Archive for März, 2010


1. 000 Heroinabhängige werden in Österreich mit opiatähnlichen Substanzen substitutiert – Ganslwirt-Leiter Hans Haltmayer beklagt zu wenig Therapieplätze

Haltmayer: Sucht ist von der WHO als Erkrankung definiert und in den internationalen Klassifikationssystemen ICD-10 und DSM IV auch als solche beschrieben und festgehalten. Mit Willensschwäche hat eine Suchterkrankung gar nichts zu tun.

derStandard.at: Dann ist Rauchen auch eine Krankheit?

Haltmayer: Per definitionem Ja. Es gibt ja mittlerweile auch eine Reihe von Rauchertherapien und Entwöhnungsprogrammen gegen die Nikotinabhängigkeit. Im Vergleich mit der Opiatabhängigkeit wiegt die Nikotinabhängigkeit aber weniger schwer.

derStandard.at: Was die WHO definiert, scheint die Allgemeinbevölkerung aber wenig zu tangieren. Opiatabhängige sind nach wie vor eine stigmatisierte Bevölkerungsgruppe.

Haltmayer: Tatsächlich gibt es hier ein großes Informationsdefizit. Es wird Zeit, dass Experten und Politiker die Bevölkerung darüber informieren, dass die Drogenabhängigkeitserkrankung eine Krankheit ist, die man sich nicht aussuchen kann.

derStandard.at: Die Substitutionstherapie ist eine Behandlungsoption für Opiatabhängige. Ist das langfristige Ziel die völlige Drogenfreiheit?

Haltmayer: Davon kehrt man zunehmend ab, weil es sich vielfach als unrealistisch erweist. Die Substitutionsbehandlung verfolgt andere Ziele. Das wichtigste ist, dass die Patienten nicht mehr in die Illegalität gedrängt werden, sondern in ein strukturiertes medizinisch therapeutisches Behandlungssetting kommen.

Das bringt viele Vorteile. Es kommt zu einer Reduktion der Straffälligkeit und damit zu einer Verringerung von Kosten und Schaden für die Allgemeinheit. Außerdem reduziert sich die Verbreitung von Infektionserkrankungen, wie Hepatitis C oder HIV. Für die Patienten selbst ist das primäre Ziel der Drogenersatztherapie eine Verringerung der Sterblichkeit.

Studien zeigen, dass Opiatabhängige eine 20fach erhöhte Sterblichkeit haben, verglichen mit der Durchschnittsbevölkerung der gleichen Altersgruppe. Unbehandelt sind nach 20 Jahren ungefähr 45 Prozent der Opiatabhängigen tot. Unter Substitutionsbehandlung kann dieser Prozentsatz mehr als halbiert werden.

Das ist für medizinische Maßstäbe ein sensationeller Erfolg. Allerdings sind 20 Prozent noch immer inakzeptabel hoch. Das heißt da müssen noch viele Anstrengungen getätigt werden.

derStandard.at: Wie viele Menschen werden in Österreich substituiert?

Haltmayer: Aktuell werden in Österreich knapp über 11.000 Patienten substitutiert. Der überwiegende Teil davon in Wien. Im Mai 2009 waren es in Wien exakt 7176 Patienten, die auf diese Weise behandelt wurden.

derStandard.at: Wer hat Anrecht auf ein Substitutionsprogramm?

Haltmayer: Eine Indikation wird dann gestellt, wenn eine Opiatabhängigkeit besteht und sich Arzt und Patient über die Behandlung einig sind. Ein weiteres Kriterium ist der Zugang zur Behandlung. Das heißt, wie viele Therapiestellen und Ärzte gibt es, die diese Behandlung anbieten und wie weit ist die nächste Möglichkeit zur Substitutionsbehandlung entfernt.

Im Ganslwirt bieten wir ein sogenanntes niedrigschwelliges Substitutionsprogramm an. Damit gewährleisten wir den Drogenabhängigen einen hürdenlosen Zugang. Vorbedingungen oder hohe Anforderungen werden an den Patienten nicht gestellt. Das Ambulatorium Ganslwirt trägt beispielsweise die Kosten einer Substitutionsbehandlung für nicht versicherte Patienten.

derStandard.at: Mit welchen Substanzen wird in Österreich substituiert?

Haltmayer: Es gibt vier pharmazeutische Hauptprodukte mit denen derzeit substitutiert wird: Methadon, Morphin retard, Buprenorphin und ein Buprenorphin/Naloxon Gemisch. Das sind alles opiatähnliche Substanzen, teilweise natürliche, teilweise künstlich hergestellte.

derStandard.at: Methadon findet bei Patienten angeblich eine relativ geringe Akzeptanz. Warum?

Haltmayer: Zum einen besitzt Methadon viele Nebenwirkungen. Es macht müde, träge und besitzt eine depressionsfördernde beziehungsweise -auslösende Wirkung. Es reduziert die Libido und kann außerdem zu Impotenz führen. Das sind unter anderem Gründe, warum Patienten lieber auf eine andere Substanz umsteigen. In Österreich haben wir hier eine besondere Situation, weil wir als Alternative Morphin retard anbieten können. Substitol, Compensan und Kapanol sind die handelsüblichen Präparate. Der Vorteil dieser Substanzen ist, dass die chemische Wirkung am Beginn der Behandlung Heroin näher ist und daher von den Patienten deutlich bevorzugt wird.

derStandard.at: Experten fordern immer wieder das Verbot von Morphin retard. Warum?

Haltmayer: Das sind Einzelpositionen, meist von Personen die ihren Arbeitsschwerpunkt gar nicht in diesem Bereich haben. Argumentiert wird mit der missbräuchlichen Verwendung dieser Medikamente durch die Patienten. Dabei werden oft mehrere Dinge vermischt.

Der Missbrauch von Medikamenten wird einzelnen Substanzen zugeschrieben und nicht der Abhängigkeitserkrankung selbst. Der Missbrauch von Medikamenten ist aber ein Symptom der Abhängigkeitserkrankung und keine Eigenschaft des Medikaments per se.

derStandard.at: Macht die heroinähnliche Wirkung, Morphin retard nicht auch am Schwarzmarkt attraktiver?

Haltmayer: Natürlich sind sämtliche Morphin retard-Präparate aufgrund ihrer Wirkung auch am Schwarzmarkt erhältlich. Es ist immer eine Frage der Verfügbarkeit. Welche Substanzen sind im Land verfügbar und diese Substanzen finden sich dann auch am Schwarzmarkt.

In Deutschland ist Morphin retard nicht Bestandteil des Drogenersatzprogramms. Dort wird darüber diskutiert, dass Methadon am Schwarzmarkt angeboten wird.

derStandard.at: Warum eignet sich Subutex nur für psychosozial stabile Patienten?

Haltmayer: Subutex ist eine Mischung aus einem Opiat und einem Opiatblocker. Das heißt es besitzt eine opiatähnliche Wirkung die gleichzeitig etwas abgeschwächt und aufgehoben wird. Damit sind die Patienten unter Behandlung dem nüchternen Zustand näher als bei den anderen Drogenersatzpräparaten.

Verständlicherweise kommen Patienten mit einer sehr ausgeprägten Suchterkrankung mit dieser Klarheit nicht zurande. Psychosozial stabil ist in diesem Zusammenhang als Synonym für „weniger krank“ zu verstehen.

derStandard.at: Jeder Opiatabhängige braucht also ein sehr individuelles Behandlungsschema?

Haltmayer: Genau. Es sind zwar prinzipiell alle Medikamente für die Drogenersatztherapie gleich gut geeignet. Die Wahl des richtigen Medikaments muss aber ganz individuell beim einzelnen Patienten erfolgen. Ebenso wie die Höhe der Dosis.

derStandard.at: Welches Mittel in der Dorgenersatztherapie erste beziehungsweise zweite Wahl ist, wurde in Österreich aber von der Politik entschieden?

Haltmayer: Das stimmt und damit ist es auch das einzige Beispiel in der Medizin wo die Politik ein Mittel der ersten Wahl festlegt hat. Diese Entscheidung ist wissenschaftlich nicht fundiert, sollte sie aber sein. Denn die Wissenschaft ist sehr schnelllebig, jedenfalls schnelllebiger als es Verordnungen des Ministeriums sind. Das bedeutet: Es kann sein, dass sich hier auf wissenschaftlicher Ebene was ändert, während die Verordnung immer noch Gültigkeit besitzt.

derStandard.at: Wie sieht es mit der psychischen Unterstützung der Patienten aus?

Haltmayer: Das ist ein ganz wesentlicher zusätzlicher Faktor, der unbedingt berücksichtigt werden muss. Die Substitutionsbehandlung besteht nicht allein aus der Abgabe eines Medikamentes, sondern es braucht auch eine psychosoziale Betreuung. Im Idealfall erhalten die Patienten auch eine Psychotherapie, weil es doch im Laufe der Erkrankung zu vielen Traumatisierungen kommt. Das ist natürlich immer eine Frage des Angebotes. Derzeit gibt es sehr wenig krankenkassenfinanzierte Plätze.

Tatsache ist aber, dass die meisten Suchtkranken wirtschaftlich nicht gut gestellt sind und sich eine private Therapie gar nicht leisten können. Hier gibt es einen Versorgungsengpass. Allerdings – und da lege ich Wert darauf – muss eine psychosoziale Betreuung freiwillig bleiben. Es kann nicht sein, dass sie als Vorraussetzung für die Substitutionsbehandlung definiert wird. Es muss dem Patienten überlassen bleiben, ob er eine Behandlung in Anspruch nehmen will oder nicht.

Hier brauchen wir dringend zusätzliche Plätze, vor allem im psychotherapeutischen Bereich. Eine Ausweitung der Kassenbehandlungsplätze würde eine große Verbesserung in diesem Bereich bringen.

derStandard.at: Wo sehen sie noch Verbesserungsbedarf?

Haltmayer: Es gibt noch zu wenige Substitutionsbehandlungsplätze. In Wien ist die Deckungsrate mit zumindest 50% derer die es benötigen würden, schon recht gut. Aber natürlich müssen in ganz Österreich Therapieplätze geschaffen werden. Ein zweiter wichtiger Punkt ist die Ausweitung der Applikationsform. Wir haben derzeit ein ausschließlich orales Substitutionsbehandlungsprogramm, also nur mit Tabletten. Es sollte auch ein spritzbares Substitutionsmittel angeboten werden. (derStandard.at, 23.02.2010)

Werbeanzeigen

1. ALLGEMEIN 2
2. RECHTSGRUNDLAGE 2
3. SUBSTITUTION 2
3.1 Voraussetzungen für die Substitution 2
3.2 Durchführung der Substitution 3
3.2.1 Der behandelnde Arzt 3
3.2.2 Die Suchtberatungsstelle 3
4. BEWILLIGUNGSVERFAHREN 3
4.1 Ordentliches Verfahren (definitive Bewilligung) 3
4.2 Eilverfahren (provisorische Bewilligung) 3
4.3 Verlängerung der Bewilligung 3
4.4 Beendigung der Substitutionsabgabe 3
4.5 Entzug der Bewilligung 4
5. PERSONENDATENSCHUTZ 4
6. EVALUATION 4
7. INKRAFTTRETEN / ÜBERGANGSREGELUNG 4
8. ANHÄNGE 5
8.1 Anhang: Ablaufschema bei einer Erst-Bewilligung 5
8.2 Anhang: Ablaufschema bei einer Verlängerung der Bewilligung (jährlich) 6
8.3 Anhang: Antrags-/Eintrittsfragebogen 7
8.4 Anhang: Verlaufs-/Abschlussberichtsfragebogen 9
8.5 Anhang: Empfehlungen für die Methadonbehandlung 11
8.6 Anhang: Empfehlungen für die Buprenorphinbehandlung 14
8.7 Anhang: Behandlungsvertrag 17

Volle Fassung:ao_bm_substitutionsrichtlinie


METHADONE-ASSOCIATED OVERDOSE DEATHS
Factors Contributing to Increased Deaths and Efforts to Prevent Them
March 2009
GAO-09-

GAOmethadonedeaths

Dr Lewis is one of the world’s leading experts in drug testing. His speaking manner combines what T. S. Eliot might have termed a lugubrious drollery with a profound grasp on his subject. It is easy to be light-hearted about ‘piss tests’ but it is also deadly serious if your own job, drivers licence or liberty depend upon such a result.

We were reminded first up what urine testing can NEVER determine with any accuracy: (1) the dose, (2) the time it was taken or (3) the pharmacological effect of any substance being tested.

The most common drug assays they perform are for methadone and metabolites, cannabinoids, opiates, cocaine, benzodiazepines and amphetamines. Barbiturates often omitted these days since their illicit use seems to have ceased for all practical purposes. The term ‘amphetamine type substances’ (ATS) is now superseding ‘sympathomimetic amines’.

This group includes dexamphetamine, methylamphetamine, ecstasy (MDMA), methylenedioxyamphetamine (MDA), and other ‘designer’ drugs such as paramethoxyamphetamine (PMA) and their metabolites, but also ephedrine, pseudoephedrine. One needs to know the particular immunoassay ‘kit’ being used to be sure what exactly is detected and at what level.

Laboratories are asked to perform tests both in a clinical setting as well as for forensic, workplace or medico-legal reasons. For clinical purposes a cost effective and fast turn-around time approach is used. This starts with an inexpensive immunoassay which is very sensitive for most of the drugs being tested for, but generally not specific. Hence a negative batch of tests can yield a fast, efficient response to the clinician. Positive immunoassay results for any of the drug groups (or negative for methadone) may indicate further testing, typically using GCMS (gas chromatography/mass spectrometry), which is considered the ‘gold standard’.

Although thin layer chromatography (TLC) is not commonly used nowadays, Dr Lewis says it still has a place: it presents information on a large range of drugs to view at a single glance, and is inexpensive. Because the TLC depends upon the human factor of recognising patterns, it is subjective and unless the spot patterns correspond to known medication, confirmatory testing by mass spectrometry is usually conducted. Although it is not used for medico legal work, it still has a place in clinical settings, as an adjunct to mass spectrometry in presumptively identifying a wide range of therapeutic substances not amenable to immunoassay.

In particular cases there will need to be specific tests done, especially for suspected drug use which may not be detected by the usual immunoassays. These include tests for doctors, nurses or other health care workers on conditional registration due to drug use. Such drugs include pethidine, tramadol and the short acting anaesthetic propofol. Abuse of these drugs outside the medical setting is exceptional.

Note that buprenorphine is also hard to detect by simple methods. Although there is an immunoassay for the drug, toxicologists must be aware of possible false positives from a number of unrelated therapeutic substances. However, like methadone, when the dose is taken under supervision such testing is less important than, say, in England where much treatment is unsupervised and testing for the prescribed medication can be crucial in determining compliance and overall stability.

Dr Lewis then detailed the limitations and strengths of modern immunoassays in determining a class of drug but only in two cases can they detect specific metabolites, EDDP (for methadone) and 6-mono acetyl morphine (heroin). The value of a negative test was pointed out. We were reminded that testing was almost pointless in hospital casualty cases: for overdoses, the results are usually not available until either the patient is dead or else recovered.

Also, medications are used so routinely and such patients may have injuries necessitating local anaesthetics, dressings, iodine, etc in the course of their treatment in the casualty ward that results are close to meaningless.

Specifically, Dr Lewis said that positive opiate and ATS immunoassays should be taken with caution as there are many causes of false positives. These include poppy seeds, cough mixtures, decongestants and common analgesics. Dr Lewis told us that his own urine remained positive for ‘opiates’ for nine days after a dose of the cough suppressant pholcodine. The main value of these screening tests is when the result is negative. Note that ‘opiate’ immunoassays do not detect the ‘opioids’ methadone, buprenorphine, pethidine and others. Oxycodone has only a very weak response to “opiate” immunoassays.

We were then shown the plates used for thin layer chromatography and a list of 20 common drugs which can be definitively determined using this method (eg. morphine, codeine, oxazepam, pseudo-ephedrine, paracetamol and nicotine). GCMS was then described in response to a question from the floor.

In essence it appears that there are two properties of each substance which are identified in the method, causing a unique fingerprint from the two derived figures. It is more expensive than other methods, but more accurate and specific, being able to detect both the original base compound as well as ‘derivatised’ products.

Then we had a brief tutorial on the use of testing for alcohol consumption. Everyone knows about breath testing, but 5% of alcohol is excreted in the urine and there is a direct correlation between plasma and urine alcohol concentration of 1.3:1. However, due to the short half life of alcohol, such testing is only of any use within hours of the drug use. And, as with other drugs, a certain level could be associated with a small amount of drug used very recently, or equally, a large amount used quite some time before.

There are also unexpected false positives, including a case Dr Lewis described where urine from a diabetic in a rehabilitation facility had undergone fermentation (probably by yeasts) before being tested; the calculated blood alcohol concentration (0.34) would have been lethal. A less ‘gross’ error might not have been discovered, and this would have led to the automatic expulsion of the person from the rehab facility.

Tests for cannabis are of limited value since, for most, its use is not relevant to the treatment or supervision being given. Hence Dr Lewis only performs cannabis tests when specifically requested, such as in patients being treated for cannabis dependence, to assess progress.

We were then taken through some metabolic pathways. Heroin breaks down within minutes into 6-acetyl morphine, then to morphine. This then is broken down into morphine-6 or -3 glucuronide which are excreted. Codeine is largely conjugated into codeine-6 glucuronide, but importantly, a small proportion is transformed into morphine. A positive test for morphine can therefore sometimes occur due to codeine use (but not the other way around). A warning: most tests underestimate the amount of codeine in urine, as the metabolite codeine-6 glucuronide is hard to „bust“ into codeine, which can be detected.

It is important to know the relative amounts of morphine and codeine in a urine sample as the ratios affect correct interpretation as to what may or may not have been ingested.

Diazepam is broken down into another active metabolite, oxazepam. This can occur via two intermediaries, nordiazepam and temazepam. Most of the common sedatives and related drugs such as clobazam will show up as benzos on the initial immunoassay. However, specific confirmatory testing must be done when clobazam is used in therapeutic trials to test against ‘street’ benzos.

Stimulants were then covered including the new definition of ice in an age of global warming (ice-bergs and all!). Amphetamine was first synthesised by the Germans in 1887. It was heavily marketed in the US in the 1930s as ‘Benzedrine’. Methylamphetamine is easier to manufacture, especially if one has the base product pseudoephedrine. We were then told that the latest ‘craze’ for stimulants is purely based on stronger, highly purified drug being available in the form of ‘crystal meth’ or ‘ice’.

Methylamphetamine powder is a salt, „crystal“ a highly purified salt, and „base“ is an oil. Urine testing cannot distinguish between them as these are the same drug. While Dr Lewis’ lab has found 2005 was the year with highest mean amphetamine levels, in 2006 the maximum levels found each week continued to climb to being 5 fold the 2003 levels. While these are dramatic findings, it is hard to know their significance overall except to imply that some users are taking very large amounts of methylamphetamine, viz, “ice”.

Cannabis has many metabolites which are detected on screening, and confirmed with carboxy –THC on GCMS. It is very lipophilic, and gets stored in the fat cells of the body. Cannabinoid urine tests may be negative within a few hours of a single smoke; daily use may take many days, and heavy use a month or more. If a high level is found then it is easy to know that there is continuous use. Carboxy-THC: creatinine ratios can indicate increasing or decreasing use (see case vignettes below).

Then there was a discussion about laboratory ‘cut-offs’ which are essential for legal purposes, but less meaningful for clinical purposes, except to reduce the numbers of false positives. Cut-offs are also necessarily somewhat arbitrary, like the drink driving limits – and can vary from place to place or from time to time. Currently 50ng/ml is used for immunoassays of cannabinoids, and 15 ng/ml for the specific GCMS for carboxy-THC (plus or minus a figure for lab uncertainty; this means an actual cut off of around 18-19 ng/ml). Dr Lewis believes there is a case for higher cut-offs to be used for cannabinoids, to identify substantial cannabis use, rather than low level or more importantly residual drug from previous heavy use.

Some case vignettes in the second half illustrated common problems. Three patients with positive immunoassay for opiates claimed only to have taken codeine-based analgesics. One had codeine and morphine on GCMS, and this could be explained by metabolism of codeine to morphine, or other sources or morphine such as poppy seeds, morphine sulphate etc. Another had urine positive for morphine, and negative for codeine: this could occur if there was extensive metabolism of codeine to morphine (for example by cytochrome CYP2D6 ultrarapid metabolisers) and especially if the laboratory test underestimated the amount of codeine (see above). In the last case, urine was positive for morphine and monoacetyl-morphine: the latter can only come from heroin use.

In a case of roadside drug testing, a woman justified her positive salivary cannabis test by saying „I never smoke pot, but my partner smokes it all the time“. Dr Lewis explained that this test does not pick up metabolites of THC, only the parent drug, and is not very sensitive, missing a large proportion of cannabis users (as reported by the European ROSITA study). Thus passive smoking could not cause a positive test. A man on methadone, who had not had a positive urine test for many years, blamed his positive urine cannabinoid test on his partner, who ‘smoked 30 cones each day’. A positive immunoassay test result is unlikely to be a result of passive inhalation. It is more likely be a false positive due to other medication, cross contamination or else laboratory error.

Dr Lewis described the benefits of using carboxy-THC:creatinine levels to help allow for variation in urine concentrations due to level of hydration. Cases were shown from the Drug Court, where declining THC:creatinine ratios were consistent with ongoing abstinence; in another case a spike in ration of THC:creatinine led to punitive action, but might have been explained by the person going to the gym, and mobilising cannabinoids stored in fat cells. Another case from the Drug Court showed how the sequence of appearance or disappearance of diazepam metabolites (nordiazepam, oxazepam and temazepam) could be used to make inferences about recent diazepam use. In this case, as in almost every example discussed, Dr Lewis was able to give examples of exceptions, where other causes than the most obvious might account for the result. So urine tests should never be interpreted uncritically by untrained people.

In another case, a worker was suspended for producing „dilute urine“ (wrongly described as a „false negative urine test“) because of low creatinine urine (1.4 mmol/L), and allegedly told he would need to produce two urine tests with creatinine higher than 5 mmol/L. However, this worker’s serum creatinine was low owing to lean body build, while urea, electrolytes, specific gravity, osmolality were consistent with physiological urine. THC:creatinine ratios might help adjust for hydration (some people deliberately drink lots of water to dilute their urine) but could also discriminate against people with naturally low creatinine. A urine creatinine level as low as 0.9 mmol/L is physiologically achievable. Below this suggests the likelihood, and below 0.5 mmol/L the near certainty, of external interference with the sample, usually meaning dilution after urination.

Methadone maintenance is somewhat of a mystery to clinicians not involved in addiction medicine, and opioid addicts don’t fare well in the emergency medical system. Many nurses and physicians have trouble dealing with them objectively and don’t want to be involved. Well-managed methadone maintenance is, however, a different story. Few EPs dole out methadone, but maintenance patients show up in the ED with legitimate complaints. Patients on high-dose methadone can experience painful conditions or injuries requiring additional analgesia. It’s not easy, but if one can put aside preconceived notions about addiction, methadone maintenance presents a fascinating challenge to the EP.

Figure. Clients line…

Most  have treated methadone maintenance therapy (MMT) clients in the ED, and have dealt with withdrawal, missed appointments, and overdose. I have visited a few methadone clinics, and the whole concept is fascinating, giving great insight into a government-sponsored medical entity.

Treatment Improvement Protocol Series 43: Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Program

This massive document summarizes the consensus of the U.S. Health and Human Services on MMT, which is administered through the Substance Abuse and Mental Health Services Administration and the Center for Substance Abuse Treatment, branches of HHS. This 14-chapter document has everything you want to know about MMT.

Edit by Exilope: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hssamhsatip&part=A82676

Initial Screening: Anyone can walk into an MMT clinic and request treatment. Initial screening exams and interviews determine the applicant’s eligibility and the process includes an assessment of their readiness to accept treatment. Ongoing, if not daily interventions, are required to keep the patient in the system and off the opioid. The addiction severity index collects basic information, and it can be used to track progress. Much of the information is supplied by the addict, and truthfulness on their part is paramount for success.

Comment: I suspect most people don’t walk in off the street thinking about MMT for the first time. All potential clients likely consider it many times or talk about it with fellow addicts. They are often prompted to try MMT by those who have been through the process, some more than one time. One would assume that an opioid addict who shows up at the clinic has hit rock bottom or finally has accepted they have an addiction they cannot control. Many are in overt withdrawal. They are ready to sign up.

First impressions are lasting ones. The HHS recommends a plethora of warm and fuzzy approaches to help the addict adjust and feel supported. A nonconfrontational and nonaccusatory attitude is stressed. Unlike the ED, MMT clinics want to be in the business of dispensing methadone. Clinics are usually prepared to provide immediate information, if not methadone treatment, on the first day.

A variety of preprinted documents are handed out that describe the services, rules, and expectations of the program. Policies are in place to deal with disruptive and violent clients and pregnant women. Clinics also try to identify treatment barriers and offer financial assistance and psychiatric crisis intervention. Many patients also have underlying psychiatric disorders, legal difficulties, child care issues, and transportation and family concerns. Cultural, ethical, and spiritual factors also complicate MMT. Those patients who seem in crisis can be referred for inpatient medical facility or psychiatric care. The correlation between opioid addiction and the risk of suicide is well known, and initial screening and periodic assessment helps determine that ongoing risk.

Admission Issues: A significant delay between the first contact, initial screening, and methadone treatment, especially failure to quickly address withdrawal, adversely affects the number of applicants who enter the program. It’s difficult to deal with an opioid addict in withdrawal; his patience wears thin, and he wants treatment now. Recognizing the realities of crowding and limited resources, MMT clinics can provide an interim maintenance program without formal screening or actual admission to the site. By federal regulation, medication can be administered for up to 120 days with only minimal screening procedures.

Violent or threatening patients can be turned down, but I have been amazed at how understanding and supportive some of the staff are; it’s similar to the mentality emergency physicians use to treat those who are not the nicest people. MMT, like emergency medicine, is a service industry, and the customers often possess the mentality of the McDonald’s client. They want it now, they want it their way, and they don’t want to pay much for it. Frustrated clients who elope are, however, a loss for everyone. Programs are not free, and cash and insurance are accepted, but often the down-and-out addict qualifies for local aid.

Information, Collection, and Dissemination: During the first few visits, a substance abuse history is obtained, and treatment options are discussed. Consent to treat is elicited, and addicts must sign a bevy of documents that provide further information on the multifaceted MMT process. Patients must be 18 or have parental approval. Otherwise, the services are confidential even to family members. Confidential information is not given to any inquiry except the court. The specifics of the individual’s opioid addiction, including recent pattern changes and binges, are gathered. Other drugs such as benzodiazepines and alcohol are often confounding issues, and the patient’s daily pattern of opioid abuse is determined, essentially by his own admission.

The opioid withdrawal history and the energy required to maintain the addiction is sought. Many patients are in withdrawal when they come to the clinic, making historical information open to exaggeration, but many downplay their use (like the alcohol history obtained in the ED). Some withhold a history of other addictions, perhaps thinking they might supplement the methadone if needed. Blood tests for specific drugs are not required nor usually performed to quantify use. A serum drug level is of no value in this scenario. Questioning the history can intimidate the prospective client and set up an adversarial relationship at the beginning. Again, unlike the ED, MMT clinics put a lot of trust in the truthfulness of the addict.

Medical Assessment: The aim of medical assessment is to determine the safety of methadone use. The drug is often dispensed on the first visit because of withdrawal. It is generally required that someone be addicted for one year before admission. There appears to be some flexibility in this criterium, especially for prisoners, pregnant women, or those previously treated. There may be uncertainty about past narcotic use, but generally a broad definition is accepted for opioid addiction, and one need not administer Narcan to test for withdrawal.

Generally, the staff obtains a medical history that documents drug-related diseases such as hepatitis, AIDS, tuberculosis, or STDs. Within 14 days of admission, a basic physical examination is performed, including blood tests for HIV, syphilis, and hepatitis. Federal regulations do not require a full panel of laboratory tests; that appears to be a state issue. Patients usually are tested randomly by a urine screen immunoassay test for additional drug abuse at least eight times each year per SAMHSA. Because methadone does not yield a positive opioid result unless specifically tested, a positive opioid screen usually means exogenous drugs.

Multiple Substance Abuse: It is common knowledge that opioid addicts often abuse other substances, especially alcohol, amphetamines, benzodiazepines, prescription opioids, cocaine, sedatives, and marijuana. CNS depressants are particularly dangerous when combined with opioids. Patients generally are asked to report other substances they used in the past. The accuracy of this form depends, of course, on patient honesty. Alcohol is a favorite of most, and heroin addicts particularly like to add cocaine for additional euphoria. Benzodiazepines are commonly used to boost methadone and enhance the high. Patients also self-medicate because of withdrawal symptoms or because they are anxious, depressed, or lonely.

MMT clients all know using an exogenous substance can kill them and defeat the purpose of MMT. Using exogenous drugs negatively affects attendance rates and cooperation with other programs. Interestingly, patients are not frequently discharged from MMT because they abuse other substances. The main goal is to retain the patient in MMT, allowing for human frailty, lack of self-control, and poor judgment. MMT clients are given multiple chances despite violating explicit rules and regulations.

Drug Testing: Clients are randomly tested for other drugs, usually with an immunoassay urine screen. This is not a perfect system because it only identifies those using other substances frequently and only detects drugs that show up on a urine screen. Of course, it has to be your urine, and there is always someone around who wants to give a clean sample for the right price.

Periodic drug testing provides objective evidence of treatment success and monitors patient progress. Typical urine testing evaluates for commonly abused substances with a qualitative immunoassay technique that has cutoff concentrations. Testing drug levels in the blood is not helpful because tolerance, time of use, and the need to send the test to a reference lab does not allow for meaningful interpretation of data. Most drugs remain in the system and are excreted in the urine for two to four days following use. Measuring methadone serum levels during treatment has minimal value and is not done routinely, but this may be used to identify a rapid or slow metabolizer. Obviously, urine tests are not quantitative; they merely give positive or negative results.

Urine collection may be monitored to avoid contamination or substitution. There are no firm and fast rules for the method of testing, and direct observation is not mandatory. The most common test is an enzyme-multiplied immunoassay technique (EMIT), which uses antibodies to specific drugs or metabolites. Oxycodone is often not identified with this test; nor are clonazepam, Seroquel, hallucinogens, fentanyl, Demerol, dextromethorphan, propoxyphene, and a variety of street drugs. On-site dipstick urine testing is common, but some clinics will confirm the initial clinic screen via a reference laboratory. Many clinics test patients at intake to prove they used opioids recently. The continued use of heroin or other opioids may prompt an increase in the methadone dose because it’s common to supplement during withdrawal.

Retaining Patients in MMT: The longer the patient stays in MMT, the less likely he will revert to using opioids. Staying in MMT for more than a year is associated with constructive lifestyles changes, decreased criminal behavior, and less transmission of infectious diseases. Older patients and those not in the criminal justice system tend to stay in the program longer. Those who have tried it before and failed are better candidates for retention the next time around.

But the key to MMT success, as this HHS publication notes, is: Adequate individualized medication dosages are probably the most important factor in patient retention because they contribute to patient comfort and satisfaction by reducing withdrawal symptoms and craving. The serum half-life of methadone is stated to be 24 to 36 hours, but in reality there is an extremely wide range (13-58 hours). Excessive methadone use occurs when daily visits and individual dose adjustment are not made.

Take-Home Medication: Methadone is usually dispensed daily in a liquid form, and ingestion is witnessed. This keeps patients from diverting tablets. Methadone diversion is a huge problem in this country, but that methadone is usually not obtained from clinics. A single take-home dose is common on Sundays and holidays. After six months to a year, compliant and reliable patients can take home one to four weeks of methadone, but initially, doses are only dispensed daily at the clinic. The requirement to show up every day can be problematic.

Figure. Christine Ad…

Dosing Schedule: A dose of 30 mg to 40 mg of methadone is the upper limit for the initial dose, per regulation. Initial dosing should be followed by increases over subsequent days until withdrawal symptoms are suppressed. A steady state of a dose is not reached for three to five, sometime seven days after a dosage change. The goal is to reach 80 mg to 120 mg methadone per day, a level that has been proven to improve compliance to the program. Using smaller doses or failing to increase the dose when withdrawal is still present is ineffectual and counterproductive. Withdrawal often prompts exogenous drug use or elopement.

The actual schedule is not set in stone, but daily dose increases of 5 mg to 10 mg a day for the first five to seven days to reach 60 mg a day are common. The 60 mg per day dose is maintained under daily observation to reach a steady state. The first week or two of MMT are the most dangerous for the patient and the time during which most fatalities occur. With daily observation and individual dose adjustments, induction is safe and effective as long as the patient is truthful and abstains from other drugs.

The quoted serum half-life of methadone can be misleading, and provides only a rough estimate to forecast dosing requirements and effectiveness. Methadone is eliminated more quickly from the blood and the effects wear off sooner until sufficient levels are obtained to saturate tissues, especially the liver. Smokers have increased clearance, and significant liver damage slows clearance. The optimal dose can only be determined by observing the individual daily, debriefing him on how he feels, and altering dosages in a safe, effective manner.

There is no uniformly suitable dose range or limit for all patients. Some require 400 mg to 700 mg a day while others do well on 80 mg to 120 mg a day. During induction, clinical observation and patient symptoms are the best indicators of whether a dose is too small or large. When this protocol is followed, methadone induction is safe and effective.

Comment: There are eight MMT clinics in Philadelphia, usually for heroin addiction, but more frequently for prescription opioid addiction. Most opioid addicts know the concepts of MMT well, and visit various clinics off and on throughout their addiction. The rules of MMT are straightforward, and each state is allowed some latitude on various issues. Some addicts have learned to work or abuse the system, but MMT is a godsend, if not a true lifeline, for many opioid addicts.

Addiction to hydrocodone, hydromorphone, and oxycodone is likely more widespread than street heroin. There is little difference between the prescription pill addict and the hardcore street heroin user on everyday issues or potential benefit from MMT. The well-to-do business man, the bored housewife, the professional athlete, or the Hollywood celebrity seem to prefer pills over the needle. Some physicians readily prescribe a slew of addicting medications, prescriptions are stolen or altered, and anyone can buy a few Percocet at the local high school. The Internet provides drugs as well as directions on use and how to beat drug tests and avoid overdose. Of course, heroin can be smoked and snorted as well, but there is less of a stigma involved with popping a pill than buying a bag of heroin on a lonely street corner.

I am quite impressed with the understanding approach to MMT and the dedication of the clinic personnel. Methadone manufacturers stress that their product should be used only under strict HHS guidelines, and they actually reference the Federal Register code in the package insert. The dangers of inappropriate methadone use are well-reported in the literature, but it’s likely an underused drug for chronic pain control.

Society has written off many opioid addicts or would drop them in a heartbeat at any sign of deceit or additional drug use. Not so for MMT clinics; they bend over backwards to give everyone yet another chance. Using additional substances during MMT is very common. Klonopin, Xanax, Soma, and Seroquel are popular in my area to boost methadone’s high, and none show on a urine screen. It’s easy to buy any of these on the street, usually right outside the door of the clinic. It’s best to never underestimate the ingenuity or resourcefulness of an opioid addict so MMT works best in an environment of mutual trust and truthfulness. Lying to the counselor about past or present drug use or beating the drug test is tempting, but in the end, it can be a fatal error.

Buprenorphine interactions

Although there is significant confusion in the literature, buprenorphine is most commonly classified as a (partial) mu agonist/kappa antagonist. There is consensus that in the relatively ‘low doses’ used in clinical pain management, (5-100 mcg per hour), buprenorphine behaves like a ‚full‘ mu agonist. The partial agonist/antagonist effects seem only to become relevant for analgesia in very high doses used to treat opioid addiction (8-32 mg per day).

In patients on ‘analgesic doses’ of buprenorphine (eg transdermal), one can continue to use opioid analgesics for breakthrough pain in the usual way with good effect. The partial agonist/antagonist effect on supplemental opioid analgesia is not a major clinical issue. Other alternatives include sublingual buprenorphine or tramadol.

When treating acute pain after major surgery or trauma in patients on ‘high dose’ sublingual buprenorphine for addiction, continue the buprenorphine, using maximal multimodal analgesia including ketamine and neural blockade, supplemented with opioid PCA (using higher bolus doses) and monitoring the patient closely for adverse effects. In our experience, many patients undergoing major emergency surgery seem to do well with continuation of high dose sublingual buprenorphine and PCA fentanyl or morphine in appropriate doses. Conversion to standard opioids is complicated and often unnescessary.

Methadone interactions

Because methadone ‘saturates’ CYP450 (3A4) at low plasma levels (low hepatic clearance) compared with other opioids, it’s very ’susceptible‘ to;

  • The effects of a 30-fold variation in CYP450 enzyme activity between patients (fast, medium or slow methadone metabolisers), thus explaining the wide range of t1/2 (5-150 hours) and in part, highly variable clinical responses to methadone loading.
  • ‘Plasma accumulation‘, as the dose or frequency increases (the ’saturated‘ CYP450 can’t ‚burn off‘ the excess methadone):
  • Complex interactions with many drugs that share CYP450 for metabolism, particularly anticonvulsants, antidepressants, anti-microbial and antiretrovirals.

When prescribing methadone, always think about drug interactions at CYP450. Interactions are complex, with either induction (eg. phenytoin, rifamycins) or suppression (eg. fluvoxamine, fluoroquinalones, macrolides) of enzyme activity affecting methadone clearance, sometimes resulting in either withdrawal or accumulation respectively.

Methadone is highly-bound to plasma acute phase reactants (a1-acid glycoprotein), with the free methadone concentration decreasing when the level of phase reactants is raised (the free methadone is ‘mopped up’) such as in cancer or sepsis, leading to reduced analgesia or in rare cases withdrawal.

There are also substantial risks of over-sedation when methadone is combined with benzodiazepines, alcohol or THC.

Methadone, prolongs the QT interval in a dose dependent fashion (usually in doses greater than 200 mg per day) with case reports of Torsades de Pointes and VT. Check an ECG before commencing methadone, keep doses low and consider potential interaction with other drugs and conditions that prolong the QT interval.

Executive Summary_ _______________________________________________________________ 5
Introduction_______________________________________________________________________ 7
Methodology_____________________________________________________________________ 10
Summaries of Published Studies
Evaluating Insite: Why and How
Reasons for evaluating Insite_______________________________________________________________ 13
How Insite is studied_ ____________________________________________________________________14
Early Results
Attendance, drug use patterns and referrals__________________________________________________ 15
Who Uses Insite?
Characteristics of Insite users_ _____________________________________________________________ 17
Frequent Insite users_ ____________________________________________________________________18
Hepatitis C infection among Insite users_____________________________________________________19
HIV prevalence among Insite users__________________________________________________________21
Younger Insite users______________________________________________________________________22
Does Insite Promote Drug Use?
A before and after study_ _________________________________________________________________ 23
Insite and initiation of injection drug use_____________________________________________________25
Insite and Addiction Treatment
Insite users and detox____________________________________________________________________26
Detox before and after Insite_______________________________________________________________ 27
Impact on Crime and Public Disorder
Insite’s impact on drug-related crime________________________________________________________29
Insite’s impact on public order______________________________________________________________30
Insite and Overdose Prevention
Drug overdoses at Insite_ _________________________________________________________________ 31
Are there more overdoses now because of Insite?_____________________________________________ 33
Insite’s impact on overdose risk____________________________________________________________34
Overdose deaths prevented by Insite________________________________________________________ 35
Impact on High-Risk Behaviour
Insite’s effect on syringe sharing____________________________________________________________ 37
Characteristics of Insite users who share syringes _ ____________________________________________38
Reduced syringe sharing and HIV prevention _________________________________________________39
Insite’s effect on condom use_ _____________________________________________________________40
Safer injecting education at Insite__________________________________________________________41
Insite’s effect on safer injecting practices_____________________________________________________43
Women benefitting from safer injecting education at Insite_____________________________________44
Insite users’ perspectives on safer injecting education at Insite___________________________________45

Read more about Canada:insite_report-eng

Canada’s war on drugs has failed to curb the illicit drug trade, and proposed legal interventions to disrupt the drug market may actually boost rates of drug-related violence, according to the latest report by the Urban Health Research Initiative. The report’s findings are significant in the context of Bill C-15.

Read the full Report: violence-eng

By Farzana Shah

Monday, 23 February 2009.

In Afghanistan, U.S./NATO have put the blame on Taliban for poppy cultivation to finance their resistance to allied forces. Ironically, it was only in Taliban era when the world had seen a sharp decline in opium crop in Afghanistan. The Afghan Taliban had banned opium cultivation nationwide, probably for the first time in Afghan history. A more important question is how and when this business of drug production and trafficking started in region? CIA has been using drug money since long to generate money to support its operations all over the world. It did not start in Afghanistan it was brought here after experimenting somewhere else. This is something which is not a lead story in international media for obvious reasons despite the fact it is harming millions of lives around the globe.

1. CIA’s secret Operations

Central Intelligence Agency (CIA) on of the most active and dynamic intelligence setups in the world needs massive amount of money to carry on its clandestine operations all over the world. It has happened when CIA used local sources to conduct a coups, assassinations, regime change, etc. As U.S. has a long history to support democracy by hook and crook until and unless a dictator is ready to serve U.S. interests to prolong its rule.

Operations like the one completed in Iran in 1953 to remove Prime Minister Mussadaq and backing Shah’s regime by using assets in civil society, or in Iraq in 1975 to arm Iraqi Kurds to destabilize Pre-Saddam Iraq or more recently using its assets in Pakistan to pave the way of direct U.S. intervention in Pakistan under pretext of hunting Al-Qaeda.

These kinds of operations need a lot of financial input. Usually CIA arranges revenue from its own means for this kind of operations where expenses can’t be predicted by any measure. Funds from Whitehouse always need a complete audit and detailed reports about usage of these funds. There are numerous occasions when CIA never shared details of operations with its own analytical wing nor with any other public office in Washington. Most of the time it is drug money that compensates these expenses.

CIA operations are not only single expenditure fulfilled by drugs there are also other deficiencies which are compensated with this money like financial institutes and banks in current financial crisis. UNODC Executive Director Antonio Maria Costa based in Vienna revealed that drug money often became the only available capital when the crisis spiraled out of control last year.

The United Nations Office on Drugs and Crime had found evidence that “inter bank loans were funded by money that originated from drug trade and other illegal activities,” Costa was quoted as saying. There were “signs that some banks were rescued in that way.”

It is not only CIA anymore in trade for using it as gold mine to finance its illegal operations all over the world but U.S. economy also need some liquidity in its banks, it doesn’t matter if it is coming by drug trade.

2. Drug Production & Consumption

Afghanistan is largest producer of heroin’s main ingredient; opium and opium is nothing new in this part of the world. In Afghanistan and FATA, Pakistan it is being produced since centuries; used as remedy for various diseases. Commercial production of opium began just during the Russian invasion in Afghanistan where it is estimated to produce some 8250 metric tons (Source: AmericanFreePress.net, November 24, 2008) of opium per year which makes 85% to 90%

of the world’s supply of opium. This also contributes towards Afghan warlords’ wealth directly. This is what CIA brought to the region: Opium production without a brand name obviously. Today’s world opium production map is as under;

Left: Demand and trafficking of drugs globally. U.S. is one of very high concentration drug trafficking territory thanks to Regan’s National Security Council who turned a blind eye towards South American cocaine socking into U.S. in 1980 when CIA was backing all the drug traffickers of Contra movements in Nicaragua.

Markets for these drugs stretched world over from Western Europe to Far East, From Canada to Latin America and From China to Morocco, Africa. Profits related to this business also vary along with market’s location.

This business enriches not only the United States-friendly Afghan warlords but also elements of the Northern Alliance, the U.S. key ally in the country. More disturbing is fact that this money also contributes in CIA’s operations against Pakistan as well.

3. Contra Movements (1980)

In Asia demand for heroin is more than any other drug but it is not the case world over. Cocaine is favourite drug which is consumed the most. Cocaine was nothing new in South American countries but it was only during Nicaraguan contra movements against the then dictator it got shoot up. It was again CIA’s regime change operation to bring “democracy” in Nicaragua. It was during this period when the whole region saw an unprecedented surge in cocaine trafficking in 1980. This has been investigated none other than but by CIA’s inspector general in later years.

Was CIA a part of this?

Answer is not only CIA was aiding these cocaine traffickers and money-launderers but Ronald Reagon’s National Security Council also turned a blind eye towards these drug trades despite the fact that later these very drug traffickers brought cocaine to mainland U.S.. According to CIA’s inspector general report, published in online magazine The Consortium magazine, Oct. 15, 1998, it was Reagan’s National Security Council which cleared proven drug traffickers and CIA inspector general Frederick Hitz confirmed long standing allegations of cocaine traffickers. The NSC’s covert airline was the main transportation mean to do this trade in safest possible way.
Figure
1: Armed men of Nicaragua insurgency during 1980s, armed with CIA weapons bought with drug money.

Most stunning part of all this contra movements and CIA involvement is methods these movements used to dismantle the then Nicaraguan government including bombing and killing of civilians and CIA withheld all evidence of contra crimes from Justice Department, the Congress and even its own analytical division just to conceal its connection with drug traffickers.

4. Afghanistan

As it is mentioned earlier that Afghanistan was not a hub of drug supply to world before Russian invasion in 1979. It was CIA once again to implement what it successfully implemented in Nicaragua in 1980. Now, Afghanistan is biggest contributor in drug production with its massive opium production.

Russian Afghan War (1979-1989)

CIA was not fully done with contra movements when Russia invaded Afghanistan in 1979 threatening the region with her expansionist design to gain control over Afghanistan and Baluchistan province of Pakistan to reach Arabian Sea. Pakistan decided to confront Russia inside Afghanistan to thwart communist designs. CIA found an opportunity in Afghanistan to settle its long standing duel with Russian for global dominion, after initial successes by Afghan fighters. CIA once again brought tested formula of drug to finance this war which it used in South America with only difference in prescription where cocaine was replaced with heroin. Poppy cultivation was nothing new to Afghan but it was level of production and demand created by international traffickers in the world which shocked many in vicinity of these poppy fields.

Profit gained by these drugs was main driving force behind all this trade and with heroin it was much more than what it was with cocaine. Ironically U.S. and Europe became biggest markets of heroin prepared produced in Afghanistan.

Regan’s administration is also a common factor in both Afghan heroin trade and contra cocaine traffickers. Role of CIA in first Afghan war was not overt as it could provoke Russians in more direct retaliation albeit Cuban missile crisis of 1960s. To avoid that kind of hostility it was more suitable for CIA to have silent links with Afghan warlords and providing sources to grow poppy. “By the end of Russian invasion in 1989 Afghanistan was second largest opium production spot with 1350 Metric ton after notorious Golden Triangle including countries like Laos, Thailand, Burma and Vietnam which was producing 2645 Metric ton at that time leaving Latin America way behind with just 112 Metric ton”, as per U.S. Drug Enforcement Administration.

Pre and Post Taliban Era (1994-2001)

In 1994 unrest and lawlessness in Afghanistan gave rise to Taliban. Motivated with their strict religious background and education they put ban on all kinds of drugs in territory under their control but this was not the cure for chronically infected Afghan economy and society. Non availability of any job market and strong hold of Northern Alliance of Northern part of country remained biggest challenge to these efforts to cut down poppy cultivation in Afghanistan. But despite all the challenges Talibans were able to put a serious cut on opium production in Afghanistan by start of 2001 when they were about to capture Northern Alliance’s strong hold Mazar-e-Sharif but post 9/11 scenario not only changed the geopolitical dynamics of the whole world but also destroyed the efforts of Taliban to control opium production.

Figure 2: Afghan opium sells in cheap at home, worth a fortune in U.S. market

Left: In year 2001, just before U.S./NATO invasion into Afghanistan, Taliban were able to cut down opium production by a decisive margin. This was also one of core reasons against Taliban along with other excuses. After year 2002, when Taliban were removed from power there is a historical increase in opium production in Afghanistan, money is going to pentagon to carry on Afghan and Iraq war despite a historical recession in U.S..

Recent Afghan Conflict (2002 – To date)

Afghanistan is leading opium production in world today but after the invasion of U.S. in 2002 Afghanistan is also attributed to have largest heroin production in the world as well.

Without active support of Pentagon and CIA it is not possible to export drug prepared with more than 8000 metric tons of opium. U.S. relations with Northern Alliance in Afghanistan after Taliban have given a free license to drug producers, traffickers. CIA and Pentagon both have their links to all these criminals in order to get supplies of the drugs and export it in U.S. Army planes. It has been reported that CIA used U.S. Army planes leaving Afghanistan carrying coffins which were filled with drugs instead of bodies.

To make sure undisturbed trade U.S. appointed all Northern Alliance drug lords at key posts in Afghanistan and most prominent appointment was none other than President Hamid Karzai. Karzai’s brother, head of Kandahar’s provincial council is proven drug trafficker facilitating the transportation of heroin from Kandahar eastward through Helmand and out across the Iranian border.

There is no reason to believe that CIA is not aware of this but as it is all one big enterprise where Karzai is also a partner so no danger to his brother.

Bush administration pushed the level of poppy cultivation to next level in Afghanistan just to keep Wall Streets alive in crisis. Many top Bush administration’s officials were worried about growing influence of countries in Golden Triangle (Loas, Thailand, Vietnam, Burma) in Russian and Chinese drug markets. Like Oil in Iraq this was just another opportunity for the Bush administration to have some quick bucks.

Blames for using drugs to fight with NATO and U.S. forces is always put on Taliban. But looking at areas of Taliban’s active zones one can easily understand where all this poppy cultivation is taking place. Taliban put ban on poppy when they were incharge of majority of Afghan territories and Kabul, the capital. Afghanistan was suffering worst economic crisis at that time but Taliban never went to build their economy with heroin trade. Now it is just ridiculous to blame Taliban to have vast fields of poppy and having enough peace and time to grow and process it into heroin and then trade it in Pakistan and Iran to dens it to destinations in Eastern Europe. Below is map of Afghanistan indicating high poppy cultivation provinces and it is quite evident that Taliban dominant

Hamid Karzai, to represent Kandahar province in Kabul. According to media reports he is main player in exporting heroin and opium to European countries through Turkmenistan.

Provinces like Kunar, Pektika,Paktya has low poppy cultivation and other provinces where all U.S./CIA supported warlords are holding key positions are growing most of opium crop. It was only after U.S. invasion there was a 4400% increase in opium production.

U.S. role in Afghan social debacle will go in history as described The Huffington Post on October 15, 2008When the history of U.S. involvement in Afghanistan is written, Washington’s sordid involvement in the heroin trade and its alliance with drug lords and war criminals of the Afghan Communist Party will be one of the most shameful chapters.”

5. Pakistan: Indirect Victim of the CIA’s Drug business

Almost the whole world is affected by this drug trade but countries which lie in routes of drug traffickers are worst effected after the original drug markets. Countries like Pakistan are paying a very high price for U.S./CIA drug trade as there is a constant increase in drug addiction in Pakistan. Iran is another country which happens to be in route of international drug traffickers so it is also facing problem of smuggling of heroin and morphine from Afghanistan and Pakistan to Turkey and Europe. After U.S. invasion of Afghanistan this route has become active manifold then it was previously.

Effects of this trade are not limited to drug usage only but it destroys the social fabric in a society and gives rise to street crimes in order to get some cash to buy drugs from street market. A more horrible outcome is spread of HIV virus among addicted persons when they share the injection syringes. This threat is increasing with each passing day as number of HIV positive is increasing.

Another disastrous effect it brought to Pakistan and Afghanistan other neighbors is serious law and order situation in bordering area of each country with Afghanistan. Combating this evil trade is not possible until a holistic effort is made by international community in this regards but its chances are bleak as this trade is needed by global imperialism (Israel, U.S., UK) more than ever before to give some support to their dying economies.

Above: Pakistan has become main artery in heroin trafficking route and it has a lot of implication on Pakistani security. Level of drug addicted also increased over the year due to high availability of drugs in street market. Afghanistan is main producer but Pakistan us where most of drugs are seized.

6. Conclusion

Under current situation it is very important for countries like Pakistan, Iran, Afghanistan and Russia to think about how to put jinni of drug back to the bottle before international drug mafia takes over these countries by destroying their social norms and values.

CIA not only has a long history of having links with traffickers but also encouraging the drug trade to get its own interests served. CIA always encourages this trade even if it affected its own citizens like in Contra movements of 1980.

Afghanistan became leader in opium production and main hub for providing heroin and its main ingredient to whole world. All this happened under the control of champion of human rights U.S. and its intelligence setup mainly CIA.

Situation is becoming more and bleaker unless Pakistan, China, Russia, Iran and Afghanistan governments start thinking about this trade and its far reaching affects on U.S. economy and CIA’s funding. It is time when the whole region should become equivocal against this trade and ask U.S. to leave the region for greater good of the billions of people in region.

Farzana Shah is a Pakistani researcher and journalist based in Peshawar. She can be reached at janashah_1ATyahoo.com

Dies ist ein ziemlicher Brocken an Information (160 Seiten)

aber meiner wirklich ganz bescheidenen meinung nach lesenswert,

denn immerhin bildet sich das Bild ueber Drogen-User and Abuser

durch solche Artikel!

Ich poste dennoch solch dinge weil es keine 100% Wahrheit beim Thema Sucht und Drogen geben kann/ wird!

Der Artikel ist Deutsch-Sprachig!

Hier klicken und lesen: SuchtmedReihe_Drogen

MORE THAN TWO THIRDS OF
people with addiction see a
primary care or urgent care
physician every 6 months, and many
others are regularly seen by other medical
specialists.1,2

These physicians are
therefore in a prime position to help patients
who may have drug abuse problems
by recognizing and diagnosing the
addiction, helping to direct patients to
a program that can meet their treatment
needs, and helping to monitor
progress after specialty treatment and
during recovery.3-6

Many physicians,
however, find the domain of drug abuse
particularly daunting and often avoid
the issue with their patients. This is understandable
given the relatively short
shrift drug abuse is given in formal
medical education. There is a widespread
misperception that drug abuse
treatment is not effective, which may
account for the reluctance of physicians
to even broach the subject of drug
abuse or treatment with their patients.
On the other hand, over the past 15
to 20 years, advances in science have
revolutionized our fundamental understanding
of the nature of drug abuse
and addiction and what to do about it.
In addition, there are now extensive
data showing that addiction is eminently
treatable if the treatment is welldelivered
and tailored to the needs of
the particular patient.

There is an array
of both behavioral and pharmacological
treatments that can effectively
reduce drug use, help manage drug
cravings and prevent relapses, and restore
people to productive functioning
in society.7-9
Of course, not all drug abuse treatments
are equally effective, and there
is no single treatment appropriate for
all patients. Fortunately, recent scientific
advances have provided insights
both into the nature of drug abuse and
addiction and into the principles that
characterize the most effective treatment
approaches and programs.10 These
treatment principles should make the
primary care or nonaddiction specialty
care physician’s tasks of screening
and referral much easier.

Read more: 20.03.10

Context Substance use disorders among physicians are important and persistent
problems. Considerable debate exists over whether use of major opioids, especially
among anesthesiologists, is associated with a higher relapse rate compared with alcohol
and nonopioids. Moreover, the risk factors for relapse with current treatment and
monitoring strategies are unknown.
Objective To test the hypothesis that chemically dependent health care professionals
using a major opioid (eg, fentanyl, sufentanil, morphine, meperidine) as drug of
choice are at higher risk of relapse.
Design, Setting, and Participants Retrospective cohort study of 292 health care
professionals enrolled in the Washington Physicians Health Program, an independent
posttreatment monitoring program, followed up between January 1, 1991, and December
31, 2001.
Main Outcome Measure Factors associated with relapse, defined as the
resumption of substance use after initial diagnosis and completion of primary treatment
for chemical dependency.
Results Twenty-five percent (74 of 292 individuals) had at least 1 relapse. A family
history of a substance use disorder increased the risk of relapse (hazard ratio
[HR], 2.29; 95% confidence interval [CI], 1.44-3.64). The use of a major opioid
increased the risk of relapse significantly in the presence of a coexisting psychiatric
disorder (HR, 5.79; 95% CI, 2.89-11.42) but not in the absence of a coexisting
psychiatric disorder (HR, 0.85; 95% CI, 0.33-2.17). The presence of all 3 factors—
major opioid use, dual diagnosis, and family history—markedly increased the risk of
relapse (HR, 13.25; 95% CI, 5.22-33.59). The risk of subsequent relapses increased
after the first relapse (HR, 1.69; 95% CI, 1.13-2.53).
Conclusions The risk of relapse with substance use was increased in health care
professionals who used a major opioid or had a coexisting psychiatric illness or a family
history of a substance use disorder. The presence of more than 1 of these risk factors
and previous relapse further increased the likelihood of relapse. These observations
should be considered in monitoring the recovery of health care professionals.
JAMA. 2005;293:1453-1460

Read more: 1453 rueckfall beim aerzlichen personal

Studies in Europe have suggested that injectable diacetylmorphine, the active ingredient
in heroin, can be an effective adjunctive treatment for chronic, relapsing opioid
dependence.
Methods
In an open-label, phase 3, randomized, controlled trial in Canada, we compared
injectable diacetylmorphine with oral methadone maintenance therapy in patients
with opioid dependence that was refractory to treatment. Long-term users of injectable
heroin who had not benefited from at least two previous attempts at treatment
for addiction (including at least one methadone treatment) were randomly assigned
to receive methadone (111 patients) or diacetylmorphine (115 patients). The primary
outcomes, assessed at 12 months, were retention in addiction treatment or drugfree
status and a reduction in illicit-drug use or other illegal activity according to
the European Addiction Severity Index.

Read more: heroin_vs_methadone_2009

Background: The objective of this research was to evaluate data from a randomized clinical trial that tested injectable
diacetylmorphine (DAM) and oral methadone (MMT) for substitution treatment, using a multi-domain dichotomous index, with
a Bayesian approach.
Methods: Sixty two long-term, socially-excluded heroin injectors, not benefiting from available treatments were randomized
to receive either DAM or MMT for 9 months in Granada, Spain. Completers were 44 and data at the end of the study period
was obtained for 50. Participants were determined to be responders or non responders using a multi-domain outcome index
accounting for their physical and mental health and psychosocial integration, used in a previous trial. Data was analyzed with
Bayesian methods, using information from a similar study conducted in The Netherlands to select a priori distributions. On
adding the data from the present study to update the a priori information, the distribution of the difference in response rates
were obtained and used to build credibility intervals and relevant probability computations.

Read more: heroin_vs_methadone_2_2009

Abhängigkeit (Allgemeines)
Die Frage nach den Ursachen, die zu einer Abhängigkeit führen, ist auch eine Frage
nach der Motivation, überhaupt eine Substanz zu sich zu nehmen, bzw. eine
diesbezügliche Handlung auszuführen, zunächst eingeschränkt auf den
Drogenkonsum: Warum werden Drogen genommen?
Drogen sind neben den illegalen Substanzen auch legale Alltagsdrogen (Nikotin,
Koffein, Alkohol, Chinin, Capsaicin, Kakao) und zudem das breite Spektrum mehr
oder weniger psychoaktiver Medikamente.
Der menschliche Körper selbst produziert eine große Zahl solcher Substanzgruppen,
um unser Wohlbefinden, unsere physischen und psychischen Befindlichkeiten
maßgeblich zu steuern. Eine physische Beeinflussung korreliert daher bei einem
mehr oder weniger regelmäßigen Abusus (Missbrauch) psychotroper Substanzen
letztendlich mit einem tiefen Eingriff in das körpereigene Regelkreis-System (s.a.
Kybernetik) der Hormone und Neurotransmitter, infolgedessen der psychologische
Zustand eines Individuums verändert und gestört wird. Die Zufuhr körperfremder
(exogener) Stoffe (i.e.S. der eigentlichen Droge) und deren Verstoffwechselung
respektive Metabolismus hat dabei oft große Ähnlichkeit mit jenen Stoffen, die der
eigene Körper produziert, um in spezifischen Situationen allerdings nur kurzzeitig
eine notwendige Befindlichkeit sicherzustellen. Im Normalfall ohne Drogenkonsum
kommt es jedoch niemals zu einer Dauerausschüttung von diesbezüglich initiierten
Hormonen und Neurotransmittern, die eine derartige (drogeninitiierte) Gefühlslage
hervorrufen würden. Durch die Dauerausschüttung solcher Botenstoffe im Gehirn
(besonders Substanzen mit eminentem Pons-Passage-Wirkprofil) und den primär
hormonellen und additiv dopaminergen Auswirkungen auf das vegetative
Nervensystem (s.a. Sympathikus/Parasympatikus) kann durch anhaltenden Konsum
ein nachhaltiger Gewöhnungseffekt (Toleranzbildung) eintreten. Der regelmäßige
Missbrauch führt besonders bei potenten Wirkstoffen zum Ceiling-Effekt, den
Drogenabhängige fürchten wie der Teufel das Weihwasser.

Die Rohstoffabhängigkeit
übernimmt zunehmend alle vorgesehenen Bindungsstellen (Rezeptoren) des Körpers
und unterwirft dessen Funktionalität und Befindlichkeit – ohne die Droge – nachhaltig.
Zudem ist es nicht immer nur der chemischen Substanz, sondern vor allem auch
ihren symbolischen Attributen geschuldet, auf welche Droge die Wahl des Einzelnen
fällt. „Manche Drogen besitzen aus den verschiedensten Gründen ein jugendliches,
andere ein Außenseiter-Image, und bei wieder anderen bemüht sich die Industrie
offenbar nicht völlig erfolglos, ihnen ein Image von Freiheit und Abenteuer zu
verleihen.“ (Leitfaden Drogentherapie,S.41/Campus Verl.1997).

weiter lesen: 070101_Lexikon_Neurobiologie

A) ALLGEMEINE GRUNDLAGEN 2
1. Verhaltensbiologie 2
2. Das Gehirn – Strukturen, Prozesse und Funktionen 3
2.1 Anatomie (Makroanatomie) 3
2.2 Struktur hirnlokaler Netzwerke (Mikroanatomie,
Histologie) 9
2.3 Die Nervenzelle und ihre Verknüpfungen 11
2.4 Die Nervenzelle – chemische Impulse 15
2.5 Innerzelluläre molekulare Signalketten 17
2.6 Neurophilosophie – das „Gehirn-Geist“-Problem
und das „Mikro-Makro“-Problem 19
B) NEUROBIOLOGIE DER SUCHT 20
3. Drogen 20
4. Neurochemische Dynamik 24
5. Neuroanatomie der Sucht 28
5.1 Die zentrale Rolle des Dopamin-Systems 28
5.2 Das Gesamtbild der funktionellen Architektur des
süchtigen Gehirns 30
5.3 Hirn-Schädigungen als Konsumfolge 31
C) LITERATUR 32

Weiter lesen: 001_070402_BAS_Skript_Neurobiologie_der_Sucht_Tretter

ABSTRACT
Six cases heroin abusers, during withdrawal, were given iv normal saline and
dynorphin-(1-13), respectively. After saline a slight placebo effect was noticed.
When dynorphin-(1-13) given iv, withdrawal scores were lowered significantly. This
result suggests that dynorphin-(1-13) can suppress withdrawal syndrome. The side
effects due to dynorphin-(1-13) were very minimal.

Get more Information here:2000175 dynorphin!

Opioid dependence is a chronic disorder that produces changes in brain pathways that remain long after the patient stops taking the drug. These protracted brain changes put the dependent person at greater risk of relapse. Detoxification can be successful in cleansing the person of drugs and withdrawal symptoms; it does not address the underlying disorder, and thus is not the adequate treatment. Maintenance with methadone or naltrexone is the usual practice in the long-term management of opioid dependence but both drugs have their own disadvantages because no single medication is appropriate for every individual for treating their opioid dependence, it is important that clinicians have a variety of the therapeutic agents available to them.

Calcium channel blockers, such as verapamil, diltiazem, nifedipine, nimodipine, and felodipine are useful drugs being used in cardiovascular disorders, such as hyper-tension, arrhythmias, and ischaemic heart disease. Research on calcium channel blockers has proved their therapeutic potential in a variety of disorders such as asthma, diarrhoea, premature labour, and diseases of central nervous system such as epilepsy, and opioid dependence. Modern drugs are not only expensive and beyond the reach of majority of the population of world but also have multiple side effects. Hence there is a need to explore such drugs from indigenous sources and to observe if combination of desired therapeutic efficacy exists in nature.

Nigella Sativa is in use for the treatment of variety of ailments since ancient times. Research has based its many effects on their efficacy of blocking calcium channels. As calcium channels have been tried for the treatment of opioid dependence, so Nigella Sativa was used in this study. This study was carried out on 50 patients who were divided into two groups. Patients were admitted for 12 days and then weekly followed up for 12 weeks.

Each patient received placebo orally during day-1 and day-2 of admission. Thereafter Nigella Sativa was given to the patients from day-3 of admission to eighth week. Then the dose of each drug was tapered off during 9th and 10th weeks and then no treatment was given during last two weeks.

It was observed that Nigella Sativa showed a rapid improvement in signs and symptoms of acute opioid abstinence. It was also observed that Nigella Sativa prevented the development of significant craving and relapse. It is concluded that Nigella Sativa is effective in long term management of opioid dependence and it is suggested that further long term follow up studies may be designed with greater number of patients.

First Time the Full Research Paper here:1742 niglea sativa

Opioid use whether acute or chronic, illicit or therapeutic is prevalent in Western societies. Opioid receptors are located in the same nuclei that are active in sleep regulation and opioid peptides are suggested to be involved in the induction and maintenance of the sleep state. mu-Opioids are the most commonly used opioids and are recognized respiratory depressants that cause abnormal awake ventilatory responses to hypercapnia and hypoxia. Abnormal sleep architecture has been reported during the process of opioids induction, maintenance and withdrawal. During induction and maintenance of opioid use there is reduction of rapid eye movement (REM) sleep and slow wave sleep. More recently, central sleep apnoea (CSA) has been reported with chronic opioid use and 30% of stable methadone maintenance treatment patients have CSA. Given these facts, it is sobering to note the paucity of human data available regarding the effects of short and long-term opioid use on sleep architecture and respiration during sleep. In this manuscript, we review the current knowledge regarding the effects of mu-opioids on sleep and respiration during sleep and suggest research pathways to advance our knowledge and to explore the possible responsible mechanisms related to these effects.

Opioid use whether therapeutic or illicit is common worldwide. In year 2000, approximately 1.2% of the American population reported heroin use at least once in their lifetime.1 In Australia, the estimate of recent illicit opioid users was 0.6% of the 14 yrs and older population in 2001 compared to 1% in 1998.2 Australian Institute of Health and Welfare. 2001 National Drug Strategy House Hold Survey: first results. Canberra, Australia, 2002.2 More than 140,000 patients were receiving methadone maintenance treatment (MMT) in 1998 in the United States,3 and in Australia 30,000 were receiving MMT in year 2000.4 Opioids are also commonly used for acute and chronic pain management and as an adjunct to anaesthesia and occasionally for the restless legs syndrome.5 and 6 An American study reported that 80% of 2118 cancer patients referred to a pain service were prescribed opioids.6 In year 2004, there were more than 410,000 registrants for opioid use in American pharmacies compared to around 390,000 in 1997.7 The average gram weight per registrant increased 7.3 fold for oxycodone, 5 fold for methadone, 4.6 fold for fentanyl base and 3 fold for hydrocodone from 1997 to 2004.7 Prescribed opioids related deaths account for most of non-illicit drug poisoning deaths in America and the problem has been increasing in the past decade.8 Abuse of opioid analgesics is very common and in 2005, 9.5% of American 12th graders reported using Vicodin and 5.5% of these students reported using OxyContin in the past year.9

Many opioid receptors are located in the same nuclei that are active in sleep regulation10 and it has been suggested opioid peptides are involved in the induction and maintenance of the sleep state.11 Chronic opioid use has been hypothesized to cause disturbed sleep as well as excessive day-time sleepiness and fatigue.12 A few studies have reported abnormal sleep architecture in opioid users but most were performed prior to 1990 and few tested breathing during sleep though opioids are well-known respiratory depressants.5 In recent studies, central sleep apnoea (CSA) has been found in stable MMT patients and in patients prescribed time-release opioid analgesic management.13, 14 and 15 Abnormal ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR) have also been noted in stable MMT patients.16 Infants born to substance-abusing mothers have a higher prevalence of periodic breathing during sleep and a 5–10 times increased risk of sudden infant death syndrome (SIDS) compared to normal infants.17 and 18 The potential symptoms and other sequelae related to CSA and periodic breathing have not been discussed in reviews of opioid use for chronic pain or in methadone substitution programs.6

Morphine-like μ-opioids are clinically the most commonly used opioids and this review focuses on their effects on sleep and respiration during sleep in humans. Where evidence is available, we will discuss the pathogenesis of abnormalities described and will also discuss future research directions given the considerable lack of knowledge in this important area of medicine. The scope of this review includes sleep and respiration during sleep in acute and chronic opioid analgesic use, opioid abuse and in MMT programs.

Opioids and control of sleep

There are four major classes of endogenous opioid receptors in the central nervous system: μ, δ, κ and nociceptin/orphanin FQ (N/OFQ) receptor.5 Each of these receptor subtypes has a distinct profile in terms of its pharmacology as well as its distribution within the brain and spinal cord. Most of the clinically used opioids are relatively selective for μ receptors, such as morphine and methadone.5 It appears that REM suppression is associated primarily with the actions of μ-opioid receptor agonists.19 Three classes of opioid peptides have been identified: the enkephalins, endorphins and dynorphins.5 These have been shown to have a role in sensory modulation and analgesia and may be important in the onset and maintenance of sleep, and therefore be involved in attenuation of arousal and waking.20 Enkephalin is contained in neurons that are widely distributed through the brain and regions involved in slow wave sleep (SWS) such as the solitary tract nucleus, the preoptic area and the raphe, where it is colocalized with serotonin receptors.20 Enkephalin containing fibres innervate the locus coeruleus noradrenergic neurons which are inhibited by locally delivered opioids and produce decreased awakenings and increased SWS.20 β-Endorphin is derived from prepro-opiomelanocortin (POMC) which is also processed into the non-opioid peptides adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (α-MSH) and β-lipotropin (β-LPH).5 ACTH is the hormone closely related to stress and α-MSH has been suggested to induce sleep and increase SWS. The association of sharing the same precursors implies a close physiological linkage between stress, sleep and the opioid systems.5

The mechanism of opioid peptide action on sleep control remains unclear. It has been hypothesized that opioid peptides in conjunction with the peptide neurohormone vasopressin are involved in the induction and maintenance of the sleep state through a complex and modifiable circadian mechanism driven by the suprachiasmatic nuclei (SCN).11 Vasopressin, one of the neurohormones in the circadian pacemaker SCN, has been shown to have a close relationship to circadian rhythms.21 Vasopressin causes the secretion of endorphins into the cerebro–spinal fluid (CSF), while pain and opioids stimulate the secretion of vasopressin from the pituitary.22 In the supraoptic and paraventricular nuclei, vasopressin is stored with the opioid peptide dynorphin which also shows circadian variability of its blood levels.23 It is possible that both vasopressin and the opioids are part of the neurochemical mechanism driven by SCN to maintain the daily sleep and wake rhythm.11

Exogenous opioids may affect the activity of opioid receptors by binding to the same sites as those of endogenous opioid peptides.24 Endogenous enkephalin production is linked by a negative feedback mechanism to the serum level of opioids which are high in chronic opioid users.25 Given the possible links between endogenous opioids and control of sleep previously discussed, it is reasonable to suggest that acute and chronic opioid use may have an effect on sleep hygiene and sleep architecture.

Opioids and control of respiration when awake and during anaesthesia

In humans, the primary opioid receptors involved in control of respiration are assumed to be μ-receptor type.5 δ-Receptors may exert modest respiratory depressant effects, whereas κ-receptors have little respiratory depressant activity.26 Acute use of μ-receptor stimulating opioids can cause dose dependant depression of respiration.5 Opioid receptors in brain stem (medulla, pons, nucleus tractus solitarius, and nucleus ambiguous), spinal cord, and peripheral sites such as lung tissue are involved in the respiratory depression. However, the brain stem respiratory centres predominate with regard to this effect.5, 26 and 27 Both HCVR and HVR can be significantly reduced by acute use of opioids.26 and 28 Opioids can also blunt the increase in respiratory drive normally associated with increased loads such as increased airway resistance.27 Acute opioid use may cause increased respiratory pauses, delays in expiration, irregular and/or periodic breathing and decreased/normal tidal volume.27 The prolonged expiratory time in the respiratory cycle induced by opioids often results in greater reductions in respiratory rate than in tidal volume.26 Increased tidal volume variability was reported to be a better predictor of respiratory depression than a fall in respiratory rate when remifentanil was infused during dental anaesthesia.29

Waters et al. studied 13 children with OSA and 24 normal subjects undergoing tonsillectomy.30 They found that under inhalational anaesthetic and spontaneous ventilation, the OSA group hypoventilated and tended to have higher end tidal CO2 levels than the normal group. Following fentanyl injection, 6 of the OSA group exhibited central apnoea compared with one of the normal subjects. The production of central apnoea post opioid injection in both groups was related to end tidal CO2 higher than 50 Torr.30 Though this study has methodological flaws, the data suggests that at least in children, subjects prone to hypoventilation may progress to central apnoea when given a μ-opioid, however, whether this equates to CSA in these children is unknown.

With long-term use of opioids, subjects have reduced HCVR although tolerance appears to develop.16 and 31 An early study assessing HVR in MMT patients suggested blunting of HVR in both the acute and chronic stages of methadone use.31 However, this study should be interpreted with caution as there was no baseline data from normal subjects available for comparison.31 In contrast, in our study of stable MMT patients, HVR appears to be increased (Fig. 1).16 The causes for this finding are not clearly known and may relate to long-term stimulation of the hypoxic response by long-term intermittent hypoxia.16 The high HVR and low HCVR we found in the stable MMT patients related to changes in respiratory rate and not tidal volume response.16

Opioid use, sleep and respiration during sleep

Given the large opioid using population and the possible close link between endogenous opioids and control of sleep, there is a scarcity of studies investigating sleep in human adult subjects using opioids.12 There are studies assessing sleep in animals that show changes in sleep architecture with acute and chronic μ-opioid use.32 and 33 We were unable to find data related to effects of chronic use of μ-opioids on respiration during sleep in animals. Breathing during sleep in human subjects using opioids has been poorly studied despite the fact that the commonly used μ-opioids are known to depress respiration and sleep-disordered breathing in its own right can significantly affect sleep architecture.5

Table 1 shows the findings and methodologies of 18 human studies available on PUBMED published between 1966 and 2005 investigating sleep and respiration during sleep in adult humans using opioids. We cite only those studies using objective measurements and reported in English. Studies assessing the effects of opioids on sleep and respiration during sleep in post-operative surgical patients and restless legs syndrome patients are not included in the table. Restless legs syndrome itself can significantly disturb sleep and the studies in the anaesthetic literature are often confounded by poor patient selection, use of concomitant anaesthetic agents, analgesics and post-operative pain. In addition, natural sleep is clearly different to anaesthesia which is a state of unrousable unconsciousness.34 During anaesthesia, there is dose-dependant depression to most of the vital functions including respiration.34 Abnormal breathing patterns in anaesthesia are different to sleep-disordered breathing although the tendency to upper airway obstruction during sleep and during anaesthesia are probably related.35 Of the studies listed in Table 1, 16 used morphine like μ-opioids and 3 used opioid antagonists.

Summary of opioid effects on sleep

Despite the inherent methodological limitations discussed above, the studies provide useful information about the effects of opioids on sleep. There are four basic phases of opioid dependence and withdrawal: drug induction phase, drug maintenance phase, acute abstinence phase and protracted abstinence phase.38 Sleep architecture changes are different for each of the 4 phases. In general, during the induction phase, the use of morphine-like opioids significantly disrupts sleep with reduced REM sleep and SWS and increased wakefulness and arousals from sleep. TST and SE are usually reduced while percentage stage 2 sleep and REM sleep latency are often increased. During the maintenance phase of μ-opioid use, the decreases in SWS and REM sleep tend to normal as do the increases of wakefulness, arousal and REM sleep latency. Vocalization during REM sleep, significant delta burst and increased daytime sleepiness may commonly appear in this phase. Limited evidence is available regarding sleep during acute withdrawal from chronic opioid use.38 Changes in sleep from withdrawal of short-term opioid administration39 may be different to the changes seen in withdrawal from chronic opioid use. Significant insomnia is the major complaint during chronic opioid withdrawal, accompanied by frequent arousals and decreased REM sleep. During the protracted abstinence phase, TST significantly increases with rebound of SWS and REM sleep. After chronic methadone use, the rebound of SWS and REM sleep usually occurs between 13 and 22 weeks following withdrawal of the opioid.40 and 41

Chronic opioid use is associated with symptoms of fatigue and excessive daytime sleepiness.12 and 14 The abnormal sleep architecture discussed above can affect daytime functioning in its own right. However, it is difficult to know how much the abnormal sleep architecture noted in these studies impacts on daytime function and excess daytime sleepiness.

Within the opioid class, morphine and methadone have comparable effects on sleep and are half as potent as heroin with regard to EEG measures.42 The difference between morphine and methadone on sleep is that chronic morphine use gives measures of persistent sleep architecture disturbances which are not found with chronic methadone use.40, 41 and 43 Further studies employing larger subject numbers and improved methodology are necessary to gain a clearer and more comprehensive understanding of opioid effects on sleep and to explore the long-term affects of sleep architecture changes on the subjects’ daytime function.

Respiration during sleep with acute opioid use

There are only two human studies assessing respiration during sleep with acute μ–opioid use. Robinson et al. assessed awake pharyngeal resistance, HCVR, HVR and respiration during sleep in 12 healthy adult humans after ingestion of 2 and 4 mg of oral hydromorphone.44 Awake pharyngeal resistance, HCVR and breathing during sleep did not change significantly following either dose of the drug, although there is a trend toward increased apneas (more than doubled) and decreased hypopneas with the 4 mg dose. Awake HVR was significantly reduced after 4 mg of the drug.44 Similarly, Shaw et al. measured breathing during sleep on 7 healthy adults after injection of morphine (0.1 mg/kg) and did not find an increase in sleep-disordered breathing compared to either baseline or placebo use.45 Further studies with larger sample size are needed to test the effects of acute opioid use on respiration during sleep.

Respiration during sleep with chronic opioid use

Few studies have investigated respiration during sleep in subjects using opioids long term.13, 14, 15 and 46 The studies include two that assessed stable MMT subjects;13 and 14 one assessed 3 subjects using chronic time release opioid analgesics;15 and one assessed subjects with restless legs syndrome.46 The stable MMT subject studies were the only studies that matched patients and normal subjects for age, sex and BMI.13 and 14 CSA was noted in 20 of 60 subjects in the MMT cohort and no CSA was noted in the normal subjects.13 and 14

In the largest cohort study assessing respiration during sleep in subjects using opioids chronically, CSA was found in 30% of 50 stable MMT patients while obstructive sleep-disordered breathing was similar in the MMT cohort and normal subjects.14 The CSA in the MMT patients is more prominent in NREM sleep than in REM sleep and did not cause increased arousals compared to normal control subjects.14 The CSA described in stable MMT patients is of periodic and non-periodic type.13 and 14 During sleep, MMT patients have only mildly reduced arterial oxygen saturation and mildly increased transcutaneous arterial carbon dioxide tension.14

CSA, periodic breathing and Biot’s breathing pattern (i.e. “ataxic breathing” with unpredictable irregular pattern) was reported in 3 females using opioids chronically for pain relief.15 This report lacks data regarding a clear definition of “ataxic breathing” and whether the irregular breathing was or was not related to arousals or transitional sleep.15 This breathing pattern appears to be similar to sub-criteria CSA or the non periodic breathing CSA we describe in the stable MMT patients14 *D. Wang, H. Teichtahl, O.H. Drummer, C. Goodman, G. Cherry and D. Cunnington et al., Central sleep apnea in stable methadone maintenance treatment patients, Opioids have been suggested to interfere with pontine and medullary respiratory centres that regulate respiratory rhytmicity based on various cats studies.27 To date there is however no evidence regarding the prevalence and possible mechanisms of the ataxic/Biot’s breathing pattern during human sleep in chronic opioid use.

Seven patients with restless legs syndrome were studied with PSG before and after long-term opioid monotherapy over an average of 7 years.46 Two of the seven patients developed sleep apnoea with respiratory disturbance index of 10 and 15 and a third patient developed worsening of pre-existing sleep apnoea. The type of sleep apnoea found in the 3 patients was not reported.46 It therefore appears that further studies with larger sample size and improved methodology are needed to elucidate if the CSA noted in stable MMT patients also exists in the patients using opioids chronically for pain relief and restless legs syndrome.

The outcome of the CSA observed in these groups of patients is unknown. For example, we do not know if these patients with CSA have higher morbidity or mortality than those patients using long-term opioids but without CSA. We also do not know whether the CSA noted in these patients contributes to daytime dysfunction, though it is clear that stable MMT patients are more depressed and sleepier during the day, and have poorer general health than normal subjects.14 and 47 What we do know is that CSA is not the sole cause of excess daytime sleepiness in the MMT patients.14

Potential mechanisms for CSA with chronic opioid use

Though the human studies showing CSA with chronic opioid use are of interest, only 2 have assessed potential mechanisms related to this finding.14 and 16 One of the major problems with using human subjects for investigating the pathogenesis of CSA in these populations is that chronic opioid use is usually associated with a number of other medical and psychiatric conditions.47 Therefore, these subjects often use concomitant therapy such as benzodiazapines and antidepressants, and many have a history of cigarette abuse.47 These confounders make it difficult to reach conclusions regarding pathogenetic mechanisms for CSA without testing large numbers of subjects and this can be difficult in these patient populations. We therefore suggest that future research be targeted at further developing animal models to better assess the mechanisms involved in CSA with chronic opioid use. However, even with the above caveats, the data obtained from our previous studies can give direction for further animal and human research and we will in detail discuss some of the information we have obtained in a cohort of stable MMT patients.14 These MMT patients were on stable doses of methadone and had been in the treatment program for a minimum of 2 months.

The CSA noted in the MMT patients appears to be different to the Cheyne–Stokes respiration seen in congestive heart failure patients.14 For example, the CSA of MMT patients shown in Fig. 2 are not of the crescendo–decrescendo type and have much shorter cycle time than the Cheyne–Stokes respiration of congestive heart failure.14 and 48 In addition these MMT patients had normal cardiac function.49 The CSA in the MMT patients is not of the idiopathic type as these subjects lacked the typical characteristics of idiopathic CSA, such as male preponderance and significant arousals during sleep.14 and 50 Hypercapnia alone does not seem to explain the CSA in these stable MMT patients as their lung function tests were only mildly abnormal and their awake arterial CO2 tension was marginally raised in only 10 of the 50 patients.48

We currently believe that no simple cause and effect relationship can explain CSA with chronic opioid use. An important clue is that methadone blood concentration is the best predicting variable for CSA in stable MMT patients.14 Another important lead is that stable MMT patients have blunted central chemosensitivity but elevated peripheral chemosensitivity.16 We therefore believe that the pathogenesis for CSA in this group is most likely multifactorial in nature and related to a variable interplay of abnormalities of central controller function and central and peripheral chemoreceptor sensitivity. μ-Opioids are well known central respiratory depressants.5 The significant association between CSA and methadone blood concentration suggests that depressed central controller plays a critical role in the genesis of CSA.14 Structural brain damage has been reported to occur secondary to cerebrovascular accidents associated with prior illicit drug use.51 This brain damage particularly if it occurs in the midbrain or brainstem would lead to central respiratory controller dysfunction in these MMT patients. Functional and structural MRI studies are required in this group of patients to assess this hypothesis.

As shown in Fig. 1, stable MMT patients have significantly reduced HCVR but increased HVR, which may suggest blunted central chemosensitivity but elevated peripheral chemosensitivity.16 An imbalance of central and peripheral chemosensitivity has been suggested to pose a greater risk for periodic breathing.52 When carotid chemoreceptor stimulation becomes the dominant sensory input to the respiratory controller relative to the input of the medullary chemoreceptors, the breathing pattern tends to become instable.52 The combination of antidepressant and methadone use may further reduce the already blunted HCVR16 and lead to an increased risk of CSA.14 We have shown that of the stable MMT patients with CSA, 57% of those receiving both antidepressant and methadone had central apnoea index >10.14 These patients had significantly reduced central chemosensitivity compared to the patients taking methadone alone.16 This mechanism is therefore similar to that of hypercapnic-type CSA.50 Acute opioids use can significantly reduce HVR, however, long-term application of opioids may lead to recurrent episodic hypoxia which may continuously stimulate peripheral chemosensitivity and lead to an increased HVR.14 and 28 It has been reported that exposing subjects to very mild and short-term hypoxia can cause an increase in HVR.53 High peripheral chemosensitivity itself is a predisposing factor for sleep-disordered breathing54 and has been shown to occur in high altitude periodic breathing55 and in CSA of congestive heart failure.48

The above mechanisms may contribute to the CSA seen in chronic opioid use. Each mechanism may occur in isolation or in variable combinations with other mechanisms.

Opioid use and SIDS

The SIDS is acknowledged as a major cause of death in infancy.56 In Australia in the late 1990s’, SIDS killed approximately one in every 1200 infants. Neonatal life of infants born to substance abusing mothers or born to those using opioids chronically is similar to that of chronic opioid use followed by a natural opioid abstinence period. Following birth there is an acute withdrawal of supply of exogenous opioids through placental circulation while endogenous opioids production is low. This may cause functional impairment in the CNS and altered sleep patterns.57 In pregnant MMT patients, foetal breathing movements and the response to carbon dioxide are significantly less than in normal subjects, and are further decreased after receiving methadone.58 Infants born to substance-abusing mothers have been shown to have an impaired repertoire of protective responses to hypoxia and hypercapnia during sleep.59 They have higher prevalence of periodic breathing during sleep and a 5–10 times increased risk of SIDS compared to normal infants.17, 18 and 59 In a population-based study, more than 1.2 million infants born in New York City between 1979 and 1989 were investigated and infants born to mothers in MMT were found to have 3.6 times increased chance of having SIDS compared to infants born to mothers not using methadone.60

Practice points

• There is increasing acute and chronic use of illicit and prescribed opioids in Western societies.
• Sleep architecture is abnormal with opioid use and the abnormalities of sleep architecture are different across the four basic phases of opioid dependence and withdrawal.

• CSA including periodic and non-periodic breathing pattern have been reported with chronic opioid use and 30% of stable MMT patients have CSA. The potential impacts on patient outcomes of these findings are unknown.

• The mechanisms producing CSA with chronic opioid use probably involve changes in central and peripheral ventilatory control mechanisms.

• Infants born to substance abusing mothers have a higher prevalence of periodic breathing during sleep than normal infants and a 5–10 times increased risk of SIDS compared to infants born to non-substance abusing mothers.

Research agenda

• Assess the prevalence of sleep-disordered breathing in patients using opioids long-term.
• Animal and human studies are required to explore the pathogenesis of sleep-disordered breathing noted with chronic opioid use.

• Assess the short and long-term effects of sleep architecture changes and sleep-disordered breathing with chronic opioid use and investigate strategies to prevent the complications.

• Data is required regarding the acute and chronic interactions of opioids, antidepressants and benzodiazapines on sleep architecture and respiration during sleep.

• Animal and human studies with improved methodology are needed to assess the effects of acute opioid use on respiration during sleep.

• Data is required for patients with OSA undergoing surgery to assess the effects of opioid anaesthesia and of opioid analgesia on post-operative respiration both awake and during sleep.

• Develop clinical guidelines as to when patients using opioids should be investigated for sleep disorders including sleep-disordered breathing.


Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. μ-Opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.

Read more: http://informahealthcare.com/doi/abs/10.1517/14740338.6.6.641

INTRODUCTION: Subjects using opioids on a chronic basis have been reported to have a high prevalence of abnormal sleep architecture and central sleep apnea (CSA). The severity of CSA is, in part, related to blood opioid concentration. The aim of this study was to investigate subjective daytime sleepiness and daytime function in patients who are on stable methadone maintenance treatment (MMT) and to assess the possible mechanisms involving abnormal sleep architecture, CSA severity, and blood methadone concentration. METHODS: Fifty patients on MMT and 20 normal control subjects matched for age and body mass index were tested using polysomnography, blood toxicology, Epworth Sleepiness Scale (ESS), Functional Outcome of Sleep Questionnaire (FOSQ), and Beck Depression Inventory (BDI). RESULTS: The patients receiving MMT had significantly worse daytime function, were depressed, and had increased daytime sleepiness when compared with the control subjects (FOSQ 15.47 +/- 3.19 vs 19.4 +/- 0.47, BDI 14.64 +/- 10.58 vs 2.05 +/- 2.46, ESS 7.1 +/- 5 vs 2.05 +/- 1.76; all p values < 0.001). Nevertheless, daytime sleepiness in the patients receiving MMT was, on average, within the normal range (ESS < or = 10). Multiple regression analysis demonstrated that the severity of CSA, blood methadone concentration, and abnormalities in sleep architecture were not significant in predicting the variance of ESS or FOSQ (all p values > 0.05) in these patients receiving MMT. The BDI was the best predictive variable for FOSQ, explaining 16% of the variance (p = 0.004). CONCLUSIONS: Patients on stable MMT have, in general, normal subjective daytime sleepiness but impaired daytime function that partially relates to depression. The changes in sleep architecture, presence of CSA, and blood methadone concentrations do not significantly affect subjective daytime sleepiness and daytime function in these patients.

Study objectives: Methadone, a long-acting μ-opioid agonist, is an effective treatment for heroin addiction. Our previous data show that 6 of 10 methadone maintenance treatment (MMT) patients had central sleep apnea (CSA). This study aims to confirm these results and to investigate the pathogenesis of the CSA.

Methods: Twenty-five male and 25 female MMT patients and 20 age-, sex-, and body mass index (BMI)-matched normal subjects were tested with polysomnography, blood toxicology, and ventilatory responses to hypoxia and hypercapnia. Resting cardiorespiratory tests were performed in the MMT group

Results: MMT patients and normal subjects were 35 ± 9 years old (mean ± SD), and BMI values were 27 ± 6 kg/m2 and 27 ± 5 kg/m2, respectively. Thirty percent of MMT patients had a central apnea index (CAI) > 5, and 20% had a CAI > 10. All normal subjects had a CAI < 1, and no difference was found in obstructive apnea-hypopnea index between the two groups. Methadone blood concentration was the only significant variable (t = 2.33, p = 0.025) associated with CAI and explains 12% of the variance. Awake Paco2, antidepressant use, reduced ventilatory response to hypercapnia, and widened awake alveolar-arterial oxygen pressure gradient together explain a further 17% of the CAI variance.

Conclusions: Thirty percent of stable MMT patients have CSA, a minority of which can be explained by blood methadone concentration. Other physiologic variables may also play a role in the pathogenesis of CSA in MMT patients, and further research is indicated in this area.

1) Indikation von Buprenorphin: Buprenorphin wird einerseits zur
Opiatsubstitutionsbehandlung sowie andererseits i.R. eines
Opiatentzuges verwendet. Im Übrigen wird Buprenorphin in Form von
Temgesic ®, Transtec ®)) als Analgetikum in der Behandlung von
starken Schmerzen eingesetzt.
2) Wirkungen von Buprenorphin:
Rezeptorprofil: Buprenorphin ist ein partieller Opioidagonist an den
mü-Opioidrezeptoren sowie ein Antagonist an den Kappa-
Opioidrezeptoren. Damit erzeugt Buprenorphin eine im Vergleich mit
Morphin maximal 60%-ige Aktivität an den mü-Opioidrezeptoren. Der
antagonistischen Wirkung am Kappa-Rezeptor wird eine positive
Beeinflussung von dysphorischen Verstimmungszuständen
zugeschrieben.
Einnahmeart: Aufgrund eines ausgeprägten enterohepatischen
Kreislaufes führt eine orale Einnahme von Buprenorphin zu einer nur
unzureichenden Wirkungsstärke (ca. 16%-ige biologische
Wirksamkeit). Subutextabletten müssen deshalb sublingual
eingenommen werden (ca. 50%-ige biologische Wirkungsamkeit).
Die Sublingualtabletten sollen ca. 3-5 Minuten unter der Zunge
vergehen lassen werden.
Intrinsische Sicherheit: Aufgrund der nur maximal 60%-igen mü-
Aktivität ist die Gefahr einer möglichen Intoxikation mit letalen Folgen
unter Buprenorphin bei Monokonsum praktisch ausgeschlossen. Eine
atemdepressive Wirkung fehlt weitgehend. Buprenorphin weist
deshalb eine hohe intrinsische Sicherheit und therapeutische Breite
auf (Auch bei Personen mit vollständig fehlender Opiattoleranz ist
eine Intoxikation mit letalem Ausgang auch unter hohen
Buprenorphindosen nicht möglich, Überdosierungen von 10-20-fach
erhöhter Dosis wurden ohne ausgeprägte Nebenwirkungen
überstanden (In Frankreich wurden allerdings vereinzelte Todesfälle
bei sehr hohen Buprenorphindosen und gleichzeitiger Einnahme von
Alkohol und Benzodiazepinen festgestellt).
Bei einer Dosis von 32mg und mehr kommt es zu einem sogenannten
„Ceiling Effect“, d.h. einem Wirkungsplateau bzw. einer maximalen
Opioidwirkung.
Aufgrund einer nur langsamen Resorption fehlt eine entsprechende
Rauschwirkung auch bei hohen Buprenorphindosen weitgehend.
Opioidrezeptoraffinität: Buprenorphin zeigt eine sehr starke
Opioidrezeptoraffinität, die diejenige von Methadon, Heroin,
Morphin, Codein, Dihydrocodein sowie Naltrexon und Naloxon
(letztere beide reine Opioidantagonisten) klar übertrifft. Dies erklärt,
weshalb unter vorgängiger Einnahme eines der oben genannten
Opioide und darauffolgender Einnahme von Buprenorphin ein
Opioidentzugssyndrom ausgelöst werden kann. Gleichzeitig lässt sich
die Opioidwirkung von Buprenorphin nur sehr schwer antagonisieren:
Die dafür notwendige Dosis beträgt das 10-30-fache der sonst
üblichen Morphindosis.
Rezeptordissoziationskinetik: Buprenorphin weist eine sehr langsame
Dissoziationskinetik an den Opioidrezeptoren auf. Dies führt einerseits
im Falle eines buprenorphingestützten Opiatentzuges zu geringeren
Entzugserscheinungen als dies bei schrittweiser Dosisreduktion mit
Methadon der Fall ist. Andererseits führt dies zu einer im Vergleich zu
Methadon und Heroin verlängerten Halbwertszeit am Rezeptor.
Dieser Effekt der verlängerten Wirkung wird durch die hohe Lipophilie
mit Speicherung von Buprenorphin im Fettgewebe und nur
langsamer Freisetzung noch verstärkt.
Wirkungszeit: Eine weitere Besonderheit von Buprenorphin ist seine
dosisabhängige Wirkungszeit: Mit Zunahme der Dosis (von 16-
32mg/die) kommt es weniger zu einer Zunahme der Wirkungsstärke
als mehr zu einer Verlängerung der Wirkungszeit (Wirkungsdauer
unter 2-4mg: bis zu 12 Stunden, unter 16-32mg bis zu 48-72 Stunden).
Dies ermöglicht bei Erhöhung der Dosis eine Ausweitung des
Dosisintervalles auf eine 2 bis sogar 3-tägliche Einnahme.
Metabolismus: Buprenorphin wird in der Leber von Mikrosomen NDealkyliert
und später glukoronidiert. Im Vergleich zum Metabolismus
des Methadons ist die Beteiligung des Zytochrom P450-
Enzymsystemes beim Buprenorphin nur sehr gering. Es wird zu 80%
über die Fäzes und 20% renal ausgeschieden.
Weitere Vorteile: Buprenorphin hat ein im Vergleich mit Methadon
geringeres Abhängigkeitspotenzial. Buprenorphin wird eine
antidepressive Wirkung zugeschrieben, was es bei gleichzeitigen
depressiven Zuständen als sinnvoll erscheinen lässt.
Bei gleichzeitig vorhandener Kokainabhängigkeit konnte eine
positive Wirkung in Bezug auf das Craving nach Kokain
nachgewiesen werden, was im Vergleich mit Methadon zu einer
stärkeren Verminderung des Kokainkonsumes und erhöhter
Kokainabstinenzrate führte.
Unter Buprenorphin waren die im Vergleich zu unter Methadon
gehäuft auftretenden Nebenwirkungen wie Schwitzen, Potenz- und
Libidostörungen, Obstipation und Gefühl der Affektabflachung
deutlich geringer.
Unter Buprenorphin fühlen sich die Patienten im Vergleich zu
Methadon oft wacher und nehmen intensivere Gefühle jeder Art
wahr. Letzteres kann für die Patienten sowohl ein Vor- wie auch ein
Nachteil bedeuten: Bei Patienten mit gewissen komorbiden
psychiatrischen Störungen (PTSD, Borderline Persönlichkeitsstörung
etc.) kann der stimmungsausgleichende Effekt von Methadon
(„Gefühle wie in Watte verpackt“) gegenüber Buprenorphin ein
Schutz vor ausgeprägten Stimmungsschwankungen / negativen
Gefühlszuständen bedeuten und deshalb eine Umstellung von
Methadon auf Buprenorphin kontraindiziert sein!
3.Umstellungen von Heroin / Methadon auf Buprenorphin:
Heroin auf Buprenorphin: Für eine Umstellung von Heroin auf
Buprenorphin wird eine Wartezeit von ca. 8 Stunden mit Auftreten
von leicht bis mittelgradiger Opiatentzugssymptomatik gefordert, um
so die Gefahr eines sogenannten „forzierten Entzuges“ zu vermeiden
(„forzierter Enzug“ : Unter der Wirkung von Heroin / Methadon und
gleichzeitiger Einnahme von Buprenorphin kommt es zu einem
Entzugssyndrom, da Buprenorphin das Heroin / Methadon aufgrund
seiner stärkeren Rezeptoraffinität aus den mü-Rezeptoren verdrängt
und selbst eine im Vergleich zu Heroin und Methadon geringere
Opioidaktivität aufweist. Eine Umstellung von Heroin auf
Buprenorphin ist i.a. bei niedrig bis mittleren Heroindosen
erfolgversprechend. Bei hohen Heroindosen ist die durch
Buprenorphin ausgeübte Opiatwirkung teilweise zu gering.
Methadon auf Buprenorphin: Vor einer Umstellung wird i.a. eine
vorgängige Reduktion der Methadondosis bis auf 30mg und weniger
empfohlen. Sodann nach Wartezeit von 24-36 Stunden erfolgt die
Umstellung nach Auftreten eines mittelgradigen Entzugssyndromes.
Eine Umstellung von Methadon im Bereich zwischen 30-60mg/die ist
ebenfalls möglich, dabei sollte jedoch ein ausgeprägtes
Entzugssyndrom vorliegen, um die Gefahr eines forzierten Entzuges zu
vermeiden. Bei Methadondosen höher als 60mg/die wird von einer
Umstellung auf Buprenorphin abgeraten.
Einstellung der Buprenorphindosis: Es wird am 1.Tag mit einer Erstdosis
zwischen 4-8mg Subutex begonnen. Dabei wird mit dem Patient
nach 3 Stunden eine erneute Kurzkonsultation vereinbart. Im Falle
von dann noch bestehenden Entzugserscheinungen erfolgt eine
weitere Gabe von 2-8mg Subutex am gleichen Tag. Der Patient
erscheint in der Folge am 2. und am 3.Tag zu einer Kurzkonsultation,
in welcher pro Tag eine weitere Dosissteigerung von 2-8mg
vorgenommen wird. Tagesdosen von mehr als 32mg erbringen i.d.R.
keine zusätzliche Opiatwirkung.
Bezugsunterbrüche: Bei Bezugsunterbrüchen von 72 Stunden und
mehr kann von einer fehlenden Buprenorphinwirkung ausgegangen
werden. Um einen allfälligen forzierten Entzug bei vorgängigem
Heroinkonsum und erneuter Buprenorphingabe zu vermeiden, ist
deshalb durch den zuständigen Therapeuten eine individuelle
Beurteilung der Drogenzwischenanamnese (letzter Heroinkonsum,
allfälliger Mischkonsum von anderen sedierenden Substanzen) des
Patienten und Planung einer Dosisneueinstellung vorzunehmen.
4) Buprenorphingestützter Opiatentzug: Ein Opiatentzug mit
Buprenorphin kann im Vergleich zu einem methadongestüzten
Opiatentzug, welcher mindestens mehrere Wochen dauert, oft
deutlich schneller durchgeführt werden: Grund für im Vergleich mit
Methadon geringere Entzugssymptomatik ist die langsamere
Rezeptordissoziationskinetik von Buprenorphin.
Ein Buprenorphingestützter Opiatentzug kann grundsätzlich in 5
Tagen gemäss folgendem Schema durchgeführt werden:
1.Tag 16mg Subutex
2. Tag 8mg Subutex
3.Tag 4mg Subutex
4. Tag 2mg Subutex
5.Tag 1mg Subutex
6.Tag Subutex stoppen
Alternativ kann der Patient jedoch auch individuell die Dauer seines
Opiatentzuges und die damit verbundenen Dosisreduktionsintervalle
festlegen.
5) Interaktionen von Buprenorphin mit anderen Pharmaka:
Besondere Vorsicht ist bei der gleichzeitigen Verordnung von
antiviralen Medikamenten bei HIV-positiven Patienten unter Therapie
mit Buprenorphin geboten: Protease-Inhibitoren wie Ritonavir,
Indinavir und Saquinavir blockieren in vitro Untersuchungen an 13
humanen Lebermikrosomen den Abbau von Buprenorphin. Da sich
beide Substanzgruppen in ihrer Metabolisierung durch die
Leberenzyme P450 3A4 behindern, steigt damit das Risiko einer
Überdosierung.
Weitere Interaktionen von Buprenorphin sind mit folgenden
Medikamenten möglich:
Analgetika: Oxycodon: verstärkender atemdepressiver Effekt
Alfentanil: Wirkungsverstärkung
Anxiolytika: Alprazolam (Xanax®), Diazepam (Valium ®, Paceum ®),
bzw. jegliche Arten von Benzodiazepinen: Buprenorphimissbrauch in
Kombination mit Benzodiazepinen führte zu Todesfällen in Frankreich!
Antipsychotika: Chlorprothixen (Truxal ®), Triflupromazin (Psyquil ®):
Hypotension, verstärkter atemdepressiver Effekt; bzw. jegliche
sedierende Neuroleptika
Anticholinergika: Biperiden (Akineton ®): verstärkter atemdepressiver
Effekt
Hypnotika: Flurazepam (Dalmadorm ®), Flunitrazepam (Rohypnol ®),
Phenobarbital (Luminal ®): verstärkter atemdepressiver Effekt
Bei nur geringer Metabolisierung durch das Zytochrom P450-System
sind die potenziellen Medikamenteninteraktionen im Vergleich mit
Methadon geringer. Trotzdem sind Pharmaka, welche nicht oder nur
in geringem Ausmasse über das Zytochrom P450-Oxydase-System
metabolisiert werden gegenüber Pharmaka mit ausgeprägter
Beteiligung des Zytochrom P450-System vorzuziehen.

Pa­ti­en­ten­ mi­t chro­n­i­schen­ Schmerzen­ stel­l­en­ ei­n­e der größ­ten­ Pa­ti­en­ten­grup­p­en­ i­n­
der i­n­tern­i­sti­schen­ Pra­xi­s da­r. Zen­tra­l­e di­a­gn­o­sti­sche Ma­ß­n­a­hmen­ si­n­d sp­ezi­el­l­e
Schmerza­n­a­mn­ese un­d körp­erl­i­che Un­tersuchun­g. Si­e geben­ wesen­tl­i­che Hi­n­wei­se
a­uf di­e Schmerzgen­ese. Tro­tzdem bl­ei­bt der Schmerz ei­n­ Symp­to­m, da­ss a­usschl­i­eß­l­i­ch
durch di­e Wa­hrn­ehmun­g des Pa­ti­en­t en­ ko­mmun­i­zi­er- un­d da­mi­t messba­r wi­rd. Di­e
Schmerzstärke ka­n­n­ verei­n­fa­cht un­d sta­n­da­rdi­si­ert mi­ttel­s va­l­i­di­erter Ska­l­en­ erfa­sst
werden­. Di­e Mul­ti­di­men­si­o­n­a­l­i­tät vo­n­ Schmerzen­ (bi­o­p­sycho­so­zi­a­l­es Ko­n­zep­t) wi­rd
i­n­ sp­ezi­el­l­en­ Fra­gebögen­ (z. B. DGSS-Schmerzfra­gebo­gen­) a­bgebi­l­det. Di­e medi­ka­men­-
töse Thera­p­i­e erfo­l­gt a­n­a­l­o­g den­ WHO-Lei­tl­i­n­i­en­ zur Tumo­rschmerzthera­p­i­e, wo­bei­
zumei­st jedo­ch mul­ti­mo­da­l­e Ko­n­zep­te un­ter Ei­n­bezi­ehun­g p­sycho­thera­p­euti­scher Beha­n­dl­un­gen­
o­der kra­n­ken­gymn­a­sti­sche Verfa­hren­ n­o­twen­di­g werden­.

siehe Anhang: 2006_11_07

siehe Anhang: Opioide Umrechnen

Diese Tabelle erhaelt unheimlich viel zulauf,

ich bitte jedoch folgendes zu beachten, „man kann Opioide nicht einfach umrechnen“!

Methadone and Other Opioids Not Always

Equivalent,


Conversion Can Be Lethal!

In a comprehensive literature review of poisoning deaths involving opioids from 1999 – 2009, the deaths involving methadone were found to be disproportionately high.
(Edit by me: to get a inside-view via the „GAO-Report“)

Methadone represented less than five percent of all opioid prescriptions but is responsible for a third of the deaths. After four years of investigation, the major underlying cause was found to be fundamental misunderstandings about the properties of the medicine — a „knowledge deficit“ — especially when converting patients from other opioids.

After a rapid increase of opioid-related deaths was reported in Utah, then president of the Utah Academy of Pain Medicine, Dr. Lynn Webster decided to find out why, and then find a solution. By reviewing state and federal sources as well as PubMed, he was able to assess demographics, prevalence, and other risk factors related to this significant increase in poisoning deaths involving opioids.

Webster found that methadone deaths had more to do with misunderstandings about when to prescribe it, how to convert patients to it from other pain medicines, and how to inform patients about its risks. The research also showed that one-third of the deaths occurred within five days after a dosage change — also suggesting that unfamiliarity with the medicine could lead to accidental deaths.

Webster then brought this information to a consensus conference sponsored by the LifeSource Foundation where a panel of colleagues helped him determine root causes of the problem. After reviewing and discussing the data, the panel identified the following as probable causes underlying the spike: physician error due to knowledge deficits, patient non-adherence to medication regimen, unanticipated medical and psychiatric co-morbidities (including substance abuse), and payer policies that mandate methadone as a first-line coverage.

„Not all pain medicines — even within a class — and not all patients — are created equally,“ said Dr. Webster. „Methadone is a safe and effective opioid with pharmacokinetics and pharmacodynamics unlike other opioids, so knowledge about it and how it may affect a specific patient is paramount to a positive clinical outcome. Education about pain medicine is the best safeguard against the unintended deaths and side effects we’ve seen with methadone in the last decade.“

According to Webster, simple conversion from one opioid twice a day to another twice a day is not safe. Patient pharmacogenetics (a patient’s unique response to medicine based on his or her genetics), especially when converting between opioids, along with the properties of the medicine, must be taken under advisement to determine appropriate therapy.

In addition, he advises that switching a patient to methadone must be done slowly and over time: start with a low dose, and titrate from there in increments that make sense for the patient and the pain condition.

Source: PRNewswire.com — February 4, 2010

Utah study emphasizes need for unused pills to be tossed out, experts say

By Steven Reinberg, HealthDay Reporter

(HealthDay News) — Almost all people who illegally use or abuse opioid painkillers such as Oxycontin or Vicodin get the drugs from a friend or relative who had a prescription, a new report shows.

In the study, which involved a 2008 survey of more than 5,300 Utah adults, almost 2 percent of respondents said they had taken an opioid pain medicine not prescribed to them over the past year.

Ninety-seven percent of the time, the drug came from a friend or relative, and in most cases the drug was handed over willingly.

The study is published in the Feb. 19 issue of the U.S. Center for Disease Control and Prevention’s Morbidity and Mortality Weekly Report.

Many Utah residents do have at least one prescription for opioid painkillers, according to the Utah Department of Health researchers.

„We found that one in five patients are prescribed opioids and the majority of those have leftover medication,“ said report co-author Erin Johnson, project coodinator for the department’s Pain Medication Management & Education Program.

The majority of patients (71 percent) keep their leftover medication, she added.

Johnson and her team warned that holding on to unused prescription opioid painkillers can result in fatal overdoses, especially among people who were not prescribed the drugs.

According to the report, 85.2 percent of people who used an opioid without a prescription said the drug was given to them by someone who did have a prescription, and 9.8 percent said they took the medication without the knowledge or permission of the owner.

Only 4.1 percent said they had bought the drug.

„With all these excess pills, there is a great likelihood of misuse and abuse that could result from that,“ Johnson said. „So dispose of your leftover pain medication immediately,“ she added.

From 1999 to 2007, deaths in Utah from poisoning by prescription pain drugs increased almost 600 percent, from 39 in 1999 to 261 in 2007, according to the report.

Johnson pointed out that any misuse of a prescription in Utah is a felony. That even includes taking your prescribed medication for an illness or pain episode other than what it was prescribed for.

The best thing to do with leftover opioids: throw them out, Johnson said. „The recommended way is to mix the pills with something undesirable in a separate bag and take the bottle and cross out any identifying information and throw that away separately,“ she said.

Although the U.S. Food and Drug Administration recommends flushing unused prescription drugs, in Utah experts would prefer that people do not dispose of medicines this way, to avoid contaminating the environment, Johnson said.

In Utah, police stations also have drop boxes to collect unused medications, she added.

Johnson noted that most people are reluctant to get rid of their unused drugs. The main reason: They paid for these drugs and may need them again, she said.

Although enforcing drug disposal is hard, Johnson hopes that public awareness of the dangers of keeping unused opioids around will encourage people to dispose of these drugs.

In addition, Utah is trying to get doctors to prescribe only the number of pills they think a patient will need to deal with their pain, Johnson said.

„It not a big deal for someone to call in and say they are running low,“ she said. „The doctors are understanding and they will write more.“

Dr. James Garbutt, a professor of psychiatry at the University of North Carolina at Chapel Hill, said that, „increased use and misuse of opioid medication is a significant health problem.“

Overdose deaths from opioids have risen significantly over the past 10 years, and „this a particular problem in young people who are not aware of the risks of these medications,“ he noted.

„The net effect is that more opioid medications are available, and perhaps one consequence of this is that more individuals are getting into trouble with opioid medications,“ he said.

The Utah report encourages physicians to only use opioids when clearly indicated, not to prescribe excessive quantities, to avoid long-acting opioids such as Oxycontin unless needed, and to encourage patients to discard leftover medication, Garbutt said.

„The report is more evidence of the increasing problem of opioid misuse in the United States. This problem is costing lives, including the lives of young healthy people,“ he said. „Education of both physicians and the public is needed.“

SOURCES: Erin Johnson, M.P.H., Pain Medication Management & Education Program Project Coordinator, Utah Department of Health, Salt Lake City; James Garbutt, M.D., professor, psychiatry, University of North Carolina at Chapel Hill; Feb. 19, 2010, Morbidity and Mortality Weekly Report

Key findings   11
Operation of the world drugs market   11
Production   11
Consumption   11
Revenues   12
Drug-related problems   13
Policies   13
Policy assessment   15
Conclusions   16
Main report: Assessing changes in global drug problems, 1998-2007 19
Peter Reuter
1. Introduction and methodology   21
2. Markets and quantities   23
2.1 Operation of the markets   23
2.2 Production   25
2.3 Consumption   28
2.4 Revenues 31
3. Drug-related problems 35
3.1 Introduction 35
3.2 Drug-related deaths   35
3.3 HIV   36
3.4 Crime   36
3.5 Economic cost estimates 3  6
4. Policies   39
4.1 Introduction   39
4.2 Prevention   40
4.3 Treatment   40
4.4 Harm reduction   41
4.5 Enforcement   41
5. Policy assessment   45
5.1 Introduction   45
5.2 Unintended consequences   46
5.3 Drug epidemics   47
5.4 Production and trafficking controls   49
5.5 Domestic enforcement  51
5.6 Methodological issues  51
6. Conclusions  53
References   55

Abstracts 59
Report 1 59
The operation of the global drug market
Peter Reuter
Report 2 61
Estimating the size of the global drug market: A demand-side approach
Beau Kilmer
Rosalie Pacula
Report 3 63
Issues in estimating the economic cost of drug abuse in consuming nations
Rosalie Liccardo Pacula
Stijn Hoorens
Beau Kilmer
Peter Reuter
Jim Burgdorf
Priscilia Hunt
Report 4 65
Drugs problem and drug policy, developments between 1998 – 2007
Franz Trautmann
Peter Reuter
André van Gageldonk
Daan van der Gouwe
Report 5 67
The unintended consequences of drug policies
Peter Reuter
Report 6 69
Methodological challenges in the country studies
André van Gageldonk
Peter Reuter
Franz Trautmann

Read more :report_short_10_03_09_en

We are all naturally dependent on opioids for our emotional health. Both narcotics and internally generated endorphins exert their action on the body by interacting with specific membrane receptor-proteins on our nerve cells.

The body produces three large pro-compounds: proenkephalin, prodynorphin, and pro-opiomelanocortin. Endorphins can further decompose to small fragments, oligomers, which are still active. Oligomers pass the blood-brain barrier more readily. Enzymatic degradation of small-chain endorphins is accomplished by dipeptidyl carboxypeptidase, enkephalinases, angiotensinases, and other enzymes. This limits their lifetime in the unbound state.

Opioid receptors presynaptically inhibit transmission of excitatory pathways. These pathways include acetylcholine, the catecholamines, serotonin, and substance P. Substance P is a neuropeptide active in neurons that mediate our sense of pain; antagonists of substance P are currently under investigation as clinical antidepressants. Endorphins are also involved in glucose regulation. Opioid receptors are functionally designated as mu, delta, kappa, etc. These categories can be further sub-classified by function or structure. Decoding the human genome has allowed the genetic switching-mechanisms that control the expression of each opioid receptor to be determined at the transcriptional and post-transcriptional level.

All classes of opioid receptor share key similarities. Opioid-driven inhibition of neuronal excitability is mediated by the activation of a variety of potassium channels in the plasma membrane. The disparate subjective and behavioural effects evoked by activation of the different categories of opioid receptor are typically not the outcome of different cellular responses, but reflect the different anatomical distributions of each receptor. Unlike kappa opioid receptors, however, both mu and delta opioid receptors internalise on exposure to agonists. Activation of any type of opioid receptor inhibits adenylate cyclase, resulting in a fall in intracellular cAMP and diminished action potential firing. This causes a reduced flow of nociceptive information to the brain. Conversely, opioid addicts undergoing withdrawal suffer elevated cAMP levels and enhanced protein kinase A activity, resulting in increased neurotransmitter release.

The opioid receptors all have a common general structure. They are characteristically G protein-linked receptors embedded in the plasma membrane of neurons. Once the receptors are bound, a portion of the G protein is activated, allowing it to diffuse within the plasma membrane. The G protein moves within the membrane until it reaches its target – either an enzyme or an ion channel. These targets normally alter protein phosphorylation and/or gene transcription. Whereas protein phosphorylation alters short-term neuronal activity, gene transcription acts over a longer timescale.

Two new classes of opioid neuropeptide have recently been identified. These are nociceptin and the endomorphins.

Nociceptin (also known as orphanin) was first identified in 1995. It is the endogenous ligand of the opioid receptor-like 1 receptor. Depending dosage and site, nociceptin has subjectively extremely nasty hyperalgesic effects. Nociceptin receptor antagonists are candidate antidepressants and analgesics.

Endomorphin1 and endomorphin2 are newly-discovered ligands with the highest affinity and selectivity for the mu opioid receptor of all the endogenous opioids. Critically, endomorphin1 increases dopamine efflux in the nucleus accumbens via mu-1 opioid receptors. In the absence of selective endogenous mu-opioid receptor agonists, our vulnerability to pain and suffering would be even worse. Several novel, peripherally administered endomorphin1 analogues are under investigation that are more resistant to enzymatic hydrolysis. They should offer new opportunities for euphoric well-being, enriched mental health and more effective pain-relief.

Morphine itself is produced naturally by the human body and brain, albeit in much lower concentrations than in the opium poppy Papaver somniferum. Morphine is synthesised in human neuroblastoma cells via a biosynthetic route similar to that of the opium poppy. It is also present in healthy neurons, where it undergoes Ca2+-dependent release suggestive of a neurotransmitter or neuromodulator role. But the physiological role of endogenous morphine is still obscure.

Opioidergic neurons are particularly concentrated in the ventral tegmental area. The VTA is an important nerve tract in the limbic system. The VTA passes messages to clusters of nerve cells in the nucleus accumbens and the frontal cortex. This forms the brain’s primary reward pathway, the mesolimbic dopamine system. Its neurons are called dopaminergic because dopamine is manufactured, transported down the length of the neuron, and packaged for release into the synapses.

GABA normally plays a braking role on the dopaminergic cells. Opioids and endogenous opioid neurotransmitters activate the presynaptic opioid receptors on GABA neurons. This inhibits the release of GABA in the ventral tegmental area. Inhibiting GABA allows the dopaminergic neurons to fire more vigorously. The release of extra dopamine in the nucleus accumbens is intensely pleasurable.

Both delta opioid agonists and inhibitors of enkephalin catabolism have anxiolytic and antidepressant activity. Kappa opioid receptor antagonists have antidepressant activity; the first orally active selective kappa receptor antagonist is the investigational drug JDC-2. Mu receptor activation is crucial to the rewarding, analgesic and addictive properties of opioids. Government researchers and pharmaceutical companies are searching for powerful analgesics that won’t make the user feel happy [„high“] too.

Mu-receptors are found mainly in the brainstem and the medial thalamus. There are two primary sub-types: mu-1 and mu-2. More than 100 polymorphisms have been identified in the human mu opioid peptide receptor gene. Stimulation of the mu-1 receptors is primarily responsible for the beautiful sense of euphoria, serenity and analgesia induced by a potent and selective mu opioid agonist. Receptor activation by mu opioid agonists increases cell firing in the ventral tegmental area. This triggers dopamine release in the nucleus accumbens by reducing GABA’s tonic inhibitory control of the dopaminergic neurons. By contrast, at the height of the opioid withdrawal syndrome, typical firing rates and burst firings of VTA-nucleus accumbens neurons are reduced to around 30% of normal. The withdrawal syndrome can be quickly remedied by the administration of a potent mu agonist such as morphine. Care is needed: stimulation of the mu-2 opioid receptors helps modulate respiratory depression. For obvious reasons, this is potentially dangerous. The endogenous ligands for the mu opioid receptors have recently been discovered. They are endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2).

Unfortunately, we still lack clinically available opioids specific to the mu-1 receptor. Their advent will (potentially) be a tremendous boon to mental and physical health.

Im Anhang koennt Ihr die aktuellste Version (vom 19. Februar 2010) finden und nachlesen,

besonders dem Wegfall der starren „Take-Home“ Richtlinen ist beachtung zu schenken:

RL-Substitution_19-Februar-2010

Most definitions of drug addiction or substance dependence include (i) descriptions of „overwhelming involvement with the use of a drug (compulsive use)“ (1) and (ii) a number of symptoms or criteria that reflect a loss of control over drug intake and a narrowing of the number of different behavioral responses toward drug-seeking (2). Drug addiction can be equated with substance dependence as defined by the American Psychiatric Association (3). However, it is important to distinguish between what is termed substance use, substance abuse, and substance dependence (addiction) (4).

In humans, most drug users do not become drug abusers or drug-dependent (4). Similarly, stable drug intake can be observed in animals without pronounced signs of dependence, even with intravenous drug administration under limited-access situations. Many factors such as availability (route of administration), genetics, history of drug use, stress, and life events contribute to the transition from drug use to drug addiction. The current challenge is to discover what neurobiological elements convey the individual differences in vulnerability to this transition to drug addiction.

In this article we will draw from recent formulations in behavioral neuroscience and other disciplines to construct a framework to view addiction as a continuous process of hedonic homeostatic dysregulation. Multiple sources of reinforcement are identified in the spiralling cycle of addiction, and the symptoms of this hedonic dysregulation form the well-known criteria for substance dependence or addiction (2, 3). Critical neurotransmitters, hormones, and neurobiological sites have been identified that may mediate the hedonic dysregulation and may provide the substrates that convey both vulnerability to, and protection against, drug addiction (5) (Fig. 1).


Fig. 1. Diagram describing the spiralling distress-addiction cycle from four conceptual perspectives: social psychological, psychiatric, dysadaptational, and neurobiological. (A) The three major components of the addiction cycle, preoccupation-anticipation, binge-intoxication, and withdrawal-negative affect, and some of the sources of potential self-regulation failure in the form of underregulation and misregulation. (B) The same three major components of the addiction cycle with the different criteria for substance dependence from DSM-IV incorporated. (C) The places of emphasis for the theoretical constructs of sensitization and counteradaptation. (D) The hypothetical role of different neurochemical and endocrine systems in the addiction cycle. Small arrows refer to increased functional activity. DA, dopamine, CRF, corticotropin-releasing factor. Note that the addiction cycle is conceptualized as a spiral that increases in amplitude with repeated experience, ultimately resulting in the pathological state known as addiction. (fuer groesseres Bild unten gucken!)


Spiralling Distress and the Addiction Cycle

Important elements that may be involved in the failure to self-regulate drug use, as well as other behaviors such as compulsive gambling and binge eating, have derived from social psychology (6). It is of interest to conceptualize how these regulation failures ultimately lead to addiction in the case of drug use or an addiction-like pattern with nondrug behaviors. Lapse-activated causal patterns, that is, patterns of behavior that contribute to the transition from an initial lapse in self-regulation to a large-scale breakdown in self-regulation, can lead to spiralling distress (6). Spiralling distress describes how, in some cases, the first self-regulation failure can lead to emotional distress, which sets up a cycle of repeated failures to self-regulate, and where each violation brings additional negative affect (6). For example, a failure of strength may lead to initial drug use or relapse, and other self-regulation failures can be recruited to prevent an exit from the addiction cycle. Here, spiralling distress will be used to describe the progressive dysregulation of the brain reward system within the context of repeated addiction cycles (Fig. 1A).

Psychiatry and experimental psychology, in effect, address the same addiction cycle (Fig. 1B), and neurobiology has begun to identify the neurobiological elements that contribute to the break with hedonic homeostasis, known as addiction. Although animal models provide a critical part of the study of the neurobiology of addiction, no animal models incorporate all the elements of addiction. Alternatively, animal models can be established and validated for different symptoms or constructs associated with addiction (7). There is much evidence for valid animal models of many of the criteria in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (3) and the sources of reinforcement associated with addiction (7).

Neurobiology of Drug Reinforcement

The focus for the neurobiological mechanism for the positive-reinforcing effects of drugs of abuse has been the mesocorticolimbic dopamine system and its connections in the basal forebrain (8, 9). For cocaine, amphetamine, and nicotine, the facilitation of dopamine neurotransmission in the mesocorticolimbic dopamine system appears to be critical for the acute reinforcing actions of these drugs [for reviews, see (8, 9)]. Multiple dopamine receptors including D-1, D-2, and D-3 have been implicated in this reinforcing action (10, 11). Neuropharmacological studies support both a dopamine-dependent and a dopamine-independent contribution to the positive-reinforcing effects of opiates such as heroin (8, 9, 12). Ethanol appears to interact with ethanol-sensitive elements in multiple neurotransmitter receptor systems, and these interactions may contribute to ethanol’s positive-reinforcing actions (13). The neurotransmitters and receptor systems implicated include actions on the gamma -aminobutyric acid (GABA), glutamate, dopamine, serotonin, and opioid peptide systems, all of which are within the mesocorticolimbic dopamine system and its connections to the nucleus accumbens and amygdala (13). Limited study has implicated the release of dopamine in the nucleus accumbens in the positive-reinforcing actions of tetrahydrocannabinol (THC) (14).

A major question still challenging drug abuse research, however, is whether the neurobiology of reward and drug reinforcement changes with chronic use and during the manifestation of an abstinence syndrome when the drug is no longer self-administered. Historically, substance dependence has focused on the manifestation of an abstinence syndrome upon abrupt cessation of drug administration that was characterized by physical signs such as the well-documented tremor and autonomic hyperactivity of ethanol withdrawal and the discomfort and pain associated with opiate withdrawal. However, recent conceptualizations of abstinence symptoms have begun to focus on aspects of abstinence that are common to all drugs of abuse and may be considered more motivational in nature and perhaps are best described as a negative affective state (5, 15, 16). These symptoms include various negative emotions such as dysphoria, depression, irritability, and anxiety (3, 15, 16).

Consistent with these clinical observations, animal studies in which intracranial self-stimulation was used as a measure of reward function have revealed pronounced decreases in reward (or increases in the reward threshold) associated with withdrawal from all major drugs of abuse tested to date (Fig. 2). These effects vary with dose and duration of exposure to the drug, but can last as long as 96 hours after withdrawal from the drug in rodent models (15, 16).


Fig. 2. Changes in reward threshold associated with chronic administration of three major drugs of abuse. Reward thresholds were determined by a rate-independent discrete trials threshold procedure for intracranial self-stimulation (ICSS) of the medial forebrain bundle. (A) Rats equipped with intravenous catheters were allowed to self-administer cocaine for 12 hours before withdrawal and reward threshold determinations. Elevations in threshold were dose-dependent with longer bouts of cocaine self-administration yielding larger and longer-lasting elevations in reward thresholds (51). Asterisks refer to significant differences between treatment and control values. Values are mean ± SEM. (B) Elevations in reward thresholds with the same ICSS technique after chronic exposure to ethanol of about 200 mg% in ethanol vapor chambers (52). (C) Elevations in reward thresholds measured with the same ICSS technique after administration of very low doses (in milligrams per kilogram of body weight) of the opiate antagonist naloxone to animals made dependent on morphine with two, 75-mg morphine (base) pellets implanted subcutaneously (53). (fuer groesseres Bild unten gucken!)


The significance of drug abstinence syndromes remains controversial as a basis for compulsive use (1, 7), but increasing evidence both in animal and human studies suggests that the presence of a negative affective state may not only signal the beginning of the development of dependence (17), but may contribute to vulnerability to relapse and may also have motivational significance. Rats made dependent on opiates and ethanol show increases in drug self-administration (18). Thus, exposure to sufficient amounts of drug to produce dependence as measured by elevations in reward thresholds can increase the motivation for a drug. This increase could result from additive or even synergistic sources of positive and negative reinforcement (19) and may contribute to the addiction cycle.

Neural Substrates for Sensitization and Counteradaptation of Reward

At the neurobiologial level, two neuroadaptive models have been conceptualized to explain the changes in motivation for drug-seeking that reflect compulsive use: counteradaptation and sensitization. Counteradaptation hypotheses (20) were intimately linked to the development of hedonic tolerance by the formulation known as opponent process theory (21). In contrast, sensitization, a progressive increase in a drug’s effect with repeated administration, has been conceptualized to be a shift in an incentive-salience state (21).

Both of these conceptual positions focus on neurobiological changes at the molecular, cellular, and system levels, and both may involve what have been described as „within-system“ and „between-system“ changes (8). At the neurochemical level, changes associated with the same neurotransmitters implicated in the acute reinforcing effects of drugs that are altered during the development of substance dependence would be examples of within-system changes.

Counteradaptive, within-system neurochemical events include decreases in dopaminergic and serotonergic neurotransmission in the nucleus accumbens during drug withdrawal (22). At the molecular and cellular levels, changes in opiate receptor function during withdrawal from chronic opiates and decreased GABAergic and increased glutamatergic transmission during ethanol withdrawal have been observed [(23), and Nestler and Aghajanian (24) in this issue)]. Sensitization to the locomotor stimulant effects of psychomotor stimulants and opiates also appears to involve within-system activation of the mesolimbic dopamine system. There appears to be a time-dependent chain of adaptations within the mesolimbic dopamine system that leads to the long-lasting changes produced by sensitization (25).

Changes in other neurotransmitter systems that are not linked to the acute reinforcing effects of the drug but are recruited during chronic drug administration have been conceptualized as between-system adaptations. Examples of between-system counteradaptations include increases in dynorphin function in the nucleus accumbens during chronic cocaine administration, increases in anti-opioid peptides associated with chronic opioid administration, and augmentation of brain stress systems such as corticotropin-releasing factor (CRF) associated with cocaine, opiates, ethanol, and THC (15, 16, 26).

Recent neuroanatomical, neurochemical, and neuropharmacological observations have provided support for a distinct brain circuit within the basal forebrain that may mediate both the within-system and between-system neurochemical changes associated with drug reward. The extended amygdala (27) is a hypothesized macrostructure consisting of several basal forebrain structures that share similarities in morphology, neurochemistry, and connectivity (27). Support for the role of the extended amygdala in the acute reinforcing effects of drugs of abuse can be found in a series of in vivo microdialysis and neuropharmacological studies that showed selective activation of dopamine in the shell of the nucleus accumbens by most of the major drugs of abuse (28). In addition, GABAergic and opioidergic mechanisms in the central nucleus of the amygdala may participate in the acute reinforcing actions of ethanol (29). Also, the central nucleus of the amygdala may function in counteradaptation of the brain reward system during the development of drug dependence. Chronic administration of drugs can alter both CRF and proopiomelanocortin gene expression in the amygdala (30). An increased CRF response in the central nucleus of the amygdala is associated with acute withdrawal from ethanol, opiates, cocaine, and THC (31).

Limited data suggest a specific role for parts of the extended amygdala in sensitization. The mesolimbic dopamine system is clearly involved, but no specific subregion has been delineated. Glucocorticoids can activate the mesolimbic dopamine system by increasing dopamine synthesis, decreasing dopamine metabolism, and decreasing catecholamine uptake (5). The participation of a specific subprojection of the mesolimbic system in sensitization is under investigation.

Relapse: Neural Substrates and Vulnerability

Relapse and vulnerability to relapse are key elements in the maintenance of a chronic relapsing disorder such as addiction [see O’Brien (32), this issue]. Animal models predictive of relapse are being developed. Studies suggest that stresslike stimuli and neuropharmacological agents that activate the mesocorticolimbic dopamine system can rapidly reinstate intravenous drug self-administration that has been previously extinguished (33), and drugs that modulate dopamine receptors can block reinstatement of cocaine self-administration in rats (11). Naltrexone and acamprosate decrease relapse rates in alcoholics (34) and can modify excessive drinking in rodents in various models (35). Thus, a rich source for study of the neurobiological mechanisms of relapse will be the same neurotransmitters and neurocircuitry implicated in the within- and between-system adaptations of sensitization and counteradaptation.

The vulnerability to relapse will have both genetic and environmental bases resulting in a susceptible host, from a medical perspective (36). Animal studies have begun to address both these contributions. While genetic vulnerability is beyond the scope of this review, there are rodent strains that show preferences for drinking ethanol, and there is mounting evidence of alterations in the same reward neurotransmitters that may form the basis of such preferences (37). In addition, new techniques such as quantitative trait loci analysis and the study of knock-out and transgenic mice are revealing potential genetic sites associated with vulnerability (38).

Environmental factors involved in vulnerability have largely focused on the role of stress. An atypical responsivity to stress in former opiate- and cocaine-dependent subjects has been well documented and hypothesized to be linked to chronic relapse (39). Exposure to repeated stressors also increases the propensity to develop initial intravenous drug self-administration (acquisition) (40) and can facilitate reinstatement of drug self-administration after extinction (relapse) (33). These effects appear to be directly linked to activation of the hypothalamic pituitary adrenal axis. Suppression of stress-induced corticosterone secretion abolishes the enhanced behavioral responsiveness to amphetamine and morphine produced by different stressors (41). Consistent with these observations, repeated administration of corticosterone can substitute for stress and increase the behavioral effects of psychostimulants (41). It is hypothesized that glucocorticoid hormones function in the long-term maintenance of the sensitized state and may even represent a within-system change (41). In addition, vulnerability to drug-taking may be influenced by a history of drug experience and the presence of competing nondrug reinforcers altering the response to drug reinforcers (42).

The combination of genetic and environmental factors can dramatically change an animal’s response to drugs. A comparison of rats that show a high and low locomotor response to forced exposure in a novel environment revealed that high responders (HRs) show a greater propensity to develop intravenous drug self-administration compared with low responders (LRs) (43). This greater sensitivity to drugs in HRs shows a correlation with dysregulation of the hypothalamic pituitary adrenal axis (a prolonged secretion of corticosterone in response to stress) and with a higher sensitivity to the behavioral and dopamine-activating effects of glucocorticoids (41) (Fig. 3). Indeed, stress has been hypothesized to cause HR rats to express enhanced responses to drugs (43, 44). What is largely unknown is how these genetic and environmental factors combine to contribute to the development of what constitutes substance dependence (addiction) in humans. In addition, identification of the vulnerability for different parts of the addiction cycle using animal models will provide clues to relapse vulnerability in human addicts. With the use of animal models, studies of the interaction of genetics, of stress, and of the initial response to drugs on various features of the addiction cycle other than drug-taking will be informative.


Fig. 3. (A) The effects of adrenalectomy on cocaine self-administration in rats. Animals were trained to self-administer cocaine by nose-poking and subjected to a dose-effect function. Adrenalectomy produced a flattening of the dose-effect function, with decreases of cocaine intake at all the doses (54). (B) Corticosterone-induced changes in extracellular concentrations of dopamine in high-responding (HR) and low-responding (LR) animals. HR animals that drank the corticosterone solution (100 mg/ml) in the dark period showed a faster and higher increase in accumbens dopamine than LR animals (55). (fuer groesseres Bild unten gucken!)


Homeostasis of Reward, Self-Regulation, and „Natural“ Addictions

The concept of homeostasis contends that an organism maintains equilibrium in all of its systems, including the brain reward system, that is, the organism uses physiological and cognitive or behavioral capabilities to function within the appropriate limits of physiology with the help of its own resources. Environmental factors that challenge homeostasis are met with counter actions. Allostasis refers to the concept of physiology where an organism must vary all of the parameters of its internal milieu and match them appropriately to perceived and anticipated environmental demands in order to maintain stability (45). If the threats to the system continue to produce disequilibrium, the process of allostasis continues to regulate where the organism must mobilize enormous amounts of energy to maintain apparent stability at a now pathological „set point.“ The system is at the limit of its capability, and thus a small challenge can lead to breakdown (45). This is the beginning of spiralling distress and the addiction cycle. When the organism has reached a state of dysregulation so severe that it cannot recover by mobilizing its own resources, allostasis has reached the point of what is normally considered illness. The state of dysregulation of the reward system may produce loss of control over drug intake, compulsive use, or drug addiction. The mechanisms that contribute to this allostasis are normal mechanisms for homeostatic regulation of reward that have spun out of the physiological range (that is, sensitization and counteradaptation).

Addiction Cycle: Sensitization and Counteradaptation

The role of sensitization in dependence has been elaborated where a shift in an incentive-salience state, described as „wanting,“ progressively increases with repeated exposure to drugs of abuse (21). This shift is largely attributed to a pathological overactivity of mesolimbic dopamine function and, as such, represents a break with homeostasis. Other factors such as increased secretion of glucocorticoids may function in the long-term maintenance of this sensitized state (41).

Early theories of counteradaptation with chronic drug administration were based on the concept of homeostasis (20) and later extended to hedonic processes in opponent process theory (21) (Fig. 4). This theory may explain the affective withdrawal component of the addiction cycle and also may explain how repeated drug-taking can lead to spiralling distress. Indeed, the onset of a negative affective state can be used to define addiction (17). In addition, the negative affective state may have motivating properties in maintaining drug-seeking behavior, not only by direct negative reinforcement (that is, the drug is taken to relieve the negative state) but also by changing the set point for the efficacy of reinforcers and thus add motivational effectiveness to both positive drug effects and conditioned positive drug effects (7, 15, 16, 21). At least two common neurochemical elements, activation of limbic CRF systems and a decrease in mesolimbic DA function, are common neurochemical correlates of the early parts of drug withdrawal (15, 16, 31).


Fig. 4. Diagram illustrating an extension of Solomon and Corbit’s opponent-process model of motivation to incorporate the conceptual framework of this article (21). All panels represent the affective response to the presentation of the stimuli (that is, drug administration). (A) The original description of the affective stimulus, which was argued to be a sum of both an a-process and a b-process and represents the initial experience with no prior drug history. (B) The same affective stimulus in an individual with an intermittent history of drug use that may result in sensitized response. The shaded line illustrates the sametrace of the initial experience in (A). The dotted line represents the sensitized response. (C) Change in the affective stimulus hypothesized to exist in the heavily dependent individual (that is, after chronic exposure) where there is a major change in the hedonic set point. This represents a change sufficient to be considered a major break with hedonic homeostasis. The light dotted line represents the sensitized response observed in (B). (D) The hypothesized state of protracted abstinence and enhanced vulnerability to relapse with a history of chronic continuous experience. The change in this panel reflects the change in the affective response in an organism with a history of depen-dence where there is both a change in set point that is long-lasting and a residual sensitization. The bar to the right of each diagram illustrates the total peak-to-peak contrast between the lowest point in negative affect to the highest point in positive mood produced by a drug at any point in the addiction cycle. An alternative hypothesis still under consideration is that even during an intermittent sensitization pattern of drugtaking, the affective after-reaction (b-process) also may get progressively larger and larger (21). „On“ refers to the „time on“ of the hedonic stimulus, in this case the drug action. „Off“ refers to the „offset“ of the drug action. (fuer groesseres Bild unten gucken!)


At first glance, the two processes of sensitization and counteradaptation may appear to make opposite predictions about the course of drug dependence and the neurobiology of drug dependence. However, if drug dependence is viewed in the context of spiralling distress, then it is possible that both processes are active, although perhaps not concurrently, at different parts of the cycle (Figs. 1 and 4). The neurobiology of a heavily dependent person (Fig. 4C) will be very different from that of a nondependent person (Fig. 4A) and may reflect a state of severe allostasis (with a change in set point) and the part of the addiction cycle associated with negative affect and spiralling distress (Fig. 1C). For example, enhanced dopaminergic and opioidergic neurotransmission may be involved in the preoccupation-anticipation stage and result in sensitization (Figs. 1C and 4B), but compromised dopamine, serotonin, and opioidergic neurotransmission, as well as increases in stress neurotransmitters, may be responsible for the negative affective state of withdrawal (Figs. 1D and 4C). The combination of a change in hedonic set point produced by repeated counteradaptation and a separate mechanism for sensitization would provide a dramatic motivational force for continuing drug dependence (Fig. 4, C and D).

This view is similar to that of incentive motivational theory (46) and incorporates some aspects of incentive-salience theory (21). Under the current formulation, counteradaptation creates a need state that may or may not easily be labeled by subjective responses but, rather, reflects a chronic break with homeostasis such as a decrease in hedonic set point. Sensitization, in contrast, creates a facilitated incentive motivation or incentive salience that reflects enhanced responses to drug incentive stimuli (that is, wanting or craving).

According to this formulation, sensitization is assigned a relatively minor role in the ongoing process of spiralling distress, but a more important role in triggering the beginning of instability (vulnerability to drug-taking, as in the form of cross-sensitization to stress) or retriggering of instability as in the process of relapse (reentrance into the cycle of spiralling distress). Indeed, a dependent person is almost by definition already sensitized. However, there is little evidence of sensitization in drug-dependent people, and most clinical evidence points to tolerance, not sensitization. Human addicts consume enormous amounts of ethanol, opiates, and even stimulants that would easily be toxic to nonaddicted individuals (47). In addition, most of the animal studies of sensitization have focused either on locomotor activity as a dependent variable or in the drug reward domain on acquisition of drug self-administration (21). If sensitization is to gain a role as extensive as that outlined herein, more data will be required to show a link between these measures of enhanced sensitivity to drugs of abuse (locomotor activity and acquisition of drug self-administration) and other measures of dependence.

Implications for the Concept of Addiction and Treatment

The present conceptualization of addiction has important implications for the treatment of drug addiction. The social psychological components of failure to self-regulate may impact on different parts of the addiction cycle (Fig. 1A), and these different components may be reflected in changes in different components of reward neurocircuitry (Fig. 1D). For example, failure of strength may reflect increases in stress system activity, whereas failure of monitoring or attention may reflect cognitive changes that are influenced by the widely distributed brain monoamine systems.

The present conceptualization also provides a framework for studying the components of addiction most often neglected in animal studies. The role of neurobiology in different processes, such as social psychological self-regulation failures, positive and negative reinforcement, sensitization, and counteradaptation, changes dramatically over the course of transition from drug use to abuse to addiction. In addition, different drugs may act differentially on parts of the spiralling distress-addiction cycle. Young, type II alcoholics (48) may be more involved in the preoccupation-anticipation and binge components than terminal alcoholics, where a major need state has usurped most other sources of motivation. In contrast, users of opiates and nicotine may assume this need-state component at a much earlier stage (49). Studies of the neurobiology of such differences will be critical for future interventions at both the prevention and treatment levels.

There is clearly a neurobiological basis for multiple sites of treatment intervention. Eliminating affective withdrawal and the reward need state are critical (such as methadone for opiate addiction), as well as eliminating the changes that lead to facilitated incentive salience (such as naltrexone for alcohol addiction). Various forms of behavioral therapies and psychotherapy have been shown to be effective in treating addiction, particularly in combination with pharmacotherapy [(34) and O’Brien (32), this issue]. These therapies ultimately act on the same dysregulated hedonic circuitry to help return and maintain it within homeostatic boundaries. In addition, vulnerability to addiction can be conveyed at any part of the spiralling distress of the addiction cycle and should not be simply relegated to initial drug responses.

Although beyond the scope of the present review, dysregulation of hedonic homeostasis can also occur with compulsive use of nondrug reinforcers. Similar patterns of spiralling distress-addiction cycles have been observed with pathological gambling, binge eating, compulsive exercise, compulsive sex, and others (6). The same neurobiological dysregulations and breaks with homeostasis may be occurring within the same neurocircuitry implicated in drug dependence. With the advent of more sophisticated measures of brain function in humans, such questions may be pursued.

The implications of this homeostatic view for everyday existence forces one to return to social psychology, but with a biological perspective. The brain hedonic system may be a limited resource (50). One can expend this resource rapidly in a binge of drug-taking or other compulsive behavior, but at a great risk for entrance into the spiralling dysregulation of the addiction cycle. Alternately, one can adopt a more regulated, „hedonic Calvinistic“ approach (51) where use of the reward system is restricted within the homeostatic boundary (that is, without the development of subsequent negative affect). Such an ascetic view may or may not fall within certain cultural norms, but probably makes biological sense.

REFERENCES AND NOTES

  1. J. H. Jaffe, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, A. G. Gilman, T. W. Rall, A. S. Nies, P. Taylor, Eds. (Pergamon, New York, ed. 8, 1990), pp. 522-573.
  2. World Health Organization, International Statistical Classification of Diseases and Related Health Problems (World Health Organization, Geneva, 10th revision, 1990).
  3. Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, Washington, DC, ed. 4, 1994).
  4. A recent Institute of Medicine report [Institute of Medicine, Pathways of Addiction (National Academy Press, Washington, DC, 1996)] used a three-stage conceptualization of drug-taking behavior that applies to all psychoactive drugs, whether licit or illicit: use, abuse, and dependence. „Use“ of drugs is the taking of drugs, in the narrow sense, to distinguish it from a more intensified pattern of use. „Abuse“ refers to any harmful use, regardless of whether the behavior constitutes a disorder in the DSM-IV of the American Psychiatric Association. „Dependence“ refers to „substance dependence“ as defined by DSM-IV or „addiction“ as defined by International Classification of Diseases (ICD 10).
  5. G. F. Koob and E. J. Nestler, J. Neuropsychiatry Clin. Neurosci. 9, 482 (1997) [Abstract/Free Full Text] ; P. V. Piazza and M. Le Moal, Brain Res. Rev., in press.
  6. Underregulation can be defined as a „failure to exert control over one’s self.“ Conflicting or inadequate standards would be a breakdown in the basis for self-regulation. Reduction in monitoring is a failure of a person to evaluate one’s self and actions against relevant standards. Inadequate strength is analogous to the common-sense concept of willpower and is a conflict between the power of impulse/tendency to act and the self-regulatory mechanism to interrupt that response and prevent action. Misregulation can be defined as „exerting control in a way that fails to bring about the desired result or leads to some alternative result.“ Misregulation probably most often involves some kind of deficiency in knowledge, especially self-knowledge. These knowledge deficiencies include false beliefs, distorted beliefs, overgeneralizations, and misdirected control efforts. Lapse-activated causal patterns are the patterns of behavior that translate an initial lapse (break in self-regulation) into a large-scale indulgence or major binge. Many factors contribute to these patterns of behavior, including underregulation, emotional responses, stress, zero-tolerance beliefs, spiralling distress, and others [R. F. Baumeister, T. F. Heatherton, D. M. Tice, Eds., Losing Control: How and Why People Fail at Self-Regulation (Academic Press, San Diego, 1994)].
  7. The use of animal models to characterize the neurobiology of specific aspects of human disorders is a reorientation to the „top-down“ approach. Here, specific behaviors are explored at the system level, the cellular level, and ultimately the molecular level, with hypothesis testing based on an understanding of the mechanism of the behavioral response [ A. Markou, et al., Psychopharmacology 112, 163 (1993) [CrossRef] [Medline] ; G. F. Koob, in Psychopharmacology: The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds. (Raven Press, New York, 1995), pp. 759-772; G. F. Koob et al., J. Psychopharmacol., in press].
  8. G. F. Koob and F. E. Bloom, Science 242, 715 (1988) [Abstract/Free Full Text] .
  9. R. A. Wise and P.-P. Rompre, Annu. Rev. Physiol. 40, 191 (1989) ; M. Le Moal and H. Simon, Physiol. Rev. 71, 155 (1991) [Free Full Text] ; G. F. Koob, Trends Pharmacol. Sci. 13, 177 (1992) [CrossRef] [Medline] ; F. E. Pontieri, G. Tanda, F. Orzi, G. Di Chiara, Nature 382, 255 (1996) [CrossRef] [Medline] .
  10. W. L. Woolverton, Pharmacol. Biochem. Behav. 24, 531 (1986) [CrossRef] [ISI] [Medline] ; G. F. Koob, H. T. Le, I. Creese, Neurosci. Lett. 79, 315 (1987) [CrossRef] [ISI] [Medline] ; J. Bergman, J. B. Kamien, R. D. Spealman, Behav. Pharmacol. 1, 355 (1990) [Medline]; S. B. Caine and G. F. Koob, Science 260, 1814 (1993) [Abstract/Free Full Text] .
  11. D. W. Self, W. J. Barnhart, D. A. Lehman, E. J. Nestler, Science 271, 1586 (1996) [Abstract] .
  12. G. Di Chiara and R. A. North, Trends Pharmacol. Sci. 13, 185 (1992) [CrossRef] [Medline] ; T. S. Shippenberg, A. Herz, R. Spanagel, R. Bals-Kubik, C. Stein, Ann. N. Y. Acad. Sci. 65

While a great deal of current thought about drug addiction is dominated by the concept of „the hijacked brain“ altered by its exposure to drugs, such theories have little to offer to the clinician. On the other hand, the self-medication hypothesis, which proposes that addicts are using their drug of choice to relieve symptoms of an underlying disorder or condition (such as stress), provides the clinician with a useful conceptual model to guide treatment. The often mystifying problem of relapse is also clearly understandable when viewed from the perspective of the self-medication hypothesis.

The greatest inadequacy of the „hijacked brain“ model of addiction is its inability to explain why most users of drugs do not become addicted (Anthony & Helzer, 1991; Anthony, Warner, & Kessler, 1994). Population studies show that only about one out of every five users of cocaine becomes addicted or develops the sort of problems that would justify a DSM diagnosis of substance abuse or dependence. The rate of alcoholism or alcohol abuse in alcohol users is about the same. For users of heroin and marijuana the rates of addiction is more like one out of ten.

Edward J. Khantzian and David F. Duncan are usually credited with being the originators of the self-medication hypothesis but while theirs are the most fully developed versions there are earlier precedents for the idea. Both Fenichel (1945) and Rado (1957) pointed to an underlying depression as the motive for drug abuse. Glover (1956) went further in suggesting that drugs were used to cope with overwhelming and psychotogenic aggresssion and rage. Rosenfeld (1965) described drug addiction as a defense against psychotic suffering. None of these contributions, however, have had the degree of influence that Duncan and Khantzian have.

Khantzians Model of Drug Abuse as Self-Medication

One of the two major versions of the self-medication hypothesis is the psychoanalytic perspective developed by Edward J. Khantzian and his colleagues at Harvard Medical School. This model arose from Khantzians clinical experience evaluating and treating heroin addicts. He noted that his addict patients had histories of difficulties with aggression and derivative problems of rage and depression that long preceded their use of any illegal drugs. He also found that many of them reported that use of heroin gave them relief from dysphoric feelings of restlessnees, anger, and rage.

Khantzian concluded that the predisposition to become a heroin addict resulted from these problems with aggression — specifically from inadequate ego mechanisms for controlling and directing aggression. The repeated use of heroin or other opiates as a means of coping with the addicts poorly controlled aggressive drive result in the development of physical dependence. Methadones effectiveness in treating heroin addiction, he argued, is due not only to its prevention of withdrawal illness but also due to its relief of those same dysphoric feelings. This limited formulation of what would become the Self-Medication Hypothesis was published by Khantzian, Mack, and Schatzberg in 1974 in the American Journal of Psychiatry.

Eleven years later the original hypothesis about heroin addiction (Khantzian, Mack, & Schatzberg, 1974) was named the Self-Medication Hypothesis and was elaborated to include cocaine addiction as well (Khantzian, 1985). He now speculated that cocaine has its appeal because of its ability to relieve the distress associated with depression, hypomania, or hyperactivity. The hypothesis was subsequently expanded to include alcoholism, speculating that the addicts use of alcohol, permits the experience of affection, aggression, and closeness in an individuals who is otherwise cut off from their feelings and relationships (Khantzian, 1990). And finally developed into a theory of all drug addictions (Khantzian, 1997 & 1999).

In its fully developed version, Khantzians version of the Self-Medication Hypothesis holds that addiction occurs in a context of self-regulation vulnerabilities — primarily difficulties in regulating affects, self-esteem, relationships, and self-care. Potential addicts suffer severely from their feelings, either being overwhelmed with painful emotions or seeming not to feel any emotions at all. Drugs of abuse help such individuals to relieve painful emotions or to experience emotions that are confusing or threatening.

Regardless of specific symptoms or personality styles, Khantzian believes that certain character traits are typical of all drug addicts. These include problems in affect management, self esteem, object relations, judgment, and self-care. He argued that these developmentally and structurally determined problems predispose individuals to drug dependence because they are the basis of the distresses that are relieved by drug-taking.

Vulnerability to drug dependence varies greatly both between individuals and for the same individual at different times. In many cases addiction develops in a previous abstainer (or perhaps even in a non-dependent drug user) following some precipitating event that involves a severe crisis in which the individuals adaptive capacities are diminished and narcissistic vulnerability is intense.

Once drug taking has been initiated in a susceptible state and the user has experienced adaptive benefit from the use of the drug, a variety of other processes are set in motion that often lead to addiction. These processes include both regressive effects that can exacerbate the original vulnerability and progressive effects that promote stable functioning. In both cases, however, Khantzian argued that this may interfere with further emotional maturation, particularly when the onset of addiction occurs in adolescence.

The addict’s choice of drug, according to Khantzian, was a result of the interaction between the psychopharmacologic properties of the drug and the „primary feeling states“ the addict was seeking relief from. The drugs effects substitute for defective or non-existent ego mechanisms of defense. The addicts „drug of choice,“ therefore, is neither random nor simply the result of current fashion or fad, but rather, results from a process of „self selection“ that has been referred to as „preferential drug use“ (Milkman & Frosch, 1973) Thus, narcotic addicts prefer opiates because of the relief they provide from the disorganizing and threatening affects of rage and aggression. Cocaine, in turn, has its appeal due to its ability to relieve the distress associated with depression, hypomania, or hyperactivity.

According to Treece and Khantzian (1986) the development of drug dependence involves the gradual incorporation of the drug effects and the need for them into the defensive structure-building activity of the ego itself. Overcoming an addiction, therefore, involves dealing with the unconscious and conscious components of this outcome. The user must be able to relinquish behaviors and drug effects that have come to be experienced as a valued (even if also hated) part of the self-capacity to function, cope, and be comforted in distress.

Duncans Model of Drug Dependence as Self-Medication

The second major version of the self-medication hypothesis was developed by David F. Duncan of the Texas Research Institute of Mental Sciences. Duncan also based his hypothesis on extensive clinical experience with addicts. Whereas Khantzians formulation was rooted in psychoanalytic theory, Duncan took a behavioristic perspective.

Duncans version of the self-medication hypothesis was initially published in two papers in 1974. The first (Duncan, 1974a) was a discussion of reinforcement of drug abuse that appeared in the Clinical Toxicology Bulletin. The second (Duncan, 1974b) was a response in the American Journal of Psychiatry to Khantzian, Mack, and Schatzbergs (1974) paper on heroin use as a coping mechanism. It was in this second publication that Duncan compared drug abuse to a bandaid. A further elaboration of the hypothesis appeared the following year in an invited paper for the Journal of Psychedelic Drugs (Duncan, 1975).

The distinction between drug use and drug abuse is critical to Duncans model. He asserts that most of the people who take illegal drugs do not meet criteria for substance abuse, let alone for dependence. The great majority exercise control and restraint over their drug use and suffer no harm from using. His model is concerned with describing why a minority (10-20%) of those who take drugs non-medically do lose control over their use and expose themselves to serious social, interpersonal and medical riskss. He and Dr. Robert S. Gold have also explored the implications of his model for the primary prevention of drug abuse (Duncan & Gold, 1982 & 1983) and the tertiary prevention of the destructive consequences of drug abuse (Duncan,et al, 1994).

Duncan was by no means the first to develop a behavioral model of addiction. Other formulations of drug abuse and addiction as an operant behavior have dealt with the euphorogenic effects of drugs as positive reinforcement and avoidance of withdrawal sickness as negative reinforcement (Valdman & Zvartau, 1982; Schulteis & Koob, 1996; Bigelow, Brooner, & Silverman, 1998). Duncan, on the other hand, asserted that drug use is maintained by positive reinforcement (principally from the pleasurable effects of the drug) but that drug dependence is not. It is drug dependence that Duncans version of the self-medication hypothesis attempts to explain.

Drug dependence is the term which has formally replaced addiction in medical terminology. In 1964 the World Health Organizations Expert Committee on Drug Abuse proposed that the terms addiction and habituation be replaced with the term dependence and distinguished between two types psychological dependence and physical dependence. Psychological dependence „refers to the experience of impaired control over drug use“ while „physical dependence involves the development of tolerance and withdrawal symptoms upon cessation of use of the drug, as a consequence of the body’s adaptation to the continued presence of a drug“ (UNIDCP, 1998). In Duncans view, physical dependence is a lesser problem which occurs in addiction to some drugs, such as alcohol and opiates, but not in addiction to cocaine, heroin, etc., nor in non-drug addictions such as compulsive gambling.

Duncan essentially argues that drug dependence is just another name for avoidance or escape behavior when the operant behavior being reinforced is drug taking. Drug addicts, in his view, have found a drug which provided them with temporary escape from an ongoing state of emotional distress which might be due to a mental disorder, to stress, or to an aversive environment. Non-drug addictions, in his opinion, represent similar negatively reinforced behavior.

Duncan asserts that the characteristics of dependence are all typical of operant behaviors maintained by negative reinforcement. Negative reinforcement maintains high rates of behavior. Animals that have been negatively reinforced for performing a task such as pressing a bar will often do so to the exclusion of eating, sleeping, sexual activity, etc.. Avoidance behaviors are highly resistant to extinction and even when they appear to have been eliminated they tend to recur spontaneously. Thus the intensity, compulsiveness and proneness to relapse that characterize drug dependence all result, in Duncans opinion, from the fact that the behavior is maintained by negative reinforcement.

Critics of the Self-Medication Hypothesis

Dackis and Gold (1984, 1985) assert that depression in cocaine addicts, rather than being the cause of the addiction, is a direct result of abstinence symptomology. Withdrawal illness encourages increased cocaine use, which in turn results in alterations in brain chemistry (dopamine depletion). They conclude that the addiction itself is the cause of painful emotional states rather than a response to them.

Cocores et al., (1987) also advance a dopamine deficiency hypothesis as an alternative to the self-medication hypothesis, in this case as an explanation of the apparent correlation between attention deficit hyperactivity disorder (ADHD) and chronic cocaine abuse. They assert that cocaine further depletes dopamine in already dopamine-compromised individuals. They argue that the resultant dopamine deficiency may then induce a temporary and reversible ADHD even in those with no prior history of the disorder. Thus they also argue that the Self-Medication Hypothesis has causal directionality backwards and that the comorbid psychiatric condition follows rather than preceding addiction.

In the opinion of Goldsmith (1993) the Self-Medication Hypothesis ignores important biological research which has explored the mechanisms of reward, motivation to use drugs, and the impact on mood of chronic, excessive drug use. He argues that a new psychology of addiction is needed which includes this biological research as well as the psychological observations contained in the self-medication hypothesis. He believes that Self Psychology will provide the basis for such an integrated psychology for the addictions.

Frances (1997) urges that additional longitudinal research is needed on the Self-Medication Hypothesis. He warns that there is a danger that clinicians could use the hypothesis in overly reductionistic ways and that they must be alert to potential rationalization and retrospective distortion when listening to their patients‘ accounts of the causes of their substance abuse.

In particular, Frances warns that this is a „cart/horse problem“ in which it is often unclear which came first the drug abuse or the disorder that the Self-Medication Hypothesis suggests underlies the abuse. He suggests that it can be clinically useful to tease apart the temporal sequence of onset of each disorder, the ways in which the two disorders interact, and the ways in which each may amplify the suffering caused by the other. In his view, it is „the wrath of grapes that leads to the greater part of suffering in substance use disorders.“

Clinical Studies

Schiffer (1988) reported on a series of nine cocaine abusers successfully treated with long-term, in-depth, dynamic psychotherapy begun on an inpatient drug abuse unit and continued after hospitalization. He found his patients to have been victims of unrecognized psychological trauma in childhood. He argued that their cocaine abuse, in addition to functioning as a form of self-medication, was functioning as a component of a repetition compulsion in which old psychological traumas were symbolically recreated in the post-drug dysphoria. This perspective guided his clinical approach which involved: 1) identifying traumatic or abusive experiences in the patients history, 2) established emotional contact, 3) helping the patient to appreciate how they had been affected by the trauma. and 4) helping them to master the traumatic experiences.

Dixon et al. (1990) reported that substance abuse among schizophrenic patients is an increasingly recognized clinical phenomenon. They reviewed experimental and observed clinical effects of drug abuse and patients‘ subjective experiences of acute intoxication. Though drug abuse may exacerbate psychotic symptoms, abused drugs may also lead to transient symptom reduction in subgroups of schizophrenic patients. Some patients report feeling less dysphoric, less anxious, and more energetic while intoxicated. This relief from unpleasant symptoms motivates these patients to become chronic drug takers.

Silver and Abboud (1994) examined the critical issue of the relationship between the onset of drug abuse and onset of illness (defined as first hospitalization) and its correlates in 42 hospitalized schizophrenics identified as drug abusers. Sixty per cent of the patients began drug use before their first hospitalization. No differences on socio-demographic or clinical variables were found between patients who began drug use before their first hospitalization and those who began afterward. The findings are consistent with self-medication models of comorbidity of drug abuse and schizophrenia.


Comorbidity Studies in Clinical Samples

Weiss, Griffin, and Mirin (1992) examined drug effects and motivation for drug use in 494 hospitalized drug abusers. Most patients reported that they used drugs in response to depressive symptoms and that they experienced mood elevation, regardless of their drug of choice. Drug use to relieve depressive symptoms was far more likely in men if they had major depression, but was equally common in women with and without major depression.

Greene, et al. (1993) tested Khantzians assertion that the drug of choice in patients with substance dependence disorders reflects the nature of the underlying disorder or deficiency being self-medicated. Cocaine and marijuana dependent inpatients were compared using the MMPI to test this hypothesis. These two groups of patients did not differ on the standard validity and clinical scales of the MMPI, and their scores were basically similar to a group of alcohol dependent inpatients and a group of similar age psychiatric patients with non-drug disorders. There was no single MMPI code type that was characteristic of either group of substance-dependent patients. They concluded that drug of choice bore little relationship to the MMPI scores of these subgroups of substance dependent patients. Their results are not consistent with Khantzians drug of choice hypothesis or with Milkman and Froschs (1973) preferential drug use theory.

Schinka, Curtiss and Mulloy (1994) conducted a similar study utilizing the Personality Assessment Inventory instead of the MMPI. Administering the inventory to four groups of drug dependent patients they, in contrast to Greene, et al (1993), found group differences in symptomatology and personality traits. Results suggest that there are traits or symptoms that separate various groups of drug-dependent patients, but not in accordance with Khantzians predictions.

Aharonovich, Nguyen, and Nunes (2001) tested the hypothesis that opiate abusers experience difficulty managing aggression and that cocaine abusers suffer from distress associated mostly with depression. They used the State-Trait Anger Expression Inventory and the Beck Depression Inventory to examine levels of anger and depression among three groups of substance abusers — opiate, cocaine, and cannabis abusers. Anger and depression scores were elevated, but contrary to Khantzian’s hypothesis, there were few differences between groups, and if anything, opiate addicts were more depressed and the cocaine abusers were angrier on several subscales.

Abraham and Fava (1999) examined the order of onset of substance abuse and depression in a sample of depressed drug abusers. They used the Structured Clinical Interview for DSM-III-R (SCID) to assess the drug use and depression histories of 375 outpatients with major depressive disorder. They found that, on average, alcohol dependence followed the onset of first life depression by 4.7 years. Among polydrug dependent patients, each drug abused followed the onset of depression, except for LSD, which coincided with the onset of depression. Among polydrug users, cocaine dependence occurred an average of 6.8 years after the first major depressive episode and alcohol dependence 4.5 years after the onset of depression. They concluded that alcohol and cocaine use in this sample of depressed outpatients conformed to a pattern of self-medication.

Voruganti, Heslegrave, and Awad (1997) tested the hypothesisthat schizophrenic patients take to the use of illicit drugs as a way of relieving or modulating the unpleasant dysphoric feelings experienced while on neuroleptics.“ They studied 223 patients receiving outpatient antipsychotic drug therapy for schizophrenia. Dysphoric reactions to the medication were prevalent among 38.7% of the sample and later development of substance abuse was noted in 30% of the patients. There was a statistically significant association between the 2 conditions (odds ratio = 4.08; p < 0.001).

Population Studies

Anhalt and Klein (1976) surveyed illegal drug use in a population of 3,807 students at a suburban junior high school. They found that illegal drug use was strongly correlated with family instability, personal problems, and poor academic performance. Non-prescribed use of tranquilizers, amphetamines, and sedatives was often motivated by attempts at self-medicationto reduce painful feelings.

Deykin, Levy, and Wells (1987) utilized the Diagnostic Interview Schedule (DIS) to ascertain the prevalences of major depressive disorder, alcohol abuse, and substance abuse (by DSM-III criteria) in a sample of 424 college students aged 16 to 19. The prevalence of major depression was 6.8%, while that of alcohol abuse was 8.2% and that of substance abuse was 0.4%. Alcohol abuse was associated with major depression, but not with other psychiatric diagnoses. Abuse of other drugs was associated both with major depression and with other psychiatric diagnoses as well. The onset of major depression almost always preceded alcohol or substance abuse, consistent with the self-medication hypotheses.

Helzer and Pryzbeck (1988)used data from the Epidemiologic Catchment Area survey to examine the comorbidity between alcohol abuse and dependence, other substances abuse disorders and non-drug psychiatric disorders in a sample of approximately 20,000 persons drawn from the general population. Every one of the psychiatric diagnoses examined was more likely to occur in alcoholics than in non-alcoholics. Associations were particularly strong with antisocial personality disorder, other substance abuse and mania. The association between alcoholism and depressive disorders was positive but not very strong. They concluded that the impression widely reported by clinicians that depression and alcoholism are highly related is probably due to the fact that presence of depression increased the likelihood of treatment seeking by alcoholics – a fallacy known as Berksons bias.

Data derived from the National Longitudinal Alcohol Epidemiology Survey (NLAES), a national probability sample of the adult U.S. population, were examined by Grant (1995) for evidence of an association between drug use disorders and major depression. Comorbidity rates and odds ratios for associations between major depression and past-year, prior-to-past-year, and lifetime diagnoses of DSM-IV drug use disorders (i.e., prescription drugs, sedatives, tranquilizers, amphetamines, cannabis, cocaine, and hallucinogens) were calculated by gender, ethnicity. The results showed that virtually all of the odds ratios were significant, demonstrating that comorbidity of a variety of drug use disorders with major depression is pervasive in the general population. As predicted by Duncans version of the self-medication hypothesis, the association between drug dependence and major depression was greater than the association between abuse and major depression.

In further analyses of the NLAES data, Grant and Pickering (1998) examined the risk of cannabis abuse and dependence at different levels of cannabis use and in association with comorbidity with other psychiatric disorders. Two separate logistic regression analyses were conducted to determine the association between cannabis use, and abuse and dependence. The risk of cannabis abuse and dependence was found to increase with the frequency of smoking occasions and slightly decreased with age. More severe comorbidity was associated with dependence compared to abuse, suggesting that cannabis dependent persons were using cannabis to self-medicate major depression.

Gillman and Abraham (2001) used data from the first two waves of the Epidemiologic Catchment Area Study to estimate the odds of either major depression or alcohol dependence being followed by the other disorder after 1 year of follow-up. The odds of developing major depression associated with low, medium, and high levels of alcoholic symptoms at baseline were 1.66, 3.98, and 4.32 for females (P<0.001), and 1.19, 2.49, and 2.12 for males (P=0.026). Conversely, odds ratios indicating the 1-year follow-up risk of incident alcohol dependence within low, medium, and high categories of baseline depressive symptomatology were 2.75, 3.52, and 7.88 for females (P<0.001) and 1.50, 1.41, and 1.05 for males (P=0.091). Individuals with alcohol dependence appeared more likely to meet lifetime diagnostic criteria for both disorders after 1 year than individuals with depression. These results suggest that both alcohol dependence and major depression pose a significant risk for the development of the other disorder at 1 year.

Conclusions

As has already been noted, a number of critics of the self-medication hypotheses have raised what Frances (1997) calls the „cart/horse problem“ of which came first, the substance abuse disorder or the comorbid disorder. Dackis and Gold (1984, 1985), specifically argue that the clinically observed relationship between depression and cocaine dependence is due to chronic cocaine use causing dopamine depletion which, in turn, causes the depression. A similar alternative hypothesis is proposed by Cocores et al., (1987) for the reported association between cocaine dependence and ADHD. Empirical evidence, from both clinical (Abraham & Fava, 1999) and community samples (Deykin, Levy, & Wells, 1987), shows that depression generally precedes substance abuse rather than following it. These findings support of the self-medication hypothesis.

A number of studies have attempted to test Khantzians suppositions about which underlying problems motivate abuse of which drugs problems with aggression and anger motivating opiate abuse, for instance, or depression, hypomania and hyperactivity motivating cocaine abuse. Psychometric studies of clinical samples fail to support Khantzians predictions (Greene, et al., 1993; Schinka, Curtis, & Mulloy, 1994). Aharonovich, Nguyen, and Nunes (2001) found that cocaine abusers actually showed greater problems with anger and opiate abusers with depression than the opposite as Khantzians model predicted.

The Epidemiologic Catchment Area Study found that alcoholism was more strongly associated with antisocial personality disorder, abuse of other drugs, or mania than with depression as predicted by Khantzians model (Helzer & Pryzbeck, 1988). The ECA data suggest that the clinically observed association between depression and alcoholism is actually due to depressed alcoholics being more likely to seek treatment than non-depressed alcoholics.

While there are some contrary finding, much of the relevant research supports the self-medication hypothesis. Khantzians drug of choice predictions do not stand up to an empirical test. Thus, it is Duncans model of the self-medication hypothesis that appears to have continuing value to the field of addiction studies.

Background: Mu agonists have been an important component of pain
treatment for thousands of years. The usual pharmacokinetic parameters
(half-life, clearance, volume of distribution) of opioids have been known for
some time. However, the metabolism has, until recently, been poorly understood,
and there has been recent interest in the role of metabolites in modifying
the pharmacodynamic response in patients, in both analgesia and adverse
effects.

A number of opioids are available for clinical use, including
morphine, hydromorphone, levorphanol, oxycodone, and fentanyl. Advantages
and disadvantages of various opioids in the management of chronic
pain are discussed.
Objective: This review looks at the structure, chemistry, and metabolism of
opioids in an effort to better understand the side effects, drug interactions,
and the individual responses of patients receiving opioids for the treatment
of intractable pain.
Conclusion: Mu receptor agonists and agonist-antagonists have been used
throughout recent medical history for the control of pain and for the treatment
of opiate induced side effects and even opiate withdrawal syndromes.

Read more here: 2008;11;S133-S153

  • Inhaltsverzeichnis
    I. Einführung Seite 3
    I.1. Methodischer Zugang Seite 3
    II. Historische Aspekte der Entwicklung einer ärztlichen Haltung Seite 6
    II.1. Grundsätzliche Überlegungen Seite 6
    II.2. Zur Entwicklung der Substitutionsbehandlung Seite 7
    II.3. Vom Abstinenzparadigma zur Schadensminimierung Seite 10
    III. Praktische Durchführung Seite 13
    1. Bedeutung und Positionierung der Substitution in der Suchtbehandlung Seite 13
    2. Aspekte der Multiprofessionalität Seite 13
    3. Indikationsstellungen Seite 15
    Untersuchungen vor Behandlungsbeginn Seite 15
    4. Wahl des Substitutionsmittels Seite 19
    4.1. Allgemeiner Teil Seite 19
    Dosierung Seite 21
    Schmerzbehandlung Seite 21
    Auswirkungen auf die Verkehrstüchtigkeit und das Bedienen von
    Maschinen
    Seite 21
    Schwangerschaft und Stillzeit Seite 21
    4.2. Substanzen Seite 22
    Methadon Seite 22
    Buprenorphin Seite 22
    Slow-Release (SR)-Morphin Seite 23
    Codein/Dihydrocodein (DHC) Seite 23
    5. Einstellung und Dosisfindung Seite 24
    5.1. Dosierung des Substitutionsmittels Seite 24
    5.2. Einstellung auf das Substitutionsmittel Seite 25
    Methadon Seite 25
    Morphin retard Seite 26
    Buprenorphin Seite 26
    6. Umstellung von einem Opioid auf ein anderes Seite 27
    7. Mitgaben Seite 29
    8. Harntests Seite 31
    9. Beikonsum Seite 31
    10. Missbrauch/Verhinderung von Missbrauch Seite 33
    11. Beendigung Seite 34
    12. Therapieabbruch Seite 35
    Literaturverzeichnis Seite 36

Read more: Konsensus_Statement