat)
Beobachtungs
ende
(Levo
methadon)
N % N %
sehr gut 10 1,2 % 238 27,6 %
gut 147 17,1 % 524 60,8 %
mäßig 480 55,7 % 66 7,7 %
unbefriedigend 217 25,2 % 7 0,8 %
keine Angabe 8 0,9 % 27 3,1 %
Total 862 100 % 862 100 %
Tabelle 5: Globalbeurteilung zur Befindlichkeit der Patienten
3.5.5 VERGLEICH ZUR VORTHERAPIE
Die Wirksamkeit der Substitutionstherapie mit Levomethadon
wurde im Vergleich zur Vortherapie mit einem Methadon-
Razemat bei 82,3% (N = 709/862) der Patienten mit
„viel besser“ bzw. „besser“, bei 13,9% (N = 120/862) der
Patienten als „gleich“ und bei 0,9% (N = 8/862) der Patienten
als „schlechter“ bewertet (bei 2,9% fehlte diese Angabe)
(.
Abb. 5).

Die Verträglichkeit der Substitutionstherapie mit Levomethadon
wurde im Vergleich zur Vortherapie mit einem
Methadon-Razemat bei 85,7% (N = 739/862) der Patienten
mit „viel besser“ bzw. „besser“, bei 10,4% (N = 90/

Abb. 5: Beurteilung der Wirksamkeit der Substitutionstherapie mitLevomethadon im Vergleich zur Vortherapie mit Methadon-Razemat

Abb. 6: Beurteilung der Verträglichkeit der Substitutionstherapie mitLevomethadon im Vergleich zur Vortherapie mit Methadon-Razemat

4 DISKUSSION

Nach den Richtlinien der Bundesärztekammer verläuft die
Behandlung von opiatabhängigen Patienten – im Rahmen
eines umfassenden Therapiekonzeptes – in verschiedenen
Stufen und hängt stark von der individuellen Disposition
des Opiatabhängigen ab (Richtlinien der Bundesärztekammer
2002). Die zur Verfügung stehenden Substitutionsmittel
können dabei je nach Situation des Patienten zum Einsatz
kommen (Michels et al. 2009).

Pharmakologische Daten aus in vitro- und in vivo-Untersuchungen
zur stereoselektiven Verstoffwechselung lieferten
in der Vergangenheit bereits wichtige Hinweise zum differenzierten
Einsatz von Levomethadon und Methadon-Razemat.
Spätestens seit den Untersuchungen von Eap et al.
2007 sind die pharmakologischen Zusammenhänge zwischen
dem Enantiomer Dextromethadon, der genetisch festgelegten
Fähigkeit zur Methadon-Metabolisierung durch
das Cytochrom P450-Enzymsystem CPY2B6 und der Erhöhung
des Risikos für schwere kardiale Arrhythmien und
den plötzlichen Herztod deutlich. Das im Methadon-Razemat
enthaltende Enantiomer Dextromethadon wird
stereoselektiv über CYP2B6 metabolisiert und besitzt durch
Blockade der sog. kardialen hERG-Kanäle ein 350% höheres
Kardiotoxizitäts-Potenzial als Levomethadon. Da
mindestens 6% aller opiatabhängigen Patienten einen
CPY2B6-Defekt aufweisen, ist dieser Genotyp für die Praxis
von hoher Relevanz. Durch weitere Risikofaktoren wie
Hypokaliämie, Hypocalciämie, hohe Arzneimittelkonzentrationen
und pharmakokinetische Wechselwirkungen kann
die Dextromethadon-Konzentration im Blut deutlich ansteigen,
so dass das Auftreten von Torsade de pointes signifikant
erhöht wird (Elsner 2005, Soyka 2008a und b).

Da die therapeutische Aktivität allein von Levomethadon
vermittelt wird, führt die Umstellung der Patienten von
Methadon auf Levomethadon zu einer Halbierung der Substanzmenge
und zu einer daraus resultierenden Senkung
der Plasmakonzentrationen, wodurch die opioidbedingte
Toxizität und Nebenwirkungsrate deutlich gesenkt werden
kann (Soyka 2008a und b). Da es aber auch hier noch keine
evidenzbasierten Richtlinien gibt, sind empirische Anhaltspunkte
für die Praxis von übergeordneter Bedeutung.

Vor diesem Hintergrund kommt den Ein- und Ausschlusskriterien
bei Studien zur Substitutionstherapie eine besonders
wichtige Rolle zu und sie werden kontrovers diskutiert
(u.a. bei Wittchen et al. 2009). Zum einen ist es durch
die hohe Komorbiditätsrate oft schwierig zu entscheiden,
welche Einflüsse die einzelnen Faktoren auf den Allgemein-
zustand haben. Viele klinische Studien schließen daher
multimorbide Patienten aus, nur stabile und unauffällige
Patienten dürfen rekrutiert werden. Dadurch wird die resultierende
Stichprobe aber oft stark reduziert, was die Relevanz
der Studienergebnisse erheblich beeinträchtigt. Zudem
muss ein hoher Prozentsatz der opiatabhängigen Patienten
tatsächlich als multimorbid eingestuft werden. Dadurch
sind Studien, die sich an den Praxisgegebenheiten
orientieren und die auch diese Klientel repräsentieren, für
den behandelnden Arzt von höherer Relevanz. Das ist bei
den vorliegenden Daten der Fall, die ausnahmslos in niedergelassenen
Praxen erhoben wurden. Sie können dadurch
die Behandlungsverläufe in der ärztlichen Alltagsroutine
weitgehend abbilden.

Die vorliegende Untersuchung beleuchtet die Umstellung
der Substitutionsbehandlung von Methadon-Razemat auf
Levomethadon. Das Kollektiv umfasst 862 opiatabhängige
Patienten, die aufgrund einer unbefriedigenden Substitution
mit Methadon-Razemat auf Levomethadon umgestellt
wurden. Gründe für die Umstellung auf Levomethadon
konnten u.a. erhöhter Suchtdruck, nicht tolerabler Beikonsum
oder nicht beherrschbare Nebenwirkungen der Vortherapie
sein. Bemerkenswert ist dabei, dass das Patientenklientel
mehrheitlich bereits lange drogenabhängig war
(im Median 13 Jahre) und eine hohe Multimorbiditätsrate
aufwies. So litten 78,1% aller Patienten an mindestens
einer Begleiterkrankung, wobei der größte Anteil auf eine
Hepatitis C-Infektion entfiel (55,9%).

Die Ergebnisse dieser Beobachtungsstudie zeigen nach der
Umstellung der Substitutionsbehandlung von Methadon-
Razemat auf Levomethadon eine deutliche Verbesserung
der Wirksamkeit und Verträglichkeit sowie eine signifikante
Verringerung des Suchtdrucks und des Beigebrauchs. Im
Vergleich zur Vortherapie wurden unter der Behandlung
mit Levomethadon bei deutlich weniger Patienten Entzugssymptome
dokumentiert. Durch die Substitutionsbehandlung
bedingte Unverträglichkeiten wie Schwitzen, Kopf

schmerzen, Magen-Darm-Probleme, Schlafstörungen, Müdigkeit/
Sedierung, Stimmungsstörungen/psychische Probleme,
Libidostörungen, Antriebslosigkeit und Schmerzen wurden
im Vergleich zur Vortherapie unter der Behandlung mit
Levomethadon ebenfalls signifikant seltener dokumentiert.

Die Daten bestätigen die Ergebnisse einer Beobachtungsstudie
mit 1.552 Patienten (Cernaj 2006), bei denen ebenfalls
die Umstellung von Methadon-Razemat auf Levomethadon
dokumentiert wurde. Im Gegensatz zu dieser Untersuchung
wurde bei der vorliegenden Studie vorausgesetzt, dass die
Vorbehandlung mit Methadon-Razemat nach Einschätzung
des Arztes unbefriedigend verlief. Vor diesem Hintergrund
waren auch die aktuellen Ergebnisse z.B. in Bezug auf
Beigebrauch, Entzugssymptomatik und Suchtdruck im Vergleich
der Studien für die Methadon-Vorbehandlung noch
ungünstiger. Die Ausgangsbedingungen für einen positiven
Therapieverlauf nach Umstellung auf Levomethadon
waren somit deutlich schlechter.

Zum Beispiel war der Anteil von Patienten mit einem nachgewiesenen
Beigebrauch in den aktuellen Daten mit 73,5%
höher als der in der Literatur berichtete Anteil von 61,2%
(Cernaj 2006). Nach der Umstellung auf Levomethadon
war der Unterschied jedoch geringer: Während von einem
positiven Drogennachweis in der vorhergehenden Studie
bei 39,8% der Patienten berichtet wurde, beträgt der Anteil
in den vorliegenden Daten 44,1%. Die Ergebnisse zeigen
damit, dass auch Patienten mit unbefriedigendem Therapieverlauf
unter Methadon durchaus von einer Substitution
profitieren können, wenn sie entsprechend umgestellt
werden.

Diese Ergebnisse stehen in einem gewissen Widerspruch
zu denen von Verthein et al. (2007), die in einer doppelblinden
Studie bei stabil auf ein Substitutionsmittel eingestellten
Patienten keine Effekte bei der Umstellung beobachten
konnten. Untersuchte Merkmale waren in diesem Fall
psychische Befindlichkeit, depressive Verstimmungen, Ängstlichkeit,
Suchtdruck und Beigebrauch. Obwohl die kleine
Zahl von Patienten (n = 68) die Aussagekraft der Studie
ohnehin relativiert, dürfte der Unterschied zu weiten Teilen
eher auf die stark differierenden Ein- und Ausschlusskriterien
zurückzuführen sein.

Das Patientenkollektiv von Wittchen et al. (2009) ist durch
hohe Belastung mit somatischen und mentalen Krankheiten
als multimorbid charakterisiert. Die Autoren konnten
den hohen Nutzen der Substitutionstherapie für diese Gruppe
klar belegen und betonen mehrfach die hohe Praxisrelevanz,
da die in ihrer Studie gewählten Bedingungen im
niedergelassenen Bereich regelmäßig anzutreffen sind.

Die vorliegende STABIL-Studie wurde mit einem vergleichbaren
Patientenkollektiv durchgeführt, was die durchschnittliche
Dauer der Krankheit und des körperlichen und men-

talen Gesamtstatus betrifft. Die Ergebnisse untermauern
die bereits in verschiedenen pharmakokinetischen Untersuchungen
erhobenen Hinweise, dass die opioidbedingte
Toxizität und die Nebenwirkungsrate durch Umstellung der
Patienten von Methadon auf Levomethadon deutlich gesenkt
werden können. Wirksamkeit und Verträglichkeit der
Therapie werden signifikant verbessert, so dass Patienten,
die zuvor mit Methadon-Razemat nur unbefriedigend behandelt
werden konnten, deutlich von einer Umstellung
profitieren.

5 LITERATUR

Bundesministerium für Gesundheit (2009): Drogen- und Suchtbericht
2008, Referat für Öffentlichkeitsarbeit des Bundesministeriums für
Gesundheit und soziale Sicherung. Eigenverlag, Berlin

Cernaj J (2006): Levomethadon signifikant besser als Methadon. Praxis-
Depesche 23, 1-4

Eap CB, Buclin T, Baumann P (2002): Interindividual Variability of the
Clinical Pharmacokinetics of Methadone. Clin Pharmacokinet 41
(14),1153-1193

Eap CB et al. (2007): Stereoselective block of hERG channel by (S)methadone
and QT interval prolongation in CYP2B6 slow metabolizers.
Clin Pharmacol Ther 81 (5), 719-728

Elsner H (2005): Kammertachykardien („Torsade de Pointes“) und weitere
Herzrhythmusstörungen unter Methadonsubtitution: Risikominderung
durch Medikamentenumstellung. Suchtmed 7 (4), 257263

Ferrari A, Coccia CPR, Bertolini A, Sternieri E (2004): Methadone –
metabolism, pharmacokinetics and interactions; Pharmacol Res 50,
551-559

Gerlach R (2002): Drug-substitution treatment in Germany: a critical
overview of its history, legislation, and current practice. J Drug Issues
32 (2), 503-521

Judson BA, Horns WH, Goldstein A (1976): Side effects of levomethadone
and racemic methadone in a maintenance program. Clin Pharmacol
Ther 20 (4), 445-449

Kleibel F (1963): Klinisch-experimentelle Untersuchungen eines neuen
linksdrehenden Polamidonpräparates (Levomethadon). Med Welt 31,
1573-1575

Maremmani I et al. (2005): QTc interval prolongation in patients on long
term methadone maintenance therapy. Eur Addict Res 11, 44-49

Michels I, Sander G, Stöver H (2009): Praxis, Probleme und Perspektiven
der Substitutionsbehandlung Opioidabhängiger in Deutschland.
Bundesgesundheitsblatt – Gesundheitsforschung – Gesundheitsschutz
52, 111-121

Richtlinien der Bundesärztekammer zur Durchführung der substitutionsgestützten
Behandlung Opiatabhängiger. Dtsch Ärzteblatt (2002)
99 (21) A 1458-A 1461

Scherbaum N, Finkbeiner T, Leifert K, Gastpar M (1998): The efficacy of lmethadone
and racemic methadone in substitution treatment for
opiate addicts – a double blind comparison; Pharmacopsychiat 29,
212-215

Shriniwas G et al.(1992): Bioequivalence of Racemic Drugs. J Clin
Pharmacol 32, 935-943

Soyka M (2008a): Sicherheitsaspekte in der Methadonsubstitution – Teil

2: Klinisch-pharmakologische Aspekte. Suchtmed 10 (2), 119-144
Soyka M (2008b): Sicherheitsaspekte in der Methadonsubstitution – Teil
1: Rechtliche Rahmenbedingungen, Mortalität, aktuelle Ergebnisse
der Therapieforschung. Suchtmed 10 (1), 7 – 27
Soyka M, Zingg C (2009): Feasabilitity and safety of transfer from racemic
methadone to (R)-methadone in primary care: Clinical results from a
open study. World J Biol Psych 10 (3), 217-224

Ther L, Lindner E, Vogel C (1963): Zur pharmakologischen Wirkung der
optischen Isomeren des Methadons; Dtsch Apothekerzeitung 17,
514-520

Ulmer A (1995): Klinische Auffälligkeiten bei der Umstellung von Levomethadon
auf Methadon-Razemat. Der Kassenarzt 12, 49-50

Verthein U, Reimer J, Ullmann R und Haasen C (2007): Psychische Befindlichkeit
in der Substitutionsbehandlung mit Levomethadon und d-l-
Methadon – eine doppelt randomisierte cross-over-Studie. Sucht 53
(1), 32-41

Wittchen HU et al. (2008): Feasibility and outcome of substitution
treatment of heroin-dependent patients in specialized substitution
centers and primary care facilities in Germany: A naturalistic study in
2694 patients. Drug and Alcohol Depend 95(3), 245-257

Auch als File fuer bessere Graphiken:metha auf pola

 

Orginalquelle ist:  http://www.ecomed-medizin.de/sj/sfp/abstract/ArtikelId/11160

Substitution in der EU heute weit verbreitet
Die Substitutionstherapie bei
problematischen Drogenkonsumenten ist
in der Europäischen Union (EU) heute
weit verbreitet. Erste Versuche –
hauptsächlich mit Methadon – begannen
Ende der 60er-Jahre, vor allem in
Nordeuropa. Bis Mitte der 90er-Jahre
war die Drogensubstitution in allen
EU-Mitgliedstaaten umgesetzt worden.
Europaweit herrscht heute überwiegend
Konsens bezüglich des Nutzens dieser
Therapieform. Dennoch ist sie in einigen
Ländern nach wie vor ein heikles Thema.

Wissenschaftliche Nachweise lassen
darauf schließen, dass mithilfe der
Substitutionstherapie Kriminalität,
Infektionskrankheiten und
drogenbedingte Todesfälle reduziert und
das körperliche, seelische und soziale
Wohlbefinden von abhängigen
Drogenkonsumenten verbessert werden
können. Als Gegenargument wird jedoch
angeführt, sie biete keine Heilung,
sondern sei lediglich eine halbherzige
Maßnahme, die das Problem des
Drogenkonsums nicht tatsächlich löse.
Die EBDD ist der Auffassung, dass sich die
politische Debatte über dieses Thema
nicht nur auf die Vor- und Nachteile
erstrecken sollte.

Die Substitutionstherapie
sollte vielmehr als ein Element innerhalb
eines ganzen Bündels von Maßnahmen
gegen das Problem des Drogenkonsums
gesehen werden, zu dem auch die
drogenfreie Therapie zählt.

Schätzungen zufolge erhalten
weltweit ungefähr eine halbe
Million Drogenkonsumenten eine
Substitutionstherapie. Davon
befinden sich mehr als 300 000 in
Europa und schätzungsweise
110 000 in den USA [1].
Methadon ist immer noch die am
häufigsten verwendete Substanz, obwohl
sie längst nicht mehr die Einzige ist.
In Frankreich ist Buprenorphin
vorherrschend. Andere EU-Mitgliedstaaten
haben Versuche mit Substanzen wie
Dihydrocodein, Morphin mit verzögerter
Wirkung und Levo-Alpha-Acetyl-Methadol
(LAAM) durchgeführt. Auf Empfehlung
der Europäischen Agentur für die
Beurteilung von Arzneimitteln (EMEA)

wird LAAM aufgrund des Auftretens von
lebensbedrohlichen Herz-Kreislauf-
Erkrankungen unter den in LAAM-
Therapie befindlichen Personen nun
jedoch nicht mehr eingesetzt.
Die Verwendung von Heroin bei
stabilisierten chronischen
Opiatkonsumenten wird seit 1997 in den
Niederlanden und seit kurzem auch in
Deutschland untersucht und ist in
anderen Mitgliedstaaten im Gespräch.
Im Vereinigten Königreich wird Heroin
selektiv in kleinem Umfang schon seit
einigen Jahrzehnten verschrieben.

Fakten, Zahlen und Untersuchungen sind
natürlich Voraussetzung für eine rationale
Erörterung dieser Thematik.
Bis vor kurzem waren aktuelle Daten auf
EU-Ebene über die Evaluation und
Qualität von Substitutionstherapien
Mangelware.

Dann veröffentlichte die EBDD Ende 2000
in ihrer Reihe Insights: Reviewing current
practice in drug-substitution treatment in
the European Union [1] jedoch einen
umfassenden Überblick über die jüngste
Praxis der Drogensubstitution.

Definition:

Die Substitutionstherapie ist eine Form der medizinischen
Fürsorge für Opiatabhängige (insbesondere Heroinabhängige), die auf der
Verabreichung einer Substanz beruht, die der bislang eingenommenen Droge
ähnlich oder mit ihr identisch ist. Sie wird in zwei Formen durchgeführt: als
Erhaltungstherapie – durch Verabreichung einer ausreichenden Dosis zur
Vermeidung des Risikoverhaltens bzw. gesundheitsschädigenden Verhaltens –
und als Entgiftung – durch stufenweise Herabsetzung der Dosis bis auf null.
Die Therapie kann mit oder ohne psychosoziale Unterstützung erfolgen.
Wichtige politische Themen auf einen Blick
1. Die Substitutionstherapie ist wesentlicher Bestandteil eines umfassenden
Ansatzes zur Drogentherapie. Sie kann dazu beitragen, das Risiko einer
HIV-Infektion oder Überdosis zu reduzieren und den Konsum legaler und
illegaler Drogen und die drogenbedingte Kriminalität zu verringern.
2. Es spricht einiges dafür, die Substitutionstherapie durch psychosoziale Fürsorge
zu unterstützen. In der Praxis fehlen diese Programme jedoch häufig, und der
Schwerpunkt liegt mehr auf der Substitution als auf der Therapie.
3. Die derzeit verwendeten Substanzen sind u. a. Methadon, Buprenorphin,
Dihydrocodein, Morphin mit verzögerter Wirkung und Heroin. In nahezu allen
EU-Mitgliedstaaten ist eine Substanz vorherrschend. Insgesamt wird
Methadon am häufigsten eingesetzt. Um optimale Ergebnisse zu erzielen,
sollte sowohl die Auswahl der Substanz als auch deren Dosierung auf den
jeweiligen Betroffenen abgestimmt werden.
4. Der Zugang zur Substitutionstherapie ist in der EU sehr unterschiedlich.
Einige Länder und Programme beschränken den Zugang anhand strenger
Kriterien („hochschwelliger“ Zugang). Andere fordern als einzige
Zugangsvoraussetzung die Opiatabhängigkeit („niedrigschwelliger“ Zugang).
5. In den meisten EU-Ländern wird die Substitutionstherapie entweder von
praktischen Ärzten oder von Fachzentren durchgeführt. Eine Kombination aus
beiden wäre optimal. Es muss jedoch dafür Sorge getragen werden, dass kein
Abzweigen der Substanzen für den illegalen Konsum stattfindet, indem sich
Abhängige aus verschiedenen Quellen Verschreibungen beschaffen und dann
mit diesen Drogen handeln.
6. Der geschätzte Anteil der problematischen Opiatkonsumenten, die sich in der
EU in Substitutionstherapie befinden, schwankt zwischen einem Tiefstwert von
ungefähr 10 % und einem Höchstwert von über 50 % (siehe Tabelle 1, S. 3) [2].
Rua da Cruz de Santa Apolónia 23–25, P-1149-045 Lissabon • Tel. (351) 218 11 30 00 • Fax (351) 218 13 17 11 • http://www.emcdda.org

Überblick über die Substitutionstherapie

1. Ein wesentlicher
Bestandteil von
Drogentherapiesystemen
Es ist hinlänglich belegt, dass eine
Substitutionstherapie dazu beitragen
kann, die HIV-Übertragung, den
Drogenkonsum, das Risiko einer
Überdosis und die drogenbedingte
Kriminalität zu reduzieren sowie den
allgemeinen Gesundheitszustand der
Abhängigen zu verbessern. Eine
umfassende Literaturdurchsicht [3]
erbrachte das Ergebnis, dass die Rate von
HIV-Infektionen und Aids durch die
Methadontherapie dramatisch gesenkt
werden kann. Auch die Häufigkeit von
Heroininjektionen, die gemeinsame
Benutzung des Drogenbestecks und
die Arbeit in der Beschaffungsprostitution
können verringert werden. Eine deutsche
Vierjahresstudie [4] über eine ambulante
Methadontherapie hat gezeigt, dass der
Drogenkonsum abnahm, während sich
die sozialen Fertigkeiten und Beziehungen
verbesserten. Eine Evaluation der
Methadonsubstitution in Athen [5] zeigte
eine starke Abnahme des parallelen
Konsums von Heroin.

„In vielen Ländern hat sich die
Substitutionstherapie – nach
anfänglichem Widerstand – als
Maßnahme gegen das mit dem
intravenösen Konsum von Opiaten und
anderen Drogen verbundene Risiko einer
HIV-Infektion entwickelt. Ihr Nutzen ist
unter Beweis gestellt worden.
Neben anderen Maßnahmen zur
Schadensminimierung und einem
geschärften Bewusstsein hat sie Ende der
90er-Jahre in den meisten EU-Ländern
zur Eindämmung neuer HIV-Fälle unter
injizierenden Drogenkonsumenten
beigetragen.“

2. Substitution statt
Therapie?
Die Rechtsvorschriften zur
Substitutionstherapie in den meisten
EU-Ländern sehen vor, dass diese durch
psychosoziale Fürsorge unterstützt
werden sollte. Die Forschung zeigt, dass
die positiven Effekte der Therapie zum
Großteil auf solche Programme
zurückzuführen sind. Doch Theorie und
Praxis klaffen nur allzu oft auseinander –
der Schwerpunkt liegt häufig eher auf der
Substitution als auf der Therapie. Der
Bedarf an psychosozialer Fürsorge wird
durch Erkenntnisse aus der Forschung
belegt, denen zufolge Klienten in
Methadontherapie, wie andere
Drogenabhängige auch, einem
besonderen Risiko gegenüber psychischen
Erkrankungen und anderen

Gesundheitsproblemen sowie sozialer
Verelendung ausgesetzt sind [6].
Es sollte untersucht werden, inwieweit
die psychosoziale Fürsorge beim
Fortschreiten der Drogenkonsumenten
von Abhängigkeit zu Abstinenz
möglicherweise eine Katalysatorrolle spielt.

Die Versorgungsmöglichkeit von
Drogenkonsumenten mit psychischen
Gesundheitsproblemen hängt von den
Verbindungen zwischen psychiatrischen
Einrichtungen und Drogenfachstellen ab.
In einigen Ländern sind gute
Verbindungen mit spezialisierten
Dualdiagnose-Abteilungen hergestellt
worden. In anderen Ländern sind die
Verbindungen zwischen den betreffenden
Diensten weniger gut.

„Die Drogentherapie zielt darauf
ab, den Betroffenen zu
ermöglichen, die Kontrolle über
ihr Leben wiederzuerlangen.
Fachkräfte müssen fortlaufend
einschätzen, inwieweit die
Klienten, die
Ersatzverschreibungen erhalten,
bereit sind, durch einen
Entgiftungsprozess drogenfrei zu
werden. Die Bereitstellung
psychosozialer und praktischer
Hilfe während dieses Prozesses
ist besonders wichtig.“

3. Welche Ersatzsubstanzen
werden verwendet?
Nahezu alle EU-Mitgliedstaaten
verwenden eine vorherrschende
Ersatzsubstanz anstatt einer breiten
Palette von Substanzen [7]. Über 90 %
der Opiatsubstitution erfolgt in Form von
Methadon, außer in Frankreich, wo
überwiegend Buprenorphin verwendet
wird. EU-weit stieg die geschätzte Anzahl
von Drogenkonsumenten unter
Methadontherapie zwischen 1993 und
1997 um das Sechsfache an [1].

Die Ersatzsubstanzen haben
unterschiedliche Eigenschaften.
Buprenorphin birgt nicht die Gefahr einer
Überdosis; außerdem hemmt es die
Effekte eines parallelen Heroinkonsums.
Methadon hingegen ist einfach zu
verabreichen und kostengünstig – etwa 9
EUR pro Person pro Woche, im Vergleich
zu 65 EUR für Buprenorphin. Einige
Experten ziehen Buprenorphin für jüngere
Drogenkonsumenten und Methadon für
die langfristige Therapie älterer
Konsumenten vor. Buprenorphin scheint
auch besser für schwangere Frauen
geeignet zu sein und bei den

Neugeborenen weniger Probleme als
Methadon zu verursachen.
Herointherapieversuche laufen in
Deutschland und in den Niederlanden
und sind in anderen EU-Mitgliedstaaten
im Gespräch. Hierbei wird extrem
problematischen Heroinkonsumenten ihre
ursprüngliche Droge unter medizinisch
kontrollierten Bedingungen bereitgestellt.
Es ist bei allen Ersatzsubstanzen wichtig,
die Substitutionsdosis an die bisherige
Höhe des Drogenkonsums des Einzelnen
anzupassen.

4. Wie zugänglich ist die
Substitutionstherapie?
Trotz einer allgemeinen Ausweitung der
Substitutionstherapie in den letzten zehn
Jahren ist der Zugang zu ihr innerhalb der
EU weiterhin uneinheitlich. So scheint der
Erfassungsbereich in Griechenland,
Norwegen, Finnland und Schweden
begrenzt.

Die Substitution erfolgt fast ausschließlich
auf ambulanter Basis. Dies hat den
Vorteil, dass es kostengünstig ist und den
Drogenkonsumenten ermöglicht, ein
normales Alltagsleben zu führen.
Die Klienten, die sich in
Substitutionstherapie befinden, reichen
von relativ gut funktionierenden, häufig
berufstätigen Personen bis hin zu
marginalisierten und extrem
benachteiligten Drogenabhängigen auf
der Straße. Folglich benötigen manche
Klienten möglicherweise mehr Fürsorge,
als die ambulante Substitutionstherapie
leisten kann.

Die Zulassungskriterien unterscheiden sich
von einem EU-Land zum anderen
erheblich. Einige Programme und einige
Mitgliedstaaten – beispielsweise
Griechenland und Schweden – verfügen
über hochschwellige Dienste, die das
Alter, die Dauer der Drogenabhängigkeit,
die Anzahl der erfolglosen Therapien usw.
mit einbeziehen. Andere Mitgliedstaaten,
wie Dänemark, Spanien, Italien und die
Niederlande, schreiben als
Zugangskriterien lediglich
Opiatabhängigkeit und Therapiewunsch
vor. Durch den hochschwelligen Ansatz
werden Menschen mit ähnlichen
Problemen und Bedürfnissen erreicht;
dabei können allerdings diejenigen
ausgeschlossen werden, die zwar Hilfe
benötigen, den Zulassungskriterien jedoch
nicht entsprechen. Durch die
niedrigschwellige Methode werden die
meisten potenziellen Klienten erreicht,
wobei deren weit auseinander klaffende
Bedürfnisse jedoch nicht immer erfüllt
werden können. Idealerweise sollten
beide einander ergänzen. Auch bei der
Verfügbarkeit der Substitutionstherapie
in Haftanstalten gibt es sehr große
Unterschiede.

Land Geschätzte Prävalenz des Geschätzte Anzahl von Patienten

Belgien 20 200 7 000 (1996) 35 (3)
Dänemark 12 752-15 248 4 398 (4 298 Methadon, 100 Buprenorphin) 27-34
(1. Januar 1999) (4)
Deutschland 80 000-152 000 50 000 (2001) (4) 33-63
Griechenland keine Daten verfügbar 966 (1. Januar 2000) (4) –
Spanien 83 972-177 756 72 236 erhielten Methadon (1999) 41-86
Frankreich 142 000-176 000 71 260 (62 900 erhielten Buprenorphin
und 8 360 erhielten Methadon (Dezember 1999) (4) 40-50
Irland 4 694-14 804 5 032 (31. Dezember 2000) (4) 34-100 (5)
Italien 277 000-303 000 80 459 (1999) (4) 27-29
Luxemburg 1 900-2 220 864 [164 im offiziellen Programm und +/-700 38-45
Verschreibungen von Mephenon® (Methadon in
Pillenform) von praktischen Ärzten; 2000] (4)
Niederlande 25 000-29 000 11 676 (1997) 40-47
Österreich 15 984-18 731 4 232 (1. Januar 2000) (4) 23-26
Portugal 18 450-86 800 6 040 (1. Januar 2000) 7-33
Finnland 1 800-2 700 (6) 240 (170 Buprenorphin und 70 Methadon) 9-13
Schweden 1 700-3 350 (6) 621 (31. Mai 2000) (4) 19-37
Vereinigtes 88 900-341 423 (7) 19 630 6-22
Königreich
Norwegen 9 000-13 000 1 100 (2001) 8-12

(1) Methoden zur Einschätzung des problematischen Drogenkonsums schwanken erheblich zwischen den EU-Mitgliedstaaten. Weitere Einzelheiten zur nationalen
Prävalenz und zum problematischen Drogenkonsum siehe den Abschnitt über problematischen Drogenkonsum in Kapitel 1 (Jahresbericht der EBDD 2001) sowie
die Online-Tabelle 1 OL unter: http://annualreport.emcdda.org
Schätzungen des problematischen Drogenkonsums beziehen sich hauptsächlich auf Opiumkonsumenten, außer für Finnland und Schweden, wo der
Amphetaminkonsum kennzeichnend ist. In den vorliegenden Schätzungen für Finnland und Schweden sind keine Amphetaminkonsumenten enthalten.
(2) Geschätzter Anteil der problematischen Drogenkonsumenten in Substitutionstherapie.
(3) Die Prävalenzziffer umfasst nur injizierende Drogenkonsumenten, was zu einer Überschätzung der Substitutionserfassungsrate führen könnte.
(4) Unmittelbar vom nationalen Knotenpunkt gesammelte Information.
(5) Eine Substitutionserfassungsrate von 100 % scheint nicht plausibel, was darauf schließen lässt, dass die Prävalenzschätzung von 4 694 die derzeitige Prävalenz
unterschätzen könnte.
(6) Nur Opiatkonsumenten.
(7) Genauere Daten für das Vereinigte Königreich: Prävalenz des problematischen Drogenkonsums (Opiate) = 162 000-244 000; Klienten in der Substitutionstherapie =
35 000; Erfassungsrate = 14-22 %.
5. Wie wird die
Substitutionstherapie
durchgeführt?
Im Allgemeinen wird die
Substitutionstherapie entweder von
praktischen Ärzten durchgeführt oder von
Fachzentren, die über Dienste verfügen,
die speziell auf die Bedürfnisse der
Drogenabhängigen zugeschnitten sind.
Beides hat seine Vorteile: Die praktischen
Ärzte bieten einen breiten geografischen
Erfassungsbereich, während Fachzentren
über beträchtliche Erfahrung und
Fachwissen verfügen. In nahezu allen
EU-Mitgliedstaaten konzentriert sich die
Therapie jedoch auf die eine oder andere
Alternative. Eine Kombination aus beiden

– sowie gleichzeitig die Einrichtung
eines Systems, um die Abzweigung der
Substanzen für illegale Zwecke zu
verhindern – könnte wirksamer sein.
Beides hat auch seine Nachteile: Die von
praktischen Ärzten angebotenen
Dienstleistungen schwanken
beträchtlich, und die Drogenabhängigen
könnten sich unter Stammpatienten
unwohl fühlen. Fachzentren wiederum
sind geografisch nicht gleichmäßig
verteilt, was zu Nachteilen für
Drogenkonsumenten in entlegenen
Regionen führen könnte.

6. Drogenkonsumenten in
Substitutionstherapie
Tabelle 1 zeigt Schätzungen der Anzahl
von problematischen Drogenkonsumenten
(hauptsächlich Opiatkonsumenten) in der
EU und die geschätzten Prozentsätze in
Substitutionstherapie. Letztere schwanken
erheblich zwischen den Mitgliedstaaten.
In einigen Ländern liegen sie bei nur ca.
10 %, währen sie in anderen 50 %
überschreiten. Es ist zu beachten, dass es
bei den Schätzungen des problematischen
Drogenkonsums immer noch an
Genauigkeit fehlt und sie nicht leicht zu
vergleichen sind. Ein niedriger

Erfassungsbereich bedeutet, dass eine
große Anzahl von Drogenkonsumenten
möglicherweise einem erhöhten Risiko
einer Überdosis, von Gesundheitsschäden,
HIV und anderen Infektionskrankheiten
sowie der sozialen Ausgrenzung
unterliegt.

Man darf jedoch nicht vergessen, dass die
Substitution nur bei der Bekämpfung des
Problems des Opiatkonsums von Nutzen
ist. Für den Amphetamin- oder
Kokainkonsum gibt es keine derartige
Lösung. In den nördlichen EU-
Mitgliedstaaten entstehen größere
Probleme durch Amphetamine als durch
Heroin, und in der EU im Allgemeinen
lässt sich der Kokainkonsum nicht
ignorieren.

Trotz der Ausweitung der Substitutionstherapie
in den letzten Jahren berichten
die meisten Mitgliedstaaten nach wie vor
über einen Mangel an Qualitätskontrolle,
Überwachung und Evaluation einzelner
Programme.

Januar-Februar 2002

Schlussfolgerungen
Substitutionstherapie – politische Erwägungen

In der vorliegenden Kurzinformation zur Drogenpolitik werden einige der heute über den Stand der Substitutionstherapie in
der EU zur Verfügung stehenden Schlüsseldaten und Evaluationen zusammengefasst und die wichtigsten Quellen für
diejenigen angegeben, die mehr darüber wissen möchten. Ausgehend von den derzeitigen Erkenntnissen könnten folgende
Schlussfolgerungen die Grundlage für zukünftige politische Erwägungen bilden:

1. Die Substitution sollte als Teil eines umfassenden Therapiesystems für Opiatabhängige erachtet werden. In Ländern mit
einem hohen Übertragungspotenzial durch intravenösen Drogenkonsum sollte sie eine Schlüsselkomponente von
HIV-Präventionsstrategien darstellen.
2. Sie sollte systematisch durch psychosoziale Begleitprogramme unterstützt werden.
3. Das Angebot sollte eine breitere und diversifiziertere Palette von Substanzen und Dosierungen umfassen, um dem Profil
des sich in Therapie begebenden Klienten zu entsprechen.
4. Die Substitutionstherapie sollte verfügbarer und zugänglicher gemacht werden, wobei sowohl niedrigschwellige als auch
hochschwellige Optionen im Rahmen eines ausgeglichenen Ansatzes angeboten werden sollten.
5. Sowohl praktische Ärzte als auch Fachzentren sollten an der Durchführung beteiligt sein.
6. Der Anteil der in Substitutionstherapie befindlichen problematischen Drogenkonsumenten sollte regelmäßig in den
einzelnen geografischen Regionen überprüft werden, um die Durchführung der Dienstleistungen zu überwachen.

[1] Europäische Beobachtungsstelle für
Drogen und Drogensucht (EBDD)
(2000), Reviewing current practice in drugsubstitution
treatment in the European
Union, EMCDDA Insights Nr. 3,
Amt für amtliche Veröffentlichungen der
Europäischen Gemeinschaften,
Luxemburg 2000.
(Enthält eine umfassende Bibliografie zum
Thema Substitutionstherapie.)

[2] Europäische Beobachtungsstelle für
Drogen und Drogensucht (EBDD)
(2001), Jahresbericht über den Stand der
Drogenproblematik in der Europäischen
Union 2001, Tabelle 1:
Substitutionsbehandlung bei
problematischen Drogenkonsumenten,
Amt für amtliche Veröffentlichungen der
Europäischen Gemeinschaften,
Luxemburg 2001, S. 33.

[3] Drucker, E., Lurie, P., Wodak, A.,
und Alcabes, P. (1998), „Measuring harm
reduction: the effects of needle and
syringe exchange programs and
methadone maintenance on the ecology
of HIV“. Aids, 12 (suppl. A),
S. 217-230.
[4] Küfner, H., Vogt, M., und Weiler, D.
(1999), Medizinische Rehabilitation und
Methadon-Substitution, Schneider Verlag
Hohengehren, Baltmannsweiler.

[5] EDDRA-Datenbankeintrag (2001),
Second unit of the methadone
substitution programme in Athens,
(http://www.reitox.emcdda.org:8008/
eddra), EBDD, Lissabon.

[6] Farrell, M., Howes, S., Taylor, C.,
Lewis, G., Jenkins, R., Bebbington, P.,
Jarvis, M., Brugha, T., Gill, B., und
Meltzer, H. (1998), „Substance misuse
and psychiatric co-morbidity: an overview
of the OPCS national psychiatric morbidity
survey“. Addictive Behaviors, 23, Nr. 6,
Elsevier Science Ltd., Oxford, S. 909-918.
[7] Europäische Beobachtungsstelle für
Drogen und Drogensucht (EBDD)
(2000), Jahresbericht über den Stand der
Drogenproblematik in der Europäischen
Union 2000, Tabelle 1: In der EU
verwendete Ersatzsubstanzen,
Amt für amtliche Veröffentlichungen der
Europäischen Gemeinschaften, Luxemburg,
2000, S. 37.

OFFIZIELLER HERAUSGEBER: Amt für amtliche Veröffentlichungen der Europäischen Gemeinschaften
© Europäische Beobachtungsstelle für Drogen und Drogensucht, 2002

DIREKTOR: Georges Estievenart
REDAKTION: Kathy Robertson, John Wright
AUTOREN: Margareta Nilson, Ulrik Solberg, Danilo Ballotta, Lucas Wiessing
GESTALTUNG: Dutton Merrifield, UK

EUR

Printed in Italy

Informationen im WWW

Ich habe das auch als File fuer die Tabellen: att_33470_DE_Dif01de

BINGHAM, Me. — The orange signs posted throughout Chet Hibbard’s pharmacy here relay a blunt warning: We Do Not Stock OxyContin.

Matt McInnis for The New York Times

“Outside hiring an armed guard to be in here 24/7, I don’t know what else to do.” CHET HIBBARD, a Maine pharmacist who has stopped selling OxyContin.

Mr. Hibbard stopped dispensing the highly addictive painkiller last July, after two robbers in ski goggles demanded it at knifepoint one afternoon as shocked customers looked on. It was one in a rash of armed robberies at Maine drugstores last year, a sharp increase that has rattled pharmacists and put the police on high alert.

“I want people to know before they even get in the door that we don’t have it,” Mr. Hibbard said of OxyContin, which the authorities say is the most common target of pharmacy robberies here. “Outside hiring an armed guard to be in here 24/7, I don’t know what else to do.”

Maine’s problem is especially stark, but it is hardly the only state dealing with pharmacy robberies, one of the more jarring effects of the prescription drug abuse epidemic that has left drugstores borrowing heist-prevention tactics from the more traditional targets, banks. In at least one case, a tiny tracking device affixed to a bottle let the police easily track a thief after a robbery.

More than 1,800 pharmacy robberies have taken place nationally over the last three years, typically conducted by young men seeking opioid painkillers and other drugs to sell or feed their own addictions. The most common targets are oxycodone (the main ingredient in OxyContin), hydrocodone (the main ingredient in Vicodin) and Xanax.

The robbers are brazen and desperate. In Rockland, Me., one wielded a machete as he leapt over a pharmacy counter to snatch the painkiller oxycodone, gulping some before he fled. In Satellite Beach, Fla., a robber threatened a pharmacist with a cordless drill last week, and in North Highlands, Calif., a holdup last summer led to a shootout that left a pharmacy worker dead.

The crime wave has spurred pharmacists to tighten security measures and add ones they may never have imagined. Many have upgraded their surveillance cameras; some have installed bulletproof glass and counters high enough to keep would-be robbers from jumping them, giving these pharmacies the aesthetic of an urban liquor store. In Tulsa, Okla., where there was a steep increase in drugstore robberies last year, at least one pharmacist now requires customers to be buzzed in the door.

Meanwhile, the police are quietly experimenting with new tools. In Lewiston, Me., last fall, a Rite Aid pharmacist handed a robber who threatened to shoot her five bottles of OxyContin, including one that contained a tracking device.

According to court records, the device led the police to the suspect’s home on a rural road shortly after he fled the store. They gathered evidence there, arrested the suspect a few days later and indicted him last month.

The Drug Enforcement Administration does not routinely investigate reports of pharmacy robberies, and therefore “it cannot be determined what factors are contributing to these types of thefts,” a spokeswoman said.

But some local law enforcement officials have been overwhelmed enough by the incidents to seek help. Thomas Delahanty II, the United States attorney in Maine, announced recently that the federal authorities would help investigate the heists from now on and prosecute some of the cases.

Federal charges could bring more prison time, Mr. Delahanty said, describing the surge in such robberies as “staggering numbers that can’t be ignored.” There were 21 in Maine last year, according to the D.E.A., up from two in 2008 and seven in 2009.

In Biddeford, Me., a city of 21,000 that has had seven pharmacy robberies since December 2009, Roger Beaupre, the police chief, said he was urging the stores to require customers to remove hoods and sunglasses before entering and to consider caging in their pharmacy counters.

Police officers there got free training in how to investigate pharmacy heists last month from Purdue Pharma, the maker of OxyContin. The company also trains pharmacists on how to prevent robberies and what to do should they fall victim to one, said Rick Zenuch, its director of law enforcement liaison and education.

“The very first tip we give them is comply, comply, comply,” Mr. Zenuch said. “Do exactly what the suspect wants, to end the encounter as soon as possible.”

In Washington State, where more than 100 pharmacy robberies have taken place over the last three years, law enforcement officials say the penalty for second-degree robbery, when the pharmacist may be threatened but no weapon is shown, is too weak. Dan Satterberg, the King County prosecutor, said he had submitted a bill to the Legislature to increase the minimum jail time to three years from three months.

“Word travels fast on the street about what an easy target the pharmacies are and how much profit can be made and what small punishment is attached,” Mr. Satterberg said.

OxyContin goes for $1 a milligram on the street, Mr. Satterberg and other law enforcement officials said, and the most popular pill is 80 milligrams.

 

Many pharmacies in Washington have deterred would-be robbers by putting time-release locks on the safes where they store narcotics and staggering their inventory, Mr. Satterberg said. Perhaps as a result, the number of armed robberies at pharmacies there dropped to 23 in 2010 from 49 in 2008, according to the D.E.A.

Still, Mr. Satterberg said, the threat of robbery has made it difficult for retail chains in the state to recruit enough pharmacists in recent years.

“They feel very vulnerable when so many people are so desperate to get what they keep behind those counters,” he said.

In sheer numbers, Florida, Indiana, California, Ohio and Washington have had the most armed robberies of pharmacies since January 2008, according to the D.E.A. But Maine, Oklahoma and Oregon had the sharpest increases last year.

All but a handful of the Maine robberies took place at Rite Aid and CVS stores, some of which were hit multiple times.

In Tulsa, Okla., where pharmacy robberies last year far outpaced bank robberies, the police said the crimes were now more often committed by gangs who want to sell the drugs than addicts in search of a fix. Robbers there often demand Xanax, an anti-anxiety drug, along with opioids, said Sgt. Dave Walker, who runs the robbery unit of the Tulsa Police Department.

In Bingham, a remote town of about 1,000, the men who robbed Mr. Hibbard’s pharmacy, E.W. Moore & Son, were caught and sent to prison, as was another robber who held up the store at gunpoint in 2006. But despite that comforting fact and the store’s nine surveillance cameras and high-tech alarm system, Mr. Hibbard and his employees still jump when the place is quiet and they hear footsteps coming up the ramp, they said.

“I stood right between him and his knife,” said Lori Pratt, a pharmacy technician, referring to one of the robbers. “I was all ready to go on the Internet after it happened and get a Taser gun.”

Unlike Mr. Hibbard, Rite Aid has chosen to keep stocking the drugs that are popular with robbers, said Eric Harkreader, a spokesman. But the company now limits the amount of certain drugs in stores at any given time.

“If they are going for lots of quantity at once, we don’t want to help them out,” he said. “But we certainly want to have the prescription available for all its legitimate purposes.”

In Biddeford, a Rite Aid that was robbed twice last year was struck again last week. The suspect, who demanded OxyContin and fled into the night, remains at large.

 

source: http://www.nytimes.com/2011/02/07/us/07pharmacies.html?_r=1&pagewanted=2

20% of US adults get prescriptions for analgesics, yet little is known about the safety of these drugs. In recent years, a number of high profile lawsuits have caused an upheaval in the public’s trust of prescribed pain medication. If you haven’t been concerned about the safety of your pain medications, you should be.

According to Solomon, et. al, authors of „The Comparative Safety of Analgesics in Older Adults With Arthritis“, published in Archive of Internal Medicine this month, most randomized clinical trials – which includes studies the FDA requires of a drug maker before their product can be sold on the market – look at how well a pain med works, but NOT how safe it is. They say that most of the time, study subjects are healthy, unlike the people for whom the drug is meant. Add to this the fact that as a general rule, long term side effects are rarely evaluated in studies, and you have cause for doubt about pain med safety, in my opinion.

Two studies evaluating health risks associated with taking pain meds made the news recently. The news reports I read focused on the findings that giving opioids (narcotic pain medications) to people over the age of 80 increased their risk of complications, health problems and even death. Of course, conventional pain doctors who commented in the news reports tried to refute the results by saying the study had serious problems with confounding. Little information about exactly what skewed the results was given in the news reports.

Confounding happens when a researcher observes people to find out what causes or at least is associated with a particular effect. Investigators may hypothesize that one characteristic is responsible for a disease or condition.  But another characteristic, related to the one they are evaluating, emerges as a possible cause during the course of the study.  So the hypothesis just got more complicated.  In the two recent studies, confounders included any possible role that obesity, smoking, drinking and the use of over the counter pain meds (NSAIDs) may have played in the safety of those who took opioids or Cox-2 inhibitors.  In other words, the researchers were unable to factor these things in when they looked at safety events resulting in hospitalization and/or death in seniors taking opioid pain medication.

The study authors talked about this problem in their report, acknowledging the possibility that something other than the medication was at work here. They described the way in which they created comparable groups of pain med taking seniors. And as it turns out, these remaining factors (smoking, drinking, being overweight and taking NSAIDs) occupied only a small fraction of the overall possible causes of the health risks identified in the two studies.

The study compared opioid use to NSAID use, as well as to the use of Cox-2 inhibitors.

The studies found that:

  1. opioids are likely not as safe as previously thought and
  2. the different opioid medications each have different degrees of risk.

Hopefully these studies will trigger more safety studies, but the authors rather doubt that.

As with most studies, the authors end by saying more studies are necessary before we can definitely know the best course of action for patients.

Sources:

Solomon, D. MD, et. al. The Comparative Safety of Analgesics in Older Adults With Arthritis. Arch Intern Med. Vol 170 Dec 13/27 2010. Accessed: Dec 21 2010.

I recently saw a copy of Amar Farooqui’s book, Opium City. It revealed a historical detail that is very difficult to swallow: Mumbai’s prosperity is rooted in the Opium Trade of the 19th century. Some of the most respected business families today owe their fortune to that vile practice. Some of the city’s memorable buildings were financed by this terrible trade.


Illustration/ Devdutt Pattanaik

So what was this Opium Trade? The British East Indian company was one of the first companies in the world that had ’shareholders‘. To pay shareholders, the company had to make huge profits. So the Company forced Indian peasants to grow opium, instead of grain. This opium was sold in China in exchange for highly profitable tea. So India became poor, an entire generation of Chinese became opium addicts, to make the Company, and later the Empire, rich.

The best quality opium was grown in Malwa and since much of India then was not quite under the Company’s control, the only way to access this opium was to smuggle it via Rajasthan and Karachi to the Bombay fort.

Many now respectable Indian business families (allegedly and apparently, for everyone denies it now) participated in this lucrative trade and made huge fortunes.

When I watch films like Young Victoria, King’s Speech and The Queen I can’t help but feel this is subtle propaganda to re-establish the nobility of a tethering British royal family, and I wonder if the rulers portrayed ever took responsibility for the Opium Wars that filled their coffers as they blessed and taxed and finally controlled the East India Company’s shareholders. Likewise, do we?

I imagine Chinese students being taught this history: How the West abused it for its profit and how Indian business families participated in their downfall. This could be the reason why the Chinese do not have a great relationship with India, and look at everyone with suspicion. How does one rectify it?

They say children inherit the sins of the father. The Mahabharata refers to this concept again and again. How crimes committed in an earlier generation end up affecting a later generation. The epic begins with the story of Janamejaya angry that his father has been killed by a snake, until he is told that his great grand parents destroyed an entire forest that was home to thousands of snakes. Even the horrific war at Kurukshetra, like the World Wars, is not merely the fight of cousins, but the outburst of several generations of rage and denial and frustration and envy. That is why these stories look not at one generation but at several.

So long is the history and so deep is the wound that everyone assumes they are the victims and no one is prepared to take the responsibility of the villain. Such is life. There are no heroes or villains, just people who choose to exploit, people who seek retribution, people who cannot forgive and people who yearn shy away from responsibility but yearn for nobility.

he growing of opium poppies in the Afghan provinces of Helmand and Kandahar is predicted to be down for the second year running.

But a UN drugs forecast released on Monday says that poppy growing will increase elsewhere in Afghanistan.

Forecasting the Afghan crop is a tricky business, and the groundwork for this UN survey is based on the sample of only a few villages in each province.

But matched with satellite imaging, it suggests poppy growing will spread.

And that spread this year will even extend into provinces that had become poppy-free in recent years.

The United Nations Office on Drugs and Crime (UNODC) has expressed concern in particular about a predicted increase in Nangahar, a large province bordering Pakistan where poppy growing had been all but eradicated in recent years.

It is a strange market that does not conform to usual market forces.

Although the price to farmers more than doubled last year to $164 a kilogram – because of a cut in output caused by crop disease – the price paid by buyers abroad did not go up.

When you see more conflict, when you see more poverty, you will see more opium cultivation” End Quote Jean Luc Lemahieu UNODC head in Kabul

So Afghanistan’s drug barons were squeezed in the middle.

The higher prices paid to farmers played a big part in encouraging more to plant this year.

The UN survey predicts more planting across a wide swathe of central Afghanistan – from Herat and Ghor in the west to the provinces east of Kabul along the Pakistan border.

Their forecast for the northern region will come out later in the year, as the season starts later in the north.

The predicted rise in poppy planting tallies with other evidence suggesting that the Taliban insurgency has spread across a wider region of the country.

The UNODC’s head in Kabul, Jean Luc Lemahieu, said tough measures were needed so that the forecast did not become a reality.

„When you see more conflict, when you see more poverty, you will see more opium cultivation. That is why we continue saying this is not business as usual. We need to put extraordinary measures in place today,“ he said.

The silver lining in the forecast is that for the third year running, Helmand’s crop is forecast to reduce this year – and for the second year, Kandahar too will grow fewer poppies.

Foreign troops

These two provinces are by far the largest poppy-growing regions in Afghanistan – accounting for more than a third of the world’s opium between them.

Map

The surge of US troops along with British troops in the main population centres in Helmand played a big part, as did weather conditions – too cold and dry at the time farmers wanted to plant.

But the deputy head of the British mission in Helmand, Leo Tomlin, said the forecast showed that a set of policies were working.

They include public information, strong leadership from the Governor Gulab Mangal, tougher policing and better job opportunities.

„It’s almost an aligning of the stars. That’s also why counter-narcotics takes a long time. It’s not something you can start one year and expect to see immediate results,“ he said.

„It’s something that needs a long-term investment, a continued investment with a very similar type of predictable programme.“

Even these predicted reductions will leave more than 65,000 hectares under cultivation for poppies in Helmand and some 25,000 hectares in Kandahar.

It may have been pushed onto marginal land, out of sight, but it still remains a potent threat to stability and security in Afghanistan.

 

High opium price not increasing cultivation in Afghanistan: report

Jan 31, 2011, 14:14 GMT

Kabul – The United Nations said Monday in a report that the increasing price of opium had not boosted its cultivation in the main producing provinces of southern Afghanistan.

It also said opium growing was ’strongly associated with insecurity and lack of agricultural assistance.‘

The current high price of opium did not produce an increase in opium cultivation in the biggest producing provinces of Helmand and Kandahar, the report titled Afghanistan: Opium Survey 2011 said.

The opium winter assessment report prepared by the United Nations Office on Drugs and Crime and the Afghan Counter Narcotics Ministry also predicted a decrease in the opium cultivation in the two southern provinces in 2011.

The UN report said the reasons for decreasing cultivation could be dry climate conditions leading to crop failure, a changing political environment, increasing government control and more military operations by Afghan and international troops around the time of poppy planting which ‚may have‘ discouraged the farmers.

NATO-led forces with Afghan security personnel have been pushing the Taliban from the areas around Kandahar and Helmand since 2010 with ’some gains‘ in the region.

In other parts of Afghanistan, mainly the western, eastern and central provinces, the report observed an increase.

The UN report warned of ‚increasing cultivation trends‘ in the western and eastern regions, especially in Nangarhar, bordering the highly volatile Khyber-Pakhtunkhwa area in Pakistan, and said it has ‚the potential to be a major poppy cultivating province.‘

The report studied the first phase of the assessment for December and January.

‚Villages with a low level of security and which had not received agricultural assistance in the previous year were significantly more likely to grow poppy in 2011 than villages with good security and those which had received assistance,‘ the report said.

Earlier this month, the UN drug agency had said that rising opium prices could drive up Afghanistan’s production area in 2011 for the first time in four years.

The price went up by 164 per cent in 2010. The total harvest was nearly halved due to bad weather conditions and a plant disease.

Afghanistan is the world’s biggest opium-producing country with a global share of 77 per cent. At least 1.7 million farmers are directly engaged in the cultivation of poppy farms, according to the UN.

For the Taliban insurgents, poppy production is one of the main sources of income which funds their insurgency.

Opium cultivation in Afghanistan to decline despite high prices – UN

Poppy field in Afghanistan 

31 January 2011 – Poppy cultivation in Afghanistan is expected to decline slightly this year despite the current high prices of opium, the United Nations Office on Drugs and Crime (UNODC) said today, basing the information on a qualitative assessment of farmers’ intentions in the Asian country.“The findings of the Opium Winter Rapid Assessment Survey in the southern region are encouraging,” said Yury Fedotov, the Executive Director of UNODC.

“A combination of factors seemed to have contributed to this development – dry weather, efforts directed against poppy cultivation and towards increasing government control, as well as licit alternatives to poppy,” he added.

Planted poppy seeds start to germinate in winter in the main opium producing provinces in the southern, western and eastern areas of Afghanistan, while sowing takes place later in the north, according to UNODC.

The expected decline in opium cultivation, as well as prolonged drought in the south may lead to another year of reduced opium production, the agency said. An outbreak of opium blight last year cut production by half and caused prices to soar.

The survey once again highlighted the direct correlation between insecurity, lack of agricultural aid and opium cultivation, UNODC noted. Villages considered insecure and lacking agricultural assistance are more likely to grow poppy this year than those with better security and assistance.

An estimated 90 per cent of insecure villages are involved in opium cultivation, while those targeted by anti-poppy awareness campaigns are significantly less likely to grow poppy, the agency reported.

Los Angeles – Subkutane Implantate könnten die Compliance der Opiatabhängigen bei der Buprenorphin-Substitution verbessern und einen Schwarzmarkt verhindern. Eine Phase-III-Studie im US-amerikanischen Ärzteblatt JAMA 2010; 304: 1576-1583) attestiert dem Präparat eines US-Herstellers jetzt eine passable Wirksamkeit.

In der Substitutionstherapie von Heroinabhängigen ist Buprenorphin eine attraktive Alternative zu Methadon. Denn der partielle Opiat-Agonist ist weniger anfällig gegenüber Überdosierungen und auch außerhalb der großen Substitutionszentren verfügbar. In vielen Ländern ist die sublinguale Buprenorphin-Substitution deshalb sehr beliebt.

Es lässt sich allerdings kaum verhindern, dass das starke Opiat auf den Schwarzmarkt gelangt – selbst wenn es in vielen Ländern mit dem Antagonisten Naloxon versetzt ist. Bei einer unzuverlässigen Einnahme kommt es außerdem schnell zu Entzugssymptomen und die Rückfallquote der Patienten ist deshalb hoch.

Beide Probleme könnten durch subkutane Implantate gelöst werden, die den Wirkstoff über mehrere Monate kontrolliert freisetzen. Das Präparat eines US-Herstellers wurde jetzt an 18 Behandlungszentren des Landes in einer Phase-III-Studie untersucht.

108 Patienten – zu zwei Drittel Heroin-, zu einem Drittel Medikamentenabhängige – wurden jeweils vier 26 mm lange und 2,5 mm dicke Implantate in 2 bis 3 mm Tiefe ins Unterhautfettgewebe am Arm eingebracht.

Wenn notwendig konnten die Probanden ein fünftes Implantat erhalten. Nach 6 Monaten wurden alle Implantate entfernt, was einen kleinen chirurgischen Eingriff erfordert, der eine kurze Narbe hinterlässt. In einer Vergleichsgruppe von 55 Patienten wurden Implantate mit Placebo implantiert, was ethisch gerechtfertigt war, weil die Patienten in beiden Gruppen bei Bedarf zusätzlich Sublingualtabletten mit Buprenorphin erhalten konnten.

Wie Walter Ling von der Universität Los Angeles und Mitarbeiter berichten, erhöhten die Buprenorphin-Implantate den Anteil der negativen Urinkontrollen – als Hinweis auf einen fortgesetzten Drogenkonsum – von durchschnittlich 28,3 auf 40,4 Prozent.

Auch in den sekundären Endpunkten wurde eine Wirksamkeit nachgewiesen: Insgesamt 65,7 gegenüber 30,9 Prozent nahmen bis zum Schluss an der Studie teil. Auch die Häufigkeit von Entzugssymptomen wurde ebenfalls signifikant gesenkt.

Im Buprenorphin-Arm gab es keine Therapieversager: Alle kamen mit vier oder fünf Implantaten aus. Im Placebo-Arm wurden 30,9 Prozent der Patienten als Therapieversager eingestuft, weil sie häufiger als dreimal in der Woche Sublingualtabletten nachfragten.

Die Implantate lösten nur geringe Lokalreaktionen aus, wobei es zwischen Buprenorphin und Placebo keine Unterschiede gab. Der Hersteller führt derzeit eine zweite Phase-3-Studie durch und will sich nach deren Abschluss um eine Zulassung in den USA und in Europa bemühen. © rme/aerzteblatt.de

ScienceDaily (Feb. 1, 2011) — Opiate abuse is a chronic disorder and maintaining abstinence represents a major challenge for addicts.

Individuals recovering from opiate dependence have long reported that while the acute withdrawal symptoms from opiates may pass relatively quickly, they do not feel quite right for several weeks or even months thereafter. Called the „protracted abstinence syndrome,“ this cluster of vague depressive-like symptoms can include reduced concentration, low energy level, poor sleep quality, and anhedonia.

New data in animals, reported in Biological Psychiatry, now implicates the serotonin system in this phenomenon.

French researchers found that mice with chronic morphine exposure showed decreasing physical dependence during a period of abstinence, with no physical withdrawal symptoms after 4 weeks. In contrast, low sociability and despair behavior clearly developed after 4 weeks of abstinence.

Remarkably, treatment during the abstinence period with the antidepressant fluoxetine prevented the development of both social aversion and despair behavior.

This is important because fluoxetine targets the serotonin system, which is known to influence mood.

Senior author Dr. Brigitte Kieffer explained that this study „establishes a direct link between morphine abstinence and depressive-like symptoms, and strongly suggests a causal effect of serotonin dysfunction in depressive features associated with abstinence.“

„The greatest risk associated with protracted abstinence is relapse to drug use,“ comments Dr. John Krystal, Editor of Biological Psychiatry. „This study provides new insights into a process that may contribute to relapse.“

These findings should foster novel research along serotonergic pathways in drug abuse. It is hoped that these findings can lead to real-world clinic use, since serotonergic medication is already broadly available.

 

source; http://www.sciencedaily.com/releases/2011/02/110201083930.htm

Abstract: Self-injurious behavior (SIB) is a primary reason that individuals with
neurodevelopmental disabilities (NDD) are either retained in restrictive environments or
are administered psychotropic medication. There are no known causes and no universally
accepted treatments for this complex behavior among individuals with NDD. There is
developing evidence, however, that individuals exhibiting SIB have a disturbance of the
opiate-mediated pain and pleasure system. One hypothesis is that SIB reflects insensitivity
to pain and general sensory depression (hypoalgesia), perhaps related to chronic elevation
of endogenous opiates. For instance, many self-injurious individuals do not exhibit the
usual signs of pain after their “injurious” behavior. Moreover, for some individuals the
addictive properties of elevated endogenous opiates (euphoria) may be responsible for
maintaining their SIB. In this perspective, SIB may be viewed as an addiction because it
supplies the „fix“ for tolerant, down-regulated opiate receptors. Reports that levels of
endogenous opiates at rest and after SIB episodes predict positive responses to opiate
blockers (e.g., naltrexone) provide further support for opiate-mediated SIB and form the
basis for a rational treatment strategy. Although the long term effects of opiate blockers on
SIB are unknown, reduction in SIB following acute treatment provides support that a specific
biological system may be dysregulated in a subgroup of patients. It is concluded that
naltrexone produces a clinically significant reduction in the serious and life-threatening
behavior of self injury for individuals who have not been responsive to any other type of
treatment. Several suggestions and cautions are provided for regimens of naltrexone
treatment of SIB.

1. Introduction
Despite considerable research effort, self-injurious behavior (SIB) continues to be a primary reason,
together with aggression toward others, that individuals are either retained in institutional (restrictive)
environments or are administered psychotropic medication. Today, SIB remains unmanageable,
expensive ($150,000–$500,000/year/patient in institutional settings, with national costs well over
$3,000,000,000 [1]), and is often life threatening. It is surprisingly prevalent, occurring in ~30% of
individuals with developmental neurological complications, including those with autistic disorders [2,3].
Twenty-five experts invited by the National Institute of Child Health and Human Development
(NICHD) to discuss the relations among the genetic, neurobiological, and behavioral causes and
treatments for SIB reached two general conclusions. Intentional acts of harm to self, evident in many
species, (a) have no known cause and (b) no agreed upon treatment [4]. The apparent absence of
visible progress in understanding or treating SIB is not because of a lack of interest or effort. Studies of
self-injury have increased exponentially over the past 30 years, rising from just 60 published studies
between 1980 and 1984 to over 1,700 studies reported between 2005 and 2010 (Figure 1).
Figure 1. Number of studies of self-injurious behavior (SIB) conducted in 5-year intervals
from 1980 to the present.
One major obstacle in understanding the mechanisms of SIB and developing coherent treatment
plans is the absence of distinctive behavioral phenotypes. Despite the consensus that SIB has variable
expression with no known cause, the group of NICHD experts agreed that SIB could be defined,
perhaps with greater precision than most complex human behaviors. SIB is a directly observable

behavior that can be reliably counted. The NICHD group argued that data collection and analysis had
advanced so that complex patterns of SIB should replace or supplement measures of rate and
frequency [5,6]. Two distinct patterns of SIB were proposed as possible guides. One pattern consists of
bouts that are most likely maintained by environmental contingencies. The second pattern involves
protracted periods of SIB that are most likely under the primary influence of biological factors. The
vast majority of existing studies, however, have reported frequencies or rates of occurrence of SIB
often linked to a single environmental manipulation. It is a significant advantage that many forms of
SIB can be counted and time-stamped enabling contemporary studies to use sequential and time series
procedures to define their structure and their relations with other behaviors and the environment. We
subjected extensive and lengthy observations of maladaptive behavior in its natural environmental
context to time series analysis and discovered unique temporal and sequential patterns of these severe
maladaptive behaviors [2,3,7-10].
Specifically, we found for a large majority of the individuals studied, SIB was predicted only by its
own recent history. In our cohort of severely self-injurious patients, SIB was expressed consistently in
successive occurrences revealing a unique pattern of sequential dependence compatible with a
“contagious” distribution. Application of time-series methods of analysis that controlled for chance
pairings of events indicated that the contagious patterns of SIB were independent from frequency and
rate of occurrence. That is, the temporally dependent patterns we observed were not a function of high
rates of occurrence. Moreover, and surprisingly, SIB was not associated consistently with other
behaviors or with the several staff activities or environmental conditions recorded in these studies.
Thus, in a significant majority of these individuals, SIB episodes were self-perpetuating and not related
to antecedent or subsequent environmental circumstances, events, or other recorded behaviors.
This novel and surprising finding was consistent with conclusions of the NICHD group that some
expressions of SIB may have an underlying biological basis because a solely self-perpetuating
behavior is most parsimoniously explained by internal (i.e., biological) motives [2,11-13]. The vast
majority of individuals in our cohort exhibited the most primitive level of internally regulated behavioral
patterns despite years of behavioral interventions and treatment with various medications [8,9].
Anecdotal and clinical observations of these individuals also strongly suggested a biological basis for
their behavior and specifically involvement of the pain and pleasure systems. Typically, SIB is
repetitious consisting of hourly, daily, weekly, monthly, or even yearly cycles [14]. Some individuals
who repeatedly injure themselves appear immune to the normal experience of pain [12]. They abuse
and injure their bodies, hitting or biting themselves, hurling themselves to the ground, and banging
their head against solid objects resulting in broken bones, disfigurement, blindness, and even loss of
life [2,15,16]. They often work to overcome interventions designed to decrease self-injury in a manner
that is consistent with seeking positive reward. For instance, protective devices (such as helmets) may
result in individuals exerting greater effort and exhibiting greater rates of behavior to hit and harm
themselves [17].
Because many medications that treat pain or induce pleasure are addicting, it is interesting that SIB,
in addition to the obvious involvement of pain systems, shares features of addiction such as
compulsive and ritualistic (or stereotypic) patterns that either comprise or surround the self-injuring
acts. One biological system that has been implicated in SIB and the modulation of pain and pleasure is
Pharmaceuticals 2011, 4
369
the hypothalamic-pituitary-adrenal (HPA) stress axis and specifically the proopiomelanocortin (POMC)
molecule [3,18,19].

2. The Biological Stress System Pain, Pleasure, and SIB
Thompson and Caruso [6] recognized that some forms of SIB were “neurochemically driven and
independent of environmental events.” Early studies either of basal or of resting levels of a variety of
peptides, proteins, transmitters, and amines in plasma or cerebrospinal fluid from patients exhibiting
SIB, however, generated inconclusive results. This was not surprising because there was little
consistency among studies regarding the rigor of diagnosis, the molecule measured, the tissue assayed,
or the conditions assessed [20-26].

2.1. Pain and the Endogenous Opioid System
Although it is not a universal observation, most self-injurious individuals do not exhibit the usual
signs of pain after their “injurious” behavior. Despite inflicting serious physical damage to their bodies,
many of these individuals do not grimace, cry, or show other symptoms that they are experiencing pain.
It has been suggested that this absence of response to self-inflicted injury reflects insensitivity to pain
and general sensory depression induced either by elevated endogenous opiates or by supersensitive
opiate receptors [11,27-29]. This possibility is supported by classical findings that opiate receptor
blockers (a) reverse congenital insensitivity to pain [30]; (b) normalize hypothalamic-peptide
dysfunction coexisting with elevated pain threshold [31]; and (c) increase brain responses to sensory
information [32]. These observations are consistent with a venerable animal literature proving that
opiate blockers lower pain threshold [33]. In summary, these findings support an analgesia (or pain)
hypothesis that implies that self-injurious individuals do not feel pain because of chronically elevated
endogenous opiates and/or opiate receptor downregulation.
2.2. Pleasure (Addiction) and the Endogenous Opioid System
It also is possible that the addictive properties of elevated endogenous opiates are responsible for
maintaining SIB. If it is presumed SIB does result in pain and that the experience of pain results in the
release of opiates, then it can be argued that individuals commit self-inflicted harm to receive the
euphoric (pleasurable) effects of increased circulating opiates. From this perspective, SIB is an
“addiction” to the endogenous opiate system because its consequences supply a “fix.” It has been
known for over 25 years that endogenous opiates have addictive properties as indicated by the
development of tolerance [34], physical dependence [35], and euphoric-like effects [36] after repeated
administration. The repetitive, often compulsive, and ritualistic patterns of SIB (i.e., injury to one area
of head or body, stereotyped patterns of behavior, and catastrophic responses if the environment is
slightly changed) are similar to rituals and compulsive patterns often associated with addictive
behaviors. The addiction hypothesis maintains that individuals with SIB may endure the pain to enjoy
the pleasure it produces as well as to avoid a withdrawal effect. The addiction hypothesis predicts that
SIB may be reinforced both positively and negatively because it gains the individual access to the
narcotic effect of endorphins while simultaneously allowing the individual to escape the unpleasant
sensory consequences commonly associated with the absence of opiates following chronic and
sustained access.
2.3. Stress and the Endogenous Opioid System
The endogenous opioid system is tightly coupled with the general stress response. Evidence from
several laboratories indicates that functioning and processing of a stress-related molecule (POMC) in
the HPA axis may be perturbed among subgroups of individuals exhibiting SIB [15,19,21,37-43]. In
humans, most POMC is produced in the pars distalis of the anterior pituitary but also by hypothalamic
neurons and neurons in the amygdala and pituitary stalk. POMC is a well-characterized 31-K dalton,
bioinactive protein-like molecule that is post-translationally converted by enzymes (e.g., PC1 and PC2)
into biologically active fragments, including B-endorphin (BE) and adrenocorticotropic hormone (ACTH)
[15,44-48]. Normally, BE is coreleased from the anterior pituitary with ACTH in response to a variety of
stressors. However, elevated BE but not ACTH is associated with SIB either at rest or after an episode of
SIB [3,12,18]. This suggests that one consequence of SIB is the disregulation of the arousal system. The
validity of these hypotheses is not known but they have encouraged treat-ments, including opiate
receptor blockers, designed to regulate the opiate/stress system as means to control SIB.
3. Efficacy of Opiate Blockers in the Treatment of SIB

3.1. Acute Effects of Naltrexone
In a review of pre-1991 studies [49], six of eight published studies reported that injectable naloxone
significantly reduced SIB. In these eight studies, naloxone was tested in a total of ten individuals with
SIB. A decrease in SIB was reported for seven individuals. In that same review, 12 published studies
of naltrexone (Naltrexone) in MR/DD individuals were summarized. Most of the studies either were
case studies or were studies with very small samples. At that time, 45 MR/DD individuals (at least 28
with SIB) had been treated with naltrexone and 38 individuals had positive responses of various
degrees including a reduction in SIB in 24 of the 28 patients. A separate review of 13 studies
(including several in the Sandman review [49]) concluded that about one-third of the patients tested
with Naltrexone had a decrease in their SIB [50]. Several studies in this later review included juvenile
patients under the age of 8 years [51] and patients with primary behavioral problems related to
aggression and agitation [52]. Aggression toward others and agitation are not equivalent to SIB on any
obvious dimension except, perhaps, exertion, and the fact that opiate blockers were ineffective in the
control of these behaviors adds inferential support to the argument that the opioid system is uniquely
implicated in SIB and not in other maladaptive behaviors. The effects of opiate blockers in children
who self-injure may be similar to the effects observed in adults but there are too few reports to make
that conclusion.
More recently, a thorough review of the scientific literature employing stringent and appropriate
criteria for inclusion concluded that the effects of opiate blockers on SIB could be evaluated in a total
of 86 patients [53]. Eighty percent of the subjects were reported to improve relative to baseline
(i.e., SIB reduced) during naltrexone administration. Of the subjects who improved, 47% exhibited a
reduction in SIB by 50% or greater. In studies reporting dose levels in milligrams, males were more likely than females to respond. No significant relations were found between treatment outcomes and
autism status or form of self-injury.
Two relatively large, placebo-controlled studies [16,54] included in this review of naltrexone came to
very similar conclusions. In a double-blind, placebo-controlled, dose-finding study, Sandman et al. [54]
reported that 18 of 21 individuals exhibiting SIB responded favorably to at least one dose (range of
0.5–2.0 mg/kg) of naltrexone (time-sampled video records provided direct observations of the subjects).
Acute treatment (1 week at each of three doses) with naltrexone reduced the frequency of SIB without
major side-effects. Activity, stereotypy, involuntary movement, and neurological status were not
influenced by naltrexone. There were two central findings. First, the highest dose (2 mg/kg) was the most
effective, confirming earlier results in this population [55,56]. Seven of the eight patients responding best
at the highest dose, also responded favorably to the 1 mg/kg dose. Six of these eight patients also
responded at the 0.5 mg/kg dose. Eleven subjects responded positively to both the 1 and 2 mg/kg doses.
Second, subjects with the most frequent SIB were the most positive responders to higher doses of
naltrexone, consistent with earlier reports [55,56]. A small minority of subjects responded most
favorably to lower doses. These results confirmed that at least 50% of the individuals with SIB
responded favorably to treatment with opiate blockers.
Another double-blind, placebo-controlled, fixed-dose study of eight, severe to profoundly retarded
adults included in the review [16], reported that treatment with naltrexone reduced head hitting, head
banging, and self-biting. The eight individuals evaluated displayed 18 forms of SIB. Improvement was
observed in 77% of the head hitting and head banging episodes and 100% of the self-biting forms.
Episodes of high frequency SIB also were more sensitive to treatment with naltrexone. The 100-mg
(high) dose was more effective than the 50-mg (low) dose in reducing SIB. For several individuals,
some forms of SIB decreased after naltrexone (e.g., head hitting and self-biting) but other forms
(e.g., throat poking) did not change. Four of the subjects in this trial received concomitant treatment
with clonidine (alpha-2-adrenergic agonist) but no effects on SIB or interactions with naltrexone were
observed. These findings compliment previous studies and caution that although naltrexone is effective
in reducing SIB, not all forms of self-inflicted harm may be controlled by blocking the opioid system.
These two relatively large studies of acute treatment with naltrexone came to very similar
conclusions. Opiate blockers appear to be an effective treatment for a significant number of individuals
exhibiting SIB. Administration of naltrexone reduces high frequency SIB and some, but not all, selfdestructive
behavior. Both studies acknowledged that not all individuals expressing SIB were positive
responders and that a small minority may increase SIB (see also Barrett [57]).
In the single study that has evaluated the effects of naltrexone using time-series analysis,
Symons et al. [58] made very interesting observations. First, they reported that three of the four patients
evaluated had at least a 33% reduction in their SIB. (The fourth patient had a 17% reduction in SIB.)
Second, and most interesting, they discovered that in addition to the improvement with naltrexone,
there was an alteration in the sequential dependencies between staff behavior and the manifestation of
SIB. During treatment with naltrexone, there was a significant increase in the probability that staff
would “prompt” individuals proximal in time and sequence to an SIB event for three of the four
patients, and a significant decrease in the fourth. One possible conclusion from these findings is that
naltrexone exerts its effects on SIB, in part by the opioid-mediated reinforcing influences of social
interactions. Alternatively, Symons et al. [58] suggest that SIB may be “multiply determined such that
Pharmaceuticals 2011, 4
372
naltrexone may diminish opiate-mediated SIB leaving socially mediated SIB unchanged.” The overall
clinical implication is that many cases of SIB may be subserved by both opiate- and socially mediated
processes and that effective treatment for such cases would require a combination of naltrexone with
behavioral intervention strategies.

3.2. Long-Term Effects of Naltrexone Treatments
The long-term effects and consequences of continued treatment with naltrexone is not completely
known because most studies reporting treatment of individuals with SIB have been short-term
demonstrations or acute trials. Most published long-term studies have been either case studies or openlabel
designs and they have generated mixed results. Two types of studies comprise the long-term
evaluations of naltrexone, either prolonged treatment with naltrexone or extended observations
following brief periods of treatment. With these procedures, investigators have reported that about six
of eight patients examined in several studies exhibited long-term benefits in varying degrees from
treatment with naltrexone [57-59]. In the first report, a total of 24 days of naltrexone treatment resulted
in elimination of SIB in a 12-year-old girl that persisted for at least 22 months [57]. A similar finding
was reported after 1 year of continuous treatment with naltrexone in a 28-year-old woman with severe
SIB. Not only did treatment eliminate SIB but also the near-zero rate persisted through placebo and nodrug
phases of the study [59]. In their retrospective study of 56 patients, Casner et al. [60] discovered
that 57% of their patients treated with naltrexone between 3 and 878 months were considered to be
positive responders and 25% of these met objective criteria as responders.
We [61] examined the long-term (12 month) effects following acute treatment with naltrexone and
then we assessed the effects of subsequent long-term treatment with naltrexone. To accomplish this,
we enrolled 15 subjects in a double-blind, placebo-controlled acute dose-finding study. Each acute
dose was evaluated for a 1-week period with placebo weeks interspersed. Subjects were followed for a
12-month period and then they were enrolled in a multiple baseline design with a single most effective
dose (determined in the acute phase) administered to each subject for 2-, 3-month periods over an 18-
month interval with placebo periods appropriately separating the treatment phases. Again, timesampled
video records were scored using a computer-assisted program [62].

The primary finding from our study was that a subgroup of patients exhibited persisting effects
(decreased SIB) in the 12 months after acute treatment with naltrexone. Seven patients exhibited
decreased SIB over the 12-month period and five of these had a 75% reduction in SIB compared to the
placebo control period. These five patients, each with at least a 75% reduction in SIB, increased their
SIB when administered naltrexone in the long-term treatment protocol. The largest decrease in SIB was
observed in patients who had a brief exposure to naltrexone, were given a 12-month hiatus during which
they showed an increase in SIB, and then were readministered naltrexone several times in the 18-month
double-blind, placebo-controlled study.

4. Endogenous Opioid Levels Predict Response to Opiate Blockers
In our initial study to examine the relation between circulating endogenous opioids and response to
naltrexone, we collected blood samples from ten patients within 2–5 min of a self-injuring act and
during a control period [18]. At least 1 month later patients were administered three different doses of naltrexone in a double-blind, placebo-controlled crossover study over a 10-week period. All patients
were videotaped during the study and behavior was coded with a computer-assisted program. Patients
with the highest change in plasma levels of BE after SIB had the most and statistically significant
positive response to naltrexone. These results were consistent with several other reports. First,
Ernst et al. [21] reported that baseline levels of BE were positively related to changes in behavior
(clinical global impressions, CGI) after treatment with naltrexone in five young autistic children.
Second, Bouvard et al. [38] found that C-terminal BE decreased after naltrexone only in good
responders. Third, Scifo et al. [63] found that increases in SIB and response to naltrexone in some
patients, were related to high levels of endogenous opiates (i.e., good responses to naltrexone were
observed in patients with high levels of BE). Fourth, Cazzullo et al. [64] reported that patients
responding with decreased BE levels after treatment with naltrexone had better and more pervasive
behavioral improvement than patients who did not have physiological changes after naltrexone.
In a follow-up study of nine additional patients (total of nineteen), we [3] found that plasma BE was
uncoupled from the usually coreleased ACTH [65-71] after an episode of SIB. This unusual pattern was
not a function of time of day that blood was sampled, and it confirmed our earlier observations [7,18]
and provided additional support for this specific biological marker among a diverse group of subjects
who share a behavioral aberration. In addition, stronger support was generated for the effectiveness of
naltrexone in reducing SIB.
Positive responses to low doses of naltrexone were observed in subjects who did not exhibit
increased BE after SIB. That is, low doses of naltrexone were effective in reducing SIB only in
subjects either who did not exhibit a surge in BE after SIB or whose baseline level exceeded the level
after SIB. The relation between BE and response to the lowest dose of naltrexone was consistent with
our earlier results, and statistically significant with the addition of nine subjects. Previously we [3] suggested
that SIB had functional significance because it increased endogenous opiates and thereby
delivered positive consequences (i.e., pleasure/euphoria/pain modulation). We argued that the highest
dose of naltrexone most effectively blocked this mechanism in subjects with the highest levels of BE
after SIB. The results from the follow-up study suggested an alternative possibility related to baseline
levels of, or baseline relations between, POMC peptides. Because the lowest dose of naltrexone was
most effective in subjects with the highest (morning) baseline (relative to post-SIB) levels, we
speculated that the association between baseline ACTH and BE could influence the response to
naltrexone (based on evidence that supported reciprocal functions of BE and ACTH [72]]. If our
speculations were accurate, subjects with the greatest difference between morning BE and ACTH
levels would be the most responsive to low doses of naltrexone because there would be less attenuation
of the opioid influence. The test of this possibility confirmed our speculations because we found that
subjects with high levels of morning (chronic) BE and low levels of ACTH were associated with positive
responses to the low dose of naltrexone. This possibility may be compatible with findings that chronic
exposure to opioids resulted in supersensitivity to the effects of low doses of opiate antagonists [73,74].
These findings have since been extended using a fundamentally different method for quantifying
changes in the temporal patterning of SIB following treatment with naltrexone. The THEME method
developed by Magnusson [75,76] has been used to detect highly significant, nonrandom, hierarchical
patterns in the temporal organization of SIB with respect to other observed behaviors. Kemp et al. [10]
reported that these temporal patterns (“T-patterns”) of SIB were significantly correlated with basal
Pharmaceuticals 2011, 4
374
levels of BE. In the subgroup of subjects receiving naltrexone (discussed above), the percent change in
these T-patterns of SIB (between weeks the subjects were receiving placebo and weeks they were
receiving naltrexone) was found to be significantly correlated with post-SIB (i.e., samples were
collected immediately after SIB) levels of the N-terminal fragment of beta-endorphin (βEN). No such
correlations were found for changes from placebo on any “control” T-patterns (those containing noninjurious,
stereotyped behaviors or staff interactions) nor for any samples collected during other
periods. These results are shown in Table 1.
Table 1. Pearson’s r coefficients (significance) between levels of beta-endorphin (Nterminal)
collected in either the AM, PM, or following SIB, no SIB, or physical exercise
(PE) and the change in the percentages of T-patterns (by behavior type) for weeks treated
with placebo and naltrexone.
We have made similar observations in our long-term studies of naltrexone and SIB [19]. POMC
fragments were measured in twelve self-injurious patients before and after long-term (3-month)
treatment with naltrexone. POMC fragments were sampled from blood collected at the end of the
baseline and placebo-controlled treatment phases of the study. Two patterns emerged. One group
(responders) displayed persisting improvement in SIB and lower relative levels of BE after initial
exposure to naltrexone. Chronic administration of naltrexone to this group was associated with
increased SIB and elevated relative levels of BE. Return to placebo improved their behavior (reduced
SIB) and their levels of BE returned to basal levels. The second group (nonresponders) was
characterized by absence of persisting improvement after acute treatment with naltrexone and by
elevated basal BE levels. Chronic treatment with naltrexone improved their behavior but did not alter
their BE levels. Long-term positive responders to acute doses of naltrexone were associated with less
disregulation of ACTH and BE.

5. Conclusions
When it was established that the body had its own opiate system [77], the endogenous opiates
became prime suspects responsible for maintaining SIB. Perhaps individuals who self-injure have
elevated thresholds for pain or derive pleasure from painful stimulation. Exposure to, or levels of,
endogenous opiates could explain these possibilities. Reduction in SIB following treatment with opiate
blockers would provide evidence for the opiate hypothesis of self-injury. Results from studies to test
these possibilities, however, are complex. The complexity is related primarily to the fact that patients
exhibiting SIB and evaluated after treatment comprise a mixture of etiologies, pathologies, and
motivations. Despite the tremendous amount of error introduced with a heterogeneous population,
there is substantial evidence that opiate blockers are efficacious in reducing SIB.
Beta-Endorphin (N-terminal) Levels
Change in T-Pattern % by Type: AM PM Post-SIB No-SIB Post-PE
SIB 0.37 (0.47) 0.25 (0.64) 0.82 (0.04) −0.45 (0.44) 0.66 (0.22)
Stereotypy −0.76 (0.07) −0.26 (0.96) 0.52 (0.29) −0.29 (0.64) −0.10 (0.87)
Staff Interactions 0.42 (0.41) 0.54 (0.27) 0.35 (0.49) −0.63 (0.25) 0.26 (0.68)
The observations that opiate blockers reduce SIB are important for at least two reasons. First,
naltrexone produces a clinically significant reduction in a serious and life-threatening behavior for
some individuals typically who have not been responsive to any other type of treatment. We have
observed startling improvements in individuals who have failed all rational treatments. Some adults in
our studies have had protective headgear discontinued for the first time since early childhood. Others
have developed adaptive skills and have acquired the ability (or the privilege) to leave institutions for
the first time in their lives after treatment with naltrexone. Second, the results with naltrexone are
important because they suggest that a specific biological system may be disregulated in a subgroup of
patients. Because the opiate blockers have few effects in the absence of opiates [78], effective
treatment with these drugs must engage the endogenous opioid system. Reports that resting levels of
endogenous opiates or levels of endorphin after an SIB episode predict positive responses to opiate
blockers provide support for this assumption and the foundation for rational treatment strategies based
on biological criteria.
From the current review we can draw several conclusions. There is consensus in the literature that
doses between 1.0 and 2.0 mg/kg or a fixed dose of 100 mg are the most effective for reducing
SIB [16,53,54]. At these doses, at least half of the chronically self-injuring patients exhibit at least a
25% reduction in their behavior. It is important to acknowledge that the studies that have reported
reductions of 25% or greater, typically conducted direct observations of the patients and did not rely on
global clinical ratings. As reviewed by Symons et al. [53], male patients respond more favorably to
naltrexone treatment than do female patients. There is consensus that naltrexone is a safe drug without
major or contraindicating side effects. Most individuals entered into naltrexone trials exhibited the
most severe SIB for which all other forms of treatment had been ineffective. Often their behavior
presented life-threatening consequences and always their SIB prevented them from enjoying a less
restrictive environment. Against this background, the possible benefits of reduced SIB by treatment
with naltrexone exceed the risk of side-effects. We are aware of clinical decisions to treat SIB with
naltrexone even when patients presented with risk factors such as chronic hepatitis [79]. To our
knowledge, there have not been serious side effects solely due to administration of naltrexone among
MR/NDD patients. There is consensus among the studies that naltrexone is an effective treatment
because the endogenous opioid system is engaged by SIB [3,16,18,19,57]. SIB has characteristics that
resemble addictive behavior (compulsive, ritualistic, destructive) and altered pain threshold. Both of
these characteristics implicate the opioid system and support the logic of opiate blockers as reasonable
treatments. There is consensus that long-term treatment of SIB with naltrexone apparently is not
harmful and may be effective. There is consensus that generally, treatment with naltrexone appears to
be effective in about half of the adult patients examined. Following effective acute treatment with
naltrexone some patients have shown a rebound to pre-treatment levels [61]. There is consensus that
naltrexone should be avoided during periods when patients are known to be in pain requiring narcotic
analgesics, such as surgeries or with bone fractures. Alternately, nonnarcotic analgesics should be
administered to patients receiving naltrexone [80]. Finally, it should be noted that there are reports of
paradoxical increases of SIB following treatment with naltrexone [81]. In our own research [61], we
have observed increased rates of SIB in individuals who showed sustained improvements throughout a
12-month hiatus following a brief period of acute treatment with naltrexone, and then were given longterm
treatment (3 month) with naltrexone.

Acknowledgements
This research was supported by award HD-48947 from the National Institute of Child Health and
Human Development. The assistance of Mohammed Lenjavi and Paul Touchette is gratefully
acknowledged.

 

Source with References;http://www.mdpi.com/1424-8247/4/2/366/pdf

Die ehemaligen Staatsoberhäupter von Brasilien, der Schweiz, Mexiko und Kolumbien trafen sich in Genf, um den in Repression erstarrten Drogenkrieg durch den auf soziale und medizinische Aspekte konzentrierten Kampf gegen Rauschgift zu ersetzen.

 

Dieses international als neu erachtete Modell basiert auf bereits gemachten Erfahrungen in der Schweiz. Das Resultat des repressiven Ansatzes hingegen, seit 1971 von US-Präsident Nixon eingeführt, ist bekannt: Der Drogenkrieg kostet Riesensummen, hat bisher aber wenig brauchbare Resultate erbracht. Ja, oft wird die Situation durch die Repression noch verschlimmert.

Dennoch hat sich an diesem Ansatz bisher wenig verändert, höchstens werden die Vergehen je nach Land mehr oder weniger streng geahndet.

In Genf trafen sich aus diesem Grund die ehemaligen Präsidenten Fernando Henrique Cardoso (Brasilien), Cesar Gaviria (Kolumbien), Ernesto Zedillo (Mexiko) und Ruth Dreifuss (Schweiz). Sie rufen zu einem Strategiewechsel auf, denn inzwischen sind ganze Länder von den Drogenbaronen destabilisiert.

Zum Beispiel in Mexiko, wo allein 2010 der Krieg zwischen Armee und Polizei gegen die Drogenkartelle mehr als 15’000 Tote kostete.

 

Reiner Verbots-Ansatz

„Die lateinamerikanischen Länder sind erschöpft von diesem Konflikt und vom Ansatz des Prohibitionismus, den die USA weiterhin aufrecht erhalten“, sagt Gaviria. Sich rein auf Verbote abzustützen, sei eine kontraproduktive Politik, die aber auch von den UNO-Organen und den bewaffneten Behörden der Suchtmittel-Konvention von 1961 praktiziert werde.

„Sie gehen immer noch von einer Welt ohne Drogen aus, während es doch noch nie derart viel Rauschgift auf der Welt gab wie jetzt“, so der ehemalige kolumbianische Präsident.

Um aus diesem Kreislauf herauszufinden, der nur dem organisierten Verbrechen Aufschub gibt, schlagen die Politiker in Genf zwar keine Legalisierung verbotener Drogen vor, sondern ein gleichgewichtigeres Vorgehen gegen Rauschgift, das nicht nur auf Repressionsansätzen basiert.

 

Entkriminalisierung statt Legalisierung

Laut Cardoso soll ein Rauschgiftsüchtiger in erster Linie als eine Person erachtet werden, die medizinische HIlfe braucht, und nicht als Krimineller. Die Repression soll sich auf die organisierte Kriminalität konzentrieren, statt sich in der Verfolgung der Süchtigen zu verzetteln.

„In den USA sitzen rund eine halbe Million Personen im Gefängnis, die wegen einem Rauschgiftdelikt verurteilt sind. Das entspricht der Gesamtheit aller in Europa in Gefängnissen Untergebrachten“, so der Brasilianer im weiteren. Dennoch sei in den USA der Widerstand gegen eine Änderung der Drogenpolitik am grössten.

An ihrem Treffen in Genf haben die Politiker begonnen, eine globale Kommission auf die Beine zu stellen (Global commission on drug policy), weil hier in Europa die Länder im Kampf gegen die Drogen weniger ideologisch vorgingen als die USA.

Doch auch hier entfalle ein Grossteil des drogenpolitischen Budgets auf Repression statt auf soziale (Wieder-)Eingliederung und gesundheitliche Aspekte der Süchtigen.

 

Bezug zur Drogenpolitik in der Schweiz

Die Schweizerische Drogenpolitik dient dabei als Referenzpunkt für die Kommission, die sich auch auf Erfahrungen in den Niederlanden oder Portugal abstützt.

Ruth Dreifuss, ehemalige Schweizer Bundespräsidentin und Gesundheitsministerin, erklärt, weshalb der Schweizer Ansatz die Lateinamerikaner interessiert: „Die Drogenpolitik in der Schweiz ist etappenmässig vorgegangen. Eine Art Evolution, basierend auf gemachten Erfahrungen. Zum Beispiel bei der ärztlichen Verschreibung von Heroin, wobei die Resultate wissenschaftlich untersucht wurden.“ Die Folgerungen daraus seien dann die Revision des Gesetzes eingeflossen. Das habe auch dazu geführt, dass die Bevölkerung die gesetzlichen Änderungen 2006 abgesegnet habe.

Dieser pragmatische Ansatz mit den vier Säulen Prävention, Therapie, Reduktion der Risiken beim Konsumieren und Repression weckt im Ausland umso mehr Interesse, als die Schweiz „für ihre solide konservative Einstellung“ bekannt sei, wie das ein Bericht der Open Society schreibt. Die Open Society ist eine Nichtregierungsorganisation, die vom Financier Georges Soros gegründet wurde und welche die diese Woche in Genf gegründete Kommission unterstützt.

 

Kampf gegen das Rauchen

Die neu gegründete, stark vernetzte Kommission möchte Vereinigungen unterstützen, die im Bereich der Drogen aktiv sind, und die Länder auffordern, breite Diskussionen über dieses noch als Tabu erachtete Thema zu entfachen. Auch will sie die Regierungen überzeugen, dass es nur mit Repression nicht mehr weitergehen kann.

Zu diesem Zweck will die Kommission die bestehenden wissenschaftlichen Erkenntnisse in die Öffentlichkeit bringen und neue Instrumente gegen Drogen vorschlagen, wie Prävention oder Risikoreduktion.

Sie möchte sich ausserdem von den Kampagnen inspirieren lassen, die gegen Tabak und das Rauchen geführt werden, und die erwiesenermassen den Zigarettenkonsum vermindern konnten. Um die Macht der Drogenkartelle zu mindern, muss die Zahl der Süchtigen verringert werden.

 

Länder des Südens sind überflutet

Der Ursprung dieser Kommission ist Südamerika, doch möchte sie ihre Repräsentativität verbreitern und Vertreter aus allen Weltregionen integrieren.

Für nächsten Juni ist eine Zusammenkunft in den USA geplant. Dabei soll ein Aktionsplan festgeschrieben werden, der die USA und die UNO dazu bewegen soll, ihre Rauschgiftpolitik radikal zu ändern.

Denn es zeichnet sich ab, dass in den westlichen Ländern der Drogenkonsum sich langsam zu stabilisieren beginnt, während der Verbrauch in vielen Ländern des Südens stark zunimmt.

 

Frédéric Burnand, swissinfo.ch
Genf
(Übertragung aus dem Französischen: Alexander Künzle)

(Reuters) – In her one-room flat, as a small shelf of porcelain cats looks on and the smell of mold hangs in the air, Zoya pulls down the left shoulder of her black blouse and readies herself for her next hit.

A friend and ex-addict uses a lighter to heat a dark, pebble-like lump of Afghan heroin in a tiny glass jar, mixes it with filtered water and injects it into Zoya’s shoulder. The 44-year-old widow is a wreck: HIV-positive, overweight and diabetic. After 12 years of dealing and drug abuse, the veins in her forearms and feet are covered in bloody scabs and abscesses, too weak and sore to take fresh injections.

Crimson-dyed hair frames her bloated face, which is made up to match a hot pink manicure. As the syrupy brown mixture enters her system, Zoya’s eyes glass over and she ponders her fate and that of her country.

„There are a lot of us. What do they (the government) want to do? Kill us?“ she says. „They want to gather us together and drown us? I worry for tomorrow’s generation.“

If Zoya is anything to go by, today’s Russians are hardly flourishing. Russia has one of the world’s biggest heroin problems, with up to three million addicts according to local non-governmental organizations. Twenty one percent of the 375 tons of heroin produced from Afghanistan’s opium fields now finds its way through central Asia into Russia, according the United Nations. (By contrast, China, with nine times more people, consumes just 13 percent.) The Russian government estimates its citizens bought $17 billion worth of street-traded heroin last year — about seven billion doses. The addiction kills at least 30,000 Russians a year, which is a third of the world’s total heroin-related deaths, adding to pressures on the country’s already shrinking population.

So grave is the problem that President Dmitry Medvedev last year branded heroin a threat to national security.

That’s one reason why last October, 21 years after the end of the decade-long Soviet war in Afghanistan, Russian troops joined forces with U.S. soldiers for a joint drug raid on four Afghan labs. The operation, which destroyed nearly a ton of heroin, was hailed a success and the Cold War foes said they would like to see more such operations in Afghanistan, which is responsible for 90 percent of the world’s heroin production.

At home, though, Russia has been far less active in tackling the problem. Critics go as far as to accuse Moscow of wilfully neglecting its citizens and thereby fuelling what the World Health Organization says is one of the fastest growing HIV/AIDS epidemics in the world.

Unlike most countries around the world, Russia refuses to finance harm reduction programs such as needle exchanges, or to legalize methadone. Over the past few months, Moscow has decided to discontinue the work of foreign donors and NGOs with heroin addicts. It even recently blamed foreign groups for worsening the country’s HIV epidemic.

Health experts and drug addicts alike point to official inaction as the real culprit. It’s as if Moscow has misinterpreted the old U.S. anti-drugs slogan „Just Say No“ and turned its back on the crisis. „My government does nothing for me. I am no longer a person in this society,“ says Zoya, who lives in Tver, a drab city of half a million just off the Moscow-St Petersburg highway, and whose husband, also an addict, died from AIDS several years ago.

Anya Sarang from the Andrey Rylkov Foundation for Health and Social Justice, a small UN-funded Russian organization set up in June 2009, says Russia is failing its people. „For the main groups prone to the disease — drug users, sex workers, migrants — there is absolutely nothing for them,“ says Sarang.

THE PROUD BEAR

Russian officials have a long history of denying crises. From the Soviet government’s refusal to help during the famine of the 1920s to its delay in responding to the 1986 Chernobyl nuclear accident, responses from the top have often mixed disregard and cover-up. During last August’s heat wave, as peat fires and acrid smoke killed hundreds, officials kept silent on the wider health effects of the smoke for weeks.

One of the reasons for the rush to denial lies in the national psyche. Russia is a deeply patriotic country, with a long history of strong governments far removed from the everyday concerns of ordinary citizens. After the humiliating collapse of the Soviet Union 20 years ago and the calamity and poverty that followed, the strongman rule of Vladimir Putin (former president and current Prime Minister) has allowed the Russian bear to flex its muscles on the international stage again.

But while Moscow crows about hosting such high-profile sporting events as the Winter Olympics and soccer World Cup, it ignores daily reality, says health worker Sarang. „Russia is trying to preserve a certain political image, showing that everything is fine,“ she says. „This has shown to be nothing more than a lie.“

Most Russians see the truth all around them. Zoya’s story is repeated so often across the country’s nine time zones that the reality is hard to ignore. Even the government estimates there are 1.8 million heroin users; activists and doctors put the number closer to 3 million, and in a study last June, the United Nations put it at 2.34 million or 1.64 percent of Russia’s population. That’s the world’s third highest heroin abuse rate in per capita terms after Afghanistan and Iran. In absolute numbers, the UN says, Russia is number one.

Heroin was virtually unheard-of during the Soviet era, but is now easy to buy in any city in the country. In Tver, a medium-sized city with relatively little industry and few job prospects for the young, the detritus of addiction — used syringes, needles — litters the streets. Deals are a regular sight on street corners.

Russia’s anti-drugs tsar, Viktor Ivanov, who heads the Federal Drug Control Service — a powerful government body given to U.S.-style rhetoric about the ‚War on Drugs‘– blames the country’s porous Central Asian borders for the heroin hunger.

„Unfortunately, in 1991 we suddenly found ourselves without borders,“ Ivanov told reporters in December, referring to the collapse of the Soviet Union.

Ex-Soviet Tajikistan, which borders Afghanistan and is one of the world’s poorest countries, has long been a haven for drug smuggling out of Afghanistan, where the Tajiks have ethnic ties. From there the heroin flows through Kyrgyzstan and Kazakhstan and into Russia.

INTERTWINED WITH AIDS

The drug problem has now become an AIDS problem. Officially, Russia has 520,000 registered HIV-positive people. The UN and local NGOs say there are probably closer to a million, maybe even more. HIV/AIDS has spread rapidly over the past decade, especially among drug users who regularly share dirty needles. The government estimates around a third of all drug users in Russia are HIV-positive; and international and Russian health experts worry the disease is beginning to spread to the general population through heterosexual sex.

The biggest problem, say health experts, is the government’s refusal to address Russia’s drug addiction. The lack of official intervention is remarkable. There are currently just 70 needle exchange and distribution programs in Russia, reaching a mere 7 percent of heroin addicts according to the London-based International Harm Reduction Association (IHRA). In terms of needle exchanges, „Russia is not even scratching the surface,“ says Rick Lines, executive director of the IHRA.

All the programs are run with foreign funding. Government support: nil. It’s not as if the government is powerless. In the one area of the HIV/AIDS epidemic where it is active — mother-to-child transmission — it has reduced transmission rates to almost zero.

HIGHWAY AIDS TEST

In the face of government inaction, grassroots groups have mushroomed across the country.

Outside Tver, Yuri Suring parks his beat-up black Toyota at a truck stop along the Moscow-Saint Petersburg highway every night. There, between 7 pm and 4 am, he surreptitiously doles out clean needles and condoms to prostitutes, many of whom work to support their drug addictions. „If I were not here, where would these girls go? Who would help them? No one,“ Surin says as a trio of prostitutes in knee-high boots and bomber jackets approaches the car.

Surin’s organization, We And AIDS, consists of himself, a second outreach worker and a driver. The supplies he hands out every night and the kits he uses to test women come, he says, from sympathetic doctors and western groups who want to help.

On a cold night in November, 20-year-old prostitute Olga slips into Surin’s car for an AIDS test. Surin rubs a two-inch indicator on her gums and inserts it into a small plastic tray while Olga nervously smokes a cigarette and shakes her black-bobbed head from side to side in anger at her fate, her gold leaf-shaped earrings swaying.

After studying the result — negative — the prostitute flings the indicator out of the car window and then hops across the gravel into a truck cabin where customers — two large middle-aged truckers — are waiting.

The Health Ministry says it spent 10 billion roubles ($320.5 million) on HIV/AIDS testing and treatment — mostly antiretroviral drugs — in 2010. But activists and health experts say this amount compares badly with other countries in the G20 and sufferers are routinely ignored.

In a 2010 report, the World Health Organization said just a fifth of Russians who needed AIDS drugs were receiving them. South Africa, which has the biggest HIV-positive population in the world — and whose government until recently was criticised as being in denial on AIDS — gives AIDS drugs at almost twice that rate.

„Appeals, trials and public action — nothing works,“ says Alexandra Volgina, head of The Candle Foundation for HIV-positive people, a non-governmental organisationorganization in Saint Petersburg.

When asked why so many sick Russians lack access to AIDS drugs, the health ministry’s spokesman responds: „The amount spent was deemed sufficient.“

POPULATION PROBLEMS

Russians usually blame alcohol for their health problems. Official data shows the average Russian drinks 18 liters (38 pints) of pure alcohol every year, compared with 14 liters in France and eight in the United States.

Official campaigns against drinking have been pursued sporadically since Tsarist times, usually with little success. In September last year Russia banned night-time sales of heavy alcohol, following on from a proposal to double the minimum price of vodka over the next two years in an effort to curb drinking.

„They (the government) are nicer to alcoholics than they are to us,“ says 32-year-old heroin addict and Tver resident Valera, whose scaly hands and face are covered in bright pink scabs from a decade of use. Like many drug addicts, Valera does not work and refuses to say how he funds his $300-a-day habit.

The Geneva-based International Aids Society Aids Society (IAS) warns that if Moscow continues to take no measures, the number of new HIV infections in Russia is likely to grow by 5-10 percent a year, pushing the problem to „an endemic level“, according to IAS president Elly Katabira: the rate will stay constant even without any additional infections from outside the country.

That would hit Russia’s already dwindling population — recently called a „demographic crisis“ by President Medvedev. Heavy smoking, alcoholism, pollution, poverty, low birth rates in the years after the fall of Communism, as well as HIV/AIDS underpin UN projections that the population will shrink to 116 million by 2050 from 142 million now. Moscow — which now gives money to mothers bearing two or more children – targets a population of around 145 million by 2025, but concedes that it could fall to as low as 127 million by 2031.

DESPERATE FOR METHADONE

If one thing appals foreign health officials and activists more than anythappallsing else about Moscow’s response to its heroin problem, it’s the ban on methadone. The WHO regards methadone as essential in combating heroin dependence, but in Russia anyone caught using it or distributing it can face up to 20 years in prison — as harsh a sentence as that for heroin.

Called a replacement drug, methadone is taken by mouth — so reduces the risk of HIV infection by using shared needles — and is used around the world to treat opiate addiction. Russia is one of just three countries in Eastern Europe and Central Asia to ban the drug, alongside Turkmenistan and Uzbekistan, where heroin consumption is relatively low. China, which has over one million registered heroin addicts, with unofficial estimates running several times that, has more than 680 methadone sites.

Methadone is a potent synthetic opiate in its own right, but it can eliminate the agonizing withdrawal symptoms that addicts experience when they quit heroin. Its main advantages are that it has to come from a health-care source, in controlled doses and without needles. That gives addicts some chance, over months or sometimes years, to go clean for good.

In Tver, Yuri Ivanov, a doctor and the deputy head of the state-run Tver Regional Narcology Clinic, is dumbfounded by the ban. „Why do civil servants limit me from doing my work?“ he asks in his dimly lit office in the crumbling grey clinic, which sits off an unpaved muddy lane in the center of the city. „All that they are trying to do is the opposite of what we need. It is hard for me to understand… The situation is going backward. When there is no real medicine, they go right back to drugs.“

Ivanov sometimes resorts to giving his patients tropicamide, a drug used by eye surgeons to dilate the pupils and which has a similar effect to heroin.

Addicts talk of their rare encounters with methadone users with a sense of wonder and even magic. „All of us know about this drug methadone and all of us want it. People come through who have done it and we can instantly see how much brighter and better they live,“ says Tver addict Valera in jittery sentences, high after shooting up twice by midday, in an interview in the back of his tobacco-stained car.

But Moscow won’t be swayed. „The medicine has become more dangerous than the illness. It would be replacing one evil with another,“ said the anti-drugs baron Ivanov. „And why on earth would we do that?“ Gennady Onischenko, the country’s top doctor, repeatedly dismisses methadone as „still a narcotic“.

In a major government anti-drug strategy launched last June, there was no mention of substitution therapy, even though Moscow says it is now focused on reducing the demand for drugs. That means that Russia’s measly four federal and 77 regional rehabilitation centers will continue to treat addicts with psychotherapy, counseling or simple painkillers.

CHAINED TO BED FRAMES

The vacuum created by the lack of effective substitution therapies was highlighted in an incident last October in the Ural Mountains town of Nizhny Tagil. Anti-drugs activist Yegor Bychkov, 23, was sentenced to three and a half years in prison for kidnapping drug addicts. Bychkov said he had received permission from the addicts‘ parents to forcibly take their sons and chain them to steel bed frames while they underwent a painful detox.

Anti-drugs chief Ivanov praised Bychkov, saying he had acted in good will; the head of the parliamentary health committee Olga Borzova said the state was to blame for his arrest as he had become desperate.

The Russian Orthodox Church also weighed in. Though its official stance is against sex education and it regards heroin use as a sin, it has set up its own rehabilitation centers which offer religious guidance. The Church also holds regular discussions with the UN over the HIV/AIDS crisis.

Unfortunately, those sorts of initiatives may be risky. Almost two years ago, the General Prosecutor’s Office was ordered by Russia’s Security Council to beef up prosecutorial measures against non-governmental organizations which advocate substitution therapy. Since then, activists distributing free needles have been detained on charges of aiding illegal drug use.

„Russian government officials consistently promote falsehoods about harm reduction, and deter those who speak in favor of them,“ the IHRA’s Rick Lines says. „Speaking honestly about the vast body of evidence supporting the effectiveness of methadone is a dangerous thing to do (in Russia).“

That may be why relations between the UN’s Global Fund to Fight AIDS, Tuberculosis and Malaria — which has been pushing for methadone legalization — and Russia’s health ministry ruptured at the end of last year. The Global Fund provides the most finance for HIV/AIDS prevention in Russia and granted $351 million to Russia for 2004-11. Now $16 million of that allocation remains, and is at risk of being cut this year.

Worse, say global health experts and local NGOs, is the health ministry’s decision to scrap the Global Fund’s needle distribution, HIV awareness and medication programs. „They proved ineffective and we shall not continue them after 2011,“ said Alexander Vlasov, the ministry’s spokesman.

In October, the health ministry directly accused the Global Fund of making the HIV epidemic worse. „In the regions where these (Global Fund needle) programs were operating, the spread of HIV infection increased three-fold,“ minister Tatyana Golikova told a narcology conference.

The Fund says it is keeping up a dialogue with the Health Ministry. But global health experts warn that the decision to end the Global Fund’s work in Russia will be catastrophic. „Russia will fall behind and lose the achievements made so far,“ warned IAS president Katabira. „We will not be able to recover the situation.“

Heroin and coffee. These two words come to mind when Lao Ta Saenlee, 74, smiles, gestures and chats while sipping Chinese tea at his newly-opened coffee shop in his village, Ban Huay Sarn, in Chiang Mai’s Mae Ai district. While coffee is his new-found passion, Lao Ta has long been infamous and associated with drugs and heroin trafficking in the North. Although it’s been three years since he was released from jail, a renewed passion for life still bubbles from every word as he talks about plans of starting a franchise of „Lao Ta Coffee“ shops across the North.

FROM JAIL TO JAVA: Left, Lao Ta Saenlee reflects on his life. Right, at the time of his arrest in 2003.

But he will never be able to dispel decades of accusations of drug trafficking _ an image attached to prominent former Kuomintang (KMT) fighters who fled southern China into Burma in 1949 before settling in the northern hills of Doi Mae Salong in Chiang Rai in the 1960s.

His name has been associated with the now deceased „Opium King“ Chang Chi-fu, or Khun Sa, and the current drug baron, Wei Hsueh-kang of the United Wa State Army. He knew them both but vehemently denies drug links with them.

FIRED UP: New Year at Lao Ta Saenlee’s home.

Lao Ta’s story is one of a boy soldier and young fighter whose life was moulded and shaped through the barrel of the gun. It ensured his survival during times of political upheaval and in the dense jungle along the border between Burma and northern Thailand during the Cold War.

Like other prominent former KMT fighters, his leadership qualities gained him armed supporters, but invariably living in a foreign land meant agreeing to be a pawn in Thailand’s fight against the communist insurgency from 1961-1982. He fought the insurgents in exchange for a place to live, and as a result his stature and influence grew. But like so many others who often lived and trod on the shadier side of life with frequent encounters with the law, he fell from grace and was imprisoned.

Now he’s back _ but it wasn’t easy.

 

During the height of the campaign against drugs by former prime minister Thaksin Shinawatra, police arrested and seized the property of thousands of suspects. About 2,500 were killed. In June, 2003, the authorities moved against Lao Ta.

“I remember that day well. It was 4 or 5am, and about 100 troops, cavalry and police surrounded my home and village. All entrances were blocked. They blocked the road leading to my home with a tank. They searched all the houses in the village. “They searched for two days but they didn’t find any drugs. They arrested some addicts and they confiscated a lot of weapons. But it’s normal for hilltribesmen to have weapons. The villagers need the weapons to defend themselves. There was a large quantity of weapons and ammunition in my home,“ he admits.

For the next four to five days, Lao Ta _ and two of his sons, Vijarn and Sukkasem, who were also arrested _ were flown to Chiang Rai and Chiang Mai for press conferences by authorities and then flown back home. “They wanted to make a big story out of my arrest,“ he recalled.

Lao Ta spent fours in jail (from 2003-2007) and faced four separate charges of illegal possession of 336g of heroin, trafficking in 400kg of heroin with intent to sell to Malaysia, hiring a gunman to murder a man in Chiang Mai’s Fang district and illegal possession of firearms and ammunition.

By 2007, the courts dismissed the drug trafficking and attempted murder charges because of insufficient evidence _ a result of conflicting testimony from prosecution witnesses. He was slapped with an 18-month jail term for illegal possession of firearms.

THE HILLS COME ALIVE: left to right, Lao Ta Saenlee enjoys New Year’s festivities at home.

Thaksin even suggested that Lao Ta’s defence capitalised on loopholes in the law and bribed his way out.

But while he was imprisoned, a sizeable chunk of Lao Ta’s cash _ “I don’t have millions I have only 76 million“ _ along with his properties, comprising a 300-rai lychee orchard, five houses in an up-market housing estate in Chiang Mai’s Muang district, and a supermarket in Ban Huay San, were seized by the government.

All that was left was his home, a petrol station and land that he acquired as payment for fighting the communists. The government could not seize the property because he and his family do not own it but have legally-issued documents allowing him and his to occupy and earn a living off the land.

“I had nothing left. My wife [he has three] had to sell 94 cows to live off while I was in jail. I could not even afford to buy pla too [mackerel] to eat,“ he insists. At one point when he was feeling depressed, Lao Ta actually considered robbing a bank. “I called up two of my most loyal supporters and suggested the idea. But they told me ‚Boss, we’re now 70 years old,“‘ he said, smiling. He admitted thinking about selling methamphetamines but dismissed the thought quickly.

Fortunately, he got a call from “a friend who used to traffic in drugs“ who congratulated him on his release and asked how he was doing. Lao Ta told him that he needed money to get his life back on track. “I told him I needed about six million baht. A few days later my friend put two million baht into my bank account. I tried to call and thank him but there was no answer and I have not heard from him since,“ said Lao Ta.

GONE STRAIGHT: Lao Ta Saenlee, now hopes to own a chain of successful coffee-shops.

Financially replenished and feeling better, old habits die hard. Lao Ta held a party in the village to mark his freedom. “We roasted pigs and had a grand party. I spent a lot.“ But reality set in and he had to think long-term. Ironically, he thought about Mao Zedong and Chiang Kai-shek. Both gave him the inspiration to move forward.

“In those days, both leaders headed countries that faced within insurmountable problems. They had nothing. But they both made something [their countries] out of nothing,“ he said.

Lao Ta still had his home and the land. But he also had notoriety _ a name people dhremembered, at least in the North. And so the idea of Lao Ta Coffee was born.

Lao Ta’s resilience probably did not stem from his thoughts of Mao Zedong and Chiang Kai-shek alone but because he’s had a life of struggle, depending on weapons to stay alive. Lao Ta says he “dragged a gun“ in Chiang Kai-shek’s army in southern China’s Yunnan province when he was just 13. In 1954, at 17, he joined remnants of the KMT’s 5th Regiment of the 93rd Division led by Gen Tuan Shi-wen into northern Burma. These forces fled Yunnan into Burma three years earlier and continued to fight against the forces of the new Chinese Communist regime.

In 1961, Lao Ta joined Gen Tuan and about 4,000 battle-weary KMT soldiers into Doi Mae Salong of Chiang Rai. In exchange for asylum in Thailand they fought Thai communist insurgents between 1961 to 1982. During this period they grew and sold opium to pay for their weapons. “At one stage the Thai government asked us to choose between leaving for Taiwan or staying behind. Many decided to leave for Taiwan. I recall looking at a map of the world to find out where Taiwan was. We could see that we had to travel a great distance across the sea. I was scared of the sea and feared I could never return home [to China]. So I decided to stay in Thailand and Khun Sa did toowas the same like us,“ Lao Ta recalled.

But his stay in Doi Mae Salong did not last long. He decided to move back into the Burmese jungles where he spent years trading in opium and building up his forces. “We grew up with guns and weapons and over time we [including Khun Sa] started building up our forces.“ Lao Ta said each individual leader built up their influence depending on the number of people loyal to them. He built up his followers from among the Muser, Lisu and Akha villagers.

“They spoke Chinese, so we could communicate with each other. You built up your position through your supporters and alliances with other groups. You needed this to survive. Opium was a commodity,“ he said. “I admit to having been a drug dealer,“ he said in an interview in June, 2003, before his arrest. “Back in the ’70s, in Doi Mae Salong, everyone did it. Opium was put in sacks and loaded onto helicopters. We didn’t have to take it to the market, buyers came to us.“ He also admitted to having “links“ to Khun Sa after he took control of the Doi Lang area in the early ’80s. In those days Lao Ta himself controlled 700-800 armed men.

Lao Ta was not clear as to when he returned to Thailand. But when he did, he was invited to work for the Thai military. The deal was simple _ Lao Ta and his men could keep their weapons. They were paid half a million baht and given 500 sacks of rice. In exchange, they would fight the communist insurgents. Once their mission was completed, they were promised Thai citizenship and land. They would not own the land, but he and his men _ and their families and descendants _ would have the right to live off it.

“I helped the Third Army fight the communists for many years. I was involved in no fewer than 200 operations,“ he said. Lao Ta and his men fought in Phayao, Nan and Phetchabun provinces and once were trucked to fight in the northeastern province of Loei. His military career ended in 1977, when aged 40, he was granted Thai citizenship and was allowed to live near Doi Mae Salong.

He settled in Tambon Ta Ton in Mae Ai district, and founded Ban Huay Sarn, the village where he lives now and which comprises 600 families and includes four smaller surrounding villages of 40-50 families each. He started growing cash crops and raised cattle obtained from Burma. But how does that explain the millions in cash and property he amassed in Chiang Mai by the time of his arrest in 2003?

Lao Ta admits that he knew Wei Hsueh-kang, the current drug baron, when Wei was based in Fang district of Chiang Mai before he joined Khun Sa at Ban Hin Taek in the Mae Chan district of Chiang Rai. When Khun Sa was forced out of Thailand, and as his influence waned, Lao Ta admits doing business with Wei when the United Wa State Army settled in Mong Yawn inside Burma near the San Ton Du checkpoint, which is close to his village. “The Wa needed supplies, food … everything,“ he said. Lao Ta adds however that he made “a great deal of money“ selling petrol to the Wa, especially when the Ban Ton Du checkpoint was closed. He paid bribes to get his 10,000 litre fuel trucks across into Burma. “But I was never involved in drug trafficking,“ he insists.

Over the years in Mae Ai district, Lao Ta’s influence grew, not only among villagers, but local government officials as well. He was involved in many community projects aimed at helping the villagers but he made sure he involved and worked closely with local officials and government agencies. He contributed openly and regularly to cash-strapped agencies. TVs, refrigerators and other office equipment at the local police station and district office bear the name of his other brother, Charan.

Although his relatives and close associates may have been arrested for drug trafficking, and Lao Ta had been involved in clashes with the law, before his arrest in 2003, Lao Ta was nominated twice as the best village headman in Mae Ai district. But ominous signs appeared on the horizon before his arrest _ the Chiang Mai governor dismissed him as village headman. Despite serving time, Lao Ta still enjoys widespread respect among the hilltribe villagers in the area who turned up in full force for their New Year celebrations at his home earlier this month.

The celebrations lasted three days and nights. There was singing and dancing. They lit firecrackers while village leaders fired their hand guns in the sky. “It’s a chance to clean the barrels of their pistols,“ quipped Lao Ta with a broad grin. Lao Ta provided the feast _ 30 pigs and 20 jars of home-made liquor.

The party was more joyful than it had been in previous years because Lao Ta was back to Ban Huay Sarn, the village he leads. And even though he’s now into coffee, his legacy continues _ his eldest son Vijarn, who served time with his father, is now the village headman.

 

source is: http://www.bangkokpost.com/news/investigation/218928/heroin-and-coffee—the-saga-of-lao-ta-saenlee

Zusammenfassung

Bedeutungsinhalte und Konsummotive von Drogen haben sich in der Geschichte wechselseitig verändert. Das gilt auch für Substanzen, die heute unter dem Begriff hard drugs firmieren. Den Auftakt für deren weltweite Prohibition markierte die erste internationale Opiumkonvention von 1912. Gründe für dieses Abkommen sind zum einen im 19. Jahrhundert zu suchen. Die Briten intensivierten seit den 1820er Jahren den Opiumhandel mit China, der zwischen 1839 und 1860 in zwei Opiumkriege mündete, mit denen die Legalisierung des Opiums in China erzwungen wurde. Zum anderen tauchten in den um 1900 rasch wachsenden Städten der westlichen Welt Drogenkonsumenten auf, unter denen bestimmte Gruppen stigmatisiert bzw. als soziales Problem betrachtet wurden: so in den USA nicht etwa Morphinisten aus der Oberschicht, sondern Opium rauchende, chinesische Migranten und urbane Jugendgruppen, die unter anderem Heroin konsumierten. Unter dem Eindruck der Folgen des in China massenkonsumierten Opiums und der Angst vor einem expandierenden Drogenkonsum in der eigenen Gesellschaft formierte sich in den USA, Großbritannien und anderen europäischen Ländern im ausgehenden 19. Jahrhundert eine Anti-Opium-Bewegung, die auf ein globales Verbot von Opiaten, Kokain und später auch Cannabis hinarbeitete. Im Verlauf des 20. Jahrhunderts wurde das Prohibitionsregime zunehmend ausgebaut, was die Entstehung von hochprofitablen Schwarzmärkten förderte. Über Jahrzehnte konzentrierte sich die Bekämpfung des Drogenhandels auf repressive Maßnahmen und kulminierte seit den beginnenden 1970er Jahren im war on drugs. Wiederum wurden dabei nicht etwa Kokainkonsumenten aus wohlsituierten Kreisen problematisiert, sondern wegen ihrer Drogenabhängigkeit sozial gescheiterte Existenzen. Nicht zuletzt der Einsicht geschuldet, dass der Kurs dieser Prohibitionspolitik weitgehend kontraproduktiv war, sind seit einiger Zeit neue Ansätze erkennbar. Sie diffamieren Drogenkonsumenten nicht mehr als soziale Außenseiter, sondern setzen auf harm reduction. Dabei gewinnt auch die Erkenntnis an Boden, wie omnipräsent unterschiedlichste Drogen in unseren Gesellschaften sind und wie willkürlich die Grenzlinie zwischen legal und illegal in der Vergangenheit gezogen wurde.

<1>

Im historischen Rückblick zeigt sich, dass das, was zu verschiedenen Zeiten und an verschiedenen Orten als „Droge“ definiert und begehrt oder gefürchtet wurde, äußerst veränderbar war. Psychoaktive Stoffe werden mit ganz unterschiedlichen Phänomenen und Problemen, mit denen sich Gesellschaften auseinanderzusetzen haben, in Verbindung gebracht. [1] In unserem Alltagsverständnis ist der Begriff „Droge“ zudem gespalten. Zum einen wird er im weitest möglichen Sinne verwendet. Weit davon entfernt, an Materialität gebunden zu sein, kann er sich auf alles und jedes beziehen, was über das normale Mittelmaß hinausreicht und den Menschen das Gefühl gibt, dass es über die Routinen des täglichen Lebens hinaus noch eine Welt gibt, in der Außerordentliches möglich ist und auch passiert.

<2>

So analysiert etwa der Literaturwissenschaftler Peter von Matt das „Faktum“, dass die Geschichte einer Droge gleichkomme, die periodisch nationale Rauschzustände erzeuge, auf die dann der Cafard, die „graue Ernüchterung“, folge. Die „Intoxikation mit Heldenfabeln“ löse eine „gemeinschaftliche Erregung“ und eine „kollektive Anästhesie“ aus, die gegenüber den verübten Gewalttaten und dem Leiden der Opfer abstumpfe. [2] Das ist eine sehr weite Definition von Rauschdroge, die sich auch auf andere Ideologien und Betätigungen übertragen lässt, wie das Bergsteigen, die Sexualität oder das Spielen.

<3>

Zum andern finden wir eine akute Engführung des Drogenbegriffs. Der Slogan „No drugs“ propagiert Abstinenz gegenüber jenen Substanzen, die im 19. Jahrhundert zu „Rauschgiften“ umdefiniert wurden, im Verlaufe des 20. Jahrhunderts auf die Liste der Betäubungsmittel gerieten und damit zunehmend in die Illegalität und auf Schwarzmärkte abgedrängt wurden. Drogen sind hier per definitionem jene Stoffe, die verboten sind. Die Promotoren der Prohibition erklärten immerzu, das Verbot sei nötig, weil diese Substanzen zu gefährlich seien. [3] Der umgekehrte Zusammenhang und auch die Tatsache, dass mit der Prohibitionspolitik bestimmte soziale Gruppen marginalisiert und Menschen stigmatisiert, wurden so wie damit überhaupt symbolische Gesellschaftspolitik betrieben wurde, sind hingegen kein Thema. Im Folgenden soll das Drama der Drogenprohibition im Zeitraffer so nüchtern wie möglich dargestellt werden.

Heterogene Anfänge der neuen Drogenprohibition

<4>

Schon in der Frühen Neuzeit wurden viele Stoffe, die im Zuge der kolonialen Expansion nach Europa kamen, als Gefahr für die soziale Ordnung wahrgenommen und verboten. Regierungen und religiöse Gewalten richteten sich vor allem gegen den Konsum von Tabak, Tee, Schokolade und Kaffee. [4] Von diesen Bestrebungen, Drogen zu unterdrücken, führt allerdings kein direkter Weg in die moderne Prohibitionspolitik, wie sie seit Ende des 19. Jahrhunderts aufkam und sich zunächst gegen das Opium richtete.

<5>

Die Anfänge dieser Verbote sind vielfältig und sie sind in internationalen Zusammenhängen ebenso zu finden wie in nationalen Kontexten und lokalen Problemlagen. Die beiden Opiumkriege der 1840er und 1850er Jahre [5], mit denen Großbritannien die Legalisierung des Opiums in China mit Waffengewalt erzwang, um das angeschlagene, jedoch noch immer einträgliche Geschäft mit diesem in Indien angebauten Stoff zu retten, stellten einen Ausgangspunkt für moralische Empörung und eine humanitäre und auch medizinisch inspirierte Rhetorik der Opium-Abolition in Europa und den USA dar. [6] Die Tatsache, dass die Briten am anderen Ende der Welt militärische Machtmittel einsetzten, um Profite aus „Rauschgift“ zu schlagen, weckte im entfernten Europa das Bewusstsein für die Universalität dieses Problems und mobilisierte Gegenkräfte, die sich nun mit moralischen, aber auch wirtschaftlichen Argumenten gegen diese imperialistische Politik zu wenden begannen. Damals entstand jene Problemsensibilisierung, die eine Anti-Opium-Stimmung provozierte, aus der sich anderthalb Jahrzehnte später eine organisierte Antiopiumbewegung formierte.

<6>

Bereits 1840 hatte in England eine sogenannte Anti-Opium-Society Informationsbulletins gegen die britische Kolonialpolitik publiziert. 1874 wurde die Anglo-Oriental Society for the Suppression of the Opium Trade (SSOT) gegründet, eine Vereinigung, die sich bald zur wichtigen Pressure group zur Unterdrückung des Opiumkonsums auch in England selbst entwickeln sollte und die zunehmend durch die Politik der amerikanischen Regierung unterstützt wurde. Aus einem „Nicht-Problem“, das mit einem Nicht-Wissen einherging, entwickelte sich so um die Mitte des 19. Jahrhunderts eine politisch-gesellschaftliche „Frage“, die „Opiumfrage“. Wenn einmal eine solche „Frage“ in der Arena der öffentlichen Meinungsbildung angekommen war, nahm die Besorgnis über diesen Missstand im gleichen Maße zu wie das Wissen darüber.

<7>

Der Weg zu einer rechtlichen Regulierung des ganzen Komplexes wurde somit durch den Imperialismus vorgespurt. Im Gravitationszentrum der Erschütterungen, die Opium in europäischen und amerikanischen Köpfen auslöste, befand sich China. Der ganze Ferne Osten wurde zur Drogenproblemzone und als entsprechend exotisch wurde das Phänomen wahrgenommen. Als 1909 eine Kommission die „Opiumfrage“ erstmals auf dem internationalen Parkett breit aufrollte, tagte sie in Shanghai. Federführend waren allerdings schon damals die USA, die unmittelbar im Anschluss an diese sogenannte Shanghaier Kommission mit der Vorbereitung einer ersten internationalen Opium-Konferenz begannen, die nun aber in Europa stattfinden sollte.

<8>

Am 1. Dezember 1911 wurde diese unter dem Vorsitz von Bischof Charles Brent im Haag eröffnet. Die zwölf teilnehmenden Länder – eingeladen waren 14, aber Österreich-Ungarn und die Türkei hatten abgesagt – tagten bis zum 23. Januar 1912 und verabschiedeten als Resultat der Verhandlungen die Erste Internationale Opium-Konvention von 1912, das Grundlagendokument der modernen Prohibitionspolitik. Diese Haager Opium-Konvention stellte allerdings keine rechtlich verbindlichen Verhaltensregeln, Anweisungen und Maßnahmen auf; sie gab bloß Empfehlungen. Dennoch war ihre Wirkung viel weitergehender, als dies aufgrund der juristisch schwachen Konstruktion angenommen werden konnte, gab sie doch die Richtung vor, entlang der nun nach und nach in (fast) allen Ländern nationale Drogengesetze erlassen wurden. Das internationale Abkommen wurde durch eine steigende Zahl von Staaten ratifiziert und begann, eine Breitenwirkung zu entfalten.

<9>

Die USA fungierten also – dies machte das Zustandekommen dieses ersten internationalen Opium-Abkommens deutlich – als spiritus rector bei der Genese des modernen War on drugs. Die Drogenprohibition kann jedoch nicht auf die Intentionen, Interessen und Präferenzen eines nationalen Akteurs zurückgeführt werden. Sie lässt sich nicht auf Strategien von mächtigen Staaten und „Moralunternehmern“ herrunterbrechen. Vielmehr gilt es, sie als entangled history zu verstehen, in der globale Austauschbeziehungen und eine ganze Reihe von Entwicklungen in der Gesellschaft, der Wirtschaft, der Wissenschaft und in den globalen Beziehungen zusammenwirkten. [7] Gegen Ende des 19. Jahrhunderts hatten sich offenbar politische Problemstellungen, mentale Dispositionen und massenmediale Ensembles aufgebaut, welche die öffentliche Resonanz für Verbotsargumente deutlich erhöht hatten. Es sind vor allem drei transnationale Entwicklungen, auf die hier hinzuweisen ist.

Diskriminierung von Minderheiten und Professionalisierung der Moral

<10>

Erstens wurde die opiumfeindliche Haltung der USA von Anfang an in starkem Ausmaß durch rassische Gesichtspunkte und rassistische Motive bestimmt. [8] Die USA, ein Einwanderungsland par excellence, verstanden sich zwar als melting pot. Dennoch blieben ethnische Grenzziehungen virulent und einige von ihnen schlugen in offene Diskriminierung um. Nach 1850 begannen Chinesen in großer Zahl in die USA einzuwandern und viele von ihnen waren habituelle Tschandu-Raucher, wie die Pfeifen gebrauchenden Opiumkonsumenten genannt wurden. Die chinesischen Immigranten galten als äußerst leistungsfähige Arbeitskräfte, die in Bergwerken, in der Landwirtschaft, in Wäschereien und im Bau- und Transportsektor Beschäftigung fanden.

<11>

Insbesondere nach der Fertigstellung der großen transkontinentalen Eisenbahnlinien sahen die weißen (das heißt die europäischen) Amerikaner in den opiumrauchenden „Kulis“, die sich – unter anderem gerade wegen dieser Sitte – auf dem Arbeitsmarkt erfolgreich behaupteten, eine unwillkommene Arbeitsmarktkonkurrenz. Mittels einer „anti-orientalischen“ Kampagne wurde diese Minderheit nun zunehmend über ihre Droge stigmatisiert und unterdrückt. 1875 erließ die Stadt San Francisco die erste Strafnorm gegen Drogenkonsum in der westlichen Welt, und zwar ausschließlich gegen das Rauchopium der Chinesen. In der Folge wurde systematisch eine sogenannte „gelbe Gefahr“ heraufbeschworen: Phantastische Schilderungen von Opiumhöhlen, die in den Ausschmückungen von Moralaposteln alsbald zu reinen Inkarnationen aller kleinbürgerlichen Ängste, zu Orten der Unsittlichkeit und des physisch-psychischen Zerfalls gerieten, machten die Runde. Chinesen galten alsbald als ebenso gefährlich wie das Opium, das sie rauchten, und die „Höhlen“, in denen sie dies taten.

<12>

Unter diesen Umständen war der Gesetzgeber gefordert, der fortan zwischen der Unterdrückung des Opiums und der Diskriminierung der Chinesen oszillierte. Der Kongress wurde aktiv und beschloss 1887 ein Gesetz, das es den Chinesen, nicht aber den Amerikanern, untersagte, Opium zu importieren. 1889 richteten sich weitere Maßnahmen direkt gegen die Einwanderer: Der Chinese Exclusion Act schob der weiteren Einwanderung von ChinesInnen einen Riegel vor. 1890 stand dann wieder die Droge im Zentrum: Ein Gesetz behielt die Herstellung von Rauchopium exklusiv amerikanischen Staatsbürgern vor. 1909 schließlich wurde die Einfuhr von Rauchopium generell verboten. Es handelte sich hier um den ersten War on drugs, um einen amerikanischen Krieg gegen Opium und – da die Konnotation der Öffentlichkeit regelrecht eingehämmert wurde – gegen die in Amerika ansässigen Chinesen. [9]

<13>

Im heutigen Jargon könnte man von einer symbolischen Statusdegradierung einer ethnischen Minderheit durch Stigmatisierung einer Identität stiftenden, alltagskulturellen Droge sprechen. Eine herausragende Rolle spielte hierbei jener Flügel der amerikanischen Gewerkschaftsorganisationen, der sich voll auf die rassistische Rhetorik weißer Überlegenheit eingelassen hatte. Samuel Gompers (1850-1924), konservativer amerikanischer Gewerkschaftsführer, Kämpfer gegen sozialistische und anarchistische Strömungen innerhalb der Arbeiterbewegung und Mitbegründer der American Federation of Labor (AFL), deren Präsident er zwischen 1886 und 1924 war, machte den Schutz der teuren weißen gegen die billigen farbigen Arbeitskräfte zur gewerkschaftlichen Hauptforderung.

<14>

1902 veröffentlichte Gompers zusammen mit einem Co-Autor ein Pamphlet mit dem Titel: „Einige Gründe für die Fernhaltung der Chinesen: Fleisch oder Reis, amerikanische Männlichkeit oder asiatisches Kulitum, was soll überleben?“ Unter anderem ließ er verlauten: „Die überlegenen Weißen waren gezwungen, die minderwertigen Asiaten durch Gesetz oder, falls notwendig, durch Waffengewalt fernzuhalten (…). Die gelbe Rasse neigt von Natur aus zu Lüge, Betrug und Mord, und 99 von 100 Chinesen sind Glücksspieler“. Solche Haltungen können plausibel machen, weshalb die Unterdrückung des Opiums nicht beim Opiat Morphium, sondern bei der schonendsten Konsumform, beim Rauchopium einsetzte. Diese Geschichte aus den USA ist exemplarisch. Auch in andern Ländern gab es Bestrebungen, kulturelle Minderheiten über ihren Drogengebrauch zu definieren und sie mit einer Verbotspolitik zu bedrängen.

<15>

Zweitens zeichnete sich gegen Ende des 19. Jahrhunderts eine epochale Machtverschiebung ab. Mit ihrem Aufstieg zur neuen Hegemonialmacht im Pazifik, die 1898 mit dem Krieg gegen Spanien und der Eroberung der Philippinen einsetzte, erhielt der „symbolische Kreuzzug“ gegen das Opium erstmals eine globale Machtbasis. Dass nun die „Opiumfrage“, welche das britische Empire unter Zugzwang setzte, auf die Tagesordnung der internationalen Politik gesetzt wurde, resultierte auch aus der im ausgehenden 19. Jahrhundert sich verallgemeinernden Tendenz zu grenzüberschreitender Kooperation. Diese wurde angeregt durch neue weltumspannende Transport- und Kommunikationssysteme (Telegraphen- und Eisenbahnnetz, Hochseeschifffahrt). Und sie wurde nötig aufgrund der Vertiefung der internationalen Arbeitsteilung und einer zunehmenden Weltmarktverflechtung.

<16>

Derselbe Industrialisierungsschub, der über den Rüstungswettlauf die imperialistischen Rivalitäten zwischen den europäischen Großmächten steigerte und das internationale Spannungspotenzial erhöhte, setzte auch Impulse für eine transnationale Zusammenarbeit und eine assoziative Außenpolitik frei. Dabei war die Zunahme von internationalen Konferenzen, die sich „nichtpolitischer Fragen“ annahmen, charakteristisch. In deren Zentrum stand neben den technisch-infrastrukturellen Problemen und Standardisierungspostulaten vor allem der Schutz der Bevölkerung gegen einen befürchteten Sittenverfall. Neue technische Experten, professionelle Spezialisten und sachkundige Repräsentanten privater humanitärer Organisationen traten auf dem außenpolitischen Parkett auf und drängten die universaldilettantischen Diplomaten von altem Schrot und Korn in die Defensive. Die mit der „Opiumfrage“ befassten internationalen Konferenzen wären ohne diesen Trend zur „Versachlichung“ und ohne die Professionalisierung des Verhandlungsstils kaum zustande gekommen.

<17>

Die machtpolitischen Motive blieben jedoch weiterhin wirksam. So konstatierte zum Beispiel Albert Wissler in seiner 1931 veröffentlichten Basler Dissertation, „wie sehr die amerikanische Haltung in der Opiumfrage zusammenstimmt mit den weltwirtschaftlichen Interessen des Landes“. „Wie die christlichen Missionare bisher dem europäischen Kolonialimperialismus willkommene Vorarbeit geleistet haben, missioniert nun die amerikanische Moral – ebenso gutgläubig wie jene – für den amerikanischen Finanz- und Wirtschaftsimperialismus“, schrieb Wissler weiter und sah im „Missionsfanatismus der Amerikaner in der Opiumfrage“ eine „unschätzbare Waffe der amerikanischen Pazifikpolitik, der der alte europäische Kolonisator im Osten nichts Gleichwertiges entgegenzustellen hat.“ [10] Die moralisch sauberen Amerikaner im Kampf gegen die schmutzige Machtpolitik der alten, korrupten Kolonialmächte: Das war die Formel der neuen Prohibitionspolitik. [11]

Akzeptanz des Drogenkonsums und gesellschaftliche Anerkennung

<18>

Um die gesellschaftliche Neubewertung der „Drogen“ und die Ausweitung der Problemperzeption auf neue Stoffe, insbesondere auf Morphium, Heroin und Kokain zu erklären, ist es drittens nötig, die Veränderungen der Konsumentenstruktur und der Konsummuster zu analysieren. Die moderne Drogengesetzgebung war, wie gezeigt, mit einer Diffamierung „fremder Sitten“, mit der Ausgrenzung und Stigmatisierung von Minderheiten verbunden. In den USA richtete sich die Drogengesetzgebung bis ins 20. Jahrhundert hinein ausschließlich gegen Chinesen und ihre Droge „Rauchopium“.

<19>

Die Konsumentinnen und Konsumenten des weit stärker wirkenden, industriell hergestellten Morphiums hingegen wurden kaum als Problemfälle angesehen und deshalb noch bis zum Ersten Weltkrieg kaum behelligt. Zwar gab es auch in diesem Konsumsegment „einfache Leute“, insbesondere Kriegsveteranen, die während des Sezessionskrieges von 1861-65 verwundet und aufgrund der medikamentösen Behandlung mit Morphium von diesem Stoff abhängig geworden waren (oder ihn einfach schätzen gelernt hatten). Hier ging die Respektabilität der Suchtursache – Verwundung im Krieg – zusammen mit der Konformität der Süchtigen, die keinesfalls aufzufallen beabsichtigten, sondern in ihrer großen Mehrheit ein „ganz normales Leben“ führten.

<20>

Daneben wurde Morphium in Mittel- und Oberschichten, insbesondere auch in Ärztekreisen, gespritzt. Hierbei handelte es sich aber, wie die Untersuchung von Charles E. Terry und Mildred Pellens aus dem Jahre 1928 festhielt, um die „gebildetsten, anerkanntesten und nützlichsten Schichten der Gesellschaft“; in derselben Studie wurde die sogenannte „typische Konsumentin“ als eine „zarte Frau mit hellblauen Augen und flachsgelbem Haar“ geschildert. [12] Das war so ziemlich das Gegenbild zu den Chinesen; es gab also keine Anhaltspunkte, die ein Eingreifen im Milieu des Morphiumkonsums nötig gemacht hätten.

<21>

Schon vor dem Ersten Weltkrieg ereignete sich aber in den amerikanischen Großstädten eine dramatische Veränderung des Drogengebrauchs. Nun bildeten sich drogenzentrierte Subkulturen von Jugendlichen heraus. Dieselben Stoffe, die bisher in diskreter und medikalisierter Form appliziert wurden, gingen nun plötzlich mit marginalen Milieus, mit gescheiterten Individuen, kurz mit Problemen aller Art eine Verbindung ein. Das veränderte ihre Bewertung fundamental. David T. Courtwright zeigt in seiner die Opiumabhängigkeit in den USA behandelnden Untersuchung „Dark Paradise“, [13] dass die Zahl der Süchtigen zwischen der Jahrhundertwende und den 1940er Jahren insgesamt abnahm. Trotzdem führte die Anstiegstendenz in einem problematischen Sozialsegment zu einem drastischen Imageverlust der Stoffe und ihrer Konsumenten. Courtwright weist darauf hin, dass die mit der Drogenverfolgung befassten Instanzen auch mit irreführenden und gefälschten Statistiken operierten, um ihre Horrorvisionen plausibel zu machen.

<22>

Drogenkonsum wurde nun auch aus ärztlicher Sicht neu gedeutet. Wenn früher überhaupt eine Diagnose gestellt wurde, so lautete sie auf „moralische Schwäche“. Jetzt aber wurde das Problem verstärkt in Kategorien einer „mentalen Pathologie“ gefasst. Spätestens in den 1920er Jahren verfügte der durchschnittliche Doktor über die fixe Idee, bei Drogenkonsum handle es sich um ein psychopathisches Phänomen, die Betroffenen seien psychisch gespaltene, bewusstseinsgestörte, potenziell gefährliche Individuen, für die doch wohl eher Polizei und Justiz zuständig seien.

<23>

Ein repressiver, diskriminierender Hardline-approach begann sich durchzusetzen. Als „kriminelle Süchtige“, aber auch als „Geisteskranke“, wurden Drogenkonsumenten zunehmend marginalisiert, stigmatisiert, verfolgt. Wer diese Tendenz kritisierte, wurde der Schönrednerei bezichtigt und alternative Konzepte hatten keine Chance mehr angesichts der alarmierenden Rhetorik der „Rauschgiftgefahr“. Internierung und Kriminalisierung ersetzten für ein Dreivierteljahrhundert, das heißt bis ins ausgehende 20. Jahrhundert hinein, die bisherige Strategie einer diskreten Medikalisierung der Abhängigkeit.

Ansätze einer Globalisierung der Drogenprohibition

<24>

Es wird im langen Zeitverlauf deutlich, dass sich Drogenpolitik kaum mit dem Interpretationsmuster der Humanitarian reform deuten lässt, wie das die frühere Geschichtsschreibung zu tun versuchte. [14] Die Geschichte der rechtlichen Regulierung des Problems muss vielmehr mit globaler Machtpolitik, mit gesellschaftlicher Normalisierung, mit Medikalisierungs- und Verwissenschaftlichungsprozessen sowie mit medialen Strategien erklärt werden. Was 1912 im Haag beschlossen wurde, war ein noch wenig gefestigtes Rahmenwerk. 1913 und 1914 fanden zwei weitere internationale Opiumkonferenzen im Haag statt.

<25>

Nach Abschluss der dritten Zusammenkunft im Dezember 1914 – die militärische Auseinandersetzung, die sich zum Ersten Weltkrieg ausdehnen sollte, hatte inzwischen begonnen – belief sich die Zahl der Staaten, die die Konvention unterzeichnet oder entsprechende verbindliche Erklärungen abgegeben hatten, auf 46. Das reichte aus, um das Abkommen endlich in Kraft zu setzen. Mit der Ratifikation, das heißt mit der Anpassung des innerstaatlichen Rechts an die völkerrechtlichen Normen, die mit dieser Sanktionierung durch die gesetzgebenden Körperschaften einzelner Länder überhaupt erst rechtsverbindlich und konkret anwendbar wurden, haperte es jedoch beträchtlich. Das sollte sich nach Kriegsende ändern. Das Haager Opiumabkommen wurde nämlich zum Bestandteil der Pariser Friedensverträge (darunter das „Versailler Abkommen“) von 1919/20 gemacht. Auf diese Weise wurde in allen Signatarmächten eine „automatische Ratifikation“ ausgelöst.

<26>

In Folge war es der 1919 gegründete Völkerbund, der für die Narkotika zuständig war und der weitere Konferenzen zur Betäubungsmittel- oder – wie es nun verstärkt hieß – zur Rauschgiftproblematik organisierte. 1924/25 fand in Genf eine weitere internationale Konferenz statt, in deren Vorfeld heftige Konflikte zwischen den beteiligten Staaten ausgetragen wurden. Das Epizentrum der Drogenproblematik hatte sich nämlich inzwischen in die europäischen Industrieländer verlagert. Im Verlaufe des Ersten Weltkrieges waren die symbiotischen Beziehungen zwischen Krieg und Droge noch enger geworden, als sie das seit dem Krimkrieg (1853-1856) und dem amerikanischen Sezessionskrieg (1861-1865) ohnehin schon waren.

<27>

Dabei spielten die zu Beginn des 19. Jahrhunderts entdeckten und fabrikmäßig produzierten Alkaloide – Morphium, sein Derivat Diacetylmorphin (Markenname „Heroin“) und Kokain – die Hauptrolle. Morphium ist bis heute eines der leistungsfähigsten, wenn nicht überhaupt das wirksamste Analgetikum; Kokain diente vielfach als Lokalanästhetikum, das heißt als Mittel zur lokalen Betäubung bei kleineren chirurgischen Eingriffen. Dass der Erste Weltkrieg den Bedarf an solchen Stoffen dermaßen stark steigern würde, war ursprünglich nicht abzusehen gewesen; es sollte ja ein kurzer Krieg werden – ähnlich dem deutsch-französischen Krieg (1870-1871).

<28>

Die Hochrüstung durchkreuzte diesmal die Strategie der schnellen Entscheidung. Ab 1915 erstarrte die militärische Auseinandersetzung im Grabenkrieg. Es kam zu langanhaltenden, mörderischen „Materialschlachten“, die erstmals mittels Giftgas, Maschinengewehren, Tanks, Flugzeugen et cetera geführt wurden. Über 65 Millionen Soldaten standen im Einsatz; die Verlustbilanz lautete: etwa 10 Millionen Tote, über 20 Millionen Verwundete. Der Bedarf an Alkaloiden stieg unter solchen Umständen natürlich enorm an; die chemische Industrie, die eben erst den Einstieg in die Pharmaproduktion geschafft hatte, konnte europaweit mit Hochkonjunktur rechnen. Es ist nachvollziehbar, dass die entsprechenden Unternehmen nach 1918, nach dem Wegfallen eines Teils der kriegsbedingten Nachfrage, nach neuen Absatzmärkten suchten und diese zum Teil in Kolonialgebieten – etwa in China, aber auch in Nordafrika – fanden.

<29>

Angesichts dieser Entwicklung lehnte es England ab, sich durch den Völkerbund an eine internationale Konferenz zitieren zu lassen, in der erneut und exklusiv das „alte“ koloniale Opiumproblem im Vordergrund gestanden hätte. London mobilisierte nun gegen die – wie sie von A. Wissler bezeichnet wurde – „mitteleuropäische Alkaloidindustrie“, das heißt vor allem gegen Deutschland und die Schweiz, aber auch andere Länder wie Frankreich, und wies darauf hin, dass mit der massenhaften Fabrikation von Alkaloiden ein neues Drogenproblem entstanden sei. So wurde denn beschlossen, zwei Konferenzen einzuberufen, von denen sich die eine mit der allmählichen Unterdrückung des Opiumgebrauchs im Fernen Osten und die andere mit der Beschränkung der Herstellung von Alkaloiden durch die Industrieländer befassen sollte. Aus dieser letzteren Konferenz resultierte das Genfer Abkommen, das in Folge durch eine große Anzahl von Ländern unterzeichnet und auch ratifiziert wurde.

<30>

Dieses Genfer Abkommen bedeutete allerdings eine Lockerung der 1912 formulierten Zielsetzungen, den Konsum von Betäubungsmitteln über eine strikte internationale Reglementierung von Produktion und Handel zu erzielen. Von einer rigorosen Kontingentierungslösung wurde im Interesse der chemisch-pharmazeutischen Unternehmen abgesehen; die Konferenzteilnehmer einigten sich auf ein ziemlich unverbindliches Zertifizierungssystem, das viele Umgehungsmöglichkeiten sowie Verhandlungsspielräume offen ließ und die Produktion von Morphium, Heroin und Kokain in Gang hielt.

Psychoaktive Stoffe im Visier der Prohibitionisten

<31>

In einem für den weiteren Gang der Drogendiskussion bedeutsamen Punkt verschärfte das Genfer Abkommen von 1925 allerdings die Prohibition: Cannabis, das 1912 zwar schon angesprochen, jedoch noch nicht explizit erwähnt wurde, geriet nun auf die Liste der inkriminierten Stoffe. [15] Daraufhin wurde vor allem diese Droge ins Visier der Prohibitionisten genommen. Auch hier profilierten sich die USA in einer Pionierrolle. Dies hing mit einer Kampagne gegen die Chicanos, die spanisch sprechende Bevölkerung des Südwestens der USA, die durch Einwanderer aus Mexiko Zuwachs erhielt, zusammen; es handelte sich hier um eine mit dem gegen die chinesischen Arbeitsimmigranten gerichteten Antiopiumfeldzug vergleichbare Tendenz zur Stigmatisierung einer ethnischen Minderheit, die sich ohne Probleme auch auf die Afroamerikaner ausweiten ließ. Erneut diente die Droge als Vehikel. Insbesondere in der Großen Depression der 1930er Jahre zog dieser Feldzug gegen Marihuana immer weitere Kreise; der Tonfall verschärfte sich, die Öffentlichkeit wurde über die Medien mit einer neuen, heimtückischen Bedrohung gigantischen Ausmaßes bekannt gemacht.

<32>

1930 nahm das Bureau of Narcotics seinen Betrieb auf; dieses betrieb die Dramatisierung der Drogen durchaus auch im bürokratischen Eigeninteresse. Nachdem Franklin D. Roosevelt nach seinem Amtsantritt 1933 die Alkoholprohibition aufhob, wurde ein Teil der Alkoholfahnder auf Cannabis angesetzt. Harry J. Anslinger, herausragender Exponent des Abwehrkampfes gegen Marihuana, Commissioner im Bureau of Narcotics, bearbeitete die Medien nach Strich und Faden.

<33>

Ein Beispiel: In einer von 56 Zeitungen nachgedruckten Meldung, die auf Materialien von Anslinger basierte, wurde unter dem Titel „Morde durch die Mörderdroge überfluten die USA“ verlautet: „Schockierende Gewaltverbrechen nehmen zu. Metzeleien, grausame Verstümmelungen, Verunstaltungen, kaltblütig durchgeführt, als würde ein hässliches Monstrum in unserem Lande umgehen. (…) Diejenigen, die süchtig nach Marihuana sind, verlieren nach einem anfänglichen Gefühl von Lustigkeit bald jegliche Hemmung. Sie werden zu bestialischen Dämonen, voll irrer Lust zu töten.“

<34>

Marihuana als „Killerdroge“: Hier taucht der ganze Assoziationskomplex der mittelalterlichen Assassinen wieder auf, hier wurde eine lange Tradition der kulturellen Degradierung des Orients auf die Spitze getrieben und mit einer Vielzahl von modernen Klischees zu einem furchtbaren Feindbild amalgamiert. [16] Die Kampagne war aus der Sicht des Bureau of Narcotics ein Erfolg, kam doch 1937 der Marihuana Tax Act zustande, der Cannabiskonsumenten in ein System bürokratischer Kontrolle integrierte und zudem Steuereinnahmen brachte. Dieser Cannabisdiskurs wurde in der Folge auch in Europa aufgegriffen. Auch hier wurde Marihuana als gefährliches Phantom profiliert, das mit dem ursprünglichen Hanf kaum mehr etwas gemeinsam hatte; alte Bauern wollten nicht glauben, dass es sich bei dem, was sie sich in ihrer Jugend arglos-neugierig in die Pfeife gestopft hatten, um denselben Stoff gehandelt habe. [17]

<35>

Anslinger ist auch der Erfinder der sogenannten Einstiegsdrogen-Theorie, nach der auf den Konsum von Cannabis zwangsläufig das Umsteigen auf noch stärkere Mittel, insbesondere Heroin, erfolgen soll. Im Sinne einer self-fulfilling prophecy ließ sich diese These in dem Maße bestätigen, in dem die Märkte für einzelne Stoffe durch ihre Illegalisierung auf Verbund geschaltet und damit durchlässiger werden konnten.

<36>

Weitere, die Betäubungsmittel betreffende Abkommen wurden in den Jahren 1936, 1948 und 1953 abgeschlossen. Nach 1945 wurde die UNO mit dieser ganzen Materie betraut. Eine herausragende Bedeutung kam der UNO-Single Convention on Narcotic Drugs von 1961 zu. Dieses Vertragswerk ersetzte die Internationale Opiumkonvention von 1912 und die darauf aufbauenden Zusatzabkommen und steckte den rechtlichen Rahmen auch für die heutige Drogendiskussion ab. Von den gesellschaftlichen Problemlagen her war dieses Einheitsabkommen allerdings rasch überholt. Der Kulturkampf um Drogen, der schon seit 1964 entbrannte, um dann ein wichtiger Aspekt der Rebellion der 1968er Bewegung zu werden, veränderte den Umgang mit psychoaktiven Stoffen fundamental und machte ihn zu einem wichtigen Element der Konfrontation zwischen Gegenkultur und Establishment.

<37>

Drogen wurden von der aufbegehrenden oder aussteigenden Jugend als Vehikel für Entspannung, neue Erfahrungen und psychedelische Trips verwendet. 1971 wurde das Einheitsabkommen auf psychotrope Substanzen wie LSD (das in den USA schon Mitte der 1960er Jahre verboten worden war) und Ecstasy erweitert. Bereits 1972 musste das Abkommen angesichts einer gefühlten „Drogenwelle“ und des Auftauchens von Designer-Drogen erneut verschärft werden. [18]

<38>

Diese Repressionspolitik schuf indessen einen goldenen Boden für das Geschäft auf dem Schwarzmarkt. Die Umsätze im Drogenhandel stiegen astronomisch an und die fehlende Regulierung im Finanzsektor führte zu immer dreisteren Verfahren der Geldwäscherei. Seit Mitte der 1980er Jahre richtete die UNO ihr Augenmerk denn auch stärker auf die Phänomene der organisierten Kriminalität und des illegalen Handels. Das sogenannte Wiener Abkommen von 1988 wollte rechtliche Instrumente, mit denen der Handel und die Finanzierung von Drogen weltweit bekämpft werden konnten, auf globaler Ebene harmonisieren und effizienter machen. Mit dieser Regulierung wurde allerdings gleichzeitig der Spielraum für Reformen weiter beschnitten. Im ausgehenden 20. Jahrhundert stellte die Ratifizierung dieses Abkommens, das 1990 in Kraft trat, einen Schwerpunkt der internationalen Drogenpolitik dar. Ein weiterer bestand in Versuchen, mit der Zerstörung von Anbauflächen und politischen Maßnahmen in Herstellerländern die Angebotsquellen versiegen zu lassen. Global betrachtet erwiesen sich beide Anstrengungen zur „Lösung des Drogenproblems“ trotz spektakulärer Teilerfolge schon mittelfristig als wirkungslos.

Pole der Macht und steile Hierarchien auf Schwarzmärkten

<39>

Repression ist eine Form sozialer Produktion. Das Verbotsregime, das auf Unterdrückung von Stoffen setzt und um dessen Legitimität und Praktikabilität bis heute gestritten wird, hat ein Drogenproblem mit spezifischen Konturen hervorgebracht, das vor allem in den 1980er und 1990er Jahren die mediale Berichterstattung in Atem hielt. [19] Im Verlauf des 20. Jahrhunderts und insbesondere seit den 1960er Jahren wurden die „Rauschgifte“, wie sie über die internationalen und nationalen Betäubungsmittelgesetze und weitere Abkommen definiert werden, zu den lukrativsten Handelsartikeln der Welt und die entsprechenden Märkte – vor allem für Heroin und Kokain, aber auch für Cannabis und eine steigende Zahl von sogenannter Designerdrogen – setzen Hunderte Milliarden Dollar um.

<40>

Akteure, die ihr Geschäftsgebaren weder an moralischen Grundsätzen noch an Rechtsnormen orientieren und sich um ethische und rechtliche Spielregeln menschlichen Zusammenlebens nicht weiter scheren, verspüren eine starke Neigung, sich in dieser florierenden Branche bemerkbar zu machen. Und wer darüber hinaus bereit ist, sich auf Risikokapital zu spezialisieren und hohe Verlustrisiken in Kauf zu nehmen, wird im Drogenhandel auch Erfolg haben – zumindest eine Zeit lang. Die in dieser Sparte entstandenen Unternehmen und Kartelle sind mit modernster Logistik ausgestattet. Sie verfügen über effiziente Gewaltabteilungen, die sie gegenüber den Wechselfällen der Politik wappnen und die es ihnen erleichtern, mit Rückschlägen umzugehen.

<41>

Sie wenden ein großes Repertoire von üblichen, unüblichen, unorthodoxen – man könnte auch sagen innovativen und kreativen – Geschäftsmethoden an und diversifizieren, transformieren und minimieren Risiken, so dass am Schluss die Kasse klingelt. Flugzeuge, U-Boote und Ballons gehören ebenso zum Transportarsenal wie die für die Beteiligten prekäre Beförderung von Drogen im Magen-Darmtrakt. Zur Abwicklung der Operationen stehen diesen Drogenhändlern auch heute internationale Finanzplätze zur Verfügung. Über „Waschmaschinen“ – jetzt gerade ist der Derivat- und der Kunsthandel stärker ins Gerede gekommen – wird Drogengeld gesäubert, anschließend in legale Kapitalkreisläufe eingespeist und dann in vergleichsweise sicheren Werten – in Immobilien, Aktienkapital, Rohstoffen, Wertpapieren aller Art – angelegt.

<42>

An beiden Enden der kriminellen Kapitalbildung mittels Drogengeschäften befinden sich zwei ökonomisch und sozial schwache Pole: die Produzenten der Drogenrohstoffe und die Konsumenten. Der Löwenanteil der verbotenen Drogen wird in Ländern angebaut, die wirtschaftlich wenig entwickelt sind und die sich mit einem failed state-Problem herumschlagen. In einigen zunehmend verarmten less developed countries – immer wieder in die Schlagzeilen geraten Afghanistan und Kolumbien, die Ländergruppe umfasst allerdings mehr als die Hälfte der Erdbevölkerung – stellt die Kultivierung der Ausgangspflanzen für verbotene Drogen, also Mohn, Koka und Hanf, eine Überlebensstrategie für breite, weithin mittellose Bevölkerungsschichten dar. Die Mühsal, der die ländliche Familienökonomie weithin ausgesetzt ist, wird verstärkt durch Rechtlosigkeit, Klientelwirtschaft und durch eine Weltwirtschaft, die nach dem Matthäus-Prinzip („Wer hat, dem wird gegeben“) funktioniert und privilegierte Positionen verstärkt.

<43>

Am Beispiel der Kokaproduktion wurde etwa gezeigt, wie die höchst gesundheitsschädigende Aufbereitung der Blätter einhergeht mit der Vernichtung großer Anbauflächen durch gefährliche Chemikalien, die mittels Flugzeugen und Helikoptern der Regierungen flächen deckend versprüht werden. [20] Solche Praktiken finden sich auch in Afghanistan, wo allerdings strategische Überlegungen und taktische Bündnisse auch die temporäre Toleranz des Opiumanbaus zur Folge haben können. Dies und die schwer bewaffnete Präsenz jener Agenturen der „organisierten Kriminalität“, die das Multimilliardengeschäft mit den Drogen kontrollieren, sorgten bisher dafür, dass Angriffe auf die Bauern als machtloses Bodenpersonal des hochfliegenden Geschäfts angebotsseitig wirkungslos blieben.

<44>

Am andern Ende der langen Verwertungskette liegen die Hauptabsatzgebiete in den urbanen Agglomerationen wirtschaftlich entwickelter Länder. Auch wenn die Konsumpraktiken sich längst globalisiert und auf ländliche Gebiete ausgeweitet haben, sind doch die lukrativen Umsatzpole für verbotene Stoffe da zu finden, wo sich die ungleich verteilte internationale Kaufkraft konzentriert. Dank der Verknappungstendenz, welche der Prohibitionspolitik inhärent ist, profitieren die entsprechenden Geschäftssegmente durch eine staatliche Hochpreisgarantie, die zwar durch aggressive Angebotsausweitungen immer wieder unterminiert wird, jedoch längerfristig intakt bleibt. So häufen sich die sozialen Probleme, die sich aus der brutalen Logik des Schwarzmarktes ergeben, bei den Konsumentinnen und Konsumenten an, die immer auch in den Kleinhandel involviert sind. Seit den 1980er Jahren haben sich in Metropolen von Konsumgesellschaften verschiedene Probleme verdichtet: Arbeitslosigkeit, Wohnungsnot, neue Armut. Parallel zum Abbau von Sozialversicherungssystemen nahm die soziale Ausgrenzungstendenz zu.

<45>

Dass in dieser Zeit die sogenannten „Drogenszenen“ entstanden, in denen Krankheit, Gewalt und Geld syndromartig amalgamierten, hing allerdings nicht direkt mit dem seit Mitte der 1980er Jahre ansteigenden sozialen Druck und auch nicht eindimensional mit der damals auftauchenden AIDS-Epidemie zusammen, sondern war primär das Resultat politischer Entscheidungen. Staat und Gesellschaft nahmen die sozialen Probleme zunehmend als politische Herausforderungen wahr. Das „Drogenproblem“ wurde zu einem kulturellen Code, über den eine politische Verständigung gesucht wurde. Den Drogenszenen und den Jugendlichen, die sie bevölkerten, kam ein hoher negativer Symbolwert zu. Diese marginalisierten Menschen gaben einprägsame Negativikonen der Massenmedien ab und standen als traurige Sinnbilder verunglückten Lebens im medialen Rampenlicht. Sie lieferten den Stoff für Elendsreportagen, die millionenfach über die Mattscheiben flimmerten. Drogen und das, was sie in diesem politischen Regime der Stigmatisierung bewirkten, erfüllten damit eine meist unausgesprochene gesellschaftliche Funktion, indem sie der moralischen Mehrheit in drastischer Weise zeigten, wohin es führt, wenn vom Pfad der Tugend abgewichen wird.

<46>

Komplementär zum raschen Reichwerden und glamourösen Erfolg, für den die Yuppies der 1980er Jahre standen, wurde das mörderische Beispiel des totalen Versagens im Drogenelend profiliert. Die offenen Drogenszenen können als mediale Konstrukte verstanden werden, welche die Normalität, die Konformität und die Leistungsbereitschaft stützten. Es kam ihnen (bezogen auf die Gesellschaft) eine integrative und (bezogen auf die Wirtschaft) eine produktivitätssteigernde Wirkung zu.

Chronik eines angekündigten Scheiterns – und Reformansätze

<47>

Dass die Dramatisierung des „Drogenproblems“ über die „offenen Szenen“ kontrafaktisch operierte, zeigen Schätzungen, die nachweisen, dass ein großer Teil der verbotenen „Betäubungsmittel“ – insbesondere Kokain, aber auch Hanf – als Leistungs- und Partydrogen fungieren. Sie werden nicht von sozial verwahrlosten Menschen am Rande der Gesellschaft, sondern von verhaltensunauffälligen, zum Teil sehr hart arbeitenden, pflichtbewussten und kaufkräftigen Erwerbstätigen konsumiert. Aus den genannten Gründen waren es allerdings die Drogenszenen, die als Verdichtungsräume für persönliche und soziale Probleme in den Brennpunkt der öffentlichen Aufmerksamkeit gerieten. Da diese Szenen per definitionem illegal sind, werden sie durch kriminelle Netzwerke beherrscht und von der anderen Seite durch die Polizei, welche die Kriminalität bekämpft, bedrängt. Die Versuche, die Versorgung der Schwarzmärkte mit den inkriminierten Stoffen auszutrocknen, haben in groteskem Ausmaß zu deren Überschwemmung mit immer neuen Angeboten geführt.

<48>

Repressionspolitik und Kriegslogik haben sich, wenn eine Jahrhundertbilanz gezogen wird, von niederschmetternder Wirkungslosigkeit und Kontraproduktivität erwiesen. Sie dienten der Politik zur Selbstinszenierung, sie schufen mächtige bürokratische Apparate, die ihre Legitimation aus einem Kampf gegen ein gesellschaftliches Übel bezogen und deren Arbeit nie einer Effizienz- und Qualitätskontrolle unterzogen wurde, so dass sie ihr offensichtliches Versagen in einen Beweis ihrer Unverzichtbarkeit umbiegen konnten. Dies nach der verqueren Logik: je größer das Problem, das aus einer repressiven Drogenprohibition resultierte, desto unverzichtbarer die Instanzen, welche diese Repression organisieren. Obwohl im vergangenen Jahrzehnt einige geistige Lockerungsübungen und eine gewisse Entideologisierung des „Drogenproblems“ zu erkennen sind, ist doch ein abrupter Systemwechsel nicht zu erwarten. [21]

<49>

Dennoch zeichnen sich Veränderungen ab. Auf internationaler Ebene wird man sich innerhalb der UNO immer stärker bewusst, dass der „Krieg gegen die Drogen“ angesichts eines prosperierenden Angebots illegaler Drogen an Boden verliert. Seit März 2009 wird im Rahmen einer weiteren Wiener Konferenz an einem neuen Konzept für den Kampf gegen den Drogenmissbrauch gearbeitet. Der bolivianische Präsident Evo Morales, der sich für eine Streichung der Koka-Blätter von der Liste verbotener Substanzen einsetzt, kaute während seiner Rede demonstrativ eben solche. Damit setzte er sich nicht nur für die Rechte der Koka-Bauern ein, sondern unterstrich auch symbolisch den Anspruch anderer Kontinente, ihre Sichtweise in einer während des ganzen 20. Jahrhunderts eurozentrischen und US-dominierten Diskussion zur Geltung zu bringen. [22]

<50>

Die Europäische Union spricht diese Problematik in ihrem zum selben Zeitpunkt veröffentlichten Bericht ebenfalls an. Der Bericht diagnostiziert eine Sackgasse der internationalen Drogenpolitik und stellt fest, trotz leichter Verbesserungen in einigen reichen Ländern habe sich die Lage in ärmeren Staaten massiv verschlechtert. Auf nationaler Ebene ist in vielen Ländern eine Drogenpolitik nach dem Suchtmodell „more of the same“ in Rechtfertigungsschwierigkeiten geraten und zum Auslaufmodell geworden. Der Fall der Schweiz, wo seit 1994 eine sogenannte „Viersäulenpolitik“, die neben Repression auch auf Prävention, Therapie und Schadensminderung setzt, zeigt, wie der Verelendung von Drogenabhängigen aus den „offenen Drogenszenen“ erfolgreich entgegengewirkt werden kann. [23]

<51>

Die aufschlussreichsten und dynamischsten Prozesse spielen sich heute ganz allgemein in der pragmatischen Reorientierung der Drogenpolitik ab. Hier werden Ansätze einer Substitutionstherapie im Zeichen von harm reduction erprobt. [24] Grundlegend ist dafür die Einsicht, dass das Drogenproblem weder eine zu lösende noch eine lösbare Aufgabe ist. Diesbezüglich muss der Staat – in einem liberalen Sinne – proaktiv und selbstbewusst resignieren. Er hat nämlich gar kein Recht, Menschen zu ihrem Glück zu zwingen. Noch weniger ist er befugt, sie aus lauter gutem Willen ins Unglück zu stürzen. Über Jahrzehnte hinweg wurden mit dem ideologisch aufgerüsteten Schlachtruf einer „Lösung des Drogenproblems“ drogenabhängige Menschen dem Schwarzmarkt und damit der Rechtlosigkeit ausgeliefert und in Konsumpraktiken hineingezwungen, die eine hohe Ansteckungsgefahr aufweisen und die für eine große Zahl mit Krankheit und Tod endeten. Zugleich stärkt die Drogenprohibition in vielen, vor allem in verarmten Ländern Kräfte, die auf die Zerstörung der Staatlichkeit hinarbeiten. Der obsessive Ordnungswille in reichen Ländern und die Destruktion rechtsstaatlicher Ordnung in armen Ländern geraten so in eine desaströse und asymmetrische Wechselwirkung, die das Nord-Süd-Gefälle verstärkt.

<52>

Solche Vorgänge werden heute besser verstanden als noch vor einiger Zeit, als sie fast vollständig hinter der moralischen Nebelwand einer „drogenfreien Welt“ verschwanden. Obwohl dieser Slogan von jenen, die es nicht lassen können, hochgehalten wird und auch innerhalb der UNO immer wieder ertönt, könnte der Beginn des 21. Jahrhunderts dennoch den Übergang in eine neue Phase der Post-Prohibition markieren, in der sich die Drogenproblematik einerseits sozial diversifiziert und differenziert und andererseits entdramatisiert. Die Abkehr von einer einfältigen, manichäischen Problemstrukturierung könnte in einer positiven Feedbackschlaufe Drogen enttabuisieren, normalisieren und in die Konsumgesellschaft integrieren.

<53>

Dies wiederum würde zweifellos politische Folgen haben. Die willkürliche Unterscheidung von legalen und illegalen Drogen würde einbrechen. Die medizinisch fassbaren Probleme, die auf Drogengebrauch zurückgehen, würden ebenso selbstverständlich in eine ärztliche Behandlungspraxis integriert wie jene, die mit Bergsteigen, Badeferien und Übergewicht zusammenhängen. Gleichzeitig würden die stark aufstrebenden Präventionsbemühungen, die in verschiedensten Bereichen der Gesellschaft festzustellen sind und sich längst nicht mehr auf die Unterdrückung gesundheitsschädlicher Praktiken beschränken, sondern auf ein Enhancement, das heißt eine präventionsmedizinische Steigerung der Lebensmöglichkeiten, abzielen, das Drogenproblem neu formatieren. [25] Polizeiliche Repression würde weithin in sozialen Anpassungsdruck transformiert, wie das heute beim Tabakrauchen festzustellen ist. Damit werden Problemlagen erkennbar, die deutlich machen, dass die Abkehr von der Drogenprohibition nicht in einen ursprünglichen „freien Zustand“ zurückführt.

<54>

Die angedeutete Entwicklung birgt allerdings mehr Potenziale für einen selbstbestimmten Umgang mit Drogen als eine Politik, welche Drogenkonsumenten zu Sündenböcken erklärt und sie exemplarisch abstraft. Wer dies als Verlust an Lebensspannung wertet und an außerordentlichen Existenzentwürfen festhalten möchte, wer den Willen zu transzendentalem Erleben nicht aufgibt und weiterhin durch den Hunger nach Ergriffenheit getrieben wird, wer zudem den faszinierenden Drogenschreckgespenstern nachtrauert, die im 19. Jahrhundert die Poeten der Bohème und die Polizisten vom Dienst gleichermaßen beschworen haben, dem bleibt frei gestellt, sich mit Erfahrungsdrogen durch die „Pforten der Wahrnehmung“ aus der postheroischen Gesellschaft der Gegenwart in ungeahnte psychedelische Welten katapultieren zu lassen. Diese Freiheit konnte auch das Prohibitionsregime des 20. Jahrhunderts nie zunichte machen.

Autor:

Prof. Dr. Jakob Tanner
Universität Zürich
Historisches Seminar
Forschungsstelle für Sozial- und Wirtschaftsgeschichte
Rämistrasse 64
CH – 8001 Zürich
jtanner@hist.uzh.ch


[1] Für einen Überblick vgl. Richard P. Davenport-Hines: The Pursuit of Oblivion. A Global History of Narcotics, New York 2002. Grundlegend sind auch: Thomas Hengartner / Christoph Maria Merki (Hg.): Genussmittel. Ein kulturgeschichtliches Handbuch, Frankfurt a.M. 1999; Sebastian Scheerer / Irmgard Vogt (Hg.): Drogen und Drogenpolitik. Ein Handbuch, Frankfurt a.M. / New York 1989; Gisela Völger unter Mitarbeit von Karin von Welck und Aldo Legnaro (Hg.): Rausch und Realität. Drogen im Kulturvergleich, 3 Bde, Köln 1985; Wolfgang Schivelbusch: Das Paradies, der Geschmack und die Vernunft. Eine Geschichte der Genussmittel, München / Wien 1980; zur aktuellen Entwicklung vgl. Günter Amendt: No drugs no future: Drogen im Zeitalter der Globalisierung, Hamburg / Wien 2003.

[2] Peter von Matt: Die tintenblauen Eidgenossen. Über die literarische und politische Schweiz, München / Wien 2001, 9-11. Der Autor hält diese Aussagen für transnational generalisierungsfähig.

[3] Jacques Derrida: Rhétorique de la drogue, in: L’esprit des drogues. Autrement. Série mutations. No. 106, April 1989, 197-214.

[4] Gregory Austin: Die europäische Drogenkrise des 16. und 17. Jahrhunderts, in: Gisela Völger u.a. (Hg.): Rausch und Realität, I, 1982, 115–133; Annerose Menninger: Genuss im kulturellen Wandel: Tabak, Kaffee, Tee und Schokolade in Europa (16.-19. Jahrhundert), 2. Aufl., Stuttgart 2008.

[5] Vgl. dazu unter anderen Arthur Waley: The Opium War Through Chinese Eyes, London 1958; Chang Hsin-Pao: Commissioner Lin and the Opium War, Cambridge 1964; Peter W. Fay: The Opium War, 1840-1842: Barbarians in the Celestial Empire in the Early Part of the Nineteenth Century and the War by Which They Forced Her Gates Ajar, Chapel Hill 1975; Chung Tan: China and the Brave New World: a Study of the Origins of the Opium War 1840-42, Durham, N.C. 1978; Keith McMahon: The Fall of the God of Money: Opium Smoking in Nineteenth-Century China, Lanham / Oxford 2002.

[6] Paul C. Winther: Anglo-European Science and the Rhetoric of Empire: Malaria, Opium, and British Rule in India, 1756-1895, Lanham 2003; David Anthony Bello: Opium and the Limits of Empire: Drug Prohibition in the Chinese interior, 1729-1850, Cambridge 2005; Yangwen Zheng: The Social Life of Opium in China, Cambridge 2005.

[7] Vgl. Alain Ehrenberg / Patrick Miignon (Hg.): Drogues, politique et société, Paris 1992; David T. Courtwright: Forces of Habit: Drugs and the Making of the Modern World, 3. Aufl., Cambridge 2001; Geoffrey Harding: Opiate Addiction, Morality and Medicine. From Moral Illness to Pathological Disease, New York 1988.

[8] Die Darstellung der beiden folgenden Abschnitte folgt stark der Publikation: Renée Renggli / Jakob Tanner: Das Drogenproblem. Geschichte, Erfahrungen, Therapiekonzepte, Berlin / Heidelberg / New York 1994, 92ff.

[9] Elmer C. Sandmeyer: The Anti-Chinese Movement in California, Urbana 1939; Roger Daniels: Asian America. Chinese and Japanese in the United States since 1850, Seattle / London 1988.

[10] Albert Wissler: Die Opiumfrage. Eine Studie zur weltwirtschaftlichen und weltpolitischen Lage der Gegenwart, Jena 1931, 154f.

[11] Zu diesem Aspekt, der auch für die Schweiz von Bedeutung war, vgl. Jakob Tanner: Rauschgiftgefahr und Revolutionstrauma. Drogenkonsum und Betäubungsmittelgesetzgebung in der Schweiz der 1920er Jahre, in: Sebastian Brändli u.a. (Hg.): Schweiz im Wandel. Studien zur neueren Gesellschaftsgeschichte, Basel 1990, 397-416.

[12] Charles E. Terry / Pellens Mildred: The Opium Problem, New York 1928.

[13] David T. Courtwright: Dark Paradise. Opiate Addiction in America before 1940, Cambridge, Massachusetts. 1982. Vgl. auch ders.: Addicts who survived. An oral history of narcotic use in America, 1923-1965, Knoxville, Tennessee 1989.

[14] Vgl. Louise Elisabeth Eisenlohr: International Narcotic Control, London / Wokin, 1934; Peter Lowes: The Genesis of International Narcotic Control, Genf 1966; Arnold H. Taylor: American Diplomacy and the Narcotic Traffic, 1900-1939: A Study in International Humanitarian Reform, Durham N.C. 1969; David F. Musto: The American Disease: Origins of Narcotic Control, New Haven 1973. Kritischer sind: Arnold S. Trebach / Kevin B. Zeese (Hg.): Drug Prohibition and the Conscience of Nations, Washington 1990. Einen alternativen Ansatz am Beispiel der Alkoholprohibition entwickelt Joseph R. Gusfield: Symbolic Crusade: Status Politics and the American Temperence Movement, Urbana 1963. Auf dieser Argumentationslinie siehe auch: Michael Woodiwiss: Crime, Crusades and Corruption: Prohibitions in the United States 1900-1987, London 1988.

[15] Zur Geschichte der Hanfprohibition vgl. Jack Herer: Die Wiederentdeckung der Nutzpflanze Hanf, Cannabis Marihuana, Frankfurt a.M. 1997 (mit einer Kurzstudie vom Katalyse-Institut für angewandte Umweltforschung e.V, hg. von Mathias Bröckers); Hans-Georg Behr: Von Hanf ist die Rede: Kultur und Politik einer Droge, Frankfurt a.M. 2000.

[16] Vgl. dazu etwa Rudolf Gelpke: Vom Rausch im Orient und Okzident, Stuttgart 1966.

[17] Auf die lange Tradition von Hanf als Heilmittel weist hin: Christian Rätsch: Hanf als Heilmittel. Eine ethnomedizinische Bestandsaufnahme, Solothurn / Wien 1992.

[18] Über diese rechtlichen Aspekte informiert (bis Ende der 1980er Jahre) Francis Caballero: Droit de la drogue, Paris 1989.

[19] Vgl. unter anderen Pino Arlacchi: Mafiose Ethik und der Geist des Kapitalismus. Die unternehmerische Mafia, Frankfurt a.M. 1989; Observatoire géopolitique des drogues (OGD): Der Welt-Drogen-Bericht: ein Jahresbericht, München 1993; Alain Labrousse / Alain Wallon (Hg.): Der Planet der Drogen. Analyse einer kriminellen Weltmacht, Frankfurt a.M. 1996; Loretta Napoleoni: Die Zuhälter der Globalisierung: über Oligarchen, Hedge Fonds, ’Ndrangheta’, Drogenkartelle und andere parasitäre Systeme, München 2008; aus globalpolitischer Perspektive: Surya Narayan Yadav: Terrorism, Drug-Trafficking and Organised Crime: Challenges for International Peace and Security, New Delhi 2009. Konsumenten und Kleinhändler behandelt Bernd Werse (Hg.): Drogenmärkte: Strukturen und Szenen des Kleinhandels, Frankfurt a.M. / New York 2008.

[20] Zorka Domic: L’Etat Cocaïne. Science et politique de la feuille à la poudre, Paris 1992.

[21] Vgl. die kritische und zugleich ernüchternde Analyse von Andreas Bummel: Eine Ideologie am Ende: Die globale Drogenprohibition (26.06.2004) http://www.heise.de/tp/r4/artikel/17/17708/1.html <8.11.2009>.

[22] Aufschlussreiche Informationen dazu bietet Manfred Kappeler: Drogen und Kolonialismus. Zur Ideologiegeschichte des Drogenkonsums, Frankfurt a.M. 1991.

[23] Für die neuere Entwicklung und die Perspektiven in der Schweiz vgl. Bundesamt für Gesundheit (Hg.): Die Drogenpolitik der Schweiz (MaPaDro III). Drittes Maßnahmenpaket des Bundes zur Verminderung der Drogenprobleme (MaPaDro III) 2006-2011 http://www.bag.admin.ch/shop/00035/00204/index.html?lang=de <8.11.2009>.

[24] Schon früh für eine pragmatische Orientierung der Drogenpolitik plädierte Stephan Quensel: Drogenelend. Cannabis, Heroin, Methadon: für eine neue Drogenpolitik, Frankfurt a.M. 1982; vgl. auch ders.: Mit Drogen leben – Erlaubtes und Verbotenes, Frankfurt a.M. 1985. Zur aktuellen Diskussion um die Substitutionspolitik vgl. Jakob Tanner: Drogen, Abhängigkeit und Substitution: historischer Rückblick und Überlegungen zur aktuellen Situation, in: Abhängigkeiten, 2007, 6-21.

[25] Sheila M. Rothman / David J. Rothman: The Pursuit of Perfection. The Promise and Perils of Medical Enhancement, New York 2003; Linda F. Hogle: Enhancement Technologies and the Body, in: Annual review of anthropology 34 (2005), 695-716.

LAAM, or levo-alpha-acetyl-methadol, is a synthetic opioid used in the treatment of opioid addiction. Approved in 1993 by the U.S. Food and Drug Administration, LAAM is considered to be similar to methadone in its effects, which include analgesia, sedation and respiratory depression. LAAM is indicated for use in the treatment and maintenance of opioid dependence, most often when patients don’t benefit from other replacement therapies such as methadone and buprenorphine. Because of its long-acting formula, LAAM is taken 2-3 times per week, whereas methadone is a daily treatment. Doses are administered in approved medical facilities and take-home doses are prohibited under federal regulations. It works by creating a cross-tolerance to other opiates, blocking the euphoric effects and controlling drug cravings.

Laam substitution Therapy For Opiate Dependence

Narcotic maintenance therapy, or substitution therapy, came about in the late 1960s to early 1970s in response to escalating use of heroin. Interest in expanding available programs was heightened when cases of HIV, AIDS, tuberculosis and hepatitis skyrocketed among intravenous drug users who shared needles. Many experts believe that providing maintenance therapies will help to curb problems associated with drug use, including crime, disease, unemployment, child neglect and homelessness.

Laam Addiction, Warnings and Side Effects

LAAM can be highly addictive and is considered a Schedule II controlled substance in the U.S. The federal Drug Enforcement Agency classifies drugs based on their potential to be habit-forming and to lead to abuse. Tolerance and dependence can set in quickly with repeated use. This makes LAAM susceptible to illicit use and diversion. It is dangerous – potentially fatal- to mix LAAM with drugs like benzodiazepines, alcohol, sleeping pills, antidepressants or other opiates. Mixing pills can lead to sedation, drowsiness, unconsciousness and death. Side effects when used as prescribed could include body aches, flu-like symptoms, hot flashes, abdominal pain, constipation, dry mouth, diarrhea, vomiting, nausea, abnormal dreams, anxiety, depression, headaches, insomnia, rash, sweating and blurred vision.

Laam Withdrawal And Treatment For Opiate Addiction

Opiate addiction is a chronic problem with a high rate of relapse. Using an opiate to treat an opiate addiction may work for some, but is not effective for everyone. Detoxing from narcotics can cause extreme anxiety and severe withdrawal symptoms if not approached properly. Withdrawal symptoms associated with opiate addiction include cramps, spasms, diarrhea, yawning, vomiting, flu-like symptoms, cold sweats, aches, agitation, anxiety, insomnia and nightmares. Medically-supervised detox programs are often recommended to help wean users from dangerous opiates. Rapid detox programs have also been gaining ground in recent years, treating opiate addiction quickly, while eliminating the painful withdrawal phase.

LAAM maintenance vs methadone maintenance for heroin dependence

LAAM may be more effective at reducing heroin dependence than methadone, but it is associated with adverse effects, some of which may be life-threatening

Opiate drugs are used to help people reduce their dependence on heroin (an opiate drug). Methadone needs daily doses, but the effects do not last 24 hours for many people. A dose of LAAM (levomethadyl acetate hydrochloride) works for two or three days. LAAM is not as widely available internationally as methadone, and may be withdrawn from the market because of concerns about life-threatening effects on the heart. The review found that LAAM is more effective than methadone at reducing heroin dependence, but there was not enough evidence from trials to draw conclusions about safety.

LAAM

The National institute of Drug Abuse is currently testing LAAM, levo-alpha-acetylmethadol-hydrochloride, a synthetic new opiate substitute, for use in heroin-addiction treatment.

LAAM is a white, crystalline, soluble, morphine-Tike compound, a central-nervous-system depressant being investigated , as a longer-lasting alternative to methadone currently the most widespread treatment for addiction. The drug is as highly addictive as methadone, but experts are generally in agreement that opiate addiction-can be stemmed only by the substitution of: another addiction.

At present, a reformed junkie undergoing treatment must report to a methadone clinic once a day to receive his „medicine,“ while a LAAM patient’s dose can last up to seventy-two hours. This time factor is he big advantage of` LAAM. The drug produces a cross-tolerance to other- opiates: Shooting up while taking LRAM will .be a waste of the addict’s time and money, since ll of heroin’s euphoric effect will be blocked. As it is taken‘ orally, LAAM eliminate& the dangerous side effects of needle use. Another important factor is that the drug: suppresses the users uncontrollable desire: for heroin and other. opiates both during he time he is addicted and after he has been detoxified. LRAM takes effect about two to six hours after ingestion, blocking potential withdrawal symptoms. In about two weeks the patient is effectively weaned from heroin to LAAM, without discomfort.

Scientists believe infrequent cases of LAAM overdose may actually be due to multi-drug use. Alcohol and LAAM are like oil and water, not to be mixed under. any circumstances. People with low narcotics tolerance are also potential LAAM overdose cases. No illicit street sale of the drug has yet been reported. Indeed, there may never be a thriving black market in LAAM, even if it does become widely dispensed, since it lacks the one. ingredient the drug user seeks-it won’t get him high. The drug’s sustained, level effect makes the addict simply feel „normal.“ Patients do not feel sedated or euphoric, and preliminary findings :indicate they seem to be more alert than those taking methadone.

Since the addict has to visit his drug clinic for LAAM only three times a week, psychological dependency on daily heroin or methadone use is reduced, allowing for alteration of previously established negative drug behavior patterns: He begins to feel like a member‘ of the drug-free world, although present indications are that he will have to be maintained on LAAM indefinitely. He does not have to take the drug home on weekends, since the effect of a dose lasts from Friday to Monday. This factor may minimize potential abuse and diversion of LAAM to the illicit market.

Side effects vary from person to person. Mild sweating, constipation, anxiety, insomnia, and nausea have been reported sporadically. Since LAAM’s effect on pregnancy and childbearing is unknown, all six thousand test subjects thus far have been male.

If LAAM’s viability as a long-lasting, effective narcotic alternative‘ is ultimately proved, treatment of addiction may become more economical and efficient. Three times the number of addicts could be treated in existing drug centers at one third the expense of methadone therapy.

LAAM’s main advantage over heroin is its legal, although restricted, status. LAAM’s primary advantage over methadone is the necessity for less frequent administration. The junkie can trade the expensive and socially disruptive monkey on his back for the apparently safe, convenient, and free drug LAAM.

Orlaam
(levomethadyl acetate hydrochloride)

Due to its potential for serious and possibly life-threatening, proarrhythmic effects, LAAM should be reserved for use in the treatment of opiate-addicted patients who fail to show an acceptable response to other adequate treatments for opiate addiction, either because of insufficient effectiveness or the inability to achieve effective dose due to intolerable adverse effects from those drugs (see WARNINGS and Contraindications ).

Cases of QT prolongation and serious arrhythmia (torsade de pointes) have been observed during post-marketing treatment with ORLAAM. Based on these reports, all patients should undergo a 12-lead ECG prior to administration of ORLAAM to determine if a prolonged QT interval (QTc greater than 430 [male] or 450 [female] ms) is present. If there is a prolonged QT interval, ORLAAM should NOT be administered. For patients in whom the potential benefit of ORLAAM treatment is felt to outweigh the risks of potentially serious arrhythmias, an ECG should be performed prior to treatment, 12-14 days after initiating treatment, and periodically thereafter, to rule out any alterations in the QT interval.

ORLAAM should be administered with extreme caution to patients who may be at risk for development of prolonged QT syndrome (e.g., congestive heart failure, bradycardia, use of a diurectic, cardiac hypertrophy, hypokalemia, or hypomagnesemia).

ORLAAM is metabolized to active metabolites by the cytochrome P450 isoform, CYP3A4. Therefore, the addition of drugs that induce this enzyme (such as rifampin, phenobarbital, and phenytoin) or inhibit this enzyme (such as ketoconazole, erythromycin, and saquinavir) could increase the levels of parent drug or its active metabolites in a patient that was previously at steady-state, and this could potentially precipitate serious arrhythmias, including torsade de pointes (see PRECAUTIONS , Drug Interactions ).

CONDITIONS FOR DISTRIBUTION AND USE OF ORLAAM (42 CFR Part 8)

ORLAAM, used for the treatment of opiate addiction, shall be dispensed only by Opioid Treatment Programs (OTPs) certified by SAMHSA under 42 CFR Part 8, and registered by the Drug Enforcement Administration under 21. U.S.C. 823(g)(1). This does not preclude the maintenance or detoxification treatment of a patient who is hospitalized for medical conditions other than opiate addiction and who requires temporary maintenance for concurrent opiate addiction during the critical period of the patients hospitalization. Failure to abide by these requirements may result in injunction precluding operation of the program, revocation of the program approval, and possible criminal prosecution.

ORLAAM has no recommended uses outside of the treatment of opiate addiction.

 

DRUG DESCRIPTION

ORLAAM (brand of levomethadyl acetate hydrochloride) is a synthetic opiate agonist. Chemically, it is levo-alpha-6- dimethylamino-4, 4-diphenyl-3-heptyl acetate hydrochloride, C 23 H 31 NO 2 · HCl. It is also known as levo-alpha-acetyl-methadol hydrochloride (LAAM).
The compound is a white crystalline powder, soluble in water (>15 mg/mL), ethanol, and methyl ethyl ketone. The octanol:water partition coefficient of LAAM is 405:1 at physiologic pH. Doses of ORLAAM (LAAM) are always expressed as the weight of the hydrochloride salt (molecular weight 389.95).

ORLAAM is an aqueous solution which is diluted for oral administration. Each one mL of ORLAAM contains: Levomethadyl acetate hydrochloride (LAAM) 10 mg. Inactive ingredients: Methylparaben, propylparaben, hydrochloric acid and water.

Last reviewed on RxList: 12/8/2004

NDICATIONS

ORLAAM is indicated for the management of opiate dependence. ORLAAM should be reserved for the use in treatment of opiate-addicted patients who fail to show an acceptable response to other adequate treatments for opiate addiction, either because of insufficient effectiveness or the inability to achieve effective dose due to intolerable adverse effects from those drugs (see Black Box Warning ).

 

DOSAGE AND ADMINISTRATION

ORLAAM produces opioid effects and a high degree of opioid tolerance that inhibits drug-seeking behavior and blocks the euphoria produced by the usual doses of heroin. The dose of ORLAAM in each patient should be adjusted to achieve the optimal therapeutic benefit with acceptable adverse opioid effects (see INDIVIDUALIZATION OF DOSAGE ).

ORLAAM must always be diluted before administration, and should be mixed with diluent prior to dispensing. To avoid confusion between prepared doses of ORLAAM and methadone, the liquid used to dilute ORLAAM should be a different color from that used to dilute methadone in any specific clinic setting.

ORLAAM DOSING

Dosing Schedules

ORLAAM is usually administered three times a week, either on Monday, Wednesday and Friday, or on Tuesday, Thursday and Saturday. If withdrawal is a problem during the 72-hour inter-dose interval, the preceding dose may be increased. In some cases, an every-other-day schedule may be appropriate (see INDIVIDUALIZATION OF DOSAGE ).

The usual doses of ORLAAM must not be given on consecutive days because of the risk of fatal overdose. No dose mentioned in this label is ever meant to be given as a daily dose (see WARNINGS ).

INDUCTION

The initial dose of ORLAAM for street addicts should be 20 to 40 mg. Each subsequent dose, administered at 48- or 72-hour intervals, may be adjusted in increments of 5 to 10 mg until a pharmacokinetic and pharmacodynamic steady-state is reached, usually within 1 or 2 weeks (see INDIVIDUALIZATION OF DOSAGE ).

Patients dependent on methadone may require higher initial doses of ORLAAM. The suggested initial 3-times-a-week dose of ORLAAM for such patients is 1.2 to 1.3 times the daily methadone maintenance dose being replaced. This initial dose should not exceed 120 mg and subsequent doses, administered at 48- or 72-hour intervals, should be adjusted according to clinical response.

Most patients can tolerate the 72-hour inter-dose interval during the induction period. Some patients may require additional intervention (see INDIVIDUALIZATION OF DOSAGE ). If additional opioids are required, and the patient is not eligible or appropriate for take home doses of ORLAAM, supplemental methadone in small doses should be given rather than giving ORLAAM on two consecutive days. Take-home doses of ORLAAM and methadone always pose a risk in this setting and physicians should carefully weigh the potential therapeutic benefit against the risk of diversion.

In some cases, where the degree of tolerance is unknown, patients can be started on methadone to facilitate more rapid titration to an effective dose, then converted to ORLAAM after a few weeks of methadone therapy.

The crossover from methadone to ORLAAM should be accomplished in a single dose; complete transfer to ORLAAM is simpler and preferable to more complex regimens involving escalating doses of ORLAAM and decreasing doses of methadone.

Dosage should be carefully titrated to the individual; induction too rapid for the patient’s level of tolerance may result in overdose. Serious hazards, as seen in association with all narcotic analgesics, are respiratory depression and, to a lesser extent, circulatory depression.

MAINTENANCE

Most patients will be stabilized on doses in the range of 60 to 90 mg, 3-times-a-week. Doses as low as 10 mg and as high as 140 mg three times a week have been given in clinical studies.

Supplemental dosing over the 72-hour inter-dose interval (weekend) is rarely needed. For example, if a patient on a Mon./Wed./Fri. schedule complains of withdrawal on Sundays, the recommended dosage adjustment is to increase the Friday dose in 5 to 10 mg increments up to 40% over the Mon./Wed. dose or to a maximum of 140 mg.

Most patients do not experience withdrawal during the 72-hour inter-dose interval after reaching pharmacological steady-state with or without adjustment of the Friday dose. If additional opioids are required, and the patient is not eligible or appropriate for take home doses of ORLAAM, small doses of supplemental methadone should be given rather than giving ORLAAM on two consecutive days. Take-home doses of ORLAAM and methadone always pose a risk in this setting and physicians should carefully weigh the potential therapeutic benefit against the risk of diversion (see

DOSAGE AND ADMINISTRATION

).

If withdrawal symptoms persist after adjustment of dose, consideration may be given to every-other-day dosing if clinic hours permit. If the clinic is not open seven days a week and every-other day dosing is not practical, the patient’s schedule may be adjusted so the 72-hour interval occurs during the week and the patient can come to the clinic to receive a supplemental dose of methadone (see INDIVIDUALIZATION OF DOSAGE ).

The maximum total amount of ORLAAM recommended for any patient is 140-140-140 mg or 130-130-180 mg on a thrice-weekly schedule or 140 mg every other day.

TAKE-HOME DOSES

If it is determined that a patient is responsible in handling opioid drugs then ORLAAM take-home doses are permitted. Refer to 42 CFR Part 8 for specific restrictions.

REINDUCTION AFTER AN UNPLANNED LAPSE IN DOSING

Following a lapse of one ORLAAM dose:

  1. If a patient comes to the clinic to be dosed on the day following a missed scheduled dose (misses Monday, arrives Tuesday), the regular Monday dose should be administered on Tuesday, with the scheduled Wednesday dose administered on Thursday and the Friday dose given on Saturday. The patient’s regular schedule may be resumed the following Monday (misses Wednesday, receives the regular dose on Thursday and Saturday, and returns to the regular Monday/Wednesday/Friday dosing schedule the next week).
  2. If a patient misses one dose and comes to the clinic on the day of the next scheduled dose (misses Monday, arrives Wednesday), the usual dose will be well tolerated in most instances, although a reduced dose may be appropriate in selected cases.

Following a lapse of more than one ORLAAM dose:

Patients should be reinducted at an initial dose of 1/2 or 3/4 their previous ORLAAM dose, followed by increases of 5 to 10 mg every dosing day (48- or 72-hours intervals) until their previous maintenance dose is achieved. Patients who have been off of ORLAAM treatment for more than a week should be reinducted.

TRANSFER FROM ORLAAM TO METHADONE

Patients maintained on ORLAAM may be transferred directly to methadone. Because of the difference between the two compounds‘ metabolites and their pharmacological half-lives, it is recommended that methadone be started on a daily dose at 80% of the ORLAAM dose being replaced; the initial methadone dose must be given no sooner than 48 hours after the last ORLAAM dose. Subsequent increases or decreases of 5 to 10 mg in the daily methadone dose may be given to control symptoms of withdrawal or, less likely, symptoms of excessive sedation, in accordance with clinical observations.

DETOXIFICATION FROM ORLAAM

There is a limited experience with detoxifying patients from ORLAAM in a systematic manner, and both gradual reduction (5 to 10% a week) and abrupt withdrawal schedules have been used successfully. The decision to discontinue ORLAAM therapy should be made as part of a comprehensive treatment plan (see INDIVIDUALIZATION OF DOSAGE ).

SAFETY AND HANDLING

ORLAAM is a solution of a potent narcotic (LAAM). There are no known specific hazards associated with dermal and aerosol exposure to ORLAAM. In case of accidental dermal exposure, promptly remove contaminated clothing and rinse the affected skin with cool water.

Sales of ORLAAM are restricted to clinics that have received training in its use. Since ORLAAM can be potentially dangerous if diverted, appropriate security measures should be taken to safeguard stock of ORLAAM as required by 21 CFR 1301.74.

Orlaam Side Effects & Drug Interactions

 

SIDE EFFECTS

Physicians should be alert to palpitations, syncope, or other symptoms suggestive of episodes of irregular cardiac rhythm in patients taking ORLAAM and promptly evaluate such cases (see WARNINGS , Effects on Cardiac Conduction ).

Heroin or Methadone Withdrawal Reactions

Patients presenting for ORLAAM treatment are frequently in withdrawal from heroin or other opiates. They may display typical withdrawal symptoms which should be differentiated from ORLAAM’s side effects. Patients may exhibit some or all of the following signs and symptoms associated with withdrawal from opiates: lacrimation, rhinorrhea, sneezing, yawning, perspiration, gooseflesh, fever, chilliness alternating with flushing, restlessness, irritability, insomnia, weakness, anxiety, depression, dilated pupils, tremors, tachycardia, abdominal cramps, body aches, anorexia, nausea, vomiting, diarrhea, and weight loss. Control of such symptoms is a primary goal of therapy. However, because of the slow onset and long half-lives of ORLAAM, nor-LAAM and dinor-LAAM, overly aggressive increases in dosage to control these withdrawal symptoms with ORLAAM may result in overdose (see INDIVIDUALIZATION OF DOSAGE ).

Signs and Symptoms of ORLAAM Excess

The interaction between the development and maintenance of opioid tolerance and ORLAAM dose can be complex. Dose reduction is recommended in cases where patients develop signs and symptoms of excessive ORLAAM effect, characterized by complaints of „feeling wired“, poor concentration, drowsiness, and possibly dizziness on standing.

ORLAAM Withdrawal

Patients may experience withdrawal symptoms (nasal congestion, abdominal symptoms, diarrhea, muscle aches, anxiety) over the 72-hour dosing interval if the dose of ORLAAM is too low. This may be managed as described under INDIVIDUALIZATION OF DOSAGE , but physicians should be alert to the possible need for dose or dose schedule adjustments if patients complain of weekend withdrawal symptoms in the last day of the 72-hour dosing interval.

Adverse Reactions on Stable Therapy

The following adverse events were observed in the 25-site, 623-patient usage study in male and female opiate addicts (see CLINICAL TRIALS ). These signs and symptoms were reported during the second and third months of treatment with ORLAAM, and were considered severe enough to require medical evaluation. In this study, both questionnaires and spontaneous reports were used to gather information. Questionnaire-elicited symptom frequencies were about five times as frequent as the spontaneous reporting frequencies given below.

Incidence greater than 1%, Probably Causally Related

Body as a Whole Asthenia * , back pain, chills, edema, hot flashes (males 2:1), flu syndrome and malaise (11%).

Gastrointestinal Abdominal pain * , constipation * , diarrhea, dry mouth, nausea and vomiting.

Musculoskeletal Arthralgia *

Nervous System Abnormal dreams, anxiety, decreased sex drive, depression, euphoria, headache, hypesthesia, insomnia (9.1%), nervousness * , somnolence.

Respiratory Cough, rhinitis, and yawning.

Skin/appendages Rash, sweating * .

Special Senses Blurred vision.

Urogenital Difficult ejaculation * , impotence * .

*Reactions in 3-9% of patients; reactions in 1-3% are unmarked.

Incidence less than 1%, Probably Causally Related

Cardiovascular Postural hypotension.

Musculoskeletal Myalgia.

Special Senses Tearing.

Causal Relationship Unknown

These reactions were reported with low frequency in controlled and uncontrolled studies of LAAM, are not known to be causally related to the administration of the drug, and are provided as alerting information for physicians.

Cardiovascular Hypertension

Hepatic Hepatitis and abnormal liver function tests.

Urogenital Amenorrhea, pyuria.

The following adverse reactions have been reported in the post-marketing setting (all reactions in less than 1% of patients).

Body as a Whole Altered hormone level, chest pain.

Cardiovascular QT interval prolongation, torsade de pointes, cardiac arrest, ST segment elevation, ventricular tachycardia, myocardial infarction, angina pectoris, syncope, migraine.

Nervous System Convulsions, confusion, hallucination, incoordination, amnesia.

Respiratory Apnea, dyspnea.

Urogenital Breast enlargement.

DRUG DEPENDENCE

ORLAAM is a Schedule II controlled substance under the Federal Controlled Substances Act. ORLAAM produces dependence of the morphine-type and has potential for abuse. Tolerance and physical dependence will develop upon repeated administration. As with methadone and any other narcotic administered to narcotic addicts, ORLAAM is at risk for diversion and illicit use, and should be handled accordingly (see WARNINGS ).

DRUG INTERACTIONS

No interaction studies have been performed in humans. ORLAAM is metabolized by the cytochrome P450 isoform, CYP3A4. The addition of drugs that induce this enzyme could increase the levels of active metabolites in a patient that was previously at steady-state.

Potentially Arrhythmogenic Agents Any drug known to have the potential to prolong the QT interval should not be used together with ORLAAM. Possible pharmacodynamic interactions can occur between ORLAAM and potentially arrhythmogenic agents such as class I or III antiarrhythmics, antihistamines that prolong the QT interval, antimalarials, calcium channel blockers, neuroleptics that prolong the QT interval, and antidepressants

Caution should be used when prescribing concomitant drugs known to induce hypokalemia or hypomagnesemia as they may precipitate QT prolongation and interact with ORLAAM. These would include diuretics, laxatives and supraphysiological use of steroid hormones with mineralocorticoid potential.

Polydrug and Alcohol Abusers Patients who are known to abuse sedatives, tranquilizers, propoxyphene, antidepres-sants, benzodiazepines, and alcohol should be warned of the risk of serious overdose if these substances are taken while on ORLAAM maintenance.

Interaction with Narcotic Antagonists, Mixed Agonists/Antago-nists, Partial Agonists, and Pure Agonists As with other mu agonists, patients maintained on ORLAAM may experience withdrawal symptoms when administered pure narcotic antagonists, such as naloxone, naltrexone, and nalmefene, or when administered mixed agonists/antagonists or partial agonists such as pentazocine, nalbuphine, butorphanol, and buprenorphine.

In addition, agonists such as meperidine and propoxyphene, which are N-demethylated to long-acting, excitatory metabolites, should not be used by patients taking ORLAAM because they would be ineffective unless given in such high doses that the risk of toxic effects of the metabolites becomes unacceptable.

Anesthesia and Analgesia Patients receiving ORLAAM will develop a similar level of tolerance for opioids as patients receiving methadone. Anesthetists and other practitioners should be prepared to adjust their management of these patients accordingly.

Other Drug Interactions The anti-tuberculosis drug rifampin has been found to produce a marked (50%) reduction in serum methadone levels, leading to the appearance of symptoms of withdrawal in well-stabilized methadone maintenance patients. Similar effects on serum methadone levels have been observed for carbamazepine, phenobarbital, and phenytoin. The presumed mechanism for this effect is the induction of methadone metabolizing enzymes. Since ORLAAM is metabolized into a more active metabolite, nor-LAAM, administration of these drugs may increase ORLAAM’s peak activity and/or shorten its duration of action.

Conversely, drugs like erythromycin, cimetidine, and anti-fungal drugs like ketoconazole that inhibit hepatic metabolism, may slow the onset, lower the activity, and/or increase the duration of action of ORLAAM. Caution and close observation of patients receiving these drugs are advised to allow early detection of any need to adjust the dose or dosing interval.

Orlaam Warnings & Precautions

 

WARNINGS

Due to its potential for serious and possibly life-threatening, proarrhythmic effects, LAAM should be reserved for use in the treatment of opiate-addicted patients who fail to show an acceptable response to other adequate treatments for opiate addiction, either because of insufficient effectiveness or the inability to achieve effective dose due to intolerable adverse effects from those drugs (see  

WARNINGS

and Contraindications ).

Cases of QT prolongation and serious arrhythmia (torsade de pointes) have been observed during post-marketing treatment with ORLAAM. Based on these reports, all patients should undergo a 12-lead ECG prior to administration of ORLAAM to determine if a prolonged QT interval (QTc greater than 430 [male] or 450 [female] ms) is present. If there is a prolonged QT interval, ORLAAM should NOT be administered. For patients in whom the potential benefit of ORLAAM treatment is felt to outweigh the risks of potentially serious arrhythmias, an ECG should be performed prior to treatment, 12-14 days after initiating treatment, and periodically thereafter, to rule out any alterations in the QT interval.

ORLAAM should be administered with extreme caution to patients who may be at risk for development of prolonged QT syndrome (e.g., congestive heart failure, bradycardia, use of a diurectic, cardiac hypertrophy, hypokalemia, or hypomagnesemia).

ORLAAM is metabolized to active metabolites by the cytochrome P450 isoform, CYP3A4. Therefore, the addition of drugs that induce this enzyme (such as rifampin, phenobarbital, and phenytoin) or inhibit this enzyme (such as ketoconazole, erythromycin, and saquinavir) could increase the levels of parent drug or its active metabolites in a patient that was previously at steady-state, and this could potentially precipitate serious arrhythmias, including torsade de pointes (see

PRECAUTIONS

, Drug Interactions ).

CONDITIONS FOR DISTRIBUTION AND USE OF ORLAAM (42 CFR Part 8)

ORLAAM, used for the treatment of opiate addiction, shall be dispensed only by Opioid Treatment Programs (OTPs) certified by SAMHSA under 42 CFR Part 8, and registered by the Drug Enforcement Administration under 21. U.S.C. 823(g)(1). This does not preclude the maintenance or detoxification treatment of a patient who is hospitalized for medical conditions other than opiate addiction and who requires temporary maintenance for concurrent opiate addiction during the critical period of the patients hospitalization. Failure to abide by these requirements may result in injunction precluding operation of the program, revocation of the program approval, and possible criminal prosecution.

ORLAAM has no recommended uses outside of the treatment of opiate addiction.

Administration of ORLAAM on a daily basis has led to excessive drug accumulation and risk of fatal overdose.

ORLAAM has only been studied on a thrice-weekly or every-other-day dosing regimen.

Any decision to administer ORLAAM more frequently than every other day for any reason should be approached with extreme caution. Even then only very small doses (5 to 10 mg) should be considered.

Risk of Overdose

Analysis of some of the deaths from overdose observed in the development of ORLAAM has shown that when ORLAAM is diverted into channels of abuse, the uninformed addict can become impatient with the slow onset of ORLAAM (2 to 4 hours) and take illicit drugs, resulting in a potentially lethal combined overdose when the peak ORLAAM effect develops. Due to these risks of diversion and accidental death, ORLAAM has been approved for use only when dispensed by a licensed facility.

Effects on Cardiac Conduction

ORLAAM has been shown to prolong the ST segment of the electrocardiogram in beagle dogs dosed five days a week, and to inhibit the rapidly-activating delayed rectifier current I Kr in isolated myocytes in vitro . Serial EKGs performed in a human pharmacokinetics study showed a prolongation of the QTc interval in some patients which was not associated with dose.

Cases of QT prolongation and severe arrhythmias (torsade de pointes) have been observed during post-marketing treatment with ORLAAM. Based on these reports, all patients should undergo a 12-lead ECG prior to administration of ORLAAM to determine if a prolonged QT interval (QTc greater than 430 [male] or 450 [female] ms) is present. If there is a prolonged QT interval, ORLAAM should NOT be administered. For patients in whom the potential benefit of ORLAAM treatment is felt to outweigh the risks of potentially severe arrhythmias, an ECG should be performed prior to treatment and 12-14 days after initiating treatment, and periodically thereafter to rule out any alterations in the QT interval.

ORLAAM should be administered with extreme caution to patients who may be at risk for development of prolonged QT syndrome (e.g., congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia, or hypomagnesemia).

ORLAAM is metabolized to active metabolites by the cytochrome P450 isoform, CYP3A4. Therefore the addition of drugs that induce this enzyme (such as rifampin, phenobarbital, and phenytoin) or inhibit this enzyme (such as ketoconazole, erythromycin, and saquinavir) could increase the levels of parent drug or its active metabolites in a patient that was previously at steady-state, and this could potentially precipitate severe arrhythmias, including torsade de pointes (see

PRECAUTIONS

, Drug Interactions ).

Use of Narcotic Antagonists

In an individual receiving ORLAAM, the administration of the usual dose of a narcotic antagonist may precipitate an acute withdrawal syndrome. The severity of this syndrome depends on the dose of the antagonist administered and the patient’s level of physical dependence. Narcotic antagonists should be used in patients receiving ORLAAM only if needed. If a narcotic antagonist is used to treat respiratory depression in the physically dependent patient, it should be administered with care and titration should begin with much smaller-than-usual doses (0.1 to 0.2 mg recommended). If the desired effect is not achieved, escalating doses may be administered every 2 to 3 minutes. If a cumulative dose of 10 mg of naloxone has been given without effect, further administration is unlikely to be of benefit (see OVERDOSAGE ).

If the patient does respond to narcotic antagonists, physicians should remember that naloxone has a much shorter duration of action than ORLAAM. Such patients should remain under prolonged observation rather than being allowed to leave emergency treatment, since ORLAAM’s action will outlast naloxone-induced reversal, putting the unsupervised patient at risk of relapse, a return of respiratory depression and possible death if continuing medical attention is not available. Use of other parenteral opioid antagonists may be appropriate in some cases, but only if the dosage of such drugs can be readily titrated. Oral naltrexone would not be appropriate for the treatment of ORLAAM overdose, as it has been associated with the precipitation of prolonged opioid withdrawal symptoms when used in overdose settings.

Warnings to Patients

Patients must be warned that the peak activity of ORLAAM is not immediate, and that use or abuse of other psychoactive drugs, including alcohol, may result in fatal overdose, especially with the first few doses of ORLAAM, either during initiation of treatment or after a lapse in treatment. 

Cases of QT prolongation and serious arrhythmia (torsade de pointes) have been observed during post-marketing treatment with ORLAAM. If a patient taking ORLAAM experiences symptoms suggestive of an arrhythmia (such as palpitations, dizziness, lightheadedness, syncope, or seizures), that patient should seek medical attention immediately.

Use in High Risk Patients

Suicide attempts with opiates, especially in combination with tricyclic antidepressants, alcohol, and other CNS active agents, are part of the clinical pattern of addiction. Although outpatient therapy with ORLAAM and other drugs of this class is usually associated with a reduction in the risk of suicide, such risk is not eliminated. Individualized evaluation and treatment planning, including hospitalization, should be considered for patients who continue to exhibit uncontrolled drug use and persistent high-risk behavior despite adequate pharmacotherapy.

PRECAUTIONS

Initial Administration and Dosage Adjustment

Due to the long half-lives of ORLAAM and its metabolites, patients will not feel the full effects of the medication for at least several days. Consequently, extra care is needed when starting patients on ORLAAM and when making initial dosage adjustments (see INDIVIDUALIZATION OF DOSAGE and DOSAGE AND ADMINISTRATION ).

Use in Ambulatory Patients

Initiation of therapy or excessive doses of ORLAAM may impair the mental and/or physical abilities required for performance of potentially hazardous tasks, such as driving a car or operating machinery. Patients should be warned not to engage in such activities if their alertness and behavior are affected. Most patients show no detectable impairment of ordinary tasks on ORLAAM therapy.

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of increased intracranial pressure. Furthermore, narcotics produce side effects that may make it difficult to evaluate the clinical course of patients with head injuries. In view of LAAM’s profile as a mu agonist, it should be used with extreme caution and only if deemed essential in such patients.

Asthma and Other Respiratory Conditions

ORLAAM, as with other opioids, should be used with caution in patients with asthma, in those with chronic obstructive pulmonary disease or cor pulmonale, and in individuals with a substantially decreased respiratory reserve, preexisting respiratory depression, hypoxia, or hypercapnea. In such patients, even usual therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.

Special Risk Patients

Opioids should be given with caution and at reduced initial dose in certain patients, such as the elderly or debilitated and those with significant hepatic or renal dysfunction, hypothyroidism, Addison’s Disease, prostatic hypertrophy, or urethral stricture.

Acute Abdominal Conditions

As with other mu agonists, treatment with ORLAAM may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Drug Interactions

No interaction studies have been performed in humans. ORLAAM is metabolized by the cytochrome P450 isoform, CYP3A4. The addition of drugs that induce this enzyme could increase the levels of active metabolites in a patient that was previously at steady-state.

Potentially Arrhythmogenic Agents Any drug known to have the potential to prolong the QT interval should not be used together with ORLAAM. Possible pharmacodynamic interactions can occur between ORLAAM and potentially arrhythmogenic agents such as class I or III antiarrhythmics, antihistamines that prolong the QT interval, antimalarials, calcium channel blockers, neuroleptics that prolong the QT interval, and antidepressants

Caution should be used when prescribing concomitant drugs known to induce hypokalemia or hypomagnesemia as they may precipitate QT prolongation and interact with ORLAAM. These would include diuretics, laxatives and supraphysiological use of steroid hormones with mineralocorticoid potential.

Polydrug and Alcohol Abusers Patients who are known to abuse sedatives, tranquilizers, propoxyphene, antidepres-sants, benzodiazepines, and alcohol should be warned of the risk of serious overdose if these substances are taken while on ORLAAM maintenance.

Interaction with Narcotic Antagonists, Mixed Agonists/Antago-nists, Partial Agonists, and Pure Agonists As with other mu agonists, patients maintained on ORLAAM may experience withdrawal symptoms when administered pure narcotic antagonists, such as naloxone, naltrexone, and nalmefene, or when administered mixed agonists/antagonists or partial agonists such as pentazocine, nalbuphine, butorphanol, and buprenorphine.

In addition, agonists such as meperidine and propoxyphene, which are N-demethylated to long-acting, excitatory metabolites, should not be used by patients taking ORLAAM because they would be ineffective unless given in such high doses that the risk of toxic effects of the metabolites becomes unacceptable.

Anesthesia and Analgesia Patients receiving ORLAAM will develop a similar level of tolerance for opioids as patients receiving methadone. Anesthetists and other practitioners should be prepared to adjust their management of these patients accordingly.

Other Drug Interactions The anti-tuberculosis drug rifampin has been found to produce a marked (50%) reduction in serum methadone levels, leading to the appearance of symptoms of withdrawal in well-stabilized methadone maintenance patients. Similar effects on serum methadone levels have been observed for carbamazepine, phenobarbital, and phenytoin. The presumed mechanism for this effect is the induction of methadone metabolizing enzymes. Since ORLAAM is metabolized into a more active metabolite, nor-LAAM, administration of these drugs may increase ORLAAM’s peak activity and/or shorten its duration of action.

Conversely, drugs like erythromycin, cimetidine, and anti-fungal drugs like ketoconazole that inhibit hepatic metabolism, may slow the onset, lower the activity, and/or increase the duration of action of ORLAAM. Caution and close observation of patients receiving these drugs are advised to allow early detection of any need to adjust the dose or dosing interval.

Information for Patients

Patients should be provided the patient package insert for ORLAAM if they are new to the drug, and in addition should be advised that:

ORLAAM, unlike methadone, is not to be taken daily, and daily use of the usual doses will lead to serious overdose.

If a patient taking ORLAAM experiences symptoms suggestive of an arrhythmia (such as palpitations, dizziness, light-headedness, syncope, or seizures), that patient should seek medical attention immediately.

ORLAAM is slow acting and patients should be alerted to the risk of abusing any psychoactive drug, including alcohol, while on ORLAAM therapy. This is particularly important during the first 7 to 10 days of treatment, before ORLAAM has had time to exert its full pharmacologic effect.

In addition to being warned of the delay in onset of ORLAAM, patients who are transferring from ORLAAM to methadone should be informed that they should wait 48 hours after the last dose of ORLAAM before ingesting their first dose of methadone or other narcotic (see DOSAGE AND ADMINISTRATION ).

Patients should inform their adult family members that, in the event of overdose, the treating physician or emergency room staff should be told that the patient is being treated with ORLAAM, a long-acting opioid which is likely to outlast naloxone-induced reversal and which requires prolonged observation and careful monitoring. In addition, the treating physician or emergency room staff should be informed that the patient is physically dependent on narcotics and that naloxone should be administered with care so as to minimize any precipitated abstinence syndrome.

As with most mu agonists, ORLAAM may interact with other CNS depressants and should be used with caution, and in reduced dosage, in patients concurrently receiving other narcotic analgesics, antihistamines, benzodiazepines, phenothiazines or other major tranquilizers, anxiolytics, sedative-hypnotics, tricyclic antidepressants, and other CNS depressants, including alcohol. Patients should be warned of the importance of reporting the use of any of these compounds to their physicians, as serious side effects could result, including respiratory depression, hypotension, profound sedation or coma.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Two-year carcinogenicity studies with LAAM in rats at 13 mg/kg (77 mg/m 2 ) and in mice at 30 mg/kg (90 mg/m 2 ) given orally in the diet did not show carcinogenic changes. LAAM is not mutagenic in the Ames test, the unscheduled DNA synthesis and repair test, mouse lymphoma cells in vitro, or chromosomal aberration tests in rats in vivo. LAAM tested positive in the forward mutation assay in N. crassa at 150 µg/mL in vitro and in the heritable translocation assay in mice at 21 mg/kg (63 mg/m 2 ). The clinical significance of these findings is not known.

Chronic treatment with LAAM at 80 mg three times a week did not produce chromosomal aberrations in peripheral human lymphocytes. Effects of LAAM on fertility in animals has not been fully evaluated.

Use in Pregnancy: Pregnancy Category C

Animal reproduction studies are not complete and there are no clinical data on the safety of ORLAAM in pregnancy. For these reasons, ORLAAM is not recommended for use in pregnancy. Women who may become pregnant should be advised of the risks of ORLAAM therapy and of the desirability of discontinuing ORLAAM prior to a planned pregnancy.

If a female patient becomes pregnant on ORLAAM despite these precautions, it is recommended she be transferred to methadone for the remainder of the pregnancy (see TRANSFER FROM ORLAAM TO METHADONE , in DOSAGE AND ADMINISTRATION ). If it appears wiser to continue a specific patient on ORLAAM, the physician should be alert to possible respiratory depression of the newborn and other perinatal complications (see Labor and Delivery ).

Labor and Delivery

The effects of ORLAAM on labor and delivery are not known. Like other mu agonist opioids, however, ORLAAM is expected to produce respiratory depression and a possible neonatal dependence syndrome with a delayed emergence of withdrawal symptoms. Use of ORLAAM in labor and delivery is not recommended unless, in the opinion of the treating physician, the potential benefits outweigh the possible hazards.

Nursing Mothers

The effects of LAAM on infants of nursing mothers have not been studied. It is not known if LAAM is excreted in human milk in sufficient concentration to affect an infant. Use of ORLAAM in nursing mothers is not recommended unless, in the opinion of the treating physician, the potential benefits outweigh the possible hazards.

Pediatric Use

The use of ORLAAM in addicts under 18 years of age has not been studied. Its use is not recommended.

Orlaam Overdosage & Contraindications

 

OVERDOSE

Signs and Symptoms

All but a few cases of ORLAAM overdose have involved multiple drugs. Overdose on ORLAAM alone is rare and has always been the result of too frequent (daily) dosing. Overdose is primarily of concern in persons not tolerant to opiates, since in such individuals a dose of 20 to 40 mg of ORLAAM may cause somnolence, and a larger initial dose may cause serious overdose. Tolerant individuals will generally not show symptoms unless higher doses are administered.

In ORLAAM overdose, as with other mu agonist opioids, the following signs and symptoms should be anticipated: respiratory depression (decrease in respiratory rate and/or tidal volume, Cheyenne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, maximally constricted pupils, skeletal muscle flaccidity, cold and clammy skin, bradycardia, and hypotension. In severe overdose, apnea, circulatory collapse, pulmonary edema, cardiac arrest and death may occur.

Treatment

In the case of ORLAAM overdose, protect the patient’s airway and support ventilation and circulation. Absorption of ORLAAM from the gastrointestinal tract may be decreased by gastric emptying and/or administration of activated charcoal. (Safeguard the patient’s airway when employing gastric emptying or administering charcoal in any patient with diminished consciousness). Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion are unlikely to be beneficial for ORLAAM overdose due to its high lipid solubility and large volume of distribution.

In managing ORLAAM overdose, the physician should consider the possibility of multiple drugs, the interaction between drugs, and any unusual drug kinetics in the patient. Naloxone may be given to antagonize opiate effects, but the airway must be secured as vomiting may ensue. If possible, naloxone should be titrated to clinical effect rather than given as a large single bolus, since rapid reversal of opioid effects by large naloxone doses can cause severe precipitated withdrawal effects that may include cardiac instability. If a patient has received a total of 10 mg of naloxone without clinical response, the diagnosis of opioid overdose is unlikely.

If the patient does respond to naloxone, the physician should remember that the duration of ORLAAM activity is much longer (days) than that of naloxone (minutes) and repeated dosing with or continuous intravenous infusion of naloxone is likely to be required. Use of oral naltrexone in this setting is not recommended because it may precipitate prolonged opioid withdrawal symptoms (see Use of Narcotic Antagonists ).

CONTRAINDICATIONS

ORLAAM is contraindicated in patients with known or suspected QT prolongation (QTc interval greater than 430 [male] or 450 [female] ms). This would include patients with congenital long QT syndrome, or conditions which may lead to QT prolongation (see WARNINGS, Effects on Cardiac Conduction ) such as: 1) clinically significant bradycardia (less than 50 bpm), 2) any clinically significant cardiac disease, 3) treatment with Class I and Class III anti-arrhythmics, 4) treatment with monoamine oxidase inhibitors (MAOI’s), 5) concomitant treatment with other drug products known to prolong the QT interval (see PRECAUTIONS , Drug Interactions ), and 6) electrolyte imbalance, in particular hypokalemia and hypomagnesemia.

ORLAAM is contraindicated in patients with known hypersensitivity to LAAM.

ORLAAM is not recommended for any use other than for the treatment of opioid dependence (see WARNINGS ).

Orlaam Clinical Pharmacology

CLINICAL PHARMACOLOGY

LAAM is a synthetic opioid agonist with actions qualitatively similar to morphine (a prototypic mu agonist) and affecting the central nervous system (CNS) and smooth muscle. Principal actions include analgesia and sedation. Tolerance to these effects develops with repeated use. An abstinence syndrome generally occurs upon cessation of chronic administration similar to that observed with other opiates, but with slower onset, more prolonged course, and less severe symptoms.

LAAM exerts its clinical effects in the treatment of opiate abuse through two mechanisms. First, LAAM cross-substitutes for opiates of the morphine-type, suppressing symptoms of withdrawal in opiate-dependent individuals. Second, chronic oral administration of LAAM can produce sufficient tolerance to block the subjective „high“ of usual doses of parenterally administered opiates.

LAAM is metabolized by N-demethylation to nor-LAAM and dinor-LAAM, which are also opioid agonists. These metabolites are more potent than the parent drug. The opioid effect which occurs when LAAM is administered is slower in onset and longer in duration (72 hours) than that of methadone (24 hours). This extended duration of action allows three-times-weekly administration (see CLINICAL TRIALS ).

PHARMACODYNAMICS

The duration of action of a single dose of LAAM is due to the sum of the opioid activity of the parent drug and its metabolites. A single dose of orally administered LAAM has an onset of opioid effects averaging 2 to 4 hours after ingestion and a duration of action of 48 to 72 hours (as measured by pupillary constriction and suppression of abstinence signs). LAAM cross-substitutes for opiates like morphine in opiate-dependent individuals, suppressing symptoms of withdrawal from these compounds. Single oral doses of 30 to 60 mg of LAAM eliminate signs of abstinence for 24 to 48 hours in individuals maintained on high doses of morphine who are abruptly withdrawn. At higher doses (80 mg and above), suppression of withdrawal can increase to 48 to 72 hours in most individuals.

Repeated oral administration of LAAM can produce sufficient tolerance to block the effects of parenterally administered opiates. Chronic oral administration of 70 to 100 mg of LAAM three times weekly produces tolerance which blocks the „high“ of a 25 mg dose of intravenously administered heroin for up to 72 hours; maintenance on lower doses (50 mg) of LAAM produces only partial blockage for the same period.

PHARMACOKINETICS

Absorption

LAAM is rapidly absorbed from an oral solution. Plasma levels are detectable within 15 to 30 minutes after ingestion and reach their peak within 1.5 to 2 hours at steady-state. LAAM undergoes first-pass metabolism to its demethylated metabolite nor-LAAM, which is sequentially N-demethylated to dinor-LAAM. Both metabolites are active and contribute to the extent and duration of ORLAAM’s clinical activity (see PHARMACODYNAMICS ).

Pharmacokinetic Model

The steady-state pharmacokinetics of LAAM were modeled from a study in 25 healthy adult addicts using three-times-a-week dosing over a 15-day observation period. LAAM and its metabolites were found to follow a multi-compartment model with extensive tissue distribution (Vd ~ 20 L/kg). LAAM had a clearance of about 0.22 L/kg/hr, mostly by conversion to nor-LAAM. Kinetic studies of the pure metabolites in man have not yet provided accurate estimates of their clearance in the absence of the precursor, but the half-lives observed in this study were 2.6 days for LAAM, approximately 2 days for nor-LAAM, and approximately 4 days for dinor-LAAM.

The pharmacokinetic model used to estimate steady-state plasma levels for each subject in this study assumed a common 3 mg/kg/wk dosage regimen (0.94 mg/kg on Mon. and Wed., 1.125 mg/kg on Fri.). The estimates (which fit the observed data with a correlation of better than 0.95) revealed a large inter-patient variability. There was at least a 5-fold range in peak plasma concentrations for LAAM and its metabolites across the 25 subjects over the 72-hour interval from Friday to Monday on a 3-times-a-week dosage regimen. Table 1 contains these estimates of peak and trough plasma concentrations of LAAM, nor-LAAM, and dinor-LAAM.

View Enlarged Table

Table 1: Peak and Trough Estimated Steady-State Plasma Concentrations
During the 72 Hour Interval (Friday to Monday) for a 65-kg Patient
Given 3 mg/kg/Week on Mon./Wed./Fri.
LAAM
Mean (CV)
Nor-LAAM
Mean (CV)
Dinor-LAAM
Mean (CV)
Cmax(ng/mL) *
204 (34%) 173 (34%) 114 (28%)
Cmin(ng/mL) **
36 (62%) 85 (58%) 96 (34%)
*Following Friday Morning Dose
**Prior to Monday Morning Dose

Metabolism and Elimination

The cyctochrome P450 isoform, CYP3A4, plays a major role in the metabolism of LAAM. As noted above, the formation of nor-LAAM and dinor-LAAM is by sequential demethylation, such that dinor-LAAM is formed from nor-LAAM, not directly from LAAM. While N-demethylation is the primary route of metabolism, minor pathways of elimination include direct excretion and deacetylation to methadol, nor-methadol, and dinor-methadol.

Special Populations

Gender An analysis of the data from the above study showed some difference in the plasma clearance of LAAM in 8 females versus 17 males. Males showed a trend toward a slower conversion of LAAM to nor-LAAM, which may alter the plasma concentration profile of LAAM and its active opioid metabolites. Although this effect was much smaller than the observed inter-individual differences, physicians should be alert to a possible gender difference (see INDIVIDUALIZATION OF DOSAGE ).

Hepatic and Renal Disease At the present time no pharmacokinetics studies have been carried out in subjects with clinically significant hepatic insufficiency or serious renal impairment. Since both the pharmacokinetics and pharmacodynamics of opiate agonists may be altered in these subjects, and any additional risks of ORLAAM therapy are not well understood in such patients, physicians may choose to manage such patients with methadone due to its simpler metabolic profile.

CLINICAL TRIALS

ORLAAM has been studied in 2666 street addicts and 3319 methadone maintenance patients, including 5697 males and 288 females. During the course of 27 studies, 4610 patients received orally administered ORLAAM for up to three years in thrice-weekly doses ranging from 10 to 140 mg. Twenty-one studies provide the primary evidence upon which the dosing recommendations for ORLAAM are based.

The vast majority of patients who received ORLAAM were treated on a thrice-weekly basis, typically on Mondays, Wednesdays and Fridays (Mon./Wed./Fri.), although every-other-day dosing schedules were used in some settings. Most of the sites dosing patients with LAAM on a 3-times-a-week (Mon./Wed./Fri. or Tues./Thurs./Sat.) schedule increased the dose prior to the 72-hour inter-dose interval by 20 to 40% to obtain coverage for the full 72 hours.

In controlled clinical trials, treatment with ORLAAM was found to be comparable to treatment with methadone with respect to reduction in use of illicit opioids. ORLAAM doses in the range of 60 to 100 mg 3-times-a-week reduced the average frequency of urine samples positive for opiates to 15-20%, as did therapy with 50 to 100 mg a day of methadone. There was a trend for more patients to drop out of ORLAAM therapy than methadone therapy in the first 4 weeks of treatment (16% dropouts for ORLAAM v. 12% for methadone), but the dropout rates for both treatments rapidly declined and both were in the range of 1 to 2% per week for the remaining patients by the third month of the studies. Global ratings of patient acceptability and response to treatment were similar for both LAAM and methadone.

In the Phase III studies, ORLAAM tended to be more effective in patients perceived by staff to benefit from a reduced frequency of clinic visits and less effective in patients perceived as needing the added support of daily clinic visits.

Four independent studies were concerned with other research objectives, including induction regimens, methadone-to-ORLAAM (and ORLAAM-to-methadone) crossover ratios, and detoxification. This research involved 800 adults (including 11 females), approximately 440 of whom were methadone maintenance patients. The results of these studies, as well as the results of a nationwide Phase III usage study of 623 patients (including 204 females) in 25 representative clinics across the country, are reflected in the dosing recommendations.

INDIVIDUALIZATION OF DOSAGE

ORLAAM is intended for use as part of a comprehensive treatment plan for narcotic dependence of the opioid type. Supplying narcotic drugs to narcotic addicts for the treatment of addiction without appropriate medical evaluation, treatment planning, and counseling has not been shown to be effective, and is a violation of the law except in special circumstances.

The therapeutic goal early in treatment with ORLAAM is to reduce illicit opioid use. The dose of ORLAAM should be chosen and adjusted as needed to provide a dose that is high enough to suppress drug withdrawal, illicit drug seeking and usage, and related high-risk behavior. If opioid side effects persist once illicit drug use is controlled, the dose of ORLAAM may require further adjustment later in treatment to minimize adverse effects.

Physicians should be alert to patient differences in levels of opioid tolerance and inter-patient variability in the absorption, distribution and metabolism of both ORLAAM and its metabolites. As with methadone, an important contribution to continued abuse of illicit drugs is an inadequate dose of the treatment medication.

Initial dosage adjustment with ORLAAM is complex due to its delayed onset of action. If the starting dose is too high or if the dose is escalated too rapidly for the patient’s level of tolerance, symptoms characteristic of excessive opioid effect may occur, i.e., poor concentration, sedation, and orthostatic hypotension. Patients should be watched for such symptoms, and the dose should be lowered if they appear. In rare instances, serious symptoms of narcotic overdosage may occur, leading to profound CNS and respiratory depression.

ORLAAM and its metabolites quickly accumulate to toxic levels if the doses intended for 3-times-a-week dosing are given too frequently. The recommended doses are intended for every-other-day or 3-times-a-week dosing and should not be given daily.

The recommended initial dose for patients with low or unknown tolerance to opioids is 20 to 40 mg three-times-a-week or every-other-day. Successive doses may be increased by 5 to 10 mg. At least two weeks are needed to achieve a clinical plateau after a dosage adjustment. Adjustment to a dosing schedule is dependent upon the rate at which an individual develops tolerance to the increasing level of ORLAAM (and its metabolites) as well as the time required for ORLAAM and its metabolites to accumulate to steady-state levels.

The goal of dosage titration is to suppress narcotic withdrawal while avoiding excessive opioid effects due to the build-up of long-acting metabolites. It may be safer to provide extra counseling and support rather than to attempt to completely suppress a patient’s withdrawal or narcotic hunger during the first week or two of therapy. On the other hand, there is the ever-present danger that patients who receive sub-therapeutic starting doses will supplement with street drugs, resulting in overdose. Patients should be strongly warned against this practice. Later in the titration process, dosage adjustments are better made on a weekly basis whenever possible.

For patients on methadone maintenance whose level of tolerance is known, the recommended initial dose of ORLAAM is 1.2 to 1.3 times the patient’s daily dose of methadone, not to exceed 120 mg. Care should be taken not to adjust the dose too frequently thereafter (usually 5 to 10 mg changes every second or third dose) since increasing the dose too rapidly may result in oversedation.

One major advantage of ORLAAM therapy is reduction in need for daily clinic visits and for take-home medication. In some patients, ORLAAM may not provide adequate suppression of withdrawal for a full 72 hours. For such individuals, several therapeutic options are available: (1) extra support and an explanation of reasons for the effect, (2) increasing the dose given prior to the 72-hour interval, (3) switching to an every-other-day dosing schedule, (4) dispensing a supplemental methadone dose.

Most patients do not experience withdrawal during the 72-hour inter-dose interval after reaching pharmacological steady-state with or without adjustment of the Friday dose. If additional opioids are required, and the patient is not eligible or appropriate for take home doses of ORLAAM, small doses of supplemental methadone should be given rather than giving ORLAAM on two consecutive days. Take-home doses of ORLAAM and methadone always pose a risk in this setting and physicians should carefully weigh the potential therapeutic benefit against the risk of diversion (see DOSAGE AND ADMINISTRATION ).

Patients should receive extra support and counseling and be warned against supplementing with street drugs as they make the switch from methadone to ORLAAM. The variability in the clearance of LAAM, nor-LAAM, and dinor-LAAM and clinical experience suggest that there will be a small number of patients who require either lower or higher doses than those recommended.

DURATION OF ORLAAM THERAPY

There is no information from controlled clinical trials as to the appropriate duration of ORLAAM therapy. There are reports from investigators that some patients on ORLAAM may experience less variation in opioid effects and have less drug craving than with methadone, so ORLAAM should be considered for patients who need long-term maintenance during social and vocational rehabilitation.

When a patient has eliminated illicit drug use, achieved social and occupational stability, and made lifestyle changes to reduce the risk of relapse, consideration may be given to discontinuation of ORLAAM therapy. Such a decision should be carefully considered as part of an individualized treatment plan. Stable long-term ORLAAM therapy is preferable to repeated cycles of premature discontinuation of medication followed by relapse to uncontrolled addiction.

A patient is most likely to remain abstinent if discontinuation of medication is attempted after the achievement of behavioral objectives and is accompanied by appropriate non-pharmacological support. The rate of dose reduction should vary according to patient’s response. Discontinuation of ORLAAM therapy for administrative reasons or because of adverse reactions to the drug should be managed as described below under DOSAGE AND ADMINISTRATION .

Orlaam Medication Guide

PATIENT INFORMATION

Patients should be provided the patient package insert for ORLAAM if they are new to the drug, and in addition should be advised that:

ORLAAM, unlike methadone, is not to be taken daily, and daily use of the usual doses will lead to serious overdose.

If a patient taking ORLAAM experiences symptoms suggestive of an arrhythmia (such as palpitations, dizziness, light-headedness, syncope, or seizures), that patient should seek medical attention immediately.

ORLAAM is slow acting and patients should be alerted to the risk of abusing any psychoactive drug, including alcohol, while on ORLAAM therapy. This is particularly important during the first 7 to 10 days of treatment, before ORLAAM has had time to exert its full pharmacologic effect.

In addition to being warned of the delay in onset of ORLAAM, patients who are transferring from ORLAAM to methadone should be informed that they should wait 48 hours after the last dose of ORLAAM before ingesting their first dose of methadone or other narcotic (see DOSAGE AND ADMINISTRATION ).

Patients should inform their adult family members that, in the event of overdose, the treating physician or emergency room staff should be told that the patient is being treated with ORLAAM, a long-acting opioid which is likely to outlast naloxone-induced reversal and which requires prolonged observation and careful monitoring. In addition, the treating physician or emergency room staff should be informed that the patient is physically dependent on narcotics and that naloxone should be administered with care so as to minimize any precipitated abstinence syndrome.

As with most mu agonists, ORLAAM may interact with other CNS depressants and should be used with caution, and in reduced dosage, in patients concurrently receiving other narcotic analgesics, antihistamines, benzodiazepines, phenothiazines or other major tranquilizers, anxiolytics, sedative-hypnotics, tricyclic antidepressants, and other CNS depressants, including alcohol. Patients should be warned of the importance of reporting the use of any of these compounds to their physicians, as serious side effects could result, including respiratory depression, hypotension, profound sedation or coma

A randomized, open-label trial comparing methadone and Levo-Alpha-Acetylmethadol (LAAM) in maintenance treatment of opioid addiction.

Wolstein J, Gastpar M, Finkbeiner T, Heinrich C, Heitkamp R, Poehlke T, Scherbaum N.

Department of Psychiatry and Psychotherapy, Rhine State Hospital, University of Duisburg-Essen, Essen, Germany.

Abstract

INTRODUCTION: Levo-Alpha-Acetylmethadol (LAAM) is a synthetic opioid analgesic with mu-agonistic activity and a long duration of action. There are several, almost exclusively US American studies showing the efficacy of LAAM as a maintenance drug which has the advantage that it needs to be administered only three times a week. LAAM is currently not marketed in EU countries due to cardiac complications. We report on the first European multi-center, parallel group, flexible dose, open-label, randomized clinical trial comparing LAAM and methadone in patients with opioid dependence.

METHODS: Eighty-four opioid addicts in ongoing maintenance treatment with stable methadone doses were treated with methadone under study conditions for 5 weeks (run-in phase), then randomly assigned to a methadone (n=41) or a LAAM (n=43) group. Study duration was 24 weeks after randomization. Objective measures (drug urine screenings, retention rate), subjective measures (symptoms of withdrawal and craving, report of substance use), and safety data were collected weekly. The main outcome criterion was the number of opiate-free urine samples per number of weeks of study participation.

RESULTS: Non-inferiority was shown for LAAM compared to methadone. Both substances were well tolerated. There were no clinical cardiac complications in either group.

DISCUSSION: Our study confirmed the results of previous investigations with LAAM as being efficacious and well tolerated in opioid dependence. A discussion to reconsider the availability of LAAM is recommended.

and div. others!

Very interesting Study,

with a Spanish- English Translation

give it a read: drug-use-and-antiretroviral-adherence-in-EN

This paper is the twenty-ninth consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning thirty years of research. It summarizes papers published during 2006 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurological disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).

2. Endogenous Opioids and Receptors

2a. Molecular-biochemical effects
This sub-section will review current developments in the molecular and biochemical characteristics of opioid peptides and receptors by subtypes: mu agonists and receptors (2a-i), delta agonists and receptors (2a-ii), kappa agonists and receptors (2a-iii), and OFQ/N and the ORL-1 receptor (2a-iv).
2a-i. Mu agonists and receptors 

Endocytosis of the MOR-1D splice variant as well as DOR and the CB1 receptor is mediated by an agonist-independent and constitutive PLD2 activation (604). Separation of MOR desensitization and internalization effects was demonstrated with endogenous receptors in primary neuronal LC cultures (40). Exons 11 and 1 promoters of the MOR gene were characterized in transgenic mice (1249). The splice variants of MOR, SV1 and SV2 do not exhibit binding to [3H] diprenorphine (212). Five single nucleotide polymorphisms were identified for the MOR promoter, and no differences in construct activity were found in control and morphine-treated animals (297). MOR-effector coupling and trafficking occurred in DRG neurons with DAMGO producing greater internalization in MOR/partial differential opioid receptors (1180). MOR-DOR functional interactions occur through receptor-G (i1) alpha fusion (1051). The poly C binding protein 1 is a regulator of the proximal promoter of the mouse MOR gene (716). There is interplay between Sps and poly C binding protein 1 on MOR gene expression (960). The neuron-restrictive silencer factor interacts with Sp3 to synergistically repress the MOR gene (577). Mitochondrial damage decreases MOR, but not DOR function in neuronal SK-N-SH cells (941). Diffusion of MOR at the surface of human neuroblastoma SH-SY5Y cells is restricted to permeable domains (990). Differences in the intracisternal A-particle element in the 3′ noncoding region of the MOR gene in CXBK mice appear to cause this relatively insensitive phenotype (446). Although 14-methoxymetopon displayed similar binding affinities for multiple splice variants of the MOR gene, its potency varied widely for the same splice variants (713). MOR activation of ERK ½ is GRK3 and arrestin dependent in striatal neurons (712). Introduction of a hydroxyl group in position 2 of the cyclohexyl residue of spiropiperidine decreased the binding affinity of mu receptors and OFQ/N (177). Morphine displays PKC-dependent and DAMGO displays GRK2-dependent mechanisms of MOR desensitization in human embryonic kidney 293 cells (529). Null and operational models of mu opioid binding in the mouse vase deferens revealed that DAMGO and DALDA were full agonists while morphine and endomorphin derivatives acted as partial agonists (967). There is direct nose-to-brain transfer of morphine after nasal administration to rats (1216). Transport is not rate-limiting in morphine glucuronidation in the single-pass perfused liver preparation (291). Greater in vitro inhibition of M6G relative to M3G formation from morphine occurred following treatment with (R)- and (S)-methadone and structurally related opioids (804). M6G was identified in chromaffin cell secretory granules (411). Mu opioid receptors are activated by Vitex agnus-castus methanol extracts (1204). Binding of [(35) S] GTPgammaS is stimulated by endomorphin-2 and morphiceptin analogs (343). An aequorin luminescence-based calcium assay gives pharmacologically-relevant data for mu and delta opioid agonists without involving radioactivity or animal tissues (344). The latter assay also indicated that D-1-Nal or D-2-Nal substitutions in position 4 of endomorphin-2 produced mu receptor antagonists, whereas substitution in position 3 produced partial agonists (346). The tripeptides, Tyr-Pro-Ala-NH2 and Tyr-Pro-Ala-OH, which do not bind to mu receptors, are potent inhibitors of endomorphin degrading enzymes in the brain (345). A partial agonistic effect of 9-hydroxycorynatheidine was observed on MOR in the guinea pig ileum (747). Synthesis, radio labeling and receptor binding was accomplished for [3H] [(1S, 2R) ACPC2] endomorphin-2 (569).
MOR, DOR and KOR binding properties were observed for 8-[N-(4′-phenyl)-phenethyl) carboxyamido] analogues of cyclazocine and ethylketocyclazocine (1214). Pharmacokinetics of morphine was slower in flounder than in trout (837). A direct and sensitive analysis of morphine, codeine and other bioactive drugs in human urine was performed by cation-selective exhaustive injection and sweeping micellar electrokinetic chromatography (671). Alkyl chain length altered mu opioid activity of 3, 6-bis {H-Tyr/H-Dmt-NH (CH2) m, n]-2(1H) pyrazinone derivatives (1031). Determination of human urinary opiates occurred with application of poly (methacrylic acid-ethylene gycol dimethacrylate) monolith micro extraction coupled with capillary zone electrophoresis (1207). Urinary excretion of morphine and codeine occurred following the administration of single and multiple doses of opium preparations prescribed in Taiwan as “brown mixture” (680). There are natural heroin impurities derived from tetrahydrobenzylisoquinoline alkaloids (1128). [Sar2] endomorphin-2 was almost equipotent to the parent peptide in mu opioid receptor binding, and was highly resistant to enzymatic degradation (512). Morphine-3-O-propionyl-6-O-sulfate had four times greater affinity than morphine at the MOR (248). Mu opioid binding can be detected in a competitive displacement assay using a beta-imager (916). Identification of potent phenyl imidazoles such as 4-aminocarbonyl-2, 6-dimethyl-Phe as opioid receptor agonists was completed (133). A class of 4-substituted-8-(2-phenyl-cyclohexyl)-2-8-diaza-spiro[4,5]decan-1-one inhibitors was designed achieving antagonist selectivity against the mu opioid and ORL1 receptors (15) that show improved metabolic stability (16) and superior pharmacological and pharmacokinetic properties (17). Chimeric peptides containing a mu opioid receptor ligand and an ORL-1 receptor ligand, Ac-RYYRIK-amide were synthesized (560). Derivatives of 14-aminomorphinones with substitution in the aromatic ring of cinnamoylaminomorphinones and codeinones produced potent mu agonists (844).
A novel mu opioid antagonist was created by replacement of the N-terminal tyrosine residue in opioid peptides containing 3-(2, 6-dimethyl-4-carbamoylphenyl) propanoic acid (Dcp) results in a novel mu opioid antagonist (701). Lysine at the C-terminus of the Dmt-Tic opioid pharmacophore produced new lead compounds in the formation of opioid peptidomimetics (57). Multiple ligands from Dmt-Tic and morphinan pharmacophores produced agonists with MOR, KOR and DOR properties (836). Whereas maximal stimulation of [35S]GTPgammaS binding decreased in canine thalamic and spinal cord homogenates for mu > ORL1 > kappa > delta opioid compounds, cortical homogenates showed an affinity order of kappa > ORL1 > delta > mu (650). Morphine increased 5HT, Na (+), K (+)-ATPase activity differentially as a function of adulthood and adolescence (432), and reduced human 5-HT3A receptors in an ondansetron assay (1225). Bivalent ligands containing homo- and heterodimeric pharmacophores at mu, delta and kappa opioid receptors were developed and synthesized in an in vitro assay (895). Potent and highly selective chiral tri-amine and tetra-amine MOR ligands were identified by lead optimization using mixture-based libraries (831). Opioid and CCK receptors also have overlapping pharmacophores required for binding affinity and biological activity (8). QSAR studies were performed upon 4-phenylpiperidine derivatives as mu opioid agonists by a neural network method (1194). A HPLC assay for morphine was developed in small plasma samples (293). Morphine concentrations in bone marrow paralleled plasma morphine concentration for up to 14 days after death in rabbits (178). Unbound concentrations of oxycodone were three times higher in brain than in blood, indicating active influx at the blood-brain barrier (118). An implantable buprenorphine delivery system was characterized using in vitro and in vivo techniques (594). Capillary electrophoresis contributed to the identification of HMOR-3O-glucide and N-oxides in hydromorphone metabolism in humans (58). STW 5 (Iberoglast) binds to intestinal 5-HT, muscarinic M3 and opioid receptors (1038). A member of the heat shock protein 40 family, hlj1, binds to the carboxyl tail of the human MOR (31).
Pre-POMC cDNA from the ostrich pituitary gland was sequenced revealing the positions for gamma-MSH, ACTH, AMSH, gamma-LPH, beta-MSH and BEND (824). PC1/3 and PC/2 gene expression and post-translational endoproteolytic POMC processing is regulated by photoperiod in the seasonal Siberian hamster (465). BEND analysis in the hypothalamus or PAG is not affected by diurnal variation (348). BEND is present in the stallion testis, but appears to be derived from POMC gene expression in the pituitary (1057). Three POMC subtype genes and subsequent peptides were identified in the pars distalis and intermedia of the barfin flounder pituitary (1101). TAN-821 and TAN-1014 have been developed respectively as agonists and antagonists of the putative epsilon receptor (368).
Histamine was released during constant rate infusion of morphine in dogs (423). Cholinergic nicotinic stimulation of endogenous morphine release occurs from lobster nerve cord (1327). Dextrorotatory morphinans inhibited alpha3beta4 nicotinic Ach receptor subunit cRNAs-induced inward currents in the presence of Ach in Xenopus oocytes (639). Myristoylated G proteins (Galphai1 and GalphaoA) were maximally activated by DAMGO, Menk and Lenk, whereas endomorphin-1 and –2 as well as BEND produced strong, but not maximal responses. Morphine, methadone, fentanyl and buprenorphine produced statistically significant activation (983). 3-aminopropionyl substituted fentanyl analogs were synthesized and displayed opioid activity (906). New hybrid derivatives of fentanyl were found to be active at the MOR and I2-imidazoline binding sites (261). Buprenorphine and norbuprenorphine display in vivo glucuronidation as determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (488). An immunalysis microplate ELISA was validated for the detection of buprenorphine and its metabolite norbuprenorphine in urine (778). Opioid disposition occurs in human sweat after controlled oral codeine administration (1003). CYP2D6-dependent formation of morphine does not exclusively explain the central effects of codeine; codeine-6-glucuronide is an additional active moiety (696). Pharmacokinetic modeling of oxycodone in sheep displayed delayed equilibration between brain and blood levels that would be affected by changes in both cerebral blood flow and blood brain barrier permeability (1164). The principal metabolic pathway of oxycodone in humans is CYP3A-mediated N-demethylation, but circulating oxidative and reductive metabolites provide a negligible contribution to central opioid effects (627). The use of PTX-insensitive Galpha mutants revealed that the potency for mu agonists was highest for cells expressing Galpha (i3) and Galpha (o) and lowest with Galpha (i1) and Galpha (i2) (228). NalBzOH displays agonist activity at MOR, DOR and KOR, but not ORL-1 receptors expressed either in a heterologous cell system or in a native environment (862). FK33–824, a mu opioid agonist decreases enzymatic activity of PKC, adenylate cyclase and PKA in porcine granulosa cells (546). The anti-opioid actions of NPVF, a NPFF agonist was observed in a decrease to opioids to voltage-gated (N-type Ca2+ currents and enhancement of muscarinic-induced intracellular Ca2+ release in SH-SY5Y cells as they do in neurons (570).
Naltrexone increased PKCepsilon, ERK and integrin alpha 7 in SH-SY5Y neuroblastoma cells (857). Long-acting naltrexone had a 1-month pharmacokinetic activity in plasma that was proportional to dose and number of treatments (302). The dissociation of [3H] naloxone was four times faster under displacement than under infinite dilution conditions, demonstrating the retention effect of receptors confined in space (1061). Naltrexone release from biodegradable microspheres produced constant rates of release culminating in 80% over 2 months (691). Two novel tripartite codrugs of naltrexone and 6beta-naltrexol with hydroxybupropion were synthesized as potential alcohol abuse and smoking cessation agents (440). Transdermal delivery of 6-beta-naltrexol was enhanced by a codrug linked to hydroxybupropion (588). MOR antagonists were synthesized and evaluated from novel octahydro-1H-pyrido [1, 2-a] pyrazine (633) and from N-substituted trans-3, 4-dimethyl-4-(3-hydroxyphenyl) piperadine (634). The permeation of nalmefene hydrochloride was better across the middle turbinate, posterior septum and superior turbinate mucosa (301).
2a-ii. Delta agonists and receptors 

Knock-in mice expressing fluorescent DOR uncovered G protein-coupled receptor dynamics in vivo (996). Simultaneous activation of DOR and the sensory neuron-specific receptor-4 hetero-oligomer by the mixed bivalent agonist BAM-22 activates the latter, but inhibits the former (132). Morphine and pain-related stimuli enhance cell surface availability of somatic DOR in rat dorsal root ganglia (393). Delta and mu opioid receptors were cloned, heterologously expressed and pharmacologically characterized from the brain of a urodele amphibian, the rough-skinned newt, Taricha granulosa (127). Adenosine A1 and A2 receptor agonists increase c-fos in striatal GABAergic Enk, but not GABAergic DYN striatal neurons as well as increasing striatal PreEnk (553). The enrichment by 18-fold with FACS robustly increased beta-arrestin-1-GFP expression associated with strong human DOR desensitization (10). A new duplicate DOR in zebra fish was characterized (911). Enk and SP are found in reduced concentrations in primary culture striatal neurons relative to adult preparations (330). The mGluRI antagonists, LY367385 and MPEP reduce NMDA-induced expression of the Pro-Enk gene in neocortex, yet enhance AMPA-induced expression of the neocortical Pro-Enk gene (674). Pro-enk was identified in the hypothalamus and striatum using a method allowing selective isolation of neuropeptides of murine brains lacking carboxypeptidase E (268). ProEnk A 119–159 is a stable ProEnk A precursor fragment identified in human circulation (323). Only the C-terminus glucose conjugate of Lenk showed transport by glucose transporters and hPepT1 (1237). Whereas only a few samples of adherent human fetal chromaffin cells expressed Menk early in vitro, almost all of the neurosphere-like colonies appearing later expressed Menk (1321). Human Menk binds to anionic phosphatidylserine in high preference to zwitterionic phosphatidylchlorine in large unilamellar vesicles (586). Lenk binds in a turn confirmation to DOR, but it is not a (14) beta-turn (108). Nasal administration of Lenk is facilitated by a thiolated polycarbophil that slows Lenk degradation (82), and reversible lipidization is preferable for the oral delivery of Lenk (1185). 6-N, N-dimethylamino-2, 3-napthalimide was identified as a new environment-sensitive probe in delta- and mu-selective opioid peptides (1149). The novel, orally active, DOR agonist, RWJ-394674 is biotransformed to the potent MOR agonist RWJ-413216 (229). Highly potent and selective phenylmorphan-based inverse agonists of the DOR were developed (1117). AUF-1 is expressed in the developing brain, binds to AT-rich double-stranded DNA, and regulates Enk gene expression (287). Design and synthesis were completed of novel hydrazide-linked bifunctional peptides as delta/mu opioid receptor agonists and CCK1/CCK2 receptor antagonists (641). Three types of latex nanoparticles carrying NTI derivatives were identified as possessing high DOR affinity (453). A new method using HPLC with electrochemical detection was developed allowing for the simultaneous measurement of Menk, Lenk, endomorphin-1 and endomorphin-2 (677).
Selective alkylation of delta-2 opioid receptors occurred following NAC 5′Nti-isothiocyanate in the NAC and ventral caudate; beta-chlornaltrexamine was nonselective for MOR and DOR in the same site (734). Distinct subcellular localization for constitutive and agonist-modulated palmitoylation of the human DOR was described (900). Pertussis-toxin abolished DPDPE-induced inhibition of forskolin-stimulated intracellular cAMP production that was rescued by Galpha (i2), but not Galpha (i3) or Galpha (o) mutants; the former, but not latter mutants co-precipitated with DOR. Long-term DPDPE treatment allowed pertussis toxin-induced elimination of naloxone-induced superactivation of adenylyl cyclase activity, an effect again rescued by Galpha (i2) mutants (1311). DPDPE, acting through Gi-coupled DOR receptors mediate phosphorylation of CPI-17 and MLC20 through preferential activation of the PI3K/ILK pathway (486). Down-regulation of the glutamate transporter EAAC1 occurred following expression and activation of the DOR and its agonist, DPDPE (1240). Genetically-engineered human mesenchymal stem cells produce Menk at augmented higher levels in vitro (1078). Lenk caused membrane currents across lipid membranes through adsorption, transportation and desorption, effects confirmed using fluorescence spectrometry and confocal laser scanning microscopy (687). DADL induces a reversible hibernation-like state in HeLa cells (1152). DADL molecules enter the cytoplasm and nucleus of LNCap cells that are devoid of opioid receptors, and binds to perichromatin fibrils where transcription and early splicing of pre-mRNAs and pre-rMRNAs occur, thereby resulting in decreased transcription and proliferation without apoptosis (59). AVP enhances PAG synthesis and secretion of Enk and BEND, but not DYN (1263).
2a-iii. Kappa agonists and receptors 

KOR activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes (141). Netrin-1 signaling regulates de novo protein synthesis of KOR by facilitating polysomal partition of its mRNA (1133). Naloxone and NBNI, but not selective mu or delta antagonists increased, whereas DYN decreased the cell surface level of the human KOR by activation-induced down-regulation and pharmacological chaperone-mediated enhancement (200). KOR affinity in a human embryonic kidney cell system indicated a rank order of cyclazocine, naltrexone, SKF10047, xorphanol, WIN44441, nalorphine, butorphanol, nalbuphine, lofentanil, dezocine, metazocine, morphine, hydromorphone and fentanyl (399). A cDNA encoding KOR in zebra fish has been cloned and characterized (27). GEC1 interacts with the kappa opioid receptor and enhances its expression (188). Big DYN, a 32-amino acid Pro-DYN peptide consisting of DYN A and DYN B showed similar selectivity for human KOR as DYN A, was less selective than DYN A for human MOR, DOR and ORL1, but activated G proteins more potently than DYN A; DYN B was less potent and selective (771). Big DYN and DYN A, but not DYN B causes leakage effects in large unilamellar phospholipid vesicles thereby causing perturbations in the lipid bilayer (490). DYN A inserts its N-terminus into the bilayer of the bicelle, whereas DYN B resides on the surface of the bilayer (673). Bikunin was identified as an endogenous inhibitor of DYN convertase in human cerebrospinal fluid (1077). Although selective opioid agonists developed for mammalian opioid receptors did not fully recognize opioid binding sites in zebra fish brain, DYN A showed good affinities in the nanomolar range (409). Pro-DYN cDNA’s were cloned in eels and tilapia (24).
NalBzOH binding is abolished in triple MOR/KOR/DOR mice, and in vivo changes reflect that of a nonselective opiate drug (235). N-substituted 4beta-methyl-5-(3-hydroxyphenyl)-7alpha-amidomorphans are potent, selective kappa opioid receptor antagonists (171). New C (4)-modified salvinorin A analogues were synthesized as KOR agonists (636). Salvinorin A analogues were also synthesized following effects of configuration at C (2) and substitution at C (18) (73) along with those isolated from Salvia divinorum (1120). Salvinorin A, a selective KOR agonist was used in a combined ligand-based and target-based drug design approach for G-protein coupled receptors (1041). A unique binding epitope was found for salvinorin A, a non-nitrogenous KOR agonist (548). Bioisosteric modification of the C-2 thioacetate isoester of salvinorin A produced a potent and selective KOR agonist (1070). The substitution of a tert-butyl with a cyclobutyl moiety in buprenorphine created a highly selective KOR agonist with low addictive potential and dependence liability (877). 3D-QSAR studies were performed upon orvinol analogs as kappa-opioid agonists (656). The extraction fraction for NAC DA in the mouse is increased following NBNI treatment (186). The application of Schild-analysis to the antagonism of U50488H by NBNI provides pharmacological evidence for KOR in Planaria (934).
2a-iv. OFQ/N and ORL-1 receptor 

OFQ/N binding to ORL-1 receptors triggers internalization of these components into vesicular compartments that is dependent on PKC and occurs selectively for N-type calcium channels (25). OFQ/N, but not partial agonists induce concentration-dependent endocytosis and recycling of the human ORL1 receptor, enhancing up regulation of adenylyl cyclase activity (1059). OFQ/N differentially activates ERK, p38 and JNK MAPK to contribute to potentiations of prostaglandin vasoconstriction after fluid percussion brain injury (38). The induction of Pro-OFQ/N mRNA by cAMP appears to be mediated by a cAMP-response element, histone acetylation and through CREB (1301). The ORL-1 receptor utilizes both G (oA) and G (oB) for signal transduction (1136). OFQ/N and its agonist, Ro64-6198 display great regional similarities in binding assays using [(35) S]-GTPgammaS binding (390). OFQ/N and DYN A analogues with Dmp substituted for N-terminal aromatic residues show ORL-1 and opioid receptor preferences (989). A novel D-proline amide class of spiropiperidines was developed as an effective ORL-1 antagonist (410). OFQ/N (113) NH2 analogues modified in the 9 and/or 13 positions were synthesized and showed biological activity (828). An enzymatically-resistant OFQ/N peptide containing a carbamic acid residue was synthesized (665). Indole derivatives were designed, synthesized and biologically evaluated as novel OFQ/N receptor antagonists (1079). Potential ORL-1 ligands were synthesized from spiro-[piperidine-4,2′(1′H)-quinazolin]-4′ (3′H)-ones and spiro-[piperidine-4,5′ (6′H)-[1,2,4]triazolo[1,5-c]quinazolines] (809). Trap-101, an achiral analogue of J-113397 was identified as a potent ORL-1 antagonist (1132). Both 3-(4-Piperidinyl) indoles and 3-(4-piperidinyl) pyrrolo-[2, 3-b] pyridines are ligands for the ORL-1 receptor (96). A series of hexapeptides with a general formula of Ac-RYY-R/K-W/I-R/K-NH (2) were identified as novel partial agonists for the ORL-1 receptor (428).
BDNF induced expression of Pro-OFQ/N mRNA’s that in turn induced expression of immediate early genes in hippocampal cultures. OFQ/N, but not nocistatin increased both neurite length and number in hippocampal cultures (954). Mature OFQ/N and nocistatin were identified in human brain and CSF (534).
2b. Neuroanatomical localization
This sub-section will review current neuroanatomical studies indicating localization of opioid peptides and receptors by subtypes: mu agonists and receptors (2b-i), delta agonists and receptors (2b-ii), kappa agonists and receptors (2b-iii), OFQ/N and ORL-1 receptor (2b-iv), and opioid-related neuroanatomy (2b-v).
2b-i. Mu agonists and receptors 

Immunohistochemical labeling of the MOR carboxy terminal splice variant mMOR-1B4 was observed in the olfactory bulb, cerebral cortex, BNST, hippocampus, habenula, amygdala, thalamus, hypothalamus, median eminence, SN, VTA, oculomotor nucleus, red nucleus raphe nuclei, PAG, LC, trigeminal nucleus reticular formation, area postrema and Purkinje and deep cerebellar nuclei (1314). Whereas acute morphine decreased MOR gene expression in the PAG, chronic morphine decreased PAG and striatal MOR and KOR gene expression in female rats (1113). MOR, KOR and DOR receptors were found in disc-shaped and stellate cells of the inferior colliculus with MOR and GABA receptors co-localized in the central nucleus, dorsal cortex and external cortex of the inferior colliculus. BEND and GABA neurons were in close proximity to each other (1126). MOR is extensively co-localized with parvalbumin, but not somatostatin, in the hippocampal dentate gyrus (299). There is a distinct distribution of DA D1 receptor and MOR-1 receptor immunoreactivities in the amygdala and interstitial nucleus of the posterior limb of the anterior commissure (508). Reciprocal connections of endomorphin-1- and endomorphin-2-containing neurons were observed between the tubural and lateral hypothalamus on the one hand, and the medial, commissural, lateral and gelatinous parts of the NTS on the other (492). Mu opioid receptors were found in nerve fibers within the bovine pineal gland, whereas delta opioid receptors were observed on nerve fibers in the pineal perivascular space and intraparenchema. DOR, MOR and Lenk were co localized in some nerve fibers (908). Whereas BEND and TH immunoreactive axon terminals of MPOA cells that project to the SFO were predominantly axo-somatic, NPY terminals were more axo-dendritic (559). POMC co-localizes with CRF in axon terminals of the noradrenergic LC (948). Fluoxetine increased mu opioid receptor expression in obese Zucker rat C/P, dentate gyrus, lateral septum, amygdala, and frontal, parietal and piriform cortices (222).
MOR possessed little overlap with preprotachykinin B in the dorsal horn of the spinal cord (917). The seizure-resistant rodents, Proechimys guyannesis, display high DAMGO binding in the medial amygdala, dorsal dentate gyrus and PAG, and decreased DAMGO binding in the anterior olfactory tubercule, cingulate cortex, thalamus, basolateral amygdala, SN and dorsal hippocampus (963). Whereas lower medial septal, but not MPOA MOR densities were lower in older reproductively senescent male Japanese quail than females or young males, DOR densities in both the medial septum and MPOA were lower in this group (871).
Heroin decreased NPFF-immunoreactivity in the NTS and reduced NPFF fibers in the median eminence, pituitary stalk and neurohypophysis, but increased NPY neurons and fibers in the thalamic PVN and BNST (279). Both morphine and methadone increased c-Fos expression in the striatum and NAC (1111). Morphine produced up-regulation of the functional expression of neurokinin-1 receptors in cortical neurons (1181). Morphine respectively reduced and increased ascorbic acid release in the striatum and NAC of rats (421). Morphine increased fMRI signals in the NAC, extended amygdala, orbitofrontal cortex, hippocampus, PAG and hypothalamus and decreased fMRI signals in the anterior cingulated gyrus in the brains of healthy volunteers (70).
2b-ii. Delta agonists and receptors 

Enk afferents from the posterior BNST and the basomedial and cortical amygdaloid nuclei innervate the medial amygdaloid nuclei whereas Enk afferents from the anterolateral BNST as well as the cortical, medial and basomedial amygdaloid nuclei innervate the central amygdaloid nucleus (920). Striatal dendrites display co-localization of DOR and dopamine D1 receptor immunoreactivity (29). Striatal projection neurons to the SN mostly possess Enk-only and SP-only cells; Enk/SP co localized neurons primarily projecting to the SN do not appear confined to striosomes (1183). Enk is found in overlapping distributions with VP, VIP, CRF, gastrin releasing peptide, calbindin and calcretin in both mouse and rat (801). SP was more robust than Enk in their broad distribution in song control nuclei of 11 different oscine species (653). Four different Enks, but not DYN is found in synovium, bone marrow, periosteum and juxta-articular bone in rat joints (79). DOR immunoreactivity was evenly distributed throughout the neuropil of the feline reticular formation, and was very dense in the ventral and central areas of cytoplasm and medium to large dendrites of the parabrachial nuclei and LC (28). L-enk and the DOR were found most predominantly in the inner spiral bundle of the guinea pig cochlea, whereas DYN and KOR were found in both the inner and outer spiral bundles (533). Menk is found in small diameter and diffusely localized neurons throughout the superficial grey and stratum opticum of the superior colliculus of the camel (767). Enk is localized in the dorsolateral septal nucleus of the fire-bellied toad, Bombina orientalis (318).
2b-iii. Kappa agonists and receptors 

Although KOR was often co-localized with MOR, small ovoid KOR-containing cells were observed in close apposition with larger MOR-containing cells in medial thalamus, PAG and brainstem (415). KOR and GAD67 immunoreactivity have been found in OFF and NEUTRAL cells in the RVM (1222). Axonal mRNA transport and localized translational regulation of KOR occur in primary neurons of the DRG (90). KORS have been localized in the lipid rafts which are micro domains of plasma membranes rich in cholesterol and sphingolipids (1250). Unprocessed DYN was much greater than co-existent DYN peptides in the axon terminals of Pro-DYN neurons projecting to the CA3 region of the hippocampus and in the striatal projections to the VTA (1253). DYN and neurokinin B are co expressed in hypothalamic arcuate neurons extending to the ME and periventricular zone with these fibers projecting to the PVN, anterior hypothalamus, MPOA, median preoptic nucleus, anteroventral periventricular nucleus and BNST (152). DYN and neurokinin B immunoreactivity are co localized in the arcuate nucleus and median eminence of the sheep (352). Dopamine D1 receptors have subcellular distributions that are conducive to interactions with Pro-DYN in the NAC shell (449). Moreover, CART is co localized with pro-DYN and DA D1 receptors in the NAC (489). Pro-DYN mRNA labeling is in the mouse olfactory tubercule, lateral septum, C/P, central amygdala, PVN, SON, LHA, VMH, lateral reticular nucleus and NTS; it is also co-localized with NPY mRNA in the arcuate nucleus (669). Long-day exposure produces greater DYN A1–17 expression in the hypothalamo-pituitary axis, ependymal cells, subcomissural organ and lateral and third brain ventricle choroid plexus in the Siberian hamster than short-day exposure (776).
2b-iv. OFQ/N and the ORL-1 receptor 

OFQ/N was immunolocalized in the rat cochlea in tunnel fibers as well as inner and outer hair cells (571). The slow rate of divergence in the amino acid of OFQ/N precursor sequences in lungfish was analyzed (638).
2b-v. Opioid-related neuroanatomy
3. Pain and Analgesia
This section has four major parts examining recent advances in: a) pain responses especially as they may relate to opioid function, b) opioid analgesia organized as a function of receptor subtypes, c) sex, age and genetic differences in opioid analgesic responses, and d) opioid mediation of other analgesic responses. 

3a. Pain responses
The following sub-sections examine work done on spinal (3a-i) and supraspinal (3a-ii) circuits respectively.
3a-i. Spinal circuits 

Nociceptive behaviors (8–24 h) outlasted spinal c-Fos increases (2 h) following skin-muscle incisions, and after 24 h, surgically-treated animals were no different from controls in c-Fos-induced increases induced by thermal stimulation. Morphine was more effective in blocking nociceptive behaviors relative to c-Fos-induced increases (1325). Hindlimb and abdominal stretches occurred during labor, and were increased by systemic oxytocin. Morphine decreased oxytocin-induced stretching responses without altering labor duration, and decreased labor-induced c-Fos elevations in lumbosacral spinal segments (175). Although MOR mechanisms are not essential in the processing of acute noxious mechanical and electrical stimuli by WDR neurons, they may play an important role in endogenous inhibitory mechanisms that regulate the development of spinal neuronal sensitization during windup (422). Absence of Reelin results in significant reductions in mechanical sensitivity and a pronounced thermal hyperalgesia and aberrant neuronal positioning of Dab-1 immunoreactivity in the dorsal spinal cord (1163). Chronic constriction injury of the saphenous nerve in rats produce significant allodynia and hyperalgesia that is sensitive to morphine gabapentin, amitryptaline and WIN55212-2 administration, that increases c-Fos as well as MOR and CB-1 receptor expression in the spinal cord, and that leads to decreased functional receptive fields downstream to the injury accompanied by A-fiber ectopic discharges (1174). Spinalized rats laminectomized in the lumbo-sacral region displayed increased multi-unit efferent discharges from the ventral root following mechanical von Frey hair mechanical stimulation of the hindpaw. During discharges and after discharges were reduced by resiniferatoxin, a potent capsaicin analogue, whereas only after-discharges were reduced by morphine, ketamine and ezlopitant (1255). Partial injury of tail-innervating nerves creates both mechanical allodynia and non-allodynia in different subgroups of rats; the former group shows greater losses of spinal MOR, whereas the latter group displays more augmented mechanical allodynia following peripheral naloxone and spinal CTOP (49).
3a-ii. Supraspinal circuits 

A rodent pain model of gynecologic surgery involving laparotomy with tonic distension of the cervix and lower uterine segment was shown to be sensitive to systemic and intrathecal morphine (1125). There are strong pharmacological correlation between the formalin test and the neuropathic pain behavior in different species with chronic constriction injury (1166). An animal model of chronic inflammatory pain using large volumes of adjuvant to the intra-articular space of the rat knee showed sensitivity to morphine, dexamethasone and ibuprofen, but different temporal sensitivity from acute models (1221). Experimental pancreatitis produced visceral pain and increased thoracic DYN content with lidocaine injections into the RVM or nucleus gracilis or spinal DYN antisera reversing its effects (1154). Transgenic mice with early-stage pancreatic cancer displayed visceral pain that was enhanced by centrally-acting, but not peripherally-acting opioid antagonists (1008). An abdominal withdrawal reflex model of visceral pain due to colorectal distension was established in a behavioral assessment in rats (1264). NRM on cells excited by colorectal distension facilitate responses to colorectal distension itself, which in turn augments excitation of NRM off cells that then act to suppress cutaneous nociception (134). Anterior cruciate ligament transaction produced experimental osteoarthritis and joint pain accompanied by increased nitrite and inducible NO synthase, effects reduced by morphine, L-NAME, indomethacin and meloxicam (174). One can differentiate between capsaicin-induced allodynia and hyperalgesia using a thermal operant assay; both effects were blocked by morphine (835). The orofacial formalin test in the mouse appears to be a strong behavioral model for studying physiology and modulation of trigeminal nociception; morphine inhibits formalin responses in both phases (702). Formalin injection directly into the knee joints of rats produced the characteristic two phases of nociception; morphine blocked both phases in a naloxone-reversible manner, whereas diclofenac and midazolam reduced only the second phase, whereas meclizine and loratadine increased the second phase (735). Experimental pain-related responses are induced by a scorpion Buthus martensi Karsch sting (52). Zymosan applied to the tibial-tarsal joint produces hypernociception elicited by articular dorsal flexion movement, an effect blocked by morphine and indomethacin (430). Animals with chronic constriction injury had free access to a light: dark chamber, and chose the less-preferred light part of the chamber following stimulation of the injured paw in the more-preferred dark chamber. Whereas morphine, gabapentin, duloxetine and 8-OH-DPAT reinstated preferences for the dark side of the chamber, gaboxadol and WIN55,212–2 did not (890). The use of calibrated forceps are a reliable tool for pain, morphine analgesia and morphine tolerance (706). Ultrasonic vocalizations occur primarily during the interphase of the formalin test, and are suppressed by morphine in a naloxone-reversible manner (863). Hairless mice fed a special diet develop atoplic-like dry skin inducing prolonged scratching that is dose-dependently blocked by naloxone, but not H1 or 5HT(1/2) antagonists (369). Administration of 2,4,6-Trinitrochlorobenzene to hairless mice produced a naltrexone- and L-NAME-reversible itch response (1138).
3b. Opioid analgesia
The following sub-sections examine advances in our understanding of opioid-mediated analgesia in the past year especially as they pertain to the opioid receptor subtypes and their genes: i) mu agonists and receptors, ii) delta agonists and receptors, iii) kappa agonists and receptors, and iv) OFQ/N and the ORL-1 receptor. A large number of studies examine either knockout or knockdown techniques to indicate roles of the receptors, and potential splice variants in opioid analgesic function. Separate paragraphs are devoted to studies in which other transmitter and peptide systems affect opioid analgesia; the effects of opioid manipulations upon analgesia induced by other peptides and transmitters are covered in Section 3d. Finally, human studies related to opioid and particularly mu receptor-mediated analgesia is covered at the end of Section 3b-v.
3b-i. Mu agonists and receptors 

MorphineA rank-order analgesic potency of morphine was observed on the paw pressure, hot-plate and tail-withdrawal tests with the lowest on the formalin test, effects independent of stimulus intensity on all tests. A within-subject cumulative dosing procedure resulted in lower ED50 values than a between-subject procedure, and the ED50 of morphine progressively increased when the cut-off value was adjusted from 4 to 5, 6, 7 and 8 standard deviations above the mean (796). Nociceptive stimulus modality-related differences occurred in pharmacokinetic-pharmacodynamic modeling of morphine in the rat such that drug effects were more effective for mechanical relative to thermal stimuli (1015). Sub-analgesic doses of DAMGO or fentanyl enhanced morphine analgesia through induction of MOR endocytosis (454). Opiate receptor-dependent analgesia is associated with several compounds bound to Gbetagamma subunits (110). The analgesic, tolerant, dependent, rewarding and sensitizing effects of morphine, but not kappa agonists were lost in mice lacking adenylyl cyclase type 5 that is highly enriched in striatum (582). Mice lacking phospholipase Cbeta1 displayed hypersensitivity to pain and reduced morphine analgesia and tolerance formation (685).

Morphine administered systemically or directly into the ACC produced a naloxone-sensitive reduction in pain affect, as demonstrated by decreased aversiveness of noxious cutaneous stimulation in nerve-damaged animals with no concomitant alteration of response to mechanical stimulation (623). NAC morphine-induced increases in thermal and mechanical hindpaw latencies were blocked by naloxone, BFNA and NBNI, but not NTI (1244). Morphine in the thalamic nucleus submedius reduced the second phase of formalin-induced evoked spinal dorsal horn nociceptive responses in a naloxone-reversible manner (1317). Microinjections into the thalamic nucleus submedius of morphine, endomorphin-1 or DADL, but not the kappa agonist, spiradoline, dose-dependently inhibited mechanical and cold allodynia induced by spinal nerve ligation, effects blocked by general and mu, but not delta antagonism (1187). Similarly, microinjections into the ventrolateral orbital cortex of morphine, endomorphin-1 or DADL, but not the kappa agonist, U-62066, dose-dependently inhibited mechanical and cold allodynia induced by spinal nerve ligation, effects blocked by general and mu, but not delta antagonism (1318).

Morphine, gabapentin and lamotrigine produced analgesia of similar potencies in attenuating capsaicin and nerve-injury-induced mechanical hypersensitivity (535). Morphine modulated potentiation of capsaicin-evoked TRPV1 responses through a cyclic AMP-dependent PKA pathway (1160). Intrathecal naloxone or CTAP blocked systemic morphine- and fentanyl-induced analgesia on mechanical measures of nociception as well as thermal responses to the hindpaw, but not forepaw (198). However, noncompetitive interactions between the opioid antagonists, CTAP and naltrexone were observed in the rat tail-withdrawal assay (1175). Morphine-associated pruritus occurred after a single extradural injection in a horse (150).

Two studies independently demonstrated that morphine-induced decreases in intraocular pressure and pupil diameter in rabbits was blocked by naloxone and partially reversed by L-NAME or L-glutathione, indicating NO involvement (111, 296). Low-dose morphine-induced hyperalgesia was blocked by PLC inhibitors (U73122) and blockers (calphostin C), also by ketamine and MK-801, and finally by AS against PLCbeta3 (378). Acute and chronic morphine increases Phase II pain-associated behaviors on the formalin test in neonatal rats after four days of abstinence (1332).

Mu Opioid Agonists 

Human opiorphin, a physiological inhibitor of Enk-inactivating zinc endopeptidases produced potent analgesia in chemical and mechanical pain models (1223). Peripherally-mediated antinociception of the mu-opioid receptor agonist 2-[(4,5alpha-epoxy-3-hydroxy-14beta-methoxy-17-methylmorphinan-6beta-yl)amino]acetic acid (HS-731) occurred after subcutaneous and oral administration in rats with carrageenan-induced hindpaw inflammation (100).
Mu Opiate AgonistsL-methadone, but not D-methadone produced stronger anti-allodynic effects in the spinal nerve ligation model relative to morphine, oxycodone and methadone itself (646). 6-acetyl-codeine analgesia was blocked by AS probes targeting Exons 1 and 2 of the MOR gene (780). The ability of buprenorphine to increase tail-flick latencies correlated with the extent and duration of reduced numbers of mu opioid receptor binding; however, residual analgesia after 8 h was not accompanied by mu binding changes (320). Ventricular and intrathecal buprenorphine analgesia on the formalin test was blocked by ventricular and intrathecal naloxone and the ORL-1 antagonist, J113397. Methadone and morphine were more effective than buprenorphine in increasing thermal and pressure thresholds in cats (1067). Systemic buprenorphine analgesia was blocked by systemic or intrathecal, but not ventricular naloxone, and was enhanced by systemic or ventricular J113397. Systemic, but not ventricular or intrathecal buprenorphine decreased formalin-induced Fos activity in the lumbar dorsal horn (1257). Thienorphine produced a similar analgesic duration as buprenorphine, but was longer than the latter in antagonizing morphine-induced lethality (1279).

The analgesic efficacy of such partial opioid agonists as buprenorphine or tramadol was increased in mice with targeted inactivation of the alpha2A-adrenoceptor gene or in wild-type mice treated with atipamezole and yohimbine (874). Tramadol produced analgesia in MOR KO mice that was blocked by alpha-2 adrenergic antagonists alone or with naloxone, but not by methysergide (499). Isobolographic analysis revealed dual-site synergism in the systemic and intraplantar antinociceptive response of tramadol in the formalin test in rats (921). Oral and intrathecal, but not ventricular oxycodone, but not morphine produced analgesia in diabetic mice. Whereas, mu but not kappa or delta antagonism blocked oxycodone analgesia in non-diabetic mice, kappa, but not mu or delta antagonists blocked oxycodone analgesia in diabetic mice (852). Whereas subcutaneous oxycodone and oxymorphone produced potent analgesia in the hot-plate and paw pressure tests, intrathecal oxymorphone produced far more potent effects than intrathecal oxycodone (645). Liposome-encapsulated hydromorphone provided extended analgesia in a rat model of neuropathic pain (1047). Analgesic effects were observed after epidural administration of hydromorphone in horses (822), and similar effects were observed following subarachnoid hyperbaric morphine, buprenorphine and methadone (823). Systemic and intrathecal remifentanil produced naltrexone-reversible analgesia on the acetic acid test in Rana pipiens (792). Gabapentin activated the NO-cyclic GMP-K+ channels pathway in inhibiting formalin-induced pain (869). Spinal alpha-2 adrenergic and muscarinic receptors as well as the NO release cascade mediated the supraspinally-produced effectiveness of gabapentin in decreasing mechanical hypersensitivity in mice after partial nerve injury (1103).

Endomorphins 

Intrathecal endomorphin-2, but not endomorphin-1 or DAMGO analgesia was prevented by antisera directed against DYN A(117), but not DYN B(113); this effect was reversed by pretreatment with ultra-low doses of BFNA or naloxonazine that were ineffective at mu opioid receptors (788). Endomorphin-1 and endomorphin-2 produced analgesia when injected directly into an inflamed hindpaw, effects blocked by mu, but not kappa antagonists, and with delta antagonism blocking the latter but not former effect. Antibodies raised against BEND, Lenk or Menk failed to affect endomorphin-induced analgesia (622). Endomorphin-1 produced longer-lasting analgesia when injected in nanoparticles coated with polysorbate 80 (679). The analogues, guanidine-[d-Ala(2), pCl-Phe(4)] endomorphin-1, the four D-Ala-containing tetrapeptides and a chloro-halogenated d-Pro-Gly-containing pentatpetides of endormorphin-1 showed potent and prolonged analgesic activity (681). Strong opioid receptor binding and analgesic activity were found with analogues of endomorphin-2 and morphiceptin with phenylalanine mimics in position 3 or 4 (384). The novel analogue, [Dmt1]endomorphin-1 produced spinal and supraspinal analgesia that was blocked by naloxone and BFNA, but not naloxonazine, indicating mu-2 action (527). Tyr-Pro produced naloxone-reversible analgesia on the tail-flick test, and [3H]-Tyr-Pro could be found in endomorphin-related tetra- and tri-peptides in brain (968). The modulation of endomorphin-1 and –2 analgesia by L-NAME was inhibited and reversed by L-Arg and naloxone respectively (204).
BEND 

A BEND anti-serum blocks thermal analgesia noted at the initial stages of a murine osteosarcoma (47). Intraplantar BEND respectively suppressed and potentiated concanavalin A-induced paw edema at high and low doses in delta- and kappa-selective antagonist fashion in two inbred strains that differed in BEND-induced modulation of phagocytosis and NO production (1065).
Manipulations affecting Mu Analgesia 

Dextro- and levo-naloxone each reversed the attenuation of morphine analgesia induced by lipopolysaccharides in the mouse spinal cord through a non-opioid mechanism (1233). Bicuculline or picrotoxin administered into the ventrolateral orbital cortex enhanced the ability of morphine to inhibit tail-flick latencies in this region, whereas muscimol and THIP attenuated the morphine-induced response (930). Gabapentin enhances the analgesic response to morphine in an acute model of pain in male rats (775). SB203580, a p38 MAPK inhibitor reversed antianalgesia induced by dextro-morphine or morphine in the mouse spinal cord (1234).
Endothelin ETA receptor blockade potentiates morphine analgesia but does not affect gastrointestinal transit in mice (748). Mice lacking P-glycoprotein displayed enhanced analgesic effects to morphine and fentanyl, but not meperidine. Morphine and fentanyl stimulated P-glycoprotein ATPase activity as well (439). Mice lacking one allele of glial cell line-derived neurotrophic factor displayed enhanced morphine analgesia and enhanced NAC DA output (11). Enhancement and restoration of the analgesic efficacy of codeine and morphine occurred following delta9-THC (1219). Systemic morphine produced antinociception mediated by spinal 5-HT7, but not 5-HT1A and 5-HT2 receptors (290). The I2-imidazoline binding site ligand, phenyzoline enhanced morphine analgesia on the tail-flick and hot-plate tests, whereas its ortho-phenyl derivative decreased this response (394). Synergistic analgesia occurs between the phosphodiesterase inhibitor, zaprinast and morphine in the spinal cord of rats on the formalin test (1276), whereas riboflavin enhanced this measure as well (84). Blockers of the gap junction channel, carbenoxolone and Gap27 reduced morphine analgesia after intrathecal administration (1090). Co-administration of the non-competitive NMDA antagonist, MK-801 and morphine attenuated neuropathic pain (441). [Ser1]-histogranin, a peptide NMDA receptor antagonist enhanced morphine analgesia in the formalin test (438). Naloxone pretreatment and post treatment blocked the morphine-induced and dipyrone-induced analgesic potentiation in the tail-flick test in rats (467).
Hemokinin-1, a mammalian tachykinin peptide, markedly potentiated the antinociceptive effects of morphine administered at the peripheral and supraspinal level (364). Enhanced antinociceptive effects of morphine were noted in histamine H2 receptor gene KO mice (790). Lithium potentiated morphine analgesia in a time-sensitive manner near the end of the light phase of the light:dark cycle (549). Ketamine enhanced the analgesic, cataleptic and hypoactive effects of morphine in a naloxone-reversible manner, with the first effect reduced by yohimbine, but not glibenclamide (163). BIBP3226, a NPY Y1 receptor antagonist, prevented the ability of neuropeptide FF to reduce morphine analgesia on the tail-flick test (331). Rats over expressing beta-arrestin 2 in the PAG display decreased morphine analgesia (522). The analgesic effects of the CB2 receptor agonist AM1241, but not morphine were absent in CB2 KO mice (497). Animals allowed wheel-running activity displayed significantly less morphine- and M6G-induced analgesia elicited from the vlPAG than inactive rats (744). Both GABA-B and GABA-A agonists reduced morphine-induced Straub tail responses in mice (1295). Resiniferatoxin, a potent capsaicin analogue decreased individual, but not combined immunoreactivities of mu opioid receptors and transient receptor potential vanilloid type-1 neurons in the DRG and dorsal horn. This was accompanied by enhancements in the analgesic magnitude and duration following intrathecal DAMGO and morphine as well as systemic morphine; the number, but not affinity of spinal [3H-DAMGO] binding was also decreased (197). The methanolic extract of Polygala telephiodes antagonized morphine analgesia on the hot-plate test, improved morphine-induced memory impairments on the elevated plus maze, and suppressed naloxone-precipitated jumping behaviors in morphine-dependent mice (309).
Mu receptors 

The 3′ non-coding region of MOR is important is morphine analgesia, and appears to be the reason for a disrupted response in CXBK mice (555). MOR KO mice displayed spinal morphine analgesia at higher doses that was blocked by naloxone and NBNI, but not NTI. Spinal U50488H, but not DPDPE analgesia was observed in MOR KO mice (1254).
3b-ii. Delta agonists and receptors 

There is a crucial role of delivery and trafficking of DOR in opioid analgesia and tolerance (1313). Chronic pain-induced emotional dysfunction is associated with astrogliosis due to cortical DOR dysfunction (815). Protease activated receptor 2 agonists activate trigeminal nociceptors and induce functional competence in DOR (885). Dextro- and levo-morphine attenuated delta and kappa opioid-mediated analgesia in MOR KO mice (1235). The mechanical and thermal allodynic as well as the thermal hyperalgesic effects of neuropathic pain were enhanced in DOR KO mice (810). The peripheral delta agonist, [dVal(L)2,Ala(L)5]Enk produced naloxone-reversible and NTI-reversible analgesia induced by osteosarcoma cells injected into mouse femur with greater potency than morphine (131). Dmt-Tic-CH2-Bid, a potent DOR receptor agonist produced NTI-reversible analgesia and reduced immobility during forced swimming (1155). Chimeric glycosylated peptides of Menk and FMRFamide, like [O-Glu-Ser5]Yfa, display increased levels of analgesia and increased bioavailability (737).
3b-iii. Kappa agonists and receptors 

The antinociceptive and hypothermic effects of the KOR agonist, Salvinorin A are abolished in a novel strain of KOR-1 KO mice, indicating an effect mediated by KOR-1 and not KOR-2 receptors (33). The antinociceptive effects of salvinorin A in mice were blocked by NBNI, but not by BFNA or Nti (528). Elevated levels of DYN through the activation of bradykinin receptors contribute to the maintenance of neuropathic pain, an effect blocked by bradykinin B1 and B2 receptors only when elevated DYN is present (626; comment by (26)). Spinal cord DYN expression increases, but does not drive microglial prostaglandin production or mechanical hypersensitivity after incisional surgery in rats (1329). U50488H administered into the contralateral hindpaw of animals exposed to unilateral arthritis induction reduced hindpaw oedema, ankle joint inflammation, pain behaviors, inflammatory severity in both hind paws and decreased cartilage oligomeric matrix protein, effects reversed by the peripheral opioid antagonist, naloxone methiodide (99). Whereas morphine was effective in treatment of herpetic pain, the KOR agonist, nalfurafine, suppressed herpetic and post-herpetic pain to similar degrees following intrathecal administration. Spinal MOR was down regulated in the post-herpetic period (1103). Whereas stimulation of MOR and DOR induced hyperalgesia, stimulation of KOR induced analgesia in the hot-plate test in the naked mole-rat (1129). DYN A protein levels, increased in peripheral nerves and footpads of STZ diabetic mice, produces analgesia with activation of KOR and hyperalgesia with activation of NMDA receptors in these mice (531). Salvinorin A produced short-lived (10 min) analgesia on the tail-flick, hot-plate and acetic acid writhing tests, effects blocked by NBNI (755). Nalfurafine, a KOR agonist, inhibited scratching behavior secondary to cholestasis induced by chronic ethynylestradiol injections in rats (502). KT-95, an agonist binding to mu, delta and kappa receptors induced analgesia on the acetic acid writhing test that was blocked by NBNI, but not naloxone. KT-95-induced amelioration of scopolamine-induced memory impairments was unaffected by NBNI, but blocked by sigma antagonism (473).
3b-iv. OFQ/N and ORL-1 receptor 

OFQ/N continues to present a complex picture concerning its role in pain responses producing both “pro-nociceptive” and “anti-nociceptive” actions depending on such factors as site of administration, dose and time course. This section therefore presents these data separately.
Pro-nociceptive actions 

Administration of the ORL-1 antagonist, UFP-101 produced analgesia on the formalin test following ventricular administration and hyperalgesia following intrathecal administration. Mice receiving systemic administration of the ORL-1 antagonist, J-113397 or ORL-1 KO mice displayed increased nociceptive behaviors on the formalin test (961). OFQ/N administered into the vicinity of the knee caused a shift in weight bearing to the contralateral leg in rats, and reduced paw withdrawal thresholds and latencies to the affected foot, effects independent of mast cell activation (756). OFQ/N and PGE2 induced allodynia that was blocked by the ORL-1 antagonist, JTC-801 and that was absent in Pro-OFQ/N KO mice. OFQ/N-induced allodynia was unaffected by inhibition of PG production by indomethacin, and the PGE receptor agonist, AE1-329 stimulated OFQ/N from spinal slices and induced allodynia (860).
Both partial sciatic nerve transaction and administration of CFA up regulated OFQ/N and the ORL-1 receptor in the dorsal root ganglion; these effects were accompanied by increases in activating transcription factor 3, a neuronal marker of nerve injury (202). Hyperalgesia induced by OFQ/N was blocked by melatonin that in turn produced analgesia that was blocked by naloxone and the melatonin receptor antagonist, luzindole (1188). Two novel ORL-1 peptide analogues, Peptide-1 and –2 produced pro- and anti-nociceptive effects respectively with the latter block the effects of the former. Peptide-1 produced greater decreases in MAP than OFQ/N, and the latter’s hypotensive effect was blocked by Peptide-2 (896). The OFQ/N agonist Ac-RYYRIK-ol produced hyperalgesia following supraspinal administration and analgesia following intrathecal administration as well as producing decreased locomotion and increased food intake (427).
Antinociceptive actions 

Intrathecal OFQ/N produced analgesia in monkeys that was blocked by the ORL-1 antagonist, (+)J-113397, but not naltrexone with its metabolite OFQ/N(217) present at 1.5 but not 4.5 hours later (599). Intrathecal OFQ/N as well as electro acupuncture attenuated in an ORL-1-sensitive manner the hyperalgesia induced by CFA with greater effects observed when OFQ/N and electro acupuncture were combined (365).
3b-v. Human studies 

Volunteers 

The high-estrogen state was associated with regional increases in baseline MOR availability in women and a greater activation of endogenous opioid neurotransmission during the pain stressor (1050). Using [18F]-fluorodiprenorphine PET in healthy volunteers, it was found that heat pain stimulation reduced diprenorphine binding in limbic and paralimbic areas including the NAC and insula (1062). The 118A>G single nucleotide polymorphism of the MOR appears important in morphine- and M6G-induced pain control in healthy human volunteers (695) as well as reducing alfentanil-induced analgesia and respiratory depression (856). Endogenous pain-inhibitory systems activated by spatial summation are opioid-mediated given naloxone’s effectiveness in volunteer male and female subjects (538). Pain thresholds and tolerance were higher in men at high risk for hypertension, with greater ratings of pain and salivary cortisol following naltrexone treatment (13).
Oxycodone was more effective than morphine in a multimodal, tissue-differentiated experimental pain model (1064). CRF increased tolerance to pressure, but not heat pain in a naloxone-insensitive manner; the CRF-induced increases in plasma BEND and BLPH did not correlate with the pain tolerance thresholds (743). Both alfentanil and morphine reduced human experimental muscle pain (1002). Transdermal fentanyl was better tolerated than transdermal buprenorphine in terms of skin irritation as measured by erythema (997).
Dental Pain 

Both BEND and somatostatin levels were higher in exposed and inflamed dental pulps than in uninjured pulps (806).
Chronic Pain 

A meta-analysis (373) revealed that weak and strong opioids outperformed placebo for pain and function in chronic noncancer pain patients. Withholding of opioid therapy should not be a consequence of concern of hastening death in a large hospice population (919). The frequency of the minor allele of the functional A118G polymorphism of the human MOR gene was lower in patients with acute and chronic pain (514). Parental history of chronic pain appears to be correlated with impairments in endogenous opioid analgesic systems (142). Intrathecal morphine produced greater pain relief in patients with non-cancerous chronic back pain, an effect accompanied by increased pruritus, nausea and vomiting (937). Intrathecal fentanyl and sufentanil for the treatment of chronic pain was found to be potent and efficacious (1173). Intravenous morphine was effective in acute pain without much incidence of nausea or vomiting (128), but was marginally better than placebo treatment for acute abdominal pain (381). Chronic pain patients administered oral morphine for one month became hyperalgesic and tolerant on the cold presser, but not a heat model of pain (217). Chronic pain patients administered intrathecal morphine displayed significantly less OFQ/N in cerebrospinal fluid that controls (938).
Effective treatment of chronic moderate-to-severe non-malignant pain was observed with polymer-coated extended-release morphine sulfate capsules (840). Ganglionic local opioid application (GLOA) was effective for treatment of chronic headache and facial pain (451). Use of morphine and other opiates was associated with greater risk of fracture due to falls related to dizziness (1158). Opioid switching from oral slow release morphine to oral methadone improves pain control in chronic non-malignant pain over a nine-month follow-up study (359). Administration of naloxone following long-term morphine treatment produced withdrawal and reinstatement of lower morphine doses to produce analgesia in a selected group of chronic pain patients (693). CJC-1008, a long-acting parenteral opioid analgesic was effective in the treatment of postherpetic neuralgia (1177). Hydrocodone produced greater amounts of abuse liability than NSAIDs or tramadol in a female group of patients treated for chronic non-cancer pain (6). Intrathecal hydromorphone reduced intractable nonmalignant pain (304), and was shown to be safe and efficacious in acute emergency-related pain (180). Hydromorphone can be produced as a minor metabolite of morphine within minutes in chronic pain patients (234).
Daily-extended release hydromorphone was effective in patients with persistent moderate to severe chronic pain (1211). Oxytrex, a combination of oxycodone and an ultra-low naltrexone dose, minimized physical dependence while providing effective analgesia in patients with low back pain (1205). Extended release oxymorphone appeared effective in pain relief for osteoarthritis of the hip or knee (593), and was more effective and less costly than an oxycodone-acetaminophen combination for osteoarthritis pain of the hip or knee (732). A weight-based dose of oxycodone without adjustment for age between 6 months and 7 years is valuable for evaluating dosing schedules and routes (316). Although rofecoxib was more effective in ameliorating chronic osteoarthritis pain in the knee than acetaminophen, the latter reduced plasma BEND levels (1025). The analgesic effect of pamidronate is not caused by the elevation of BEND level in Paget’s disease (77). Serum BEND and IgE are useful biomarkers for itch and disease severity in patients with atopic dermatitis (635). Electro acupuncture was effective in the treatment of postthoracotomy pain (1226). Opioid expenditures and utilization increased in the Medicaid system between 1998 and 2003, particularly for morphine derivatives (135).
Cancer Pain 

The use of low morphine doses in opioid-naïve cancer patients with pain appeared to be a reliable method in pain treatment (769). Epidural morphine produced greater analgesia than intravenous morphine for oral cancer surgery with pectoralis major myocutaneous flap reconstruction (1042). Oxycodone was as efficacious and tolerable as morphine for cancer pain treatment (945). Three-cycle fentanyl patch system significantly improves pain control in gynecologic cancer (547). Even though oral morphine is not contra-indicated, there is a trend to use a fentanyl patch as the first-choice strong opioid in cancer patients undergoing titration, in the presence of intractable pain and in the absence of dysphagia (956). S-methadone had a shorter half-life and shorter population pharmacokinetics than R-methadone in hospice patients with cancer pain (45). There was a beneficial effect of low-dose Ketamine addition to epidural administration of morphine-bupivacaine mixture for cancer pain (1007). Midazolam was an effective adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer (827).
Surgical Pain 

The A118G single nucleotide polymorphism of MOR appears to moderate, but does not mediate the effects of the anger-out trait on postoperative pain responses (144). Age and the prior use of psychotropic agents before surgery were positively associated with a higher rate of postoperative morphine consumption (240). Intrathecal morphine was similar to epidural morphine during liver resection surgery for postoperative pain relief (276), but improved pain relief after abdominal aortic surgery (105), and is effective in treating elderly patients in a regular post surgical ward (667). Intrathecal morphine combined with bupivacaine reduced pain scores following dorsal rhizotomy in children (469). Morphine and Entonox were not very effective analgesics in children undergoing chest drain removal (140). Rectal morphine administered in solution or gel form administered as premedications were effective analgesics (707). Following laparoscopic cholecystectomy surgery, children with sickle-cell disease consume twice as much morphine, report more pain and have longer hospital stays than non-sickle cell children (246).
No adverse events in pediatric ketamine sedations occurred with morphine pretreatment (1200). There was an association of MOR gene polymorphism (A118G) with increased morphine consumption for analgesia after total knee arthroplasty (214). Both perioperative and PCA morphine were effective analgesics for total knee arthroplasty (1153). DepoDur, an epidural extended-release morphine formulation produced extended pain relief after knee arthroplasty (452), and high doses of oral morphine were effective after total hip arthroplasty (720). Addition of morphine and ketolorac to ropivacine enhanced pain levels in patients with arthroscopic knee surgery (838). The level of post-operative pain after hip or knee arthroplasty correlated with plasma levels of ACTH, BLPH and BEND (741). Moreover, there was an inverse correlation between the level of post-operative pain and pre-operative levels of CSF BLPH, but not ACTH or BEND (742).
Intraoperative administration of tramadol for postoperative nurse-controlled analgesia resulted in earlier awakening and less sedation than morphine in children after cardiac surgery (218).
Tramadol is comparable to morphine during adenotonsillectomy for obstructive sleep apnea in children (494). Tramadol with lornoxicam had the least immunity depression during postoperative analgesia relative to morphine or tramadol alone (1196). Postoperative cognitive function and pain relief was more effective with tramadol as compared to fentanyl patient-controlled analgesia (839). Preemptive gabapentin reduces postoperative pain and opioid demand following thyroid surgery (23), but a meta-analysis still finds its clinical significance undetermined (1005).
Acute opioid tolerance developed during infusion of remifentanil for pediatric scoliosis surgery (245). A combination of low ropivacine and morphine doses was not more effective than a higher ropivacaine dose in post-operative analgesia for arterial bypass surgery of the lower extremities (354), and ropivacaine had opiate sparing effects following total knee arthroplasty (1004). The use of continuous epidural infusion or PCA of levobupivacaine produced comparable analgesia in terms of postoperative morphine consumption (278). Caudal bupivacine into the sacral hiatus was more effective than morphine in attenuating intraoperative and postoperative pain and stress responses in children undergoing abdominal surgery (1116). Oxycodone absorption is similar after buccal and sublingual instillation during surgery in children (605). Hydrocodone and acetaminophen combinations produced similar pain relief to rofecoxib in functional endoscopic sinus surgery (221), whereas acetaminophen and ketoprofen produced pain relief in children after soft tissue or orthopedic surgery (471).
Remifentanil is a reasonable alternative to fentanyl when using a target controlled propofol infusion in patients undergoing craniotomy for supratentorial lesions (271). Rofecoxib decreased pain scores and morphine consumption after orthopedic, breast and spine surgery (951). Propofol prevented post-operative pruritus induced by epidural morphine with ropivacaine (607). Intravenous bolus of ultra-low-dose naloxone added to morphine does not enhance analgesia in emergency department patients (97). Preoperative flurbiprofen axetil reduced postoperative pain and morphine needs for spinal fusion surgery (1258). Intraoperative infusion of dexmedetomidine reduces postoperative analgesic requirements (429), and can substitute for fentanyl for bariatric surgery (340).
Caesarean Pain 

Oral morphine was better than intravenous morphine PCA in controlling pain after cesarean delivery (264). Chloroprocaine failed to affect epidural morphine for post cesarean delivery analgesia (468). Droperidol, allzapride and propofol, but not promethazine had prophylactic effects on spinal morphine-induced pruritus following caesarean section (480). However, ondansetron and tropisetron did not prevent intraspinal morphine- and fentanyl-induced pruritus in elective cesarean delivery (988). Sufentanil and morphine added to hyperbaric bupivacaine in supraspinal anesthesia for caesarean section improved pain relief (551). Naloxone is rarely used to reverse opiate effects in newborn infants, and its use can be curtailed further without increasing respiratory morbidity (121).
Pre-operative intrathecal morphine enhanced the quality of postoperative analgesia for total abdominal hysterectomy (552). Human opioid receptor A118G polymorphism increased intravenous PCA morphine consumption after total abdominal hysterectomy (213). Intrathecal bupivacaine, clonidine and morphine were more effective than general anesthesia for pain relief and functional status after vaginal hysterectomy (1063). Lornoxicam and ketoprofen reduced post-operative pain and morphine consumption following hysterectomy (550). Women undergoing hysterectomy with a genetic polymorphism of the interleukin IL-1Ra receptor, but not polymorphisms in interleukin-1 displayed greater variability in post-operative morphine consumption for pain (85). Gabapentin attenuated late, but not acute pain after abdominal hysterectomy (335). Intrathecal adenosine was not efficacious for postoperative pain relief following abdominal hysterectomy (1023).
3c. Sex, age and genetic differences
So-called organismic variables play vital roles in the mediation of opioid analgesic responses, and continue to attract a great deal of attention. The first variable is the sex or gender of the animal, and opioid receptor subtypes appear to play important roles in whether there is a sex differences in analgesia and whether it is mediated by circulating gonadal hormones. Test-specific and route-specific variables also come into play that not only informs us about sex differences in opioid analgesic function, but other functions covered in other parts of the review. Aging factors, and especially genetic factors from both inbred and transgenic models continue to play a vital role in our understanding of opioid analgesic function.
3c-i. Sex 

Female rats have more PAG-RVM output neurons than males, but males have more activated PAG-RVM cells than females during inflammatory pain. Systemic morphine significantly suppressed CFA-induced Fos in males only (700). Testosterone produces anti-hyperalgesic effects during development in male animals that is maintained during adulthood. Morphine analgesia inhibits inflammation-induced pain in adult gonadectomized, but not neonatally-gonadectomized animals (114). Male rodents and nonhuman primates display greater analgesic responses than females following mu and kappa opioids, particularly those that display low efficacy such that they appear to act as full agonists in males, but antagonists in females. These effects interact with drug history, genotype and the modality, duration and intensity of the nociceptive stimulus (67). Whereas estrogen attenuates OFQ/N analgesia elicited from the spinal cord in the female, testosterone is required for OFQ/N analgesia in the male rat (227). Male rats displayed greater analgesic and antihyperalgesic effects of morphine than females on CFA-induced pain over a 3-week time course (1192). Male rats displayed greater analgesia on a visceromotor pain test following systemic loperamide and inventricular, but not intrathecal morphine than female rats (521). Female rats, and particularly ovariectomized females displayed more marked leftward shifts in morphine’s dose-response curve following the barbiturate, pentobarbital (243). Testosterone levels that affected male sexual behavior and reproductive physiology did not similarly alter basal nociception or morphine analgesia (1085).
Chronic sucrose intake reduced the antagonist effect of BFNA on morphine-induced analgesia in female, but not male rats (241). Whereas female Fischer rats showed greater enhancements of contact hypersensitivity following spiradoline, but not SNC80, both sexes showed comparable analgesic and antidiuretic effects following both compounds (314). Neurokinin-1 receptor antagonism decreased mu and kappa opioid-induced enhancement of contact hypersensitivity in females but not males (315). Female rats displayed greater analgesia following oxycodone and U50488H than males, and male rats showed greater hyperalgesia following low oxycodone and U50488H doses (477).
Gender differences in sensitivity to short duration cold pain were associated with variations in the genes for transient receptor potential A subtype 1, catecol-O-methyltransferase and fatty acid amide hydroxylase (579). Placebo analgesia occurred in males with female experimenters, suggesting the importance of the social context in which the pain is recorded (350). Women undergoing dental procedures displayed greater nalbuphine analgesia than men with men displaying a late onset anti-analgesia following nalbuphine. Pretreatment with chlorpromazine or haloperidol enhanced nalbuphine analgesia eliminating any sex difference, and abolished the male anti-analgesia (389).
3c-ii. Aging 

Morphine analgesia did not differ between young and aged rats using tail-flick latencies, but older animals showed a decreased analgesic response using a method measuring tail-flick thresholds as well as escape thresholds from electrical stimulation of the mesencephalic reticular formation (249).
3c-iii. Genetic differences 

Opioid-induced hyperalgesia that occurs after repeated morphine was strongly strain-dependent in 15 inbred groups of mice with genetic analysis identifying a genetic locus near the beta-2 adrenergic receptor gene. The selective beta2-adrenergic antagonist, butoxamine blocked opioid-induced hyperalgesia (662). Low doses of naltrexone enhanced morphine analgesia and attenuated the development of morphine tolerance in Sprague-Dawley and Long-Evans rat strains, but not in F344 or Lewis rat strains (1115). Fischer rats displayed greater carrageenan-induced swelling and pain as well as lower circulating levels of TNF-alpha and higher levels of IL-6 as compared to Lewis rats. Although morphine reduced carrageenan-induced behaviors in both strains, low morphine doses produced a mechanical allodynia and hyperalgesia in the noninflamed paw of Fischer, but not Lewis rats (337). Lewis rats displayed lower thresholds for CRF-induced analgesia, and higher doses of the CRF antagonist, astressin to produce hyperalgesia that was blocked by morphine pretreatment (1167).
3d. Opioid mediation of other analgesic responses
This section summarizes studies that indicate that analgesia elicited by a wide range of peptides and transmitters can alternatively and respectively be sensitive (3d-i) or insensitive (3d-ii) to opioid manipulations using agonists, antagonists and transgenic knockouts.
3d-i. Opioid-sensitive analgesic responses 

Central galanin-induced analgesia was reduced in morphine-tolerant rats, and these animals displayed an up-regulation of galanin-like immunoreactivity in the hypothalamic arcuate nucleus (1238). The neurotensin agonist NT1 displayed analgesia and tolerance on the hot-plate test that was not cross-tolerant with morphine, but was sensitive to naloxone on the jumping, but not licking response. The neurotensin-2 receptor antagonist blocked neurotensin, but not morphine analgesia on the hot-plate test (130). Intrathecal naloxone inhibited but was less effective than an Oxy antagonist in blocking the ability of Oxy or PVN stimulation to reduce the withdrawal responses to mechanical and cold stimuli in sciatic nerve-ligated rats (782). KOR and DOR antagonists block the antinociceptive effect of Oxy in formalin-induced pain responses in mice (945). VP-induced analgesia elicited from the PAG was blocked by naloxone and V2, but not V1 receptor antagonists (1260). Ghrelin inhibited inflammatory pain induced by carrageenan that was reversed by naloxone (1037). The COX-2 inhibitor, SC236 produced hypoalgesic effects in carrageenan-treated rats that were blocked by naltrexone and absent in morphine-tolerant animals (357). The PKC inhibitor, chelerythrine blocked basic spinal c-Fos expression to formalin pain as well as the naloxone-induced increases in spinal c-Fos expression to formalin pain (842). The analgesic effects of fatty acid amide hydrolase inhibition with URB597 in a rat model of neuropathic pain were blocked by naloxone and CB-1 antagonism (520). Intraplantar injection of CXCL2/3, but not CXCL12 elicited naloxone-reversible mechanical and thermal analgesia that was abolished by systemic polymorphonuclear cell depletion (958). Central melatonin produced antihyperalgesic, but antiallodynic actions in sciatic nerve-injured mice, effects blocked by naloxone and L-arginine (1140), and naloxone blocked melatonin-induced analgesia (723). The SSRI, fluvoxamine produced analgesia that was blocked by intrathecal and systemic administration of general, mu and delta, but not kappa antagonists in sciatic nerve-injured mice (851).
Fluoxetine-induced analgesia on the tail immersion and hot-plate assays was significantly less potent in STZ-induced diabetic mice, and reversed by opioid and muscarinic, but not alpha-2 adrenergic antagonists (32). Inhibition of the jaw opening reflex and single neurons in the trigeminal subnucleus caudalis by activation of striatal D2 dopamine receptors was suppressed by striatal quinpirole and reversed by systemic naloxone (991). Desimiprimine and trimipramine-induced analgesia were blocked by Nti, but only by high doses of naltrexone (875). A chlorinated chimeric peptide of Menk and FMRFa, [p-Cl Phe(4)], produced a naloxone-reversible analgesia (447). Analgesia induced by AMPA receptor antagonism in the spinal cord was blocked by mu and delta opioid antagonists (606). L-arginine and a NO donor each produced analgesia that were blocked by naloxone and NBNI, and that was more greatly reduced by antisera directed against DYN(113) than against Menk (219). Nitrous oxide produced analgesia on the acetic acid writhing test that was markedly reduced in mice lacking the ORL-1 receptor; acetic acid induced greater increases in plasma ACTH in this KO mice (472). Ketamine produced analgesia in the electrical stimulation test in singly-housed, but not group-housed rats. Whereas ketamine decreased mu opioid binging in the hippocampus in group-housed animals, it increased mu opioid binding in the frontal cortex and hippocampus of singly-housed animals (72). Transfer of CD4+ T-cell lymphocytes blocked visceral hyperalgesia in mice that was reversed by naloxone methiodide (1156).
Intrathecal Tyr-d-Arg-Phe-Sar produced analgesia that was blocked by BFNA, naloxonazine and NBNI, but not Nti as well as by an antiserum directed against DYN B, but not DYN A, alpha-neo-endorphin, Menk or Lenk. Pro-DYN KO mice also showed a lesser analgesic response as well (786). Intrathecal Tyr-d-Arg-Phe-Sar produced analgesia that was blocked by selective mu-1, but not mu-2 opioid peptide antagonists (787). Inhibition of fatty acid amide hydrolase produced naloxone-reversible analgesia on the spinal nerve ligation and mild thermal injury tests (181). Naloxone-sensitive analgesia on the acetic acid and formalin tests was observed following (+/−)-cis-(6-ethyl-tetrahydropyran-2-yl)-formic acid (728). Analgesic effects induced by automatically controlled rotating acupuncture in rats were blocked by naloxone (583). Acupuncture inhibited in a naloxone-reversible manner the ability of noxious tooth pulp stimulation to induce Fos expression in the trigeminal nucleus subcaudalis, the transitional region between the subnucleus caudalis and subnucleus interpolaris, the inferior olivary nucleus, the ventrolateral and centrolateral thalamic nuclei, SON, PVN, NTS and rostral ventrolateral medulla (539). Analgesia, but not freezing behaviors elicited by electrical stimulation of the ventrolateral PAG was blocked by naltrexone, whereas midazolam blocked both behaviors (272). The NE and 5HT reuptake inhibitor, venlafaxine produced analgesia that was blocked by high naloxone doses, but not by N-omega-nitro-L-arginine (426). Mu, but not delta and kappa opioid receptor antagonists block interferon-alpha-induced analgesia from the thalamic nucleus submedius (1186). Tolerance to nicotine-induced analgesia occurred faster in MOR KO mice, nicotine-induced tolerance decreased MOR in C/P and the core and shell of the NAC, but not the spinal cord (377).
The visceral analgesic effects of the anti-viral drug, ribavirin were partially blocked by naloxone, enhanced by D2 receptor antagonists, and unaffected by alpha-2 NE or Ach antagonism (1). Whereas carrageenan produced hyperalgesia in control animals, this procedure produced naloxone-reversible analgesia in rats deficient in polyamine (325). NSAID drugs produce analgesia in sheep that are blocked by intrathecal naloxone or atipamezole (692). Artemin reduces herpes-related pain responses in mice inoculated with herpes simplex, an effect associated with decreased spinal DYN, but not BEND (41). Analgine, ketrolac and xefocam each produced analgesia that developed tolerance and cross-tolerance with morphine, but was not blocked by naloxone (1135).
The pyrazolyl-thiazole derivative (B50) produced naloxone-sensitive analgesia on the writhing, but not tail immersion test with removal of the methyl group or substitution of a bromo group resulting in loss of analgesia (924). Moderate hypercapnia reduced nociceptive behaviors on the formalin test in a naloxone-reversible manner, but failed to alter arcuate BEND (372). Exposure to an extremely low frequency magnetic field for four days produced analgesia and increased hypothalamic BEND and SP as well as brainstem 5HT (62).
Mu opioid antagonism is observed for the analgesic and GI transit inhibition induced by 7-hydroxymitragynine, isolated from Thai herbal medicine Mitragyna speciosa (746).
Analgesia induced by the ethanolic extract from the flowers of Combretum leprosum was observed on formalin-, capsaicin- and glutamate-induced pain tests, effects reversed by naloxone, 5HT1A and 5HT2A antagonists, but not by NO precursors or 5HT3 antagonism (909). The antinociceptive effects of Thymus broussonetli Boiss extracts on the formalin test in mice and rats were blocked by naloxone (310). GDHCF, the active ingredient of the stem bark of Hintonia standleyana increases hot-plate latencies and decreases acetic acid-induced writhing, effects blocked by naloxone, L-NAME and glibenclamide (270). Analgesia on the formalin and hot-plate tests induced by an extract of echium amonenum Fisch & C.A. Mey was blocked by naloxone (460).
The tonic and phasic analgesic, anti-depressant and hypothermic effects of the aqueous root extract of Securidaca longepedunculata were blocked by naloxone pretreatment (7). The antinociceptive effect of Hyptis pectinata leaves extract was blocked by naloxone (676). Attenuation of visceral nociception by alpha- and beta-amyrin, a triterpenoid mixture isolated from the resin of Protium heptaphyllum produced naloxone-reversible actions in mice (668). Further, oleanolic acid, a pentacyclic triterpene attenuated mustard oil-induced colonic nociception, an effect blocked by naloxone, but not yohimbine (714). Mechanical allodynia and thermal hyperalgesia caused by chronic constriction injury were blocked by processed Aconiti tuber in a NBNI-sensitive, but naloxone-insensitive manner (1247).
A recombinant herpes simplex vector encoding human Pro-Enk to macaque feet induced Enk peptide production in the application area that resulted in a long-acting anti-hyperalgesic and analgesic response to C-fiber stimulation of the application area (1271). Irradiation of osteolytic sarcoma cells improved pain-related behaviors in a manner similar to ketorolac; decreases in spinal pain mediators including DYN and COX-2 were noted (1168).
3d-ii. Opioid-insensitive analgesic responses 

Intrathecal, but not ventricular administration of neuropeptide W-23 or Neuropeptide B, endogenous ligands of GPR7 reduced mechanical allodynia induced by sciatic nerve ligation in a naloxone-insensitive manner (1256). Intrathecal CART (55102) attenuated hyperalgesia and allodynia in as mouse model of neuropathic, but not inflammatory pain in a naloxone-independent manner (259). Intrathecal sensory neuron-specific receptor agonists, bovine adrenal medulla 8–22 and (Tyr6)-gamma2-MSH-6-12, inhibit formalin-induced nociception and neuronal Fos-like immunoreactivity in the spinal cord in a naloxone-insensitive manner (199). Whereas mGlu1 and mGlu5 antagonist co treatment enhanced inhibition of formalin-induced pain, neither antagonist paired with morphine showed enhanced effects on this measure (1009). L-glutamate sodium in the PVN enhanced acupuncture analgesia, an effect abolished by VP antisera, but only mildly affected by naloxone. PVN L-glutamate sodium increased VP, but not OXY, Lenk, BEND or DYN A(113) concentrations (1262).
Analgesic activity of a non-peptide imidazolidinedione somatostatin agonist was not reversed by naloxone (521). Although morphine and the 5HT3 agonist, m-CPBG, each reduced phase 1 and phase 2 nociceptive responses on the formalin test, the former was unaffected by intrathecal 5HT3 antagonism, and the latter was unaffected by intrathecal naloxone (1275). The 5HT1A receptor antagonist, WAY-100635 administered systemically or in the RVM attenuated mechanical hypersensitivity in rats with spinal nerve injury in a 5HT-1A antagonist sensitive, but not naloxone-sensitive manner (1208). The SSRI, fluvoxamine produced stronger analgesic effects than fluoxetine or citalopram, but all were naloxone-insensitive (1000). The antinociceptive activity of chemical congeners of improgan optimizing side chain length was nonpioid (484). Delta9-THC and R-methanandamide produced analgesia on the phenyl-p-quinone stretch test in mice that was not blocked by opioid antagonism (437). Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain is mediated by Group II/III metabotropic glutamate, but not opioid receptors (925). Vinpocetine and piracetam exerted antinociceptive effects in visceral pain that was potentiated by naloxone (2).
The antinociceptive effects of the flavenoid myricitrin following glutamate, phorbol myriusate acetate, bradykinin and acetic acid, but not epinephrine or prostaglandin E(2), were blocked by the NO precursor, L-arginine, but not naloxone (768). A nonpioid pharmacological profile was observed for the novel analgesic M58996 in rat models of persistent and neuropathic pain (12). The antinociceptive effect of thalidomide on zymosan-induced experimental articular incapacitation was insensitive to naloxone antagonism (1142). Mice deficient in CD26, a multifunctional cell surface glycoprotein showed decreases in endopeptidase activity, increased SP, normal endomorphin-2, and short nociceptive latencies that were normalized by a SP NK1 antagonist or dipeptidyl-peptidase activity (424). A long-form alpha-neurotoxin from cobra venom produced potent opioid-independent analgesia (203). Analgesia induced by crotoxin isolated from crotalus durissus terrificus venom was opiate- and Ach-independent (1305). 12-acetyoxyhawtriwaic acid lactone, a diterpene from Egletes viscose, attenuated capsaicin-induced ear edema and hindpaw nociception in mice through a naloxone-independent response (764). The anti-inflammatory and analgesic effects of bee venom acupuncture were blocked by yohimbine, but not naloxone (50). Two compounds derived from bis selenide increased pain thresholds in the acetic acid, capsaicin and tail-flick tests in a naloxone-insensitive manner (993).
4. Stress and Social Status
In comparison with previous years, the amount of studies investigating the role of stressors in analgesic responses has dramatically declined as the use of selective opioid agonists and antagonists as well as the use of animals with knockouts of opioid receptor genes in analgesic processes has dramatically increased. This prompted us to include Section 3b in the present review. This section will continue to examine the phenomenon of stress-induced analgesia (4a), emotional responses in opioid-mediated behaviors (4b), and opioid involvement in stress response regulation (4c). 

4a. Stress-induced analgesia
One major theme of stress-induced analgesia is to examine its role vis a vis the opioid system. Ecologically relevant, parametric and sex/age variables continue to play an important role in the neurobiological substrates mediating these responses. Female rats placed on an exercise schedule on running wheels displayed decreased sensitivity to analgesia elicited by morphine, levorphanol, buprenorphine and butorphanol with the sensitivity restored upon return to sedentary conditions (1048). Mice placed on a restricted feeding schedule displayed more potent analgesic effects to morphine during that time in the light:dark schedule in which feeding was entrained; this effect was not observed in adrenalectomized mice, suggesting a role for endogenous glucocorticoid secretion (1277).
Increased opioid mediated warm water swim analgesia, but no changes in CWS analgesia were observed in mice lacking the proneuropeptide convertase PC2 (247).
CWS, but not fentanyl analgesia was blocked by an anti-neural-cell-adhesion molecule that in cultured DRG neurons, was reduced by BEND in a naloxone-reversible manner (485). Immobility induced by clamping the neck of mice produced a naloxone-reversible analgesia on a tonic pain test, the acetic acid writhing test (781). Rats repeatedly exposed to swim stress developed thermal hyperalgesia that was blocked by naloxone and naloxonazine, but not NTI or NBNI only if the antagonist was administered before each forced swimming episode (1075). Chronic restraint stress induced increased responsiveness in formalin-induced pain in the temporomandibular joint and decreases in the effectiveness of morphine analgesia. In contrast, fluoxetine produced greater analgesic effects in the stressed group (382). Swim stress-induced analgesia on the hot-plate test observed in wild-type male and female mice was reversed in MOR-KOR-DOR KO mice and in MOR-DOR KO females. Swim stress-induced analgesia delayed front- and hindpaw behaviors on the hot plate test, increased tail-flick latencies and increased ACTH and corticosterone levels in both wild-type and KO females (236).
4b. Emotional responses in opioid-mediated behaviors
Anxiogenic responses were elicited by CFA or sciatic nerve ligation as well as by ventricular administration of mu or delta antagonists or DYN. CFA or neuropathic pain decreased [35S]GTPgammaS binding induced by DAMGO or SNC80 in amygdala neurons, but increased this response following kappa agonists in the amygdala (812). Ventricular morphine produced anxiolytic effects on the elevated plus maze that was mediated by vasopressinergic system and nitric oxide pathways (544). Prenatal exposure to unpredictable shock enhanced subsequent morphine-induced CPP and greater depressive behaviors on the forced swim test; these behaviors were blocked by postnatal exposure to an enriched environment (1261). Morphine and naloxone administered into the inferior colliculus respectively decreased and increased defensive attention, immobility and escape behavior thresholds. Whereas morphine stimulated bicuculline-induced increases in fear thresholds when administered into the inferior colliculus, naloxone reduced those thresholds (161).
Lateral, but not medial septal injections of morphine produced naloxonazine-sensitive reductions in open-arm exploration in the plus maze, and reduced head-dipping frequency in the hole board, effects associated with decreased Fos in ventral septum, dorsal hippocampus and anterior hypothalamus (647). Morphine, U50488H and SNC80 decreased rearing and climbing activity in the staircase paradigm with naloxone blocking the first and second, but not third agonist. Morphine produced analgesia on the hot-plate test, but failed to alter anxiety-related behaviors on the four-plate test. In contrast, alprazolam and diazepam reduced anxiogenesis, but failed to alter hot-plate latencies (957). CRF produced anxiogenesis, locomotion and grooming behaviors that were reduced by low doses of chronic morphine and increased by high doses of chronic morphine (104). Naltrexone microinjections into the central, but not the basolateral amygdala blocked the anxiolytic effects of diazepam in the plus maze (151).
There was an atypical anxiolytic-like response to naloxone, but not selective opioid receptor subtype antagonists in benzodiazepine-resistant 129S2/SvHsd mice relative to C57BL/6JOlaHsd mice (965). Whereas Nti attenuated diazepam-induced anxiolytic effects in rats over expressing Pro-Enk in the amygdala, neither Nti nor BFNA altered diazepam-induced anxiolytic effects in normal animals (923). Social defeat stress-induced behavioral responses were mediated by the endogenous kappa opioid system such that NBNI and lack of the pre-pro-DYN gene blocked this immobility and subsequent cocaine-induced preferences in stressed mice (759). OFQ/N produces anxiolytic-like effects in the elevated plus maze and in the conditioned defensive burying test in rats that was blocked by the ORL-1 antagonist, UFP-101 (1169). Coupling of ORL-1 receptors to G proteins was decreased in the NAC of anxious relative to non-anxious mice (644). The anxiogenic, hyperactive and impairments in spontaneous alternation induced by buprenorphine were impaired by high doses of clorazepate; buprenorphine-induced memory impairments were unaffected (643).
Combinations of nalorphine and naloxone reduced climbing and rearing as well (779). SNC80 produced anxiolytic effects that were blocked by NTI, whereas Nti produced anxiogenic behaviors (898). Aged mice displayed increased anxiety-related behaviors on the light-dark and elevated plus-maze tests that were accompanied by increased astrocytes in the cingulated cortex due to dysfunction of DOR systems (816). Naltrexone reduced the reinforcing effects of ultraviolet preference in subjects who were frequent tanners (558).
4c. Opioid involvement in stress response regulation
Centrally-administered OFQ/N activates the hypothalamic-pituitary axis through and ORL-1 receptor-mediated up-regulation of CRF and POMC mRNA and stimulation of corticosterone release in rats (642). Prenatal morphine exposure blocks prenatal stress-induced up-regulation of mineralcorticoid and glucocorticoid receptors in the hippocampus in male, but not female rats. However, prenatal morphine exposure blocks prenatal stress-induced decreases in mineralcorticoid binding in the hippocampus of diestrous females, and glucocorticoid binding in the hypothalamus of estrous females (953). Blood-brain barrier increases in protein tracers were observed by the second day of morphine withdrawal that was accompanied by stress symptoms, whereas acute methamphetamine produced extravasation of endogenous serum protein (1020); the former effect was blocked by the 5HT modulator, AP-267 (1021). Naloxone and CRF increased deoxycorticosterone levels in cynomogolus monkeys (918).
Both in vivo restraint in carp and in vitro administration of carp interleukin-1beta stimulated AMSH and n-acetylated BEND from the pituitary (774). Graded exercise increased plasma BEND levels in both young and old horses, whereas it failed to alter plasma cortisol levels in old horses (717). Whereas baseline Enk and DYN levels in the hippocampal dentate gyrus were lower in the Flinders Sensitive relative to the Flinders Resistant line of mice, running failed to affect opioid levels in the former group, but decreased dentate DYN mRNA in the latter group (102). The increases in ProEnk mRNA in developing Syrian hamsters by glucocorticoids are dependent on age and adrenal versus brain tissue (358).
Plasma BEND, ACTH and cortisol responses were all higher and similar for arm and leg exercises at two exercise intensities in untrained subjects (725). Human exercise increased plasma Pro-Enk peptide F immediately and 15 min later, with peptide content in white and red blood cell layers increased after 15 min (153). Naloxone enhanced the ability of heat to induce exhaustion during high intensity exercise, an effect accompanied by increased in plasma BEND and ACTH. In contrast, cold attenuated these naloxone-induced effects (39). A polymorphism in MOR at A118G enhanced increased cortisol responses to naloxone, but lowered increased cortisol responses to social stress in volunteer subjects (211).
Greater levels of basal cortisol, but not ACTH were found in healthy subjects with a 118G allele in exon 1 of the MOR gene (68). Male subjects had greater HPA axis responses to a psychological stressor, whereas female subjects had greater cortisol reactivity to a naloxone challenge (1139). Interference with pre-pro-orexin, but not co-localized pre-pro-DYN in the perifornical hypothalamus reduced rapid eye movement sleep (192). Basal release of opioids appears not to affect eNOS expression in normal in vitro culture conditions, but might do so under stress (1006). Preoperative extradural bupivacaine and morphine lowered the cortisol stress response in dogs undergoing femoral-tibial joint surgery (1036). The ability of methanolic, ethanolic and aqueous extracts of Spondias mombin L to reduce novelty-induced rearing behaviors was insensitive to naltrexone (46).
5. Tolerance and Dependence
The most-often studied variables in the functional analysis of opioid-mediated responses next to analgesic processes are the underlying neurobiological roles of tolerance and dependence. This has continued unabated through the years, and continues to be a focus in this review. Developments will be reviewed for animal models in tolerance (Section 5a), and animal models in dependence and withdrawal responses (Section 5b).
5a. Animal models in tolerance
This section will be divided into the following sub-sections: (i) cellular effects on morphine tolerance, (ii) organismic effects on morphine tolerance, (iii) opioid effects on morphine tolerance, (iv) peptide-transmitter effects on morphine tolerance, and (v) other forms of opioid tolerance.
5a-i. Cellular effects on morphine tolerance 

A review (402) analyzes the post-opioid receptor adaptations to chronic morphine focusing on altered functionality and associations with signaling molecules. Another review (53) indicates a crucial role for PKC in MOR desensitization and morphine tolerance. Adenylyl cyclase superactivation induced by long-term morphine, etorphine or methadone is dependent on receptor localized within lipid rafts and is independent of receptor internalization (1315). A proteonomic analysis of rat cerebral cortex, hippocampus and striatum after pellet exposure to morphine revealed 26 distinct proteins that were differentially expressed (94). DeltaFosB over expression in the mouse NAC produced faster development of morphine tolerance and dependence, less morphine analgesia and increased sensitivity to morphine-induced reward through a DYN-sensitive system (1284).
Chronic treatment with fentanyl produces a different pattern from morphine in altering internalization or resensitization of MORs in the spinal cord under a pain-like state (501). Whereas morphine and buprenorphine produce tolerance and locomotor sensitization with non-internalization of MOR, etonitazene, which produces rapid endocytosis of MOR shows weak tolerance and a lack of locomotor sensitization (416). Acute and chronic morphine respectively increased and decreased neuroglycan C levels in the NAC, striatum, hippocampus, VTA and amygdala (505). Increased phosphorylation of neurogranin, protein kinase C and Ca2+/calmodulin dependent protein kinase II occurs in opioid tolerance and dependence (1035).
Chronic morphine treatment increased the expression of the neural cell adhesion molecule in the dorsal horn of the mouse spinal cord (1091). Chronic morphine-mediated adenylyl cyclase superactivation is attenuated by the Raf-1 inhibitor, GW5074 (1283). The Gbetagamma that interacts with adenylyl cyclase in morphine tolerance originated from a Gs protein (1184). Chronic morphine treatment also increased the expression of vesicular glutamate transporter 1 in the mouse spinal cord (1092). A subpopulation of dorsal horn neurons displays enhanced NMDA receptor function after chronic morphine exposure (1316). Chronic morphine, but not D-amphetamine or nicotine, elevated autoantibodies to the MOR-DOR receptor and to the AMPA Glu1, but not NMDA NR2 subunit receptors (414). Dexamethasone mimics the inhibitory effect of chronic pain on the development of tolerance to morphine analgesia and compensates for morphine induced changes in G protein gene expression (518). Long-term exposure of SH-SY5Y cells to morphine revealed variations in 45 proteins using a whole cell proteomic analysis (830). Inhibition of neuronal nitric oxide synthase antagonizes morphine antinociceptive tolerance by decreasing the activation of p38 MAPK in the spinal microglia (689).
Chronic morphine decreased proDYN gene expression in the striatum, but not NAC or hippocampus, whereas chronic oxycodone-6-oxime increased proDYN gene expression in the striatum and hippocampus, but not NAC. Chronic 14-methoxymetopon increased proDYN gene expression in the NAC and hippocampus, but not striatum (589). Chronic morphine decreases MOR signaling and reduces Ca2+ current density in sensory neurons (530). Chronic morphine increased lactate and myo-inositol, but decreased glutamate in thalamus and somatosensory cortex using nuclear magnetic resonance spectroscopy (1242). Intermittent, but chronic morphine alters protein expression in the NAC (654).
Whereas chronic morphine inhibited spinal GABA release, recurrent morphine withdrawal reversed this effect and elevated spinal glutamate levels. In contrast, acute morphine withdrawal increased both spinal GABA and glutamate release (303). Whereas chronic etorphine, but not morphine increased spinal G-protein-coupled receptor kinase 2, dynamin II, beta-arrestin 2 and phosphorylated-conventional PKC, chronic morphine, but not etorphine increased spinal glial fibrillary acidic protein. Manipulations that modulate glial fibrillary protein altered morphine-induced, but not etorphine-induced analgesic tolerance (820).
Whereas acute morphine increases adenylate cyclase II activity by Galphas or PKC stimulation regulated by Gbetagamma subunits, chronic morphine decreases adenylate cyclase II activity upon stimulation of the Galphas, but not PKC pathway (994). Down-regulation in dopamine transporter function in striatum occurred during acute morphine addiction and its abstinence in rhesus monkey (1243).
5a-ii. Organismic effects on morphine tolerance 

Antinociceptive tolerance was observed following cumulative intracranial microinjections of morphine into the PAG in the rat (795). Morphine analgesic tolerance in 129P3/J and 129S6/SvEv mice was largely absent because of differences in tail-flick responsivity between these strains and C57BL/6J mice (148). Acute morphine tolerance was observed in proestrous, but not ovariectomized female rats; chronic estradiol in ovariectomized animals reinstated acute morphine tolerance. Both forms of tolerance were blocked by the NMDA antagonist, memantine (1024). Chronic morphine drinking establishes morphine tolerance, but not addiction in Wistar rats (101). PKC and PKA inhibitors reinstate morphine-induced behaviors in morphine tolerant mice (1045).
Lithium chloride reduced the development and expression of morphine-induced tolerance, but only the development of morphine-induced dependence in isolated guinea pig ileum (18). Continuous naltrexone opioid receptor antagonism abolished continuous morphine analgesia and potentiated morphine hyperalgesia with the latter, but not former effect blocked by the NMDA antagonist, MK-801. After subsiding, morphine hyperalgesia could be reinstated by a low, but not high morphine dose as well as the morphine metabolite, M3G (541). The ability of processed Aconiti tuber to increase the duration of repeated morphine analgesia before inducing tolerance was prevented by both mu (C-CAM) and kappa (NBNI) opioid antagonists (1034).
5a-iii. Opioid effects on morphine tolerance 

Chronic morphine pretreatment reduced subsequent morphine-induced, but not heroin-induced, overdose lethality, and failed to form toxic concentrations of M6G (1072). OFQ/N KO mice or normal mice treated with the ORL-1 antagonist J113397 fail to display morphine tolerance when morphine is administered at the same dose. Escalating doses of morphine produce tolerance but not withdrawal symptoms in OFQ/N KO mice (220). Pro-Enk KO mice displayed a blunted morphine analgesic tolerance, but not changes in morphine-induced CPP or morphine-induced motor sensitization (731). Morphine-tolerant rats displayed increased DOR levels in varicosities that appose the postsynaptic membrane and interact with increased GAD. Delta agonists reduced morphine tolerance and significantly inhibited presynaptic GABA release (710). Attenuation of morphine tolerance and withdrawal syndromes was observed by co administration of nalbuphine (513).
Intrathecal administration of BAM 22 produced analgesia in both opiate-naïve and morphine-tolerant rats, resumed morphine analgesia in morphine-tolerant rats, but produced hyperalgesia following chronic administration (522).
5a-iv. Peptide-transmitter effects on morphine tolerance 

Calmodulin-stimulated adenylyl cyclase gene deletion reduced morphine-induced tolerance and dependence, but not acute analgesia (655). Glycogen synthase kinase 3beta and cyclin-dependent kinase 5 inhibitors abolished morphine-induced tolerance, but not analgesia (880). NRM administration of GABA-A receptor antagonists augmented the development of morphine tolerance, whereas NRM GABA-A agonists attenuated morphine tolerance development. The GABA-A receptor-mediated IPSC was significantly increased in morphine-tolerant animals, an effect blocked by PKA inhibition (709). Whereas co treatment with the 5HT1A agonist, 8-OH-DPAT in the dorsal, but not median raphe nucleus delayed morphine analgesic tolerance, the 5HT2 antagonist, ketanserin failed to exert effects in the same sites (829). The CCK-2 antagonist, LY225910 administered into the NAC blocked morphine-induced tolerance, but failed to affect the acute antinociceptive effect of morphine (1245).
Neuropeptide SF facilitated spinal morphine analgesia in normal and morphine tolerant animals (519). Supraspinal agmatine prevented the development of supraspinal morphine analgesic tolerance (592). The tricyclic antidepressant amitryptaline prevented morphine tolerance during its development and following a subsequent morphine challenge, and up regulated the spinal glutamate transporters GLAST and GLT-1 expression (1099). The NMDA antagonists MK-801 and CPP attenuated morphine tolerance in male, but not intact or ovariectomized female mice. MK-801 also facilitated morphine-induced hyperalgesia in male, but not female mice (147). There was an additive effect of dextromethorphan on the inhibitory effect of anti-NT4 on morphine tolerance (455). The glycine site-specific NMDA antagonist, (+)-HA966 reversed morphine tolerance and enhanced morphine antinociception in morphine-tolerant rats (5). Opioid tolerance was attenuated by AS targeting the regulator of PKC and Ca2+/calmodulin-dependent protein kinase II (1108) as well as by the antagonist, KN93, but not KN92. KN93 also prevented morphine dependence (1109). Inactivation of p38MAPK in spinal microglia inhibits morphine analgesic tolerance (254). Nicotine and morphine produced analgesic cross-tolerance that was blocked by the Ca2+ channel antagonists, nimodipine, diltiazem and flunarizine, but not verapamil (94).
The endothelin receptor antagonist, BMS182874 reinstated morphine-induced GTP stimulation in tolerant animals to acute levels, and reduced the EC50 value in tolerant cells to that like acute morphine (87). The induction of morphine hyperallodynia in infraorbital nerve-injured rats was blocked by the 5HT1A agonist, F13640 before or after allodynia induction; F13640 also blocked morphine CPP and naloxone-induced conditioned place aversion (230). Administration of combined calcium-magnesium gels, but not calcium alone attenuated the development of morphine tolerance, morphine dependence and morphine withdrawal (933).
5a-v. Other forms of opioid tolerance 

Chronic morphine administration resulted in tolerance to delta opioid receptor-mediated antinociception induced by Delt (922). Intrathecal administration of (−)-oxymorphone, but not (+)-oxymorphone up regulated spinal DYN, produced thermal and tactile hypersensitivity, and produced analgesic tolerance (386).
5b. Animal models in dependence and withdrawal responses
This section will be divided into the following sub-sections: (i) cellular effects on morphine dependence and withdrawal, (ii) organismic effects on morphine dependence and withdrawal, (iii) opioid effects on morphine dependence and withdrawal, (iv) peptide-transmitter effects on morphine dependence and withdrawal, and (v) other forms of opioid dependence and withdrawal.
5b-i. Cellular effects on morphine dependence and withdrawal responses 

Morphine dependence was associated with changes in cytoplasmic and mitochondrial enzymes including proteins belonging to GTPase and GST super families, ATPase, asparaginase or proteasome subunit p27 families (93). Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence (661). Inhibition of adenylyl cyclase II activity following chronic opioid agonist exposure and withdrawal is modulated by phosphorylation (995). Both adenosine and naloxone increased regional cerebral blood flow in morphine-dependent rats accompanied by elevated blood pressure and heart rate (572). Altered periodicity and expression of circadian clock gene, mPer1, occurred in mouse brain and kidney under morphine dependence and withdrawal (1193). Heroin produced oxidative stress and exogenous antioxidant-alleviated withdrawal responses (1246). MOR and orexin/hypocretin mRNA levels in the LH and striatum are enhanced by morphine withdrawal (1323). Opiate withdrawal induces dynamic expressions of AMPA receptors and its regulatory molecule CaMKIIalpha in hippocampal synapses (1320). Although acute and withdrawal-induced morphine and nicotine increased central and peripheral concentrations of pregnenolone, progesterone and allopregnanolone that was abolished by either adrenalectomy or gonadectomy, a challenge dose of morphine or nicotine 24 h after withdrawal failed to induce effects (233).
Agmatine decreased the calcium signal in morphine-dependent CHO cells by activation of IRAS, a candidate for imidazoline I1 receptor (1236). The non-competitive NMDA antagonist reversed the decreases in postsynaptic density proteins in the hippocampus of rat offspring of morphine-addicted mothers (1268). Naloxone-precipitated morphine withdrawal up regulated MOR labeling in NAC, C/P, medial-basal thalamus, basolateral and basomedial amygdala, and VTA in prepubertal male, but not female mice with the GABA B agonist, baclofen re-establishing MOR levels in the first three brain areas in males (281). Naloxone-precipitated, but not spontaneous withdrawal in morphine-dependent rats increased MAPK1/2 phosphorylation in cortex and striatum in a manner similar to acute sufentanil, morphine and SNC-80, but not U50488H; morphine tolerance did not change MAPK ½ activity (42). Consumption of low naltrexone doses in the drinking water of morphine-dependent rats decreased withdrawal signs and increased MOR mRNA expression in the NTS, but not the LC, VTA, frontal cortex, striatum or amygdala (1145).
Pregnant females treated with morphine pellets had offspring with higher morphine-induced and endothelin-1-induced G-protein stimulation (927). Acute and chronic morphine treatment respectively stimulated and decreased Na+, K+-ATPase activity with the latter effect augmented by naloxone precipitated withdrawal; these effects were inversely correlated with cAMP accumulation, and were modulated by PKA inhibitors and protein phosphatase inhibitors (1239). There is a lack of cAMP-specific phosphodiesterase 4 activation during naloxone-precipitated morphine withdrawal in rats (585). Chronic morphine increased NR1 NMDA mRNA in the central amygdala, and NR1 and NR2B NMDA protein in the NAC (55).
Persistent and reversible morphine withdrawal-induced morphological reductions in spine density were observed in the NAC shell, but not core (280). Enhanced Fos expression was observed in glutamic acid decarboxylase immunoreactive neurons of the mouse PAG during opioid withdrawal (433). Galanin attenuates CREB phosphorylation induced by chronic morphine and naloxone challenge in Cath.a cells and primary striatal cultures (457).
5b-ii. Organismic effects on morphine dependence and withdrawal responses 

A requirement for protein synthesis was proposed in the modeling of the onset of drug dependence (536). By adding a transient early phase and a delay of the buildup of protein, a modified ‘Joyce model’ of opioid dependence and withdrawal shows excellent fit of data (936). Genetic differences were noted among 12 strains of inbred mice in the ability of CFA to lower the ED50 of morphine analgesia, enhance morphine tolerance and alter physical dependence signs precipitated by naloxone (660). Global opiate withdrawal scores were evident 56 h later in female relative to male mice, but males display earlier signs of opiate withdrawal using paw tremors and wet dog shakes (876). Maternal deprivation specifically enhanced vulnerability to opiate dependence in rats (1150). Brief early handling increased morphine dependence in adult rats without differences in pre-pro-Enk or MOR levels in the limbic system (1151). Heroin self-administration respectively lowered and elevated ICSS thresholds in naïve and dependent rats. Naloxone increased heroin consumption and reversed heroin-lowering of ICSS thresholds in naïve rats, and increased heroin consumption and elevated ICSS thresholds further in dependent rats (568). Conditioned withdrawal is readily established to discrete cues associated with naloxone-precipitated withdrawal from acute, infrequent opioid exposure (30). Morphine withdrawal for 18 h and 4 days reduced subsequent morphine analgesia, but the latter response was restored 20 days after withdrawal; this effect was augmented by stress applied after 18 hours. RU38486, a glucocorticoid receptor antagonist increased morphine analgesia four days after withdrawal (294). Naloxone-precipitated withdrawal from morphine produced potentiated startle responses which on the first day were blocked by inactivation of the basolateral or central nuclei of the amygdala or BNST, but not NAC, and which on the second day were blocked by inactivation of the NAC, but not the basolateral or central nuclei of the amygdala or BNST (450).
Although the major human metabolite, 6beta-naltrexol, was as potent as naltrexone in precipitating withdrawal in opiate-dependent monkeys, it was far less potent than naltrexone in MOR binding, shifting alfentanil-induced analgesia to the right, and blocking opiate-induced respiratory depression and itching/scratching responses (598).
5b-iii. Opioid effects on morphine dependence and withdrawal responses 

Novel depots of buprenorphine suspended in sesame oil have long-acting ameliorating effects for the management of physical dependence to morphine in mice (684).
5b-iv. Peptide-transmitter effects on morphine dependence and withdrawal responses 

Whereas over expression of CREBGFP in the LC aggravated morphine withdrawal behaviors and sensitized the cAMP-signaling pathway, dnCREBGFP in the LC attenuated morphine withdrawal behaviors and hyperpolarized LC neurons (442). Mice lacking calcium-calmodulin-dependent protein kinase IV displayed less morphine analgesic tolerance, but no changes in acute morphine analgesia or physical dependence (600). Spinal modulation of CGRP by endocannabinoids participates in the development of opioid physical dependence (1131). ATP-dependent K+ channel blockade decreased nicotine-induced inhibition of withdrawal in morphine-dependent rats (1299). Morphine withdrawal responses were enhanced by inhibition of spinal phosphoinositide 3-kinase (1266). The D1 receptor agonist, SKF82958 was rewarding in morphine-dependent rats, and blocked naloxone-induced conditioned place aversions and somatic signs of opioid withdrawal while increasing P-Glu-R1, but not P-CREB in the NAC. Naloxone reduced SKF 82958-mediated P-GluR1 induction in morphine-dependent rats (183). Yohimbine pretreatment potentiated the efficiency of clonidine to decrease naloxone-precipitated opioid withdrawal signs (1073). Scopolamine attenuated such naloxone-precipitated withdrawal signs as jumping, writhing, weight loss, genital grooming, teeth chattering, ptosis, diarrhea and irritability (1241). Lack of neuropeptide Y attenuates the somatic signs of opiate withdrawal (864). RF9, a neuropeptide FF receptor antagonist, prevented opioid-induced tolerance associated with hyperalgesia (1039).
Cross-talk between NO and ERK1/2 signaling pathways in the spinal cord mediates naloxone-precipitated withdrawal in morphine-dependent rats (165). Conantoxins and variants derived from cone snail venom inhibit naloxone-induced withdrawal jumping in morphine-dependent mice (1209). The aqueous and methanolic, but not chloroform extracts of rhizome and aerial parts of Valeriana officinalis L reduced naloxone-induced jumping in morphine-dependent mice (1017). Withdrawal responses from morphine, DAMGO and U50488H as well as the induced Ach response are reduced by isoquinoline alkaloid derivatives from A. mexicana and A. constricta as well as papaverine (166).
5b-v. Other forms of opioid dependence and withdrawal responses 

Elevations in ICSS reward thresholds and somatic withdrawal signs are noted following spontaneous and naloxone-precipitated withdrawal from fentanyl (145). Caffeine paired with naloxone produced a quasi-morphine withdrawal syndrome in wild-type, but not adenosine A(2A)R(−/−) KO mice, although both groups had similar levels of striatal mu opioid receptors (98). MOR and KOR agonists antagonize icilin-induced wet-dog shaking in rats (1215).
6. Learning and Memory
Learning and memory effects of endogenous opioid peptides, their receptors, their agonists and their antagonists, as well as genetically altered animals continue to be studied extensively. Recent developments will be reviewed for animal models in CPP (Section 6a), conditioned aversion paradigms (Section 6b), drug discrimination and spatial learning (Section 6c), as well as memory and amnesia (Section 6d). 

6a. Opiates and conditioned place preferences (CPP)
The following sections examine opioid CPP, non-opioid effects upon opioid CPP, and opioid effects upon non-opioid CPP respectively.
6a-i. Opioid CPP 

CPP can be induced by both morphine and its metabolite, M6G in mice (1165). Rats that displayed high levels of seeking for novelty displayed greater morphine-induced CPP and increased morphine self-consumption (894). Prenatal morphine exposure during the time of opiate receptor appearance does not alter adult morphine-induced CPP or self-administration (952). Restraint, tail-pinch and social defeat in an agonistic encounter each produce the reinstatement of morphine-induced CPP that had been extinguished (950). Involvement of endogenous ligands for mu-, delta- and kappa-opioid receptors was observed in modulating morphine-induced CPP expression in rats (663). Morphine-induced CPP was increased by combinations of methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate and restraint stress in out bred Sprague-Dawley and inbred Fischer 344 rats, yet this treatment decreased morphine-induced CPP in inbred Lewis rats (412). Naloxone, but neither proglumide nor MK-801, altered effects of morphine pre exposure on morphine-induced taste aversions to saccharin (355). Artificial rearing produced a greater morphine-induced CPP as adults than maternal rearing (694). There were differential changes in CREB in rat hippocampus, prefrontal cortex and NAC during the three phases of morphine-induced CPP in rats (1322).
6a-ii. Non-opioid effects on Opioid CPP 

Inhibition of the ERK pathway or protein synthesis during re-exposure to morphine or cocaine erases previously learned place preferences (1143). Administration of protein synthesis blockers such as anisomycin or cycloheximide into the hippocampus, amygdala, or NAC, but not the VTA after a conditioning session blocked a morphine-induced CPP which did not return after further conditioning (777). However, another study (1272) failed to observe any effect of the protein synthesis inhibitor, anisomycin in the basolateral amygdala following retrieval to impair expression of morphine CPP. Intrahippocampal inhibition of protein kinase A attenuates morphine-induced conditioned place preference (1018).
Inhibition of the cyclooxygenase pathway attenuated morphine-induced conditioned place preference in mice (398). D1/D2 dopamine receptor antagonists and D3 dopamine receptor agonists block foot shock stress-induced enhancement of morphine conditioned place preference (257). Mice lacking dopamine beta-hydroxylase fail to show morphine-induced CPP or hyper locomotion with viral restoration of dopamine beta-hydroxylase in the NTS, but not LC restoring morphine-induced CPP; the enzyme in both sites partially restores hyper locomotion (865). CCK B receptors in the NAC are necessary for the expression of morphine conditioned place preference by acting through D2 dopamine receptors (783). Ultra-low doses of nicotine reduce the expression of morphine-induced conditioned place preference in mice that was reversed by hexamethonium (1013). Theophylline inhibits tolerance and sensitization induced by morphine in a conditioned place preference paradigm (981). The too few mutant zebra fish displays food-induced, but not morphine-induced CPP (630). Administration of l-threo-3,4-dihydroxyphenylserine or carbidopa restored morphine-induced CPP in DBH KO mice that was then blocked by NK1 receptor antagonism (517). Corticosterone suppression can affect in the absence of an inescapable stressor block a morphine-induced CPP and induced changes in NAC DA, indicating that corticosterone is involved in the expression, but not the induction of stress-induced sensitization of morphine CPP (277).
Microinjection of D1 (SCH39166) or D2 (L-sulpiride) antagonists into the NAC shell, and to a lesser degree, the NAC core impaired the acquisition, but not the expression of a single-trial morphine-induced CPP (342). Repeated administration of apomorphine, SKF38393, quinpirole and sulpiride into the NAC enhanced morphine-induced CPP, whereas repeated NAC SCH23390 reduced morphine-induced CPP (1293). Ifenprodil, a NR2B subunit of the NMDA receptor antagonist, blocked CPP induced by morphine, but not natural rewards or social interaction. CPP induced by morphine, but not natural rewards or social interaction augments NR2B NMDA expression in the NAC and hippocampus (711). Intra-ventral pallidal glutamate antagonists block expression of morphine-induced CPP (258). The glycine site/NMDA receptor antagonist, MRZ2/576, reduced the acquisition and expression of CPP and locomotor activity induced by morphine in mice (1330). Ventricular administration of a neuropeptide FF agonist blocked the acquisition of a morphine CPP (724). Agmatine enhanced CPP induced by low morphine doses, an effect augmented by L-arginine, a NO precursor and blocked by L-NAME and aminoguanidine, NOS inhibitors (574); this potentiation was also modulated by alpha2-adrenoceptors (1098). An inhibitory effect of paeonol on morphine-induced locomotor sensitization and conditioned place preference was observed in mice (328). Mice that either lacked the pre-pro-orexin gene or received the orexin antagonist, SB334867A into the VTA failed to display morphine CPP or locomotor sensitization while reducing morphine-induced increases in DA levels (819). Prenatal cocaine exposure blocked morphine CPP as well as increased threat, avoidance and fleeing during a social encounter after isolation (326). Post-training and post-reactivation administration of amphetamine enhances morphine CPP (103).
6a-iii. Opioid effects on non-opioid CPP 

The kappa and partial mu opioid agonist, nalbuphine blocked morphine-induced CPP and increased NAC DA metabolites, but failed to affect morphine-induced locomotor sensitization (1110). Glycyl-glutamine, an inhibitory dipeptidyl synthesized from BEND(131) inhibited the acquisition and expression a nicotine CPP, and blocked acquisition of a conditioned place aversion induced by chronic nicotine paired with mecamylamine, but not one paired with the kappa agonist, U50488H (404).
6b. Opiates and conditioned aversion paradigms
Morphine administration 20 h prior to naloxone produced greater conditioned place aversion than naloxone alone and better than morphine-6-beta-naloxol pairing, implicating constitutively active mu receptors in this process (1032). The glutamate release inhibitor riluzole attenuated the formation of conditioned place aversion induced by naloxone in rats undergoing a single morphine exposure (525).
6c. Opiates and drug discrimination and spatial learning
The VTA and PAG appear more critical than the parabrachial nucleus in mediating antagonist-induced disruptions of the discriminative stimulus effects of systemic morphine for food reinforcement in both sexes of rats (613). Olfactory repeated discrimination reversal in rats was impaired by morphine but only at doses that affected performance of the well-learned performance discrimination (380). Discriminative-stimulus effects of methamphetamine and morphine are attenuated by cAMP-related compounds (1259). The NMDA antagonist, LY235959 produced additive and supra-additive effects on schedule-controlled responding when paired with butorphanol and nalbuphine, but only additive or sub-additive effects when paired with morphine or buprenorphine. LY235959 potentiated analgesia induced by all opioid agonists (349). Chlordiazepoxide and dizocilpine, but not morphine, selectively impair acquisition under a novel repeated-acquisition and performance task in rats (913). The NMDA antagonists, ketamine, phencyclidine and MK-801 generalized to the discriminative stimulus effects of U50488H, but not TRK-820 in rats. (800). Old mice lacking liver-derived IGF-I had impairments in the acquisition of spatial memory that were accompanied by increased hippocampal Enk and DYN immunoreactivity but lower mRNA levels of the opioid peptides in the hippocampus (1094).
6d. Opiates and memory
Mu and kappa, but not delta opioid receptor agonists in the NAC regulate attentional learning in the blocking paradigm (504). Odor paired with tactile stroking in rat neonates produced odor preferences, and the acquisition and consolidation of this response was blocked by naltrexone (974). Odor-shock pairings in neonatal animals produce an odor preference that activates c-Fos in the granule cell layer of the olfactory bulb and the anterior piriform cortex. Post-training naltrexone treatment in the amygdala turned the odor preference into an aversion, blocked Fos expression in the piriform cortex, and activated Fos expression in the central nucleus of the amygdala (973). Beta-casomorphin-5, a mu-opioid agonist from bovine milk ameliorated scopolamine-induced impairments in spontaneous alternation behavior and passive avoidance in a mu- and mu1-antagonist sensitive manner (984). Morphine-induced state-dependent memory of passive avoidance was blocked by centrally-acting muscarinic and nicotinic antagonists, but not peripheral nicotinic antagonists. Centrally-acting, but not peripherally-acting anticholinesterase drugs enhanced morphine-induced retrieval (510). Morphine-induced amnesia in passive avoidance was decreased by L-arginine, whereas L-NAME and low morphine doses produced amnesia. Apomorphine inhibited morphine-induced amnesia, and the L-NAME-induced inhibition of morphine amnesia was blocked by DA D1 or D2 receptor antagonists (949).
Morphine-induced deficits in passive avoidance learning were ameliorated in part by treadmill running exercise (14). Opioid receptor antagonism in the PAG prevented blocking of prediction errors during Pavlovian fear conditioning (762). Central, but not peripheral opioid receptor antagonism alleviated retrieval of infant fear memories in developing rats (1202). Big DYN increased step-through latencies on a passive avoidance task, increased locomotor activity and increased anxiolytic behaviors on the open field and elevated plus maze with all effects blocked by MK-801. In contrast, DYN A and DYN B increased memory through a NBNI-dependent mechanism, and failed to affect locomotor or anxiolytic responses (621).
Mecamylamine-induced reductions in passive avoidance responses were blocked by DYN A (113) and DYN A (213) with the latter effect insensitive to NBNI antagonism. Mecamylamine-induced extracellular Ach decreases were also abolished by DYN A(213) in a kappa antagonist-insensitive manner (474). Ventricular administration of D1 and D2 agonists as well as D2 antagonists on a passive avoidance test day reversed morphine’s pre-test amnestic effects, whereas central D1 antagonism prevented the restoration of passive avoidance responses by morphine administration on the test day (1294). Central L-glutamate and MK-801 administered prior to a passive avoidance test respectively reversed and enhanced amnesia induced by pretraining morphine, and respectively increased and decreased morphine state-dependent learning (1296). Morphine state-dependent learning sensitization was decreased by pretreatment with L-NAME and L-arginine (1292). The CB1 agonist, WIN55,212–2, mimicked the ability of pre-test morphine to restore passive avoidance learning, and enhanced morphine’s ability as well; the CB1 antagonist AM-251 blocked morphine’s and WIN55,212–2’s memory-restorative effect (1297). Histamine administration prior to passive avoidance training decreased learning, whereas pre-test histamine reversed this amnestic effect. Mice sensitized with morphine or apomorphine exhibit reversals of histamine’s pre-training amnestic effects with morphine’s effects blocked by naloxone, SCH23390 or sulpiride (1298). Nicotine reversed morphine-induced amnesia and morphine-induced state-dependent learning, effects blocked by atropine (1300).
7. Eating and Drinking
This section will review ingestive effects as functions of opioid agonists (Section 7a), opioid antagonists (Section 7b), and the interaction of POMC-derived peptides (Section 7c). 

7a. Opioid agonists and ingestive behavior
Whereas DAMGO in the NAC increased consumption of two types of flavored food pellets, intake of the preferred pellet in a choice test was respectively enhanced and reduced by DAMGO and naltrexone in the NAC; systemic naltrexone had no effect (1230). DAMGO-induced increases in high-fat feeding were blocked by naltrexone and muscarinic antagonism, but not by antagonists of DA, glutamate or nicotinic receptors (1218). Administration of morphine, but not DAMGO, Dyn or U50488H into the rostral lateral hypothalamus induced feeding, whereas naltrexone into the same site elicited c-Fos activation (652).
Whereas bicuculline administered into the ventral pallidum increased saccharin, but not quinine or water in water-deprived rats, pallidal muscimol and SCH23390 reduced this response. Pallidal DAMGO initially suppressed, but then stimulated saccharin intake in water-deprived rats (1029). DAMGO increased fat preference and increased food intake in Osborne-Mendel fat-preferring rats, but only switched preference in S5B/PI fat-resistant rats. Osborne-Mendel rats also had increased MOR and MOR mRNA in the arcuate nucleus (65). Morphine time-dependently prevented acetic acid-induced writhing and the suppression of palatable food intake; haloperidol inhibited the former, but not latter response (1069). Mice with deletion of the DA transporter and thus elevated levels of DA enhances their tendency to work for a food reward without affects on Pavlovian or operant learning for that reward; increased DYN in the C/P and in the core, but not shell of the NAC were observed (156). Chronic infusion of OFQ/N increases food and ethanol intake in alcohol-preferring rats (224). Whereas OFQ/N prolongs feeding induced by food deprivation by decreasing activity of AMSH neurons involved in feeding termination, AMSH at doses capable of reducing deprivation-induced feeding, failed to affect OFQ/N-induced feeding (109). Novel ORL-1 agonists, OS-500 and OS-462 produced greater degrees of feeding than OFQ/N following ventricular, but not systemic administration, an effect blocked by the ORL-1 antagonist, UFP-101, but not NC-797 (308).
The ability of the CRF2 receptor agonists, urocortin II and III to inhibit food intake was unaffected by OFQ/N (338). OFQ/N-induced feeding was respectively stimulated by muscimol and inhibited by bicuculline in cockerels (1100). BEND KO mice displayed increased systolic blood pressure, increased MPOA c-Fos activity and higher levels of urinary epinephrine secretion following a high-sodium diet relative to heterozygotes and controls (155). Preoperative epidural morphine together with postoperative transdermal fentanyl restored normal behavior and weight gain in pigs receiving abdominal surgery (715).
7b. Opioid antagonists and ingestive behavior
Increased body weight was observed in MOR KO mice, an effect accompanied by increased hypothalamic NPY mRNA (445). A diaryl ether derivative, (6-(4-{[(3-methylbutyl)amino]methyl}phenoxy)- nicotinamide, capable of displacing MOR, KOR and DOR agonists, suppressed food intake and weight gain in obese rats and mice, but failed to do so in MOR KO mice (1306). Naloxone decreased palatable food intake and increased latency to feed in sated, but not food-restricted rats without affecting food-anticipatory activity (63). Administration of BFNA or CTAP into the dorsal caudomedial shell of the NAC significantly reduced sucrose intake, but did not alter overall chow intake or body weight in rabbits, and also produced specific losses of MOR coupling to their G-proteins (1197). Chronic prevention of MOR G-protein coupling by BFNA in the pontine parabrachial nucleus persistently decreased consumption of standard but not palatable food (1198).
CPPs induced by exposure to either high-sugar (Fruit Loops) or high-fat (Cheetos) snack foods were each dose-dependently suppressed by naltrexone (516). Food-induced behavioral sensitization that conditioned activity was cross-sensitized with cocaine and morphine, and blocked by naltrexone and noncompetitive AMPA antagonism (648). Naloxone failed to reduce sucrose intake in mice with Enk deleted, with BEND and Enk deleted, and with DYN deleted, but showed normal inhibitory responses in mice with only BEND deleted (458). Naltrexone reduced sucrose intake, particularly in a group of rats exposed to a consummatory contrast paradigm and only for the relatively more valuable sucrose solution (1097). Naloxone reduced the ability of orexin and NPY to increase saccharin intake (374). Two studies by the same laboratory showed that central naloxone blocked the ability of central administration of interleukin-1beta to suppress water and salt intake in fluid-deprived and sodium-depleted rats induced by hypernatremia and hypovolemia; interleukin-1beta failed to affect saccharin intake (269, 708).
7c. POMC-derived peptides and ingestion
Anticipation of ingestion of a corn oil emulsion increased hypothalamic POMC and orexin mRNA expression for up to 30 min of presentation and until ingestion (789). Mice lacking 11 beta-hydroxysteroid dehydrogenase type 1 show lower levels of arcuate CART and MC-4 receptors, but higher levels of melanin-concentrating hormone, and when on a high-fat diet display an up-regulation of AGRP concomitant with high-fat-induced hyperphagia (274). Starvation in Xenopus laevis produced significant reductions of immunopositive Menk, CART, Fos and urocortin-1 in the hypothalamic magnocellular nucleus accompanied by an increase in CRF (159).
Electroacupuncture produced greater decreases in weight loss and serum leptin levels, coupled with greater increases in serum BEND than diet restriction in female obese subjects (154).
8. Alcohol and Drugs of Abuse
The interaction between opiates and other drugs of abuse, particularly alcohol, continues to be a vigorous area of investigation. This section is organized into a consideration of how the opioid system works in the general area of drugs of abuse (Section 8a), in opiate self-administration (Section 8b) and in interactions with ethanol (Section 8c), THC (Section 8d), stimulants such as cocaine and amphetamine (Section 8e) and other abused drug classes (Section 8f). 

8a. Opiates and drugs of abuse: reviews
New challenges and opportunities are reviewed in managing substance abuse in Malaysia (751).
8b. Opiates and self-administration studies
8b-i. Animal studies 

Disrupting reconsolidation of conditioned withdrawal memories in the basolateral amygdala reduces suppression of heroin seeking in rats (463). A novel bivalent morphine/heroin vaccine prevented relapse to heroin addiction in rodents (34). Unlimited access to heroin increased daily self-administration across the circadian cycle with decreased levels of food intake occurring across the circadian cycle with daytime intake increasing meal frequency and nocturnal intake displaying smaller and briefer meals; this reduced body weight gain (196). Conditioned heroin-seeking, but not sucrose-seeking behaviors increased early gene expression of ania-3, MKP-1, c-fos and Nr4a3 in the medial frontal cortex, and of ania-3 in the orbitofrontal cortex and NAC (609). Destruction of dopamine neurons in the rostral linear nucleus and periaqueductal gray blocked the rewarding and sensitizing properties of heroin (351).
Activation of group II metabotropic glutamate receptors in the NAC shell attenuates context-induced relapse to heroin seeking (117). Adenosine A2a blockade prevented the synergy between MOR and cannabinoid CB1 receptors and eliminated heroin-seeking behavior in addicted rats (1269). CRF antagonism, but not adrenalectomy blocked acute food-deprivation-induced reinstatement of heroin seeking in rats (1012). Nondependent monkeys increased choice of heroin over food as the heroin dose increased with chronic naloxone and buprenorphine, but not methadone blocking this response. Heroin-dependent monkeys in withdrawal also showed increased heroin choice over food with methadone more effective than buprenorphine in blocking this latter effect (832). Whereas heroin and DAMGO reduced VTA GABA firing rats and internal capsule stimulation post-spike discharges, acquisition of heroin self-administration behavior increased the firing rate of VTA GABA neurons (1068). Prenatal heroin exposure disrupted the development of cholinergic-induced translocation and activation of PKC isoforms (493). Expression of NR1/NR2B N-methyl-D-aspartate receptors enhances heroin toxicity in HEK293 cells (292). 18-methoxycoronaridine acted in the medial habenula and interpedunuclar nucleus to decrease morphine self-administration in rats (403). Cardiovascular responses failed to change after naloxone administration in propofol-sedated piglets during opioid overdose (125).
Although a CS previously paired with naltrexone-precipitated withdrawal suppressed heroin seeking in extinction, it elevated responding if rats had prior experience of heroin taking in the presence of the withdrawal CS (464).
8b-ii. Human studies 

The prescribing of naloxone to actively-injecting heroin users in Chicago has been associated with a reversal in heroin-induced deaths between 2000 and 2003 (749). Diamorphine (heroin) prescriptions were a long-term commitment in the United Kingdom and were not associated with serious drug, health or social problems (773). The use of “take home naltrexone” for homeless drug users was evaluated for awareness and risk perception (1232). An intranasal diamorphine spray was effective as an alternative to injectable diamorphine for maintenance treatment (784). The incidence of heroin use in Zurich, Switzerland rose between 1975 and 1990, and then declined between 1990 and 2002 (850). There was an association between the availability of heroin and methadone and fatal poisoning in England and Wales between 1993 and 2004 (797).
The greatest increases and then declines in methadone deaths happened on Saturdays (798). Heroin-using drivers displayed impairments that correlated with morphine and M6G blood levels (48). Massive decreases in Canadian heroin supply coincided with an Australian heroin shortage (1227). Malay subjects displayed a higher prevalence of current injection drug use, needle sharing and HIV infection than Chinese subjects (184). Methadone-induced overdose deaths were associated with testing positive for a tricyclic anti-depressant or benzodiazepine (179). Methadone maintenance patients are cross-tolerant to morphine analgesia at very high plasma morphine concentrations (44). Methadone-stabilized pregnant patients were safely transferred to buprenorphine using an immediate release morphine transition (532). S(+)-ketamine attenuated the increase in EEG activity and amplitude height of sensory-evoked potentials during rapid opioid detoxification (362). Nonketotic hyperglycemia coma occurred in toddlers after unintentional methadone ingestion (1122). Effective and ineffective methadone dosages overlap considerably for individual opioid-dependent patients (1130). Central morphine concentrations are on average twice as high as peripheral morphine concentrations in heroin overdose victims (244). Although most overdoses occur within 5 min after buying a drug and administering it alone, knowledge of dangers of mixing benzodiazepines with heroin actually increases the likelihood of such behaviors (284).
Opioid-dependent individuals who had used heroin, had injected drugs, had witnessed a drug overdose or who had a history of one or more accidental overdoses were significantly more willing to treat with naloxone a companion who had overdosed (624). Opiate overdoses in Rhode Island were more likely in males under 54 in a private residence on weekends around 9 PM (770). Hydrocodone-related fatalities in Ontario typically occurred in the presence of another drug (1179). A strict correlation was not observed for the relationship between plasma cortisol levels, withdrawal symptoms and craving in abstinent and treated heroin addicts (825). Salvia divinorum, which contains the psychotropic, diterpene and the KOR agonist, salvinorin A is mostly smoked to achieve a short-lived but intense psychedelic experience in recreational users (408).
Post-mortum analyses of heroin abusers indicated that subjects with MOR A118G polymorphisms displayed exaggerated down-regulation of prepro-Enk, but also prepro-DYN especially in the NAC shell (300). The ability of levomethadone to reduce pupil size and miosis was attenuated in healthy human volunteers possessing the 118A>G single-nucleotide polymorphism of the MOR gene (697). However, a meta-analysis failed to find a relationship for a risk of substance dependence with the Asn40Asp (A118G) single nucleotide polymorphism of the human MOR (36). Sex, body weight, benzodiazepine use and creatinine clearance are not factors in prescription of heroin for heroin dependency (969). Subjective heroin effects were rated more positively in heroin inhaling than in injecting patients (970); mast cell mediator tryptase concentrations occurred in the latter, but not former treatment (971).
Heroin addicts display increased polysialic neural cell adhesion molecule expression in the hippocampus (1203). 6-acetylmorphine assays are more accurate than morphine assays in detecting heroin use in urine samples (71). Analyses for papaverine metabolites were more sensitive for detecting illicit heroin use than analysis of 6-monacetylmorphine (884). DRI and CEDIA, but not REMEDi systems are best for preliminary tests of opiates in human urine (487). Pericardial fluid can be used in forensic assays of heroin and cocaine use (237). Straws used to inhaled heroin vapors contained heroin, its main metabolite, 6-acetylmorphine, caffeine and morphine (595); this was confirmed in an in vitro simulation of ‘chasing the dragon’ (596).
The greater incidence of anesthesiologists to fentanyl abuse might be explained by second-hand exposure of fentanyl in air around the mouth of patients during surgery (406). Detoxified opioid-dependent individuals showed greater improvement on all assessment measures following implantation of naltrexone pellets relative to levomethadone treatment (420). Implants of 1.8–3.6 g of naltrexone in opioid dependent individuals maintained plasma levels of naltrexone above 1 nl/ml for 4 to 6 months respectively (1172). Sustained-release naltrexone treatment dose-dependently increased retention in treatment and increased the percentage of negative urine samples in opioid dependent individuals (231). Depot naltrexone was used in lieu of incarceration for coerced treatment for addicted offenders (730), and antagonized the reinforcing, subjective and physiological effects of heroin (1084). Judicially mandated naltrexone by opioid-dependent criminal offenders was analyzed (112, 855), and provision of naloxone to injection drug users as an overdose prevention strategy in New York City proved efficacious (376, 1231). Intranasal naloxone should be used earlier in a tiered-response emergency medical service unit (76). A minority of patients showed recurrent opioid toxicity within 12 h after pre-hospital care of presumed heroin overdose (124) with survival success greater when cardiac arrest is witnessed by emergency workers (123). Slow tapering from methadone maintenance in a program encouraging indefinite maintenance was generally ineffective in opioid-dependent individuals (160). Buprenorphine maintenance was more effective than tramadol detoxification in increasing outpatient treatment participation in opioid-dependent subjects (158). Naltrexone and buprenorphine was more effective than naltrexone alone in opioid dependent individuals in terms of retention (947) as well as lower positive urine samples for morphine and cocaine metabolites (397).
Buprenorphine/naloxone doses greater than 8/2 mg provide minimal incremental value in terms of withdrawal suppression (238). Integrated buprenorphine and naloxone were effective for HIV clinical care in opioid-dependent individuals (1082), and its efficacy was maintained as a function of counseling sessions (347). Introduction of buprenorphine for treatment of substance abuse was robustly predicted by a facility’s prior use of naltrexone and medically-offered withdrawal programs (603). Earlier adoption of buprenorphine was found in private rather than public substance abuse treatment centers (597). Buprenorphine-based outpatient treatment was far more cost-effective than conventional outpatient and inpatient as well as anesthesia-induced detoxification procedures in Australian opiate-dependent individuals (1014), but adverse effects were observed in children after unintentional buprenorphine exposure (391). Slow-release buprenorphine or methadone was better than slow-release morphine in treating heroin addicts in terms of quality of life, symptoms and additional consumption (400). Interactions between buprenorphine and nonnucleoside reverse-transcriptase inhibitor and protease inhibitor antiretrovirals were evaluated in opioid-dependent, buprenorphine/naloxone maintained HIV-negative volunteers (752, 753). Oral slow release morphine over 6 months was safe and efficacious for maintenance treatment in heroin addicts (1148). Buprenorphine tablets were more effective than solutions in producing drug steady state in opiate-dependent individuals (232).
Analgesia and sedation in the presence of a naltrexone implant presented a novel pharmacological challenge for emergency care (854). Naloxone and naltrexone, but not tramadol increased measures of opioid withdrawal in opioid-dependent patients (170). Although most patients in a Veterans Administration study successfully detoxified from opioid use following naltrexone treatment, a one-year follow-up revealed that very few remained engaged and stabilized in abstinence-oriented outpatient treatment (266). Predictors of retention in naltrexone maintenance for opioid dependence included methadone use and higher average bags per day of heroin (1083). Low-dose treatment with naltrexone may help reducing the manifestation of opioid withdrawal in dependent populations (719). Further, although behavioral naltrexone therapy improved retention in treatment for heroin-dependent patients, it generally achieved abstinence from opioids after three months, but only in 22% after six months (853). Naltrexone with fluoxetine prevented relapse to heroin addiction in Russian women (615). Anesthetic opioid detoxification did not differ from clonidine detoxification treatment when combined with psychosocial support in opioid dependent patients (336). Opioid demand in heroin-dependent individuals not in treatment is a function of drug supply, unit price and cocaine use (417).
In two psychonautic studies, concomitant administration of naltrexone with codeine obviated opioid withdrawal syndrome in a single subject (870). Generic controlled release oxycodone approval was not followed by an increase in misuse or abuse (54). A patient genotyped as CYP2D6 PM could not metabolize oxycodone, but had better success with hydrocodone (1089). An automated DOI kit for urinary oxycodone was more reliable that a point-of-care assay (436).
8c. Opiates and ethanol
8c-i. Animal behavioral models 

Enhanced morphine-induced ethanol drinking occurs in alcohol-preferring alko rats sensitized to morphine (859). Spontaneous opioid-mediated and withdrawal-associated CRF1-mediated ethanol drinking was observed in Sardinian alcohol-preferring rats (978). The Naples low-excitability rat line displayed greater alcohol intake and preferences as well as greater sensitivity to quinine and naltrexone than Naples high-excitability rats (892). The greater preferences for ethanol noted in C57BL/6J and hybrid C57BL/6J x CD-1 mice relative to CD-1 mice could not be linked to mesolimbic DA transporter neurochemistry and/or Enk levels, but rather with D2 receptor expression (1033). Whereas mu, but not delta opioid antagonism blocked ethanol-induced sensitization, this effect was not attributable to putative mu1 or mu3 opioid receptors (881). Both MOR and KOR antagonism blocked the reinforcing effects of ethanol on an artificial nipple administered to neonatal rats (846). GABAB receptor stimulation attenuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol (476). KOR antagonism blocks Nac Da concentrations during operant ethanol, but not sucrose self-administration (298). Low and high doses of buprenorphine respectively increased and decreased ethanol consumption with the latter effect more effectively eliminated by the ORL-1 antagonist, UFP-101 relative to naltrexone (223). OFQ/N agonists reduce ethanol intake while increasing food intake in alcohol-preferring rats in a naloxone-sensitive manner (307). OFQ/N blocked ethanol-induced increases of GABA release, and decreased presynaptic GABA transmission in the central amygdala (962).
Although Roman high avoidance strains consume more alcohol than Roman low avoidance strains, the latter show enhanced responsiveness on the hole board test following systemic ethanol. Whereas Roman high avoidance rats have higher Pro-DYN in the NAC shell and Pro-Enk in the cingulate, Roman low avoidance rats have higher Enk gene transcription in the dorsal striatum (425). Female, but not male mice lacking prepro-DYN show lower preferences and consumption of alcohol, but not changes in ethanol-induced loss of righting reflexes, ethanol withdrawal, ethanol-induced CPP or conditioned taste aversions to ethanol (106). Estradiol valerate increased alcohol intake, decreased body weight and food intake, and reduced the number, but not content of arcuate BEND neurons (537). Losers in a social defeat test consumed more ethanol than winners, and thereby displayed lower anxiety levels. U50488H stimulated ethanol intake more in losers than winners, but only increased approach behaviors in losing mice not consuming ethanol (619). Antagonism of endogenous KOR systems potentiated the increased responsiveness of mesoaccumbal Da neurons to ethanol (1290). Naltrexone pretreatment blocked reinstatement behaviors on an operant ethanol lever induced by ethanol-associated context cues (149). Naltrexone reduced ethanol intake, but not craving behaviors in heavy- and light-drinking mice (329). Naltrexone was more effective in blocking the acquisition of alcohol intake in periadolescent relative to adult alcohol-preferring rats whereas greater tolerance to repeated naltrexone dosing was noted in adult relative to periadolescent rats (979). Both naltrexone and acamprosate reduced alcohol and water intake in a schedule-induced polydipsia task, and reduced head entries for food following the highest antagonist doses (324). Naloxone blocked analgesia induced by alcohol and nicotine alone as well as its synergistic combination (162).
8c-ii. Ethanol-induced changes in opioid systems 

Whereas acute ethanol respectively decreased and increased Pro-Enk mRNA expression in the VTA and prefrontal cortex, chronic ethanol increased Pro-Enk mRNA in the core and shell of the NAC (765). Chronic ethanol decreased brain interstitial levels of Menk using in vivo microdialysis (1141). Intubated ethanol perinatally from Days 1–22 increased hypothalamic Menk levels in males and females, NAC Menk levels in females, and lowered Menk levels in the central nucleus of the amygdala in male and female animals (704). Alcohol administration increased extracellular levels of DYN A(18) in the rat NAC (727). Alcohol, nicotine and cocaine evoked release of endogenous morphine from the M.edulis pedal ganglia (1326). Chronic naltrexone prevented acute ethanol-induced increases in BEND plasma levels in Warsaw low-ethanol preferring, but not high-ethanol preferring rat strains (1289).
Ethanol induces apoptotic death of developing fetal rat BEND neurons through suppression of cAMP production and activation of transforming growth factor-beta 1-linked apoptotic signaling (191). Ethanol suppression of hypothalamic POMC levels and splenic natural killer cell cytolytic activity is associated with a reduction in the expression of proinflammatory cytokines, but not anti-inflammatory cytokines in neuroendocrine and immune cells (189). Prenatal ethanol exposure altered the expression of period genes governing the circadian function of BEND neurons in the hypothalamic suprachiasmatic nucleus (190). Chronic ethanol inhibits natural killer cell function by suppressing the influences of BEND, CRF and the autonomic nervous system signals to the spleen (122). Rats exposed to ethanol through breast-feeding displayed decreased BEND in thymic cells whereas pre-natally ethanol-exposed rats displayed decreased 5HT content in immune cells (250).
8c-iii. Human studies 

There are associations between the promoter and 3′ end of Pro-DYN as well as intron 2 of the human KOR with alcohol dependence in human individuals (1251). Acamprosate and naltrexone prevented decreases in ACTH and cortisol during alcohol abstinence, and this was associated with a reduced risk of relapse (575). Acamprosate increased BEND plasma concentrations in patients with high, but not low alcohol preference (576). Naltrexone was found to be superior to acamprosate in relapse prevention of alcoholism among individuals with low levels of clinical depression and alcohol dependence (803). Alcohol-dependent and PTSD subjects displayed significantly higher stress ratings and decreased ACTH responses on the cold pressor task response (129). Targeted naltrexone was better than daily naltrexone in affecting average daily drinking (466). Naltrexone’s reduction in blood alcohol level following acute ethanol intoxication accounted for the changes in subjective and behavioral responses to alcohol but not the reduction in HR (902). Naltrexone appeared effective in the treatment of alcohol dependence particularly with respect to heavy drinking (907). Cognitive behavioral therapy when combined with both naltrexone and acamprosate produced the greatest improvement in outcome measures in alcohol dependent individuals relative to each treatment alone (35, 339; but see (289)). Naltrexone produced strong positive associations between the number of positive social celebratory events and drinking although such events occurred on a minority of days (37). Although naltrexone failed to alter the Positive and Negative Syndrome Scale in alcoholic patients, it further augmented the dose-dependent effects of low, but not high doses of ketamine (616). G-hydroxybutyrate was more effective than naltrexone or disulfiram in reducing craving and altered biological markers of alcohol abuse (826). Although there was no clear advantage of naltrexone, disulfiram or their combination in the treatment of alcohol abuse in patients with psychotic spectrum disorders (903), they were effective in patients suffering from PTSD (904). Asp40 carriers acted as genetic moderators of naltrexone’s effects on alcohol cue reactivity (757). Both the A118G polymorphism in the MOR gene and a polymorphism, G1510A, in the acetaldehyde dehydrogenase 2 gene were associated with alcohol dependence in a Japanese population (845). Intervention with morphine at the level of the neuroendocrine-immune axis decreased post-operative pneumonia rate in long-term alcoholics (1060). Nonalcoholic subjects with a family history of alcoholism exhibit lower plasma ACTH and BEND levels following stress and CRF stimulation conditions (1026).
8d. Opiates and THC
CB1 knockout mice display significant increases in striatal preproEnk and preproDYN as well as D4 DA receptor gene expression (396). Both morphine and the CB1 agonist HU210 inhibited Ach and GABA release in the NAC core that was blocked respectively by naloxone and the CB1 antagonist, SR141716 A. Co treatment of the two antagonists reversed their respective blockade of the agonist-induced inhibitory effects (999). MOR and CB1 receptors display reciprocal inhibition of receptor signaling and neuritogenesis (955), thereby failing to form hetero-oliogomers (215). Correspondingly, the acute and chronic suppression by the CB1 cannabinoid receptor inverse agonist AM251 on food intake and body weight was observed in both wild type and MOR KO mice (195). The CB-1 antagonist, SR 141716A blocked the ability of morphine to significantly reduce ventral pallidal GABA efflux, and blocked heroin, but not cocaine self-administration following administration into the NAC, but not the pallidum (157). Morphine in the PVN inhibited in a naloxone-sensitive manner the penile erections induced by PVN administration of the CB1 antagonist SR 141716A as well as the concomitant increases in PVN glutamic acid and NO (1076). Tolerance occurred to the reinforcing effects of morphine in delta9-tetrahydrocannibinol-treated mice (515). Cannabinoid type 2 agonists induce transcription of the MOR gene in Jurkat T cells (113). The acquisition of self-administration of the CB1 agonist WIN 55,212–2 was enhanced by both NBNI administered prior to the session in wild-type mice and in pro-DYN KO mice (766). Prenatal cannabis exposure was associated with increased MOR in the amygdala, reduced KOR mRNA in the mediodorsal thalamus and reduced Pro-Enk expression in the C/P. Prenatal alcohol exposure decreased KOR mRNA in the amygdala, claustrum, putamen and insula cortex (1191).
Cannabidiol, a major constituent of cannabis, is an allosteric modulator at mu- and delta-opioid receptors (556). Whereas systemic naloxone and naltrexone prevented THC-induced release of Ach from prefrontal cortex and hippocampus, VTA administration of naloxonazine and the D1 DA receptor antagonist, SCH39,166 produced the same pattern of effects (912).
8e. Opiates and stimulants
8e-i. Animal behavioral studies 

An AS to the MOR coding sequence 16–32 attenuated cocaine-induced behavioral sensitization and reward (495). Both contingent and non-contingent administration of cocaine increased Pro-DYN, but not Pro-Enk mRNA levels in the C/P, but not in the NAC or central nucleus of the amygdala (1331). Acute and chronic administration of the selective delta opioid agonist SNC80 decreased both cocaine- and food-maintained responding in rhesus monkeys (288). Context-dependent extinction occurs for both cocaine- and morphine-induced floor preferences (878). Like repeated forced swim stress, prior activation of kappa opioid receptors with U50488H potentiates cocaine place preference conditioning (758). A combination of cocaine and heroin self-administered at a maximum of three infusions per hour was preferred to either drug alone, and continued during all hours of the light:dark schedule; increased fixed ratio schedules led to extinction (733). Discrete-trials heroin self-administration produced sensitization to the reinforcing effects of cocaine in rats (1199). Administration of estradiol valerate to 8-week old female rats destroyed arcuate BEND neurons and attenuated the acquisition of cocaine self-administration both with and without estrogen replacement therapy (975).
The NK-1 receptor antagonist, GR82334 failed to affect cocaine self-administration or hyper locomotion, but attenuated morphine-induced locomotor activity while increasing heroin self-administration (914). Chronic buprenorphine enhanced acute cocaine-, but not acute heroin-induced locomotor increases early in buprenorphine treatment (1056). A combination of morphine and buprenorphine was more effective than U50488H in reducing self-injurious behavior induced by methamphetamine in mice (799). Sub-additive withdrawal occurs from cocaine and kappa opioid agonist combinations in Planaria (935).
8e-ii. Anatomical, molecular and neurochemical studies 

MOR KO mice display reduced psycho stimulant effects on Da dynamics in the NAC (745). Cocaine-induced locomotor activity and Fos expression in enkephalinergic D2-type neurons in the NAC are sensitized for six months after repeated cocaine administration outside the home cage (478). Prenatal administration of morphine alone or in combination with cocaine significantly increased mu opioid receptor binding and MOR mRNA on post-natal days 1 and 7, but not 14 in the offspring, effects blocked by the D2 receptor antagonist, sulpiride (88). Prenatal cocaine and morphine respectively increase and decrease brain cyclin-dependent kinase (Cdk5) in rat pups (89). The mu antagonist, clocinnamox blocked cocaine- and methamphetamine-induced preDYN mRNA expression only in the rostral patch compartment of the dorsal striatum, attenuated zif/268 mRNA throughout the dorsal striatum, but did not alter regional psycho stimulant-induced Fos expression (479). DA D2 receptor antagonism in the arcuate nucleus attenuated cocaine-induced NAC BEND increases, and produced extinction behavior in cocaine self-administering rats (295).
DYN KO mice showed decreased NAC DA levels, but no changes in DA uptake under baseline and cocaine conditions, an effect enhanced by kappa agonists and blocked by antagonists. DYN KO mice showed less cocaine-induced locomotor activity, and NBNI failed to alter this response (185). In repeated cocaine-treated animals, CREB responses to DYN are mediated in opposite directions by drugs affecting the D1 and D3 DA receptors (1308). Mice lacking glucocorticoid receptors display decreased DYN and SP as well as D1 and D2 receptors in the dorsal striatum, but not NAC under baseline, but not following cocaine behavioral sensitization. In contrast, Enk mRNA levels are altered during cocaine use in glucocorticoid receptor KO mice (507).
Increased striatal c-fos and SP, but not Enk gene expressions were noted in animals given access to running wheels and cocaine than either manipulation alone, an effect that peaked after two exposures (1220).
Methamphetamine-induced increases in striatal dopamine transmission were potentiated by morphine treatment (897). Amphetamine-induced increases in activity as well as striatal Pre-Enk and Pre-DYN mRNA and gene expression were blocked by SL327 and U0126, inhibitors of MAPK and ERK (1027). Chronic methamphetamine down-regulated MOR after 8 days, and after drug cessation, MOR levels returned to normal on Day 11 and then were up-regulated on Day 21 (210). L-methamphetamine and selective MAO inhibitors decrease morphine-reinforced and non-reinforced behavior in rats (459). Acute and chronic amphetamine treatment decreased concanavalin A-lymphocyte proliferation together with increased Menk in the NAC, prefrontal cortex, spleen, thymus and splenic macrophages (43). The rewarding effects of morphine and methamphetamine were respectively aggravated and enhanced by administration of an astrocyte-conditioned medium into the NAC and cingulated cortex respectively. The glial modulator propentofylline suppressed both morphine’s and methamphetamine’s rewarding effects (818).
Ecstasy, 3,4-methylenedioxy-N-methylamphetamine, increased pro-DYN mRNA in the C/P following acute and chronic treatment, the prefrontal cortex following acute treatment, the NAC and hypothalamus following chronic treatment, but decreased gene expression in the VTA following acute and chronic treatment. Accordingly, DYN A levels were increased in the VTA following chronic Ecstasy treatment, and decreased in the NAC, prefrontal cortex and hypothalamus after acute Ecstasy treatment (282).
8e-iii. Human studies 

Comparisons between heroin and heroin-cocaine polyabusers were made in terms of incidence of psychopathology (61). There was an association of DOR gene polymorphisms in methamphetamine dependence and psychosis (602). A 3- or 4-repeat allele of a 68-bp element in the promoter region of the Pro-DYN gene was found significantly more frequently in patients with methamphetamine dependence than in controls (849). Linkages between an IVS2+G691C single-nucleotide polymorphism and methamphetamine patients and transient psychosis were found (498). The Cocaine- and Heroin-Craving Questionnaires appear to predict dropout rates and in-treatment drug use by clients relative to visual analog scores (462).
8f. Opiates and other drug abuse classes
Three-marker haplotypes of the MOR gene were significant for smoking initiation, but were marginal for nicotine dependence (1309). Morphine increased locomotor activity to a greater degree in nicotine-withdrawn as compared to control mice, and effect accompanied by increased Da and 5HT in the striatum (1162). Beta2 nicotinic Ach receptor KO mice fail to display intra-VTA nicotine self-administration, but have normal morphine self-administration and normal nicotine withdrawal behaviors (86). Reinstatement of nicotine-induced place preferences was produced by nicotine or morphine, effects blocked by the calcium channel antagonists, nimodipine and flunarizine (91). Nicotine induced c-fos within CRF and Enk, but not DYN cells within the PVN (698).
Norlaudanosoline and nicotine increase endogenous invertebrate ganglionic morphine (1328). Chronic swim stress increased nicotine’s ability to increase plasma ACTH and BEND, but not corticosterone, whereas stress itself increased plasma corticosterone, but not ACTH or BEND (703). There was an association of the MOR A118G variant with reductions in the relative reinforcing value of nicotine in females, but not males (944). Naltrexone was efficacious in smoking cessation especially in females (587). A high dose of oral naltrexone appeared to augment the efficacy of the nicotine patch in producing smoking cessation after 4–6 weeks (866). Naltrexone and cognitive behavioral treatment based on the community reinforcement approach decreased craving in abstinent smokers (972). However, nicotine self-administration in rats was blocked by mecamylamine and hexamethonium, but not by naloxone (273).
9. Sexual Activity and Hormones, Pregnancy, Development and Endocrinology
This section will examine developments in the last year relating the endogenous opioid system to sexual activity (Section 9a), pregnancy (Section 9b), development (Section 9c), and general endocrinology (Section 9d). 

9a. Sexual activity and hormones
Fentanyl and naloxone respectively decreased and increased sexually motivated song in male European starlings, a pattern opposite to Da (1001). MOR, DOR and KOR were expressed in human spermatozoa with MOR agonists and delta antagonists reducing motility (9). MOR is located on the acrosomal region and the neck region of human sperm (19). Plasma testosterone was respectively decreased and increased 4 and 24 h after morphine, fentanyl and buprenorphine, whereas plasma estradiol was decreased both 4 and 24 h after morphine, tramadol and buprenorphine in male rats (176). Insulin-like growth factor and growth factor-associated signal transduction pathways inhibited estradiol and progesterone facilitation of female reproductive behaviors as well as the behavioral effects of a DOR agonist (327). DYN A and B as well as Lenk-Arg(6) were more predominant in NAC, C/P and SN during estrus than during diestrus or proestrus, effects associated with cyclic fluctuations in the enzymatic cleavage of DYN (966). Estrogen in female rats suppressed 3H-DAMGO binding in rat cortical membranes in a manner similar to that of CCK-8 and a CCK-8 agonist, JMV-180 with the latter effects blocked by the CCK1 receptor antagonist, JMV-179 (931).
Estrogen without progesterone increased ORL-1 mRNA expression in the anteroventral periventricular hypothalamus, MPOA and VMH and increased OFQ/N mRNA levels in the caudal part of the posterodorsal medial amygdala; estrogen and progesterone increased MPOA OFQ/N mRNA in the female rat (1040). LSN2120310, a selective estrogen receptor modulator for both ERalpha and ERbeta treats hot flushes in a morphine-dependent rat model (1178). Different progestins differentially modulate estradiol-induced BEND synthesis and release (915). The reproduction phase-related expression of BEND-like immunoreactivity in the nucleus lateralis tuberis of the female Indian major carp correlates with the number of leutinizing hormone cells and ovary during spawning (985). OFQ/N reduced tuberoinfindibular DA neurons just preceding its stimulation of the prolactin secretory response, effects blocked by ORL-1 antagonism that in turn inhibited the suckling-induced prolactin response (207). Naloxone acts as an antagonist of estrogen receptor activity in MCF-7 cells (334). DORs are found in a subpopulation of GnRH nerve terminals, primarily in the external layer of the ME. DPDPE-induced inhibition of cAMP accumulation and Go down regulation in a GnRH-secreting cell line is blocked by pertussis toxin (910). Estradiol valerate blocked ovariectomy-induced reductions in BEND and allopregnanolone, whereas progesterone increased plasma, hypothalamic and intermediate pituitary BEND. In contrast, medroxyprogesterone increased BEND only in hippocampus and intermediate pituitary (81). Oral tibolone maximally increased BEND in frontal lobe, hypothalamus and neurointermediate pituitary, also increased BEND in parietal lobe, anterior pituitary and plasma, but failed to alter hippocampal BEND in ovariectomized rats in parallel to allopregnanolone increases (392). Sexual dimorphism was observed in the organization of glutaminergic cells in the rat hypothalamic infindibular area for neurokinin B, but not for DYN (225). There was no role for endogenous opioid peptides in the reproductive suppression in subordinate female highveld mole-rats (1124).
Decreased BEND is found in serum and seminal plasma in infertile men (313). Exercise failed to elevate Pro-Enk peptide F during either follicular or luteal phases of the menstrual cycle in women (611). Both fluoxetine and clomipramine prevent premature ejaculation induced by naltrexone in opioid detoxification treatment (3). Normalization of hyperinsulinemia by chronic opioid receptor blockade occurred in hyperandrogenemic women (434).
9b. Pregnancy
Fetal morphine metabolism and clearance are constant during late gestation (387). Naloxone increased serum prolactin, but not the DOPAC/DA ratio in anti-progesterone-treated, but not control pregnant rats, and failed to affect mifepristone-induced decreases in TH immunoreactivity in the arcuate and periventricular hypothalamic nuclei (1052). Pro-Enk A mRNA in the luminal and glandular epithelium fell and GABA A receptor subunit in the luminal epithelium and stromal cells fell during endometrial receptivity (932). Interleukin-1beta increased SON Oxy secretion and electrical activity in virgin, but not pregnant rats, whereas naloxone enhanced interleukin-1beta-induced SON Oxy secretion and electrical activity in pregnant, but not virgin rats (146). Caesarean section is associated with lower maternal concentrations of epinephrine, NE, ACTH, cortisol, prolactin and BEND compared with other modes of delivery (1171). Elevations in heat pain, but not cold pressor pain were not before and after parturition in pregnant women relative to non-pregnant women (172).
9c. Development
DAMGO and U69593, mu and kappa opioids, induced the differentiation of embryonic stem cells to neural progenitors (578). NMDA lesions placed in the rostral lateral PAG prevented morphine-induced inhibition of maternal behavior. Morphine-sensitized dams would choose to hunt insects rather than engage in maternal behavior, and lesions of the rostral lateral PAG restored the maternal response (1081). DYN induced a kappa receptor-sensitive immediate unconditioned increase in neonatal responsiveness to a surrogate nipple in newborn rats, but did not alter water intake through an intra-oral cannula. Pairing Dyn and suckling on a nipple increased responsiveness 1 day later, indicating conditioning (905). MOR and ORL-1 receptor binding are significantly and respectively increased in the NAC and VTA of two-day old rat pups relative to their dams, effects attributable to increased G-protein coupling which in turn showed greater effects in female relative to male pups in the NAC (483). Neonatally-handled male mice display greater body weights, increased plasma ACTH and corticosterone and decreased hypothalamic ACTH and CRF as adults, effects blocked by neonatal administration of AS directed against POMC (379). Neonatal treatment with naloxone increased the population of Sertoli cells and sperm production in adult rats (262). Facial expressions of pain, high activity levels, poor response to routine care and poor ventilator synchrony were associated with placebo versus morphine therapy, and could be used as markers for persistent pain in preterm infants (126).
9d. Endocrinology
Oxytocin increased ACTH, BEND, LH and prolactin secretion of cycling porcine pituitary cells, with oxytocin and CRF producing additive increases in pituitary BEND (608). The endocrine disruptor, bisphenol-A administered prenatally and postnatally led to an enhancement of the DA-dependent rewarding effect induced by morphine (785). DAMGO reversed the inhibitory effects of PGE1 upon Na,K-ATPase activity in SH SY5Y neuroblastoma cells; DAMGO increased this activity itself through a cyclosporine- and nifedipine-dependent Ca2+ channel system (1229).
10. Mental Illness and Mood
This section summarizes the few studies examining opioid involvement in mental illness (Section 10a) and mood (Section 10b). 

10a. Mental Illness
Manipulations of Dyn, CREB, BDNF, MCH or Clock proteins in the NAC and VTA in rodents produce unique behavioral phenotypes directly relevant to depression (834). The kappa agonist, salvinorin A, induced two animal models of depression, namely increased immobility on the forced swim test and increased thresholds for ICSS without altering locomotor activity in an open field. These effects were accompanied by decreased DA, but not 5HT concentrations in the NAC (169). Delta agonists, including DPDPE and Delt II, decreased immobility in the forced swim test and increased frontal cortical BDNF mRNA expression in a NTI-sensitive manner, suggestive of anti-depressant actions (1127). The DOR agonist, (+)BW373U86 decreased immobility and increased BDNF mRNA in the frontal cortex, effects blocked by NTI, but not naltrexone or NBNI. Lenk and Menk produced similar patterns of effects, but up regulated BDNF mRNA in the hippocampus through DOR- and MOR-sensitive mechanisms. In contrast, BEND, endomorphin-1 and endomorphin-2 increased BDNF mRNA expression in frontal cortex, hippocampus and amygdala in a naltrexone-sensitive manner without affecting immobility (1304). The enkephalinase inhibitor, RB101 produced antidepressant and increased locomotor effects without inducing seizures, convulsions of alterations in BDNF mRNA expression (543). Whereas ORL-1 agonists produce anxiolytic-type effects on the elevated plus maze, light:dark aversion, operant conflict, startle, ultrasonic vocalizations and hole board tests, either ORL-1 antagonists and OFQ/N KO animals display anti-depressant effects on the forced swimming and tail suspension tests (388). The ORL-1 agonist, Ro64-6198, produced selective inhibition of marble burying in mice without affecting locomotor activity, thereby exhibiting anxiolytic and antidepressant actions (841).
Sustained sadness in depressed women was associated with decreased MOR binding potential in the left inferior temporal cortex, and in the anterior cingulate in those who did not respond to anti-depressants (567). Adherence to naltrexone in opioid-dependent patients produced less depression symptoms (267). Naltrexone reduced alcohol use and craving as well as symptoms measured by the Hamilton Rating Scale for Depression and Young Mania Rating Scale in patients with bipolar disorder and alcohol dependence (137). Nalmefene significantly improved scores on the Yale-Brown Obsessive-Compulsive Scale modified for Pathological Gambling markedly improving 59% of the subjects (413). Naltrexone rendered one-session exposure less effective for phobia treatment (610). Long-term use of high-dose oral naltrexone is safe using hepatic transaminase profiles in otherwise healthy patients with impulse-control disorders who restrict their intake of over-the-counter analgesics (584).
10b. Mood
People with high neuroticism displayed a graded cortisol, but not ACTH response to naloxone, whereas those with low neuroticism displayed a cortisol response that plateau (718). Reductions by naltrexone were observed on repressive coping and disclosure of emotional material (1278). Volunteers displayed less alertness, increased sedation and increased effort to perform a driving test following oxycodone/paracetamol relative to the NSAID, bromfenac (1157). Midgestational women who were battered showed higher levels of anxiety and depression than non-battered pregnant women, and plasma ACTH and BEND levels showed a significant linear relationship in battered, but not non-battered women (1105).
11. Seizures and Neurological Disorders
11a. Seizures
Alfentanil enhanced the amplitude and number of hippocampal CA1 population spikes in control animals, but reduced in such spikes in pilocarpine-treated epileptic rats because of an increase in eliptiform population spikes; these effects were naloxone-reversible (986). Morphine enhanced pilocarpine-induced seizures and status epilepticus (360). The non-peptide delta agonists, SNC80 and (+)BW373U86 produced bilateral ictal and paroxysmal spike and discharges and brief changes in EEG recordings that were subject to quick tolerance and sensitivity to compounds used to treat absence seizures (542). A ketogenic diet decreased Pro-Enk gene expression induced by KA of the granular cells of the hippocampus as well as diminishing KA-induced AP-1 DNA-binding activity, Fos and Jun expression, and the phophorylated form of the three types of JNKs (848). EEG and convulsant effects were noted following the delta opioid agonist SNC80 in one of four rhesus monkeys (260). Encephalitis induced by neurotrophic Borna disease virus induced seizures and DYN loss through hippocampal dentate cell loss. Kappa agonists prevented the seizure activity that was associated with an absence of DYN in dentate gyrus granule cells and an up regulation of Enk in CA1 interneurons (1054). Kappa agonists and antagonists respectively decreased and increased handling-induced convulsions in ethanol withdrawal-seizure prone, but not ethanol withdrawal-seizure resistant mice (69). HSV-1 infection caused loss of hippocampal DYN A reactivity, and the kappa agonist, U50488H blocked ictal activity (1055). Single nucleotide polymorphisms in the MOR subunit gene were not associated with idiopathic generalized epilepsy (66).
11b. Neurological disorders
Estradiol benzoate, but not tamoxifen was capable of blocking the methamphetamine-induced increase in striatal PPE mRNA levels as well as prevent loss of striatal dopamine transporter binding (263). In Parkinson Disease-related research, MPTP-treated monkeys displayed striatal DA denervation and dyskinesia accompanied by an increase in Pro-Enk-A mRNA levels in the rostral and lateral putamen and rostral caudate, effects blocked by pretreatment with the NR1A/2B NMDA antagonist, CI-1041, but not levodopa (802). Primates with Parkinsonian features with or without L-DOPA-induced dyskinesia displayed normal phenotypes of striatal medium spiny neurons, but showed axonal collateralization of striatofugal cells containing Dyn that project to the pars interna and externa of the globus pallidus (811). Naltrexone is one of eight nondopaminergic drugs in which the MPTP-lesioned promate correctly predicted phase II efficacy (356). Mice lacking preproOFQ/N gene expression display less loss of TH neurons in the SN and CP of MPTP-treated mice, but failed to show changes in methamphetamine-induced losses of DA in the CP (138). Aphakia mice that possess a naturally-occurring Pitx3 deficiency, display levo-dopa-sensitive locomotor deficits and such neuronal losses as DA transporter binding and DA receptor expression, Enk, DYN and neurotensin in a manner similar to adult animals receiving neurotoxin administration (1146). Hemiparkinsonian Nur77 KO mice showed exacerbated rotational responses to L-DOPA, and failed to show up-regulation of striatal Enk mRNA levels; DYN levels were unchanged (1071). SP induced toxic effects on SN DA neurons in a microglia-dependent manner in neuron-glial cultures, an effect reversed by DYN (107). The G-allele of the A118G single nucleotide coding region polymorphism of the MOR gene as well as a history of never smoking were independently associated with increased risk of earlier onset of levodopa-induced dyskinesia in Parkinson’s disease (1074).
R6/2 transgenic mice that display symptoms of Huntington’s disease display decreases in NR2A NMDA receptors in proportionally more striatal cells that contain Enk (20). Huntingtin inclusions do not down-regulate Pro-Enk genes in the R6/2 Huntington’s disease mouse (980). Endomorphin-2 protects against the beta-amyloid aggregate creator, Abeta1–42 in vitro and in vivo (1095). Perinatal 6-OHDA lesions decreased striatal DA and SP and increased striatal Menk, effects reversed by chronic perinatal administration of D1 (SKF-38393), but not D2 (quinpirole) agonists (1044). An adenosine A2A antagonist, CSC, but not U50488H produced a reversion of decreases in the duration of levo-dopa-induced rotations in 6-OHDA-treated rats that was accompanied by an increase in levo-dopa-induced preproDYN mRNA in the lesioned ventromedial striatum (120). Animals receiving traumatic brain injury displayed poor motor function for up to five days post-trauma when treated with morphine (1066). Oral exposure to manganese increased manganese levels and neuron injury in striatum and GP with apoptotic cells containing NOS, Enk and ChAT; these effects reduced locomotor activity and striatal DA content (690).
Decoy peptides that bind DYN noncovalently prevent NMDA receptor-mediated neurotoxicity in the spinal cord as well as DYN-induced paralysis and allodynia (1228). Mice bearing the G93A SOD1 mutation that leads to clinical symptoms of familial amyotrophic lateral sclerosis display prolonged survival with daily administration of morphine and taineptine (216). Intrathecal mu and delta, but not kappa agonists dose-dependently and opioid receptor-selectively induced spastic paraparesis in animals exposed to spinal ischemia (545). Intrathecal nicorandil and small-dose morphine can induce spastic paraparesis after a noninjurious interval of spinal cord ischemia in the rat (366). There was a transient loss of motor-evoked responses associated with caudal injection of morphine in a patient with spondylolisthesis undergoing spinal fusion (401). Unilateral labyrinthectomy causing vestibular behavioral deficits was accompanied by pre-pro-Enk up regulation and increased Fos activity in the medial vestibular nucleus. Blockade of this up regulation with naloxone or antisense probes increased the behavioral deficits (590). DYN anti-sera applied soon after spinal cord ischemia attenuated NOS up-regulation, and reduced both spinal edema and cell injury (1022). Endomorphin-1 and to a lesser extent endomorphin-2 inhibited Cu2+ and AAPH, a water-soluble initiator in inducing oxidation of low density lipoprotein, showing protection against free radical-induced neurodegenerative disorders (670). Naloxone failed to alter a postoperative coma in a patient with complete basilar syndrome after anterior cervical disectomy (1134). Neuroprotection by endogenous and exogenous PACAP following stroke was mediated in part by Enk (201).
Gastrointestinal, Renal and Hepatic Functions
14a. Gastric Function
Naloxone or vagotomy does not influence centrally octreotide-induced inhibition of gastric acid secretion in rats. (383). Morphine and opium dependence reduced the severity of postoperative adhesions following abdominal gastric surgery (573).
14b. Intestinal Function
Morphine increased GI transit in horses over a 6 h period decreasing fecal weight and moisture as well as defecation frequency (115). The peripherally-acting opioid antagonist, N-methylnaltrexone reversed these effects (116). Morphine tolerance and dependence increased c-Kit expression in duodenum and ascending colon in a CTOP-sensitive manner (60). Morphine and WIN55212-2 each reduced GI transit, but CB1 antagonism or CB1 KO mice failed to affect morphine-induced inhibition. Similarly, neither naloxone nor naltrexone altered CB1 agonist-induced inhibition of GI transit (168). Morphine delivered by pellets produced far greater Salmonella infection in Peyer’s patches, mesenteric lymph nodes and spleen than morphine delivered by minipump, an effect attributable to greater inhibition of GI transit. Whereas BEND relaxed rabbit jejunum contractility, naloxone respectively increased and decreased contractility at low and high concentrations respectively (239). Chemical coding of Type I myenteric neurons with different axonal projection patterns in the porcine ileum revealed 78% immunoreacted to Enk (540). Delt II, but not DPDPE or U50488H administered by minipump induced moderate Salmonella infection in the spleen, but did not affect GI transit (341). Both salvia divinorum and its active ingredient, Salvinorin A inhibited electrically-induced contractions of the guinea pig ileum, effects reduced by naloxone and NBNI, but not CTOP or NTI (167). Kappa and delta, but not mu opioid agonists enhanced the inhibition of plasma extravasation during chronic relative to acute intestinal inflammation; these effects were reversed by receptor-selective antagonists and NOS inhibitors. Chronic inflammation increased KOR and DOR protein levels in the whole jejunum and mucosa (524). Pro-Enk A mRNA expression is widely expressed in human GI tract, esophagus, pancreas and gallbladder (794). An inherent acceleratory effect of insulin on small intestinal transit could be observed in naloxone-induced inhibition of this response (889). Chronic desipramine treatment produced subsentivity to kappa agonist-induced inhibition of the peristaltic reflex, but supersensitivity to mu agonist-induced inhibition of propulsion velocity. Chronic desipramine treatment decreased both MOR and KOR in the myenteric plexus and colon of guinea pigs (164). The selective mu opioid receptor antagonist, alvimopan, improves delayed GI transit of postoperative ileus in rats (371). Long pulses of intestinal electrical stimulation inhibited canine intestinal motility in a naloxone-insensitive and NO-insensitive manner, but that was reversed by Ach and NE antagonists (686). Enteral naloxone was effective in treating opioid-induced constipation in a pediatric intensive care unit (1123). Low-dose naltrexone was effective for the treatment of irritable bowel syndrome (554).
14c. Nausea and Emesis
Ondansetron, but not droperidol was an effective prophylaxis of nausea and vomiting after intrathecal morphine in women undergoing caesarean section (891). Loperamide reduced kinetosis-induced nausea, and reduced the increases in ACTH and antidiuretic hormone induced by kinetosis in human volunteers (872).
14d. Glucose Function
DYN A(117) increased glucagon release from pancreatic islets with pancreatic beta cells treated with high glucose eliminating DREAM interactions with the Pro-DYN promoter downstream regulatory element, and thereby increasing Pro-DYN promoter activity. DREAM-KO beta cells show increased Pro-DYN activity as well (509). Metformin decreases plasma glucose in STZ-induced diabetic rats through an increase in adrenal BEND secretion to stimulate mu opioid receptors that leads to an increase in GLUT-4 gene expression and a decrease of hepatic PEPCK gene expression (205). Metaformin also decreased fasting plasma glucose in healthy humans that was accompanied by an increase in plasma BEND and a decrease in serum cholesterol (873). The ginsenoside, Rh2 lowered plasma glucose and increased plasma BEND in a naloxone-sensitive manner in control, but not MOR KO STZ rats (625). Exocrine pancreatic secretion is inhibited by both OFQ/N and DOR agonists (672). The plasma glucose lowering action of Hei-Shug-Pian, the fire-processed product of the root of Aconitum was naloxone-reversible in STZ-induced diabetic rats (675). Myricetin lowered plasma glucose and increased plasma BEND in STZ-induced diabetic mice, effects eliminated by bilateral adrenalectomy, opioid receptor antagonists and by deletion of the MOR gene (682).
14e. Hepatic and Pancreatic Function
The analgesic effects of cholestasis induced by bile duct ligation were reduced by peripheral and direct intraplantar injections of naloxone and naloxone methiodide (833). Delta opioid agonists diminished the growth of the biliary tree in the development of cholestasis (736). Menk regulated oxidant-antioxidant status in the liver of CBA mice (1053). Chronic morphine produced pro-oxidant effects in hepatic glutathione concentrations and its synthesis pathway in a naltrexone-sensitive manner (887). Naltrexone and NOS inhibitors corrected the blunted chronotopic and inotropic responses to beta-adrenergic stimulation in cirrhotic rats (305). Naltrexone reduced development of hepatic fibrosis and cirrhosis, MMP2 activity, and decreased the number of hepatic stellate cells in bile duct ligated rats. Activation of hepatic stellate cells increased expressed delta-1 receptors and increased TIMP-1 expression following delta-1 and delta-2 agonists respectively (306). Monocytes and granulocytes from bile duct-ligated rats increased the percentage of opioid receptor labeling, but a decrease in opioid receptor expression on leukocytes due to cholestasis (793).
There is a low utility of plasma OFQ/N in patients with hepatocellular carcinoma (1058). Cholestatic patients with pruritus found limited relief in visual analogue scales for pruritus following naltrexone with virtually half showing withdrawal symptoms associated with the antagonist (721). Pro-Enk hypermethylation was enhanced in pure pancreatic juice compared with p53 mutation in the diagnosis of pancreatic carcinoma (858). A patient with pancreatic cancer with metastases to the liver has survived after four years of treatment with intravenous alpha-lipoic acid and naltrexone (80). Rifampin-mediated induction of oxycodone hepatic metabolism resulted in negative urine opioid screening (637). Naltrexone administration in alcoholic patients did not induce hepatic abnormalities and indeed alanine aminotrasferase and aspartate aminotransferase declined across the 12-week treatment (1270).
14f. Renal Function
PVN OFQ/N decreased RSNA, increased urine flow rate, decreased urinary sodium and potassium excretion, and increased free water clearance, effects that were blocked by renal denervation, [Arg8]VP and ORL-1 receptor antagonism. The ORL-1 antagonist, UFP-101 in the PVN increased RSNA and decreased urine flow (614). OFQ/N increased cystomanometric bladder capacity and voiding and decreased maximum bladder pressure and urine leakage in controlling neurogenic detrusor overactivity in patients (631). Naloxone abolished the recurrent inhibition of the bladder C fiber reflex in the cat (750). Renal failure and elevated creatinine kinase in a heroin addict was treated by fasciotomy and hyberbaric oxygen therapy (4).
Cardiovascular Responses
15a. Heart rate
Morphine stimulated vascular endothelial growth factor-like signaling in mouse retinal endothelial cells (187). U50488H increased HR, but decreased both MAP and renal blood flow in lambs aged 1 and 6 weeks (929). KOR is most abundant in the ventricular and atrial myocardium of the heart; DOR, but not MOR is found more in the atria than ventricles. Ligation of a renal artery increased Pro-Enk levels in ventricular myocardium, whereas isoprenaline administration decreased it (1210). Whereas the vagotonic influence of a Menk analogue was not dependent upon a sympatholytic influence, kappa stimulation with U50488H produced a sustained sympatholytic effect that was not easily reversed by NBNI (64). Mu receptor agonism with DAMGO and antagonism with BFNA respectively increased and decreased HR and systolic blood pressure in control rats, but not rats maintained on a high-fat diet despite the latter’s baseline increases in systolic blood pressure (470). Activation of DOR through the opening of KATP channels reduces the severity of post resuscitation myocardial dysfunction (332). The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of delta2-opioid receptor stimulation (265). Repeated delta-1 opioid receptor stimulation reduces delta2-opioid receptor responses in the sinoarterial node (275). Bradycardia induced by D-Ala2, Leu5, Arg6-enkephalin (dalargin) is associated with activation of peripheral KOR (738). Negative inotropic and chronotropic effects of DOR antagonists are mediated through non-opioid receptors (739). Naloxone-precipitated morphine withdrawal induced PKC inhibitor-sensitive increases in Fos in right and left ventricles, and induced PKC inhibitor-insensitive increases in TH and NE in the heart (22). Baroreceptor activation by pressure in the carotid sinus or by electrical stimulation produced depressor and bradycardic responses that were attenuated by NTS administration of endomorphin-2, but not naloxone (1161). The opioid dipeptide, kytorphin inhibited isoprenaline-induced increases in twitch tension of cardiac muscle without affecting twitch tension itself; this effect was blocked by a kytorphin antagonist and naloxone (657). NO release from lobster heart was enhanced by morphine and decreased by naloxone and the NOS inhibitor, L-NAME (173). However, L-NAME, but not naltrexone exaggerated the hemodynamic response to clonidine in bile duct-ligated rats (1112). Naloxone reduced the immediate lethal response to severe shock in a canine model with a combination of hypertonic-hyperoncotic solutions (385). Administration of naloxone and butorphanol combined with exposure to electric foot shock increased heart and respiratory rate in the lizard, Uromastix hardwickii and the rooster, gallus domesticus (940). Buprenorphine and naloxone in combination with antiretroviral drugs increased the QT interval in HIV-negative and opioid-dependent subjects (56). Abrupt withdrawal from oxycontin decreased the left ventricular ejection fraction and produced new regional wall motion abnormalities (959). Increases in serum BEND by programmed exercise training were correlated with improvement of clinical symptoms and quality of life in female mitral valve prolapse patients (496).
15b. Cardioprotection and ischemic preconditioning
Chronic morphine was more effective than acute morphine in restoring diastolic and contractile function during cardioprotection; G(i) inhibition reduced affected both acute and chronic morphine effects. Whereas a G(s) inhibitor or PKA inhibitor blocked only chronic effects, a PKC inhibitor blocked only acute effects (888). Morphine attenuated hemorrhagic shock-induced hyper permeability (182). Morphine and naloxone respectively decreased and increased the rate of hemorrhage-induced hypovolemia in sheep (363). The JAK/STAT pathway is essential for opioid-induced cardioprotection with JAK2 acting as a mediator of STAT3, Akt and GSK-beta (418). Morphine-induced neuroprotection of hippocampal neurons following oxygen-glucose deprivation was partially blocked by single and combined treatment with chelerythrine, a PKC blocker, epsilonv(12), a nPKCepsilon antagonist and MK-801 (333). Opioid preconditioning with Tan-67 induces opioid receptor-dependent neuroprotection against ischemia in rats (1319). Opioid receptor-independent protection of ischemic rat hepatocytes was observed following morphine (581). Central and peripheral opioid receptor antagonists block the cardioprotective effects of fentanyl (649).
Myocardial ischemic tolerance occurs in the newborn rat and involves opioid receptors and mitochondrial K+ channels (807). Menk-Arg6-Phe7 produced cardioprotection in the ischemic preconditioning model (283). Activation of ERK and suppression of calcineurin interact in cardioprotection produced by DOR activation (500). The delta agonist, SNC-121 blunted the ischemic-induced increases in cardiac myocyte death produced by mineral oil layering to reduce gas exchange (882). Hypoxic preconditioning reduces glutamate-induced neuronal injury by increasing cortical DADL binding density without affecting DOR mRNA in a NTI-sensitive manner. In contrast, prolonged hypoxia causes severe neuronal injury and decreases DADL binding and DOR mRNA levels (1307). ARD-353, a nonpeptide delta agonist decreased infarct size following coronary artery occlusion that was blocked by a delta-1 antagonist (1201). Kappa agonists significantly reduced infarct size and plasma lactate dehydrogenase level by ischemia-reperfusion in a NBNI-sensitive manner (1312). Kappa-opioid receptor antagonism improved recovery from myocardial stunning in chronically instrumented dogs undergoing left anterior descending artery ischemia (419). Morphine and fentanyl respectively enhance and retard recovery of ventricular function after cardiopulmonary bypass (808).
15c. Blood pressure
Morphine exposure increased MAP and HR, and spontaneous morphine withdrawal produced a prolonged 72 h increase in MAP as measured by telemetry (761). BEND acts in limbic circuits as a depressor in regulation of arterial pressure as it relates to the development of essential hypertension (617). Blockade of endothelin-1 release contributes to the anti-angiogenic effect of POMC over expression in endothelial cells (628). Endomorphins restore the endothelium-dependent relaxation of the rabbit aorta rings exposed to high D-glucose through a NO-c-GMP pathway (683). Endomorphin2-ol was more potent than endomorphin2, but endomorphin1-ol was less potent than endomorphin1 in reducing systolic arterial pressure and heart rate with the former measure reversed by pretreatment with naloxone, atropine, L-NAME and bilateral vagotomy (1281). Morphine, meperidine, fentanyl and remifentanil all produced a concentration-dependent vasorelaxation of human artery rings that was insensitive to naloxone (431). Vasorelaxation induced by U50488H in the pulmonary artery was blocked by the K(V) channel blocker 4-AP, but not glibenclamide or TEA (1088). Arterial partial pressure of oxygen was significantly in horses receiving morphine during upper respiratory tract surgery (699). Stimulation of sensory neuropeptide release by OFQ/N leads to hyperaemia in acutely inflamed rat knees (1303). Remifentanil, sufentanil and fentanyl each induced a dose-dependent vasodepressor response in the cat pulmonary vascular bed that was attenuated by naloxone and diphenhydramine, but not glibenclamide (562,564,565). In contrast, meperidine induced a dose-dependent vasodilator response in the cat pulmonary vascular bed that was attenuated by naloxone and diphenhydramine, but not glibenclamide (563). The dextro-, but not levo-isomer of tramadol produces a concentration-dependent and naloxone-reversible relaxation of rodent aorta precontracted with phenylephrine (939). Tramadol stereoselectively attenuated endothelium-dependent relaxation in isolated rat aorta induced by Ach (1030). Spinal estrogen attenuates the exercise pressor reflex without changing gene expression of opiate receptors in the DRG (998). Hemorrhage induces c-Fos in arcuate POMC neurons and increases POMC mRNA in the MBH. Caudal arcuate administration of lidocaine inhibited hemorrhagic hypotension and bradycardia without affecting MAP or HR (405). Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis through receptor transactivation (1043). Transcutaneous magnetic stimulation of the Jianshi-Neiguan acupoints decreased the reflex pressor response, effects blocked by median nerve denervation or by pretreatment with general, kappa, delta, but not mu antagonists (1324). Naloxone blocked the ability of SP(17) to inhibit SP-induced vasodilation in a rodent model of inflammation of the hindpaw (1217).
Exaggerated opioid analgesia is observed in persons at enhanced risk for hypertension (754). Combined spinal-epidural anesthesia with intrathecal bupivacaine produced analgesia with lower incidence of maternal hypotension for cesarean delivery (1114). Low, but not high levels of trait anger in chronic low back pain sufferers were associated by naloxone-induced impairments in post-pain blood pressure (143). Formation clearance of morphine to M3G is reduced during the first 10 days in neonates undergoing venoarterial extra corporeal membrane oxygenation (901). Remifentanil attenuated hemodynamic changes after induction and tracheal intubation during cesarean delivery (566).
Respiration and Thermoregulation
DAMGO applied to the rostral ventrolateral medulla of newborn rats depressed fourth cervical ventral root inspiratory activity with facial nerve activity continuing to synchronize with pre-inspiratory bursts both in normal pups and pups receiving transverse sectioning between the pre-Botzinger complex and the parafacial respiratory group (867). DAMGO also depressed confocally imaged respiratory center neurons in on-line-calibrated newborn rat brainstem slices (977). Fentanyl-induced modulation of inspiration and expiration in juvenile rats was dissociated with caudal transactions at the level of the facila nerve blocked the latter response, but not the former response (511). Recurrent hypoxia in rats during development increases subsequent respiratory sensitivity to fentanyl (805). Morphine increases the transmesothelial resistance of the sheep parietal pleura in an in vitro preparation (1170). Morphine decreases gill ciliary activity through coupling to NO release in a bivalve mollusk (722). Optimal assessment of anesthesia associated with regular respiration, loss of blink, papillary and pedal withdrawal reflexes was obtained with intra-nasal doses of fentanyl, droperidol and medetomidine in mice (632). Both naloxone and peripherally-acting naloxone methiodide reversed the respiratory depression and analgesia induced by morphine, methadone and heroin, effects that did not appear to be sex-dependent in mice (651). Naloxone and epinephrine were equally effective for cardiopulmonary resuscitation in a rat asphyxia model (193, 194). Naloxone reversed buprenorphine-induced respiratory depression (1147). Naloxone did not increase the minimum alveolar anesthetic concentration of sevoflurane in mice (664). Lenk decreased the burst frequency of the membrane potential of pre-Botzinger complex respiratory center neurons (503). OFQ/N reduced respiratory frequency in an apnea model of isolated brainstem-spinal cord newborn rat preparation, effects reversed by an ORL-1 antagonist, an activator of adenylyl cyclase and a phosphodiesterase-4 (but not 3 or 5) inhibitor (976). OFQ/N inhibited acid-invoked cough in guinea pigs by blocking acid-induced increases in Ca2+ in vagal jugular ganglionic neurons by inhibiting the sustained component of acid-induced inward current (640). Two analogues of OFQ/N, but not nocistatin reversed the inhibition by OFQ/N of electric field stimulation-induced excitatory nonadrenergic-non cholinergic and cholinergic constriction of the guinea pig isolated bronchus (1267). Endomorphin-1 and endomorphin-2 inhibited the response to electrical field stimulation in rat isolated bronchus at low, but not higher frequencies, and also inhibited cholinergic constriction in a naloxone-reversible manner, but had no effect upon the contractile response to exogenous Ach (1280); these effects were present in diabetic rats, but the endomorphin response was less marked (1282). 

The acute agonal period during heroin overdose death is characterized by variations in respiratory distress (482). Heroin produced contact allergy and respiratory and mucosal complaints (475). Maximal buprenorphine-induced decreases in respiratory rate and pupil diameter did not vary across doses in experienced opiate users, nor did subjective effects change (226). High doses of buprenorphine cause naloxone-insensitive respiratory depression, particularly in conjunction with benzodiazepine use (763). Whereas fentanyl produced dose-dependent decreases in respiratory rate in volunteers undergoing anesthesia, buprenorphine caused respiratory depression that leveled at 50% of baseline rates (255). Midazolam and morphine can produce harmful effects on cerebral oxygenation and hemodynamics in ventilated premature infants (1144). In neonates receiving central line placement for ventilation, combinations of morphine and tetracine provided superior analgesia with the former producing respiratory depression and the latter producing erythema (1096). Codeine was no more effective than placebo in an objective measurement of cough in chronic obstructive pulmonary disease (1046). There was no significant difference in the time to extubation after use of remifentanil and sufentanil in combination with propofol as anesthesia in adults undergoing nonemergency intracranial surgery (285).
16b. Thermoregulation
DAMGO administered into the NRM blocked noxious stimulation-evoked suppression of PGE2-induced BAT temperature increases (821). SNC80-induced hypothermia was attenuated by central L-NAME administration as well as by combined peripheral L-NAME and 7-NI administration (942). SNC80-induced produced hypothermia in a NTI-sensitive manner, an effect blocked by the 5HT1A antagonist, WAY100635, and enhanced by non-hypothermic doses of fluoxetine (943). Hydromorphone produced post anesthetic hyperthermia in cats (843). The ability of the GABA B agonist, baclofen in the pre-optic/anterior hypothalamus to decrease tonic activity and increase temperature sensitivity through membrane hyper polarization and decrease of input resistances was inhibited by the mu-opioid agonist, PL-017 (1252). Bile duct-ligated rats displayed hypothermia that was reversed by opioid antagonism and NOS inhibition (791). Naloxone restored heat stress-induced declines in GABA and glycine and prevented heat stress-induced increases in glutamate and aspartate (1019). The SSRI fluoxetine abated naloxone-induced increases in tail-skin temperature in ovariectomized rats (740). The 5HT2A antagonist mirtazapine increased tail temperatures following naloxone administration in morphine-dependent rats (886). Post-burn local hyperthermia in reducing burn injury was blocked by naloxone (1011). Intrathecal morphine intensified the intra-operative hypothermia induced by bupivacaine spinal anaesthesia for caesarean section (491).
Immunological Responses
Intrathecal chronic administration at the maximum tolerated doses of morphine hydromorphone, L-methadone, and naltrexone produced granulomas (21). POMC gene transfer, and particularly AMSH, reduced anchorage-dependent growth of melanoma cells in mice by reducing foci formation in lung attenuating their migratory and adhesive capabilities (678). Morphine decreased metalloproteinase activity through the NO-NOS system, implicating it in the treatment of fibrosarcoma (1016). Morphine stimulated CCL2 production by human neurons (964). Chronic, but not acute morphine induces apoptosis in neurons and astrocytes accompanied by up-regulation of FasL, Fas, Bad and active fragments of caspases-8 and –3 (317). Morphine promoted Jurkat cell apoptosis through pro-apoptotic FADD/P53 and anti-apoptotic PI3K/Akt/NF-kappaB pathways (1273). Morphine enhanced apoptosis of cultured human colonic cells in a NOS inhibitor-sensitive fashion, and produced a breach in the host defense barrier in a NOS inhibitor-insensitive fashion (361). Non-apoptotic cell death is induced by morphinone in human promyelocytic leukemia HL-60 cells (1104). Reduction of the brain apoptosis-related proteins, Fas, FasL, Bad and Bax occurred following naltrexone in mice (987). Morphine-induced suppression of natural killer cell activity was blocked by the NPY Y1 antagonist, BIBP3226 (992). Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation (772). Morphine, DAMGO, DPDPE and U-69593 all produced neuroprotective effects against low-temperature-induced cell death in cultured hamster hippocampal neurons (1106). TPA increases expression and regulation of MOR in TPA-differentiated HL-60 promyelocytic leukemia cells (75). Interferon-gamma down-regulates transcription of the MOR gene in neuronal and immune cells (612). Morphine modulates the monocyte-macrophage conversion phase in an opiate antagonist-sensitive manner (456), and naloxone inhibits macrophage activation and atherosclerosis formation in mice (688). Acute morphine and morphine withdrawal inhibit phagocytosis through pertussis toxin-sensitive and –insensitive mechanisms respectively with the latter, but not former manipulation increasing cAMP levels (705). Over expression and blockade of cyclin-dependent kinase 5 respectively augmented and diminished DAMGO-induced neuroprotection from serum deprivation (1195). DAMGO induced up-regulation of annexin V apoptosis-inducing gene expression in PC12 cells stably transfected with MOR (1291). DAMGO inhibited ERK-1 and Akt signaling pathways activated by the chemokine receptor CXCL12 and abolished its neuroprotective effects during NMDA-induced neurotoxicity, effects reversed by general and mu antagonists (883). SNC, but not mu or kappa agonists promoted neural differentiation from multipotent stem cells through the activation of Trk-dependent tyrosine kinase (814). There is a requirement for Id1 in BEND opioid-induced oligodendrogensis in cultured adult rat hippocampal progenitors (899). Insulin decreased histamine and 5HT, but not BEND content in the thymus of in vitro preparations (251). The nucleus of rat peritoneal mast cells contained serotonin and histamine, but not BEND, insulin or triiodothyronine (252). EDAC fixation increases histamine, but not BEND, levels in such cells relative to paraformaldehyde (253). 

Loperamide reversed the inhibition of insulin-stimulated 2DG uptake by tumor necrosis factor alpha in myoblast C2C12 cells (601). Chimeric DNA vaccine reverses morphine-induced immunosuppression and tumorigenesis (206). Morphine dependence diminished virus evolution in SHIV/SIV-infected rhesus macaques with an inverse relation between virus evolution and onset of clinical symptoms (1121). Chronic morphine exposure causes pronounced virus replication in the cerebral compartment and accelerated onset of AIDS in SIV/SHIV-infected Indian rhesus macaques (620). HIV-1 gp120 up-regulation of MOR occurred in TPA-differentiated HL-60 cells (74). Menk maintained the viability of SIV-infected cells through suppression of the expression of caspase-3 (1248). Delta opioid agonists attenuate HIV protein TAT(172)-induced oxidative stress in SK-N-SH cells (1176). The increased vulnerability of ApoE4 neurons to HIV proteins and opiates were provided protection by diosgenin and L-deprenyl (1137). HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines (312). CCR2 mediates the increases in glial activation by exposure to HIV-1 Tat and opiates (311). There was a correlation between SIV Tat evolution and AIDS progression in cerebrospinal fluid of morphine-dependent as compared to control macaques infected with SIV and SHIV (847). Naltrexone inhibits alcohol-mediated enhancement of HIV infection of T lymphocytes (1189). Further, an in vitro model of morphine withdrawal manifests the enhancing effect of HIV infection of human T lymphocytes through the induction of substance P (1190). Acupuncture reduced leukocyte migration into the mouse air pouch in a peripheral, but not spinal naloxone-reversible manner, but did not produce an anti-inflammatory effect (580).
Down-regulation of the opioid growth factor receptor is associated with progression of squamous cell carcinoma of the head and neck (760), yet the opioid growth factor receptor is unaltered with the progression of human pancreatic and colon cancers (1286). Regulation of corneal repair was effectuated by particle-mediated gene transfer of opioid growth factor receptor complementary DNA (1287) with corneal safety of topically applied naltrexone validated (1285). Adaptation of the homeostatic ocular surface epithelium occurred following chronic treatment with naltrexone (1288). Pro-ENK KO mice developed less severe clinical signs of experimental autoimmune encephalomyelitis than wild-type mice that was accompanied by a reduction in MOG(3555)-specific IFNgamma-producing cells (1212). Tumor-cell-targeted Menk analogues containing unnatural amino acids display in vitro antitumor activity (481). DADL stimulates Akt-dependent phosphorylation of c-jun in T cells (1010). DPDPE triggers monocyte adhesion even in pertussis toxin-treated cells, indicating involvement of G proteins other than Gi. This adhesion requires integrins, PI3Kgamma activation, and involves Src kinases, a guanine nucleotide exchange factor and a small GTPase (893). Chemotaxis of human and rat leukocytes is observed following the delta-selective non-peptidergic opioid SNC 80 (868). Deletion of the DOR in mice increases skin differentiation and delays wound healing (95). Kappa opioids induce a reversible inhibition of CFU-GM from CD133(+) cord blood cells (286). OFQ/N and ORL-1 KO respectively stimulate and reduce TNFalpha and IFNgamma transcripts in the spleen when challenged with staphylococcal enterotoxin A (407). Lipopolysaccharide induces ProEnk transcription in hypophysiotropic neurons of the rat periventricular hypothalamic nucleus suggesting a neuroendocrine role for Enk during immune stress (321). Interleukin-1 beta contributed to the up regulation of KOR mRNA in the DRG in response to peripheral inflammation (926). Lipopolysaccharide-induced interleukin-6 production in a mouse monocyte cell line is reduced by the kappa agonist, U50488H in a NBNI-sensitive manner (879). Lipopolysaccharide induced PC1/3 and PC2 substrate pro-Enk in the marginal zone of rat spleens (629). The expression of Pro-DYN gene is down-regulated by activation with lipopolysaccharide in U-937 macrophage cells (1086).
Source and Footnotes, as well as some capitals i dont copy: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693002/?tool=pubmed

Abstract

In preparation for a trial on co-prescription of heroin to chronic treatment-resistant addicts, a pharmaceutical dosage form for smokable heroin was developed. During development of this product (a mixture of diacetylmorphine and caffeine), in vitro experiments were performed simulating ‚chasing the dragon‘: the technique used by addicts for inhalation of heroin after volatilisation. Samples were heated on aluminium foil using a heating device and the vapours were collected and analysed using a HPLC-UV method. The recovery of diacetylmorphine and caffeine in vapours was studied after volatilisation of different powder mixtures at temperatures between 200 and 350 degrees C. Furthermore, the volatilisation set-up was combined with an Andersen sampler to determine the sizes of aerosol particles. Only small differences in recovery of diacetylmorphine and caffeine were found between temperatures and between powder mixtures: 46-62% of diacetylmorphine from the sample was recovered in vapour and 65-83% of caffeine. The only degradation product detected in vapour was 6-acetylmorphine (4.1-7.1%). In the temperature range studied, temperature mainly influenced the volatilisation rate. Mass median aerodynamic diameters of aerosols from diacetylmorphine-containing samples ranged from 1.8-4.1 microm; 45-60% of each sample was recovered as aerosol particles <5 microm. Volatilising pharmaceutical smokable heroin resulted in sufficient amounts of diacetylmorphine in vapour and in particles suitable for effective deposition in the lungs.

Pharmaceutical heroin for inhalation was developed for a clinical trial on co-prescription of heroin and methadone to chronic treatment-resistant heroin addicts. Diacetylmorphine base was selected as the active pharmaceutical ingredient for this product with caffeine anhydrate added as an excipient. Differential scanning calorimetry and thermogravimetric analysis showed that addition of caffeine resulted in a lower melting temperature and a higher volatilisation rate for the mixture than for diacetylmorphine base alone. Recovery experiments showed that 40.8+/-5.3% of diacetylmorphine base could be found in smoke condensate after volatilisation of diacetylmorphine-caffeine tablets. All of the caffeine from each tablet was recovered unchanged in the fumes, while 85.6% of the diacetylmorphine from each tablet was recovered, either unchanged in the fumes or as non-volatilised residue. Recovery was found to be reproducible and only small differences were found between the tablet types. The experimental set-up was found to efficiently collect the vapours resulting from heating the powder. Under the tested experimental conditions, no evidence was found that degradation products of diacetylmorphine or caffeine, other than 6-acetylmorphine (5.9%) had volatilised, even though a decomposed residue was present after heating diacetylmorphine-caffeine samples. Diacetylmorphine-caffeine was found to be a suitable basis for pharmaceutical heroin to be used by ‚chasing the dragon‘.

source: http://www.ncbi.nlm.nih.gov/pubmed/16039820

In diacetylmorphine prescription programs for heavily dependent addicts, diacetylmorphine is usually administered intravenously, but this may not be possible due to venosclerosis or when heroin abuse had occurred via non-intravenous routes. Since up to 25% of patients administer diacetylmorphine orally, we characterised morphine absorption after single oral doses of immediate and extended release diacetylmorphine in 8 opioid addicts. Plasma concentrations were determined by liquid chromatography-mass spectrometry. Non-compartmental methods and deconvolution were applied for data analysis. Mean (±SD) immediate and extended release doses were 719 ± 297 mg and 956 ± 404 mg, with high absolute morphine bioavailabilities of 56% to 61%, respectively. Immediate release diacetylmorphine caused rapid morphine absorption, peaking at 10 to 15 min. Morphine absorption was considerably slower and more sustained for extended release diacetylmorphine, with only ~30% of maximal immediate release absorption being reached after 10 min and maintained for 3 to 4 h, with no relevant food interaction. The relative extended to immediate release bioavailability was calculated to be 86% by non-compartmental analysis and 93% by deconvolution analysis. Thus, immediate and extended release diacetylmorphine produce the intended morphine exposures. Both are suitable for substitution treatments. Similar doses can be applied if used in combination or sequentially.

Opioid misuse and addiction embody a grave public health issue. Treatment in most countries is primarily based on methadone and buprenorphine maintenance programs (Van den Brink and Haasen, 2006, Amato et al., 2005). However, treatment response is often incomplete, and many heavily dependent narcotic addicts cannot be included or retained in these programs. Therefore, Switzerland and several other countries now include diacetylmorphine as an additional option for heavily dependent narcotic addicts (Fischer et al., 2007, van den Brink et al., 2003, Sheldon, 2008, Haasen et al., 2007, Brissette, 2001). Based on the three most relevant clinical studies in Switzerland, the Netherlands, and Germany, heroin-assisted treatment is superior to other opiod-assisted treatments such as methadone (Rehm et al., 2001, van den Brink et al., 2003, Haasen et al., 2007, Verthein et al., 2008). In particular, this treatment targets previously untreated intravenous drug users or non-responders to conventional methadone treatments, who subsequently show improvements in health status, often dramatically, less treatment dropout, reduced consumption of other psychotropic substances, and other social improvements. Based on these successful study outcomes, the Swiss and the Dutch health authorities have registered an intravenous diacetylmorphine formulation, and oral formulations have been submitted in Switzerland for marketing approval. In addition, other countries such as Spain, Belgium, Denmark, Canada, and the United Kingdom are planning or have already completed clinical trials with heroin-assisted treatments.

 

Treatment based solely on injected heroin as a substitution medication can be problematic. While effective, it requires considerable resources as patients usually inject three times a day under supervised conditions at treatment centres, which requires long operating hours and puts high demands on personnel and security. Moreover, not all patients fulfil the admission criteria; in many countries, a considerable fraction of opioid dependents do not inject. In the Netherlands, for instance, most users (i.e. 75% to 90%) inhale heroin by ‘chasing the dragon’. Also in other countries, many users do not inject opioids for various reasons, including fear of infection risk or inability to puncture their veins. Moreover, an increasing number of patients participating in heroin-assisted treatment programs suffer from venosclerosis, preventing them from performing intravenous administration. These situations require other means of administering heroin as a substitute medication: oral substitution with diacetylmorphine has been used in Switzerland for a decade. Frick et al. demonstrated that the one year retention rate for solely orally-substituted subjects within the Swiss heroin-assisted treatment programs was 80%, which was above the 70% obtained from historical controls treated intravenously with diacetylmorphine (Frick et al., 2006). In 2006, one third of all diacetylmorphine used in the Swiss heroin prescription program was given as tablets (National Prevention Programmes of the Swiss Federal Office of Public Health, 2007) Furthermore, up to 25% of patients in this program receive diacetylmorphine doses orally (Bundesamt für Gesundheit, 2004).
It is often straightforward to characterise the absorption of oral immediate release preparations by model-independent estimation of bioavailability, maximal concentrations (Cmax), and time of maximal concentration (tmax). Alternatively, compartmental analysis may be used under the assumption of zero or first order absorption. For extended release preparations, analysis requires parameters describing the extent of fluctuation in plasma concentrations (Steinijans, 1990). Ignorance of the appropriate in vivo extended release absorption function often requires the use of deconvolution techniques (Fattinger and Verotta, 1995a, Fattinger and Verotta, 1995b, Fattinger et al., 2000, Pitsiu et al., 2001). This approach provides not only parameter estimates characterising plasma level fluctuations, but also yields the entire drug absorption rate profile over time, allowing comparison of in vivo absorption rate with in vitro dissolution profiles (Pitsiu et al., 2001).
We have shown previously that even large doses of oral immediate release diacetylmorphine yield only negligible systemic diacetylmorphine and monoacetylmorphine exposure, but result in an unexpectedly high morphine bioavailability of 67% (Girardin et al., 2003). Since many patients use extended release diacetylmorphine in addition to or instead of the immediate release form, often switching between formulations, we now characterise and compare morphine absorption of the two formulations in 8 opioid-addicted patients. For the extended release formulation, the study also explores the influence of a high-fat breakfast on morphine absorption.
2.1. Materials
Diacetylmorphine hydrochloride as immediate and extended release tablets of 200 mg were obtained from DiaMo Narcotics Ltd. (Thun, Switzerland). Deuterium-labelled morphine (morphine-N-methyl-d3, morphine-d3) was obtained from Lipomed (Arlesheim, Switzerland) and doses for intravenous administration were prepared by the canton Zurich pharmacy (Kantonsapotheke Zürich, Switzerland). Diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, morphine-d3, morphine-d3-3-glucuronide, morphine-d3-6-glucuronide, and codeine-d3 used as assay standards were purchased from Lipomed (Arlesheim, Switzerland).
2.2. Immediate and extended release diacetylmorphine preparation
The immediate release preparation is a coated tablet with 200 mg diacetylmorphine hydrochloride as the active ingredient. At least 80% of the dose is released within 15 min (Conditions: Water, 37°C, Paddle 50 rpm). The immediate release preparation shows a fast disintegration within 300 s in water at 37°C. In contrast, the extended release preparation is a coated matrix formulation, which releases the 200 mg of diacetylmorphine hydrochloride gradually over 12 h under the same conditions as above. The in vitro dissolution is specified with 20–40% release within 1 h, 45–65% within 4 h, and 80–100% within 10 h. Figure 1 shows the in vitro dissolution profiles of the two formulations.
 

Figure 1

 

Figure 1 

In vitro diacetylmorphine dissolution profiles of immediate and extended release tablets
 

Figure 1

 

Figure 1
In vitro diacetylmorphine dissolution profiles of immediate and extended release tablets
Six single tablets of immediate (IR) or extended release (ER) diacetylmorphine were subjected to dissolution profiling with a standard USP dissolution apparatus. Values are given as mean ± standard deviations.
2.3. Clinical study
The study protocol was approved by the ethics committee of the canton of Zürich. Volunteers requiring a stable daily parenteral and/or oral diacetylmorphine dose of at least a 300 mg parenteral dose equivalent were recruited from the Swiss heroin prescription programs. Parenteral dose equivalents were calculated by converting oral doses to parenteral doses by dividing them by three and summing them with parenteral doses. The morphine bioavailability of 67% obtained in our previous study (Girardin et al., 2003) suggests that a lower conversion rate may be feasible. However, we again used the previously applied conversion rates (Girardin et al., 2003), since no signs of overdose were observed in the previous study (Girardin et al., 2003) and our main concern was withdrawal symptoms and the need for additional opioid delivery during the 7 or 11 h study sessions. Potential volunteers were first contacted by their treating physician within the program and referred for further evaluation. Among 47 referred volunteers, 37 had to be excluded because of inaccessible veins (16), lack of cooperation (8), elevated transaminases (7), anaemia (3), concomitant medications (2), or impaired gastric emptying (1). Two further volunteers withdrew after the first study day. Written informed consent was obtained from all subjects prior to participation. A total of 8 volunteers, 4 women and 4 men, finished the study and were included in the analysis. All 8 volunteers were heavy smokers, with a mean age of 37 (28 to 50) years and a body weight of 62.3 (59 to 84.5) kg. Two volunteers reported occasional use of cannabis and another two of cocaine. On the first study day, urine drug testing for ethanol, cocaine, methadone, barbiturates, benzodiazepines, amphetamines, and lysergic acid diethylamide (LSD) were negative in all volunteers, but were positive for cannabis in two of them. All volunteers exhibited normal renal function and no signs of liver damage (i.e., normal plasma transaminases, bilirubin, INR, normal abdominal ultrasound examination, and negative hepatitis B and C serology).
Volunteers had been opioid-dependent for 3 to 20 years and had participated in the HeGeBe for an average of 2.9 years (range: 4 weeks to 7 years). The mean daily parenteral diacetylmorphine dose equivalent amounted to 471 mg/d (300 to 867 mg/d). None of the volunteers took any additional medications for at least 3 days before or during the study. The oral diacetylmorphine doses for the study sessions were selected based on daily parenteral diacetylmorphine dose equivalents. To ensure that volunteers would not be over-sedated or develop withdrawal, immediate release diacetylmorphine doses amounted to 1.5-times the individual parenteral diacetylmorphine dose equivalent and the corresponding study sessions were limited to 7 h. To extend the study sessions to 11 h after administration of the extended release preparation, we increased doses in this case to 2 times the parenteral diacetylmorphine dose equivalent.
After an overnight fast (i.e. no food or beverages except water after 11 pm), the volunteers arrived in the hospital at 7 AM and then stayed for 3 days at the Clinical Research Unit. A catheter was placed into the radial artery for blood sampling and into a vein of the other forearm for morphine-d3 administration. On the morning of the first study day, immediate release diacetylmorphine was administered orally with 100–200 ml of water. In addition, 15 mg of morphine-d3 dissolved in 30 ml NaCl was infused intravenously over 5 min starting immediately after the oral dose. Arterial blood samples (4.5 mL) were collected prior and 2.5, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 90, 120, 180, 300 and 420 min after the oral diacetylmorphine dose. On one randomly selected morning of the second or third study day, the volunteers first ate a standardized (high fat content) breakfast consisting of 200 ml whole milk, 2 slices of toast, 20 g of butter, 55 g of Emmental cheese, one boiled egg, and 30 g of corn flakes (corresponding to 51 g of fat, 53 g of carbohydrates and 33 g of proteins). Thereafter, or on an empty stomach as on the first study day, the oral diacetylmorphine extended release dose was administered with 100–200 ml of water. Four subjects fasted on the second day and 4 were fed, and patients switched groups on the third day. Arterial blood samples were collected prior and 10, 20, 30, 40, 50, 60, 80, 100, 120, 150, 180, 210, 240, 270, 300, 360, 420, 480, 540 and 660 min after the diacetylmorphine dose. All blood samples were collected directly into vials preloaded with sodium fluoride and centrifuged at 4 °C. The plasma was stored at −20 °C until analysis.
Standardized meals were served on each day for lunch (4 h after the dose) and dinner. After the first hour, the volunteers were free to smoke cigarettes. During the period between the last blood sample and 10 PM, the volunteers received additional intravenous or oral immediate release diacetylmorphine (on average, 280 mg (day 1) and 230 mg (day 2 and 3) of parenteral dose equivalents) to maintain constant daily diacetylmorphine dosing.
2.4. Determination of morphine, morphine-d3, and metabolite concentrations
Plasma concentrations of diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, morphine-d3, morphine-d3-3-glucuronide, and morphine-d3-6-glucuronide were determined by liquid chromatography-mass spectrometry (LC-MS) with a quantification limit of 10 nmol/L as described previously (between-day precision < 9.5%, accuracy for all analytes between 97.4% and 103.7%) (Rentsch et al., 2001, Girardin et al., 2003).
2.5. Non-compartmental pharmacokinetic analysis
Individual morphine and glucuronide plasma half-life (t1/2) were calculated from the pharmacokinetic data after intravenous morphine administration as t1/2 = ln2/λ, where λ represents the slope of the terminal part of the plasma concentration-time curve after semi-logarithmic transformation. The areas under the plasma concentration-time curve (AUCs) were calculated as AUC(0-∝) = AUC(t0-tlast) + Clast / λ − C0 / λ, where tlast was the time of the last measurable plasma drug or metabolite concentration above the detection limit, Clast was the plasma drug or metabolite concentration of this last sample, and C0 was the plasma drug or metabolite concentration at the time of drug administration (t0). AUC(0-tlast) was calculated by the trapezoidal rule with linear interpolation.
Total plasma clearances were calculated from AUC and dose (D) for intravenous morphine-d3 as CL = D / AUC. The volumes of distribution at steady state (Vss) were calculated as Vss = D * (AUMC) / (AUC)2, with AUMC being the total area under the first moment of the plasma concentration time curve (Gibaldi and Perrier, 1982). Absolute and relative bioavailability (F) were determined as F = (AUC1 / D1) / (AUC2 / D2), where AUC1, D1, AUC2 and D2 corresponds to AUC and dose for the oral diacetylmorphine versus the intravenous morphine-d3 dose, the oral extended versus immediate release dose, or the extended release dose administered in the fed and fasted state. To measure the fluctuation of plasma concentrations, we calculated the percent peak trough fluctuation (%PTF) as 100 * (Cmax − Cmin) / Cavg with Cavg = AUC0-11h / 11 h and the percent AUC fluctuation (%AUCF) as 100 * (AUC(above Cavg) + AUC(below Cavg)) / AUC. (Steinijans, 1990). The geometric mean of absolute and relative bioavailabilities and other parameter estimates, as well as the corresponding confidence intervals, were then calculated.
2.6. Deconvolution analysis
If we view each subject as a linear, time-invariant system characterized by its morphine disposition function, K(t), we can relate the serum concentration response C(t) of that subject to an arbitrary morphine or diacetylmorphine dosage using a convolution of the absorption rate function, A(t), with the individual disposition function, K(t): 

equation M1
The population (sample) average disposition function was estimated from the plasma concentration data collected after intravenous morphine-d3 administration using a standard two compartment model parameterised as k10, V1, k12, and k21, with interindividual variability on each parameter. A one-compartment model fitted the intravenous data considerably worse: we observed a difference in objective function (ΔOF) of 686 points, which is highly significant (the approximate 0.05% confidence level ΔOF is 3.9). No relevant improvement of the fit was achieved with the inclusion of a third compartment. As a by-product of the (population) fit, the individual empirical Bayes estimates for the bi-exponential IV disposition functions were obtained. Drug absorption was described by a positively constrained linear (population) spline function for each study occasion, i.e. the administration of the immediate release dose, the extended release dose in the fasted state, and the extended release dose after a high-fat breakfast, and estimated from the data conditional on the individual bi-exponential disposition functions obtained from the intravenous morphine-d3 data analysis. The breakpoints of the spline were set at the quantiles of the data (Fattinger and Verotta, 1995a, Fattinger and Verotta, 1995b, Fattinger et al., 2000, Pitsiu et al., 2001), and the spline(s) were parameterized to directly estimate absolute or relative bioavailabilities from the data of one or two study occasions combined (The corresponding NONMEM control stream and the data of two patients are given in Appendix 1). The 90% and 95% confidence intervals for the absolute or relative bioavailability estimates were obtained using a likelihood ratio profile (Bates and Watts, 1988).
3.1. Adverse events
All study doses were well tolerated. Only one adverse event was observed in which one volunteer requested one dose of paracetamol for a headache during the second night. Diacetylmorphine dosing was considered adequate on all study days.
3.2. Non-compartmental pharmacokinetic analysis
Intravenous morphine-d3 

The AUC(0-∝) (mean ± SD) for morphine-d3, morphine-d3-3-glucuronide, and morphine-d3-6-glucuronide was 30.7 ± 5.62, 250 ± 77, and 30 ± 9 min*μmol/l, respectively Morphine-d3 exhibited a clearance of 1.7 ± 0.3 l/min, a volume of distribution at steady state of 151 ± 42 l, and a terminal half-life of 1.74 ± 0.5 h.
Oral immediate release diacetylmorphine 

The diacetylmorphine dose (mean ± SD) was 719 ± 297 mg (1.77 ± 0.73 mmol). Similar to our previous study (Girardin et al., 2003), diacetylmorphine and monoacetylmorphine plasma concentrations were negligible. Morphine plasma concentrations peaked at 15 to 180 min, with maximal concentrations of 4.0 ± 1.27 μmol/l (Table 1, Figure 2A). The 7-h sampling period covered at least 80% of the morphine AUC. If we determine morphine bioavailability by comparing oral diacetylmorphine with intravenous morphine-d3, (absolute) morphine bioavailability was 61% ± 17% (range 44%–88%). The mean relative morphine-3-glucuronide and morphine-6-glucuronide bioavailabilities were 149% ± 64% and 184% ± 96%, respectively.
Table 1
Table 1 

Pharmacokinetic comparison of oral immediate (IR) and extended (ER) release diacetylmorphine.
 

Figure 2

 

Figure 2 

Individual morphine plasma concentration–time profiles after orally administered immediate (A) and extended release diacetylmorphine in the fasted (B) and the fed (C) state
 

Figure 2

 

Figure 2
Individual morphine plasma concentration–time profiles after orally administered immediate (A) and extended release diacetylmorphine in the fasted (B) and the fed (C) state
Solid lines connect measured plasma concentrations, dashed lines correspond to plasma concentration extrapolations based on the last sample (at 7 h) and the subject’s terminal morphine elimination rate estimated from the intravenous morphine-d3. Identical symbols are used for the same patient in all 3 panels. The mean diacetylmorphine doses were 719 mg (1.77 mmol) for immediate and 956 mg (2.36 mmol) for extended release diacetylmorphine.
Oral extended release diacetylmorphine 

The mean extended release diacetylmorphine dose was 956 ± 404 mg (2.36 ± 1.0 mmol). Diacetylmorphine and monoacetylmorphine concentrations were again negligible. The 11-h sampling period covered at least 85% of the morphine AUC. Morphine bioavailability on an empty stomach was 53% ± 15% (range 37%–79%) (Table 1, Figure 2B and C). Morphine bioavailability for extended release diacetylmorphine was lower in 4, higher in 3, and the same in 1 volunteer compared to immediate release diacetylmorphine. The geometric mean relative bioavailability of morphine after extended vs. immediate release diacetylmorphine was 86% (90% CI, 73%–103%). Relative bioavailabilities for the morphine-glucuronides (81% and 86%) were close to the values for morphine. A high-fat breakfast did not affect morphine bioavailability, yielding geometric mean relative bioavailabilities (fed/fasted) of 106%, 119%, and 93% for morphine, morphine-3-glucuronide, and morphine-6-glucuronide. The relative fed vs. fasted morphine bioavailability has a rather narrow 90% confidence interval from 96% to 117%, which excludes any relevant food effect.
Plasma concentration fluctuation was characterised by percent peak through fluctuation and percent AUC fluctuation. The peak-through fluctuation for the extended release preparation was about half that of the immediate release formulation (90% CI of 45% to 61%). The percent AUC fluctuation for the extended release formulation was only 0.66 (90% CI, 0.58 to 0.76) of the immediate release formulation. The presence of food did not increase either of these variability parameters. Maximal morphine concentrations were observed at 0.4 to 4.5 h in fasted and at 3 to 4.5 h in fed conditions, with peak morphine concentrations of 2.98 ± 1.72 and 2.62 ± 1.06 μmol/l (Table 1, Figure 2B and C). Thus, dose-normalised maximal morphine plasma concentrations for extended release diacetylmorphine averaged about half of the immediate release diacetylmorphine, and were observed after about double the period of time.
3.3. Deconvolution Analysis
The three panels of Figure 3 compare data and the (population) prediction (solid line) for morphine plasma concentration after the immediate (A) and the extended release diacetylmorphine preparation in the fasted state (B) and after a high-fat breakfast (C). Panel A of Figure 4 compares the (population) morphine absorption rate profiles obtained from the deconvolution analysis. For the immediate release diacetylmorphine preparation, the morphine absorption rate rapidly peaks at about 10 to 15 min and more than 50% of the dose is absorbed after about 1.5 hours, with more than 90% absorbed at 4.7 h. Morphine absorption was considerably slower and more sustained after administration of the extended release diacetylmorphine preparation, with about 1/3 of the maximal absorption rate of the immediate release preparation observed from 10 min to 3.5 h after drug intake, with at least 50% of the dose absorbed after 3 hours and at least 90% absorbed after 8.5 h. Administration after a high-fat breakfast slightly delayed initial morphine absorption for about 20 to 30 min, without much effect on later morphine absorption rates.
 

Figure 3

 

Figure 3 

Goodness-of-fit plots for immediate (A) and extended release diacetylmorphine in the fasted (B) and the fed (C) state from deconvolution analysis using a bi-exponential disposition and a linear spline absorption function
 

Figure 3

 

Figure 3
Goodness-of-fit plots for immediate (A) and extended release diacetylmorphine in the fasted (B) and the fed (C) state from deconvolution analysis using a bi-exponential disposition and a linear spline absorption function
The (X) represents the observed data and the solid lines correspond to the average predictions.
 

Figure 4

 

Figure 4 

Population morphine absorption rate function for immediate (dashed-dotted line) and extended release diacetylmorphine in the fasted (solid line) and the fed (short dashed line) state estimated by deconvolution analysis using a bi-exponential disposition (more …)
 

Figure 4

 

Figure 4
Population morphine absorption rate function for immediate (dashed-dotted line) and extended release diacetylmorphine in the fasted (solid line) and the fed (short dashed line) state estimated by deconvolution analysis using a bi-exponential disposition and a linear spline absorption function
Panel A gives the estimated absorption rate functions obtained by deconvolution analysis for the oral immediate and extended release_diacetylmorphine preparation. Panel B and C compare the morphine absorption rate functions obtained by deconvolution analysis from the drug concentration data and the corresponding diacetylmorphine release profiles from the in vitro experiments (long dashed line) for the extended release (B) and the immediate (C) preparations.
The absolute and relative bioavailability estimates for the different preparations are given in Table 2, with point estimates of 0.57, 0.55 and 0.57 for immediate release, extended release in the fasted condition, and extended release after a high-fat breakfast. Panels B and C of Figure 4 compare the estimated in vivo morphine absorption rate profile and the in vitro release rate profile for the extended release and the immediate release preparations. Absorption rate shortly after drug delivery rises considerably slower in vivo than was predicted by in vitro drug release, but the in vivo absorption rate – at least for the extended release formulation – subsequently catches up.
Table 2
Table 2 

Absolute and relative bioavailability estimates for immediate (IR) and extended release (ER) diacetylmorphine from the deconvolution analysis in NONMEM and their 90% and 95% confidence intervals.
4. Discussion
This study compared the morphine absorption characteristics of orally administered immediate and extended release diacetylmorphine in the high dose range required by opioid addicts. Both preparations exhibited a high mean absolute morphine bioavailability in the range of 56% to 61%. The immediate release preparation resulted in rapid morphine absorption, with the absorption rate peaking at 10 to 15 min after dosing. For the extended release formulation, morphine absorption rates were considerably lower and more sustained, with only about 30% of the maximal absorption rate (of the immediate release preparation) being reached after 10 min and then maintained for 3 to 4 h, with no relevant food interaction. The relative bioavailability of the two preparations was 86% for the non-compartmental or 93% for the deconvolution analysis. Therefore, it can be concluded that these two diacetylmorphine preparations produce the intended morphine exposures and are suitable for substitution with similar dosages when given sequentially or in combination to the same patient. The part of the dose given as an immediate release formulation will assure a rapid opioid effect, whereas the part given in an extended release form maintains opioid availability until the patient’s next visit to the treatment center.
The rapid absorption and concentration rise of the immediate release preparation is advantageous, since the pharmacodynamic effects of opioids depend on both the substance and the initial slope of the plasma concentration. Two factors probably contribute to the rapid initial rise in drug absorption: diacetylmorphine produces a more rapid rise in morphine levels than oral morphine (Girardin et al., 2003) and a pharmaceutical formulation designed for rapid disintegration of the tablets. Based on this absorption rate profile, a rapidly disintegrating immediate release formulation might be especially suited for addicted patients that used opioids parenterally, by inhalation, or nasally.
The extended release diacetylmorphine preparation produces a lower but more sustained morphine exposure, which could avoid a drug-related “high”. Morphine absorption reached 90% only after 8.5 hours, allowing for an extended dosing interval that could improve compliance, as dosing requires scheduled visits to treatment centres. Flexible dosing can also be achieved as food does not affect drug absorption. Clinically, these findings confirm the indications of extended release diacetylmorphine, which are recommended for situations requiring the absence of a drug “high,” such as working patients, or in patients preparing for diacetylmorphine withdrawal. Furthermore, the extended release preparation allows for prolonged dosing intervals and thus enhances the ability for employment.
In vivo absorption profiles differ clearly from the in vitro dissolution profile for both the immediate and the extended release preparations (Figure 4B and 4C). Similar differences also occur with the slow release oxybutynin OROS (Pitsiu et al., 2001), stressing the importance of in vivo studies even for drugs with high water or lipid solubility, such as diacetylmorphine.
Deconvolution analysis enabled us to characterise and visually compare the time courses of drug absorption for the different preparations, and to compare them to the in vitro dissolution profiles, as well as calculating absolute and relative bioavailability. Most parameter estimates and confidence intervals matched closely in both data analysis approaches, i.e. the standard AUC calculation and the deconvolution approach. In deconvolution analysis, the 90% confidence interval for the relative bioavailability of the extended release preparation was more narrow (80.5% to 107.2%) than AUC calculations (73.1% to 105.0%), suggesting that deconvolution analysis may be more robust with respect to outliers. The reason for the observed (but probably clinically irrelevant) differences in the point bioavailability estimates of 61% vs. 57% (immediate release) and 53% vs. 55% (extended release) for the two data analysis approaches remains unresolved.
The slightly lower bioavailability of extended as compared to immediate release diacetylmorphine could result from lower maximal concentrations leading to more efficient first pass elimination in the intestine and liver, or lower mucosal diacetylmorphine and/or morphine permeability in the distal than the proximal intestine.
In conclusion, orally administered immediate and extended release diacetylmorphine both exhibit a high absolute morphine bioavailability of 56% to 61% in the dose range required by opioid addicts. The immediate release preparation produces rapid morphine absorption, whereas absorption rates are considerably lower and more sustained for the extended release formulation, with 90% of morphine absorption reached only after 8.5 h, which would allow for extending dosing intervals. Morphine absorption was not significantly affected by a high-fat breakfast. The relative bioavailability of the two preparations was 86% (non-compartmental analysis) or 93% (deconvulution analsyis), indicating they can be substituted for each other with a one to one ratio. The absorption characteristics could improve outcomes in patients switching from parenteral opioids or for well-integrated patients under chronic treatment to enhance employability.
Table thumbnail
Acknowledgments
We thank Mathias Markert, Andreas Ryser, and the physicians involved in the Swiss heroin trials for their help with volunteer recruitment and all volunteers for their good cooperation. We also thank the physicians of the Division of Clinical Pharmacology in Zürich for their help during the study sessions.
The study was funded by the Swiss Federal Office of Public Health. Karin Fattinger was supported by a Swiss National Science Foundation Grant, 3200B0-109352. Davide Verottta was supported by a National Institutes of Health Grant, RO1 A150587.

Auswirkungen von Drogen auf Menstruation, Schwangerschaft, Geburt und Kindesentwicklung

Opiate haben neben vielfältigen Wirkungen auch neuroendokrine Effekte. Sie führen u.a. zu einer Abnahme des luteinisierenden Hormons (LH) und des Follikel-stimulierenden Hormons (FSH). Die Prolaktinspiegel steigen dagegen an.
Die Gonadotropine LH und FSH werden im Hypophysenvorderlappen gebildet. Erniedrigte Werte bei Heroinabhängigkeit, Anorexie und durch Einnahme von Ovulationshemmern
Diese hormonellen Effekte sind zusammen mit psychosozialen Stressfaktoren dafür verantwortlich, dass viele abhängige Frauen an Amenorrhoe oder Oligomenorrhoe leiden.
Unter oral eingenommenen Substituten mit langsamerer Anflutungsgeschwindigkeit als bei i.v. oder nasal eingenommenem Heroin kommt es meist zu einer Normalisierung der Menstruation.
Ein Opioid induzierter Östrogenmangel kann langfristig zu einer Osteoporose führen.

Bei Frauen, die Drogen nehmen, ist die Schwangerschaft mit besonderen Risiken verbunden. Dies gilt für legale wie für illegale Drogen. Das ungeborene Kind ist an den Blutkreislauf der Mutter angeschlossen. Konsumiert eine schwangere Frau Drogen, können diese auf das Kind übergehen. Das Kind kann dadurch schwere, z.T. auch lebenslange Schäden davontragen. Es gibt bei den Drogen/Alkohol/Medikamenten keine Dosis, die eventuell toleriert werden kann. Bei Opiaten wie Heroin ist allerdings dringend zu empfehlen auf ein Substitut umzusteigen.

Die Risiken des Nikotin Konsums:
20 % der Schwangeren rauchen. Auswirkungen sind fetale Wachstumsverzögerung, Spontanabort, Tabakentzugssyndrom, plötzlicher Kindstod. Die Ursache ist wahrscheinlich die erhöhte Kohlenmonoxidbelastung. 30 Zigaretten/ Tag führen zu einer 60% Reduktion der fetalen Sauerstoffversorgung. Die Kinder wiegen bei Geburt im Durchschnitt 200gr. weniger.
Sie haben auch ein erhöhtes Risiko für die spätere Entwicklung einer Leukämie.

Die Risiken des Alkohol Konsums:
Alkohol gelangt über die Nabelschnur rasch in den Blutkreislauf des ungeborenen Kindes, und verbreitet sich im ganzen Körper. In ganz kurzer Zeit haben Mutter und Kind denselben Alkoholspiegel.
Die schädigende Wirkung des Alkohols hält aber beim ungeborenen Kind länger an, als bei der Mutter, weil der noch nicht vollständig entwickelte Organismus Alkohol sehr langsam abbaut. Die Blutalkoholspiegel sind nach Konsum eine Zeit lang deutlich höher, als bei der Mutter.
Alkohol hat beim Feten eine teratogene Wirkung. In hohen Dosen (tägl.> 60gr) kann es zum fetalen Alkoholsyndrom (FAS) kommen, dazu gehören Wachstumsverzögerung, Gesichtsmissbildungen wie Lippen-, Kiefer-, Gaumenspalte, Herzfehler, Funktionsstörungen des ZNS , motorische und intellektuelle Fehlentwicklungen, die zu lebenslangen Beeinträchtigungen führen können. Es gibt aber auch bei geringerem Alkohol Konsum auch „leichtere“ Verhaltensauffälligkeiten und intellektuelle Beeinträchtigungen, die dann oft nicht auf den Alkohol Konsum in der Schwangerschaft zurückgeführt werden.

Die Risiken des Cannabis Konsums:
Untersuchungen zeigen, dass die Schadstoffaufnahme eines Joints, etwa der von 5 Zigaretten entspricht. Der Konsum von THC führt zu einer deutlichen Reduktion des Geburtsgewichts.
Es gibt nur wenige Untersuchungen, aber Hinweise, dass es später zu Verhaltensauffälligkeiten kommen kann. Diskutiert werden auch Sprach-, Gedächtnis-; und Lernstörungen. Die Wahrscheinlichkeit einer Risikoschwangerschaft ist erhöht, da THC die Einnistung des Embryos in die Gebärmutter verhindern kann.

Die Risiken des Kokain Konsums:
Die gefäßverengende Wirkung des Kokains hat Durchblutungsstörungen der Gebärmutter und der Plazenta zur Folge. Dadurch wird das werdende Kind schlechter mit Sauerstoff und Nährstoffen versorgt, es kann zu einer vorzeitigen Placenta Ablösung (Fehlgeburt) und vorzeitigen Wehen kommen (Frühgeburt).
Kokain passiert die Plazentaschranke und führt zu einer 4 x höheren Konzentration, verglichen mit der Schwangeren.
Es kommt gehäuft zu Missbildungen vor allem im Urogenitaltrakt und zu Schädigungen der neuronalen Entwicklung. Postpartal zeigen die Kinder häufig Anzeichen der Neurotoxizität, wie Zittrigkeit, erhöhte Irritabilität, aber auch Lethargie und erhöhtes Schlafbedürfnis.

Die Risiken des Amphetamin und Ecstasy Konsums:
Amphetamine bewirken einen erhöhten Gefäßtonus mit Hypertonie und Tachykardie und als Folge eine fetale Mangelversorgung (s.Kokain). Es besteht die Gefahr einer Fehl- o. Frühgeburt, und eines geringeren Geburtsgewichtes.
Es gibt Hinweise auf eine erhöhte Rate von Fehlbildungen.

Die Risiken des Benzodiazepin Konsums:
Es gibt Hinweise auf vermehrte Fehlbildungen im Bereich des Gesichtes, Lippen-Kiefer-Gaumenspalten, besonders wenn Benzodiazepine im ersten Trimenon konsumiert werden. Ebenso Herz- und Gefäßmissbildungen, und geistige Entwicklungsverzögerungen.
Neugeborene zeigen bei Benzodiazepin – Konsum der Mutter das am längsten dauernde und intensivste Entzugssyndrom (NAS) mit starkem Zittern, anhaltender Nervosität, leichter Irritierbarkeit, Blutdruckkrisen, Temperaturabfall, Erbrechen, Durchfall usw. Der Entzug von Benzodiazepinen kann länger als 4 Wochen dauern, und mit epileptischen Anfällen einhergehen.

Die Risiken des Opiat Konsums:
Opiate wie Heroin gehen direkt in den Blutkreislauf des Kindes über. Nach bisherigen wissenschaftlichen Erkenntnissen haben sie keine teratogen, d.h. fruchtschädigenden Wirkungen. Die Risiken fürs Kind sind aber niedriges Geburtsgewicht und Frühgeburten. Ist das Straßenheroin mit Streckmitteln wie Diazepam u.a. versetzt bestehen hier weitere Risiken.
Besonders gravierend ist das neonatale Abstinenzsyndrom (NAS), das bei Heroin 24-48 Stunden nach der Geburt auftritt, und mehrere Wochen dauern kann.
Therapie der Wahl ist die Substitution mit synthetischen Opioiden, nicht nur zur Verhinderung von Entzugserscheinungen, Vermeidung von Rückfällen und Zusatzkonsum, sondern auch zur gesundheitlichen und zur sozialen Stabilisierung.
Die Dosis sollte ausreichend sein. Im dritten Trimenon kommt es durch Enzyminduktion zu einem erhöhten Bedarf. Dosiserhöhung u.o. Dosissplitting kann notwendig sein.
In 60 – 80 % kommt es nach der Geburt zu einem neonatalen Entzugssyndrom, das nach heutigen Erkenntnissen bezgl. Dauer und Ausprägung unabhängig von der Dosis des Substituts ist. Subutex scheint günstiger zu sein, das NAS schwächer und kürzer, allerdings ist die Datenlage bezgl. Methadon/Polamidon besser.
Die Behandlung des NAS sollte mit oralen Morphinen erfolgen, nicht mit Barbituraten.

Cable dated:2006-05-23T11:49:00
C O N F I D E N T I A L SECTION 01 OF 03 PHNOM PENH 000983
SIPDIS
SENSITIVE

SIPDIS
STATE FOR EAP/MLS, INL/AAE–PETER PRAHAR AND YANTI KAPOYOS, INL/C–GREG STANTON
E.O. 12958: DECL: 05/23/2016
TAGS: SNAR, PGOV, CB, TW
SUBJECT: CAMBODIA: DRUG SEIZURES AND ARRESTS UP

1. (U) SUMMARY: May 19 and 20 arrests of two Taiwanese nationals attempting to smuggle a total of nearly 7 kg of heroin to Taiwan highlight increased drug arrests and seizures in Cambodia. The quantity of heroin seized during the weekend airport busts is large by Cambodian standards–authorities seized just 11 kg of heroin in 2005. Seizures of amphetamine-type stimulants are more than double last year’s levels. Police and international observers credit USG and other foreign training with providing skills, motivation, and international pressure for the increase, but say that narcotics trafficking may also be on the rise. END SUMMARY.

Heroin Seizures at Phnom Penh International Airport

——————————————— ——-

2. (U) Police and customs officials seized nearly 7 kg of heroin and arrested three Taiwanese nationals in two separate incidents at Phnom Penh International Airport on May 19 and 20. These two cases represent an impressive intake for one weekend given that in 2005 Cambodian authorities seized just over 11 kg of heroin.

3. (SBU) Chen Hsin Hung, 57, was arrested on May 19 carrying 4.75 kg of heroin with a local street value of USD 95,000 to 133,000. Customs officials became suspicious when they noticed that Hung was carrying several bags of imported Taiwanese foil-wrapped candies back to Taiwan in his hand luggage. The candies turned out to be foil-wrapped packages of heroin. Hung, who was due to travel to Taiwan via Kuala Lumpur on Malaysian Airlines flight 755, had arrived in Phnom Penh the previous day. During his police interrogation, Hung said that he had been picked up at the airport and returned to the airport by a couple, whom the police identified as a Cambodian woman and a mainland Chinese or Taiwanese man. Police are attempting to locate the couple.

4. (SBU) A second Taiwanese man, who was standing near Chen Hsin Hung during the security process, appeared to be quite interested in the proceedings and upset by Hung’s arrest, and had tickets for the same flight as Hung, was also arrested on suspicion of drug trafficking. Moek Dara noted that the investigation had revealed no evidence to indicate that the second individual was also involved in drug smuggling, but that it was the prosecutor’s decision how to proceed in the case.

5. (SBU) On May 20, a 90-year-old Taiwanese national named Huang Sang Hou was arrested at Phnom Penh International Airport with 1.9 kg of heroin, worth USD 38,000 to USD 53,000. Hou reportedly came to Cambodia as a tourist intending to gamble. Over the course of a week, he lost the USD 4,000 he brought with him, borrowed an additional USD 2,000 from a Taiwanese national in Phnom Penh, and then lost that money as well. The Taiwanese lender then persuaded Hou to carry the heroin back to Taiwan. Airport customs officials were tipped off by the sloppy manner in which the heroin was packed on Hou’s body, making him appear bloated. Hou cooperated with the police in identifying the Taiwanese lender, and Cambodian government officials have already passed his name, address, and passport information to the Drug Enforcement Administration (DEA). Hou had been planning to fly Dragon Airlines flight 207 to Hong Kong, and then to continue on to Taiwan.

Amphetamine Seizures, Prices on the Rise

—————————————-

6. (SBU) According to statistics from the Ministry of Interior’s Anti-Drug Police and the National Authority for Combating Drugs (NACD), seizures of amphetamine-type stimulant (ATS) tablets more than doubled when comparing the first four months of 2006 with the first four months of 2005. From January to April 2006, more than 220,000 ATS tablets were seized, whereas from January to April 2005, approximately 87,000 ATS tablets were seized. The number of offenders arrested also rose from 154 from January to April 2005 to 204 during January to April 2006.

7. (U) Both Brigadier General Moek Dara, Director of the Anti-Drugs Department, and World Health Organization XXXXXXXXXXXX noted that prices for ATS tablets have risen in the past few years, with particularly dramatic increases in the past 12 months. One year ago, a single ATS tablet sold for approximately one dollar in Phnom Penh, but now costs two to three dollars. Moek Dara noted that prices rise as the ATS tablets make their way along the drug route, from fifty cents per tablet in Laos, where the

PHNOM PENH 00000983 002 OF 003

majority are produced, to USD 3 in Cambodia, and then even higher prices in two destination countries: USD 4 in Vietnam and USD 7.50 in Thailand. XXXXXXXXXXXX cited anecdotal evidence from NGOs that some ATS users are switching to injecting heroin, currently available for USD 1.50 to 2 in Phnom Penh, as a cheaper alternative to rising ATS prices.

Lower Ecstasy Seizures Likely Point to Disrupted Network ——————————————— ———–

8. (U) In contrast to the dramatic rise in ATS seizures, seizures of ecstasy tablets are down sharply, from 1,900 in January to April 2005 to less than 800 in January to April 2006. Moek Dara and XXXXXXXXXXXX believe that lower levels of ecstasy seizures are a sign that supply has been disrupted following a cooperative DEA/Anti-Drug Police controlled delivery operation against the Peter Brown drug ring in 2004 and continued Anti-Drug Police action against the ring in 2005.

USG Training Provides Needed Skills, International Pressure

——————————————— ————–

9. (SBU) Moek Dara gave much of the credit for the dramatic increase in heroin and ATS seizures and drug arrests to counternarcotics training funded by the State Department’s Bureau of International Narcotics and Law Enforcement Affairs (INL) and conducted by the DEA. Before the training sessions, which were conducted in January and April 2006, police officers along Cambodia’s porous northern border were not very active and would not even conduct foot patrols in the forest, according to Moek Dara. Now, however, the officers have more skills and are more motivated to patrol actively, he said, and have seized drugs and a lot of drug production equipment as well. Customs, immigration, and police officials at the airports are also better trained and more active, and Moek Dara noted that all of the officials involved in the weekend’s airport arrests had completed DEA training.

10. (C) XXXXXXXXXXXX gave partial credit for increased anti-drug activity to counternarcotics training by the US and other foreign donors. Some high-ranking Cambodian police and military officials are rumored to be complicit in narcotics trafficking, he noted. He speculated that the training and pressure on the Cambodian government to clamp down on drug activity has finally made an impression on higher ranking officials, and lower-level officers are „being allowed“ to make more seizures. At the same time, such a dramatic increase is probably also an indication of efforts to traffic increased amounts of ATS through Cambodia, he opined.

Trainees Enthusiastic about INL/DEA Courses

——————————————-

11. (U) Provincial Anti-Drug Police officers who attended the January Basic Counternarcotics course reported uniformly enthusiastic assessments to an embassy follow-up survey. Participating police captains reported an increased awareness of drug smuggling tactics, best practices in seizing and preparing evidence, and how to identify drugs using field test kits. Captain Preap Sovann of the Svay Rieng Anti-Drug Police noted that the training also promoted inter-agency and inter-province cooperation as well. All captains reported training their staffs in the key topics covered by the DEA training, and captains in Koh Kong and Pursat provinces reported conducting anti-drug outreach to primary and secondary school students as well. Trainees suggested that future courses provide written materials in Khmer as well as English, include information on money laundering, have more laboratory equipment available for in-class practice in drug identification, and include more time in simulations.

Police Officer Arrested on Drug Charges

—————————————

11. (C) Nov Sophal, a municipal police officer in the southern city of Kep, was arrested on April 15 and charged with trafficking 1 kg of heroin. Moek Dara was not expansive when asked about the case, noting simply that it is not uncommon for low-ranking police and military officials to be arrested for drug trafficking. In contrast, XXXXXXXXXXXX noted that drug investigations of police or military officials are very rare, and speculated that the individual involved may even have run afoul of rumored higher-level police involvement in narcotics.

12. (SBU) COMMENT: While increased smuggling activity may

PHNOM PENH 00000983 003 OF 003

account for some of the increased seizures and arrests, it is clear that the Cambodian government is turning up the heat on the country’s drug smugglers. Training from the USG and other countries is playing a critical role in supporting this effort–both through the skills and enthusiasm imparted to the participants, and also through the implicit expectations of improved performance on the part of the police and other officials.

STORELLA

 

source: http://www.guardian.co.uk/world/us-embassy-cables-documents/65065

MOSCOW — They look like addicts anywhere in the world: tattered and vacant-eyed, they circle Moscow pharmacies known to sell prescription drugs illicitly, looking for something to inject for a quick high.

James Hill for The New York Times

Pyotr Nikitenko, right, distributed medical supplies and literature outside a pharmacy in Moscow with a drug outreach center colleague, left. Mr. Nikitenko, a former heroin user, said most of his friends were now H.I.V. positive.

Though public examples of Russia’s problem with heroin are not new and seldom bring even raised eyebrows among locals, the issue has recently come to symbolize a broader failure. The country has become one of the world’s low points in the effort to fight the spread of H.I.V., and unchecked intravenous drug use is the biggest cause, international health officials say.

The epidemic here has defied worldwide trends, expanding more rapidly year by year than almost anywhere else. Nearly 60,000 new cases of H.I.V., the virus that causes AIDS, were documented in Russia in 2009, an 8 percent increase from 2008, according to Unaids, the United Nations H.I.V./AIDS program. Of those new cases, more than 60 percent were believed to have been caused by intravenous drug use, and many of the others were believed to have been infected through sex with addicts.

Though South Africa, with more infections than any other country, far outstripped that total number, with an estimated 390,000 new infections in 2009, the rate of new infections annually has decreased there by nearly half since its peak in the late 1990s.

“I’ve been researching the problem of H.I.V. infection for 25 years, and I must say that the situation has become significantly worse” in Russia, said Dr. Vadim V. Pokrovsky, the head of the country’s Federal AIDS Center.

While in recent years the government has increased its efforts to fight the disease, Dr. Pokrovsky said, current programs almost completely neglect those groups at the heart of it.

Officials estimate that well over a million people abuse drugs intravenously in Russia, often sharing and infecting one another with tainted needles. They are among Russian society’s most marginalized people, more likely to face a few weeks handcuffed to a clinic bed than to receive basic treatment to break their addictions. Meanwhile, officials have treated sex education and other preventative programs with open hostility.

“Which are the main infected groups? Injecting-drug users and sex workers,” said Lev Zohrabyan, the Europe and Central Asia adviser for Unaids. “It turns out that these are the groups where the money must be directed to change the picture. But if you open the budget, you will see that for prevention work among these groups for the next two years there is nothing.”

Top officials have consistently blamed the United States’ failure to eradicate heroin production in Afghanistan for Russia’s intravenous drug problem. About 90 percent of Russian addicts use Afghan heroin, according to the Federal Drug Control Service.

Yet once the drugs pass through Russia’s porous borders with former Soviet republics in Central Asia, dealers find a ready market of addicts with few tools to help them quit. While some regions have experimented with needle-exchange programs, the practice, which has proven effective at reducing the spread of H.I.V. in other countries, has not been adopted on a national level.

The country’s top medical and political officials have roundly condemned drug substitution therapy for heroin addicts — the use of methadone or other narcotics, widely considered an effective way to wean people off the drug — on the basis that it substitutes one form of addiction for another. Doctors who have flouted the official ban on the treatment have faced prosecution and even harassment by Kremlin-backed youth groups.

The Russian Orthodox Church, which has become a significant voice in the country’s political affairs in the past decade, has also expressed strong opposition to such preventative measures.

Even a new antinarcotics strategy ordered by President Dmitri A. Medvedev last summer acknowledges Russia’s failure to adequately confront the problem. “Prophylactic activities, medical aid and rehabilitation of patients with drug addiction are not sufficiently effective,” said the document, posted on Mr. Medvedev’s Web site.

Many of the addicts gathered outside one pharmacy in southern Moscow said they had often tried to stop. “You want to quit, and you don’t,” said a graying 33-year-old named Maxim who had the scarred arms of a dedicated user. Another man, who had quarter-size holes gouged into his body from injection-related infections and would not give his name, said he feared that he would be arrested if he sought treatment — a worry that is not completely unfounded here.

The police often arrest drug users, sending them to special detoxification centers where doctors encourage, and sometimes force, immediate abstinence, which can in some rare cases be fatal. Last summer, organizers of the 18th annual International AIDS Conference held in Vienna issued a declaration — aimed at Russia and the countries of the former Soviet Union, in particular — arguing that such practices drove addicts underground, complicating H.I.V.-prevention efforts.

It is not that the government has failed completely to recognize the gravity of the epidemic. Russia’s national security strategy, approved by Mr. Medvedev, identifies the spread of H.I.V. and AIDS as “one of the main threats to national security in the sphere of medicine and health.”

Russia now has more than 500,000 officially registered cases of H.I.V., though Unaids and other experts have estimated the actual number to be closer to one million, as many as in the United States, which has more than twice the population.

Part of the problem is that the government came late to the fight. The epidemic has been raging since the Soviet collapse two decades ago, but a major government response came only in 2006 when Russia’s obligations as host of the Group of 8 summit meeting pushed officials to take a more active role in fighting the disease. Vladimir V. Putin, who was president at the time and is now prime minister, ordered the largest increase in financing in any area in Russia’s history, and spending has grown annually ever since.

This year, the government plans to nearly double spending on H.I.V. drugs to about $600 million and expand prevention programs focusing on youth, said Galina G. Chistyakova, a Health Ministry official who helps oversee Russia’s H.I.V. and AIDS policies. She denied that Russia was having trouble curbing the epidemic, noting that the ministry had documented a slight dip in the number of new infections in 2010 compared with a year earlier.

Dr. Pokrovsky and others said that government programs often became ensnared in Russia’s large and inefficient bureaucracies. Even efforts to provide AIDS patients with treatment, which constitute the bulk of government financing, have fallen short.

Patients and doctors have complained of frequent shortages of antiretroviral drugs to the point where patients have created online communities, like pereboi.ru, that monitor drug deficits and help those in need of medicines connect with people who have extra supplies. Patients have also held street protests, and others have sued.

Many addicts who become infected do not even know that medicines are available, said Pyotr Nikitenko, 28, a former heroin user who now works for a Moscow-based outreach group called Yasen. He said he was able to wean himself off heroin with the help of his family, escaping the fate of most of his friends, who he said now were H.I.V. positive.

“I continue to bury them,” Mr. Nikitenko said. “They continue to die from AIDS, or rather they are dying more and more frequently.”

Russia has one of the fastest spreading HIV epidemics in the world, driven largely by the government’s refusal to institute measures to treat the country’s drug addicts — measures that have dramatically reduced HIV infections in drug addicts in other countries, including the U.S.

The New York Times reported yesterday that 60,000 new cases of HIV were seen in Russia in 2009, up 8% from the prior year. At least 60% of those new cases were spread by intravenous drug use, according to the Times, and a good portion of the rest of the new cases were likely the result of sex with drug addicts. (More on Time.com: Drug Policy Backfires: Controlling Meth Ingredients Fails to Cut Drug Supply)

Writes the Times‘ Michael Schwirtz:

Officials estimate that well over a million people abuse drugs intravenously in Russia, often sharing and infecting one another with tainted needles. They are among Russian society’s most marginalized people, more likely to face a few weeks handcuffed to a clinic bed than to receive basic treatment to break their addictions. Meanwhile, officials have treated sex education and other preventative programs with open hostility.

“Which are the main infected groups? Injecting-drug users and sex workers,” said Lev Zohrabyan, the Europe and Central Asia adviser for Unaids. “It turns out that these are the groups where the money must be directed to change the picture. But if you open the budget, you will see that for prevention work among these groups for the next two years there is nothing.”

According to Schwirtz, Russia blames America’s failure to eradicate Afghanistan’s opium crops for the IV drug problem in Russia. But if the U.K.’s current shortage of heroin, due to Afghan crop failures this year, are any indication, the international heroin supply has actually been significantly reduced. Regardless, changes in the supply side have never had any impact on the HIV epidemic.

So, what’s really driving Russia’s problem? Politics. The country has a long-standing ideological opposition to the use of “substitute” maintenance drugs like methadone and buprenorphine to treat IV drug addicts. Yet methadone is the best known treatment for heroin addiction: according to numerous reviews of the voluminous international data, it reduces relapse and death rates better than any other treatment, including all therapies based on abstinence. The effectiveness of buprenorphine treatment for heroin addiction is also well-supported by research. (More on Time.com: Salvia, a Mexican Hallucinogen Piques Scientists‘ and Regulators‘ Interest)

In all countries that have successfully reduced HIV infection rates among intravenous drug users, health officials have instituted maintenance treatment programs. But they have all also simultaneously increased clean-needle availability — the other public-health measure that undergirds many effective AIDS-prevention programs. In that respect, Russia has not been entirely remiss: it does offer some needle-exchange programs that provide addicts with clean syringes and educate them not to share.

Alone, methadone maintenance programs and legal needle-and-syringe exchanges cannot stop an epidemic. But the evidence is pretty clear that together, they can. Case in point: New York City.

In the not too distant past, New York was the epicenter of the AIDS epidemic among America’s drug addicts. In the early 1990s, at least half of all intravenous drug users in the city were HIV-positive. But a recent study of HIV infection rates among injected-drug users in New York found that while 21% of addicts tested positive for HIV between 1984 and 1994, that figure dropped to just 6% in people who used IV drugs between 1995 and 2008.

What changed? The two groups are distinguished by the prevention measures most available to them. In the 1980s and early ’90s, New York City had a large methadone treatment system, but awareness of the spread of HIV among drug addicts was initially low; at the time, syringe exchange programs were also either illegal or just getting started, and needle possession was illegal. (More on Time.com: The Most Dangerous Drugs? Alcohol, Heroin and Crack — in That Order)

In 1992, needle exchanges were legalized in New York City, and massively expanded by 1995. Over-the-counter sales of syringes in New York became legal in 2001.

Nationally, the AIDS epidemic in addicts has subsided too, with only 12% of new cases linked to IV drug use, down from more than 1 in 3.

Given that the data overwhelmingly show that maintenance programs and needle exchanges, together, can significantly reduce the spread of HIV, Russia’s refusal to treat the country’s million-plus drug users is putting millions more of its citizens — including nonusers who may be partners of drug users or of infected former partners — at deadly risk.

Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events.

CYP = cytochrome P450; M1 = O-desmethyltramadol; M3G = morphine-3-glucuronide; M6G = morphine-6-glucuronide; UGT = uridine diphosphate glucuronosyltransferase

Opioids are a cornerstone of the management of cancer pain1 and postoperative pain2 and are used increasingly for the management of chronic noncancer pain.3,4 Understanding the metabolism of opioids is of great practical importance to primary care clinicians. Opioid metabolism is a vital safety consideration in older and medically complicated patients, who may be taking multiple medications and may have inflammation, impaired renal and hepatic function, and impaired immunity. Chronic pain, such as lower back pain, also occurs in younger persons and is the leading cause of disability in Americans younger than 45 years.5 In younger patients, physicians may be more concerned with opioid metabolism in reference to development of tolerance, impairment of skills and mental function, adverse events during pregnancy and lactation, and prevention of abuse by monitoring drug and metabolite levels.

Experienced clinicians are aware that the efficacy and tolerability of specific opioids may vary dramatically among patients and that trials of several opioids may be needed before finding one that provides an acceptable balance of analgesia and tolerability for an individual patient.69 Pharmacodynamic and pharmacokinetic differences underlie this variability of response. Pharmacodynamics refers to how a drug affects the body, whereas pharmacokinetics describes how the body alters the drug. Pharmacokinetics contributes to the variability in response to opioids by affecting the bioavailability of a drug, the production of active or inactive metabolites, and their elimination from the body. Pharmacodynamic factors contributing to variability of response to opioids include between-patient differences in specific opioid receptors and between-opioid differences in binding to receptor subtypes. The receptor binding of opioids is imperfectly understood; hence, matching individual patients with specific opioids to optimize efficacy and tolerability remains a trial-and-error procedure.69

This review primarily considers drug metabolism in the context of pharmacokinetics. It summarizes the basics of opioid metabolism; discusses the potential influences of patient-specific factors such as age, genetics, comorbid conditions, and concomitant medications; and explores the differences in metabolism between specific opioids. It aims to equip physicians with an understanding of opioid metabolism that will guide safe and appropriate prescribing, permit anticipation and avoidance of adverse drug-drug interactions, identify and accommodate patient-specific metabolic concerns, rationalize treatment failure, inform opioid switching and rotation strategies, and facilitate therapeutic monitoring. To that end, recommendations for tailoring opioid therapy to individual patients and specific populations will be included.

METHODS

Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed databases for literature published between January 1980 and June 2008. The opioid medication search terms used were as follows: codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, opioid, opioid analgesic, oxycodone, oxymorphone, and tramadol. Each medication search term was combined with the following general search terms: metabolism, active metabolites, pharmacokinetics, lipophilicity, physiochemical properties, pharmacology, genetics, receptor, receptor binding, receptor genetics or variation, transporter, formulations, AND adverse effects, safety, or toxicity. The reference lists of relevant papers were examined for additional articles of interest.

BASICS OF OPIOID METABOLISM

Metabolism refers to the process of biotransformation by which drugs are broken down so that they can be eliminated by the body. Some drugs perform their functions and then are excreted from the body intact, but many require metabolism to enable them to reach their target site in an appropriate amount of time, remain there an adequate time, and then be eliminated from the body. This review refers to opioid metabolism; however, the processes described occur with many medications.

Altered metabolism in a patient or population can result in an opioid or metabolite leaving the body too rapidly, not reaching its therapeutic target, or staying in the body too long and producing toxic effects. Opioid metabolism results in the production of both inactive and active metabolites. In fact, active metabolites may be more potent than the parent compound. Thus, although metabolism is ultimately a process of detoxification, it produces intermediate products that may have clinically useful activity, be associated with toxicity, or both.

Opioids differ with respect to the means by which they are metabolized, and patients differ in their ability to metabolize individual opioids. However, several general patterns of metabolism can be discerned. Most opioids undergo extensive first-pass metabolism in the liver before entering the systemic circulation. First-pass metabolism reduces the bioavailability of the opioid. Opioids are typically lipophilic, which allows them to cross cell membranes to reach target tissues. Drug metabolism is ultimately intended to make a drug hydrophilic to facilitate its excretion in the urine. Opioid metabolism takes place primarily in the liver, which produces enzymes for this purpose. These enzymes promote 2 forms of metabolism: phase 1 metabolism (modification reactions) and phase 2 metabolism (conjugation reactions).

Phase 1 metabolism typically subjects the drug to oxidation or hydrolysis. It involves the cytochrome P450 (CYP) enzymes, which facilitate reactions that include N-, O-, and S-dealkylation; aromatic, aliphatic, or N-hydroxylation; N-oxidation; sulfoxidation; deamination; and dehalogenation. Phase 2 metabolism conjugates the drug to hydrophilic substances, such as glucuronic acid, sulfate, glycine, or glutathione. The most important phase 2 reaction is glucuronidation, catalyzed by the enzyme uridine diphosphate glucuronosyltransferase (UGT). Glucuronidation produces molecules that are highly hydrophilic and therefore easily excreted. Opioids undergo varying degrees of phase 1 and 2 metabolism. Phase 1 metabolism usually precedes phase 2 metabolism, but this is not always the case. Both phase 1 and 2 metabolites can be active or inactive. The process of metabolism ends when the molecules are sufficiently hydrophilic to be excreted from the body.

FACTORS INFLUENCING OPIOID METABOLISM

Metabolic Pathways

Opioids undergo phase 1 metabolism by the CYP pathway, phase 2 metabolism by conjugation, or both. Phase 1 metabolism of opioids mainly involves the CYP3A4 and CYP2D6 enzymes. The CYP3A4 enzyme metabolizes more than 50% of all drugs; consequently, opioids metabolized by this enzyme have a high risk of drug-drug interactions. The CYP2D6 enzyme metabolizes fewer drugs and therefore is associated with an intermediate risk of drug-drug interactions. Drugs that undergo phase 2 conjugation, and therefore have little or no involvement with the CYP system, have minimal interaction potential.

Phase 1 Metabolism

The CYP3A4 enzyme is the primary metabolizer of fentanyl10 and oxycodone,11 although normally a small portion of oxycodone undergoes CYP2D6 metabolism to oxymorphone (Table 11018). Tramadol undergoes both CYP3A4- and CYP2D6-mediated metabolism.16 Methadone is primarily metabolized by CYP3A4 and CYP2B6; CYP2C8, CYP2C19, CYP2D6, and CYP2C9 also contribute in varying degrees to its metabolism.1923 The complex interplay of methadone with the CYP system, involving as many as 6 different enzymes, is accompanied by considerable interaction potential.

Each of these opioids has substantial interaction potential with other commonly used drugs that are substrates, inducers, or inhibitors of the CYP3A4 enzyme (Table 2).24,25 Administration of CYP3A4 substrates or inhibitors can increase opioid concentrations, thereby prolonging and intensifying analgesic effects and adverse opioid effects, such as respiratory depression. Administration of CYP3A4 inducers can reduce analgesic efficacy.10,11,16 In addition to drugs that interact with CYP3A4, bergamottin (found in grapefruit juice) is a strong inhibitor of CYP3A4,26 and cafestol (found in unfiltered coffee) is an inducer of the enzyme.27

Induction of CYP3A4 may pose an added risk in patients treated with tramadol, which has been associated with seizures when administered within its accepted dosage range.16 This risk is most pronounced when tramadol is administered concurrently with potent CYP3A4 inducers, such as carbamazepine, or with selective serotonin reuptake inhibitors, tricyclic antidepressants, or other medications with additive serotonergic effects.16

View this table: 

TABLE 1. 

Metabolic Pathway/Enzyme Involvement

The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone,14 codeine,13 and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively), which in turn undergo phase 2 glucuronidation. These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with selective serotonin reuptake inhibitors, tricyclic antidepressants, β-blockers, and antiarrhythmics; an array of other drugs are substrates, inducers, or inhibitors of the CYP2D6 enzyme (Table 328).

Although CYP2D6-metabolized drugs have lower interaction potential than those metabolized by CYP3A4, genetic factors influencing the activity of this enzyme can introduce substantial variability into the metabolism of hydrocodone, codeine, and to a lesser extent oxycodone. An estimated 5% to 10% of white people possess allelic variants of the CYP2D6 gene that are associated with reduced clearance of drugs metabolized by this isoenzyme,2931 and between 1% and 7% of white people carry CYP2D6 allelic variants associated with rapid metabolism.32,33 The prevalence of poor metabolizers is lower in Asian populations (≤1%)34 and highly variable in African populations (0%-34%).3539 The prevalence of rapid metabolizers of opioids has not been reported in Asian populations; estimates in African populations are high but variable (9%-30%).35,36

The clinical effects of CYP2D6 allelic variants can be seen with codeine administration. Patients who are poor opioid metabolizers experience reduced efficacy with codeine because they have a limited ability to metabolize codeine into the active molecule, morphine. In contrast, patients who are rapid opioid metabolizers may experience increased opioid effects with a usual dose of codeine because their rapid metabolism generates a higher concentration of morphine.40 Allelic variants altering CYP2D6-mediated metabolism can be associated with reduced efficacy of hydrocodone or increased toxicity of codeine, each of which relies entirely on the CYP2D6 enzyme for phase 1 metabolism.41,42 In patients treated with oxycodone, which relies on CYP3A4 and to a lesser extent on CYP2D6, inhibition of CYP2D6 activity by quinidine increases noroxycodone levels and reduces oxymorphone production. In one study, such alterations were not accompanied by increased adverse events.30 However, individual cases of reduced oxycodone efficacy42 or increased toxicity41 in CYP2D6 poor metabolizers have been reported.

Phase 2 Metabolism

Morphine, oxymorphone, and hydromorphone are each metabolized by phase 2 glucuronidation17,18,43 and therefore have little potential for metabolically based drug interactions. Oxymorphone, for example, has no known pharmacokinetic drug-drug interactions,18 and morphine has few.43 Of course, pharmacodynamic drug-drug interactions are possible with all opioids, such as additive interactions with benzodiazepines, antihistamines, or alcohol, and antagonistic interactions with naltrexone or naloxone.

View this table: 

TABLE 2. 

Cytochrome P450 3A4 Substrates, Inhibitors, and Inducers

However, the enzymes responsible for glucuronidation reactions may also be subject to a variety of factors that may alter opioid metabolism. The most important UGT enzyme involved in the metabolism of opioids that undergo glucuronidation (eg, morphine, hydromorphone, oxymorphone)12,44 is UGT2B7. Research suggests that UGT2B7-mediated opioid metabolism may be altered by interactions with other drugs that are either substrates or inhibitors of this enzyme.45 Moreover, preliminary data indicate that UGT2B7 metabolism of morphine may be potentiated by CYP3A4, although the clinical relevance of this finding is unknown.4648

The activity of UGT2B7 shows significant between-patient variability, and several authors have identified allelic variants of the gene encoding this enzyme.12,44 Although the functional importance of these allelic variants with respect to glucuronidation of opioids is unknown, at least 2 allelic variants (the UGT2B7-840G and -79 alleles) have been linked to substantial reduction of morphine glucuronidation, with resulting accumulation of morphine and reduction in metabolite formation.49,50 Moreover, research has shown that variation in the amount of messenger RNA for hepatic nuclear factor 1α, a transcription factor responsible for regulating expression of the UGT2B7 gene, is associated with interindividual variation in UGT2B7 enzyme activity.51

Clinical Implications of Metabolic Pathways

Most opioids are metabolized via CYP-mediated oxidation and have substantial drug interaction potential. The exceptions are morphine, hydromorphone, and oxymorphone, which undergo glucuronidation. In patients prescribed complicated treatment regimens, physicians may consider initiating treatment with an opioid that is not metabo