Archive for Januar, 2011

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

Laam substitution Therapy For Opiate Dependence

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

Laam Addiction, Warnings and Side Effects

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

Laam Withdrawal And Treatment For Opiate Addiction

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

LAAM maintenance vs methadone maintenance for heroin dependence

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

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


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

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

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

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

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

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

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

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

(levomethadyl acetate hydrochloride)

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

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

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

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


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

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



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

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

Last reviewed on RxList: 12/8/2004


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



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

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


Dosing Schedules

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

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


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

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

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

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

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

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


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

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

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



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

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


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


Following a lapse of one ORLAAM dose:

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

Following a lapse of more than one ORLAAM dose:

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


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


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


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

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

Orlaam Side Effects & Drug Interactions



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

Heroin or Methadone Withdrawal Reactions

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

Signs and Symptoms of ORLAAM Excess

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

ORLAAM Withdrawal

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

Adverse Reactions on Stable Therapy

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

Incidence greater than 1%, Probably Causally Related

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

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

Musculoskeletal Arthralgia *

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

Respiratory Cough, rhinitis, and yawning.

Skin/appendages Rash, sweating * .

Special Senses Blurred vision.

Urogenital Difficult ejaculation * , impotence * .

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

Incidence less than 1%, Probably Causally Related

Cardiovascular Postural hypotension.

Musculoskeletal Myalgia.

Special Senses Tearing.

Causal Relationship Unknown

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

Cardiovascular Hypertension

Hepatic Hepatitis and abnormal liver function tests.

Urogenital Amenorrhea, pyuria.

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

Body as a Whole Altered hormone level, chest pain.

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

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

Respiratory Apnea, dyspnea.

Urogenital Breast enlargement.


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


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

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

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

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

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

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

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

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

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

Orlaam Warnings & Precautions



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


and Contraindications ).

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

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

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


, Drug Interactions ).


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

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

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

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

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

Risk of Overdose

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

Effects on Cardiac Conduction

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

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

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

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


, Drug Interactions ).

Use of Narcotic Antagonists

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

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

Warnings to Patients

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

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

Use in High Risk Patients

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


Initial Administration and Dosage Adjustment

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

Use in Ambulatory Patients

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

Head Injury and Increased Intracranial Pressure

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

Asthma and Other Respiratory Conditions

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

Special Risk Patients

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

Acute Abdominal Conditions

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

Drug Interactions

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

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

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

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

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

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

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

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

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

Information for Patients

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

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

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

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

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

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

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

Carcinogenesis, Mutagenesis and Impairment of Fertility

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

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

Use in Pregnancy: Pregnancy Category C

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

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

Labor and Delivery

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

Nursing Mothers

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

Pediatric Use

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

Orlaam Overdosage & Contraindications



Signs and Symptoms

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

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


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

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

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


ORLAAM is contraindicated in patients with known or suspected QT prolongation (QTc interval greater than 430 [male] or 450 [female] ms). This would include patients with congenital long QT syndrome, or conditions which may lead to QT prolongation (see WARNINGS, Effects on Cardiac Conduction ) such as: 1) clinically significant bradycardia (less than 50 bpm), 2) any clinically significant cardiac disease, 3) treatment with Class I and Class III anti-arrhythmics, 4) treatment with monoamine oxidase inhibitors (MAOI’s), 5) concomitant treatment with other drug products known to prolong the QT interval (see PRECAUTIONS , Drug Interactions ), and 6) electrolyte imbalance, in particular hypokalemia and hypomagnesemia.

ORLAAM is contraindicated in patients with known hypersensitivity to LAAM.

ORLAAM is not recommended for any use other than for the treatment of opioid dependence (see WARNINGS ).

Orlaam Clinical Pharmacology


LAAM is a synthetic opioid agonist with actions qualitatively similar to morphine (a prototypic mu agonist) and affecting the central nervous system (CNS) and smooth muscle. Principal actions include analgesia and sedation. Tolerance to these effects develops with repeated use. An abstinence syndrome generally occurs upon cessation of chronic administration similar to that observed with other opiates, but with slower onset, more prolonged course, and less severe symptoms.

LAAM exerts its clinical effects in the treatment of opiate abuse through two mechanisms. First, LAAM cross-substitutes for opiates of the morphine-type, suppressing symptoms of withdrawal in opiate-dependent individuals. Second, chronic oral administration of LAAM can produce sufficient tolerance to block the subjective „high“ of usual doses of parenterally administered opiates.

LAAM is metabolized by N-demethylation to nor-LAAM and dinor-LAAM, which are also opioid agonists. These metabolites are more potent than the parent drug. The opioid effect which occurs when LAAM is administered is slower in onset and longer in duration (72 hours) than that of methadone (24 hours). This extended duration of action allows three-times-weekly administration (see CLINICAL TRIALS ).


The duration of action of a single dose of LAAM is due to the sum of the opioid activity of the parent drug and its metabolites. A single dose of orally administered LAAM has an onset of opioid effects averaging 2 to 4 hours after ingestion and a duration of action of 48 to 72 hours (as measured by pupillary constriction and suppression of abstinence signs). LAAM cross-substitutes for opiates like morphine in opiate-dependent individuals, suppressing symptoms of withdrawal from these compounds. Single oral doses of 30 to 60 mg of LAAM eliminate signs of abstinence for 24 to 48 hours in individuals maintained on high doses of morphine who are abruptly withdrawn. At higher doses (80 mg and above), suppression of withdrawal can increase to 48 to 72 hours in most individuals.

Repeated oral administration of LAAM can produce sufficient tolerance to block the effects of parenterally administered opiates. Chronic oral administration of 70 to 100 mg of LAAM three times weekly produces tolerance which blocks the „high“ of a 25 mg dose of intravenously administered heroin for up to 72 hours; maintenance on lower doses (50 mg) of LAAM produces only partial blockage for the same period.



LAAM is rapidly absorbed from an oral solution. Plasma levels are detectable within 15 to 30 minutes after ingestion and reach their peak within 1.5 to 2 hours at steady-state. LAAM undergoes first-pass metabolism to its demethylated metabolite nor-LAAM, which is sequentially N-demethylated to dinor-LAAM. Both metabolites are active and contribute to the extent and duration of ORLAAM’s clinical activity (see PHARMACODYNAMICS ).

Pharmacokinetic Model

The steady-state pharmacokinetics of LAAM were modeled from a study in 25 healthy adult addicts using three-times-a-week dosing over a 15-day observation period. LAAM and its metabolites were found to follow a multi-compartment model with extensive tissue distribution (Vd ~ 20 L/kg). LAAM had a clearance of about 0.22 L/kg/hr, mostly by conversion to nor-LAAM. Kinetic studies of the pure metabolites in man have not yet provided accurate estimates of their clearance in the absence of the precursor, but the half-lives observed in this study were 2.6 days for LAAM, approximately 2 days for nor-LAAM, and approximately 4 days for dinor-LAAM.

The pharmacokinetic model used to estimate steady-state plasma levels for each subject in this study assumed a common 3 mg/kg/wk dosage regimen (0.94 mg/kg on Mon. and Wed., 1.125 mg/kg on Fri.). The estimates (which fit the observed data with a correlation of better than 0.95) revealed a large inter-patient variability. There was at least a 5-fold range in peak plasma concentrations for LAAM and its metabolites across the 25 subjects over the 72-hour interval from Friday to Monday on a 3-times-a-week dosage regimen. Table 1 contains these estimates of peak and trough plasma concentrations of LAAM, nor-LAAM, and dinor-LAAM.

View Enlarged Table

Table 1: Peak and Trough Estimated Steady-State Plasma Concentrations
During the 72 Hour Interval (Friday to Monday) for a 65-kg Patient
Given 3 mg/kg/Week on Mon./Wed./Fri.
Mean (CV)
Mean (CV)
Mean (CV)
Cmax(ng/mL) *
204 (34%) 173 (34%) 114 (28%)
Cmin(ng/mL) **
36 (62%) 85 (58%) 96 (34%)
*Following Friday Morning Dose
**Prior to Monday Morning Dose

Metabolism and Elimination

The cyctochrome P450 isoform, CYP3A4, plays a major role in the metabolism of LAAM. As noted above, the formation of nor-LAAM and dinor-LAAM is by sequential demethylation, such that dinor-LAAM is formed from nor-LAAM, not directly from LAAM. While N-demethylation is the primary route of metabolism, minor pathways of elimination include direct excretion and deacetylation to methadol, nor-methadol, and dinor-methadol.

Special Populations

Gender An analysis of the data from the above study showed some difference in the plasma clearance of LAAM in 8 females versus 17 males. Males showed a trend toward a slower conversion of LAAM to nor-LAAM, which may alter the plasma concentration profile of LAAM and its active opioid metabolites. Although this effect was much smaller than the observed inter-individual differences, physicians should be alert to a possible gender difference (see INDIVIDUALIZATION OF DOSAGE ).

Hepatic and Renal Disease At the present time no pharmacokinetics studies have been carried out in subjects with clinically significant hepatic insufficiency or serious renal impairment. Since both the pharmacokinetics and pharmacodynamics of opiate agonists may be altered in these subjects, and any additional risks of ORLAAM therapy are not well understood in such patients, physicians may choose to manage such patients with methadone due to its simpler metabolic profile.


ORLAAM has been studied in 2666 street addicts and 3319 methadone maintenance patients, including 5697 males and 288 females. During the course of 27 studies, 4610 patients received orally administered ORLAAM for up to three years in thrice-weekly doses ranging from 10 to 140 mg. Twenty-one studies provide the primary evidence upon which the dosing recommendations for ORLAAM are based.

The vast majority of patients who received ORLAAM were treated on a thrice-weekly basis, typically on Mondays, Wednesdays and Fridays (Mon./Wed./Fri.), although every-other-day dosing schedules were used in some settings. Most of the sites dosing patients with LAAM on a 3-times-a-week (Mon./Wed./Fri. or Tues./Thurs./Sat.) schedule increased the dose prior to the 72-hour inter-dose interval by 20 to 40% to obtain coverage for the full 72 hours.

In controlled clinical trials, treatment with ORLAAM was found to be comparable to treatment with methadone with respect to reduction in use of illicit opioids. ORLAAM doses in the range of 60 to 100 mg 3-times-a-week reduced the average frequency of urine samples positive for opiates to 15-20%, as did therapy with 50 to 100 mg a day of methadone. There was a trend for more patients to drop out of ORLAAM therapy than methadone therapy in the first 4 weeks of treatment (16% dropouts for ORLAAM v. 12% for methadone), but the dropout rates for both treatments rapidly declined and both were in the range of 1 to 2% per week for the remaining patients by the third month of the studies. Global ratings of patient acceptability and response to treatment were similar for both LAAM and methadone.

In the Phase III studies, ORLAAM tended to be more effective in patients perceived by staff to benefit from a reduced frequency of clinic visits and less effective in patients perceived as needing the added support of daily clinic visits.

Four independent studies were concerned with other research objectives, including induction regimens, methadone-to-ORLAAM (and ORLAAM-to-methadone) crossover ratios, and detoxification. This research involved 800 adults (including 11 females), approximately 440 of whom were methadone maintenance patients. The results of these studies, as well as the results of a nationwide Phase III usage study of 623 patients (including 204 females) in 25 representative clinics across the country, are reflected in the dosing recommendations.


ORLAAM is intended for use as part of a comprehensive treatment plan for narcotic dependence of the opioid type. Supplying narcotic drugs to narcotic addicts for the treatment of addiction without appropriate medical evaluation, treatment planning, and counseling has not been shown to be effective, and is a violation of the law except in special circumstances.

The therapeutic goal early in treatment with ORLAAM is to reduce illicit opioid use. The dose of ORLAAM should be chosen and adjusted as needed to provide a dose that is high enough to suppress drug withdrawal, illicit drug seeking and usage, and related high-risk behavior. If opioid side effects persist once illicit drug use is controlled, the dose of ORLAAM may require further adjustment later in treatment to minimize adverse effects.

Physicians should be alert to patient differences in levels of opioid tolerance and inter-patient variability in the absorption, distribution and metabolism of both ORLAAM and its metabolites. As with methadone, an important contribution to continued abuse of illicit drugs is an inadequate dose of the treatment medication.

Initial dosage adjustment with ORLAAM is complex due to its delayed onset of action. If the starting dose is too high or if the dose is escalated too rapidly for the patient’s level of tolerance, symptoms characteristic of excessive opioid effect may occur, i.e., poor concentration, sedation, and orthostatic hypotension. Patients should be watched for such symptoms, and the dose should be lowered if they appear. In rare instances, serious symptoms of narcotic overdosage may occur, leading to profound CNS and respiratory depression.

ORLAAM and its metabolites quickly accumulate to toxic levels if the doses intended for 3-times-a-week dosing are given too frequently. The recommended doses are intended for every-other-day or 3-times-a-week dosing and should not be given daily.

The recommended initial dose for patients with low or unknown tolerance to opioids is 20 to 40 mg three-times-a-week or every-other-day. Successive doses may be increased by 5 to 10 mg. At least two weeks are needed to achieve a clinical plateau after a dosage adjustment. Adjustment to a dosing schedule is dependent upon the rate at which an individual develops tolerance to the increasing level of ORLAAM (and its metabolites) as well as the time required for ORLAAM and its metabolites to accumulate to steady-state levels.

The goal of dosage titration is to suppress narcotic withdrawal while avoiding excessive opioid effects due to the build-up of long-acting metabolites. It may be safer to provide extra counseling and support rather than to attempt to completely suppress a patient’s withdrawal or narcotic hunger during the first week or two of therapy. On the other hand, there is the ever-present danger that patients who receive sub-therapeutic starting doses will supplement with street drugs, resulting in overdose. Patients should be strongly warned against this practice. Later in the titration process, dosage adjustments are better made on a weekly basis whenever possible.

For patients on methadone maintenance whose level of tolerance is known, the recommended initial dose of ORLAAM is 1.2 to 1.3 times the patient’s daily dose of methadone, not to exceed 120 mg. Care should be taken not to adjust the dose too frequently thereafter (usually 5 to 10 mg changes every second or third dose) since increasing the dose too rapidly may result in oversedation.

One major advantage of ORLAAM therapy is reduction in need for daily clinic visits and for take-home medication. In some patients, ORLAAM may not provide adequate suppression of withdrawal for a full 72 hours. For such individuals, several therapeutic options are available: (1) extra support and an explanation of reasons for the effect, (2) increasing the dose given prior to the 72-hour interval, (3) switching to an every-other-day dosing schedule, (4) dispensing a supplemental methadone dose.

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

Patients should receive extra support and counseling and be warned against supplementing with street drugs as they make the switch from methadone to ORLAAM. The variability in the clearance of LAAM, nor-LAAM, and dinor-LAAM and clinical experience suggest that there will be a small number of patients who require either lower or higher doses than those recommended.


There is no information from controlled clinical trials as to the appropriate duration of ORLAAM therapy. There are reports from investigators that some patients on ORLAAM may experience less variation in opioid effects and have less drug craving than with methadone, so ORLAAM should be considered for patients who need long-term maintenance during social and vocational rehabilitation.

When a patient has eliminated illicit drug use, achieved social and occupational stability, and made lifestyle changes to reduce the risk of relapse, consideration may be given to discontinuation of ORLAAM therapy. Such a decision should be carefully considered as part of an individualized treatment plan. Stable long-term ORLAAM therapy is preferable to repeated cycles of premature discontinuation of medication followed by relapse to uncontrolled addiction.

A patient is most likely to remain abstinent if discontinuation of medication is attempted after the achievement of behavioral objectives and is accompanied by appropriate non-pharmacological support. The rate of dose reduction should vary according to patient’s response. Discontinuation of ORLAAM therapy for administrative reasons or because of adverse reactions to the drug should be managed as described below under DOSAGE AND ADMINISTRATION .

Orlaam Medication Guide


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

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

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

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

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

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

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

A randomized, open-label trial comparing methadone and Levo-Alpha-Acetylmethadol (LAAM) in maintenance treatment of opioid addiction.

Wolstein J, Gastpar M, Finkbeiner T, Heinrich C, Heitkamp R, Poehlke T, Scherbaum N.

Department of Psychiatry and Psychotherapy, Rhine State Hospital, University of Duisburg-Essen, Essen, Germany.


INTRODUCTION: Levo-Alpha-Acetylmethadol (LAAM) is a synthetic opioid analgesic with mu-agonistic activity and a long duration of action. There are several, almost exclusively US American studies showing the efficacy of LAAM as a maintenance drug which has the advantage that it needs to be administered only three times a week. LAAM is currently not marketed in EU countries due to cardiac complications. We report on the first European multi-center, parallel group, flexible dose, open-label, randomized clinical trial comparing LAAM and methadone in patients with opioid dependence.

METHODS: Eighty-four opioid addicts in ongoing maintenance treatment with stable methadone doses were treated with methadone under study conditions for 5 weeks (run-in phase), then randomly assigned to a methadone (n=41) or a LAAM (n=43) group. Study duration was 24 weeks after randomization. Objective measures (drug urine screenings, retention rate), subjective measures (symptoms of withdrawal and craving, report of substance use), and safety data were collected weekly. The main outcome criterion was the number of opiate-free urine samples per number of weeks of study participation.

RESULTS: Non-inferiority was shown for LAAM compared to methadone. Both substances were well tolerated. There were no clinical cardiac complications in either group.

DISCUSSION: Our study confirmed the results of previous investigations with LAAM as being efficacious and well tolerated in opioid dependence. A discussion to reconsider the availability of LAAM is recommended.

and div. others!

Very interesting Study,

with a Spanish- English Translation

give it a read: drug-use-and-antiretroviral-adherence-in-EN

This paper is the twenty-ninth consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning thirty years of research. It summarizes papers published during 2006 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurological disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).

2. Endogenous Opioids and Receptors

2a. Molecular-biochemical effects
This sub-section will review current developments in the molecular and biochemical characteristics of opioid peptides and receptors by subtypes: mu agonists and receptors (2a-i), delta agonists and receptors (2a-ii), kappa agonists and receptors (2a-iii), and OFQ/N and the ORL-1 receptor (2a-iv).
2a-i. Mu agonists and receptors 

Endocytosis of the MOR-1D splice variant as well as DOR and the CB1 receptor is mediated by an agonist-independent and constitutive PLD2 activation (604). Separation of MOR desensitization and internalization effects was demonstrated with endogenous receptors in primary neuronal LC cultures (40). Exons 11 and 1 promoters of the MOR gene were characterized in transgenic mice (1249). The splice variants of MOR, SV1 and SV2 do not exhibit binding to [3H] diprenorphine (212). Five single nucleotide polymorphisms were identified for the MOR promoter, and no differences in construct activity were found in control and morphine-treated animals (297). MOR-effector coupling and trafficking occurred in DRG neurons with DAMGO producing greater internalization in MOR/partial differential opioid receptors (1180). MOR-DOR functional interactions occur through receptor-G (i1) alpha fusion (1051). The poly C binding protein 1 is a regulator of the proximal promoter of the mouse MOR gene (716). There is interplay between Sps and poly C binding protein 1 on MOR gene expression (960). The neuron-restrictive silencer factor interacts with Sp3 to synergistically repress the MOR gene (577). Mitochondrial damage decreases MOR, but not DOR function in neuronal SK-N-SH cells (941). Diffusion of MOR at the surface of human neuroblastoma SH-SY5Y cells is restricted to permeable domains (990). Differences in the intracisternal A-particle element in the 3′ noncoding region of the MOR gene in CXBK mice appear to cause this relatively insensitive phenotype (446). Although 14-methoxymetopon displayed similar binding affinities for multiple splice variants of the MOR gene, its potency varied widely for the same splice variants (713). MOR activation of ERK ½ is GRK3 and arrestin dependent in striatal neurons (712). Introduction of a hydroxyl group in position 2 of the cyclohexyl residue of spiropiperidine decreased the binding affinity of mu receptors and OFQ/N (177). Morphine displays PKC-dependent and DAMGO displays GRK2-dependent mechanisms of MOR desensitization in human embryonic kidney 293 cells (529). Null and operational models of mu opioid binding in the mouse vase deferens revealed that DAMGO and DALDA were full agonists while morphine and endomorphin derivatives acted as partial agonists (967). There is direct nose-to-brain transfer of morphine after nasal administration to rats (1216). Transport is not rate-limiting in morphine glucuronidation in the single-pass perfused liver preparation (291). Greater in vitro inhibition of M6G relative to M3G formation from morphine occurred following treatment with (R)- and (S)-methadone and structurally related opioids (804). M6G was identified in chromaffin cell secretory granules (411). Mu opioid receptors are activated by Vitex agnus-castus methanol extracts (1204). Binding of [(35) S] GTPgammaS is stimulated by endomorphin-2 and morphiceptin analogs (343). An aequorin luminescence-based calcium assay gives pharmacologically-relevant data for mu and delta opioid agonists without involving radioactivity or animal tissues (344). The latter assay also indicated that D-1-Nal or D-2-Nal substitutions in position 4 of endomorphin-2 produced mu receptor antagonists, whereas substitution in position 3 produced partial agonists (346). The tripeptides, Tyr-Pro-Ala-NH2 and Tyr-Pro-Ala-OH, which do not bind to mu receptors, are potent inhibitors of endomorphin degrading enzymes in the brain (345). A partial agonistic effect of 9-hydroxycorynatheidine was observed on MOR in the guinea pig ileum (747). Synthesis, radio labeling and receptor binding was accomplished for [3H] [(1S, 2R) ACPC2] endomorphin-2 (569).
MOR, DOR and KOR binding properties were observed for 8-[N-(4′-phenyl)-phenethyl) carboxyamido] analogues of cyclazocine and ethylketocyclazocine (1214). Pharmacokinetics of morphine was slower in flounder than in trout (837). A direct and sensitive analysis of morphine, codeine and other bioactive drugs in human urine was performed by cation-selective exhaustive injection and sweeping micellar electrokinetic chromatography (671). Alkyl chain length altered mu opioid activity of 3, 6-bis {H-Tyr/H-Dmt-NH (CH2) m, n]-2(1H) pyrazinone derivatives (1031). Determination of human urinary opiates occurred with application of poly (methacrylic acid-ethylene gycol dimethacrylate) monolith micro extraction coupled with capillary zone electrophoresis (1207). Urinary excretion of morphine and codeine occurred following the administration of single and multiple doses of opium preparations prescribed in Taiwan as “brown mixture” (680). There are natural heroin impurities derived from tetrahydrobenzylisoquinoline alkaloids (1128). [Sar2] endomorphin-2 was almost equipotent to the parent peptide in mu opioid receptor binding, and was highly resistant to enzymatic degradation (512). Morphine-3-O-propionyl-6-O-sulfate had four times greater affinity than morphine at the MOR (248). Mu opioid binding can be detected in a competitive displacement assay using a beta-imager (916). Identification of potent phenyl imidazoles such as 4-aminocarbonyl-2, 6-dimethyl-Phe as opioid receptor agonists was completed (133). A class of 4-substituted-8-(2-phenyl-cyclohexyl)-2-8-diaza-spiro[4,5]decan-1-one inhibitors was designed achieving antagonist selectivity against the mu opioid and ORL1 receptors (15) that show improved metabolic stability (16) and superior pharmacological and pharmacokinetic properties (17). Chimeric peptides containing a mu opioid receptor ligand and an ORL-1 receptor ligand, Ac-RYYRIK-amide were synthesized (560). Derivatives of 14-aminomorphinones with substitution in the aromatic ring of cinnamoylaminomorphinones and codeinones produced potent mu agonists (844).
A novel mu opioid antagonist was created by replacement of the N-terminal tyrosine residue in opioid peptides containing 3-(2, 6-dimethyl-4-carbamoylphenyl) propanoic acid (Dcp) results in a novel mu opioid antagonist (701). Lysine at the C-terminus of the Dmt-Tic opioid pharmacophore produced new lead compounds in the formation of opioid peptidomimetics (57). Multiple ligands from Dmt-Tic and morphinan pharmacophores produced agonists with MOR, KOR and DOR properties (836). Whereas maximal stimulation of [35S]GTPgammaS binding decreased in canine thalamic and spinal cord homogenates for mu > ORL1 > kappa > delta opioid compounds, cortical homogenates showed an affinity order of kappa > ORL1 > delta > mu (650). Morphine increased 5HT, Na (+), K (+)-ATPase activity differentially as a function of adulthood and adolescence (432), and reduced human 5-HT3A receptors in an ondansetron assay (1225). Bivalent ligands containing homo- and heterodimeric pharmacophores at mu, delta and kappa opioid receptors were developed and synthesized in an in vitro assay (895). Potent and highly selective chiral tri-amine and tetra-amine MOR ligands were identified by lead optimization using mixture-based libraries (831). Opioid and CCK receptors also have overlapping pharmacophores required for binding affinity and biological activity (8). QSAR studies were performed upon 4-phenylpiperidine derivatives as mu opioid agonists by a neural network method (1194). A HPLC assay for morphine was developed in small plasma samples (293). Morphine concentrations in bone marrow paralleled plasma morphine concentration for up to 14 days after death in rabbits (178). Unbound concentrations of oxycodone were three times higher in brain than in blood, indicating active influx at the blood-brain barrier (118). An implantable buprenorphine delivery system was characterized using in vitro and in vivo techniques (594). Capillary electrophoresis contributed to the identification of HMOR-3O-glucide and N-oxides in hydromorphone metabolism in humans (58). STW 5 (Iberoglast) binds to intestinal 5-HT, muscarinic M3 and opioid receptors (1038). A member of the heat shock protein 40 family, hlj1, binds to the carboxyl tail of the human MOR (31).
Pre-POMC cDNA from the ostrich pituitary gland was sequenced revealing the positions for gamma-MSH, ACTH, AMSH, gamma-LPH, beta-MSH and BEND (824). PC1/3 and PC/2 gene expression and post-translational endoproteolytic POMC processing is regulated by photoperiod in the seasonal Siberian hamster (465). BEND analysis in the hypothalamus or PAG is not affected by diurnal variation (348). BEND is present in the stallion testis, but appears to be derived from POMC gene expression in the pituitary (1057). Three POMC subtype genes and subsequent peptides were identified in the pars distalis and intermedia of the barfin flounder pituitary (1101). TAN-821 and TAN-1014 have been developed respectively as agonists and antagonists of the putative epsilon receptor (368).
Histamine was released during constant rate infusion of morphine in dogs (423). Cholinergic nicotinic stimulation of endogenous morphine release occurs from lobster nerve cord (1327). Dextrorotatory morphinans inhibited alpha3beta4 nicotinic Ach receptor subunit cRNAs-induced inward currents in the presence of Ach in Xenopus oocytes (639). Myristoylated G proteins (Galphai1 and GalphaoA) were maximally activated by DAMGO, Menk and Lenk, whereas endomorphin-1 and –2 as well as BEND produced strong, but not maximal responses. Morphine, methadone, fentanyl and buprenorphine produced statistically significant activation (983). 3-aminopropionyl substituted fentanyl analogs were synthesized and displayed opioid activity (906). New hybrid derivatives of fentanyl were found to be active at the MOR and I2-imidazoline binding sites (261). Buprenorphine and norbuprenorphine display in vivo glucuronidation as determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (488). An immunalysis microplate ELISA was validated for the detection of buprenorphine and its metabolite norbuprenorphine in urine (778). Opioid disposition occurs in human sweat after controlled oral codeine administration (1003). CYP2D6-dependent formation of morphine does not exclusively explain the central effects of codeine; codeine-6-glucuronide is an additional active moiety (696). Pharmacokinetic modeling of oxycodone in sheep displayed delayed equilibration between brain and blood levels that would be affected by changes in both cerebral blood flow and blood brain barrier permeability (1164). The principal metabolic pathway of oxycodone in humans is CYP3A-mediated N-demethylation, but circulating oxidative and reductive metabolites provide a negligible contribution to central opioid effects (627). The use of PTX-insensitive Galpha mutants revealed that the potency for mu agonists was highest for cells expressing Galpha (i3) and Galpha (o) and lowest with Galpha (i1) and Galpha (i2) (228). NalBzOH displays agonist activity at MOR, DOR and KOR, but not ORL-1 receptors expressed either in a heterologous cell system or in a native environment (862). FK33–824, a mu opioid agonist decreases enzymatic activity of PKC, adenylate cyclase and PKA in porcine granulosa cells (546). The anti-opioid actions of NPVF, a NPFF agonist was observed in a decrease to opioids to voltage-gated (N-type Ca2+ currents and enhancement of muscarinic-induced intracellular Ca2+ release in SH-SY5Y cells as they do in neurons (570).
Naltrexone increased PKCepsilon, ERK and integrin alpha 7 in SH-SY5Y neuroblastoma cells (857). Long-acting naltrexone had a 1-month pharmacokinetic activity in plasma that was proportional to dose and number of treatments (302). The dissociation of [3H] naloxone was four times faster under displacement than under infinite dilution conditions, demonstrating the retention effect of receptors confined in space (1061). Naltrexone release from biodegradable microspheres produced constant rates of release culminating in 80% over 2 months (691). Two novel tripartite codrugs of naltrexone and 6beta-naltrexol with hydroxybupropion were synthesized as potential alcohol abuse and smoking cessation agents (440). Transdermal delivery of 6-beta-naltrexol was enhanced by a codrug linked to hydroxybupropion (588). MOR antagonists were synthesized and evaluated from novel octahydro-1H-pyrido [1, 2-a] pyrazine (633) and from N-substituted trans-3, 4-dimethyl-4-(3-hydroxyphenyl) piperadine (634). The permeation of nalmefene hydrochloride was better across the middle turbinate, posterior septum and superior turbinate mucosa (301).
2a-ii. Delta agonists and receptors 

Knock-in mice expressing fluorescent DOR uncovered G protein-coupled receptor dynamics in vivo (996). Simultaneous activation of DOR and the sensory neuron-specific receptor-4 hetero-oligomer by the mixed bivalent agonist BAM-22 activates the latter, but inhibits the former (132). Morphine and pain-related stimuli enhance cell surface availability of somatic DOR in rat dorsal root ganglia (393). Delta and mu opioid receptors were cloned, heterologously expressed and pharmacologically characterized from the brain of a urodele amphibian, the rough-skinned newt, Taricha granulosa (127). Adenosine A1 and A2 receptor agonists increase c-fos in striatal GABAergic Enk, but not GABAergic DYN striatal neurons as well as increasing striatal PreEnk (553). The enrichment by 18-fold with FACS robustly increased beta-arrestin-1-GFP expression associated with strong human DOR desensitization (10). A new duplicate DOR in zebra fish was characterized (911). Enk and SP are found in reduced concentrations in primary culture striatal neurons relative to adult preparations (330). The mGluRI antagonists, LY367385 and MPEP reduce NMDA-induced expression of the Pro-Enk gene in neocortex, yet enhance AMPA-induced expression of the neocortical Pro-Enk gene (674). Pro-enk was identified in the hypothalamus and striatum using a method allowing selective isolation of neuropeptides of murine brains lacking carboxypeptidase E (268). ProEnk A 119–159 is a stable ProEnk A precursor fragment identified in human circulation (323). Only the C-terminus glucose conjugate of Lenk showed transport by glucose transporters and hPepT1 (1237). Whereas only a few samples of adherent human fetal chromaffin cells expressed Menk early in vitro, almost all of the neurosphere-like colonies appearing later expressed Menk (1321). Human Menk binds to anionic phosphatidylserine in high preference to zwitterionic phosphatidylchlorine in large unilamellar vesicles (586). Lenk binds in a turn confirmation to DOR, but it is not a (14) beta-turn (108). Nasal administration of Lenk is facilitated by a thiolated polycarbophil that slows Lenk degradation (82), and reversible lipidization is preferable for the oral delivery of Lenk (1185). 6-N, N-dimethylamino-2, 3-napthalimide was identified as a new environment-sensitive probe in delta- and mu-selective opioid peptides (1149). The novel, orally active, DOR agonist, RWJ-394674 is biotransformed to the potent MOR agonist RWJ-413216 (229). Highly potent and selective phenylmorphan-based inverse agonists of the DOR were developed (1117). AUF-1 is expressed in the developing brain, binds to AT-rich double-stranded DNA, and regulates Enk gene expression (287). Design and synthesis were completed of novel hydrazide-linked bifunctional peptides as delta/mu opioid receptor agonists and CCK1/CCK2 receptor antagonists (641). Three types of latex nanoparticles carrying NTI derivatives were identified as possessing high DOR affinity (453). A new method using HPLC with electrochemical detection was developed allowing for the simultaneous measurement of Menk, Lenk, endomorphin-1 and endomorphin-2 (677).
Selective alkylation of delta-2 opioid receptors occurred following NAC 5′Nti-isothiocyanate in the NAC and ventral caudate; beta-chlornaltrexamine was nonselective for MOR and DOR in the same site (734). Distinct subcellular localization for constitutive and agonist-modulated palmitoylation of the human DOR was described (900). Pertussis-toxin abolished DPDPE-induced inhibition of forskolin-stimulated intracellular cAMP production that was rescued by Galpha (i2), but not Galpha (i3) or Galpha (o) mutants; the former, but not latter mutants co-precipitated with DOR. Long-term DPDPE treatment allowed pertussis toxin-induced elimination of naloxone-induced superactivation of adenylyl cyclase activity, an effect again rescued by Galpha (i2) mutants (1311). DPDPE, acting through Gi-coupled DOR receptors mediate phosphorylation of CPI-17 and MLC20 through preferential activation of the PI3K/ILK pathway (486). Down-regulation of the glutamate transporter EAAC1 occurred following expression and activation of the DOR and its agonist, DPDPE (1240). Genetically-engineered human mesenchymal stem cells produce Menk at augmented higher levels in vitro (1078). Lenk caused membrane currents across lipid membranes through adsorption, transportation and desorption, effects confirmed using fluorescence spectrometry and confocal laser scanning microscopy (687). DADL induces a reversible hibernation-like state in HeLa cells (1152). DADL molecules enter the cytoplasm and nucleus of LNCap cells that are devoid of opioid receptors, and binds to perichromatin fibrils where transcription and early splicing of pre-mRNAs and pre-rMRNAs occur, thereby resulting in decreased transcription and proliferation without apoptosis (59). AVP enhances PAG synthesis and secretion of Enk and BEND, but not DYN (1263).
2a-iii. Kappa agonists and receptors 

KOR activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes (141). Netrin-1 signaling regulates de novo protein synthesis of KOR by facilitating polysomal partition of its mRNA (1133). Naloxone and NBNI, but not selective mu or delta antagonists increased, whereas DYN decreased the cell surface level of the human KOR by activation-induced down-regulation and pharmacological chaperone-mediated enhancement (200). KOR affinity in a human embryonic kidney cell system indicated a rank order of cyclazocine, naltrexone, SKF10047, xorphanol, WIN44441, nalorphine, butorphanol, nalbuphine, lofentanil, dezocine, metazocine, morphine, hydromorphone and fentanyl (399). A cDNA encoding KOR in zebra fish has been cloned and characterized (27). GEC1 interacts with the kappa opioid receptor and enhances its expression (188). Big DYN, a 32-amino acid Pro-DYN peptide consisting of DYN A and DYN B showed similar selectivity for human KOR as DYN A, was less selective than DYN A for human MOR, DOR and ORL1, but activated G proteins more potently than DYN A; DYN B was less potent and selective (771). Big DYN and DYN A, but not DYN B causes leakage effects in large unilamellar phospholipid vesicles thereby causing perturbations in the lipid bilayer (490). DYN A inserts its N-terminus into the bilayer of the bicelle, whereas DYN B resides on the surface of the bilayer (673). Bikunin was identified as an endogenous inhibitor of DYN convertase in human cerebrospinal fluid (1077). Although selective opioid agonists developed for mammalian opioid receptors did not fully recognize opioid binding sites in zebra fish brain, DYN A showed good affinities in the nanomolar range (409). Pro-DYN cDNA’s were cloned in eels and tilapia (24).
NalBzOH binding is abolished in triple MOR/KOR/DOR mice, and in vivo changes reflect that of a nonselective opiate drug (235). N-substituted 4beta-methyl-5-(3-hydroxyphenyl)-7alpha-amidomorphans are potent, selective kappa opioid receptor antagonists (171). New C (4)-modified salvinorin A analogues were synthesized as KOR agonists (636). Salvinorin A analogues were also synthesized following effects of configuration at C (2) and substitution at C (18) (73) along with those isolated from Salvia divinorum (1120). Salvinorin A, a selective KOR agonist was used in a combined ligand-based and target-based drug design approach for G-protein coupled receptors (1041). A unique binding epitope was found for salvinorin A, a non-nitrogenous KOR agonist (548). Bioisosteric modification of the C-2 thioacetate isoester of salvinorin A produced a potent and selective KOR agonist (1070). The substitution of a tert-butyl with a cyclobutyl moiety in buprenorphine created a highly selective KOR agonist with low addictive potential and dependence liability (877). 3D-QSAR studies were performed upon orvinol analogs as kappa-opioid agonists (656). The extraction fraction for NAC DA in the mouse is increased following NBNI treatment (186). The application of Schild-analysis to the antagonism of U50488H by NBNI provides pharmacological evidence for KOR in Planaria (934).
2a-iv. OFQ/N and ORL-1 receptor 

OFQ/N binding to ORL-1 receptors triggers internalization of these components into vesicular compartments that is dependent on PKC and occurs selectively for N-type calcium channels (25). OFQ/N, but not partial agonists induce concentration-dependent endocytosis and recycling of the human ORL1 receptor, enhancing up regulation of adenylyl cyclase activity (1059). OFQ/N differentially activates ERK, p38 and JNK MAPK to contribute to potentiations of prostaglandin vasoconstriction after fluid percussion brain injury (38). The induction of Pro-OFQ/N mRNA by cAMP appears to be mediated by a cAMP-response element, histone acetylation and through CREB (1301). The ORL-1 receptor utilizes both G (oA) and G (oB) for signal transduction (1136). OFQ/N and its agonist, Ro64-6198 display great regional similarities in binding assays using [(35) S]-GTPgammaS binding (390). OFQ/N and DYN A analogues with Dmp substituted for N-terminal aromatic residues show ORL-1 and opioid receptor preferences (989). A novel D-proline amide class of spiropiperidines was developed as an effective ORL-1 antagonist (410). OFQ/N (113) NH2 analogues modified in the 9 and/or 13 positions were synthesized and showed biological activity (828). An enzymatically-resistant OFQ/N peptide containing a carbamic acid residue was synthesized (665). Indole derivatives were designed, synthesized and biologically evaluated as novel OFQ/N receptor antagonists (1079). Potential ORL-1 ligands were synthesized from spiro-[piperidine-4,2′(1′H)-quinazolin]-4′ (3′H)-ones and spiro-[piperidine-4,5′ (6′H)-[1,2,4]triazolo[1,5-c]quinazolines] (809). Trap-101, an achiral analogue of J-113397 was identified as a potent ORL-1 antagonist (1132). Both 3-(4-Piperidinyl) indoles and 3-(4-piperidinyl) pyrrolo-[2, 3-b] pyridines are ligands for the ORL-1 receptor (96). A series of hexapeptides with a general formula of Ac-RYY-R/K-W/I-R/K-NH (2) were identified as novel partial agonists for the ORL-1 receptor (428).
BDNF induced expression of Pro-OFQ/N mRNA’s that in turn induced expression of immediate early genes in hippocampal cultures. OFQ/N, but not nocistatin increased both neurite length and number in hippocampal cultures (954). Mature OFQ/N and nocistatin were identified in human brain and CSF (534).
2b. Neuroanatomical localization
This sub-section will review current neuroanatomical studies indicating localization of opioid peptides and receptors by subtypes: mu agonists and receptors (2b-i), delta agonists and receptors (2b-ii), kappa agonists and receptors (2b-iii), OFQ/N and ORL-1 receptor (2b-iv), and opioid-related neuroanatomy (2b-v).
2b-i. Mu agonists and receptors 

Immunohistochemical labeling of the MOR carboxy terminal splice variant mMOR-1B4 was observed in the olfactory bulb, cerebral cortex, BNST, hippocampus, habenula, amygdala, thalamus, hypothalamus, median eminence, SN, VTA, oculomotor nucleus, red nucleus raphe nuclei, PAG, LC, trigeminal nucleus reticular formation, area postrema and Purkinje and deep cerebellar nuclei (1314). Whereas acute morphine decreased MOR gene expression in the PAG, chronic morphine decreased PAG and striatal MOR and KOR gene expression in female rats (1113). MOR, KOR and DOR receptors were found in disc-shaped and stellate cells of the inferior colliculus with MOR and GABA receptors co-localized in the central nucleus, dorsal cortex and external cortex of the inferior colliculus. BEND and GABA neurons were in close proximity to each other (1126). MOR is extensively co-localized with parvalbumin, but not somatostatin, in the hippocampal dentate gyrus (299). There is a distinct distribution of DA D1 receptor and MOR-1 receptor immunoreactivities in the amygdala and interstitial nucleus of the posterior limb of the anterior commissure (508). Reciprocal connections of endomorphin-1- and endomorphin-2-containing neurons were observed between the tubural and lateral hypothalamus on the one hand, and the medial, commissural, lateral and gelatinous parts of the NTS on the other (492). Mu opioid receptors were found in nerve fibers within the bovine pineal gland, whereas delta opioid receptors were observed on nerve fibers in the pineal perivascular space and intraparenchema. DOR, MOR and Lenk were co localized in some nerve fibers (908). Whereas BEND and TH immunoreactive axon terminals of MPOA cells that project to the SFO were predominantly axo-somatic, NPY terminals were more axo-dendritic (559). POMC co-localizes with CRF in axon terminals of the noradrenergic LC (948). Fluoxetine increased mu opioid receptor expression in obese Zucker rat C/P, dentate gyrus, lateral septum, amygdala, and frontal, parietal and piriform cortices (222).
MOR possessed little overlap with preprotachykinin B in the dorsal horn of the spinal cord (917). The seizure-resistant rodents, Proechimys guyannesis, display high DAMGO binding in the medial amygdala, dorsal dentate gyrus and PAG, and decreased DAMGO binding in the anterior olfactory tubercule, cingulate cortex, thalamus, basolateral amygdala, SN and dorsal hippocampus (963). Whereas lower medial septal, but not MPOA MOR densities were lower in older reproductively senescent male Japanese quail than females or young males, DOR densities in both the medial septum and MPOA were lower in this group (871).
Heroin decreased NPFF-immunoreactivity in the NTS and reduced NPFF fibers in the median eminence, pituitary stalk and neurohypophysis, but increased NPY neurons and fibers in the thalamic PVN and BNST (279). Both morphine and methadone increased c-Fos expression in the striatum and NAC (1111). Morphine produced up-regulation of the functional expression of neurokinin-1 receptors in cortical neurons (1181). Morphine respectively reduced and increased ascorbic acid release in the striatum and NAC of rats (421). Morphine increased fMRI signals in the NAC, extended amygdala, orbitofrontal cortex, hippocampus, PAG and hypothalamus and decreased fMRI signals in the anterior cingulated gyrus in the brains of healthy volunteers (70).
2b-ii. Delta agonists and receptors 

Enk afferents from the posterior BNST and the basomedial and cortical amygdaloid nuclei innervate the medial amygdaloid nuclei whereas Enk afferents from the anterolateral BNST as well as the cortical, medial and basomedial amygdaloid nuclei innervate the central amygdaloid nucleus (920). Striatal dendrites display co-localization of DOR and dopamine D1 receptor immunoreactivity (29). Striatal projection neurons to the SN mostly possess Enk-only and SP-only cells; Enk/SP co localized neurons primarily projecting to the SN do not appear confined to striosomes (1183). Enk is found in overlapping distributions with VP, VIP, CRF, gastrin releasing peptide, calbindin and calcretin in both mouse and rat (801). SP was more robust than Enk in their broad distribution in song control nuclei of 11 different oscine species (653). Four different Enks, but not DYN is found in synovium, bone marrow, periosteum and juxta-articular bone in rat joints (79). DOR immunoreactivity was evenly distributed throughout the neuropil of the feline reticular formation, and was very dense in the ventral and central areas of cytoplasm and medium to large dendrites of the parabrachial nuclei and LC (28). L-enk and the DOR were found most predominantly in the inner spiral bundle of the guinea pig cochlea, whereas DYN and KOR were found in both the inner and outer spiral bundles (533). Menk is found in small diameter and diffusely localized neurons throughout the superficial grey and stratum opticum of the superior colliculus of the camel (767). Enk is localized in the dorsolateral septal nucleus of the fire-bellied toad, Bombina orientalis (318).
2b-iii. Kappa agonists and receptors 

Although KOR was often co-localized with MOR, small ovoid KOR-containing cells were observed in close apposition with larger MOR-containing cells in medial thalamus, PAG and brainstem (415). KOR and GAD67 immunoreactivity have been found in OFF and NEUTRAL cells in the RVM (1222). Axonal mRNA transport and localized translational regulation of KOR occur in primary neurons of the DRG (90). KORS have been localized in the lipid rafts which are micro domains of plasma membranes rich in cholesterol and sphingolipids (1250). Unprocessed DYN was much greater than co-existent DYN peptides in the axon terminals of Pro-DYN neurons projecting to the CA3 region of the hippocampus and in the striatal projections to the VTA (1253). DYN and neurokinin B are co expressed in hypothalamic arcuate neurons extending to the ME and periventricular zone with these fibers projecting to the PVN, anterior hypothalamus, MPOA, median preoptic nucleus, anteroventral periventricular nucleus and BNST (152). DYN and neurokinin B immunoreactivity are co localized in the arcuate nucleus and median eminence of the sheep (352). Dopamine D1 receptors have subcellular distributions that are conducive to interactions with Pro-DYN in the NAC shell (449). Moreover, CART is co localized with pro-DYN and DA D1 receptors in the NAC (489). Pro-DYN mRNA labeling is in the mouse olfactory tubercule, lateral septum, C/P, central amygdala, PVN, SON, LHA, VMH, lateral reticular nucleus and NTS; it is also co-localized with NPY mRNA in the arcuate nucleus (669). Long-day exposure produces greater DYN A1–17 expression in the hypothalamo-pituitary axis, ependymal cells, subcomissural organ and lateral and third brain ventricle choroid plexus in the Siberian hamster than short-day exposure (776).
2b-iv. OFQ/N and the ORL-1 receptor 

OFQ/N was immunolocalized in the rat cochlea in tunnel fibers as well as inner and outer hair cells (571). The slow rate of divergence in the amino acid of OFQ/N precursor sequences in lungfish was analyzed (638).
2b-v. Opioid-related neuroanatomy
3. Pain and Analgesia
This section has four major parts examining recent advances in: a) pain responses especially as they may relate to opioid function, b) opioid analgesia organized as a function of receptor subtypes, c) sex, age and genetic differences in opioid analgesic responses, and d) opioid mediation of other analgesic responses. 

3a. Pain responses
The following sub-sections examine work done on spinal (3a-i) and supraspinal (3a-ii) circuits respectively.
3a-i. Spinal circuits 

Nociceptive behaviors (8–24 h) outlasted spinal c-Fos increases (2 h) following skin-muscle incisions, and after 24 h, surgically-treated animals were no different from controls in c-Fos-induced increases induced by thermal stimulation. Morphine was more effective in blocking nociceptive behaviors relative to c-Fos-induced increases (1325). Hindlimb and abdominal stretches occurred during labor, and were increased by systemic oxytocin. Morphine decreased oxytocin-induced stretching responses without altering labor duration, and decreased labor-induced c-Fos elevations in lumbosacral spinal segments (175). Although MOR mechanisms are not essential in the processing of acute noxious mechanical and electrical stimuli by WDR neurons, they may play an important role in endogenous inhibitory mechanisms that regulate the development of spinal neuronal sensitization during windup (422). Absence of Reelin results in significant reductions in mechanical sensitivity and a pronounced thermal hyperalgesia and aberrant neuronal positioning of Dab-1 immunoreactivity in the dorsal spinal cord (1163). Chronic constriction injury of the saphenous nerve in rats produce significant allodynia and hyperalgesia that is sensitive to morphine gabapentin, amitryptaline and WIN55212-2 administration, that increases c-Fos as well as MOR and CB-1 receptor expression in the spinal cord, and that leads to decreased functional receptive fields downstream to the injury accompanied by A-fiber ectopic discharges (1174). Spinalized rats laminectomized in the lumbo-sacral region displayed increased multi-unit efferent discharges from the ventral root following mechanical von Frey hair mechanical stimulation of the hindpaw. During discharges and after discharges were reduced by resiniferatoxin, a potent capsaicin analogue, whereas only after-discharges were reduced by morphine, ketamine and ezlopitant (1255). Partial injury of tail-innervating nerves creates both mechanical allodynia and non-allodynia in different subgroups of rats; the former group shows greater losses of spinal MOR, whereas the latter group displays more augmented mechanical allodynia following peripheral naloxone and spinal CTOP (49).
3a-ii. Supraspinal circuits 

A rodent pain model of gynecologic surgery involving laparotomy with tonic distension of the cervix and lower uterine segment was shown to be sensitive to systemic and intrathecal morphine (1125). There are strong pharmacological correlation between the formalin test and the neuropathic pain behavior in different species with chronic constriction injury (1166). An animal model of chronic inflammatory pain using large volumes of adjuvant to the intra-articular space of the rat knee showed sensitivity to morphine, dexamethasone and ibuprofen, but different temporal sensitivity from acute models (1221). Experimental pancreatitis produced visceral pain and increased thoracic DYN content with lidocaine injections into the RVM or nucleus gracilis or spinal DYN antisera reversing its effects (1154). Transgenic mice with early-stage pancreatic cancer displayed visceral pain that was enhanced by centrally-acting, but not peripherally-acting opioid antagonists (1008). An abdominal withdrawal reflex model of visceral pain due to colorectal distension was established in a behavioral assessment in rats (1264). NRM on cells excited by colorectal distension facilitate responses to colorectal distension itself, which in turn augments excitation of NRM off cells that then act to suppress cutaneous nociception (134). Anterior cruciate ligament transaction produced experimental osteoarthritis and joint pain accompanied by increased nitrite and inducible NO synthase, effects reduced by morphine, L-NAME, indomethacin and meloxicam (174). One can differentiate between capsaicin-induced allodynia and hyperalgesia using a thermal operant assay; both effects were blocked by morphine (835). The orofacial formalin test in the mouse appears to be a strong behavioral model for studying physiology and modulation of trigeminal nociception; morphine inhibits formalin responses in both phases (702). Formalin injection directly into the knee joints of rats produced the characteristic two phases of nociception; morphine blocked both phases in a naloxone-reversible manner, whereas diclofenac and midazolam reduced only the second phase, whereas meclizine and loratadine increased the second phase (735). Experimental pain-related responses are induced by a scorpion Buthus martensi Karsch sting (52). Zymosan applied to the tibial-tarsal joint produces hypernociception elicited by articular dorsal flexion movement, an effect blocked by morphine and indomethacin (430). Animals with chronic constriction injury had free access to a light: dark chamber, and chose the less-preferred light part of the chamber following stimulation of the injured paw in the more-preferred dark chamber. Whereas morphine, gabapentin, duloxetine and 8-OH-DPAT reinstated preferences for the dark side of the chamber, gaboxadol and WIN55,212–2 did not (890). The use of calibrated forceps are a reliable tool for pain, morphine analgesia and morphine tolerance (706). Ultrasonic vocalizations occur primarily during the interphase of the formalin test, and are suppressed by morphine in a naloxone-reversible manner (863). Hairless mice fed a special diet develop atoplic-like dry skin inducing prolonged scratching that is dose-dependently blocked by naloxone, but not H1 or 5HT(1/2) antagonists (369). Administration of 2,4,6-Trinitrochlorobenzene to hairless mice produced a naltrexone- and L-NAME-reversible itch response (1138).
3b. Opioid analgesia
The following sub-sections examine advances in our understanding of opioid-mediated analgesia in the past year especially as they pertain to the opioid receptor subtypes and their genes: i) mu agonists and receptors, ii) delta agonists and receptors, iii) kappa agonists and receptors, and iv) OFQ/N and the ORL-1 receptor. A large number of studies examine either knockout or knockdown techniques to indicate roles of the receptors, and potential splice variants in opioid analgesic function. Separate paragraphs are devoted to studies in which other transmitter and peptide systems affect opioid analgesia; the effects of opioid manipulations upon analgesia induced by other peptides and transmitters are covered in Section 3d. Finally, human studies related to opioid and particularly mu receptor-mediated analgesia is covered at the end of Section 3b-v.
3b-i. Mu agonists and receptors 

MorphineA rank-order analgesic potency of morphine was observed on the paw pressure, hot-plate and tail-withdrawal tests with the lowest on the formalin test, effects independent of stimulus intensity on all tests. A within-subject cumulative dosing procedure resulted in lower ED50 values than a between-subject procedure, and the ED50 of morphine progressively increased when the cut-off value was adjusted from 4 to 5, 6, 7 and 8 standard deviations above the mean (796). Nociceptive stimulus modality-related differences occurred in pharmacokinetic-pharmacodynamic modeling of morphine in the rat such that drug effects were more effective for mechanical relative to thermal stimuli (1015). Sub-analgesic doses of DAMGO or fentanyl enhanced morphine analgesia through induction of MOR endocytosis (454). Opiate receptor-dependent analgesia is associated with several compounds bound to Gbetagamma subunits (110). The analgesic, tolerant, dependent, rewarding and sensitizing effects of morphine, but not kappa agonists were lost in mice lacking adenylyl cyclase type 5 that is highly enriched in striatum (582). Mice lacking phospholipase Cbeta1 displayed hypersensitivity to pain and reduced morphine analgesia and tolerance formation (685).

Morphine administered systemically or directly into the ACC produced a naloxone-sensitive reduction in pain affect, as demonstrated by decreased aversiveness of noxious cutaneous stimulation in nerve-damaged animals with no concomitant alteration of response to mechanical stimulation (623). NAC morphine-induced increases in thermal and mechanical hindpaw latencies were blocked by naloxone, BFNA and NBNI, but not NTI (1244). Morphine in the thalamic nucleus submedius reduced the second phase of formalin-induced evoked spinal dorsal horn nociceptive responses in a naloxone-reversible manner (1317). Microinjections into the thalamic nucleus submedius of morphine, endomorphin-1 or DADL, but not the kappa agonist, spiradoline, dose-dependently inhibited mechanical and cold allodynia induced by spinal nerve ligation, effects blocked by general and mu, but not delta antagonism (1187). Similarly, microinjections into the ventrolateral orbital cortex of morphine, endomorphin-1 or DADL, but not the kappa agonist, U-62066, dose-dependently inhibited mechanical and cold allodynia induced by spinal nerve ligation, effects blocked by general and mu, but not delta antagonism (1318).

Morphine, gabapentin and lamotrigine produced analgesia of similar potencies in attenuating capsaicin and nerve-injury-induced mechanical hypersensitivity (535). Morphine modulated potentiation of capsaicin-evoked TRPV1 responses through a cyclic AMP-dependent PKA pathway (1160). Intrathecal naloxone or CTAP blocked systemic morphine- and fentanyl-induced analgesia on mechanical measures of nociception as well as thermal responses to the hindpaw, but not forepaw (198). However, noncompetitive interactions between the opioid antagonists, CTAP and naltrexone were observed in the rat tail-withdrawal assay (1175). Morphine-associated pruritus occurred after a single extradural injection in a horse (150).

Two studies independently demonstrated that morphine-induced decreases in intraocular pressure and pupil diameter in rabbits was blocked by naloxone and partially reversed by L-NAME or L-glutathione, indicating NO involvement (111, 296). Low-dose morphine-induced hyperalgesia was blocked by PLC inhibitors (U73122) and blockers (calphostin C), also by ketamine and MK-801, and finally by AS against PLCbeta3 (378). Acute and chronic morphine increases Phase II pain-associated behaviors on the formalin test in neonatal rats after four days of abstinence (1332).

Mu Opioid Agonists 

Human opiorphin, a physiological inhibitor of Enk-inactivating zinc endopeptidases produced potent analgesia in chemical and mechanical pain models (1223). Peripherally-mediated antinociception of the mu-opioid receptor agonist 2-[(4,5alpha-epoxy-3-hydroxy-14beta-methoxy-17-methylmorphinan-6beta-yl)amino]acetic acid (HS-731) occurred after subcutaneous and oral administration in rats with carrageenan-induced hindpaw inflammation (100).
Mu Opiate AgonistsL-methadone, but not D-methadone produced stronger anti-allodynic effects in the spinal nerve ligation model relative to morphine, oxycodone and methadone itself (646). 6-acetyl-codeine analgesia was blocked by AS probes targeting Exons 1 and 2 of the MOR gene (780). The ability of buprenorphine to increase tail-flick latencies correlated with the extent and duration of reduced numbers of mu opioid receptor binding; however, residual analgesia after 8 h was not accompanied by mu binding changes (320). Ventricular and intrathecal buprenorphine analgesia on the formalin test was blocked by ventricular and intrathecal naloxone and the ORL-1 antagonist, J113397. Methadone and morphine were more effective than buprenorphine in increasing thermal and pressure thresholds in cats (1067). Systemic buprenorphine analgesia was blocked by systemic or intrathecal, but not ventricular naloxone, and was enhanced by systemic or ventricular J113397. Systemic, but not ventricular or intrathecal buprenorphine decreased formalin-induced Fos activity in the lumbar dorsal horn (1257). Thienorphine produced a similar analgesic duration as buprenorphine, but was longer than the latter in antagonizing morphine-induced lethality (1279).

The analgesic efficacy of such partial opioid agonists as buprenorphine or tramadol was increased in mice with targeted inactivation of the alpha2A-adrenoceptor gene or in wild-type mice treated with atipamezole and yohimbine (874). Tramadol produced analgesia in MOR KO mice that was blocked by alpha-2 adrenergic antagonists alone or with naloxone, but not by methysergide (499). Isobolographic analysis revealed dual-site synergism in the systemic and intraplantar antinociceptive response of tramadol in the formalin test in rats (921). Oral and intrathecal, but not ventricular oxycodone, but not morphine produced analgesia in diabetic mice. Whereas, mu but not kappa or delta antagonism blocked oxycodone analgesia in non-diabetic mice, kappa, but not mu or delta antagonists blocked oxycodone analgesia in diabetic mice (852). Whereas subcutaneous oxycodone and oxymorphone produced potent analgesia in the hot-plate and paw pressure tests, intrathecal oxymorphone produced far more potent effects than intrathecal oxycodone (645). Liposome-encapsulated hydromorphone provided extended analgesia in a rat model of neuropathic pain (1047). Analgesic effects were observed after epidural administration of hydromorphone in horses (822), and similar effects were observed following subarachnoid hyperbaric morphine, buprenorphine and methadone (823). Systemic and intrathecal remifentanil produced naltrexone-reversible analgesia on the acetic acid test in Rana pipiens (792). Gabapentin activated the NO-cyclic GMP-K+ channels pathway in inhibiting formalin-induced pain (869). Spinal alpha-2 adrenergic and muscarinic receptors as well as the NO release cascade mediated the supraspinally-produced effectiveness of gabapentin in decreasing mechanical hypersensitivity in mice after partial nerve injury (1103).


Intrathecal endomorphin-2, but not endomorphin-1 or DAMGO analgesia was prevented by antisera directed against DYN A(117), but not DYN B(113); this effect was reversed by pretreatment with ultra-low doses of BFNA or naloxonazine that were ineffective at mu opioid receptors (788). Endomorphin-1 and endomorphin-2 produced analgesia when injected directly into an inflamed hindpaw, effects blocked by mu, but not kappa antagonists, and with delta antagonism blocking the latter but not former effect. Antibodies raised against BEND, Lenk or Menk failed to affect endomorphin-induced analgesia (622). Endomorphin-1 produced longer-lasting analgesia when injected in nanoparticles coated with polysorbate 80 (679). The analogues, guanidine-[d-Ala(2), pCl-Phe(4)] endomorphin-1, the four D-Ala-containing tetrapeptides and a chloro-halogenated d-Pro-Gly-containing pentatpetides of endormorphin-1 showed potent and prolonged analgesic activity (681). Strong opioid receptor binding and analgesic activity were found with analogues of endomorphin-2 and morphiceptin with phenylalanine mimics in position 3 or 4 (384). The novel analogue, [Dmt1]endomorphin-1 produced spinal and supraspinal analgesia that was blocked by naloxone and BFNA, but not naloxonazine, indicating mu-2 action (527). Tyr-Pro produced naloxone-reversible analgesia on the tail-flick test, and [3H]-Tyr-Pro could be found in endomorphin-related tetra- and tri-peptides in brain (968). The modulation of endomorphin-1 and –2 analgesia by L-NAME was inhibited and reversed by L-Arg and naloxone respectively (204).

A BEND anti-serum blocks thermal analgesia noted at the initial stages of a murine osteosarcoma (47). Intraplantar BEND respectively suppressed and potentiated concanavalin A-induced paw edema at high and low doses in delta- and kappa-selective antagonist fashion in two inbred strains that differed in BEND-induced modulation of phagocytosis and NO production (1065).
Manipulations affecting Mu Analgesia 

Dextro- and levo-naloxone each reversed the attenuation of morphine analgesia induced by lipopolysaccharides in the mouse spinal cord through a non-opioid mechanism (1233). Bicuculline or picrotoxin administered into the ventrolateral orbital cortex enhanced the ability of morphine to inhibit tail-flick latencies in this region, whereas muscimol and THIP attenuated the morphine-induced response (930). Gabapentin enhances the analgesic response to morphine in an acute model of pain in male rats (775). SB203580, a p38 MAPK inhibitor reversed antianalgesia induced by dextro-morphine or morphine in the mouse spinal cord (1234).
Endothelin ETA receptor blockade potentiates morphine analgesia but does not affect gastrointestinal transit in mice (748). Mice lacking P-glycoprotein displayed enhanced analgesic effects to morphine and fentanyl, but not meperidine. Morphine and fentanyl stimulated P-glycoprotein ATPase activity as well (439). Mice lacking one allele of glial cell line-derived neurotrophic factor displayed enhanced morphine analgesia and enhanced NAC DA output (11). Enhancement and restoration of the analgesic efficacy of codeine and morphine occurred following delta9-THC (1219). Systemic morphine produced antinociception mediated by spinal 5-HT7, but not 5-HT1A and 5-HT2 receptors (290). The I2-imidazoline binding site ligand, phenyzoline enhanced morphine analgesia on the tail-flick and hot-plate tests, whereas its ortho-phenyl derivative decreased this response (394). Synergistic analgesia occurs between the phosphodiesterase inhibitor, zaprinast and morphine in the spinal cord of rats on the formalin test (1276), whereas riboflavin enhanced this measure as well (84). Blockers of the gap junction channel, carbenoxolone and Gap27 reduced morphine analgesia after intrathecal administration (1090). Co-administration of the non-competitive NMDA antagonist, MK-801 and morphine attenuated neuropathic pain (441). [Ser1]-histogranin, a peptide NMDA receptor antagonist enhanced morphine analgesia in the formalin test (438). Naloxone pretreatment and post treatment blocked the morphine-induced and dipyrone-induced analgesic potentiation in the tail-flick test in rats (467).
Hemokinin-1, a mammalian tachykinin peptide, markedly potentiated the antinociceptive effects of morphine administered at the peripheral and supraspinal level (364). Enhanced antinociceptive effects of morphine were noted in histamine H2 receptor gene KO mice (790). Lithium potentiated morphine analgesia in a time-sensitive manner near the end of the light phase of the light:dark cycle (549). Ketamine enhanced the analgesic, cataleptic and hypoactive effects of morphine in a naloxone-reversible manner, with the first effect reduced by yohimbine, but not glibenclamide (163). BIBP3226, a NPY Y1 receptor antagonist, prevented the ability of neuropeptide FF to reduce morphine analgesia on the tail-flick test (331). Rats over expressing beta-arrestin 2 in the PAG display decreased morphine analgesia (522). The analgesic effects of the CB2 receptor agonist AM1241, but not morphine were absent in CB2 KO mice (497). Animals allowed wheel-running activity displayed significantly less morphine- and M6G-induced analgesia elicited from the vlPAG than inactive rats (744). Both GABA-B and GABA-A agonists reduced morphine-induced Straub tail responses in mice (1295). Resiniferatoxin, a potent capsaicin analogue decreased individual, but not combined immunoreactivities of mu opioid receptors and transient receptor potential vanilloid type-1 neurons in the DRG and dorsal horn. This was accompanied by enhancements in the analgesic magnitude and duration following intrathecal DAMGO and morphine as well as systemic morphine; the number, but not affinity of spinal [3H-DAMGO] binding was also decreased (197). The methanolic extract of Polygala telephiodes antagonized morphine analgesia on the hot-plate test, improved morphine-induced memory impairments on the elevated plus maze, and suppressed naloxone-precipitated jumping behaviors in morphine-dependent mice (309).
Mu receptors 

The 3′ non-coding region of MOR is important is morphine analgesia, and appears to be the reason for a disrupted response in CXBK mice (555). MOR KO mice displayed spinal morphine analgesia at higher doses that was blocked by naloxone and NBNI, but not NTI. Spinal U50488H, but not DPDPE analgesia was observed in MOR KO mice (1254).
3b-ii. Delta agonists and receptors 

There is a crucial role of delivery and trafficking of DOR in opioid analgesia and tolerance (1313). Chronic pain-induced emotional dysfunction is associated with astrogliosis due to cortical DOR dysfunction (815). Protease activated receptor 2 agonists activate trigeminal nociceptors and induce functional competence in DOR (885). Dextro- and levo-morphine attenuated delta and kappa opioid-mediated analgesia in MOR KO mice (1235). The mechanical and thermal allodynic as well as the thermal hyperalgesic effects of neuropathic pain were enhanced in DOR KO mice (810). The peripheral delta agonist, [dVal(L)2,Ala(L)5]Enk produced naloxone-reversible and NTI-reversible analgesia induced by osteosarcoma cells injected into mouse femur with greater potency than morphine (131). Dmt-Tic-CH2-Bid, a potent DOR receptor agonist produced NTI-reversible analgesia and reduced immobility during forced swimming (1155). Chimeric glycosylated peptides of Menk and FMRFamide, like [O-Glu-Ser5]Yfa, display increased levels of analgesia and increased bioavailability (737).
3b-iii. Kappa agonists and receptors 

The antinociceptive and hypothermic effects of the KOR agonist, Salvinorin A are abolished in a novel strain of KOR-1 KO mice, indicating an effect mediated by KOR-1 and not KOR-2 receptors (33). The antinociceptive effects of salvinorin A in mice were blocked by NBNI, but not by BFNA or Nti (528). Elevated levels of DYN through the activation of bradykinin receptors contribute to the maintenance of neuropathic pain, an effect blocked by bradykinin B1 and B2 receptors only when elevated DYN is present (626; comment by (26)). Spinal cord DYN expression increases, but does not drive microglial prostaglandin production or mechanical hypersensitivity after incisional surgery in rats (1329). U50488H administered into the contralateral hindpaw of animals exposed to unilateral arthritis induction reduced hindpaw oedema, ankle joint inflammation, pain behaviors, inflammatory severity in both hind paws and decreased cartilage oligomeric matrix protein, effects reversed by the peripheral opioid antagonist, naloxone methiodide (99). Whereas morphine was effective in treatment of herpetic pain, the KOR agonist, nalfurafine, suppressed herpetic and post-herpetic pain to similar degrees following intrathecal administration. Spinal MOR was down regulated in the post-herpetic period (1103). Whereas stimulation of MOR and DOR induced hyperalgesia, stimulation of KOR induced analgesia in the hot-plate test in the naked mole-rat (1129). DYN A protein levels, increased in peripheral nerves and footpads of STZ diabetic mice, produces analgesia with activation of KOR and hyperalgesia with activation of NMDA receptors in these mice (531). Salvinorin A produced short-lived (10 min) analgesia on the tail-flick, hot-plate and acetic acid writhing tests, effects blocked by NBNI (755). Nalfurafine, a KOR agonist, inhibited scratching behavior secondary to cholestasis induced by chronic ethynylestradiol injections in rats (502). KT-95, an agonist binding to mu, delta and kappa receptors induced analgesia on the acetic acid writhing test that was blocked by NBNI, but not naloxone. KT-95-induced amelioration of scopolamine-induced memory impairments was unaffected by NBNI, but blocked by sigma antagonism (473).
3b-iv. OFQ/N and ORL-1 receptor 

OFQ/N continues to present a complex picture concerning its role in pain responses producing both “pro-nociceptive” and “anti-nociceptive” actions depending on such factors as site of administration, dose and time course. This section therefore presents these data separately.
Pro-nociceptive actions 

Administration of the ORL-1 antagonist, UFP-101 produced analgesia on the formalin test following ventricular administration and hyperalgesia following intrathecal administration. Mice receiving systemic administration of the ORL-1 antagonist, J-113397 or ORL-1 KO mice displayed increased nociceptive behaviors on the formalin test (961). OFQ/N administered into the vicinity of the knee caused a shift in weight bearing to the contralateral leg in rats, and reduced paw withdrawal thresholds and latencies to the affected foot, effects independent of mast cell activation (756). OFQ/N and PGE2 induced allodynia that was blocked by the ORL-1 antagonist, JTC-801 and that was absent in Pro-OFQ/N KO mice. OFQ/N-induced allodynia was unaffected by inhibition of PG production by indomethacin, and the PGE receptor agonist, AE1-329 stimulated OFQ/N from spinal slices and induced allodynia (860).
Both partial sciatic nerve transaction and administration of CFA up regulated OFQ/N and the ORL-1 receptor in the dorsal root ganglion; these effects were accompanied by increases in activating transcription factor 3, a neuronal marker of nerve injury (202). Hyperalgesia induced by OFQ/N was blocked by melatonin that in turn produced analgesia that was blocked by naloxone and the melatonin receptor antagonist, luzindole (1188). Two novel ORL-1 peptide analogues, Peptide-1 and –2 produced pro- and anti-nociceptive effects respectively with the latter block the effects of the former. Peptide-1 produced greater decreases in MAP than OFQ/N, and the latter’s hypotensive effect was blocked by Peptide-2 (896). The OFQ/N agonist Ac-RYYRIK-ol produced hyperalgesia following supraspinal administration and analgesia following intrathecal administration as well as producing decreased locomotion and increased food intake (427).
Antinociceptive actions 

Intrathecal OFQ/N produced analgesia in monkeys that was blocked by the ORL-1 antagonist, (+)J-113397, but not naltrexone with its metabolite OFQ/N(217) present at 1.5 but not 4.5 hours later (599). Intrathecal OFQ/N as well as electro acupuncture attenuated in an ORL-1-sensitive manner the hyperalgesia induced by CFA with greater effects observed when OFQ/N and electro acupuncture were combined (365).
3b-v. Human studies 


The high-estrogen state was associated with regional increases in baseline MOR availability in women and a greater activation of endogenous opioid neurotransmission during the pain stressor (1050). Using [18F]-fluorodiprenorphine PET in healthy volunteers, it was found that heat pain stimulation reduced diprenorphine binding in limbic and paralimbic areas including the NAC and insula (1062). The 118A>G single nucleotide polymorphism of the MOR appears important in morphine- and M6G-induced pain control in healthy human volunteers (695) as well as reducing alfentanil-induced analgesia and respiratory depression (856). Endogenous pain-inhibitory systems activated by spatial summation are opioid-mediated given naloxone’s effectiveness in volunteer male and female subjects (538). Pain thresholds and tolerance were higher in men at high risk for hypertension, with greater ratings of pain and salivary cortisol following naltrexone treatment (13).
Oxycodone was more effective than morphine in a multimodal, tissue-differentiated experimental pain model (1064). CRF increased tolerance to pressure, but not heat pain in a naloxone-insensitive manner; the CRF-induced increases in plasma BEND and BLPH did not correlate with the pain tolerance thresholds (743). Both alfentanil and morphine reduced human experimental muscle pain (1002). Transdermal fentanyl was better tolerated than transdermal buprenorphine in terms of skin irritation as measured by erythema (997).
Dental Pain 

Both BEND and somatostatin levels were higher in exposed and inflamed dental pulps than in uninjured pulps (806).
Chronic Pain 

A meta-analysis (373) revealed that weak and strong opioids outperformed placebo for pain and function in chronic noncancer pain patients. Withholding of opioid therapy should not be a consequence of concern of hastening death in a large hospice population (919). The frequency of the minor allele of the functional A118G polymorphism of the human MOR gene was lower in patients with acute and chronic pain (514). Parental history of chronic pain appears to be correlated with impairments in endogenous opioid analgesic systems (142). Intrathecal morphine produced greater pain relief in patients with non-cancerous chronic back pain, an effect accompanied by increased pruritus, nausea and vomiting (937). Intrathecal fentanyl and sufentanil for the treatment of chronic pain was found to be potent and efficacious (1173). Intravenous morphine was effective in acute pain without much incidence of nausea or vomiting (128), but was marginally better than placebo treatment for acute abdominal pain (381). Chronic pain patients administered oral morphine for one month became hyperalgesic and tolerant on the cold presser, but not a heat model of pain (217). Chronic pain patients administered intrathecal morphine displayed significantly less OFQ/N in cerebrospinal fluid that controls (938).
Effective treatment of chronic moderate-to-severe non-malignant pain was observed with polymer-coated extended-release morphine sulfate capsules (840). Ganglionic local opioid application (GLOA) was effective for treatment of chronic headache and facial pain (451). Use of morphine and other opiates was associated with greater risk of fracture due to falls related to dizziness (1158). Opioid switching from oral slow release morphine to oral methadone improves pain control in chronic non-malignant pain over a nine-month follow-up study (359). Administration of naloxone following long-term morphine treatment produced withdrawal and reinstatement of lower morphine doses to produce analgesia in a selected group of chronic pain patients (693). CJC-1008, a long-acting parenteral opioid analgesic was effective in the treatment of postherpetic neuralgia (1177). Hydrocodone produced greater amounts of abuse liability than NSAIDs or tramadol in a female group of patients treated for chronic non-cancer pain (6). Intrathecal hydromorphone reduced intractable nonmalignant pain (304), and was shown to be safe and efficacious in acute emergency-related pain (180). Hydromorphone can be produced as a minor metabolite of morphine within minutes in chronic pain patients (234).
Daily-extended release hydromorphone was effective in patients with persistent moderate to severe chronic pain (1211). Oxytrex, a combination of oxycodone and an ultra-low naltrexone dose, minimized physical dependence while providing effective analgesia in patients with low back pain (1205). Extended release oxymorphone appeared effective in pain relief for osteoarthritis of the hip or knee (593), and was more effective and less costly than an oxycodone-acetaminophen combination for osteoarthritis pain of the hip or knee (732). A weight-based dose of oxycodone without adjustment for age between 6 months and 7 years is valuable for evaluating dosing schedules and routes (316). Although rofecoxib was more effective in ameliorating chronic osteoarthritis pain in the knee than acetaminophen, the latter reduced plasma BEND levels (1025). The analgesic effect of pamidronate is not caused by the elevation of BEND level in Paget’s disease (77). Serum BEND and IgE are useful biomarkers for itch and disease severity in patients with atopic dermatitis (635). Electro acupuncture was effective in the treatment of postthoracotomy pain (1226). Opioid expenditures and utilization increased in the Medicaid system between 1998 and 2003, particularly for morphine derivatives (135).
Cancer Pain 

The use of low morphine doses in opioid-naïve cancer patients with pain appeared to be a reliable method in pain treatment (769). Epidural morphine produced greater analgesia than intravenous morphine for oral cancer surgery with pectoralis major myocutaneous flap reconstruction (1042). Oxycodone was as efficacious and tolerable as morphine for cancer pain treatment (945). Three-cycle fentanyl patch system significantly improves pain control in gynecologic cancer (547). Even though oral morphine is not contra-indicated, there is a trend to use a fentanyl patch as the first-choice strong opioid in cancer patients undergoing titration, in the presence of intractable pain and in the absence of dysphagia (956). S-methadone had a shorter half-life and shorter population pharmacokinetics than R-methadone in hospice patients with cancer pain (45). There was a beneficial effect of low-dose Ketamine addition to epidural administration of morphine-bupivacaine mixture for cancer pain (1007). Midazolam was an effective adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer (827).
Surgical Pain 

The A118G single nucleotide polymorphism of MOR appears to moderate, but does not mediate the effects of the anger-out trait on postoperative pain responses (144). Age and the prior use of psychotropic agents before surgery were positively associated with a higher rate of postoperative morphine consumption (240). Intrathecal morphine was similar to epidural morphine during liver resection surgery for postoperative pain relief (276), but improved pain relief after abdominal aortic surgery (105), and is effective in treating elderly patients in a regular post surgical ward (667). Intrathecal morphine combined with bupivacaine reduced pain scores following dorsal rhizotomy in children (469). Morphine and Entonox were not very effective analgesics in children undergoing chest drain removal (140). Rectal morphine administered in solution or gel form administered as premedications were effective analgesics (707). Following laparoscopic cholecystectomy surgery, children with sickle-cell disease consume twice as much morphine, report more pain and have longer hospital stays than non-sickle cell children (246).
No adverse events in pediatric ketamine sedations occurred with morphine pretreatment (1200). There was an association of MOR gene polymorphism (A118G) with increased morphine consumption for analgesia after total knee arthroplasty (214). Both perioperative and PCA morphine were effective analgesics for total knee arthroplasty (1153). DepoDur, an epidural extended-release morphine formulation produced extended pain relief after knee arthroplasty (452), and high doses of oral morphine were effective after total hip arthroplasty (720). Addition of morphine and ketolorac to ropivacine enhanced pain levels in patients with arthroscopic knee surgery (838). The level of post-operative pain after hip or knee arthroplasty correlated with plasma levels of ACTH, BLPH and BEND (741). Moreover, there was an inverse correlation between the level of post-operative pain and pre-operative levels of CSF BLPH, but not ACTH or BEND (742).
Intraoperative administration of tramadol for postoperative nurse-controlled analgesia resulted in earlier awakening and less sedation than morphine in children after cardiac surgery (218).
Tramadol is comparable to morphine during adenotonsillectomy for obstructive sleep apnea in children (494). Tramadol with lornoxicam had the least immunity depression during postoperative analgesia relative to morphine or tramadol alone (1196). Postoperative cognitive function and pain relief was more effective with tramadol as compared to fentanyl patient-controlled analgesia (839). Preemptive gabapentin reduces postoperative pain and opioid demand following thyroid surgery (23), but a meta-analysis still finds its clinical significance undetermined (1005).
Acute opioid tolerance developed during infusion of remifentanil for pediatric scoliosis surgery (245). A combination of low ropivacine and morphine doses was not more effective than a higher ropivacaine dose in post-operative analgesia for arterial bypass surgery of the lower extremities (354), and ropivacaine had opiate sparing effects following total knee arthroplasty (1004). The use of continuous epidural infusion or PCA of levobupivacaine produced comparable analgesia in terms of postoperative morphine consumption (278). Caudal bupivacine into the sacral hiatus was more effective than morphine in attenuating intraoperative and postoperative pain and stress responses in children undergoing abdominal surgery (1116). Oxycodone absorption is similar after buccal and sublingual instillation during surgery in children (605). Hydrocodone and acetaminophen combinations produced similar pain relief to rofecoxib in functional endoscopic sinus surgery (221), whereas acetaminophen and ketoprofen produced pain relief in children after soft tissue or orthopedic surgery (471).
Remifentanil is a reasonable alternative to fentanyl when using a target controlled propofol infusion in patients undergoing craniotomy for supratentorial lesions (271). Rofecoxib decreased pain scores and morphine consumption after orthopedic, breast and spine surgery (951). Propofol prevented post-operative pruritus induced by epidural morphine with ropivacaine (607). Intravenous bolus of ultra-low-dose naloxone added to morphine does not enhance analgesia in emergency department patients (97). Preoperative flurbiprofen axetil reduced postoperative pain and morphine needs for spinal fusion surgery (1258). Intraoperative infusion of dexmedetomidine reduces postoperative analgesic requirements (429), and can substitute for fentanyl for bariatric surgery (340).
Caesarean Pain 

Oral morphine was better than intravenous morphine PCA in controlling pain after cesarean delivery (264). Chloroprocaine failed to affect epidural morphine for post cesarean delivery analgesia (468). Droperidol, allzapride and propofol, but not promethazine had prophylactic effects on spinal morphine-induced pruritus following caesarean section (480). However, ondansetron and tropisetron did not prevent intraspinal morphine- and fentanyl-induced pruritus in elective cesarean delivery (988). Sufentanil and morphine added to hyperbaric bupivacaine in supraspinal anesthesia for caesarean section improved pain relief (551). Naloxone is rarely used to reverse opiate effects in newborn infants, and its use can be curtailed further without increasing respiratory morbidity (121).
Pre-operative intrathecal morphine enhanced the quality of postoperative analgesia for total abdominal hysterectomy (552). Human opioid receptor A118G polymorphism increased intravenous PCA morphine consumption after total abdominal hysterectomy (213). Intrathecal bupivacaine, clonidine and morphine were more effective than general anesthesia for pain relief and functional status after vaginal hysterectomy (1063). Lornoxicam and ketoprofen reduced post-operative pain and morphine consumption following hysterectomy (550). Women undergoing hysterectomy with a genetic polymorphism of the interleukin IL-1Ra receptor, but not polymorphisms in interleukin-1 displayed greater variability in post-operative morphine consumption for pain (85). Gabapentin attenuated late, but not acute pain after abdominal hysterectomy (335). Intrathecal adenosine was not efficacious for postoperative pain relief following abdominal hysterectomy (1023).
3c. Sex, age and genetic differences
So-called organismic variables play vital roles in the mediation of opioid analgesic responses, and continue to attract a great deal of attention. The first variable is the sex or gender of the animal, and opioid receptor subtypes appear to play important roles in whether there is a sex differences in analgesia and whether it is mediated by circulating gonadal hormones. Test-specific and route-specific variables also come into play that not only informs us about sex differences in opioid analgesic function, but other functions covered in other parts of the review. Aging factors, and especially genetic factors from both inbred and transgenic models continue to play a vital role in our understanding of opioid analgesic function.
3c-i. Sex 

Female rats have more PAG-RVM output neurons than males, but males have more activated PAG-RVM cells than females during inflammatory pain. Systemic morphine significantly suppressed CFA-induced Fos in males only (700). Testosterone produces anti-hyperalgesic effects during development in male animals that is maintained during adulthood. Morphine analgesia inhibits inflammation-induced pain in adult gonadectomized, but not neonatally-gonadectomized animals (114). Male rodents and nonhuman primates display greater analgesic responses than females following mu and kappa opioids, particularly those that display low efficacy such that they appear to act as full agonists in males, but antagonists in females. These effects interact with drug history, genotype and the modality, duration and intensity of the nociceptive stimulus (67). Whereas estrogen attenuates OFQ/N analgesia elicited from the spinal cord in the female, testosterone is required for OFQ/N analgesia in the male rat (227). Male rats displayed greater analgesic and antihyperalgesic effects of morphine than females on CFA-induced pain over a 3-week time course (1192). Male rats displayed greater analgesia on a visceromotor pain test following systemic loperamide and inventricular, but not intrathecal morphine than female rats (521). Female rats, and particularly ovariectomized females displayed more marked leftward shifts in morphine’s dose-response curve following the barbiturate, pentobarbital (243). Testosterone levels that affected male sexual behavior and reproductive physiology did not similarly alter basal nociception or morphine analgesia (1085).
Chronic sucrose intake reduced the antagonist effect of BFNA on morphine-induced analgesia in female, but not male rats (241). Whereas female Fischer rats showed greater enhancements of contact hypersensitivity following spiradoline, but not SNC80, both sexes showed comparable analgesic and antidiuretic effects following both compounds (314). Neurokinin-1 receptor antagonism decreased mu and kappa opioid-induced enhancement of contact hypersensitivity in females but not males (315). Female rats displayed greater analgesia following oxycodone and U50488H than males, and male rats showed greater hyperalgesia following low oxycodone and U50488H doses (477).
Gender differences in sensitivity to short duration cold pain were associated with variations in the genes for transient receptor potential A subtype 1, catecol-O-methyltransferase and fatty acid amide hydroxylase (579). Placebo analgesia occurred in males with female experimenters, suggesting the importance of the social context in which the pain is recorded (350). Women undergoing dental procedures displayed greater nalbuphine analgesia than men with men displaying a late onset anti-analgesia following nalbuphine. Pretreatment with chlorpromazine or haloperidol enhanced nalbuphine analgesia eliminating any sex difference, and abolished the male anti-analgesia (389).
3c-ii. Aging 

Morphine analgesia did not differ between young and aged rats using tail-flick latencies, but older animals showed a decreased analgesic response using a method measuring tail-flick thresholds as well as escape thresholds from electrical stimulation of the mesencephalic reticular formation (249).
3c-iii. Genetic differences 

Opioid-induced hyperalgesia that occurs after repeated morphine was strongly strain-dependent in 15 inbred groups of mice with genetic analysis identifying a genetic locus near the beta-2 adrenergic receptor gene. The selective beta2-adrenergic antagonist, butoxamine blocked opioid-induced hyperalgesia (662). Low doses of naltrexone enhanced morphine analgesia and attenuated the development of morphine tolerance in Sprague-Dawley and Long-Evans rat strains, but not in F344 or Lewis rat strains (1115). Fischer rats displayed greater carrageenan-induced swelling and pain as well as lower circulating levels of TNF-alpha and higher levels of IL-6 as compared to Lewis rats. Although morphine reduced carrageenan-induced behaviors in both strains, low morphine doses produced a mechanical allodynia and hyperalgesia in the noninflamed paw of Fischer, but not Lewis rats (337). Lewis rats displayed lower thresholds for CRF-induced analgesia, and higher doses of the CRF antagonist, astressin to produce hyperalgesia that was blocked by morphine pretreatment (1167).
3d. Opioid mediation of other analgesic responses
This section summarizes studies that indicate that analgesia elicited by a wide range of peptides and transmitters can alternatively and respectively be sensitive (3d-i) or insensitive (3d-ii) to opioid manipulations using agonists, antagonists and transgenic knockouts.
3d-i. Opioid-sensitive analgesic responses 

Central galanin-induced analgesia was reduced in morphine-tolerant rats, and these animals displayed an up-regulation of galanin-like immunoreactivity in the hypothalamic arcuate nucleus (1238). The neurotensin agonist NT1 displayed analgesia and tolerance on the hot-plate test that was not cross-tolerant with morphine, but was sensitive to naloxone on the jumping, but not licking response. The neurotensin-2 receptor antagonist blocked neurotensin, but not morphine analgesia on the hot-plate test (130). Intrathecal naloxone inhibited but was less effective than an Oxy antagonist in blocking the ability of Oxy or PVN stimulation to reduce the withdrawal responses to mechanical and cold stimuli in sciatic nerve-ligated rats (782). KOR and DOR antagonists block the antinociceptive effect of Oxy in formalin-induced pain responses in mice (945). VP-induced analgesia elicited from the PAG was blocked by naloxone and V2, but not V1 receptor antagonists (1260). Ghrelin inhibited inflammatory pain induced by carrageenan that was reversed by naloxone (1037). The COX-2 inhibitor, SC236 produced hypoalgesic effects in carrageenan-treated rats that were blocked by naltrexone and absent in morphine-tolerant animals (357). The PKC inhibitor, chelerythrine blocked basic spinal c-Fos expression to formalin pain as well as the naloxone-induced increases in spinal c-Fos expression to formalin pain (842). The analgesic effects of fatty acid amide hydrolase inhibition with URB597 in a rat model of neuropathic pain were blocked by naloxone and CB-1 antagonism (520). Intraplantar injection of CXCL2/3, but not CXCL12 elicited naloxone-reversible mechanical and thermal analgesia that was abolished by systemic polymorphonuclear cell depletion (958). Central melatonin produced antihyperalgesic, but antiallodynic actions in sciatic nerve-injured mice, effects blocked by naloxone and L-arginine (1140), and naloxone blocked melatonin-induced analgesia (723). The SSRI, fluvoxamine produced analgesia that was blocked by intrathecal and systemic administration of general, mu and delta, but not kappa antagonists in sciatic nerve-injured mice (851).
Fluoxetine-induced analgesia on the tail immersion and hot-plate assays was significantly less potent in STZ-induced diabetic mice, and reversed by opioid and muscarinic, but not alpha-2 adrenergic antagonists (32). Inhibition of the jaw opening reflex and single neurons in the trigeminal subnucleus caudalis by activation of striatal D2 dopamine receptors was suppressed by striatal quinpirole and reversed by systemic naloxone (991). Desimiprimine and trimipramine-induced analgesia were blocked by Nti, but only by high doses of naltrexone (875). A chlorinated chimeric peptide of Menk and FMRFa, [p-Cl Phe(4)], produced a naloxone-reversible analgesia (447). Analgesia induced by AMPA receptor antagonism in the spinal cord was blocked by mu and delta opioid antagonists (606). L-arginine and a NO donor each produced analgesia that were blocked by naloxone and NBNI, and that was more greatly reduced by antisera directed against DYN(113) than against Menk (219). Nitrous oxide produced analgesia on the acetic acid writhing test that was markedly reduced in mice lacking the ORL-1 receptor; acetic acid induced greater increases in plasma ACTH in this KO mice (472). Ketamine produced analgesia in the electrical stimulation test in singly-housed, but not group-housed rats. Whereas ketamine decreased mu opioid binging in the hippocampus in group-housed animals, it increased mu opioid binding in the frontal cortex and hippocampus of singly-housed animals (72). Transfer of CD4+ T-cell lymphocytes blocked visceral hyperalgesia in mice that was reversed by naloxone methiodide (1156).
Intrathecal Tyr-d-Arg-Phe-Sar produced analgesia that was blocked by BFNA, naloxonazine and NBNI, but not Nti as well as by an antiserum directed against DYN B, but not DYN A, alpha-neo-endorphin, Menk or Lenk. Pro-DYN KO mice also showed a lesser analgesic response as well (786). Intrathecal Tyr-d-Arg-Phe-Sar produced analgesia that was blocked by selective mu-1, but not mu-2 opioid peptide antagonists (787). Inhibition of fatty acid amide hydrolase produced naloxone-reversible analgesia on the spinal nerve ligation and mild thermal injury tests (181). Naloxone-sensitive analgesia on the acetic acid and formalin tests was observed following (+/−)-cis-(6-ethyl-tetrahydropyran-2-yl)-formic acid (728). Analgesic effects induced by automatically controlled rotating acupuncture in rats were blocked by naloxone (583). Acupuncture inhibited in a naloxone-reversible manner the ability of noxious tooth pulp stimulation to induce Fos expression in the trigeminal nucleus subcaudalis, the transitional region between the subnucleus caudalis and subnucleus interpolaris, the inferior olivary nucleus, the ventrolateral and centrolateral thalamic nuclei, SON, PVN, NTS and rostral ventrolateral medulla (539). Analgesia, but not freezing behaviors elicited by electrical stimulation of the ventrolateral PAG was blocked by naltrexone, whereas midazolam blocked both behaviors (272). The NE and 5HT reuptake inhibitor, venlafaxine produced analgesia that was blocked by high naloxone doses, but not by N-omega-nitro-L-arginine (426). Mu, but not delta and kappa opioid receptor antagonists block interferon-alpha-induced analgesia from the thalamic nucleus submedius (1186). Tolerance to nicotine-induced analgesia occurred faster in MOR KO mice, nicotine-induced tolerance decreased MOR in C/P and the core and shell of the NAC, but not the spinal cord (377).
The visceral analgesic effects of the anti-viral drug, ribavirin were partially blocked by naloxone, enhanced by D2 receptor antagonists, and unaffected by alpha-2 NE or Ach antagonism (1). Whereas carrageenan produced hyperalgesia in control animals, this procedure produced naloxone-reversible analgesia in rats deficient in polyamine (325). NSAID drugs produce analgesia in sheep that are blocked by intrathecal naloxone or atipamezole (692). Artemin reduces herpes-related pain responses in mice inoculated with herpes simplex, an effect associated with decreased spinal DYN, but not BEND (41). Analgine, ketrolac and xefocam each produced analgesia that developed tolerance and cross-tolerance with morphine, but was not blocked by naloxone (1135).
The pyrazolyl-thiazole derivative (B50) produced naloxone-sensitive analgesia on the writhing, but not tail immersion test with removal of the methyl group or substitution of a bromo group resulting in loss of analgesia (924). Moderate hypercapnia reduced nociceptive behaviors on the formalin test in a naloxone-reversible manner, but failed to alter arcuate BEND (372). Exposure to an extremely low frequency magnetic field for four days produced analgesia and increased hypothalamic BEND and SP as well as brainstem 5HT (62).
Mu opioid antagonism is observed for the analgesic and GI transit inhibition induced by 7-hydroxymitragynine, isolated from Thai herbal medicine Mitragyna speciosa (746).
Analgesia induced by the ethanolic extract from the flowers of Combretum leprosum was observed on formalin-, capsaicin- and glutamate-induced pain tests, effects reversed by naloxone, 5HT1A and 5HT2A antagonists, but not by NO precursors or 5HT3 antagonism (909). The antinociceptive effects of Thymus broussonetli Boiss extracts on the formalin test in mice and rats were blocked by naloxone (310). GDHCF, the active ingredient of the stem bark of Hintonia standleyana increases hot-plate latencies and decreases acetic acid-induced writhing, effects blocked by naloxone, L-NAME and glibenclamide (270). Analgesia on the formalin and hot-plate tests induced by an extract of echium amonenum Fisch & C.A. Mey was blocked by naloxone (460).
The tonic and phasic analgesic, anti-depressant and hypothermic effects of the aqueous root extract of Securidaca longepedunculata were blocked by naloxone pretreatment (7). The antinociceptive effect of Hyptis pectinata leaves extract was blocked by naloxone (676). Attenuation of visceral nociception by alpha- and beta-amyrin, a triterpenoid mixture isolated from the resin of Protium heptaphyllum produced naloxone-reversible actions in mice (668). Further, oleanolic acid, a pentacyclic triterpene attenuated mustard oil-induced colonic nociception, an effect blocked by naloxone, but not yohimbine (714). Mechanical allodynia and thermal hyperalgesia caused by chronic constriction injury were blocked by processed Aconiti tuber in a NBNI-sensitive, but naloxone-insensitive manner (1247).
A recombinant herpes simplex vector encoding human Pro-Enk to macaque feet induced Enk peptide production in the application area that resulted in a long-acting anti-hyperalgesic and analgesic response to C-fiber stimulation of the application area (1271). Irradiation of osteolytic sarcoma cells improved pain-related behaviors in a manner similar to ketorolac; decreases in spinal pain mediators including DYN and COX-2 were noted (1168).
3d-ii. Opioid-insensitive analgesic responses 

Intrathecal, but not ventricular administration of neuropeptide W-23 or Neuropeptide B, endogenous ligands of GPR7 reduced mechanical allodynia induced by sciatic nerve ligation in a naloxone-insensitive manner (1256). Intrathecal CART (55102) attenuated hyperalgesia and allodynia in as mouse model of neuropathic, but not inflammatory pain in a naloxone-independent manner (259). Intrathecal sensory neuron-specific receptor agonists, bovine adrenal medulla 8–22 and (Tyr6)-gamma2-MSH-6-12, inhibit formalin-induced nociception and neuronal Fos-like immunoreactivity in the spinal cord in a naloxone-insensitive manner (199). Whereas mGlu1 and mGlu5 antagonist co treatment enhanced inhibition of formalin-induced pain, neither antagonist paired with morphine showed enhanced effects on this measure (1009). L-glutamate sodium in the PVN enhanced acupuncture analgesia, an effect abolished by VP antisera, but only mildly affected by naloxone. PVN L-glutamate sodium increased VP, but not OXY, Lenk, BEND or DYN A(113) concentrations (1262).
Analgesic activity of a non-peptide imidazolidinedione somatostatin agonist was not reversed by naloxone (521). Although morphine and the 5HT3 agonist, m-CPBG, each reduced phase 1 and phase 2 nociceptive responses on the formalin test, the former was unaffected by intrathecal 5HT3 antagonism, and the latter was unaffected by intrathecal naloxone (1275). The 5HT1A receptor antagonist, WAY-100635 administered systemically or in the RVM attenuated mechanical hypersensitivity in rats with spinal nerve injury in a 5HT-1A antagonist sensitive, but not naloxone-sensitive manner (1208). The SSRI, fluvoxamine produced stronger analgesic effects than fluoxetine or citalopram, but all were naloxone-insensitive (1000). The antinociceptive activity of chemical congeners of improgan optimizing side chain length was nonpioid (484). Delta9-THC and R-methanandamide produced analgesia on the phenyl-p-quinone stretch test in mice that was not blocked by opioid antagonism (437). Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain is mediated by Group II/III metabotropic glutamate, but not opioid receptors (925). Vinpocetine and piracetam exerted antinociceptive effects in visceral pain that was potentiated by naloxone (2).
The antinociceptive effects of the flavenoid myricitrin following glutamate, phorbol myriusate acetate, bradykinin and acetic acid, but not epinephrine or prostaglandin E(2), were blocked by the NO precursor, L-arginine, but not naloxone (768). A nonpioid pharmacological profile was observed for the novel analgesic M58996 in rat models of persistent and neuropathic pain (12). The antinociceptive effect of thalidomide on zymosan-induced experimental articular incapacitation was insensitive to naloxone antagonism (1142). Mice deficient in CD26, a multifunctional cell surface glycoprotein showed decreases in endopeptidase activity, increased SP, normal endomorphin-2, and short nociceptive latencies that were normalized by a SP NK1 antagonist or dipeptidyl-peptidase activity (424). A long-form alpha-neurotoxin from cobra venom produced potent opioid-independent analgesia (203). Analgesia induced by crotoxin isolated from crotalus durissus terrificus venom was opiate- and Ach-independent (1305). 12-acetyoxyhawtriwaic acid lactone, a diterpene from Egletes viscose, attenuated capsaicin-induced ear edema and hindpaw nociception in mice through a naloxone-independent response (764). The anti-inflammatory and analgesic effects of bee venom acupuncture were blocked by yohimbine, but not naloxone (50). Two compounds derived from bis selenide increased pain thresholds in the acetic acid, capsaicin and tail-flick tests in a naloxone-insensitive manner (993).
4. Stress and Social Status
In comparison with previous years, the amount of studies investigating the role of stressors in analgesic responses has dramatically declined as the use of selective opioid agonists and antagonists as well as the use of animals with knockouts of opioid receptor genes in analgesic processes has dramatically increased. This prompted us to include Section 3b in the present review. This section will continue to examine the phenomenon of stress-induced analgesia (4a), emotional responses in opioid-mediated behaviors (4b), and opioid involvement in stress response regulation (4c). 

4a. Stress-induced analgesia
One major theme of stress-induced analgesia is to examine its role vis a vis the opioid system. Ecologically relevant, parametric and sex/age variables continue to play an important role in the neurobiological substrates mediating these responses. Female rats placed on an exercise schedule on running wheels displayed decreased sensitivity to analgesia elicited by morphine, levorphanol, buprenorphine and butorphanol with the sensitivity restored upon return to sedentary conditions (1048). Mice placed on a restricted feeding schedule displayed more potent analgesic effects to morphine during that time in the light:dark schedule in which feeding was entrained; this effect was not observed in adrenalectomized mice, suggesting a role for endogenous glucocorticoid secretion (1277).
Increased opioid mediated warm water swim analgesia, but no changes in CWS analgesia were observed in mice lacking the proneuropeptide convertase PC2 (247).
CWS, but not fentanyl analgesia was blocked by an anti-neural-cell-adhesion molecule that in cultured DRG neurons, was reduced by BEND in a naloxone-reversible manner (485). Immobility induced by clamping the neck of mice produced a naloxone-reversible analgesia on a tonic pain test, the acetic acid writhing test (781). Rats repeatedly exposed to swim stress developed thermal hyperalgesia that was blocked by naloxone and naloxonazine, but not NTI or NBNI only if the antagonist was administered before each forced swimming episode (1075). Chronic restraint stress induced increased responsiveness in formalin-induced pain in the temporomandibular joint and decreases in the effectiveness of morphine analgesia. In contrast, fluoxetine produced greater analgesic effects in the stressed group (382). Swim stress-induced analgesia on the hot-plate test observed in wild-type male and female mice was reversed in MOR-KOR-DOR KO mice and in MOR-DOR KO females. Swim stress-induced analgesia delayed front- and hindpaw behaviors on the hot plate test, increased tail-flick latencies and increased ACTH and corticosterone levels in both wild-type and KO females (236).
4b. Emotional responses in opioid-mediated behaviors
Anxiogenic responses were elicited by CFA or sciatic nerve ligation as well as by ventricular administration of mu or delta antagonists or DYN. CFA or neuropathic pain decreased [35S]GTPgammaS binding induced by DAMGO or SNC80 in amygdala neurons, but increased this response following kappa agonists in the amygdala (812). Ventricular morphine produced anxiolytic effects on the elevated plus maze that was mediated by vasopressinergic system and nitric oxide pathways (544). Prenatal exposure to unpredictable shock enhanced subsequent morphine-induced CPP and greater depressive behaviors on the forced swim test; these behaviors were blocked by postnatal exposure to an enriched environment (1261). Morphine and naloxone administered into the inferior colliculus respectively decreased and increased defensive attention, immobility and escape behavior thresholds. Whereas morphine stimulated bicuculline-induced increases in fear thresholds when administered into the inferior colliculus, naloxone reduced those thresholds (161).
Lateral, but not medial septal injections of morphine produced naloxonazine-sensitive reductions in open-arm exploration in the plus maze, and reduced head-dipping frequency in the hole board, effects associated with decreased Fos in ventral septum, dorsal hippocampus and anterior hypothalamus (647). Morphine, U50488H and SNC80 decreased rearing and climbing activity in the staircase paradigm with naloxone blocking the first and second, but not third agonist. Morphine produced analgesia on the hot-plate test, but failed to alter anxiety-related behaviors on the four-plate test. In contrast, alprazolam and diazepam reduced anxiogenesis, but failed to alter hot-plate latencies (957). CRF produced anxiogenesis, locomotion and grooming behaviors that were reduced by low doses of chronic morphine and increased by high doses of chronic morphine (104). Naltrexone microinjections into the central, but not the basolateral amygdala blocked the anxiolytic effects of diazepam in the plus maze (151).
There was an atypical anxiolytic-like response to naloxone, but not selective opioid receptor subtype antagonists in benzodiazepine-resistant 129S2/SvHsd mice relative to C57BL/6JOlaHsd mice (965). Whereas Nti attenuated diazepam-induced anxiolytic effects in rats over expressing Pro-Enk in the amygdala, neither Nti nor BFNA altered diazepam-induced anxiolytic effects in normal animals (923). Social defeat stress-induced behavioral responses were mediated by the endogenous kappa opioid system such that NBNI and lack of the pre-pro-DYN gene blocked this immobility and subsequent cocaine-induced preferences in stressed mice (759). OFQ/N produces anxiolytic-like effects in the elevated plus maze and in the conditioned defensive burying test in rats that was blocked by the ORL-1 antagonist, UFP-101 (1169). Coupling of ORL-1 receptors to G proteins was decreased in the NAC of anxious relative to non-anxious mice (644). The anxiogenic, hyperactive and impairments in spontaneous alternation induced by buprenorphine were impaired by high doses of clorazepate; buprenorphine-induced memory impairments were unaffected (643).
Combinations of nalorphine and naloxone reduced climbing and rearing as well (779). SNC80 produced anxiolytic effects that were blocked by NTI, whereas Nti produced anxiogenic behaviors (898). Aged mice displayed increased anxiety-related behaviors on the light-dark and elevated plus-maze tests that were accompanied by increased astrocytes in the cingulated cortex due to dysfunction of DOR systems (816). Naltrexone reduced the reinforcing effects of ultraviolet preference in subjects who were frequent tanners (558).
4c. Opioid involvement in stress response regulation
Centrally-administered OFQ/N activates the hypothalamic-pituitary axis through and ORL-1 receptor-mediated up-regulation of CRF and POMC mRNA and stimulation of corticosterone release in rats (642). Prenatal morphine exposure blocks prenatal stress-induced up-regulation of mineralcorticoid and glucocorticoid receptors in the hippocampus in male, but not female rats. However, prenatal morphine exposure blocks prenatal stress-induced decreases in mineralcorticoid binding in the hippocampus of diestrous females, and glucocorticoid binding in the hypothalamus of estrous females (953). Blood-brain barrier increases in protein tracers were observed by the second day of morphine withdrawal that was accompanied by stress symptoms, whereas acute methamphetamine produced extravasation of endogenous serum protein (1020); the former effect was blocked by the 5HT modulator, AP-267 (1021). Naloxone and CRF increased deoxycorticosterone levels in cynomogolus monkeys (918).
Both in vivo restraint in carp and in vitro administration of carp interleukin-1beta stimulated AMSH and n-acetylated BEND from the pituitary (774). Graded exercise increased plasma BEND levels in both young and old horses, whereas it failed to alter plasma cortisol levels in old horses (717). Whereas baseline Enk and DYN levels in the hippocampal dentate gyrus were lower in the Flinders Sensitive relative to the Flinders Resistant line of mice, running failed to affect opioid levels in the former group, but decreased dentate DYN mRNA in the latter group (102). The increases in ProEnk mRNA in developing Syrian hamsters by glucocorticoids are dependent on age and adrenal versus brain tissue (358).
Plasma BEND, ACTH and cortisol responses were all higher and similar for arm and leg exercises at two exercise intensities in untrained subjects (725). Human exercise increased plasma Pro-Enk peptide F immediately and 15 min later, with peptide content in white and red blood cell layers increased after 15 min (153). Naloxone enhanced the ability of heat to induce exhaustion during high intensity exercise, an effect accompanied by increased in plasma BEND and ACTH. In contrast, cold attenuated these naloxone-induced effects (39). A polymorphism in MOR at A118G enhanced increased cortisol responses to naloxone, but lowered increased cortisol responses to social stress in volunteer subjects (211).
Greater levels of basal cortisol, but not ACTH were found in healthy subjects with a 118G allele in exon 1 of the MOR gene (68). Male subjects had greater HPA axis responses to a psychological stressor, whereas female subjects had greater cortisol reactivity to a naloxone challenge (1139). Interference with pre-pro-orexin, but not co-localized pre-pro-DYN in the perifornical hypothalamus reduced rapid eye movement sleep (192). Basal release of opioids appears not to affect eNOS expression in normal in vitro culture conditions, but might do so under stress (1006). Preoperative extradural bupivacaine and morphine lowered the cortisol stress response in dogs undergoing femoral-tibial joint surgery (1036). The ability of methanolic, ethanolic and aqueous extracts of Spondias mombin L to reduce novelty-induced rearing behaviors was insensitive to naltrexone (46).
5. Tolerance and Dependence
The most-often studied variables in the functional analysis of opioid-mediated responses next to analgesic processes are the underlying neurobiological roles of tolerance and dependence. This has continued unabated through the years, and continues to be a focus in this review. Developments will be reviewed for animal models in tolerance (Section 5a), and animal models in dependence and withdrawal responses (Section 5b).
5a. Animal models in tolerance
This section will be divided into the following sub-sections: (i) cellular effects on morphine tolerance, (ii) organismic effects on morphine tolerance, (iii) opioid effects on morphine tolerance, (iv) peptide-transmitter effects on morphine tolerance, and (v) other forms of opioid tolerance.
5a-i. Cellular effects on morphine tolerance 

A review (402) analyzes the post-opioid receptor adaptations to chronic morphine focusing on altered functionality and associations with signaling molecules. Another review (53) indicates a crucial role for PKC in MOR desensitization and morphine tolerance. Adenylyl cyclase superactivation induced by long-term morphine, etorphine or methadone is dependent on receptor localized within lipid rafts and is independent of receptor internalization (1315). A proteonomic analysis of rat cerebral cortex, hippocampus and striatum after pellet exposure to morphine revealed 26 distinct proteins that were differentially expressed (94). DeltaFosB over expression in the mouse NAC produced faster development of morphine tolerance and dependence, less morphine analgesia and increased sensitivity to morphine-induced reward through a DYN-sensitive system (1284).
Chronic treatment with fentanyl produces a different pattern from morphine in altering internalization or resensitization of MORs in the spinal cord under a pain-like state (501). Whereas morphine and buprenorphine produce tolerance and locomotor sensitization with non-internalization of MOR, etonitazene, which produces rapid endocytosis of MOR shows weak tolerance and a lack of locomotor sensitization (416). Acute and chronic morphine respectively increased and decreased neuroglycan C levels in the NAC, striatum, hippocampus, VTA and amygdala (505). Increased phosphorylation of neurogranin, protein kinase C and Ca2+/calmodulin dependent protein kinase II occurs in opioid tolerance and dependence (1035).
Chronic morphine treatment increased the expression of the neural cell adhesion molecule in the dorsal horn of the mouse spinal cord (1091). Chronic morphine-mediated adenylyl cyclase superactivation is attenuated by the Raf-1 inhibitor, GW5074 (1283). The Gbetagamma that interacts with adenylyl cyclase in morphine tolerance originated from a Gs protein (1184). Chronic morphine treatment also increased the expression of vesicular glutamate transporter 1 in the mouse spinal cord (1092). A subpopulation of dorsal horn neurons displays enhanced NMDA receptor function after chronic morphine exposure (1316). Chronic morphine, but not D-amphetamine or nicotine, elevated autoantibodies to the MOR-DOR receptor and to the AMPA Glu1, but not NMDA NR2 subunit receptors (414). Dexamethasone mimics the inhibitory effect of chronic pain on the development of tolerance to morphine analgesia and compensates for morphine induced changes in G protein gene expression (518). Long-term exposure of SH-SY5Y cells to morphine revealed variations in 45 proteins using a whole cell proteomic analysis (830). Inhibition of neuronal nitric oxide synthase antagonizes morphine antinociceptive tolerance by decreasing the activation of p38 MAPK in the spinal microglia (689).
Chronic morphine decreased proDYN gene expression in the striatum, but not NAC or hippocampus, whereas chronic oxycodone-6-oxime increased proDYN gene expression in the striatum and hippocampus, but not NAC. Chronic 14-methoxymetopon increased proDYN gene expression in the NAC and hippocampus, but not striatum (589). Chronic morphine decreases MOR signaling and reduces Ca2+ current density in sensory neurons (530). Chronic morphine increased lactate and myo-inositol, but decreased glutamate in thalamus and somatosensory cortex using nuclear magnetic resonance spectroscopy (1242). Intermittent, but chronic morphine alters protein expression in the NAC (654).
Whereas chronic morphine inhibited spinal GABA release, recurrent morphine withdrawal reversed this effect and elevated spinal glutamate levels. In contrast, acute morphine withdrawal increased both spinal GABA and glutamate release (303). Whereas chronic etorphine, but not morphine increased spinal G-protein-coupled receptor kinase 2, dynamin II, beta-arrestin 2 and phosphorylated-conventional PKC, chronic morphine, but not etorphine increased spinal glial fibrillary acidic protein. Manipulations that modulate glial fibrillary protein altered morphine-induced, but not etorphine-induced analgesic tolerance (820).
Whereas acute morphine increases adenylate cyclase II activity by Galphas or PKC stimulation regulated by Gbetagamma subunits, chronic morphine decreases adenylate cyclase II activity upon stimulation of the Galphas, but not PKC pathway (994). Down-regulation in dopamine transporter function in striatum occurred during acute morphine addiction and its abstinence in rhesus monkey (1243).
5a-ii. Organismic effects on morphine tolerance 

Antinociceptive tolerance was observed following cumulative intracranial microinjections of morphine into the PAG in the rat (795). Morphine analgesic tolerance in 129P3/J and 129S6/SvEv mice was largely absent because of differences in tail-flick responsivity between these strains and C57BL/6J mice (148). Acute morphine tolerance was observed in proestrous, but not ovariectomized female rats; chronic estradiol in ovariectomized animals reinstated acute morphine tolerance. Both forms of tolerance were blocked by the NMDA antagonist, memantine (1024). Chronic morphine drinking establishes morphine tolerance, but not addiction in Wistar rats (101). PKC and PKA inhibitors reinstate morphine-induced behaviors in morphine tolerant mice (1045).
Lithium chloride reduced the development and expression of morphine-induced tolerance, but only the development of morphine-induced dependence in isolated guinea pig ileum (18). Continuous naltrexone opioid receptor antagonism abolished continuous morphine analgesia and potentiated morphine hyperalgesia with the latter, but not former effect blocked by the NMDA antagonist, MK-801. After subsiding, morphine hyperalgesia could be reinstated by a low, but not high morphine dose as well as the morphine metabolite, M3G (541). The ability of processed Aconiti tuber to increase the duration of repeated morphine analgesia before inducing tolerance was prevented by both mu (C-CAM) and kappa (NBNI) opioid antagonists (1034).
5a-iii. Opioid effects on morphine tolerance 

Chronic morphine pretreatment reduced subsequent morphine-induced, but not heroin-induced, overdose lethality, and failed to form toxic concentrations of M6G (1072). OFQ/N KO mice or normal mice treated with the ORL-1 antagonist J113397 fail to display morphine tolerance when morphine is administered at the same dose. Escalating doses of morphine produce tolerance but not withdrawal symptoms in OFQ/N KO mice (220). Pro-Enk KO mice displayed a blunted morphine analgesic tolerance, but not changes in morphine-induced CPP or morphine-induced motor sensitization (731). Morphine-tolerant rats displayed increased DOR levels in varicosities that appose the postsynaptic membrane and interact with increased GAD. Delta agonists reduced morphine tolerance and significantly inhibited presynaptic GABA release (710). Attenuation of morphine tolerance and withdrawal syndromes was observed by co administration of nalbuphine (513).
Intrathecal administration of BAM 22 produced analgesia in both opiate-naïve and morphine-tolerant rats, resumed morphine analgesia in morphine-tolerant rats, but produced hyperalgesia following chronic administration (522).
5a-iv. Peptide-transmitter effects on morphine tolerance 

Calmodulin-stimulated adenylyl cyclase gene deletion reduced morphine-induced tolerance and dependence, but not acute analgesia (655). Glycogen synthase kinase 3beta and cyclin-dependent kinase 5 inhibitors abolished morphine-induced tolerance, but not analgesia (880). NRM administration of GABA-A receptor antagonists augmented the development of morphine tolerance, whereas NRM GABA-A agonists attenuated morphine tolerance development. The GABA-A receptor-mediated IPSC was significantly increased in morphine-tolerant animals, an effect blocked by PKA inhibition (709). Whereas co treatment with the 5HT1A agonist, 8-OH-DPAT in the dorsal, but not median raphe nucleus delayed morphine analgesic tolerance, the 5HT2 antagonist, ketanserin failed to exert effects in the same sites (829). The CCK-2 antagonist, LY225910 administered into the NAC blocked morphine-induced tolerance, but failed to affect the acute antinociceptive effect of morphine (1245).
Neuropeptide SF facilitated spinal morphine analgesia in normal and morphine tolerant animals (519). Supraspinal agmatine prevented the development of supraspinal morphine analgesic tolerance (592). The tricyclic antidepressant amitryptaline prevented morphine tolerance during its development and following a subsequent morphine challenge, and up regulated the spinal glutamate transporters GLAST and GLT-1 expression (1099). The NMDA antagonists MK-801 and CPP attenuated morphine tolerance in male, but not intact or ovariectomized female mice. MK-801 also facilitated morphine-induced hyperalgesia in male, but not female mice (147). There was an additive effect of dextromethorphan on the inhibitory effect of anti-NT4 on morphine tolerance (455). The glycine site-specific NMDA antagonist, (+)-HA966 reversed morphine tolerance and enhanced morphine antinociception in morphine-tolerant rats (5). Opioid tolerance was attenuated by AS targeting the regulator of PKC and Ca2+/calmodulin-dependent protein kinase II (1108) as well as by the antagonist, KN93, but not KN92. KN93 also prevented morphine dependence (1109). Inactivation of p38MAPK in spinal microglia inhibits morphine analgesic tolerance (254). Nicotine and morphine produced analgesic cross-tolerance that was blocked by the Ca2+ channel antagonists, nimodipine, diltiazem and flunarizine, but not verapamil (94).
The endothelin receptor antagonist, BMS182874 reinstated morphine-induced GTP stimulation in tolerant animals to acute levels, and reduced the EC50 value in tolerant cells to that like acute morphine (87). The induction of morphine hyperallodynia in infraorbital nerve-injured rats was blocked by the 5HT1A agonist, F13640 before or after allodynia induction; F13640 also blocked morphine CPP and naloxone-induced conditioned place aversion (230). Administration of combined calcium-magnesium gels, but not calcium alone attenuated the development of morphine tolerance, morphine dependence and morphine withdrawal (933).
5a-v. Other forms of opioid tolerance 

Chronic morphine administration resulted in tolerance to delta opioid receptor-mediated antinociception induced by Delt (922). Intrathecal administration of (−)-oxymorphone, but not (+)-oxymorphone up regulated spinal DYN, produced thermal and tactile hypersensitivity, and produced analgesic tolerance (386).
5b. Animal models in dependence and withdrawal responses
This section will be divided into the following sub-sections: (i) cellular effects on morphine dependence and withdrawal, (ii) organismic effects on morphine dependence and withdrawal, (iii) opioid effects on morphine dependence and withdrawal, (iv) peptide-transmitter effects on morphine dependence and withdrawal, and (v) other forms of opioid dependence and withdrawal.
5b-i. Cellular effects on morphine dependence and withdrawal responses 

Morphine dependence was associated with changes in cytoplasmic and mitochondrial enzymes including proteins belonging to GTPase and GST super families, ATPase, asparaginase or proteasome subunit p27 families (93). Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence (661). Inhibition of adenylyl cyclase II activity following chronic opioid agonist exposure and withdrawal is modulated by phosphorylation (995). Both adenosine and naloxone increased regional cerebral blood flow in morphine-dependent rats accompanied by elevated blood pressure and heart rate (572). Altered periodicity and expression of circadian clock gene, mPer1, occurred in mouse brain and kidney under morphine dependence and withdrawal (1193). Heroin produced oxidative stress and exogenous antioxidant-alleviated withdrawal responses (1246). MOR and orexin/hypocretin mRNA levels in the LH and striatum are enhanced by morphine withdrawal (1323). Opiate withdrawal induces dynamic expressions of AMPA receptors and its regulatory molecule CaMKIIalpha in hippocampal synapses (1320). Although acute and withdrawal-induced morphine and nicotine increased central and peripheral concentrations of pregnenolone, progesterone and allopregnanolone that was abolished by either adrenalectomy or gonadectomy, a challenge dose of morphine or nicotine 24 h after withdrawal failed to induce effects (233).
Agmatine decreased the calcium signal in morphine-dependent CHO cells by activation of IRAS, a candidate for imidazoline I1 receptor (1236). The non-competitive NMDA antagonist reversed the decreases in postsynaptic density proteins in the hippocampus of rat offspring of morphine-addicted mothers (1268). Naloxone-precipitated morphine withdrawal up regulated MOR labeling in NAC, C/P, medial-basal thalamus, basolateral and basomedial amygdala, and VTA in prepubertal male, but not female mice with the GABA B agonist, baclofen re-establishing MOR levels in the first three brain areas in males (281). Naloxone-precipitated, but not spontaneous withdrawal in morphine-dependent rats increased MAPK1/2 phosphorylation in cortex and striatum in a manner similar to acute sufentanil, morphine and SNC-80, but not U50488H; morphine tolerance did not change MAPK ½ activity (42). Consumption of low naltrexone doses in the drinking water of morphine-dependent rats decreased withdrawal signs and increased MOR mRNA expression in the NTS, but not the LC, VTA, frontal cortex, striatum or amygdala (1145).
Pregnant females treated with morphine pellets had offspring with higher morphine-induced and endothelin-1-induced G-protein stimulation (927). Acute and chronic morphine treatment respectively stimulated and decreased Na+, K+-ATPase activity with the latter effect augmented by naloxone precipitated withdrawal; these effects were inversely correlated with cAMP accumulation, and were modulated by PKA inhibitors and protein phosphatase inhibitors (1239). There is a lack of cAMP-specific phosphodiesterase 4 activation during naloxone-precipitated morphine withdrawal in rats (585). Chronic morphine increased NR1 NMDA mRNA in the central amygdala, and NR1 and NR2B NMDA protein in the NAC (55).
Persistent and reversible morphine withdrawal-induced morphological reductions in spine density were observed in the NAC shell, but not core (280). Enhanced Fos expression was observed in glutamic acid decarboxylase immunoreactive neurons of the mouse PAG during opioid withdrawal (433). Galanin attenuates CREB phosphorylation induced by chronic morphine and naloxone challenge in Cath.a cells and primary striatal cultures (457).
5b-ii. Organismic effects on morphine dependence and withdrawal responses 

A requirement for protein synthesis was proposed in the modeling of the onset of drug dependence (536). By adding a transient early phase and a delay of the buildup of protein, a modified ‘Joyce model’ of opioid dependence and withdrawal shows excellent fit of data (936). Genetic differences were noted among 12 strains of inbred mice in the ability of CFA to lower the ED50 of morphine analgesia, enhance morphine tolerance and alter physical dependence signs precipitated by naloxone (660). Global opiate withdrawal scores were evident 56 h later in female relative to male mice, but males display earlier signs of opiate withdrawal using paw tremors and wet dog shakes (876). Maternal deprivation specifically enhanced vulnerability to opiate dependence in rats (1150). Brief early handling increased morphine dependence in adult rats without differences in pre-pro-Enk or MOR levels in the limbic system (1151). Heroin self-administration respectively lowered and elevated ICSS thresholds in naïve and dependent rats. Naloxone increased heroin consumption and reversed heroin-lowering of ICSS thresholds in naïve rats, and increased heroin consumption and elevated ICSS thresholds further in dependent rats (568). Conditioned withdrawal is readily established to discrete cues associated with naloxone-precipitated withdrawal from acute, infrequent opioid exposure (30). Morphine withdrawal for 18 h and 4 days reduced subsequent morphine analgesia, but the latter response was restored 20 days after withdrawal; this effect was augmented by stress applied after 18 hours. RU38486, a glucocorticoid receptor antagonist increased morphine analgesia four days after withdrawal (294). Naloxone-precipitated withdrawal from morphine produced potentiated startle responses which on the first day were blocked by inactivation of the basolateral or central nuclei of the amygdala or BNST, but not NAC, and which on the second day were blocked by inactivation of the NAC, but not the basolateral or central nuclei of the amygdala or BNST (450).
Although the major human metabolite, 6beta-naltrexol, was as potent as naltrexone in precipitating withdrawal in opiate-dependent monkeys, it was far less potent than naltrexone in MOR binding, shifting alfentanil-induced analgesia to the right, and blocking opiate-induced respiratory depression and itching/scratching responses (598).
5b-iii. Opioid effects on morphine dependence and withdrawal responses 

Novel depots of buprenorphine suspended in sesame oil have long-acting ameliorating effects for the management of physical dependence to morphine in mice (684).
5b-iv. Peptide-transmitter effects on morphine dependence and withdrawal responses 

Whereas over expression of CREBGFP in the LC aggravated morphine withdrawal behaviors and sensitized the cAMP-signaling pathway, dnCREBGFP in the LC attenuated morphine withdrawal behaviors and hyperpolarized LC neurons (442). Mice lacking calcium-calmodulin-dependent protein kinase IV displayed less morphine analgesic tolerance, but no changes in acute morphine analgesia or physical dependence (600). Spinal modulation of CGRP by endocannabinoids participates in the development of opioid physical dependence (1131). ATP-dependent K+ channel blockade decreased nicotine-induced inhibition of withdrawal in morphine-dependent rats (1299). Morphine withdrawal responses were enhanced by inhibition of spinal phosphoinositide 3-kinase (1266). The D1 receptor agonist, SKF82958 was rewarding in morphine-dependent rats, and blocked naloxone-induced conditioned place aversions and somatic signs of opioid withdrawal while increasing P-Glu-R1, but not P-CREB in the NAC. Naloxone reduced SKF 82958-mediated P-GluR1 induction in morphine-dependent rats (183). Yohimbine pretreatment potentiated the efficiency of clonidine to decrease naloxone-precipitated opioid withdrawal signs (1073). Scopolamine attenuated such naloxone-precipitated withdrawal signs as jumping, writhing, weight loss, genital grooming, teeth chattering, ptosis, diarrhea and irritability (1241). Lack of neuropeptide Y attenuates the somatic signs of opiate withdrawal (864). RF9, a neuropeptide FF receptor antagonist, prevented opioid-induced tolerance associated with hyperalgesia (1039).
Cross-talk between NO and ERK1/2 signaling pathways in the spinal cord mediates naloxone-precipitated withdrawal in morphine-dependent rats (165). Conantoxins and variants derived from cone snail venom inhibit naloxone-induced withdrawal jumping in morphine-dependent mice (1209). The aqueous and methanolic, but not chloroform extracts of rhizome and aerial parts of Valeriana officinalis L reduced naloxone-induced jumping in morphine-dependent mice (1017). Withdrawal responses from morphine, DAMGO and U50488H as well as the induced Ach response are reduced by isoquinoline alkaloid derivatives from A. mexicana and A. constricta as well as papaverine (166).
5b-v. Other forms of opioid dependence and withdrawal responses 

Elevations in ICSS reward thresholds and somatic withdrawal signs are noted following spontaneous and naloxone-precipitated withdrawal from fentanyl (145). Caffeine paired with naloxone produced a quasi-morphine withdrawal syndrome in wild-type, but not adenosine A(2A)R(−/−) KO mice, although both groups had similar levels of striatal mu opioid receptors (98). MOR and KOR agonists antagonize icilin-induced wet-dog shaking in rats (1215).
6. Learning and Memory
Learning and memory effects of endogenous opioid peptides, their receptors, their agonists and their antagonists, as well as genetically altered animals continue to be studied extensively. Recent developments will be reviewed for animal models in CPP (Section 6a), conditioned aversion paradigms (Section 6b), drug discrimination and spatial learning (Section 6c), as well as memory and amnesia (Section 6d). 

6a. Opiates and conditioned place preferences (CPP)
The following sections examine opioid CPP, non-opioid effects upon opioid CPP, and opioid effects upon non-opioid CPP respectively.
6a-i. Opioid CPP 

CPP can be induced by both morphine and its metabolite, M6G in mice (1165). Rats that displayed high levels of seeking for novelty displayed greater morphine-induced CPP and increased morphine self-consumption (894). Prenatal morphine exposure during the time of opiate receptor appearance does not alter adult morphine-induced CPP or self-administration (952). Restraint, tail-pinch and social defeat in an agonistic encounter each produce the reinstatement of morphine-induced CPP that had been extinguished (950). Involvement of endogenous ligands for mu-, delta- and kappa-opioid receptors was observed in modulating morphine-induced CPP expression in rats (663). Morphine-induced CPP was increased by combinations of methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate and restraint stress in out bred Sprague-Dawley and inbred Fischer 344 rats, yet this treatment decreased morphine-induced CPP in inbred Lewis rats (412). Naloxone, but neither proglumide nor MK-801, altered effects of morphine pre exposure on morphine-induced taste aversions to saccharin (355). Artificial rearing produced a greater morphine-induced CPP as adults than maternal rearing (694). There were differential changes in CREB in rat hippocampus, prefrontal cortex and NAC during the three phases of morphine-induced CPP in rats (1322).
6a-ii. Non-opioid effects on Opioid CPP 

Inhibition of the ERK pathway or protein synthesis during re-exposure to morphine or cocaine erases previously learned place preferences (1143). Administration of protein synthesis blockers such as anisomycin or cycloheximide into the hippocampus, amygdala, or NAC, but not the VTA after a conditioning session blocked a morphine-induced CPP which did not return after further conditioning (777). However, another study (1272) failed to observe any effect of the protein synthesis inhibitor, anisomycin in the basolateral amygdala following retrieval to impair expression of morphine CPP. Intrahippocampal inhibition of protein kinase A attenuates morphine-induced conditioned place preference (1018).
Inhibition of the cyclooxygenase pathway attenuated morphine-induced conditioned place preference in mice (398). D1/D2 dopamine receptor antagonists and D3 dopamine receptor agonists block foot shock stress-induced enhancement of morphine conditioned place preference (257). Mice lacking dopamine beta-hydroxylase fail to show morphine-induced CPP or hyper locomotion with viral restoration of dopamine beta-hydroxylase in the NTS, but not LC restoring morphine-induced CPP; the enzyme in both sites partially restores hyper locomotion (865). CCK B receptors in the NAC are necessary for the expression of morphine conditioned place preference by acting through D2 dopamine receptors (783). Ultra-low doses of nicotine reduce the expression of morphine-induced conditioned place preference in mice that was reversed by hexamethonium (1013). Theophylline inhibits tolerance and sensitization induced by morphine in a conditioned place preference paradigm (981). The too few mutant zebra fish displays food-induced, but not morphine-induced CPP (630). Administration of l-threo-3,4-dihydroxyphenylserine or carbidopa restored morphine-induced CPP in DBH KO mice that was then blocked by NK1 receptor antagonism (517). Corticosterone suppression can affect in the absence of an inescapable stressor block a morphine-induced CPP and induced changes in NAC DA, indicating that corticosterone is involved in the expression, but not the induction of stress-induced sensitization of morphine CPP (277).
Microinjection of D1 (SCH39166) or D2 (L-sulpiride) antagonists into the NAC shell, and to a lesser degree, the NAC core impaired the acquisition, but not the expression of a single-trial morphine-induced CPP (342). Repeated administration of apomorphine, SKF38393, quinpirole and sulpiride into the NAC enhanced morphine-induced CPP, whereas repeated NAC SCH23390 reduced morphine-induced CPP (1293). Ifenprodil, a NR2B subunit of the NMDA receptor antagonist, blocked CPP induced by morphine, but not natural rewards or social interaction. CPP induced by morphine, but not natural rewards or social interaction augments NR2B NMDA expression in the NAC and hippocampus (711). Intra-ventral pallidal glutamate antagonists block expression of morphine-induced CPP (258). The glycine site/NMDA receptor antagonist, MRZ2/576, reduced the acquisition and expression of CPP and locomotor activity induced by morphine in mice (1330). Ventricular administration of a neuropeptide FF agonist blocked the acquisition of a morphine CPP (724). Agmatine enhanced CPP induced by low morphine doses, an effect augmented by L-arginine, a NO precursor and blocked by L-NAME and aminoguanidine, NOS inhibitors (574); this potentiation was also modulated by alpha2-adrenoceptors (1098). An inhibitory effect of paeonol on morphine-induced locomotor sensitization and conditioned place preference was observed in mice (328). Mice that either lacked the pre-pro-orexin gene or received the orexin antagonist, SB334867A into the VTA failed to display morphine CPP or locomotor sensitization while reducing morphine-induced increases in DA levels (819). Prenatal cocaine exposure blocked morphine CPP as well as increased threat, avoidance and fleeing during a social encounter after isolation (326). Post-training and post-reactivation administration of amphetamine enhances morphine CPP (103).
6a-iii. Opioid effects on non-opioid CPP 

The kappa and partial mu opioid agonist, nalbuphine blocked morphine-induced CPP and increased NAC DA metabolites, but failed to affect morphine-induced locomotor sensitization (1110). Glycyl-glutamine, an inhibitory dipeptidyl synthesized from BEND(131) inhibited the acquisition and expression a nicotine CPP, and blocked acquisition of a conditioned place aversion induced by chronic nicotine paired with mecamylamine, but not one paired with the kappa agonist, U50488H (404).
6b. Opiates and conditioned aversion paradigms
Morphine administration 20 h prior to naloxone produced greater conditioned place aversion than naloxone alone and better than morphine-6-beta-naloxol pairing, implicating constitutively active mu receptors in this process (1032). The glutamate release inhibitor riluzole attenuated the formation of conditioned place aversion induced by naloxone in rats undergoing a single morphine exposure (525).
6c. Opiates and drug discrimination and spatial learning
The VTA and PAG appear more critical than the parabrachial nucleus in mediating antagonist-induced disruptions of the discriminative stimulus effects of systemic morphine for food reinforcement in both sexes of rats (613). Olfactory repeated discrimination reversal in rats was impaired by morphine but only at doses that affected performance of the well-learned performance discrimination (380). Discriminative-stimulus effects of methamphetamine and morphine are attenuated by cAMP-related compounds (1259). The NMDA antagonist, LY235959 produced additive and supra-additive effects on schedule-controlled responding when paired with butorphanol and nalbuphine, but only additive or sub-additive effects when paired with morphine or buprenorphine. LY235959 potentiated analgesia induced by all opioid agonists (349). Chlordiazepoxide and dizocilpine, but not morphine, selectively impair acquisition under a novel repeated-acquisition and performance task in rats (913). The NMDA antagonists, ketamine, phencyclidine and MK-801 generalized to the discriminative stimulus effects of U50488H, but not TRK-820 in rats. (800). Old mice lacking liver-derived IGF-I had impairments in the acquisition of spatial memory that were accompanied by increased hippocampal Enk and DYN immunoreactivity but lower mRNA levels of the opioid peptides in the hippocampus (1094).
6d. Opiates and memory
Mu and kappa, but not delta opioid receptor agonists in the NAC regulate attentional learning in the blocking paradigm (504). Odor paired with tactile stroking in rat neonates produced odor preferences, and the acquisition and consolidation of this response was blocked by naltrexone (974). Odor-shock pairings in neonatal animals produce an odor preference that activates c-Fos in the granule cell layer of the olfactory bulb and the anterior piriform cortex. Post-training naltrexone treatment in the amygdala turned the odor preference into an aversion, blocked Fos expression in the piriform cortex, and activated Fos expression in the central nucleus of the amygdala (973). Beta-casomorphin-5, a mu-opioid agonist from bovine milk ameliorated scopolamine-induced impairments in spontaneous alternation behavior and passive avoidance in a mu- and mu1-antagonist sensitive manner (984). Morphine-induced state-dependent memory of passive avoidance was blocked by centrally-acting muscarinic and nicotinic antagonists, but not peripheral nicotinic antagonists. Centrally-acting, but not peripherally-acting anticholinesterase drugs enhanced morphine-induced retrieval (510). Morphine-induced amnesia in passive avoidance was decreased by L-arginine, whereas L-NAME and low morphine doses produced amnesia. Apomorphine inhibited morphine-induced amnesia, and the L-NAME-induced inhibition of morphine amnesia was blocked by DA D1 or D2 receptor antagonists (949).
Morphine-induced deficits in passive avoidance learning were ameliorated in part by treadmill running exercise (14). Opioid receptor antagonism in the PAG prevented blocking of prediction errors during Pavlovian fear conditioning (762). Central, but not peripheral opioid receptor antagonism alleviated retrieval of infant fear memories in developing rats (1202). Big DYN increased step-through latencies on a passive avoidance task, increased locomotor activity and increased anxiolytic behaviors on the open field and elevated plus maze with all effects blocked by MK-801. In contrast, DYN A and DYN B increased memory through a NBNI-dependent mechanism, and failed to affect locomotor or anxiolytic responses (621).
Mecamylamine-induced reductions in passive avoidance responses were blocked by DYN A (113) and DYN A (213) with the latter effect insensitive to NBNI antagonism. Mecamylamine-induced extracellular Ach decreases were also abolished by DYN A(213) in a kappa antagonist-insensitive manner (474). Ventricular administration of D1 and D2 agonists as well as D2 antagonists on a passive avoidance test day reversed morphine’s pre-test amnestic effects, whereas central D1 antagonism prevented the restoration of passive avoidance responses by morphine administration on the test day (1294). Central L-glutamate and MK-801 administered prior to a passive avoidance test respectively reversed and enhanced amnesia induced by pretraining morphine, and respectively increased and decreased morphine state-dependent learning (1296). Morphine state-dependent learning sensitization was decreased by pretreatment with L-NAME and L-arginine (1292). The CB1 agonist, WIN55,212–2, mimicked the ability of pre-test morphine to restore passive avoidance learning, and enhanced morphine’s ability as well; the CB1 antagonist AM-251 blocked morphine’s and WIN55,212–2’s memory-restorative effect (1297). Histamine administration prior to passive avoidance training decreased learning, whereas pre-test histamine reversed this amnestic effect. Mice sensitized with morphine or apomorphine exhibit reversals of histamine’s pre-training amnestic effects with morphine’s effects blocked by naloxone, SCH23390 or sulpiride (1298). Nicotine reversed morphine-induced amnesia and morphine-induced state-dependent learning, effects blocked by atropine (1300).
7. Eating and Drinking
This section will review ingestive effects as functions of opioid agonists (Section 7a), opioid antagonists (Section 7b), and the interaction of POMC-derived peptides (Section 7c). 

7a. Opioid agonists and ingestive behavior
Whereas DAMGO in the NAC increased consumption of two types of flavored food pellets, intake of the preferred pellet in a choice test was respectively enhanced and reduced by DAMGO and naltrexone in the NAC; systemic naltrexone had no effect (1230). DAMGO-induced increases in high-fat feeding were blocked by naltrexone and muscarinic antagonism, but not by antagonists of DA, glutamate or nicotinic receptors (1218). Administration of morphine, but not DAMGO, Dyn or U50488H into the rostral lateral hypothalamus induced feeding, whereas naltrexone into the same site elicited c-Fos activation (652).
Whereas bicuculline administered into the ventral pallidum increased saccharin, but not quinine or water in water-deprived rats, pallidal muscimol and SCH23390 reduced this response. Pallidal DAMGO initially suppressed, but then stimulated saccharin intake in water-deprived rats (1029). DAMGO increased fat preference and increased food intake in Osborne-Mendel fat-preferring rats, but only switched preference in S5B/PI fat-resistant rats. Osborne-Mendel rats also had increased MOR and MOR mRNA in the arcuate nucleus (65). Morphine time-dependently prevented acetic acid-induced writhing and the suppression of palatable food intake; haloperidol inhibited the former, but not latter response (1069). Mice with deletion of the DA transporter and thus elevated levels of DA enhances their tendency to work for a food reward without affects on Pavlovian or operant learning for that reward; increased DYN in the C/P and in the core, but not shell of the NAC were observed (156). Chronic infusion of OFQ/N increases food and ethanol intake in alcohol-preferring rats (224). Whereas OFQ/N prolongs feeding induced by food deprivation by decreasing activity of AMSH neurons involved in feeding termination, AMSH at doses capable of reducing deprivation-induced feeding, failed to affect OFQ/N-induced feeding (109). Novel ORL-1 agonists, OS-500 and OS-462 produced greater degrees of feeding than OFQ/N following ventricular, but not systemic administration, an effect blocked by the ORL-1 antagonist, UFP-101, but not NC-797 (308).
The ability of the CRF2 receptor agonists, urocortin II and III to inhibit food intake was unaffected by OFQ/N (338). OFQ/N-induced feeding was respectively stimulated by muscimol and inhibited by bicuculline in cockerels (1100). BEND KO mice displayed increased systolic blood pressure, increased MPOA c-Fos activity and higher levels of urinary epinephrine secretion following a high-sodium diet relative to heterozygotes and controls (155). Preoperative epidural morphine together with postoperative transdermal fentanyl restored normal behavior and weight gain in pigs receiving abdominal surgery (715).
7b. Opioid antagonists and ingestive behavior
Increased body weight was observed in MOR KO mice, an effect accompanied by increased hypothalamic NPY mRNA (445). A diaryl ether derivative, (6-(4-{[(3-methylbutyl)amino]methyl}phenoxy)- nicotinamide, capable of displacing MOR, KOR and DOR agonists, suppressed food intake and weight gain in obese rats and mice, but failed to do so in MOR KO mice (1306). Naloxone decreased palatable food intake and increased latency to feed in sated, but not food-restricted rats without affecting food-anticipatory activity (63). Administration of BFNA or CTAP into the dorsal caudomedial shell of the NAC significantly reduced sucrose intake, but did not alter overall chow intake or body weight in rabbits, and also produced specific losses of MOR coupling to their G-proteins (1197). Chronic prevention of MOR G-protein coupling by BFNA in the pontine parabrachial nucleus persistently decreased consumption of standard but not palatable food (1198).
CPPs induced by exposure to either high-sugar (Fruit Loops) or high-fat (Cheetos) snack foods were each dose-dependently suppressed by naltrexone (516). Food-induced behavioral sensitization that conditioned activity was cross-sensitized with cocaine and morphine, and blocked by naltrexone and noncompetitive AMPA antagonism (648). Naloxone failed to reduce sucrose intake in mice with Enk deleted, with BEND and Enk deleted, and with DYN deleted, but showed normal inhibitory responses in mice with only BEND deleted (458). Naltrexone reduced sucrose intake, particularly in a group of rats exposed to a consummatory contrast paradigm and only for the relatively more valuable sucrose solution (1097). Naloxone reduced the ability of orexin and NPY to increase saccharin intake (374). Two studies by the same laboratory showed that central naloxone blocked the ability of central administration of interleukin-1beta to suppress water and salt intake in fluid-deprived and sodium-depleted rats induced by hypernatremia and hypovolemia; interleukin-1beta failed to affect saccharin intake (269, 708).
7c. POMC-derived peptides and ingestion
Anticipation of ingestion of a corn oil emulsion increased hypothalamic POMC and orexin mRNA expression for up to 30 min of presentation and until ingestion (789). Mice lacking 11 beta-hydroxysteroid dehydrogenase type 1 show lower levels of arcuate CART and MC-4 receptors, but higher levels of melanin-concentrating hormone, and when on a high-fat diet display an up-regulation of AGRP concomitant with high-fat-induced hyperphagia (274). Starvation in Xenopus laevis produced significant reductions of immunopositive Menk, CART, Fos and urocortin-1 in the hypothalamic magnocellular nucleus accompanied by an increase in CRF (159).
Electroacupuncture produced greater decreases in weight loss and serum leptin levels, coupled with greater increases in serum BEND than diet restriction in female obese subjects (154).
8. Alcohol and Drugs of Abuse
The interaction between opiates and other drugs of abuse, particularly alcohol, continues to be a vigorous area of investigation. This section is organized into a consideration of how the opioid system works in the general area of drugs of abuse (Section 8a), in opiate self-administration (Section 8b) and in interactions with ethanol (Section 8c), THC (Section 8d), stimulants such as cocaine and amphetamine (Section 8e) and other abused drug classes (Section 8f). 

8a. Opiates and drugs of abuse: reviews
New challenges and opportunities are reviewed in managing substance abuse in Malaysia (751).
8b. Opiates and self-administration studies
8b-i. Animal studies 

Disrupting reconsolidation of conditioned withdrawal memories in the basolateral amygdala reduces suppression of heroin seeking in rats (463). A novel bivalent morphine/heroin vaccine prevented relapse to heroin addiction in rodents (34). Unlimited access to heroin increased daily self-administration across the circadian cycle with decreased levels of food intake occurring across the circadian cycle with daytime intake increasing meal frequency and nocturnal intake displaying smaller and briefer meals; this reduced body weight gain (196). Conditioned heroin-seeking, but not sucrose-seeking behaviors increased early gene expression of ania-3, MKP-1, c-fos and Nr4a3 in the medial frontal cortex, and of ania-3 in the orbitofrontal cortex and NAC (609). Destruction of dopamine neurons in the rostral linear nucleus and periaqueductal gray blocked the rewarding and sensitizing properties of heroin (351).
Activation of group II metabotropic glutamate receptors in the NAC shell attenuates context-induced relapse to heroin seeking (117). Adenosine A2a blockade prevented the synergy between MOR and cannabinoid CB1 receptors and eliminated heroin-seeking behavior in addicted rats (1269). CRF antagonism, but not adrenalectomy blocked acute food-deprivation-induced reinstatement of heroin seeking in rats (1012). Nondependent monkeys increased choice of heroin over food as the heroin dose increased with chronic naloxone and buprenorphine, but not methadone blocking this response. Heroin-dependent monkeys in withdrawal also showed increased heroin choice over food with methadone more effective than buprenorphine in blocking this latter effect (832). Whereas heroin and DAMGO reduced VTA GABA firing rats and internal capsule stimulation post-spike discharges, acquisition of heroin self-administration behavior increased the firing rate of VTA GABA neurons (1068). Prenatal heroin exposure disrupted the development of cholinergic-induced translocation and activation of PKC isoforms (493). Expression of NR1/NR2B N-methyl-D-aspartate receptors enhances heroin toxicity in HEK293 cells (292). 18-methoxycoronaridine acted in the medial habenula and interpedunuclar nucleus to decrease morphine self-administration in rats (403). Cardiovascular responses failed to change after naloxone administration in propofol-sedated piglets during opioid overdose (125).
Although a CS previously paired with naltrexone-precipitated withdrawal suppressed heroin seeking in extinction, it elevated responding if rats had prior experience of heroin taking in the presence of the withdrawal CS (464).
8b-ii. Human studies 

The prescribing of naloxone to actively-injecting heroin users in Chicago has been associated with a reversal in heroin-induced deaths between 2000 and 2003 (749). Diamorphine (heroin) prescriptions were a long-term commitment in the United Kingdom and were not associated with serious drug, health or social problems (773). The use of “take home naltrexone” for homeless drug users was evaluated for awareness and risk perception (1232). An intranasal diamorphine spray was effective as an alternative to injectable diamorphine for maintenance treatment (784). The incidence of heroin use in Zurich, Switzerland rose between 1975 and 1990, and then declined between 1990 and 2002 (850). There was an association between the availability of heroin and methadone and fatal poisoning in England and Wales between 1993 and 2004 (797).
The greatest increases and then declines in methadone deaths happened on Saturdays (798). Heroin-using drivers displayed impairments that correlated with morphine and M6G blood levels (48). Massive decreases in Canadian heroin supply coincided with an Australian heroin shortage (1227). Malay subjects displayed a higher prevalence of current injection drug use, needle sharing and HIV infection than Chinese subjects (184). Methadone-induced overdose deaths were associated with testing positive for a tricyclic anti-depressant or benzodiazepine (179). Methadone maintenance patients are cross-tolerant to morphine analgesia at very high plasma morphine concentrations (44). Methadone-stabilized pregnant patients were safely transferred to buprenorphine using an immediate release morphine transition (532). S(+)-ketamine attenuated the increase in EEG activity and amplitude height of sensory-evoked potentials during rapid opioid detoxification (362). Nonketotic hyperglycemia coma occurred in toddlers after unintentional methadone ingestion (1122). Effective and ineffective methadone dosages overlap considerably for individual opioid-dependent patients (1130). Central morphine concentrations are on average twice as high as peripheral morphine concentrations in heroin overdose victims (244). Although most overdoses occur within 5 min after buying a drug and administering it alone, knowledge of dangers of mixing benzodiazepines with heroin actually increases the likelihood of such behaviors (284).
Opioid-dependent individuals who had used heroin, had injected drugs, had witnessed a drug overdose or who had a history of one or more accidental overdoses were significantly more willing to treat with naloxone a companion who had overdosed (624). Opiate overdoses in Rhode Island were more likely in males under 54 in a private residence on weekends around 9 PM (770). Hydrocodone-related fatalities in Ontario typically occurred in the presence of another drug (1179). A strict correlation was not observed for the relationship between plasma cortisol levels, withdrawal symptoms and craving in abstinent and treated heroin addicts (825). Salvia divinorum, which contains the psychotropic, diterpene and the KOR agonist, salvinorin A is mostly smoked to achieve a short-lived but intense psychedelic experience in recreational users (408).
Post-mortum analyses of heroin abusers indicated that subjects with MOR A118G polymorphisms displayed exaggerated down-regulation of prepro-Enk, but also prepro-DYN especially in the NAC shell (300). The ability of levomethadone to reduce pupil size and miosis was attenuated in healthy human volunteers possessing the 118A>G single-nucleotide polymorphism of the MOR gene (697). However, a meta-analysis failed to find a relationship for a risk of substance dependence with the Asn40Asp (A118G) single nucleotide polymorphism of the human MOR (36). Sex, body weight, benzodiazepine use and creatinine clearance are not factors in prescription of heroin for heroin dependency (969). Subjective heroin effects were rated more positively in heroin inhaling than in injecting patients (970); mast cell mediator tryptase concentrations occurred in the latter, but not former treatment (971).
Heroin addicts display increased polysialic neural cell adhesion molecule expression in the hippocampus (1203). 6-acetylmorphine assays are more accurate than morphine assays in detecting heroin use in urine samples (71). Analyses for papaverine metabolites were more sensitive for detecting illicit heroin use than analysis of 6-monacetylmorphine (884). DRI and CEDIA, but not REMEDi systems are best for preliminary tests of opiates in human urine (487). Pericardial fluid can be used in forensic assays of heroin and cocaine use (237). Straws used to inhaled heroin vapors contained heroin, its main metabolite, 6-acetylmorphine, caffeine and morphine (595); this was confirmed in an in vitro simulation of ‘chasing the dragon’ (596).
The greater incidence of anesthesiologists to fentanyl abuse might be explained by second-hand exposure of fentanyl in air around the mouth of patients during surgery (406). Detoxified opioid-dependent individuals showed greater improvement on all assessment measures following implantation of naltrexone pellets relative to levomethadone treatment (420). Implants of 1.8–3.6 g of naltrexone in opioid dependent individuals maintained plasma levels of naltrexone above 1 nl/ml for 4 to 6 months respectively (1172). Sustained-release naltrexone treatment dose-dependently increased retention in treatment and increased the percentage of negative urine samples in opioid dependent individuals (231). Depot naltrexone was used in lieu of incarceration for coerced treatment for addicted offenders (730), and antagonized the reinforcing, subjective and physiological effects of heroin (1084). Judicially mandated naltrexone by opioid-dependent criminal offenders was analyzed (112, 855), and provision of naloxone to injection drug users as an overdose prevention strategy in New York City proved efficacious (376, 1231). Intranasal naloxone should be used earlier in a tiered-response emergency medical service unit (76). A minority of patients showed recurrent opioid toxicity within 12 h after pre-hospital care of presumed heroin overdose (124) with survival success greater when cardiac arrest is witnessed by emergency workers (123). Slow tapering from methadone maintenance in a program encouraging indefinite maintenance was generally ineffective in opioid-dependent individuals (160). Buprenorphine maintenance was more effective than tramadol detoxification in increasing outpatient treatment participation in opioid-dependent subjects (158). Naltrexone and buprenorphine was more effective than naltrexone alone in opioid dependent individuals in terms of retention (947) as well as lower positive urine samples for morphine and cocaine metabolites (397).
Buprenorphine/naloxone doses greater than 8/2 mg provide minimal incremental value in terms of withdrawal suppression (238). Integrated buprenorphine and naloxone were effective for HIV clinical care in opioid-dependent individuals (1082), and its efficacy was maintained as a function of counseling sessions (347). Introduction of buprenorphine for treatment of substance abuse was robustly predicted by a facility’s prior use of naltrexone and medically-offered withdrawal programs (603). Earlier adoption of buprenorphine was found in private rather than public substance abuse treatment centers (597). Buprenorphine-based outpatient treatment was far more cost-effective than conventional outpatient and inpatient as well as anesthesia-induced detoxification procedures in Australian opiate-dependent individuals (1014), but adverse effects were observed in children after unintentional buprenorphine exposure (391). Slow-release buprenorphine or methadone was better than slow-release morphine in treating heroin addicts in terms of quality of life, symptoms and additional consumption (400). Interactions between buprenorphine and nonnucleoside reverse-transcriptase inhibitor and protease inhibitor antiretrovirals were evaluated in opioid-dependent, buprenorphine/naloxone maintained HIV-negative volunteers (752, 753). Oral slow release morphine over 6 months was safe and efficacious for maintenance treatment in heroin addicts (1148). Buprenorphine tablets were more effective than solutions in producing drug steady state in opiate-dependent individuals (232).
Analgesia and sedation in the presence of a naltrexone implant presented a novel pharmacological challenge for emergency care (854). Naloxone and naltrexone, but not tramadol increased measures of opioid withdrawal in opioid-dependent patients (170). Although most patients in a Veterans Administration study successfully detoxified from opioid use following naltrexone treatment, a one-year follow-up revealed that very few remained engaged and stabilized in abstinence-oriented outpatient treatment (266). Predictors of retention in naltrexone maintenance for opioid dependence included methadone use and higher average bags per day of heroin (1083). Low-dose treatment with naltrexone may help reducing the manifestation of opioid withdrawal in dependent populations (719). Further, although behavioral naltrexone therapy improved retention in treatment for heroin-dependent patients, it generally achieved abstinence from opioids after three months, but only in 22% after six months (853). Naltrexone with fluoxetine prevented relapse to heroin addiction in Russian women (615). Anesthetic opioid detoxification did not differ from clonidine detoxification treatment when combined with psychosocial support in opioid dependent patients (336). Opioid demand in heroin-dependent individuals not in treatment is a function of drug supply, unit price and cocaine use (417).
In two psychonautic studies, concomitant administration of naltrexone with codeine obviated opioid withdrawal syndrome in a single subject (870). Generic controlled release oxycodone approval was not followed by an increase in misuse or abuse (54). A patient genotyped as CYP2D6 PM could not metabolize oxycodone, but had better success with hydrocodone (1089). An automated DOI kit for urinary oxycodone was more reliable that a point-of-care assay (436).
8c. Opiates and ethanol
8c-i. Animal behavioral models 

Enhanced morphine-induced ethanol drinking occurs in alcohol-preferring alko rats sensitized to morphine (859). Spontaneous opioid-mediated and withdrawal-associated CRF1-mediated ethanol drinking was observed in Sardinian alcohol-preferring rats (978). The Naples low-excitability rat line displayed greater alcohol intake and preferences as well as greater sensitivity to quinine and naltrexone than Naples high-excitability rats (892). The greater preferences for ethanol noted in C57BL/6J and hybrid C57BL/6J x CD-1 mice relative to CD-1 mice could not be linked to mesolimbic DA transporter neurochemistry and/or Enk levels, but rather with D2 receptor expression (1033). Whereas mu, but not delta opioid antagonism blocked ethanol-induced sensitization, this effect was not attributable to putative mu1 or mu3 opioid receptors (881). Both MOR and KOR antagonism blocked the reinforcing effects of ethanol on an artificial nipple administered to neonatal rats (846). GABAB receptor stimulation attenuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol (476). KOR antagonism blocks Nac Da concentrations during operant ethanol, but not sucrose self-administration (298). Low and high doses of buprenorphine respectively increased and decreased ethanol consumption with the latter effect more effectively eliminated by the ORL-1 antagonist, UFP-101 relative to naltrexone (223). OFQ/N agonists reduce ethanol intake while increasing food intake in alcohol-preferring rats in a naloxone-sensitive manner (307). OFQ/N blocked ethanol-induced increases of GABA release, and decreased presynaptic GABA transmission in the central amygdala (962).
Although Roman high avoidance strains consume more alcohol than Roman low avoidance strains, the latter show enhanced responsiveness on the hole board test following systemic ethanol. Whereas Roman high avoidance rats have higher Pro-DYN in the NAC shell and Pro-Enk in the cingulate, Roman low avoidance rats have higher Enk gene transcription in the dorsal striatum (425). Female, but not male mice lacking prepro-DYN show lower preferences and consumption of alcohol, but not changes in ethanol-induced loss of righting reflexes, ethanol withdrawal, ethanol-induced CPP or conditioned taste aversions to ethanol (106). Estradiol valerate increased alcohol intake, decreased body weight and food intake, and reduced the number, but not content of arcuate BEND neurons (537). Losers in a social defeat test consumed more ethanol than winners, and thereby displayed lower anxiety levels. U50488H stimulated ethanol intake more in losers than winners, but only increased approach behaviors in losing mice not consuming ethanol (619). Antagonism of endogenous KOR systems potentiated the increased responsiveness of mesoaccumbal Da neurons to ethanol (1290). Naltrexone pretreatment blocked reinstatement behaviors on an operant ethanol lever induced by ethanol-associated context cues (149). Naltrexone reduced ethanol intake, but not craving behaviors in heavy- and light-drinking mice (329). Naltrexone was more effective in blocking the acquisition of alcohol intake in periadolescent relative to adult alcohol-preferring rats whereas greater tolerance to repeated naltrexone dosing was noted in adult relative to periadolescent rats (979). Both naltrexone and acamprosate reduced alcohol and water intake in a schedule-induced polydipsia task, and reduced head entries for food following the highest antagonist doses (324). Naloxone blocked analgesia induced by alcohol and nicotine alone as well as its synergistic combination (162).
8c-ii. Ethanol-induced changes in opioid systems 

Whereas acute ethanol respectively decreased and increased Pro-Enk mRNA expression in the VTA and prefrontal cortex, chronic ethanol increased Pro-Enk mRNA in the core and shell of the NAC (765). Chronic ethanol decreased brain interstitial levels of Menk using in vivo microdialysis (1141). Intubated ethanol perinatally from Days 1–22 increased hypothalamic Menk levels in males and females, NAC Menk levels in females, and lowered Menk levels in the central nucleus of the amygdala in male and female animals (704). Alcohol administration increased extracellular levels of DYN A(18) in the rat NAC (727). Alcohol, nicotine and cocaine evoked release of endogenous morphine from the M.edulis pedal ganglia (1326). Chronic naltrexone prevented acute ethanol-induced increases in BEND plasma levels in Warsaw low-ethanol preferring, but not high-ethanol preferring rat strains (1289).
Ethanol induces apoptotic death of developing fetal rat BEND neurons through suppression of cAMP production and activation of transforming growth factor-beta 1-linked apoptotic signaling (191). Ethanol suppression of hypothalamic POMC levels and splenic natural killer cell cytolytic activity is associated with a reduction in the expression of proinflammatory cytokines, but not anti-inflammatory cytokines in neuroendocrine and immune cells (189). Prenatal ethanol exposure altered the expression of period genes governing the circadian function of BEND neurons in the hypothalamic suprachiasmatic nucleus (190). Chronic ethanol inhibits natural killer cell function by suppressing the influences of BEND, CRF and the autonomic nervous system signals to the spleen (122). Rats exposed to ethanol through breast-feeding displayed decreased BEND in thymic cells whereas pre-natally ethanol-exposed rats displayed decreased 5HT content in immune cells (250).
8c-iii. Human studies 

There are associations between the promoter and 3′ end of Pro-DYN as well as intron 2 of the human KOR with alcohol dependence in human individuals (1251). Acamprosate and naltrexone prevented decreases in ACTH and cortisol during alcohol abstinence, and this was associated with a reduced risk of relapse (575). Acamprosate increased BEND plasma concentrations in patients with high, but not low alcohol preference (576). Naltrexone was found to be superior to acamprosate in relapse prevention of alcoholism among individuals with low levels of clinical depression and alcohol dependence (803). Alcohol-dependent and PTSD subjects displayed significantly higher stress ratings and decreased ACTH responses on the cold pressor task response (129). Targeted naltrexone was better than daily naltrexone in affecting average daily drinking (466). Naltrexone’s reduction in blood alcohol level following acute ethanol intoxication accounted for the changes in subjective and behavioral responses to alcohol but not the reduction in HR (902). Naltrexone appeared effective in the treatment of alcohol dependence particularly with respect to heavy drinking (907). Cognitive behavioral therapy when combined with both naltrexone and acamprosate produced the greatest improvement in outcome measures in alcohol dependent individuals relative to each treatment alone (35, 339; but see (289)). Naltrexone produced strong positive associations between the number of positive social celebratory events and drinking although such events occurred on a minority of days (37). Although naltrexone failed to alter the Positive and Negative Syndrome Scale in alcoholic patients, it further augmented the dose-dependent effects of low, but not high doses of ketamine (616). G-hydroxybutyrate was more effective than naltrexone or disulfiram in reducing craving and altered biological markers of alcohol abuse (826). Although there was no clear advantage of naltrexone, disulfiram or their combination in the treatment of alcohol abuse in patients with psychotic spectrum disorders (903), they were effective in patients suffering from PTSD (904). Asp40 carriers acted as genetic moderators of naltrexone’s effects on alcohol cue reactivity (757). Both the A118G polymorphism in the MOR gene and a polymorphism, G1510A, in the acetaldehyde dehydrogenase 2 gene were associated with alcohol dependence in a Japanese population (845). Intervention with morphine at the level of the neuroendocrine-immune axis decreased post-operative pneumonia rate in long-term alcoholics (1060). Nonalcoholic subjects with a family history of alcoholism exhibit lower plasma ACTH and BEND levels following stress and CRF stimulation conditions (1026).
8d. Opiates and THC
CB1 knockout mice display significant increases in striatal preproEnk and preproDYN as well as D4 DA receptor gene expression (396). Both morphine and the CB1 agonist HU210 inhibited Ach and GABA release in the NAC core that was blocked respectively by naloxone and the CB1 antagonist, SR141716 A. Co treatment of the two antagonists reversed their respective blockade of the agonist-induced inhibitory effects (999). MOR and CB1 receptors display reciprocal inhibition of receptor signaling and neuritogenesis (955), thereby failing to form hetero-oliogomers (215). Correspondingly, the acute and chronic suppression by the CB1 cannabinoid receptor inverse agonist AM251 on food intake and body weight was observed in both wild type and MOR KO mice (195). The CB-1 antagonist, SR 141716A blocked the ability of morphine to significantly reduce ventral pallidal GABA efflux, and blocked heroin, but not cocaine self-administration following administration into the NAC, but not the pallidum (157). Morphine in the PVN inhibited in a naloxone-sensitive manner the penile erections induced by PVN administration of the CB1 antagonist SR 141716A as well as the concomitant increases in PVN glutamic acid and NO (1076). Tolerance occurred to the reinforcing effects of morphine in delta9-tetrahydrocannibinol-treated mice (515). Cannabinoid type 2 agonists induce transcription of the MOR gene in Jurkat T cells (113). The acquisition of self-administration of the CB1 agonist WIN 55,212–2 was enhanced by both NBNI administered prior to the session in wild-type mice and in pro-DYN KO mice (766). Prenatal cannabis exposure was associated with increased MOR in the amygdala, reduced KOR mRNA in the mediodorsal thalamus and reduced Pro-Enk expression in the C/P. Prenatal alcohol exposure decreased KOR mRNA in the amygdala, claustrum, putamen and insula cortex (1191).
Cannabidiol, a major constituent of cannabis, is an allosteric modulator at mu- and delta-opioid receptors (556). Whereas systemic naloxone and naltrexone prevented THC-induced release of Ach from prefrontal cortex and hippocampus, VTA administration of naloxonazine and the D1 DA receptor antagonist, SCH39,166 produced the same pattern of effects (912).
8e. Opiates and stimulants
8e-i. Animal behavioral studies 

An AS to the MOR coding sequence 16–32 attenuated cocaine-induced behavioral sensitization and reward (495). Both contingent and non-contingent administration of cocaine increased Pro-DYN, but not Pro-Enk mRNA levels in the C/P, but not in the NAC or central nucleus of the amygdala (1331). Acute and chronic administration of the selective delta opioid agonist SNC80 decreased both cocaine- and food-maintained responding in rhesus monkeys (288). Context-dependent extinction occurs for both cocaine- and morphine-induced floor preferences (878). Like repeated forced swim stress, prior activation of kappa opioid receptors with U50488H potentiates cocaine place preference conditioning (758). A combination of cocaine and heroin self-administered at a maximum of three infusions per hour was preferred to either drug alone, and continued during all hours of the light:dark schedule; increased fixed ratio schedules led to extinction (733). Discrete-trials heroin self-administration produced sensitization to the reinforcing effects of cocaine in rats (1199). Administration of estradiol valerate to 8-week old female rats destroyed arcuate BEND neurons and attenuated the acquisition of cocaine self-administration both with and without estrogen replacement therapy (975).
The NK-1 receptor antagonist, GR82334 failed to affect cocaine self-administration or hyper locomotion, but attenuated morphine-induced locomotor activity while increasing heroin self-administration (914). Chronic buprenorphine enhanced acute cocaine-, but not acute heroin-induced locomotor increases early in buprenorphine treatment (1056). A combination of morphine and buprenorphine was more effective than U50488H in reducing self-injurious behavior induced by methamphetamine in mice (799). Sub-additive withdrawal occurs from cocaine and kappa opioid agonist combinations in Planaria (935).
8e-ii. Anatomical, molecular and neurochemical studies 

MOR KO mice display reduced psycho stimulant effects on Da dynamics in the NAC (745). Cocaine-induced locomotor activity and Fos expression in enkephalinergic D2-type neurons in the NAC are sensitized for six months after repeated cocaine administration outside the home cage (478). Prenatal administration of morphine alone or in combination with cocaine significantly increased mu opioid receptor binding and MOR mRNA on post-natal days 1 and 7, but not 14 in the offspring, effects blocked by the D2 receptor antagonist, sulpiride (88). Prenatal cocaine and morphine respectively increase and decrease brain cyclin-dependent kinase (Cdk5) in rat pups (89). The mu antagonist, clocinnamox blocked cocaine- and methamphetamine-induced preDYN mRNA expression only in the rostral patch compartment of the dorsal striatum, attenuated zif/268 mRNA throughout the dorsal striatum, but did not alter regional psycho stimulant-induced Fos expression (479). DA D2 receptor antagonism in the arcuate nucleus attenuated cocaine-induced NAC BEND increases, and produced extinction behavior in cocaine self-administering rats (295).
DYN KO mice showed decreased NAC DA levels, but no changes in DA uptake under baseline and cocaine conditions, an effect enhanced by kappa agonists and blocked by antagonists. DYN KO mice showed less cocaine-induced locomotor activity, and NBNI failed to alter this response (185). In repeated cocaine-treated animals, CREB responses to DYN are mediated in opposite directions by drugs affecting the D1 and D3 DA receptors (1308). Mice lacking glucocorticoid receptors display decreased DYN and SP as well as D1 and D2 receptors in the dorsal striatum, but not NAC under baseline, but not following cocaine behavioral sensitization. In contrast, Enk mRNA levels are altered during cocaine use in glucocorticoid receptor KO mice (507).
Increased striatal c-fos and SP, but not Enk gene expressions were noted in animals given access to running wheels and cocaine than either manipulation alone, an effect that peaked after two exposures (1220).
Methamphetamine-induced increases in striatal dopamine transmission were potentiated by morphine treatment (897). Amphetamine-induced increases in activity as well as striatal Pre-Enk and Pre-DYN mRNA and gene expression were blocked by SL327 and U0126, inhibitors of MAPK and ERK (1027). Chronic methamphetamine down-regulated MOR after 8 days, and after drug cessation, MOR levels returned to normal on Day 11 and then were up-regulated on Day 21 (210). L-methamphetamine and selective MAO inhibitors decrease morphine-reinforced and non-reinforced behavior in rats (459). Acute and chronic amphetamine treatment decreased concanavalin A-lymphocyte proliferation together with increased Menk in the NAC, prefrontal cortex, spleen, thymus and splenic macrophages (43). The rewarding effects of morphine and methamphetamine were respectively aggravated and enhanced by administration of an astrocyte-conditioned medium into the NAC and cingulated cortex respectively. The glial modulator propentofylline suppressed both morphine’s and methamphetamine’s rewarding effects (818).
Ecstasy, 3,4-methylenedioxy-N-methylamphetamine, increased pro-DYN mRNA in the C/P following acute and chronic treatment, the prefrontal cortex following acute treatment, the NAC and hypothalamus following chronic treatment, but decreased gene expression in the VTA following acute and chronic treatment. Accordingly, DYN A levels were increased in the VTA following chronic Ecstasy treatment, and decreased in the NAC, prefrontal cortex and hypothalamus after acute Ecstasy treatment (282).
8e-iii. Human studies 

Comparisons between heroin and heroin-cocaine polyabusers were made in terms of incidence of psychopathology (61). There was an association of DOR gene polymorphisms in methamphetamine dependence and psychosis (602). A 3- or 4-repeat allele of a 68-bp element in the promoter region of the Pro-DYN gene was found significantly more frequently in patients with methamphetamine dependence than in controls (849). Linkages between an IVS2+G691C single-nucleotide polymorphism and methamphetamine patients and transient psychosis were found (498). The Cocaine- and Heroin-Craving Questionnaires appear to predict dropout rates and in-treatment drug use by clients relative to visual analog scores (462).
8f. Opiates and other drug abuse classes
Three-marker haplotypes of the MOR gene were significant for smoking initiation, but were marginal for nicotine dependence (1309). Morphine increased locomotor activity to a greater degree in nicotine-withdrawn as compared to control mice, and effect accompanied by increased Da and 5HT in the striatum (1162). Beta2 nicotinic Ach receptor KO mice fail to display intra-VTA nicotine self-administration, but have normal morphine self-administration and normal nicotine withdrawal behaviors (86). Reinstatement of nicotine-induced place preferences was produced by nicotine or morphine, effects blocked by the calcium channel antagonists, nimodipine and flunarizine (91). Nicotine induced c-fos within CRF and Enk, but not DYN cells within the PVN (698).
Norlaudanosoline and nicotine increase endogenous invertebrate ganglionic morphine (1328). Chronic swim stress increased nicotine’s ability to increase plasma ACTH and BEND, but not corticosterone, whereas stress itself increased plasma corticosterone, but not ACTH or BEND (703). There was an association of the MOR A118G variant with reductions in the relative reinforcing value of nicotine in females, but not males (944). Naltrexone was efficacious in smoking cessation especially in females (587). A high dose of oral naltrexone appeared to augment the efficacy of the nicotine patch in producing smoking cessation after 4–6 weeks (866). Naltrexone and cognitive behavioral treatment based on the community reinforcement approach decreased craving in abstinent smokers (972). However, nicotine self-administration in rats was blocked by mecamylamine and hexamethonium, but not by naloxone (273).
9. Sexual Activity and Hormones, Pregnancy, Development and Endocrinology
This section will examine developments in the last year relating the endogenous opioid system to sexual activity (Section 9a), pregnancy (Section 9b), development (Section 9c), and general endocrinology (Section 9d). 

9a. Sexual activity and hormones
Fentanyl and naloxone respectively decreased and increased sexually motivated song in male European starlings, a pattern opposite to Da (1001). MOR, DOR and KOR were expressed in human spermatozoa with MOR agonists and delta antagonists reducing motility (9). MOR is located on the acrosomal region and the neck region of human sperm (19). Plasma testosterone was respectively decreased and increased 4 and 24 h after morphine, fentanyl and buprenorphine, whereas plasma estradiol was decreased both 4 and 24 h after morphine, tramadol and buprenorphine in male rats (176). Insulin-like growth factor and growth factor-associated signal transduction pathways inhibited estradiol and progesterone facilitation of female reproductive behaviors as well as the behavioral effects of a DOR agonist (327). DYN A and B as well as Lenk-Arg(6) were more predominant in NAC, C/P and SN during estrus than during diestrus or proestrus, effects associated with cyclic fluctuations in the enzymatic cleavage of DYN (966). Estrogen in female rats suppressed 3H-DAMGO binding in rat cortical membranes in a manner similar to that of CCK-8 and a CCK-8 agonist, JMV-180 with the latter effects blocked by the CCK1 receptor antagonist, JMV-179 (931).
Estrogen without progesterone increased ORL-1 mRNA expression in the anteroventral periventricular hypothalamus, MPOA and VMH and increased OFQ/N mRNA levels in the caudal part of the posterodorsal medial amygdala; estrogen and progesterone increased MPOA OFQ/N mRNA in the female rat (1040). LSN2120310, a selective estrogen receptor modulator for both ERalpha and ERbeta treats hot flushes in a morphine-dependent rat model (1178). Different progestins differentially modulate estradiol-induced BEND synthesis and release (915). The reproduction phase-related expression of BEND-like immunoreactivity in the nucleus lateralis tuberis of the female Indian major carp correlates with the number of leutinizing hormone cells and ovary during spawning (985). OFQ/N reduced tuberoinfindibular DA neurons just preceding its stimulation of the prolactin secretory response, effects blocked by ORL-1 antagonism that in turn inhibited the suckling-induced prolactin response (207). Naloxone acts as an antagonist of estrogen receptor activity in MCF-7 cells (334). DORs are found in a subpopulation of GnRH nerve terminals, primarily in the external layer of the ME. DPDPE-induced inhibition of cAMP accumulation and Go down regulation in a GnRH-secreting cell line is blocked by pertussis toxin (910). Estradiol valerate blocked ovariectomy-induced reductions in BEND and allopregnanolone, whereas progesterone increased plasma, hypothalamic and intermediate pituitary BEND. In contrast, medroxyprogesterone increased BEND only in hippocampus and intermediate pituitary (81). Oral tibolone maximally increased BEND in frontal lobe, hypothalamus and neurointermediate pituitary, also increased BEND in parietal lobe, anterior pituitary and plasma, but failed to alter hippocampal BEND in ovariectomized rats in parallel to allopregnanolone increases (392). Sexual dimorphism was observed in the organization of glutaminergic cells in the rat hypothalamic infindibular area for neurokinin B, but not for DYN (225). There was no role for endogenous opioid peptides in the reproductive suppression in subordinate female highveld mole-rats (1124).
Decreased BEND is found in serum and seminal plasma in infertile men (313). Exercise failed to elevate Pro-Enk peptide F during either follicular or luteal phases of the menstrual cycle in women (611). Both fluoxetine and clomipramine prevent premature ejaculation induced by naltrexone in opioid detoxification treatment (3). Normalization of hyperinsulinemia by chronic opioid receptor blockade occurred in hyperandrogenemic women (434).
9b. Pregnancy
Fetal morphine metabolism and clearance are constant during late gestation (387). Naloxone increased serum prolactin, but not the DOPAC/DA ratio in anti-progesterone-treated, but not control pregnant rats, and failed to affect mifepristone-induced decreases in TH immunoreactivity in the arcuate and periventricular hypothalamic nuclei (1052). Pro-Enk A mRNA in the luminal and glandular epithelium fell and GABA A receptor subunit in the luminal epithelium and stromal cells fell during endometrial receptivity (932). Interleukin-1beta increased SON Oxy secretion and electrical activity in virgin, but not pregnant rats, whereas naloxone enhanced interleukin-1beta-induced SON Oxy secretion and electrical activity in pregnant, but not virgin rats (146). Caesarean section is associated with lower maternal concentrations of epinephrine, NE, ACTH, cortisol, prolactin and BEND compared with other modes of delivery (1171). Elevations in heat pain, but not cold pressor pain were not before and after parturition in pregnant women relative to non-pregnant women (172).
9c. Development
DAMGO and U69593, mu and kappa opioids, induced the differentiation of embryonic stem cells to neural progenitors (578). NMDA lesions placed in the rostral lateral PAG prevented morphine-induced inhibition of maternal behavior. Morphine-sensitized dams would choose to hunt insects rather than engage in maternal behavior, and lesions of the rostral lateral PAG restored the maternal response (1081). DYN induced a kappa receptor-sensitive immediate unconditioned increase in neonatal responsiveness to a surrogate nipple in newborn rats, but did not alter water intake through an intra-oral cannula. Pairing Dyn and suckling on a nipple increased responsiveness 1 day later, indicating conditioning (905). MOR and ORL-1 receptor binding are significantly and respectively increased in the NAC and VTA of two-day old rat pups relative to their dams, effects attributable to increased G-protein coupling which in turn showed greater effects in female relative to male pups in the NAC (483). Neonatally-handled male mice display greater body weights, increased plasma ACTH and corticosterone and decreased hypothalamic ACTH and CRF as adults, effects blocked by neonatal administration of AS directed against POMC (379). Neonatal treatment with naloxone increased the population of Sertoli cells and sperm production in adult rats (262). Facial expressions of pain, high activity levels, poor response to routine care and poor ventilator synchrony were associated with placebo versus morphine therapy, and could be used as markers for persistent pain in preterm infants (126).
9d. Endocrinology
Oxytocin increased ACTH, BEND, LH and prolactin secretion of cycling porcine pituitary cells, with oxytocin and CRF producing additive increases in pituitary BEND (608). The endocrine disruptor, bisphenol-A administered prenatally and postnatally led to an enhancement of the DA-dependent rewarding effect induced by morphine (785). DAMGO reversed the inhibitory effects of PGE1 upon Na,K-ATPase activity in SH SY5Y neuroblastoma cells; DAMGO increased this activity itself through a cyclosporine- and nifedipine-dependent Ca2+ channel system (1229).
10. Mental Illness and Mood
This section summarizes the few studies examining opioid involvement in mental illness (Section 10a) and mood (Section 10b). 

10a. Mental Illness
Manipulations of Dyn, CREB, BDNF, MCH or Clock proteins in the NAC and VTA in rodents produce unique behavioral phenotypes directly relevant to depression (834). The kappa agonist, salvinorin A, induced two animal models of depression, namely increased immobility on the forced swim test and increased thresholds for ICSS without altering locomotor activity in an open field. These effects were accompanied by decreased DA, but not 5HT concentrations in the NAC (169). Delta agonists, including DPDPE and Delt II, decreased immobility in the forced swim test and increased frontal cortical BDNF mRNA expression in a NTI-sensitive manner, suggestive of anti-depressant actions (1127). The DOR agonist, (+)BW373U86 decreased immobility and increased BDNF mRNA in the frontal cortex, effects blocked by NTI, but not naltrexone or NBNI. Lenk and Menk produced similar patterns of effects, but up regulated BDNF mRNA in the hippocampus through DOR- and MOR-sensitive mechanisms. In contrast, BEND, endomorphin-1 and endomorphin-2 increased BDNF mRNA expression in frontal cortex, hippocampus and amygdala in a naltrexone-sensitive manner without affecting immobility (1304). The enkephalinase inhibitor, RB101 produced antidepressant and increased locomotor effects without inducing seizures, convulsions of alterations in BDNF mRNA expression (543). Whereas ORL-1 agonists produce anxiolytic-type effects on the elevated plus maze, light:dark aversion, operant conflict, startle, ultrasonic vocalizations and hole board tests, either ORL-1 antagonists and OFQ/N KO animals display anti-depressant effects on the forced swimming and tail suspension tests (388). The ORL-1 agonist, Ro64-6198, produced selective inhibition of marble burying in mice without affecting locomotor activity, thereby exhibiting anxiolytic and antidepressant actions (841).
Sustained sadness in depressed women was associated with decreased MOR binding potential in the left inferior temporal cortex, and in the anterior cingulate in those who did not respond to anti-depressants (567). Adherence to naltrexone in opioid-dependent patients produced less depression symptoms (267). Naltrexone reduced alcohol use and craving as well as symptoms measured by the Hamilton Rating Scale for Depression and Young Mania Rating Scale in patients with bipolar disorder and alcohol dependence (137). Nalmefene significantly improved scores on the Yale-Brown Obsessive-Compulsive Scale modified for Pathological Gambling markedly improving 59% of the subjects (413). Naltrexone rendered one-session exposure less effective for phobia treatment (610). Long-term use of high-dose oral naltrexone is safe using hepatic transaminase profiles in otherwise healthy patients with impulse-control disorders who restrict their intake of over-the-counter analgesics (584).
10b. Mood
People with high neuroticism displayed a graded cortisol, but not ACTH response to naloxone, whereas those with low neuroticism displayed a cortisol response that plateau (718). Reductions by naltrexone were observed on repressive coping and disclosure of emotional material (1278). Volunteers displayed less alertness, increased sedation and increased effort to perform a driving test following oxycodone/paracetamol relative to the NSAID, bromfenac (1157). Midgestational women who were battered showed higher levels of anxiety and depression than non-battered pregnant women, and plasma ACTH and BEND levels showed a significant linear relationship in battered, but not non-battered women (1105).
11. Seizures and Neurological Disorders
11a. Seizures
Alfentanil enhanced the amplitude and number of hippocampal CA1 population spikes in control animals, but reduced in such spikes in pilocarpine-treated epileptic rats because of an increase in eliptiform population spikes; these effects were naloxone-reversible (986). Morphine enhanced pilocarpine-induced seizures and status epilepticus (360). The non-peptide delta agonists, SNC80 and (+)BW373U86 produced bilateral ictal and paroxysmal spike and discharges and brief changes in EEG recordings that were subject to quick tolerance and sensitivity to compounds used to treat absence seizures (542). A ketogenic diet decreased Pro-Enk gene expression induced by KA of the granular cells of the hippocampus as well as diminishing KA-induced AP-1 DNA-binding activity, Fos and Jun expression, and the phophorylated form of the three types of JNKs (848). EEG and convulsant effects were noted following the delta opioid agonist SNC80 in one of four rhesus monkeys (260). Encephalitis induced by neurotrophic Borna disease virus induced seizures and DYN loss through hippocampal dentate cell loss. Kappa agonists prevented the seizure activity that was associated with an absence of DYN in dentate gyrus granule cells and an up regulation of Enk in CA1 interneurons (1054). Kappa agonists and antagonists respectively decreased and increased handling-induced convulsions in ethanol withdrawal-seizure prone, but not ethanol withdrawal-seizure resistant mice (69). HSV-1 infection caused loss of hippocampal DYN A reactivity, and the kappa agonist, U50488H blocked ictal activity (1055). Single nucleotide polymorphisms in the MOR subunit gene were not associated with idiopathic generalized epilepsy (66).
11b. Neurological disorders
Estradiol benzoate, but not tamoxifen was capable of blocking the methamphetamine-induced increase in striatal PPE mRNA levels as well as prevent loss of striatal dopamine transporter binding (263). In Parkinson Disease-related research, MPTP-treated monkeys displayed striatal DA denervation and dyskinesia accompanied by an increase in Pro-Enk-A mRNA levels in the rostral and lateral putamen and rostral caudate, effects blocked by pretreatment with the NR1A/2B NMDA antagonist, CI-1041, but not levodopa (802). Primates with Parkinsonian features with or without L-DOPA-induced dyskinesia displayed normal phenotypes of striatal medium spiny neurons, but showed axonal collateralization of striatofugal cells containing Dyn that project to the pars interna and externa of the globus pallidus (811). Naltrexone is one of eight nondopaminergic drugs in which the MPTP-lesioned promate correctly predicted phase II efficacy (356). Mice lacking preproOFQ/N gene expression display less loss of TH neurons in the SN and CP of MPTP-treated mice, but failed to show changes in methamphetamine-induced losses of DA in the CP (138). Aphakia mice that possess a naturally-occurring Pitx3 deficiency, display levo-dopa-sensitive locomotor deficits and such neuronal losses as DA transporter binding and DA receptor expression, Enk, DYN and neurotensin in a manner similar to adult animals receiving neurotoxin administration (1146). Hemiparkinsonian Nur77 KO mice showed exacerbated rotational responses to L-DOPA, and failed to show up-regulation of striatal Enk mRNA levels; DYN levels were unchanged (1071). SP induced toxic effects on SN DA neurons in a microglia-dependent manner in neuron-glial cultures, an effect reversed by DYN (107). The G-allele of the A118G single nucleotide coding region polymorphism of the MOR gene as well as a history of never smoking were independently associated with increased risk of earlier onset of levodopa-induced dyskinesia in Parkinson’s disease (1074).
R6/2 transgenic mice that display symptoms of Huntington’s disease display decreases in NR2A NMDA receptors in proportionally more striatal cells that contain Enk (20). Huntingtin inclusions do not down-regulate Pro-Enk genes in the R6/2 Huntington’s disease mouse (980). Endomorphin-2 protects against the beta-amyloid aggregate creator, Abeta1–42 in vitro and in vivo (1095). Perinatal 6-OHDA lesions decreased striatal DA and SP and increased striatal Menk, effects reversed by chronic perinatal administration of D1 (SKF-38393), but not D2 (quinpirole) agonists (1044). An adenosine A2A antagonist, CSC, but not U50488H produced a reversion of decreases in the duration of levo-dopa-induced rotations in 6-OHDA-treated rats that was accompanied by an increase in levo-dopa-induced preproDYN mRNA in the lesioned ventromedial striatum (120). Animals receiving traumatic brain injury displayed poor motor function for up to five days post-trauma when treated with morphine (1066). Oral exposure to manganese increased manganese levels and neuron injury in striatum and GP with apoptotic cells containing NOS, Enk and ChAT; these effects reduced locomotor activity and striatal DA content (690).
Decoy peptides that bind DYN noncovalently prevent NMDA receptor-mediated neurotoxicity in the spinal cord as well as DYN-induced paralysis and allodynia (1228). Mice bearing the G93A SOD1 mutation that leads to clinical symptoms of familial amyotrophic lateral sclerosis display prolonged survival with daily administration of morphine and taineptine (216). Intrathecal mu and delta, but not kappa agonists dose-dependently and opioid receptor-selectively induced spastic paraparesis in animals exposed to spinal ischemia (545). Intrathecal nicorandil and small-dose morphine can induce spastic paraparesis after a noninjurious interval of spinal cord ischemia in the rat (366). There was a transient loss of motor-evoked responses associated with caudal injection of morphine in a patient with spondylolisthesis undergoing spinal fusion (401). Unilateral labyrinthectomy causing vestibular behavioral deficits was accompanied by pre-pro-Enk up regulation and increased Fos activity in the medial vestibular nucleus. Blockade of this up regulation with naloxone or antisense probes increased the behavioral deficits (590). DYN anti-sera applied soon after spinal cord ischemia attenuated NOS up-regulation, and reduced both spinal edema and cell injury (1022). Endomorphin-1 and to a lesser extent endomorphin-2 inhibited Cu2+ and AAPH, a water-soluble initiator in inducing oxidation of low density lipoprotein, showing protection against free radical-induced neurodegenerative disorders (670). Naloxone failed to alter a postoperative coma in a patient with complete basilar syndrome after anterior cervical disectomy (1134). Neuroprotection by endogenous and exogenous PACAP following stroke was mediated in part by Enk (201).
Gastrointestinal, Renal and Hepatic Functions
14a. Gastric Function
Naloxone or vagotomy does not influence centrally octreotide-induced inhibition of gastric acid secretion in rats. (383). Morphine and opium dependence reduced the severity of postoperative adhesions following abdominal gastric surgery (573).
14b. Intestinal Function
Morphine increased GI transit in horses over a 6 h period decreasing fecal weight and moisture as well as defecation frequency (115). The peripherally-acting opioid antagonist, N-methylnaltrexone reversed these effects (116). Morphine tolerance and dependence increased c-Kit expression in duodenum and ascending colon in a CTOP-sensitive manner (60). Morphine and WIN55212-2 each reduced GI transit, but CB1 antagonism or CB1 KO mice failed to affect morphine-induced inhibition. Similarly, neither naloxone nor naltrexone altered CB1 agonist-induced inhibition of GI transit (168). Morphine delivered by pellets produced far greater Salmonella infection in Peyer’s patches, mesenteric lymph nodes and spleen than morphine delivered by minipump, an effect attributable to greater inhibition of GI transit. Whereas BEND relaxed rabbit jejunum contractility, naloxone respectively increased and decreased contractility at low and high concentrations respectively (239). Chemical coding of Type I myenteric neurons with different axonal projection patterns in the porcine ileum revealed 78% immunoreacted to Enk (540). Delt II, but not DPDPE or U50488H administered by minipump induced moderate Salmonella infection in the spleen, but did not affect GI transit (341). Both salvia divinorum and its active ingredient, Salvinorin A inhibited electrically-induced contractions of the guinea pig ileum, effects reduced by naloxone and NBNI, but not CTOP or NTI (167). Kappa and delta, but not mu opioid agonists enhanced the inhibition of plasma extravasation during chronic relative to acute intestinal inflammation; these effects were reversed by receptor-selective antagonists and NOS inhibitors. Chronic inflammation increased KOR and DOR protein levels in the whole jejunum and mucosa (524). Pro-Enk A mRNA expression is widely expressed in human GI tract, esophagus, pancreas and gallbladder (794). An inherent acceleratory effect of insulin on small intestinal transit could be observed in naloxone-induced inhibition of this response (889). Chronic desipramine treatment produced subsentivity to kappa agonist-induced inhibition of the peristaltic reflex, but supersensitivity to mu agonist-induced inhibition of propulsion velocity. Chronic desipramine treatment decreased both MOR and KOR in the myenteric plexus and colon of guinea pigs (164). The selective mu opioid receptor antagonist, alvimopan, improves delayed GI transit of postoperative ileus in rats (371). Long pulses of intestinal electrical stimulation inhibited canine intestinal motility in a naloxone-insensitive and NO-insensitive manner, but that was reversed by Ach and NE antagonists (686). Enteral naloxone was effective in treating opioid-induced constipation in a pediatric intensive care unit (1123). Low-dose naltrexone was effective for the treatment of irritable bowel syndrome (554).
14c. Nausea and Emesis
Ondansetron, but not droperidol was an effective prophylaxis of nausea and vomiting after intrathecal morphine in women undergoing caesarean section (891). Loperamide reduced kinetosis-induced nausea, and reduced the increases in ACTH and antidiuretic hormone induced by kinetosis in human volunteers (872).
14d. Glucose Function
DYN A(117) increased glucagon release from pancreatic islets with pancreatic beta cells treated with high glucose eliminating DREAM interactions with the Pro-DYN promoter downstream regulatory element, and thereby increasing Pro-DYN promoter activity. DREAM-KO beta cells show increased Pro-DYN activity as well (509). Metformin decreases plasma glucose in STZ-induced diabetic rats through an increase in adrenal BEND secretion to stimulate mu opioid receptors that leads to an increase in GLUT-4 gene expression and a decrease of hepatic PEPCK gene expression (205). Metaformin also decreased fasting plasma glucose in healthy humans that was accompanied by an increase in plasma BEND and a decrease in serum cholesterol (873). The ginsenoside, Rh2 lowered plasma glucose and increased plasma BEND in a naloxone-sensitive manner in control, but not MOR KO STZ rats (625). Exocrine pancreatic secretion is inhibited by both OFQ/N and DOR agonists (672). The plasma glucose lowering action of Hei-Shug-Pian, the fire-processed product of the root of Aconitum was naloxone-reversible in STZ-induced diabetic rats (675). Myricetin lowered plasma glucose and increased plasma BEND in STZ-induced diabetic mice, effects eliminated by bilateral adrenalectomy, opioid receptor antagonists and by deletion of the MOR gene (682).
14e. Hepatic and Pancreatic Function
The analgesic effects of cholestasis induced by bile duct ligation were reduced by peripheral and direct intraplantar injections of naloxone and naloxone methiodide (833). Delta opioid agonists diminished the growth of the biliary tree in the development of cholestasis (736). Menk regulated oxidant-antioxidant status in the liver of CBA mice (1053). Chronic morphine produced pro-oxidant effects in hepatic glutathione concentrations and its synthesis pathway in a naltrexone-sensitive manner (887). Naltrexone and NOS inhibitors corrected the blunted chronotopic and inotropic responses to beta-adrenergic stimulation in cirrhotic rats (305). Naltrexone reduced development of hepatic fibrosis and cirrhosis, MMP2 activity, and decreased the number of hepatic stellate cells in bile duct ligated rats. Activation of hepatic stellate cells increased expressed delta-1 receptors and increased TIMP-1 expression following delta-1 and delta-2 agonists respectively (306). Monocytes and granulocytes from bile duct-ligated rats increased the percentage of opioid receptor labeling, but a decrease in opioid receptor expression on leukocytes due to cholestasis (793).
There is a low utility of plasma OFQ/N in patients with hepatocellular carcinoma (1058). Cholestatic patients with pruritus found limited relief in visual analogue scales for pruritus following naltrexone with virtually half showing withdrawal symptoms associated with the antagonist (721). Pro-Enk hypermethylation was enhanced in pure pancreatic juice compared with p53 mutation in the diagnosis of pancreatic carcinoma (858). A patient with pancreatic cancer with metastases to the liver has survived after four years of treatment with intravenous alpha-lipoic acid and naltrexone (80). Rifampin-mediated induction of oxycodone hepatic metabolism resulted in negative urine opioid screening (637). Naltrexone administration in alcoholic patients did not induce hepatic abnormalities and indeed alanine aminotrasferase and aspartate aminotransferase declined across the 12-week treatment (1270).
14f. Renal Function
PVN OFQ/N decreased RSNA, increased urine flow rate, decreased urinary sodium and potassium excretion, and increased free water clearance, effects that were blocked by renal denervation, [Arg8]VP and ORL-1 receptor antagonism. The ORL-1 antagonist, UFP-101 in the PVN increased RSNA and decreased urine flow (614). OFQ/N increased cystomanometric bladder capacity and voiding and decreased maximum bladder pressure and urine leakage in controlling neurogenic detrusor overactivity in patients (631). Naloxone abolished the recurrent inhibition of the bladder C fiber reflex in the cat (750). Renal failure and elevated creatinine kinase in a heroin addict was treated by fasciotomy and hyberbaric oxygen therapy (4).
Cardiovascular Responses
15a. Heart rate
Morphine stimulated vascular endothelial growth factor-like signaling in mouse retinal endothelial cells (187). U50488H increased HR, but decreased both MAP and renal blood flow in lambs aged 1 and 6 weeks (929). KOR is most abundant in the ventricular and atrial myocardium of the heart; DOR, but not MOR is found more in the atria than ventricles. Ligation of a renal artery increased Pro-Enk levels in ventricular myocardium, whereas isoprenaline administration decreased it (1210). Whereas the vagotonic influence of a Menk analogue was not dependent upon a sympatholytic influence, kappa stimulation with U50488H produced a sustained sympatholytic effect that was not easily reversed by NBNI (64). Mu receptor agonism with DAMGO and antagonism with BFNA respectively increased and decreased HR and systolic blood pressure in control rats, but not rats maintained on a high-fat diet despite the latter’s baseline increases in systolic blood pressure (470). Activation of DOR through the opening of KATP channels reduces the severity of post resuscitation myocardial dysfunction (332). The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of delta2-opioid receptor stimulation (265). Repeated delta-1 opioid receptor stimulation reduces delta2-opioid receptor responses in the sinoarterial node (275). Bradycardia induced by D-Ala2, Leu5, Arg6-enkephalin (dalargin) is associated with activation of peripheral KOR (738). Negative inotropic and chronotropic effects of DOR antagonists are mediated through non-opioid receptors (739). Naloxone-precipitated morphine withdrawal induced PKC inhibitor-sensitive increases in Fos in right and left ventricles, and induced PKC inhibitor-insensitive increases in TH and NE in the heart (22). Baroreceptor activation by pressure in the carotid sinus or by electrical stimulation produced depressor and bradycardic responses that were attenuated by NTS administration of endomorphin-2, but not naloxone (1161). The opioid dipeptide, kytorphin inhibited isoprenaline-induced increases in twitch tension of cardiac muscle without affecting twitch tension itself; this effect was blocked by a kytorphin antagonist and naloxone (657). NO release from lobster heart was enhanced by morphine and decreased by naloxone and the NOS inhibitor, L-NAME (173). However, L-NAME, but not naltrexone exaggerated the hemodynamic response to clonidine in bile duct-ligated rats (1112). Naloxone reduced the immediate lethal response to severe shock in a canine model with a combination of hypertonic-hyperoncotic solutions (385). Administration of naloxone and butorphanol combined with exposure to electric foot shock increased heart and respiratory rate in the lizard, Uromastix hardwickii and the rooster, gallus domesticus (940). Buprenorphine and naloxone in combination with antiretroviral drugs increased the QT interval in HIV-negative and opioid-dependent subjects (56). Abrupt withdrawal from oxycontin decreased the left ventricular ejection fraction and produced new regional wall motion abnormalities (959). Increases in serum BEND by programmed exercise training were correlated with improvement of clinical symptoms and quality of life in female mitral valve prolapse patients (496).
15b. Cardioprotection and ischemic preconditioning
Chronic morphine was more effective than acute morphine in restoring diastolic and contractile function during cardioprotection; G(i) inhibition reduced affected both acute and chronic morphine effects. Whereas a G(s) inhibitor or PKA inhibitor blocked only chronic effects, a PKC inhibitor blocked only acute effects (888). Morphine attenuated hemorrhagic shock-induced hyper permeability (182). Morphine and naloxone respectively decreased and increased the rate of hemorrhage-induced hypovolemia in sheep (363). The JAK/STAT pathway is essential for opioid-induced cardioprotection with JAK2 acting as a mediator of STAT3, Akt and GSK-beta (418). Morphine-induced neuroprotection of hippocampal neurons following oxygen-glucose deprivation was partially blocked by single and combined treatment with chelerythrine, a PKC blocker, epsilonv(12), a nPKCepsilon antagonist and MK-801 (333). Opioid preconditioning with Tan-67 induces opioid receptor-dependent neuroprotection against ischemia in rats (1319). Opioid receptor-independent protection of ischemic rat hepatocytes was observed following morphine (581). Central and peripheral opioid receptor antagonists block the cardioprotective effects of fentanyl (649).
Myocardial ischemic tolerance occurs in the newborn rat and involves opioid receptors and mitochondrial K+ channels (807). Menk-Arg6-Phe7 produced cardioprotection in the ischemic preconditioning model (283). Activation of ERK and suppression of calcineurin interact in cardioprotection produced by DOR activation (500). The delta agonist, SNC-121 blunted the ischemic-induced increases in cardiac myocyte death produced by mineral oil layering to reduce gas exchange (882). Hypoxic preconditioning reduces glutamate-induced neuronal injury by increasing cortical DADL binding density without affecting DOR mRNA in a NTI-sensitive manner. In contrast, prolonged hypoxia causes severe neuronal injury and decreases DADL binding and DOR mRNA levels (1307). ARD-353, a nonpeptide delta agonist decreased infarct size following coronary artery occlusion that was blocked by a delta-1 antagonist (1201). Kappa agonists significantly reduced infarct size and plasma lactate dehydrogenase level by ischemia-reperfusion in a NBNI-sensitive manner (1312). Kappa-opioid receptor antagonism improved recovery from myocardial stunning in chronically instrumented dogs undergoing left anterior descending artery ischemia (419). Morphine and fentanyl respectively enhance and retard recovery of ventricular function after cardiopulmonary bypass (808).
15c. Blood pressure
Morphine exposure increased MAP and HR, and spontaneous morphine withdrawal produced a prolonged 72 h increase in MAP as measured by telemetry (761). BEND acts in limbic circuits as a depressor in regulation of arterial pressure as it relates to the development of essential hypertension (617). Blockade of endothelin-1 release contributes to the anti-angiogenic effect of POMC over expression in endothelial cells (628). Endomorphins restore the endothelium-dependent relaxation of the rabbit aorta rings exposed to high D-glucose through a NO-c-GMP pathway (683). Endomorphin2-ol was more potent than endomorphin2, but endomorphin1-ol was less potent than endomorphin1 in reducing systolic arterial pressure and heart rate with the former measure reversed by pretreatment with naloxone, atropine, L-NAME and bilateral vagotomy (1281). Morphine, meperidine, fentanyl and remifentanil all produced a concentration-dependent vasorelaxation of human artery rings that was insensitive to naloxone (431). Vasorelaxation induced by U50488H in the pulmonary artery was blocked by the K(V) channel blocker 4-AP, but not glibenclamide or TEA (1088). Arterial partial pressure of oxygen was significantly in horses receiving morphine during upper respiratory tract surgery (699). Stimulation of sensory neuropeptide release by OFQ/N leads to hyperaemia in acutely inflamed rat knees (1303). Remifentanil, sufentanil and fentanyl each induced a dose-dependent vasodepressor response in the cat pulmonary vascular bed that was attenuated by naloxone and diphenhydramine, but not glibenclamide (562,564,565). In contrast, meperidine induced a dose-dependent vasodilator response in the cat pulmonary vascular bed that was attenuated by naloxone and diphenhydramine, but not glibenclamide (563). The dextro-, but not levo-isomer of tramadol produces a concentration-dependent and naloxone-reversible relaxation of rodent aorta precontracted with phenylephrine (939). Tramadol stereoselectively attenuated endothelium-dependent relaxation in isolated rat aorta induced by Ach (1030). Spinal estrogen attenuates the exercise pressor reflex without changing gene expression of opiate receptors in the DRG (998). Hemorrhage induces c-Fos in arcuate POMC neurons and increases POMC mRNA in the MBH. Caudal arcuate administration of lidocaine inhibited hemorrhagic hypotension and bradycardia without affecting MAP or HR (405). Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis through receptor transactivation (1043). Transcutaneous magnetic stimulation of the Jianshi-Neiguan acupoints decreased the reflex pressor response, effects blocked by median nerve denervation or by pretreatment with general, kappa, delta, but not mu antagonists (1324). Naloxone blocked the ability of SP(17) to inhibit SP-induced vasodilation in a rodent model of inflammation of the hindpaw (1217).
Exaggerated opioid analgesia is observed in persons at enhanced risk for hypertension (754). Combined spinal-epidural anesthesia with intrathecal bupivacaine produced analgesia with lower incidence of maternal hypotension for cesarean delivery (1114). Low, but not high levels of trait anger in chronic low back pain sufferers were associated by naloxone-induced impairments in post-pain blood pressure (143). Formation clearance of morphine to M3G is reduced during the first 10 days in neonates undergoing venoarterial extra corporeal membrane oxygenation (901). Remifentanil attenuated hemodynamic changes after induction and tracheal intubation during cesarean delivery (566).
Respiration and Thermoregulation
DAMGO applied to the rostral ventrolateral medulla of newborn rats depressed fourth cervical ventral root inspiratory activity with facial nerve activity continuing to synchronize with pre-inspiratory bursts both in normal pups and pups receiving transverse sectioning between the pre-Botzinger complex and the parafacial respiratory group (867). DAMGO also depressed confocally imaged respiratory center neurons in on-line-calibrated newborn rat brainstem slices (977). Fentanyl-induced modulation of inspiration and expiration in juvenile rats was dissociated with caudal transactions at the level of the facila nerve blocked the latter response, but not the former response (511). Recurrent hypoxia in rats during development increases subsequent respiratory sensitivity to fentanyl (805). Morphine increases the transmesothelial resistance of the sheep parietal pleura in an in vitro preparation (1170). Morphine decreases gill ciliary activity through coupling to NO release in a bivalve mollusk (722). Optimal assessment of anesthesia associated with regular respiration, loss of blink, papillary and pedal withdrawal reflexes was obtained with intra-nasal doses of fentanyl, droperidol and medetomidine in mice (632). Both naloxone and peripherally-acting naloxone methiodide reversed the respiratory depression and analgesia induced by morphine, methadone and heroin, effects that did not appear to be sex-dependent in mice (651). Naloxone and epinephrine were equally effective for cardiopulmonary resuscitation in a rat asphyxia model (193, 194). Naloxone reversed buprenorphine-induced respiratory depression (1147). Naloxone did not increase the minimum alveolar anesthetic concentration of sevoflurane in mice (664). Lenk decreased the burst frequency of the membrane potential of pre-Botzinger complex respiratory center neurons (503). OFQ/N reduced respiratory frequency in an apnea model of isolated brainstem-spinal cord newborn rat preparation, effects reversed by an ORL-1 antagonist, an activator of adenylyl cyclase and a phosphodiesterase-4 (but not 3 or 5) inhibitor (976). OFQ/N inhibited acid-invoked cough in guinea pigs by blocking acid-induced increases in Ca2+ in vagal jugular ganglionic neurons by inhibiting the sustained component of acid-induced inward current (640). Two analogues of OFQ/N, but not nocistatin reversed the inhibition by OFQ/N of electric field stimulation-induced excitatory nonadrenergic-non cholinergic and cholinergic constriction of the guinea pig isolated bronchus (1267). Endomorphin-1 and endomorphin-2 inhibited the response to electrical field stimulation in rat isolated bronchus at low, but not higher frequencies, and also inhibited cholinergic constriction in a naloxone-reversible manner, but had no effect upon the contractile response to exogenous Ach (1280); these effects were present in diabetic rats, but the endomorphin response was less marked (1282). 

The acute agonal period during heroin overdose death is characterized by variations in respiratory distress (482). Heroin produced contact allergy and respiratory and mucosal complaints (475). Maximal buprenorphine-induced decreases in respiratory rate and pupil diameter did not vary across doses in experienced opiate users, nor did subjective effects change (226). High doses of buprenorphine cause naloxone-insensitive respiratory depression, particularly in conjunction with benzodiazepine use (763). Whereas fentanyl produced dose-dependent decreases in respiratory rate in volunteers undergoing anesthesia, buprenorphine caused respiratory depression that leveled at 50% of baseline rates (255). Midazolam and morphine can produce harmful effects on cerebral oxygenation and hemodynamics in ventilated premature infants (1144). In neonates receiving central line placement for ventilation, combinations of morphine and tetracine provided superior analgesia with the former producing respiratory depression and the latter producing erythema (1096). Codeine was no more effective than placebo in an objective measurement of cough in chronic obstructive pulmonary disease (1046). There was no significant difference in the time to extubation after use of remifentanil and sufentanil in combination with propofol as anesthesia in adults undergoing nonemergency intracranial surgery (285).
16b. Thermoregulation
DAMGO administered into the NRM blocked noxious stimulation-evoked suppression of PGE2-induced BAT temperature increases (821). SNC80-induced hypothermia was attenuated by central L-NAME administration as well as by combined peripheral L-NAME and 7-NI administration (942). SNC80-induced produced hypothermia in a NTI-sensitive manner, an effect blocked by the 5HT1A antagonist, WAY100635, and enhanced by non-hypothermic doses of fluoxetine (943). Hydromorphone produced post anesthetic hyperthermia in cats (843). The ability of the GABA B agonist, baclofen in the pre-optic/anterior hypothalamus to decrease tonic activity and increase temperature sensitivity through membrane hyper polarization and decrease of input resistances was inhibited by the mu-opioid agonist, PL-017 (1252). Bile duct-ligated rats displayed hypothermia that was reversed by opioid antagonism and NOS inhibition (791). Naloxone restored heat stress-induced declines in GABA and glycine and prevented heat stress-induced increases in glutamate and aspartate (1019). The SSRI fluoxetine abated naloxone-induced increases in tail-skin temperature in ovariectomized rats (740). The 5HT2A antagonist mirtazapine increased tail temperatures following naloxone administration in morphine-dependent rats (886). Post-burn local hyperthermia in reducing burn injury was blocked by naloxone (1011). Intrathecal morphine intensified the intra-operative hypothermia induced by bupivacaine spinal anaesthesia for caesarean section (491).
Immunological Responses
Intrathecal chronic administration at the maximum tolerated doses of morphine hydromorphone, L-methadone, and naltrexone produced granulomas (21). POMC gene transfer, and particularly AMSH, reduced anchorage-dependent growth of melanoma cells in mice by reducing foci formation in lung attenuating their migratory and adhesive capabilities (678). Morphine decreased metalloproteinase activity through the NO-NOS system, implicating it in the treatment of fibrosarcoma (1016). Morphine stimulated CCL2 production by human neurons (964). Chronic, but not acute morphine induces apoptosis in neurons and astrocytes accompanied by up-regulation of FasL, Fas, Bad and active fragments of caspases-8 and –3 (317). Morphine promoted Jurkat cell apoptosis through pro-apoptotic FADD/P53 and anti-apoptotic PI3K/Akt/NF-kappaB pathways (1273). Morphine enhanced apoptosis of cultured human colonic cells in a NOS inhibitor-sensitive fashion, and produced a breach in the host defense barrier in a NOS inhibitor-insensitive fashion (361). Non-apoptotic cell death is induced by morphinone in human promyelocytic leukemia HL-60 cells (1104). Reduction of the brain apoptosis-related proteins, Fas, FasL, Bad and Bax occurred following naltrexone in mice (987). Morphine-induced suppression of natural killer cell activity was blocked by the NPY Y1 antagonist, BIBP3226 (992). Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation (772). Morphine, DAMGO, DPDPE and U-69593 all produced neuroprotective effects against low-temperature-induced cell death in cultured hamster hippocampal neurons (1106). TPA increases expression and regulation of MOR in TPA-differentiated HL-60 promyelocytic leukemia cells (75). Interferon-gamma down-regulates transcription of the MOR gene in neuronal and immune cells (612). Morphine modulates the monocyte-macrophage conversion phase in an opiate antagonist-sensitive manner (456), and naloxone inhibits macrophage activation and atherosclerosis formation in mice (688). Acute morphine and morphine withdrawal inhibit phagocytosis through pertussis toxin-sensitive and –insensitive mechanisms respectively with the latter, but not former manipulation increasing cAMP levels (705). Over expression and blockade of cyclin-dependent kinase 5 respectively augmented and diminished DAMGO-induced neuroprotection from serum deprivation (1195). DAMGO induced up-regulation of annexin V apoptosis-inducing gene expression in PC12 cells stably transfected with MOR (1291). DAMGO inhibited ERK-1 and Akt signaling pathways activated by the chemokine receptor CXCL12 and abolished its neuroprotective effects during NMDA-induced neurotoxicity, effects reversed by general and mu antagonists (883). SNC, but not mu or kappa agonists promoted neural differentiation from multipotent stem cells through the activation of Trk-dependent tyrosine kinase (814). There is a requirement for Id1 in BEND opioid-induced oligodendrogensis in cultured adult rat hippocampal progenitors (899). Insulin decreased histamine and 5HT, but not BEND content in the thymus of in vitro preparations (251). The nucleus of rat peritoneal mast cells contained serotonin and histamine, but not BEND, insulin or triiodothyronine (252). EDAC fixation increases histamine, but not BEND, levels in such cells relative to paraformaldehyde (253). 

Loperamide reversed the inhibition of insulin-stimulated 2DG uptake by tumor necrosis factor alpha in myoblast C2C12 cells (601). Chimeric DNA vaccine reverses morphine-induced immunosuppression and tumorigenesis (206). Morphine dependence diminished virus evolution in SHIV/SIV-infected rhesus macaques with an inverse relation between virus evolution and onset of clinical symptoms (1121). Chronic morphine exposure causes pronounced virus replication in the cerebral compartment and accelerated onset of AIDS in SIV/SHIV-infected Indian rhesus macaques (620). HIV-1 gp120 up-regulation of MOR occurred in TPA-differentiated HL-60 cells (74). Menk maintained the viability of SIV-infected cells through suppression of the expression of caspase-3 (1248). Delta opioid agonists attenuate HIV protein TAT(172)-induced oxidative stress in SK-N-SH cells (1176). The increased vulnerability of ApoE4 neurons to HIV proteins and opiates were provided protection by diosgenin and L-deprenyl (1137). HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines (312). CCR2 mediates the increases in glial activation by exposure to HIV-1 Tat and opiates (311). There was a correlation between SIV Tat evolution and AIDS progression in cerebrospinal fluid of morphine-dependent as compared to control macaques infected with SIV and SHIV (847). Naltrexone inhibits alcohol-mediated enhancement of HIV infection of T lymphocytes (1189). Further, an in vitro model of morphine withdrawal manifests the enhancing effect of HIV infection of human T lymphocytes through the induction of substance P (1190). Acupuncture reduced leukocyte migration into the mouse air pouch in a peripheral, but not spinal naloxone-reversible manner, but did not produce an anti-inflammatory effect (580).
Down-regulation of the opioid growth factor receptor is associated with progression of squamous cell carcinoma of the head and neck (760), yet the opioid growth factor receptor is unaltered with the progression of human pancreatic and colon cancers (1286). Regulation of corneal repair was effectuated by particle-mediated gene transfer of opioid growth factor receptor complementary DNA (1287) with corneal safety of topically applied naltrexone validated (1285). Adaptation of the homeostatic ocular surface epithelium occurred following chronic treatment with naltrexone (1288). Pro-ENK KO mice developed less severe clinical signs of experimental autoimmune encephalomyelitis than wild-type mice that was accompanied by a reduction in MOG(3555)-specific IFNgamma-producing cells (1212). Tumor-cell-targeted Menk analogues containing unnatural amino acids display in vitro antitumor activity (481). DADL stimulates Akt-dependent phosphorylation of c-jun in T cells (1010). DPDPE triggers monocyte adhesion even in pertussis toxin-treated cells, indicating involvement of G proteins other than Gi. This adhesion requires integrins, PI3Kgamma activation, and involves Src kinases, a guanine nucleotide exchange factor and a small GTPase (893). Chemotaxis of human and rat leukocytes is observed following the delta-selective non-peptidergic opioid SNC 80 (868). Deletion of the DOR in mice increases skin differentiation and delays wound healing (95). Kappa opioids induce a reversible inhibition of CFU-GM from CD133(+) cord blood cells (286). OFQ/N and ORL-1 KO respectively stimulate and reduce TNFalpha and IFNgamma transcripts in the spleen when challenged with staphylococcal enterotoxin A (407). Lipopolysaccharide induces ProEnk transcription in hypophysiotropic neurons of the rat periventricular hypothalamic nucleus suggesting a neuroendocrine role for Enk during immune stress (321). Interleukin-1 beta contributed to the up regulation of KOR mRNA in the DRG in response to peripheral inflammation (926). Lipopolysaccharide-induced interleukin-6 production in a mouse monocyte cell line is reduced by the kappa agonist, U50488H in a NBNI-sensitive manner (879). Lipopolysaccharide induced PC1/3 and PC2 substrate pro-Enk in the marginal zone of rat spleens (629). The expression of Pro-DYN gene is down-regulated by activation with lipopolysaccharide in U-937 macrophage cells (1086).
Source and Footnotes, as well as some capitals i dont copy:


In preparation for a trial on co-prescription of heroin to chronic treatment-resistant addicts, a pharmaceutical dosage form for smokable heroin was developed. During development of this product (a mixture of diacetylmorphine and caffeine), in vitro experiments were performed simulating ‚chasing the dragon‘: the technique used by addicts for inhalation of heroin after volatilisation. Samples were heated on aluminium foil using a heating device and the vapours were collected and analysed using a HPLC-UV method. The recovery of diacetylmorphine and caffeine in vapours was studied after volatilisation of different powder mixtures at temperatures between 200 and 350 degrees C. Furthermore, the volatilisation set-up was combined with an Andersen sampler to determine the sizes of aerosol particles. Only small differences in recovery of diacetylmorphine and caffeine were found between temperatures and between powder mixtures: 46-62% of diacetylmorphine from the sample was recovered in vapour and 65-83% of caffeine. The only degradation product detected in vapour was 6-acetylmorphine (4.1-7.1%). In the temperature range studied, temperature mainly influenced the volatilisation rate. Mass median aerodynamic diameters of aerosols from diacetylmorphine-containing samples ranged from 1.8-4.1 microm; 45-60% of each sample was recovered as aerosol particles <5 microm. Volatilising pharmaceutical smokable heroin resulted in sufficient amounts of diacetylmorphine in vapour and in particles suitable for effective deposition in the lungs.

Pharmaceutical heroin for inhalation was developed for a clinical trial on co-prescription of heroin and methadone to chronic treatment-resistant heroin addicts. Diacetylmorphine base was selected as the active pharmaceutical ingredient for this product with caffeine anhydrate added as an excipient. Differential scanning calorimetry and thermogravimetric analysis showed that addition of caffeine resulted in a lower melting temperature and a higher volatilisation rate for the mixture than for diacetylmorphine base alone. Recovery experiments showed that 40.8+/-5.3% of diacetylmorphine base could be found in smoke condensate after volatilisation of diacetylmorphine-caffeine tablets. All of the caffeine from each tablet was recovered unchanged in the fumes, while 85.6% of the diacetylmorphine from each tablet was recovered, either unchanged in the fumes or as non-volatilised residue. Recovery was found to be reproducible and only small differences were found between the tablet types. The experimental set-up was found to efficiently collect the vapours resulting from heating the powder. Under the tested experimental conditions, no evidence was found that degradation products of diacetylmorphine or caffeine, other than 6-acetylmorphine (5.9%) had volatilised, even though a decomposed residue was present after heating diacetylmorphine-caffeine samples. Diacetylmorphine-caffeine was found to be a suitable basis for pharmaceutical heroin to be used by ‚chasing the dragon‘.


In diacetylmorphine prescription programs for heavily dependent addicts, diacetylmorphine is usually administered intravenously, but this may not be possible due to venosclerosis or when heroin abuse had occurred via non-intravenous routes. Since up to 25% of patients administer diacetylmorphine orally, we characterised morphine absorption after single oral doses of immediate and extended release diacetylmorphine in 8 opioid addicts. Plasma concentrations were determined by liquid chromatography-mass spectrometry. Non-compartmental methods and deconvolution were applied for data analysis. Mean (±SD) immediate and extended release doses were 719 ± 297 mg and 956 ± 404 mg, with high absolute morphine bioavailabilities of 56% to 61%, respectively. Immediate release diacetylmorphine caused rapid morphine absorption, peaking at 10 to 15 min. Morphine absorption was considerably slower and more sustained for extended release diacetylmorphine, with only ~30% of maximal immediate release absorption being reached after 10 min and maintained for 3 to 4 h, with no relevant food interaction. The relative extended to immediate release bioavailability was calculated to be 86% by non-compartmental analysis and 93% by deconvolution analysis. Thus, immediate and extended release diacetylmorphine produce the intended morphine exposures. Both are suitable for substitution treatments. Similar doses can be applied if used in combination or sequentially.

Opioid misuse and addiction embody a grave public health issue. Treatment in most countries is primarily based on methadone and buprenorphine maintenance programs (Van den Brink and Haasen, 2006, Amato et al., 2005). However, treatment response is often incomplete, and many heavily dependent narcotic addicts cannot be included or retained in these programs. Therefore, Switzerland and several other countries now include diacetylmorphine as an additional option for heavily dependent narcotic addicts (Fischer et al., 2007, van den Brink et al., 2003, Sheldon, 2008, Haasen et al., 2007, Brissette, 2001). Based on the three most relevant clinical studies in Switzerland, the Netherlands, and Germany, heroin-assisted treatment is superior to other opiod-assisted treatments such as methadone (Rehm et al., 2001, van den Brink et al., 2003, Haasen et al., 2007, Verthein et al., 2008). In particular, this treatment targets previously untreated intravenous drug users or non-responders to conventional methadone treatments, who subsequently show improvements in health status, often dramatically, less treatment dropout, reduced consumption of other psychotropic substances, and other social improvements. Based on these successful study outcomes, the Swiss and the Dutch health authorities have registered an intravenous diacetylmorphine formulation, and oral formulations have been submitted in Switzerland for marketing approval. In addition, other countries such as Spain, Belgium, Denmark, Canada, and the United Kingdom are planning or have already completed clinical trials with heroin-assisted treatments.


Treatment based solely on injected heroin as a substitution medication can be problematic. While effective, it requires considerable resources as patients usually inject three times a day under supervised conditions at treatment centres, which requires long operating hours and puts high demands on personnel and security. Moreover, not all patients fulfil the admission criteria; in many countries, a considerable fraction of opioid dependents do not inject. In the Netherlands, for instance, most users (i.e. 75% to 90%) inhale heroin by ‘chasing the dragon’. Also in other countries, many users do not inject opioids for various reasons, including fear of infection risk or inability to puncture their veins. Moreover, an increasing number of patients participating in heroin-assisted treatment programs suffer from venosclerosis, preventing them from performing intravenous administration. These situations require other means of administering heroin as a substitute medication: oral substitution with diacetylmorphine has been used in Switzerland for a decade. Frick et al. demonstrated that the one year retention rate for solely orally-substituted subjects within the Swiss heroin-assisted treatment programs was 80%, which was above the 70% obtained from historical controls treated intravenously with diacetylmorphine (Frick et al., 2006). In 2006, one third of all diacetylmorphine used in the Swiss heroin prescription program was given as tablets (National Prevention Programmes of the Swiss Federal Office of Public Health, 2007) Furthermore, up to 25% of patients in this program receive diacetylmorphine doses orally (Bundesamt für Gesundheit, 2004).
It is often straightforward to characterise the absorption of oral immediate release preparations by model-independent estimation of bioavailability, maximal concentrations (Cmax), and time of maximal concentration (tmax). Alternatively, compartmental analysis may be used under the assumption of zero or first order absorption. For extended release preparations, analysis requires parameters describing the extent of fluctuation in plasma concentrations (Steinijans, 1990). Ignorance of the appropriate in vivo extended release absorption function often requires the use of deconvolution techniques (Fattinger and Verotta, 1995a, Fattinger and Verotta, 1995b, Fattinger et al., 2000, Pitsiu et al., 2001). This approach provides not only parameter estimates characterising plasma level fluctuations, but also yields the entire drug absorption rate profile over time, allowing comparison of in vivo absorption rate with in vitro dissolution profiles (Pitsiu et al., 2001).
We have shown previously that even large doses of oral immediate release diacetylmorphine yield only negligible systemic diacetylmorphine and monoacetylmorphine exposure, but result in an unexpectedly high morphine bioavailability of 67% (Girardin et al., 2003). Since many patients use extended release diacetylmorphine in addition to or instead of the immediate release form, often switching between formulations, we now characterise and compare morphine absorption of the two formulations in 8 opioid-addicted patients. For the extended release formulation, the study also explores the influence of a high-fat breakfast on morphine absorption.
2.1. Materials
Diacetylmorphine hydrochloride as immediate and extended release tablets of 200 mg were obtained from DiaMo Narcotics Ltd. (Thun, Switzerland). Deuterium-labelled morphine (morphine-N-methyl-d3, morphine-d3) was obtained from Lipomed (Arlesheim, Switzerland) and doses for intravenous administration were prepared by the canton Zurich pharmacy (Kantonsapotheke Zürich, Switzerland). Diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, morphine-d3, morphine-d3-3-glucuronide, morphine-d3-6-glucuronide, and codeine-d3 used as assay standards were purchased from Lipomed (Arlesheim, Switzerland).
2.2. Immediate and extended release diacetylmorphine preparation
The immediate release preparation is a coated tablet with 200 mg diacetylmorphine hydrochloride as the active ingredient. At least 80% of the dose is released within 15 min (Conditions: Water, 37°C, Paddle 50 rpm). The immediate release preparation shows a fast disintegration within 300 s in water at 37°C. In contrast, the extended release preparation is a coated matrix formulation, which releases the 200 mg of diacetylmorphine hydrochloride gradually over 12 h under the same conditions as above. The in vitro dissolution is specified with 20–40% release within 1 h, 45–65% within 4 h, and 80–100% within 10 h. Figure 1 shows the in vitro dissolution profiles of the two formulations.

Figure 1


Figure 1 

In vitro diacetylmorphine dissolution profiles of immediate and extended release tablets

Figure 1


Figure 1
In vitro diacetylmorphine dissolution profiles of immediate and extended release tablets
Six single tablets of immediate (IR) or extended release (ER) diacetylmorphine were subjected to dissolution profiling with a standard USP dissolution apparatus. Values are given as mean ± standard deviations.
2.3. Clinical study
The study protocol was approved by the ethics committee of the canton of Zürich. Volunteers requiring a stable daily parenteral and/or oral diacetylmorphine dose of at least a 300 mg parenteral dose equivalent were recruited from the Swiss heroin prescription programs. Parenteral dose equivalents were calculated by converting oral doses to parenteral doses by dividing them by three and summing them with parenteral doses. The morphine bioavailability of 67% obtained in our previous study (Girardin et al., 2003) suggests that a lower conversion rate may be feasible. However, we again used the previously applied conversion rates (Girardin et al., 2003), since no signs of overdose were observed in the previous study (Girardin et al., 2003) and our main concern was withdrawal symptoms and the need for additional opioid delivery during the 7 or 11 h study sessions. Potential volunteers were first contacted by their treating physician within the program and referred for further evaluation. Among 47 referred volunteers, 37 had to be excluded because of inaccessible veins (16), lack of cooperation (8), elevated transaminases (7), anaemia (3), concomitant medications (2), or impaired gastric emptying (1). Two further volunteers withdrew after the first study day. Written informed consent was obtained from all subjects prior to participation. A total of 8 volunteers, 4 women and 4 men, finished the study and were included in the analysis. All 8 volunteers were heavy smokers, with a mean age of 37 (28 to 50) years and a body weight of 62.3 (59 to 84.5) kg. Two volunteers reported occasional use of cannabis and another two of cocaine. On the first study day, urine drug testing for ethanol, cocaine, methadone, barbiturates, benzodiazepines, amphetamines, and lysergic acid diethylamide (LSD) were negative in all volunteers, but were positive for cannabis in two of them. All volunteers exhibited normal renal function and no signs of liver damage (i.e., normal plasma transaminases, bilirubin, INR, normal abdominal ultrasound examination, and negative hepatitis B and C serology).
Volunteers had been opioid-dependent for 3 to 20 years and had participated in the HeGeBe for an average of 2.9 years (range: 4 weeks to 7 years). The mean daily parenteral diacetylmorphine dose equivalent amounted to 471 mg/d (300 to 867 mg/d). None of the volunteers took any additional medications for at least 3 days before or during the study. The oral diacetylmorphine doses for the study sessions were selected based on daily parenteral diacetylmorphine dose equivalents. To ensure that volunteers would not be over-sedated or develop withdrawal, immediate release diacetylmorphine doses amounted to 1.5-times the individual parenteral diacetylmorphine dose equivalent and the corresponding study sessions were limited to 7 h. To extend the study sessions to 11 h after administration of the extended release preparation, we increased doses in this case to 2 times the parenteral diacetylmorphine dose equivalent.
After an overnight fast (i.e. no food or beverages except water after 11 pm), the volunteers arrived in the hospital at 7 AM and then stayed for 3 days at the Clinical Research Unit. A catheter was placed into the radial artery for blood sampling and into a vein of the other forearm for morphine-d3 administration. On the morning of the first study day, immediate release diacetylmorphine was administered orally with 100–200 ml of water. In addition, 15 mg of morphine-d3 dissolved in 30 ml NaCl was infused intravenously over 5 min starting immediately after the oral dose. Arterial blood samples (4.5 mL) were collected prior and 2.5, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 90, 120, 180, 300 and 420 min after the oral diacetylmorphine dose. On one randomly selected morning of the second or third study day, the volunteers first ate a standardized (high fat content) breakfast consisting of 200 ml whole milk, 2 slices of toast, 20 g of butter, 55 g of Emmental cheese, one boiled egg, and 30 g of corn flakes (corresponding to 51 g of fat, 53 g of carbohydrates and 33 g of proteins). Thereafter, or on an empty stomach as on the first study day, the oral diacetylmorphine extended release dose was administered with 100–200 ml of water. Four subjects fasted on the second day and 4 were fed, and patients switched groups on the third day. Arterial blood samples were collected prior and 10, 20, 30, 40, 50, 60, 80, 100, 120, 150, 180, 210, 240, 270, 300, 360, 420, 480, 540 and 660 min after the diacetylmorphine dose. All blood samples were collected directly into vials preloaded with sodium fluoride and centrifuged at 4 °C. The plasma was stored at −20 °C until analysis.
Standardized meals were served on each day for lunch (4 h after the dose) and dinner. After the first hour, the volunteers were free to smoke cigarettes. During the period between the last blood sample and 10 PM, the volunteers received additional intravenous or oral immediate release diacetylmorphine (on average, 280 mg (day 1) and 230 mg (day 2 and 3) of parenteral dose equivalents) to maintain constant daily diacetylmorphine dosing.
2.4. Determination of morphine, morphine-d3, and metabolite concentrations
Plasma concentrations of diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, morphine-d3, morphine-d3-3-glucuronide, and morphine-d3-6-glucuronide were determined by liquid chromatography-mass spectrometry (LC-MS) with a quantification limit of 10 nmol/L as described previously (between-day precision < 9.5%, accuracy for all analytes between 97.4% and 103.7%) (Rentsch et al., 2001, Girardin et al., 2003).
2.5. Non-compartmental pharmacokinetic analysis
Individual morphine and glucuronide plasma half-life (t1/2) were calculated from the pharmacokinetic data after intravenous morphine administration as t1/2 = ln2/λ, where λ represents the slope of the terminal part of the plasma concentration-time curve after semi-logarithmic transformation. The areas under the plasma concentration-time curve (AUCs) were calculated as AUC(0-∝) = AUC(t0-tlast) + Clast / λ − C0 / λ, where tlast was the time of the last measurable plasma drug or metabolite concentration above the detection limit, Clast was the plasma drug or metabolite concentration of this last sample, and C0 was the plasma drug or metabolite concentration at the time of drug administration (t0). AUC(0-tlast) was calculated by the trapezoidal rule with linear interpolation.
Total plasma clearances were calculated from AUC and dose (D) for intravenous morphine-d3 as CL = D / AUC. The volumes of distribution at steady state (Vss) were calculated as Vss = D * (AUMC) / (AUC)2, with AUMC being the total area under the first moment of the plasma concentration time curve (Gibaldi and Perrier, 1982). Absolute and relative bioavailability (F) were determined as F = (AUC1 / D1) / (AUC2 / D2), where AUC1, D1, AUC2 and D2 corresponds to AUC and dose for the oral diacetylmorphine versus the intravenous morphine-d3 dose, the oral extended versus immediate release dose, or the extended release dose administered in the fed and fasted state. To measure the fluctuation of plasma concentrations, we calculated the percent peak trough fluctuation (%PTF) as 100 * (Cmax − Cmin) / Cavg with Cavg = AUC0-11h / 11 h and the percent AUC fluctuation (%AUCF) as 100 * (AUC(above Cavg) + AUC(below Cavg)) / AUC. (Steinijans, 1990). The geometric mean of absolute and relative bioavailabilities and other parameter estimates, as well as the corresponding confidence intervals, were then calculated.
2.6. Deconvolution analysis
If we view each subject as a linear, time-invariant system characterized by its morphine disposition function, K(t), we can relate the serum concentration response C(t) of that subject to an arbitrary morphine or diacetylmorphine dosage using a convolution of the absorption rate function, A(t), with the individual disposition function, K(t): 

equation M1
The population (sample) average disposition function was estimated from the plasma concentration data collected after intravenous morphine-d3 administration using a standard two compartment model parameterised as k10, V1, k12, and k21, with interindividual variability on each parameter. A one-compartment model fitted the intravenous data considerably worse: we observed a difference in objective function (ΔOF) of 686 points, which is highly significant (the approximate 0.05% confidence level ΔOF is 3.9). No relevant improvement of the fit was achieved with the inclusion of a third compartment. As a by-product of the (population) fit, the individual empirical Bayes estimates for the bi-exponential IV disposition functions were obtained. Drug absorption was described by a positively constrained linear (population) spline function for each study occasion, i.e. the administration of the immediate release dose, the extended release dose in the fasted state, and the extended release dose after a high-fat breakfast, and estimated from the data conditional on the individual bi-exponential disposition functions obtained from the intravenous morphine-d3 data analysis. The breakpoints of the spline were set at the quantiles of the data (Fattinger and Verotta, 1995a, Fattinger and Verotta, 1995b, Fattinger et al., 2000, Pitsiu et al., 2001), and the spline(s) were parameterized to directly estimate absolute or relative bioavailabilities from the data of one or two study occasions combined (The corresponding NONMEM control stream and the data of two patients are given in Appendix 1). The 90% and 95% confidence intervals for the absolute or relative bioavailability estimates were obtained using a likelihood ratio profile (Bates and Watts, 1988).
3.1. Adverse events
All study doses were well tolerated. Only one adverse event was observed in which one volunteer requested one dose of paracetamol for a headache during the second night. Diacetylmorphine dosing was considered adequate on all study days.
3.2. Non-compartmental pharmacokinetic analysis
Intravenous morphine-d3 

The AUC(0-∝) (mean ± SD) for morphine-d3, morphine-d3-3-glucuronide, and morphine-d3-6-glucuronide was 30.7 ± 5.62, 250 ± 77, and 30 ± 9 min*μmol/l, respectively Morphine-d3 exhibited a clearance of 1.7 ± 0.3 l/min, a volume of distribution at steady state of 151 ± 42 l, and a terminal half-life of 1.74 ± 0.5 h.
Oral immediate release diacetylmorphine 

The diacetylmorphine dose (mean ± SD) was 719 ± 297 mg (1.77 ± 0.73 mmol). Similar to our previous study (Girardin et al., 2003), diacetylmorphine and monoacetylmorphine plasma concentrations were negligible. Morphine plasma concentrations peaked at 15 to 180 min, with maximal concentrations of 4.0 ± 1.27 μmol/l (Table 1, Figure 2A). The 7-h sampling period covered at least 80% of the morphine AUC. If we determine morphine bioavailability by comparing oral diacetylmorphine with intravenous morphine-d3, (absolute) morphine bioavailability was 61% ± 17% (range 44%–88%). The mean relative morphine-3-glucuronide and morphine-6-glucuronide bioavailabilities were 149% ± 64% and 184% ± 96%, respectively.
Table 1
Table 1 

Pharmacokinetic comparison of oral immediate (IR) and extended (ER) release diacetylmorphine.

Figure 2


Figure 2 

Individual morphine plasma concentration–time profiles after orally administered immediate (A) and extended release diacetylmorphine in the fasted (B) and the fed (C) state

Figure 2


Figure 2
Individual morphine plasma concentration–time profiles after orally administered immediate (A) and extended release diacetylmorphine in the fasted (B) and the fed (C) state
Solid lines connect measured plasma concentrations, dashed lines correspond to plasma concentration extrapolations based on the last sample (at 7 h) and the subject’s terminal morphine elimination rate estimated from the intravenous morphine-d3. Identical symbols are used for the same patient in all 3 panels. The mean diacetylmorphine doses were 719 mg (1.77 mmol) for immediate and 956 mg (2.36 mmol) for extended release diacetylmorphine.
Oral extended release diacetylmorphine 

The mean extended release diacetylmorphine dose was 956 ± 404 mg (2.36 ± 1.0 mmol). Diacetylmorphine and monoacetylmorphine concentrations were again negligible. The 11-h sampling period covered at least 85% of the morphine AUC. Morphine bioavailability on an empty stomach was 53% ± 15% (range 37%–79%) (Table 1, Figure 2B and C). Morphine bioavailability for extended release diacetylmorphine was lower in 4, higher in 3, and the same in 1 volunteer compared to immediate release diacetylmorphine. The geometric mean relative bioavailability of morphine after extended vs. immediate release diacetylmorphine was 86% (90% CI, 73%–103%). Relative bioavailabilities for the morphine-glucuronides (81% and 86%) were close to the values for morphine. A high-fat breakfast did not affect morphine bioavailability, yielding geometric mean relative bioavailabilities (fed/fasted) of 106%, 119%, and 93% for morphine, morphine-3-glucuronide, and morphine-6-glucuronide. The relative fed vs. fasted morphine bioavailability has a rather narrow 90% confidence interval from 96% to 117%, which excludes any relevant food effect.
Plasma concentration fluctuation was characterised by percent peak through fluctuation and percent AUC fluctuation. The peak-through fluctuation for the extended release preparation was about half that of the immediate release formulation (90% CI of 45% to 61%). The percent AUC fluctuation for the extended release formulation was only 0.66 (90% CI, 0.58 to 0.76) of the immediate release formulation. The presence of food did not increase either of these variability parameters. Maximal morphine concentrations were observed at 0.4 to 4.5 h in fasted and at 3 to 4.5 h in fed conditions, with peak morphine concentrations of 2.98 ± 1.72 and 2.62 ± 1.06 μmol/l (Table 1, Figure 2B and C). Thus, dose-normalised maximal morphine plasma concentrations for extended release diacetylmorphine averaged about half of the immediate release diacetylmorphine, and were observed after about double the period of time.
3.3. Deconvolution Analysis
The three panels of Figure 3 compare data and the (population) prediction (solid line) for morphine plasma concentration after the immediate (A) and the extended release diacetylmorphine preparation in the fasted state (B) and after a high-fat breakfast (C). Panel A of Figure 4 compares the (population) morphine absorption rate profiles obtained from the deconvolution analysis. For the immediate release diacetylmorphine preparation, the morphine absorption rate rapidly peaks at about 10 to 15 min and more than 50% of the dose is absorbed after about 1.5 hours, with more than 90% absorbed at 4.7 h. Morphine absorption was considerably slower and more sustained after administration of the extended release diacetylmorphine preparation, with about 1/3 of the maximal absorption rate of the immediate release preparation observed from 10 min to 3.5 h after drug intake, with at least 50% of the dose absorbed after 3 hours and at least 90% absorbed after 8.5 h. Administration after a high-fat breakfast slightly delayed initial morphine absorption for about 20 to 30 min, without much effect on later morphine absorption rates.

Figure 3


Figure 3 

Goodness-of-fit plots for immediate (A) and extended release diacetylmorphine in the fasted (B) and the fed (C) state from deconvolution analysis using a bi-exponential disposition and a linear spline absorption function

Figure 3


Figure 3
Goodness-of-fit plots for immediate (A) and extended release diacetylmorphine in the fasted (B) and the fed (C) state from deconvolution analysis using a bi-exponential disposition and a linear spline absorption function
The (X) represents the observed data and the solid lines correspond to the average predictions.

Figure 4


Figure 4 

Population morphine absorption rate function for immediate (dashed-dotted line) and extended release diacetylmorphine in the fasted (solid line) and the fed (short dashed line) state estimated by deconvolution analysis using a bi-exponential disposition (more …)

Figure 4


Figure 4
Population morphine absorption rate function for immediate (dashed-dotted line) and extended release diacetylmorphine in the fasted (solid line) and the fed (short dashed line) state estimated by deconvolution analysis using a bi-exponential disposition and a linear spline absorption function
Panel A gives the estimated absorption rate functions obtained by deconvolution analysis for the oral immediate and extended release_diacetylmorphine preparation. Panel B and C compare the morphine absorption rate functions obtained by deconvolution analysis from the drug concentration data and the corresponding diacetylmorphine release profiles from the in vitro experiments (long dashed line) for the extended release (B) and the immediate (C) preparations.
The absolute and relative bioavailability estimates for the different preparations are given in Table 2, with point estimates of 0.57, 0.55 and 0.57 for immediate release, extended release in the fasted condition, and extended release after a high-fat breakfast. Panels B and C of Figure 4 compare the estimated in vivo morphine absorption rate profile and the in vitro release rate profile for the extended release and the immediate release preparations. Absorption rate shortly after drug delivery rises considerably slower in vivo than was predicted by in vitro drug release, but the in vivo absorption rate – at least for the extended release formulation – subsequently catches up.
Table 2
Table 2 

Absolute and relative bioavailability estimates for immediate (IR) and extended release (ER) diacetylmorphine from the deconvolution analysis in NONMEM and their 90% and 95% confidence intervals.
4. Discussion
This study compared the morphine absorption characteristics of orally administered immediate and extended release diacetylmorphine in the high dose range required by opioid addicts. Both preparations exhibited a high mean absolute morphine bioavailability in the range of 56% to 61%. The immediate release preparation resulted in rapid morphine absorption, with the absorption rate peaking at 10 to 15 min after dosing. For the extended release formulation, morphine absorption rates were considerably lower and more sustained, with only about 30% of the maximal absorption rate (of the immediate release preparation) being reached after 10 min and then maintained for 3 to 4 h, with no relevant food interaction. The relative bioavailability of the two preparations was 86% for the non-compartmental or 93% for the deconvolution analysis. Therefore, it can be concluded that these two diacetylmorphine preparations produce the intended morphine exposures and are suitable for substitution with similar dosages when given sequentially or in combination to the same patient. The part of the dose given as an immediate release formulation will assure a rapid opioid effect, whereas the part given in an extended release form maintains opioid availability until the patient’s next visit to the treatment center.
The rapid absorption and concentration rise of the immediate release preparation is advantageous, since the pharmacodynamic effects of opioids depend on both the substance and the initial slope of the plasma concentration. Two factors probably contribute to the rapid initial rise in drug absorption: diacetylmorphine produces a more rapid rise in morphine levels than oral morphine (Girardin et al., 2003) and a pharmaceutical formulation designed for rapid disintegration of the tablets. Based on this absorption rate profile, a rapidly disintegrating immediate release formulation might be especially suited for addicted patients that used opioids parenterally, by inhalation, or nasally.
The extended release diacetylmorphine preparation produces a lower but more sustained morphine exposure, which could avoid a drug-related “high”. Morphine absorption reached 90% only after 8.5 hours, allowing for an extended dosing interval that could improve compliance, as dosing requires scheduled visits to treatment centres. Flexible dosing can also be achieved as food does not affect drug absorption. Clinically, these findings confirm the indications of extended release diacetylmorphine, which are recommended for situations requiring the absence of a drug “high,” such as working patients, or in patients preparing for diacetylmorphine withdrawal. Furthermore, the extended release preparation allows for prolonged dosing intervals and thus enhances the ability for employment.
In vivo absorption profiles differ clearly from the in vitro dissolution profile for both the immediate and the extended release preparations (Figure 4B and 4C). Similar differences also occur with the slow release oxybutynin OROS (Pitsiu et al., 2001), stressing the importance of in vivo studies even for drugs with high water or lipid solubility, such as diacetylmorphine.
Deconvolution analysis enabled us to characterise and visually compare the time courses of drug absorption for the different preparations, and to compare them to the in vitro dissolution profiles, as well as calculating absolute and relative bioavailability. Most parameter estimates and confidence intervals matched closely in both data analysis approaches, i.e. the standard AUC calculation and the deconvolution approach. In deconvolution analysis, the 90% confidence interval for the relative bioavailability of the extended release preparation was more narrow (80.5% to 107.2%) than AUC calculations (73.1% to 105.0%), suggesting that deconvolution analysis may be more robust with respect to outliers. The reason for the observed (but probably clinically irrelevant) differences in the point bioavailability estimates of 61% vs. 57% (immediate release) and 53% vs. 55% (extended release) for the two data analysis approaches remains unresolved.
The slightly lower bioavailability of extended as compared to immediate release diacetylmorphine could result from lower maximal concentrations leading to more efficient first pass elimination in the intestine and liver, or lower mucosal diacetylmorphine and/or morphine permeability in the distal than the proximal intestine.
In conclusion, orally administered immediate and extended release diacetylmorphine both exhibit a high absolute morphine bioavailability of 56% to 61% in the dose range required by opioid addicts. The immediate release preparation produces rapid morphine absorption, whereas absorption rates are considerably lower and more sustained for the extended release formulation, with 90% of morphine absorption reached only after 8.5 h, which would allow for extending dosing intervals. Morphine absorption was not significantly affected by a high-fat breakfast. The relative bioavailability of the two preparations was 86% (non-compartmental analysis) or 93% (deconvulution analsyis), indicating they can be substituted for each other with a one to one ratio. The absorption characteristics could improve outcomes in patients switching from parenteral opioids or for well-integrated patients under chronic treatment to enhance employability.
Table thumbnail
We thank Mathias Markert, Andreas Ryser, and the physicians involved in the Swiss heroin trials for their help with volunteer recruitment and all volunteers for their good cooperation. We also thank the physicians of the Division of Clinical Pharmacology in Zürich for their help during the study sessions.
The study was funded by the Swiss Federal Office of Public Health. Karin Fattinger was supported by a Swiss National Science Foundation Grant, 3200B0-109352. Davide Verottta was supported by a National Institutes of Health Grant, RO1 A150587.

Auswirkungen von Drogen auf Menstruation, Schwangerschaft, Geburt und Kindesentwicklung

Opiate haben neben vielfältigen Wirkungen auch neuroendokrine Effekte. Sie führen u.a. zu einer Abnahme des luteinisierenden Hormons (LH) und des Follikel-stimulierenden Hormons (FSH). Die Prolaktinspiegel steigen dagegen an.
Die Gonadotropine LH und FSH werden im Hypophysenvorderlappen gebildet. Erniedrigte Werte bei Heroinabhängigkeit, Anorexie und durch Einnahme von Ovulationshemmern
Diese hormonellen Effekte sind zusammen mit psychosozialen Stressfaktoren dafür verantwortlich, dass viele abhängige Frauen an Amenorrhoe oder Oligomenorrhoe leiden.
Unter oral eingenommenen Substituten mit langsamerer Anflutungsgeschwindigkeit als bei i.v. oder nasal eingenommenem Heroin kommt es meist zu einer Normalisierung der Menstruation.
Ein Opioid induzierter Östrogenmangel kann langfristig zu einer Osteoporose führen.

Bei Frauen, die Drogen nehmen, ist die Schwangerschaft mit besonderen Risiken verbunden. Dies gilt für legale wie für illegale Drogen. Das ungeborene Kind ist an den Blutkreislauf der Mutter angeschlossen. Konsumiert eine schwangere Frau Drogen, können diese auf das Kind übergehen. Das Kind kann dadurch schwere, z.T. auch lebenslange Schäden davontragen. Es gibt bei den Drogen/Alkohol/Medikamenten keine Dosis, die eventuell toleriert werden kann. Bei Opiaten wie Heroin ist allerdings dringend zu empfehlen auf ein Substitut umzusteigen.

Die Risiken des Nikotin Konsums:
20 % der Schwangeren rauchen. Auswirkungen sind fetale Wachstumsverzögerung, Spontanabort, Tabakentzugssyndrom, plötzlicher Kindstod. Die Ursache ist wahrscheinlich die erhöhte Kohlenmonoxidbelastung. 30 Zigaretten/ Tag führen zu einer 60% Reduktion der fetalen Sauerstoffversorgung. Die Kinder wiegen bei Geburt im Durchschnitt 200gr. weniger.
Sie haben auch ein erhöhtes Risiko für die spätere Entwicklung einer Leukämie.

Die Risiken des Alkohol Konsums:
Alkohol gelangt über die Nabelschnur rasch in den Blutkreislauf des ungeborenen Kindes, und verbreitet sich im ganzen Körper. In ganz kurzer Zeit haben Mutter und Kind denselben Alkoholspiegel.
Die schädigende Wirkung des Alkohols hält aber beim ungeborenen Kind länger an, als bei der Mutter, weil der noch nicht vollständig entwickelte Organismus Alkohol sehr langsam abbaut. Die Blutalkoholspiegel sind nach Konsum eine Zeit lang deutlich höher, als bei der Mutter.
Alkohol hat beim Feten eine teratogene Wirkung. In hohen Dosen (tägl.> 60gr) kann es zum fetalen Alkoholsyndrom (FAS) kommen, dazu gehören Wachstumsverzögerung, Gesichtsmissbildungen wie Lippen-, Kiefer-, Gaumenspalte, Herzfehler, Funktionsstörungen des ZNS , motorische und intellektuelle Fehlentwicklungen, die zu lebenslangen Beeinträchtigungen führen können. Es gibt aber auch bei geringerem Alkohol Konsum auch „leichtere“ Verhaltensauffälligkeiten und intellektuelle Beeinträchtigungen, die dann oft nicht auf den Alkohol Konsum in der Schwangerschaft zurückgeführt werden.

Die Risiken des Cannabis Konsums:
Untersuchungen zeigen, dass die Schadstoffaufnahme eines Joints, etwa der von 5 Zigaretten entspricht. Der Konsum von THC führt zu einer deutlichen Reduktion des Geburtsgewichts.
Es gibt nur wenige Untersuchungen, aber Hinweise, dass es später zu Verhaltensauffälligkeiten kommen kann. Diskutiert werden auch Sprach-, Gedächtnis-; und Lernstörungen. Die Wahrscheinlichkeit einer Risikoschwangerschaft ist erhöht, da THC die Einnistung des Embryos in die Gebärmutter verhindern kann.

Die Risiken des Kokain Konsums:
Die gefäßverengende Wirkung des Kokains hat Durchblutungsstörungen der Gebärmutter und der Plazenta zur Folge. Dadurch wird das werdende Kind schlechter mit Sauerstoff und Nährstoffen versorgt, es kann zu einer vorzeitigen Placenta Ablösung (Fehlgeburt) und vorzeitigen Wehen kommen (Frühgeburt).
Kokain passiert die Plazentaschranke und führt zu einer 4 x höheren Konzentration, verglichen mit der Schwangeren.
Es kommt gehäuft zu Missbildungen vor allem im Urogenitaltrakt und zu Schädigungen der neuronalen Entwicklung. Postpartal zeigen die Kinder häufig Anzeichen der Neurotoxizität, wie Zittrigkeit, erhöhte Irritabilität, aber auch Lethargie und erhöhtes Schlafbedürfnis.

Die Risiken des Amphetamin und Ecstasy Konsums:
Amphetamine bewirken einen erhöhten Gefäßtonus mit Hypertonie und Tachykardie und als Folge eine fetale Mangelversorgung (s.Kokain). Es besteht die Gefahr einer Fehl- o. Frühgeburt, und eines geringeren Geburtsgewichtes.
Es gibt Hinweise auf eine erhöhte Rate von Fehlbildungen.

Die Risiken des Benzodiazepin Konsums:
Es gibt Hinweise auf vermehrte Fehlbildungen im Bereich des Gesichtes, Lippen-Kiefer-Gaumenspalten, besonders wenn Benzodiazepine im ersten Trimenon konsumiert werden. Ebenso Herz- und Gefäßmissbildungen, und geistige Entwicklungsverzögerungen.
Neugeborene zeigen bei Benzodiazepin – Konsum der Mutter das am längsten dauernde und intensivste Entzugssyndrom (NAS) mit starkem Zittern, anhaltender Nervosität, leichter Irritierbarkeit, Blutdruckkrisen, Temperaturabfall, Erbrechen, Durchfall usw. Der Entzug von Benzodiazepinen kann länger als 4 Wochen dauern, und mit epileptischen Anfällen einhergehen.

Die Risiken des Opiat Konsums:
Opiate wie Heroin gehen direkt in den Blutkreislauf des Kindes über. Nach bisherigen wissenschaftlichen Erkenntnissen haben sie keine teratogen, d.h. fruchtschädigenden Wirkungen. Die Risiken fürs Kind sind aber niedriges Geburtsgewicht und Frühgeburten. Ist das Straßenheroin mit Streckmitteln wie Diazepam u.a. versetzt bestehen hier weitere Risiken.
Besonders gravierend ist das neonatale Abstinenzsyndrom (NAS), das bei Heroin 24-48 Stunden nach der Geburt auftritt, und mehrere Wochen dauern kann.
Therapie der Wahl ist die Substitution mit synthetischen Opioiden, nicht nur zur Verhinderung von Entzugserscheinungen, Vermeidung von Rückfällen und Zusatzkonsum, sondern auch zur gesundheitlichen und zur sozialen Stabilisierung.
Die Dosis sollte ausreichend sein. Im dritten Trimenon kommt es durch Enzyminduktion zu einem erhöhten Bedarf. Dosiserhöhung u.o. Dosissplitting kann notwendig sein.
In 60 – 80 % kommt es nach der Geburt zu einem neonatalen Entzugssyndrom, das nach heutigen Erkenntnissen bezgl. Dauer und Ausprägung unabhängig von der Dosis des Substituts ist. Subutex scheint günstiger zu sein, das NAS schwächer und kürzer, allerdings ist die Datenlage bezgl. Methadon/Polamidon besser.
Die Behandlung des NAS sollte mit oralen Morphinen erfolgen, nicht mit Barbituraten.

Cable dated:2006-05-23T11:49:00

E.O. 12958: DECL: 05/23/2016

1. (U) SUMMARY: May 19 and 20 arrests of two Taiwanese nationals attempting to smuggle a total of nearly 7 kg of heroin to Taiwan highlight increased drug arrests and seizures in Cambodia. The quantity of heroin seized during the weekend airport busts is large by Cambodian standards–authorities seized just 11 kg of heroin in 2005. Seizures of amphetamine-type stimulants are more than double last year’s levels. Police and international observers credit USG and other foreign training with providing skills, motivation, and international pressure for the increase, but say that narcotics trafficking may also be on the rise. END SUMMARY.

Heroin Seizures at Phnom Penh International Airport

——————————————— ——-

2. (U) Police and customs officials seized nearly 7 kg of heroin and arrested three Taiwanese nationals in two separate incidents at Phnom Penh International Airport on May 19 and 20. These two cases represent an impressive intake for one weekend given that in 2005 Cambodian authorities seized just over 11 kg of heroin.

3. (SBU) Chen Hsin Hung, 57, was arrested on May 19 carrying 4.75 kg of heroin with a local street value of USD 95,000 to 133,000. Customs officials became suspicious when they noticed that Hung was carrying several bags of imported Taiwanese foil-wrapped candies back to Taiwan in his hand luggage. The candies turned out to be foil-wrapped packages of heroin. Hung, who was due to travel to Taiwan via Kuala Lumpur on Malaysian Airlines flight 755, had arrived in Phnom Penh the previous day. During his police interrogation, Hung said that he had been picked up at the airport and returned to the airport by a couple, whom the police identified as a Cambodian woman and a mainland Chinese or Taiwanese man. Police are attempting to locate the couple.

4. (SBU) A second Taiwanese man, who was standing near Chen Hsin Hung during the security process, appeared to be quite interested in the proceedings and upset by Hung’s arrest, and had tickets for the same flight as Hung, was also arrested on suspicion of drug trafficking. Moek Dara noted that the investigation had revealed no evidence to indicate that the second individual was also involved in drug smuggling, but that it was the prosecutor’s decision how to proceed in the case.

5. (SBU) On May 20, a 90-year-old Taiwanese national named Huang Sang Hou was arrested at Phnom Penh International Airport with 1.9 kg of heroin, worth USD 38,000 to USD 53,000. Hou reportedly came to Cambodia as a tourist intending to gamble. Over the course of a week, he lost the USD 4,000 he brought with him, borrowed an additional USD 2,000 from a Taiwanese national in Phnom Penh, and then lost that money as well. The Taiwanese lender then persuaded Hou to carry the heroin back to Taiwan. Airport customs officials were tipped off by the sloppy manner in which the heroin was packed on Hou’s body, making him appear bloated. Hou cooperated with the police in identifying the Taiwanese lender, and Cambodian government officials have already passed his name, address, and passport information to the Drug Enforcement Administration (DEA). Hou had been planning to fly Dragon Airlines flight 207 to Hong Kong, and then to continue on to Taiwan.

Amphetamine Seizures, Prices on the Rise


6. (SBU) According to statistics from the Ministry of Interior’s Anti-Drug Police and the National Authority for Combating Drugs (NACD), seizures of amphetamine-type stimulant (ATS) tablets more than doubled when comparing the first four months of 2006 with the first four months of 2005. From January to April 2006, more than 220,000 ATS tablets were seized, whereas from January to April 2005, approximately 87,000 ATS tablets were seized. The number of offenders arrested also rose from 154 from January to April 2005 to 204 during January to April 2006.

7. (U) Both Brigadier General Moek Dara, Director of the Anti-Drugs Department, and World Health Organization XXXXXXXXXXXX noted that prices for ATS tablets have risen in the past few years, with particularly dramatic increases in the past 12 months. One year ago, a single ATS tablet sold for approximately one dollar in Phnom Penh, but now costs two to three dollars. Moek Dara noted that prices rise as the ATS tablets make their way along the drug route, from fifty cents per tablet in Laos, where the

PHNOM PENH 00000983 002 OF 003

majority are produced, to USD 3 in Cambodia, and then even higher prices in two destination countries: USD 4 in Vietnam and USD 7.50 in Thailand. XXXXXXXXXXXX cited anecdotal evidence from NGOs that some ATS users are switching to injecting heroin, currently available for USD 1.50 to 2 in Phnom Penh, as a cheaper alternative to rising ATS prices.

Lower Ecstasy Seizures Likely Point to Disrupted Network ——————————————— ———–

8. (U) In contrast to the dramatic rise in ATS seizures, seizures of ecstasy tablets are down sharply, from 1,900 in January to April 2005 to less than 800 in January to April 2006. Moek Dara and XXXXXXXXXXXX believe that lower levels of ecstasy seizures are a sign that supply has been disrupted following a cooperative DEA/Anti-Drug Police controlled delivery operation against the Peter Brown drug ring in 2004 and continued Anti-Drug Police action against the ring in 2005.

USG Training Provides Needed Skills, International Pressure

——————————————— ————–

9. (SBU) Moek Dara gave much of the credit for the dramatic increase in heroin and ATS seizures and drug arrests to counternarcotics training funded by the State Department’s Bureau of International Narcotics and Law Enforcement Affairs (INL) and conducted by the DEA. Before the training sessions, which were conducted in January and April 2006, police officers along Cambodia’s porous northern border were not very active and would not even conduct foot patrols in the forest, according to Moek Dara. Now, however, the officers have more skills and are more motivated to patrol actively, he said, and have seized drugs and a lot of drug production equipment as well. Customs, immigration, and police officials at the airports are also better trained and more active, and Moek Dara noted that all of the officials involved in the weekend’s airport arrests had completed DEA training.

10. (C) XXXXXXXXXXXX gave partial credit for increased anti-drug activity to counternarcotics training by the US and other foreign donors. Some high-ranking Cambodian police and military officials are rumored to be complicit in narcotics trafficking, he noted. He speculated that the training and pressure on the Cambodian government to clamp down on drug activity has finally made an impression on higher ranking officials, and lower-level officers are „being allowed“ to make more seizures. At the same time, such a dramatic increase is probably also an indication of efforts to traffic increased amounts of ATS through Cambodia, he opined.

Trainees Enthusiastic about INL/DEA Courses


11. (U) Provincial Anti-Drug Police officers who attended the January Basic Counternarcotics course reported uniformly enthusiastic assessments to an embassy follow-up survey. Participating police captains reported an increased awareness of drug smuggling tactics, best practices in seizing and preparing evidence, and how to identify drugs using field test kits. Captain Preap Sovann of the Svay Rieng Anti-Drug Police noted that the training also promoted inter-agency and inter-province cooperation as well. All captains reported training their staffs in the key topics covered by the DEA training, and captains in Koh Kong and Pursat provinces reported conducting anti-drug outreach to primary and secondary school students as well. Trainees suggested that future courses provide written materials in Khmer as well as English, include information on money laundering, have more laboratory equipment available for in-class practice in drug identification, and include more time in simulations.

Police Officer Arrested on Drug Charges


11. (C) Nov Sophal, a municipal police officer in the southern city of Kep, was arrested on April 15 and charged with trafficking 1 kg of heroin. Moek Dara was not expansive when asked about the case, noting simply that it is not uncommon for low-ranking police and military officials to be arrested for drug trafficking. In contrast, XXXXXXXXXXXX noted that drug investigations of police or military officials are very rare, and speculated that the individual involved may even have run afoul of rumored higher-level police involvement in narcotics.

12. (SBU) COMMENT: While increased smuggling activity may

PHNOM PENH 00000983 003 OF 003

account for some of the increased seizures and arrests, it is clear that the Cambodian government is turning up the heat on the country’s drug smugglers. Training from the USG and other countries is playing a critical role in supporting this effort–both through the skills and enthusiasm imparted to the participants, and also through the implicit expectations of improved performance on the part of the police and other officials.




MOSCOW — They look like addicts anywhere in the world: tattered and vacant-eyed, they circle Moscow pharmacies known to sell prescription drugs illicitly, looking for something to inject for a quick high.

James Hill for The New York Times

Pyotr Nikitenko, right, distributed medical supplies and literature outside a pharmacy in Moscow with a drug outreach center colleague, left. Mr. Nikitenko, a former heroin user, said most of his friends were now H.I.V. positive.

Though public examples of Russia’s problem with heroin are not new and seldom bring even raised eyebrows among locals, the issue has recently come to symbolize a broader failure. The country has become one of the world’s low points in the effort to fight the spread of H.I.V., and unchecked intravenous drug use is the biggest cause, international health officials say.

The epidemic here has defied worldwide trends, expanding more rapidly year by year than almost anywhere else. Nearly 60,000 new cases of H.I.V., the virus that causes AIDS, were documented in Russia in 2009, an 8 percent increase from 2008, according to Unaids, the United Nations H.I.V./AIDS program. Of those new cases, more than 60 percent were believed to have been caused by intravenous drug use, and many of the others were believed to have been infected through sex with addicts.

Though South Africa, with more infections than any other country, far outstripped that total number, with an estimated 390,000 new infections in 2009, the rate of new infections annually has decreased there by nearly half since its peak in the late 1990s.

“I’ve been researching the problem of H.I.V. infection for 25 years, and I must say that the situation has become significantly worse” in Russia, said Dr. Vadim V. Pokrovsky, the head of the country’s Federal AIDS Center.

While in recent years the government has increased its efforts to fight the disease, Dr. Pokrovsky said, current programs almost completely neglect those groups at the heart of it.

Officials estimate that well over a million people abuse drugs intravenously in Russia, often sharing and infecting one another with tainted needles. They are among Russian society’s most marginalized people, more likely to face a few weeks handcuffed to a clinic bed than to receive basic treatment to break their addictions. Meanwhile, officials have treated sex education and other preventative programs with open hostility.

“Which are the main infected groups? Injecting-drug users and sex workers,” said Lev Zohrabyan, the Europe and Central Asia adviser for Unaids. “It turns out that these are the groups where the money must be directed to change the picture. But if you open the budget, you will see that for prevention work among these groups for the next two years there is nothing.”

Top officials have consistently blamed the United States’ failure to eradicate heroin production in Afghanistan for Russia’s intravenous drug problem. About 90 percent of Russian addicts use Afghan heroin, according to the Federal Drug Control Service.

Yet once the drugs pass through Russia’s porous borders with former Soviet republics in Central Asia, dealers find a ready market of addicts with few tools to help them quit. While some regions have experimented with needle-exchange programs, the practice, which has proven effective at reducing the spread of H.I.V. in other countries, has not been adopted on a national level.

The country’s top medical and political officials have roundly condemned drug substitution therapy for heroin addicts — the use of methadone or other narcotics, widely considered an effective way to wean people off the drug — on the basis that it substitutes one form of addiction for another. Doctors who have flouted the official ban on the treatment have faced prosecution and even harassment by Kremlin-backed youth groups.

The Russian Orthodox Church, which has become a significant voice in the country’s political affairs in the past decade, has also expressed strong opposition to such preventative measures.

Even a new antinarcotics strategy ordered by President Dmitri A. Medvedev last summer acknowledges Russia’s failure to adequately confront the problem. “Prophylactic activities, medical aid and rehabilitation of patients with drug addiction are not sufficiently effective,” said the document, posted on Mr. Medvedev’s Web site.

Many of the addicts gathered outside one pharmacy in southern Moscow said they had often tried to stop. “You want to quit, and you don’t,” said a graying 33-year-old named Maxim who had the scarred arms of a dedicated user. Another man, who had quarter-size holes gouged into his body from injection-related infections and would not give his name, said he feared that he would be arrested if he sought treatment — a worry that is not completely unfounded here.

The police often arrest drug users, sending them to special detoxification centers where doctors encourage, and sometimes force, immediate abstinence, which can in some rare cases be fatal. Last summer, organizers of the 18th annual International AIDS Conference held in Vienna issued a declaration — aimed at Russia and the countries of the former Soviet Union, in particular — arguing that such practices drove addicts underground, complicating H.I.V.-prevention efforts.

It is not that the government has failed completely to recognize the gravity of the epidemic. Russia’s national security strategy, approved by Mr. Medvedev, identifies the spread of H.I.V. and AIDS as “one of the main threats to national security in the sphere of medicine and health.”

Russia now has more than 500,000 officially registered cases of H.I.V., though Unaids and other experts have estimated the actual number to be closer to one million, as many as in the United States, which has more than twice the population.

Part of the problem is that the government came late to the fight. The epidemic has been raging since the Soviet collapse two decades ago, but a major government response came only in 2006 when Russia’s obligations as host of the Group of 8 summit meeting pushed officials to take a more active role in fighting the disease. Vladimir V. Putin, who was president at the time and is now prime minister, ordered the largest increase in financing in any area in Russia’s history, and spending has grown annually ever since.

This year, the government plans to nearly double spending on H.I.V. drugs to about $600 million and expand prevention programs focusing on youth, said Galina G. Chistyakova, a Health Ministry official who helps oversee Russia’s H.I.V. and AIDS policies. She denied that Russia was having trouble curbing the epidemic, noting that the ministry had documented a slight dip in the number of new infections in 2010 compared with a year earlier.

Dr. Pokrovsky and others said that government programs often became ensnared in Russia’s large and inefficient bureaucracies. Even efforts to provide AIDS patients with treatment, which constitute the bulk of government financing, have fallen short.

Patients and doctors have complained of frequent shortages of antiretroviral drugs to the point where patients have created online communities, like, that monitor drug deficits and help those in need of medicines connect with people who have extra supplies. Patients have also held street protests, and others have sued.

Many addicts who become infected do not even know that medicines are available, said Pyotr Nikitenko, 28, a former heroin user who now works for a Moscow-based outreach group called Yasen. He said he was able to wean himself off heroin with the help of his family, escaping the fate of most of his friends, who he said now were H.I.V. positive.

“I continue to bury them,” Mr. Nikitenko said. “They continue to die from AIDS, or rather they are dying more and more frequently.”

Russia has one of the fastest spreading HIV epidemics in the world, driven largely by the government’s refusal to institute measures to treat the country’s drug addicts — measures that have dramatically reduced HIV infections in drug addicts in other countries, including the U.S.

The New York Times reported yesterday that 60,000 new cases of HIV were seen in Russia in 2009, up 8% from the prior year. At least 60% of those new cases were spread by intravenous drug use, according to the Times, and a good portion of the rest of the new cases were likely the result of sex with drug addicts. (More on Drug Policy Backfires: Controlling Meth Ingredients Fails to Cut Drug Supply)

Writes the Times‘ Michael Schwirtz:

Officials estimate that well over a million people abuse drugs intravenously in Russia, often sharing and infecting one another with tainted needles. They are among Russian society’s most marginalized people, more likely to face a few weeks handcuffed to a clinic bed than to receive basic treatment to break their addictions. Meanwhile, officials have treated sex education and other preventative programs with open hostility.

“Which are the main infected groups? Injecting-drug users and sex workers,” said Lev Zohrabyan, the Europe and Central Asia adviser for Unaids. “It turns out that these are the groups where the money must be directed to change the picture. But if you open the budget, you will see that for prevention work among these groups for the next two years there is nothing.”

According to Schwirtz, Russia blames America’s failure to eradicate Afghanistan’s opium crops for the IV drug problem in Russia. But if the U.K.’s current shortage of heroin, due to Afghan crop failures this year, are any indication, the international heroin supply has actually been significantly reduced. Regardless, changes in the supply side have never had any impact on the HIV epidemic.

So, what’s really driving Russia’s problem? Politics. The country has a long-standing ideological opposition to the use of “substitute” maintenance drugs like methadone and buprenorphine to treat IV drug addicts. Yet methadone is the best known treatment for heroin addiction: according to numerous reviews of the voluminous international data, it reduces relapse and death rates better than any other treatment, including all therapies based on abstinence. The effectiveness of buprenorphine treatment for heroin addiction is also well-supported by research. (More on Salvia, a Mexican Hallucinogen Piques Scientists‘ and Regulators‘ Interest)

In all countries that have successfully reduced HIV infection rates among intravenous drug users, health officials have instituted maintenance treatment programs. But they have all also simultaneously increased clean-needle availability — the other public-health measure that undergirds many effective AIDS-prevention programs. In that respect, Russia has not been entirely remiss: it does offer some needle-exchange programs that provide addicts with clean syringes and educate them not to share.

Alone, methadone maintenance programs and legal needle-and-syringe exchanges cannot stop an epidemic. But the evidence is pretty clear that together, they can. Case in point: New York City.

In the not too distant past, New York was the epicenter of the AIDS epidemic among America’s drug addicts. In the early 1990s, at least half of all intravenous drug users in the city were HIV-positive. But a recent study of HIV infection rates among injected-drug users in New York found that while 21% of addicts tested positive for HIV between 1984 and 1994, that figure dropped to just 6% in people who used IV drugs between 1995 and 2008.

What changed? The two groups are distinguished by the prevention measures most available to them. In the 1980s and early ’90s, New York City had a large methadone treatment system, but awareness of the spread of HIV among drug addicts was initially low; at the time, syringe exchange programs were also either illegal or just getting started, and needle possession was illegal. (More on The Most Dangerous Drugs? Alcohol, Heroin and Crack — in That Order)

In 1992, needle exchanges were legalized in New York City, and massively expanded by 1995. Over-the-counter sales of syringes in New York became legal in 2001.

Nationally, the AIDS epidemic in addicts has subsided too, with only 12% of new cases linked to IV drug use, down from more than 1 in 3.

Given that the data overwhelmingly show that maintenance programs and needle exchanges, together, can significantly reduce the spread of HIV, Russia’s refusal to treat the country’s million-plus drug users is putting millions more of its citizens — including nonusers who may be partners of drug users or of infected former partners — at deadly risk.

Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events.

CYP = cytochrome P450; M1 = O-desmethyltramadol; M3G = morphine-3-glucuronide; M6G = morphine-6-glucuronide; UGT = uridine diphosphate glucuronosyltransferase

Opioids are a cornerstone of the management of cancer pain1 and postoperative pain2 and are used increasingly for the management of chronic noncancer pain.3,4 Understanding the metabolism of opioids is of great practical importance to primary care clinicians. Opioid metabolism is a vital safety consideration in older and medically complicated patients, who may be taking multiple medications and may have inflammation, impaired renal and hepatic function, and impaired immunity. Chronic pain, such as lower back pain, also occurs in younger persons and is the leading cause of disability in Americans younger than 45 years.5 In younger patients, physicians may be more concerned with opioid metabolism in reference to development of tolerance, impairment of skills and mental function, adverse events during pregnancy and lactation, and prevention of abuse by monitoring drug and metabolite levels.

Experienced clinicians are aware that the efficacy and tolerability of specific opioids may vary dramatically among patients and that trials of several opioids may be needed before finding one that provides an acceptable balance of analgesia and tolerability for an individual patient.69 Pharmacodynamic and pharmacokinetic differences underlie this variability of response. Pharmacodynamics refers to how a drug affects the body, whereas pharmacokinetics describes how the body alters the drug. Pharmacokinetics contributes to the variability in response to opioids by affecting the bioavailability of a drug, the production of active or inactive metabolites, and their elimination from the body. Pharmacodynamic factors contributing to variability of response to opioids include between-patient differences in specific opioid receptors and between-opioid differences in binding to receptor subtypes. The receptor binding of opioids is imperfectly understood; hence, matching individual patients with specific opioids to optimize efficacy and tolerability remains a trial-and-error procedure.69

This review primarily considers drug metabolism in the context of pharmacokinetics. It summarizes the basics of opioid metabolism; discusses the potential influences of patient-specific factors such as age, genetics, comorbid conditions, and concomitant medications; and explores the differences in metabolism between specific opioids. It aims to equip physicians with an understanding of opioid metabolism that will guide safe and appropriate prescribing, permit anticipation and avoidance of adverse drug-drug interactions, identify and accommodate patient-specific metabolic concerns, rationalize treatment failure, inform opioid switching and rotation strategies, and facilitate therapeutic monitoring. To that end, recommendations for tailoring opioid therapy to individual patients and specific populations will be included.


Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed databases for literature published between January 1980 and June 2008. The opioid medication search terms used were as follows: codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, opioid, opioid analgesic, oxycodone, oxymorphone, and tramadol. Each medication search term was combined with the following general search terms: metabolism, active metabolites, pharmacokinetics, lipophilicity, physiochemical properties, pharmacology, genetics, receptor, receptor binding, receptor genetics or variation, transporter, formulations, AND adverse effects, safety, or toxicity. The reference lists of relevant papers were examined for additional articles of interest.


Metabolism refers to the process of biotransformation by which drugs are broken down so that they can be eliminated by the body. Some drugs perform their functions and then are excreted from the body intact, but many require metabolism to enable them to reach their target site in an appropriate amount of time, remain there an adequate time, and then be eliminated from the body. This review refers to opioid metabolism; however, the processes described occur with many medications.

Altered metabolism in a patient or population can result in an opioid or metabolite leaving the body too rapidly, not reaching its therapeutic target, or staying in the body too long and producing toxic effects. Opioid metabolism results in the production of both inactive and active metabolites. In fact, active metabolites may be more potent than the parent compound. Thus, although metabolism is ultimately a process of detoxification, it produces intermediate products that may have clinically useful activity, be associated with toxicity, or both.

Opioids differ with respect to the means by which they are metabolized, and patients differ in their ability to metabolize individual opioids. However, several general patterns of metabolism can be discerned. Most opioids undergo extensive first-pass metabolism in the liver before entering the systemic circulation. First-pass metabolism reduces the bioavailability of the opioid. Opioids are typically lipophilic, which allows them to cross cell membranes to reach target tissues. Drug metabolism is ultimately intended to make a drug hydrophilic to facilitate its excretion in the urine. Opioid metabolism takes place primarily in the liver, which produces enzymes for this purpose. These enzymes promote 2 forms of metabolism: phase 1 metabolism (modification reactions) and phase 2 metabolism (conjugation reactions).

Phase 1 metabolism typically subjects the drug to oxidation or hydrolysis. It involves the cytochrome P450 (CYP) enzymes, which facilitate reactions that include N-, O-, and S-dealkylation; aromatic, aliphatic, or N-hydroxylation; N-oxidation; sulfoxidation; deamination; and dehalogenation. Phase 2 metabolism conjugates the drug to hydrophilic substances, such as glucuronic acid, sulfate, glycine, or glutathione. The most important phase 2 reaction is glucuronidation, catalyzed by the enzyme uridine diphosphate glucuronosyltransferase (UGT). Glucuronidation produces molecules that are highly hydrophilic and therefore easily excreted. Opioids undergo varying degrees of phase 1 and 2 metabolism. Phase 1 metabolism usually precedes phase 2 metabolism, but this is not always the case. Both phase 1 and 2 metabolites can be active or inactive. The process of metabolism ends when the molecules are sufficiently hydrophilic to be excreted from the body.


Metabolic Pathways

Opioids undergo phase 1 metabolism by the CYP pathway, phase 2 metabolism by conjugation, or both. Phase 1 metabolism of opioids mainly involves the CYP3A4 and CYP2D6 enzymes. The CYP3A4 enzyme metabolizes more than 50% of all drugs; consequently, opioids metabolized by this enzyme have a high risk of drug-drug interactions. The CYP2D6 enzyme metabolizes fewer drugs and therefore is associated with an intermediate risk of drug-drug interactions. Drugs that undergo phase 2 conjugation, and therefore have little or no involvement with the CYP system, have minimal interaction potential.

Phase 1 Metabolism

The CYP3A4 enzyme is the primary metabolizer of fentanyl10 and oxycodone,11 although normally a small portion of oxycodone undergoes CYP2D6 metabolism to oxymorphone (Table 11018). Tramadol undergoes both CYP3A4- and CYP2D6-mediated metabolism.16 Methadone is primarily metabolized by CYP3A4 and CYP2B6; CYP2C8, CYP2C19, CYP2D6, and CYP2C9 also contribute in varying degrees to its metabolism.1923 The complex interplay of methadone with the CYP system, involving as many as 6 different enzymes, is accompanied by considerable interaction potential.

Each of these opioids has substantial interaction potential with other commonly used drugs that are substrates, inducers, or inhibitors of the CYP3A4 enzyme (Table 2).24,25 Administration of CYP3A4 substrates or inhibitors can increase opioid concentrations, thereby prolonging and intensifying analgesic effects and adverse opioid effects, such as respiratory depression. Administration of CYP3A4 inducers can reduce analgesic efficacy.10,11,16 In addition to drugs that interact with CYP3A4, bergamottin (found in grapefruit juice) is a strong inhibitor of CYP3A4,26 and cafestol (found in unfiltered coffee) is an inducer of the enzyme.27

Induction of CYP3A4 may pose an added risk in patients treated with tramadol, which has been associated with seizures when administered within its accepted dosage range.16 This risk is most pronounced when tramadol is administered concurrently with potent CYP3A4 inducers, such as carbamazepine, or with selective serotonin reuptake inhibitors, tricyclic antidepressants, or other medications with additive serotonergic effects.16

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Metabolic Pathway/Enzyme Involvement

The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone,14 codeine,13 and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively), which in turn undergo phase 2 glucuronidation. These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with selective serotonin reuptake inhibitors, tricyclic antidepressants, β-blockers, and antiarrhythmics; an array of other drugs are substrates, inducers, or inhibitors of the CYP2D6 enzyme (Table 328).

Although CYP2D6-metabolized drugs have lower interaction potential than those metabolized by CYP3A4, genetic factors influencing the activity of this enzyme can introduce substantial variability into the metabolism of hydrocodone, codeine, and to a lesser extent oxycodone. An estimated 5% to 10% of white people possess allelic variants of the CYP2D6 gene that are associated with reduced clearance of drugs metabolized by this isoenzyme,2931 and between 1% and 7% of white people carry CYP2D6 allelic variants associated with rapid metabolism.32,33 The prevalence of poor metabolizers is lower in Asian populations (≤1%)34 and highly variable in African populations (0%-34%).3539 The prevalence of rapid metabolizers of opioids has not been reported in Asian populations; estimates in African populations are high but variable (9%-30%).35,36

The clinical effects of CYP2D6 allelic variants can be seen with codeine administration. Patients who are poor opioid metabolizers experience reduced efficacy with codeine because they have a limited ability to metabolize codeine into the active molecule, morphine. In contrast, patients who are rapid opioid metabolizers may experience increased opioid effects with a usual dose of codeine because their rapid metabolism generates a higher concentration of morphine.40 Allelic variants altering CYP2D6-mediated metabolism can be associated with reduced efficacy of hydrocodone or increased toxicity of codeine, each of which relies entirely on the CYP2D6 enzyme for phase 1 metabolism.41,42 In patients treated with oxycodone, which relies on CYP3A4 and to a lesser extent on CYP2D6, inhibition of CYP2D6 activity by quinidine increases noroxycodone levels and reduces oxymorphone production. In one study, such alterations were not accompanied by increased adverse events.30 However, individual cases of reduced oxycodone efficacy42 or increased toxicity41 in CYP2D6 poor metabolizers have been reported.

Phase 2 Metabolism

Morphine, oxymorphone, and hydromorphone are each metabolized by phase 2 glucuronidation17,18,43 and therefore have little potential for metabolically based drug interactions. Oxymorphone, for example, has no known pharmacokinetic drug-drug interactions,18 and morphine has few.43 Of course, pharmacodynamic drug-drug interactions are possible with all opioids, such as additive interactions with benzodiazepines, antihistamines, or alcohol, and antagonistic interactions with naltrexone or naloxone.

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Cytochrome P450 3A4 Substrates, Inhibitors, and Inducers

However, the enzymes responsible for glucuronidation reactions may also be subject to a variety of factors that may alter opioid metabolism. The most important UGT enzyme involved in the metabolism of opioids that undergo glucuronidation (eg, morphine, hydromorphone, oxymorphone)12,44 is UGT2B7. Research suggests that UGT2B7-mediated opioid metabolism may be altered by interactions with other drugs that are either substrates or inhibitors of this enzyme.45 Moreover, preliminary data indicate that UGT2B7 metabolism of morphine may be potentiated by CYP3A4, although the clinical relevance of this finding is unknown.4648

The activity of UGT2B7 shows significant between-patient variability, and several authors have identified allelic variants of the gene encoding this enzyme.12,44 Although the functional importance of these allelic variants with respect to glucuronidation of opioids is unknown, at least 2 allelic variants (the UGT2B7-840G and -79 alleles) have been linked to substantial reduction of morphine glucuronidation, with resulting accumulation of morphine and reduction in metabolite formation.49,50 Moreover, research has shown that variation in the amount of messenger RNA for hepatic nuclear factor 1α, a transcription factor responsible for regulating expression of the UGT2B7 gene, is associated with interindividual variation in UGT2B7 enzyme activity.51

Clinical Implications of Metabolic Pathways

Most opioids are metabolized via CYP-mediated oxidation and have substantial drug interaction potential. The exceptions are morphine, hydromorphone, and oxymorphone, which undergo glucuronidation. In patients prescribed complicated treatment regimens, physicians may consider initiating treatment with an opioid that is not metabolized by the CYP system. However, interactions between opioids that undergo CYP-mediated metabolism and other drugs involved with this pathway often can be addressed by careful dose adjustments, vigilant therapeutic drug monitoring, and prompt medication changes in the event of serious toxicity.

Response to individual opioids varies substantially, and factors contributing to this variability are not clearly understood. Because an individual patient’s response to a given opioid cannot be predicted, it may be necessary to administer a series of opioid trials before finding an agent that provides effective analgesia with acceptable tolerability.69 In some patients, the most effective and well-tolerated opioid will be one that undergoes CYP-mediated metabolism. For example, in a 2001 clinical trial, 50 patients with cancer who did not respond to morphine or were unable to tolerate it were switched to methadone, which undergoes complex metabolism involving up to 6 CYP enzymes. Adequate analgesia with acceptable tolerability was obtained in 40 (80%) of these patients.52

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Cytochrome P450 2D6 Substrates, Inhibitors, and Inducers

In short, for some patients, selecting an opioid without considerable potential for drug interactions may not be possible. Under such conditions, an understanding of opioid metabolism can guide dose adjustments or the selection of a different opioid when analgesia is insufficient or adverse events are intolerable.


Some opioids produce multiple active metabolites after administration (Table 410,11,1618,28,43,5360). Altered metabolism due to medical comorbidities, genetic factors, or drug-drug interactions may disrupt the balance of metabolites, thereby altering the efficacy and/or tolerability of the drug. Moreover, opioids that produce metabolites chemically identical to other opioid medications may complicate the interpretation of urine toxicology screening.


Codeine is a prodrug that exerts its analgesic effects after metabolism to morphine. Patients who are CYP2D6 poor or rapid metabolizers do not respond well to codeine. Codeine toxicity has been reported in CYP2D6 poor metabolizers who are unable to form the morphine metabolite42 and in rapid metabolizers who form too much morphine.61,62 In fact, a recent study found that adverse effects of codeine are present irrespective of morphine concentrations in both poor and rapid metabolizers,63 suggesting that a substantial proportion of patients with CYP2D6 allelic variants predisposing to poor or rapid codeine metabolism will experience the adverse effects of codeine without benefitting from any of its analgesic effects. Codeine is also metabolized by an unknown mechanism to produce hydrocodone in quantities reaching up to 11% of the codeine concentration found in urinalysis.58 The clinical effect of the hydrocodone metabolite of codeine is unknown.


In addition to its pharmacologically active parent compound, morphine is glucuronidated to 2 metabolites with potentially important differences in efficacy, clearance, and toxicity: morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). Morphine may also undergo minor routes of metabolism, including N-demethylation to normorphine or normorphine 6-glucuronide, diglucuronidation to morphine-3, 6-diglucuronide, and formation of morphine ethereal sulfate. A recent study found that a small proportion of morphine is also metabolized to hydromorphone,55 although there are no data suggesting a meaningful clinical effect.

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Major Opioid Metabolites

Like morphine, M6G is a μ-opioid receptor agonist with potent analgesic activity. However, morphine has greater affinity than M6G for the μ2-opioid receptor thought to be responsible for many of the adverse effects of μ-receptor agonists,64,65 most notably respiratory depression, gastrointestinal effects, and sedation.65,66 Although the affinities of morphine and M6G for the μ1-opioid receptor are similar, a study of low-dose morphine, M6G, and M3G found that morphine had greater analgesic efficacy.67 The M3G metabolite of morphine lacks analgesic activity, but it exhibits neuroexcitatory effects in animals and has been proposed as a potential cause of such adverse effects as allodynia, myoclonus, and seizures in humans.6870 In a clinical trial, however, low-dose M3G exhibited no analgesic effects, did not potentiate the analgesic effects of morphine or M6G, and did not produce adverse effects.67

Clinical data regarding morphine and its glucuronide metabolites are unclear. Two studies found no correlation between plasma concentrations of morphine, M6G, or M3G in either clinical efficacy or tolerability.71,72 Moreover, in patients with impaired renal function, the pharmacokinetics of morphine appear to be less affected than that of its M6G and M3G metabolites, which were found to accumulate.7376 Although M6G appears to be better tolerated than morphine, increased toxicity in patients with reduced clearance was primarily related to the accumulation of the M6G metabolite.


The production of active metabolites is also an issue with hydromorphone. The primary metabolite of hydromorphone, hydromorphone-3-glucuronide, has neuroexcitatory potential similar to68,70 or greater than69 the M3G metabolite of morphine. Clinical data on the neuroexcitatory potential of hydromorphone during long-term therapy are unavailable. However, hydromorphone is available only in short-acting formulations and extended-release formulations are recommended in patients with chronic pain requiring long-term therapy.3,4


Like codeine, tramadol requires metabolism to an active metabolite, O-desmethyltramadol (M1), to be fully effective. The parent compound relies on both CYP3A4 and CYP2D6, with metabolism of M1 relying on CYP2D6.16 In a group of patients receiving multiple medications and treated with tramadol under steady-state conditions, the concentration of M1 after correcting for dose and the M1/ tramadol ratio were each approximately 14-fold higher in patients with a CYP2D6 allelic variant associated with extensive metabolism than in poor metabolizers.77 Both tramadol and its M1 metabolite exert analgesic effects through opioidergic mechanisms (μ-opioid receptor) and through 2 nonopioidergic mechanisms, serotonin reuptake inhibition and norepinephrine reuptake inhibition. Although M1 has more potent activity at the μ-opioid receptor,16,78 tramadol is the more potent inhibitor of serotonin and norepinephrine reuptake and the more potent promoter of serotonin and norepinephrine efflux.79,80 Although the precise function of M1 in humans remains unclear, tramadol-mediated analgesia appears to depend on the complementary contributions of an active metabolite with a route of metabolism that differs from that of the parent compound.


Oxycodone is metabolized by CYP3A4 to noroxycodone and by CYP2D6 to oxymorphone.11 Noroxycodone is a weaker opioid agonist than the parent compound, but the presence of this active metabolite increases the potential for interactions with other drugs metabolized by the CYP3A4 pathway. The central opioid effects of oxycodone are governed primarily by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites.81 Oxymorphone is present only in small amounts after oxycodone administration, making the clinical relevance of this metabolite questionable. Although the CYP2D6 pathway is thought to play a relatively minor role in oxycodone metabolism, at least 1 study has reported oxycodone toxicity in a patient with impaired CYP2D6 metabolism.41 The authors of this report suggested that failure to metabolize oxycodone to oxymorphone may have been associated with accumulation of oxycodone and noroxycodone, resulting in an inability to tolerate therapy.


Fentanyl, oxymorphone, and methadone do not produce metabolites that are likely to complicate treatment. Fentanyl is predominantly converted by CYP3A4-mediated N-dealkylation to norfentanyl, a nontoxic and inactive metabolite; less than 1% is metabolized to despropionylfentanyl, hydroxyfentanyl, and hydroxynorfentanyl, which also lack clinically relevant activity.82 An active metabolite of oxymorphone, 6-hydroxy-oxymorphone, makes up less than 1% of the administered dose excreted in urine and is metabolized via the same pathway as the parent compound, making an imbalance among metabolites unlikely.18 Methadone does not produce active metabolites, exerting its activity—both analgesic and toxic—through the parent compound. However, methadone has affinity for the N-methyl-d-aspartate receptors83; this affinity is thought to account not only for a portion of its analgesic efficacy but also for neurotoxic effects that have been observed with this opioid.8486


Opioids that produce active metabolites structurally identical to other opioid medications can complicate efforts to monitor patients to prevent abuse and diversion. Current urine toxicology tests do not provide easily interpretable information about the source or dose of detected compounds. Thus, in a patient prescribed oxycodone, both oxycodone and oxymorphone will appear in toxicology results, but the urine test results will not establish whether the patient took the prescribed oxycodone alone or also self-medicated with oxymorphone.

Patients treated with codeine will have both codeine and morphine in urine samples. If too much morphine is present, the patient may be taking heroin or ingesting morphine in addition to codeine. CYP2D6 rapid metabolizers may have an unusually high morphine-to-codeine ratio, making interpretation of the morphine-to-codeine ratio challenging.87 However, in patients taking only codeine, the codeine-to-morphine ratio is less than 6, even in rapid metabolizers.87,88 Additionally, morphine alone may be detectable in the urine 30 hours after ingestion of a single dose of codeine.8992

The urine of patients treated with morphine may contain small amounts of hydromorphone (≤2.5% of the morphine concentration).53,54 Similarly, those treated with hydrocodone may test positive for both hydrocodone and hydromorphone, making it difficult to determine whether the parent opioid was taken as prescribed or a second opioid is being abused.

Clinicians may find it easier to monitor patients for adherence and abuse if the opioid prescribed does not produce active metabolites similar to other opioid medications. If abuse is suspected, choosing opioids such as fentanyl, hydromorphone, methadone, or oxymorphone may simplify monitoring. Sometimes an inactive metabolite provides a more reliable test of adherence than does the parent opioid. Urinary concentrations of methadone depend not only on dose and metabolism but also on urine pH. In contrast, the concentration of an inactive metabolite of methadone (via N-demethylation), 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, is unaffected by pH and is therefore preferable for assessing adherence to therapy.93,94


Opioid metabolism differs with individual opioids in populations stratified according to age, sex, and ethnicity (Table 510,11,1318,43). Reduced clearance of morphine,43 codeine,13 fentanyl,10 and oxymorphone18 has been reported in older patients. Oxycodone concentrations are approximately 25% higher in women than in men after controlling for differences in body weight, making it important for physicians to consider the patient’s sex when prescribing this opioid.11 Chinese patients have higher clearance and lower concentrations of morphine.43 Similarly, codeine is a prodrug that exerts its analgesic effects after metabolism to morphine. Morphine concentrations were shown to be reduced in Chinese patients treated with codeine, providing confirmation of altered morphine metabolism in this large population.95 As already stated, altered opioid metabolism in ethnic populations is also a byproduct of allelic variants of the gene encoding CYP2D6,32,33,41 particularly in African populations.3539 Ethnic differences in the gene encoding UGT2B7 have also been identified, but these have not been associated with clinical differences in enzyme activity.44

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Demographic/Medical Factors Influencing Opioid Metabolism

In most cases, altered opioid metabolism in older patients, women, or specific ethnic groups can be addressed by careful dose adjustment. For example, morphine,43 codeine,13 fentanyl,15 and oxymorphone18 should be initiated at lower doses in older patients, and physicians prescribing oxycodone to women may consider starting at a lower dose relative to men. Morphine or codeine dose reductions may also be necessary in Asian populations. Given the genetic variability of metabolism in specific ethnic populations, it may make sense for patients with an unexplained history of poor response or an inability to tolerate a particular opioid to be switched to an opioid that relies on a different metabolic pathway.96,97


Hepatic Impairment

The liver is the major site of biotransformation for most opioids (Table 4). It is therefore not surprising that the prescribing information for most frequently prescribed opioids recommends caution in patients with hepatic impairment.10,11,13,14,17,18,43 For example, in patients with moderate to severe liver disease, peak plasma levels of oxycodone and its chief metabolite noroxycodone were increased 50% and 20%, respectively, whereas the area under the plasma concentration-time curve for these molecules increased 95% and 65%.11 Peak plasma concentrations of another active metabolite, oxymorphone, were decreased by 30% and 40%, respectively. Although oxymorphone itself does not undergo CYP-mediated metabolism, a portion of the oxycodone dose is metabolized to oxymorphone by CYP2D6. Failure to biotransform oxycodone to oxymorphone may result in accumulation of oxycodone and noroxycodone, with an associated increase in adverse events.41 The differential effect of hepatic impairment on the metabolism of oxycodone relative to its active metabolite illustrates the complexities associated with opioids that have multiple active metabolites.

Hepatic impairment may also affect metabolism of opioids that undergo glucuronidation rather than CYP-mediated metabolism, such as morphine and oxymorphone. In a 1990 study, the elimination half-life and peak plasma concentrations of morphine were significantly increased in 7 patients with severe cirrhosis.98 The bioavailability of morphine in these patients was 101% compared with approximately 47% observed in healthy participants. The ratio of morphine to its inactive metabolite M3G was significantly higher in cirrhotic patients than in controls. In another study, morphine hepatic extraction was compared in 8 healthy participants and 8 patients with cirrhosis. Hepatic extraction was 25% lower in patients with cirrhosis.99 This reduction was attributed to reduced enzyme capacity rather than to impairment in blood flow. The authors of that study suggested that cirrhosis affected the metabolism of morphine less than other high-clearance oxidized drugs, perhaps indicating that cirrhosis has less of an effect on glucuronidation relative to CYP-mediated metabolism.

Currently, no comparable data exist on metabolism of oxymorphone in patients with cirrhosis. However, hepatic disease may certainly have significant effects on oxymorphone pharmacokinetics. Specifically, the bioavailability of oxymorphone increased by 1.6-fold and 3.7-fold in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment, respectively, compared with healthy controls. In 1 patient with severe hepatic impairment (Child-Pugh class C), the bioavailability was increased by 12.2-fold.18

The pharmacokinetics of fentanyl100 and methadone,101 2 of the frequently used opioids, are not significantly affected by hepatic impairment. Although dose adjustments for these opioids may not be required in certain patients with hepatic impairment, clinicians should nonetheless be extremely cautious when prescribing any opioid for a patient with severe hepatic dysfunction.

Renal Impairment

The incidence of renal impairment increases significantly with age, such that the glomerular filtration rate decreases by an average of 0.75 to 0.9 mL/min annually beginning at age 30 to 40 years.102,103 At this rate, a person aged 80 years will have approximately two-thirds of the renal function expected in a person aged 20 or 30 years.102104 Because most opioids are eliminated primarily in urine, dose adjustments are required in patients with renal impairment.10,11,13,1618,43

However, the effects of renal impairment on opioid clearance are neither uniform nor clear-cut. For example, morphine clearance decreases only modestly in patients with renal impairment, but clearance of its M6G and M3G metabolites decreases dramatically.105107 Accumulation of morphine glucuronides in patients with renal impairment has been associated with serious adverse effects, including respiratory depression, sedation, nausea, and vomiting.73,74,108 Similarly, patients with chronic renal failure who receive 24 mg/d of hydromorphone may have a 4-fold increase in the molar ratio of hydromorphone-3-glucuronide to hydromorphone.109 Conversely, in patients treated with oxycodone, renal impairment increases concentrations of oxycodone and noroxycodone by approximately 50% and 20%, respectively.11 Although renal impairment affects oxycodone more than morphine, there is no critical accumulation of an active metabolite that produces adverse events.11 Thus, selecting an opioid in patients with renal impairment requires an understanding not only of the anticipated changes in concentrations of the opioid and its metabolites but also of the differential effects of parent compounds and metabolites when they accumulate.

As in liver disease, methadone and fentanyl may be less affected by renal impairment than other opioids. Methadone does not seem to be removed by dialysis110; in anuric patients, methadone excretion in the feces may be enhanced with limited accumulation in plasma.111 However, for patients with stage 5 chronic kidney disease, the prudent approach remains to begin with very low doses, monitor carefully, and titrate upward slowly. Fentanyl is metabolized and eliminated almost exclusively by the liver; thus, it has been assumed that its pharmacokinetics would be minimally altered by kidney failure.112 However, despite limited pharmacokinetic data, hepatic clearance and extraction of drugs with high hepatic extraction ratios (eg, fentanyl) could potentially be inhibited by uremia113; the theoretical potential for accumulation of fentanyl in patients with hepatic impairment makes caution advisable when prescribing opioids to these patients.


The selection of an opioid analgesic may be affected by comorbidities and diminished organ reserve. Health care professionals need to be especially cautious when dealing with patients with diminished metabolic capacities due to organ dysfunction. In general, dose reduction and/or prolongation of dose intervals may be necessary depending on the severity of organ impairment. Moreover, clinicians should adopt a “start low and go slow” approach to opioid titration when hepatic or renal impairment is a factor.

Although metabolism of drugs undergoing glucuronidation rather than oxidation may be less affected by hepatic impairment, this does not appear to be a major advantage with respect to opioids. Morphine clearance and accumulation of its M3G metabolite are increased in cirrhosis, making dose adjustments advisable. Oxymorphone, which also undergoes glucuronidation, is contraindicated in patients with moderate or severe hepatic dysfunction.18 Among opioids undergoing CYP-mediated metabolism, fentanyl100 and methadone101 appear to be less affected by liver disease. Nonetheless, data on these opioids are limited, making caution and conservative dosing advisable in this population.

In patients with substantial chronic kidney disease (stages 3-5), clinicians should carefully consider their options before choosing morphine. Nausea, vomiting, profound analgesia, sedation, and respiratory depression have been reported in patients who have kidney failure and are taking morphine.73,74,108,114,115 Several authors have suggested that fentanyl and methadone are preferred in end-stage renal disease112,116; however, this advice needs to be tempered by the challenges inherent in dosing potent opioids in patients with poor renal function.


Patient characteristics and structural differences between opioids contribute to differences in opioid metabolism and thereby to the variability of the efficacy, safety, and tolerability of specific opioids in individual patients and diverse patient populations. To optimize treatment for individual patients, clinicians must understand the variability in the ways different opioids are metabolized and be able to recognize the patient characteristics likely to influence opioid metabolism.


Jeffrey Coleman, MA, of Complete Healthcare Communications (Chadds Ford, PA) provided research and editorial assistance for the development of the submitted manuscript, with support from Endo Pharmaceuticals (Chadds Ford, PA).

This article is freely available on publication.


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Swat raids and paramilitary civilian police forces threaten our beliefs and our way of life.

In the United States many people still believe that our homes are private and as such should be free from government intrusion. Further many believe we have the right to defend our home and family from unlawful intruders and that the constitution guarantees this. After all we fight wars in the name of freedom and protecting our god-given as well as civil rights even now. It appears we are in danger of losing our fourth amendment rights, and once gone they may be gone forever.

The implications for Americans are huge. For some time now we have seen increasing use of militarized SWAT teams across the country invading American homes, even killing our citizens and their pets on what looks to be the flimsiest of excuses many times. Countless innocent people have been killed or injured during these raids.

According to the New York Times,

“More than 60 years ago, the Supreme Court ruled that the police were not entitled to enter a residence without a warrant merely because they smelled burning opium, this has been the law of the land since.”

The Supreme Court of the United States recently took up the issue in arguments of a case about what the police were entitled to do upon smelling marijuana outside a Kentucky apartment. Concerns have been raised and there is a very real possibility that the court may be poised to vacate the previous ruling, requiring police to get a search warrant before entering our homes.

“Aren’t we just simply saying they can just walk in whenever they smell marijuana, whenever they think there’s drugs on the other side?” said Justice Sonia Sotomayor during the recent arguments. “Why do we even bother giving them a warrant?”

The current precedent requiring search warrants was established by the Court in 1948 with Johnson v. United States: The smell of opium is insufficient cause to enter a premises without a search warrant.

Justice Jackson delivered the opinion of the court: “No reason is offered for not obtaining a search warrant except the inconvenience to the officers and some slight delay necessary to prepare papers and present the evidence to a magistrate. These are never very convincing reasons and, in these circumstances, certainly are not enough to bypass the constitutional requirement. ”

There are literally thousands of militarized raids every year (perhaps as many as 40,000). Even when police get a search warrant which is not very difficult these days they often misrepresent the facts or raid the wrong house terrorizing innocent families including children like this case in Spring Valley New York last week.

Police Terrorize 13-Year-Old Girl In Botched Pot Bust.

Police conducting drug raids early in the morning woke a family dragging them out bed, even pointed a machine gun at a 13-year-old girl and threatened to shoot the family poodle… big problem and this happens often in these full military type raids they had the wrong house and the wrong family. Luckily this time no one was killed but many other times the innocent victims of the police raid were not so lucky. Here is a list of a few of those not so lucky victims of police para military raids.

In the recent Spring Valley raid, David McKay said “Their guns were drawn, they were screaming ‘Where’s Michael, Where’s Michael. ” At least 10 heavily armed officers had stormed the house at 5:30am. McKay’s daughter was so terrified and traumatized he had to take her to Nyack Hospital, for treatment after she had an asthma attack and fainted following the ordeal.

Mckay is quoted in an article by Radley Balko on January 13 2011.

“They pulled me outside in the freezing cold in my underwear, manhandle my wife, point a gun at my daughter and they won’t even tell me what they are doing in my house,” said McKay. “It was terrifying and humiliating beyond belief.”

Thirteen law enforcement agencies (LEA’s) were involved in the raids. This was just one of the many joint federal/local drug sweeps for pot that occur daily around the U.S. In Hawaii county we recently saw something similar in the coordinated raids again by 13 agencies, against Roger Christie’s THC ministry and the “Green 14″. In that case the government brought in a C-140 Coast Guard cargo plane specifically to whisk the 14 defendants off the Big Island to federal detention in Honolulu.

The amount of money they spend on these raids is hard to pin down but mind boggling when you start adding it up. Christie still has not gotten a trial of any kind yet is being held without bail as a “danger to the community” for a marijuana crime, more than 6 months  after police found a measly 2 pounds of marijuana, and $21,000.00.

That’s it – after a 2 year investigation by the 13 law enforcement agencies – at a cost that already runs in the millions of dollars – 2 pounds of marijuana. In the recent New York raid as police were preparing to leave, McKay and his bewildered family asked them again what they were doing and why they entered the house. “They wouldn’t say,”  “All they would say was ‘You’ll read about it in the paper tomorrow.’ ”

In the search warrant case now before the U.S. Supreme court, police officers in Kentucky were looking for a suspect who they claim had sold cocaine to an informant. They further claim they smelled burning marijuana coming from an apartment, knocked loudly and announced themselves. That according to an article by Adam Liptak, published January 12, 2011 in the New York Times, and entitled Justices Look Again at How Police May Search Homes.

The article reports that police claim to have heard sounds from inside the apartment, leading them to believe evidence was being destroyed, so they kicked in the door.  While they did find marijuana and cocaine, the suspect in the original cocaine case was not there. The Kentucky Supreme Court sided with the defendants and suppressed the evidence. The court found that any risk of drugs being destroyed was the result of the decision by the police to knock and announce themselves rather than to obtain a warrant. Now the state of Kentucky and the federal government want the U.S. Supreme court to overturn Kentucky’s Supreme court ruling. Essentially the government is asking the court to take away the 4th amendment rights of all Americans.

In Mr. Liptak’s article he states Justice Sotomayor was even more direct.

“Aren’t we just doing away with ‘Johnson’?” she asked.

He also points out that Justice Ruth Bader Ginsburg asked why the police could not simply roam the hallways of apartment buildings, sniffing; knock whenever they smell marijuana; then break in if they hear something suspicious. All in all it’s a great article that points out that the other Justices seem inclined to rule in the government’s favor. If that happens we will lose even more of our ever-eroding rights in this country, and can look forward to many more military-style swat raids terrorizing families around the nation.

We continue to see ever increasing militarization of civilian law enforcement in this country, including Hawaii county, where I live. This has led to a dramatic increase in paramilitary police units (SWAT) being used for routine police work. The most common use of SWAT teams today in Hawaii county and around the nation is to serve drug warrants, usually with forced, unannounced entry into our homes. A large number of those raids are for marijuana. Swat was originally brought about to be used in hostage situations, but has been co-opted to gradually militarize civilian police departments over the last few decades. As we see, the result has been the erosion of the civil liberties we enjoy, as we have moved to the point of becoming  a virtual  police state.

With the ever-increasing numbers of SWAT raids in America, the number of nonviolent drug offenders, innocent bystanders, and wrongly accused U.S. residents, injured or even killed has been rising.  The terror of having your homes invaded while sleeping, usually by large teams of heavily armed paramilitary forces, has not escaped even the mayor of the small town of Berwyn Heights MD, very near the capitol of our nation.

A police SWAT team raided the home in 2008, shooting and killing the family’s two dogs. They falsely accused the mayor of receiving 32 pounds of marijuana. Was this military type swat raid necessary? Of course not.

“My government blew through my doors and killed my dogs,” Calvo said.  Imagine what they do to people that are not so prominent or god forbid actually guilty of a marijuana crime.  Must see articles and video here:

Gung Ho SWAT Team Kills Mayor’s Dogs In Botched Pot Raid

Maryland Mayor’s Dogs Killed During No-Knock Raid

Police shot the families 7-year-old dog Payton, handcuffed the mayor’s mother-in-law (making her lie next to the dead dog on the floor), shot the other 4-year-old dog Chase in the back, and then handcuffed Calvo in only his boxer shorts. Mrs. Calvo said, “They were my kids. All I could see was the blood and the tissue of the dogs”–the police apparently tracked the dogs’ blood through the house. The police claim they had a no-knock warrant, but failed to produce one until 71 hours later according to Mayor Calvo.

The family maintains the two black Labradors were harmless and said police apparently killed them “for sport,” gunning down one of them as it was running away.” “Our dogs were our children.”

Prince George’s County Police Chief Melvin High and other officials refuse to apologize for killing the dogs, maintaining the officers felt threatened (clearly they are in the wrong profession). We all know how scary dogs can be while they’re running away from you. Imagine if the U.S Supreme court rules police really don’t need a warrant what will happen. The only reason we heard about this is because Calvo was the mayor.

This is a much more common occurrence than most people are aware of or would like to believe. These raids are very violent in nature and are used against even nonviolent drug offenders including misdemeanors offenses, as we see many victims of these raids turn out to be completely innocent. It is clear, in many instances the raids terrorize innocents when police mistakenly target the wrong residence or people who’s only crime is being in the wrong place at the wrong time. There have been dozens of needless deaths and injuries, not only of drug offenders, but also of police officers, children, bystanders, and innocent suspects, and those responsible for this are rarely if ever held accountable or brought to justice.

There is no doubt this is happening, the scary part is it’s getting worse as the Kentucky case now at the Supreme Court demonstrates. The government and judicial system are condoning –even supporting– more attacks against us, when the real problem is the failed drug war.

The solution is to review and change the drug laws that are the underlying cause of not only everything in this article, but the majority of the drug abuse in this country. Drugs are a health problem. Criminalizing drugs has manufactured criminals and crime. In business and life the policy is responsible for the results it gets, not so in the war on drugs or it would have ended long ago. Somehow common sense and rational thought do not count when we consider the drug war.

Here are some more very disturbing police abuses that are being condoned and facilitated.

South Dakota School Officials Terrorized Kindergarten Classes with Drug-Sniffing Dogs.

“The very notion of there being a drug problem in the kindergarten is ludicrous.”“

But read what happened, this is your government doing this nobody else. Its even worse as this case has racial overtones and these laws are being used in discriminating manners as this case exemplifies.

A school official who accompanied the police instructed the students to put their hands on their desks and avoid petting or looking at the dog or making any sudden movements. In some classrooms, a school official told students that any sudden movement could cause the dog to attack. Is this what we call a free country now? The drug laws are a bigger problem than the drugs, the police are more dangerous most often than anyone else. In at least one instance, the ACLU complaint said, the dog escaped its leash in a kindergarten class and chased students around the room. Some students had been traumatized by previous dog attacks and one young girl still has the scars of a previous attack on her face. Many began crying and trembling and at least one urinated involuntarily. What lesson did this teach these children?

Again these are just some of the ones you here about, most of them are never reported:

These drug raids are far more dangerous to everyone than marijuana ever could be. In one case Police opened fire with children in the house killing the family dogs in front of those children. It’s a miracle no people were killed. Those children were endangered by the police and traumatized in ways that will be with them the rest of there lives, they did this over marijuana. They could easily have arrested the father away from the home but chose to do it this way because there are no consequences for them.

It’s time to legalize marijuana and put an end to this once and for all.  This is not only dangerous and socially destructive to families and the community it is economically unsustainable. Hundreds of billions of dollars are wasted on these raids and laws and look at the results. Look at what we get for that money. We could reduce drug abuse in this country and slice hundreds of billions from our budget while improving the lives of millions of families by simply reforming the laws and the policies of prohibition and treating this like the health problem it is. We could cripple the drug cartels over night, in fact we could hardly have a worse policy if we tried, creating crime and filling our prisons while enriching drug cartels and bankrupting our country. This may go down as the worst policy in American history when we finally wake up to the fact that it is responsible for the mess in which we find ourselves.



The public policy debate on Afghan  opium is filled with simple narratives (i.e., it is mostly opium that fuels the insurgency, poppy farmers are wealthy) justified by simple metrics and responded to with simple solutions. The problem with simplicity, of course, is that it crowds out complexity and propels us toward ineffective and even counterproductive policies.

Much of the counternarcotics debate in Afghanistan focuses obsessively on cultivation numbers produced by the United Nations Office on Drugs and Crime’s (UNODC) annual opium survey, with annual changes in cultivated area used as indicators of policy success or failure. Yet such changes are the result of a range of factors, including price shifts, household perceptions of future food insecurity and larger market forces. They are therefore transient, not necessarily indicative of fundamental changes in the rural economy.

For instance, last year’s 22 percent reduction in national opium acreage was largely attributed to the distribution of wheat seed and fertilizer in Helmand Province, which by itself produces around half of Afghanistan’s opium. But this reduction was less the result of policies and programs than farmers‘ rational response to the changing relative prices of wheat and opium. Memories of high wheat prices and concerns over insecurity in central Helmand continue to shape planting decisions, highlighting the fact that farmers give greater priority to managing the risk of food insecurity than to maximizing profits. After all, one can’t eat opium poppy no matter what its price.

The addiction to annual cultivation numbers has similarly produced praise for the firm commitment and strong hand of the provincial governors in Balkh and Nangarhar, the two provinces most lauded for success in becoming „poppy free“ in 2008 (in 2009, some poppy cultivation resumed in Nangarhar). Yet short-term reductions brought about by coercion may not be sustainable, and the side effects include migration to Pakistan (with attendant risk of radicalization), increasing enlistment in the Afghan National Security Forces under duress, sales of household assets and incurring of debt—as well as the potential undermining of support for the national government, which was seen as the driving force behind the coercion.

Fieldwork done in the areas hardest hit by the opium ban in these two provinces reveals a widespread perception that the economic impact on the general population has been too severe and that the social „contract“ under which reductions have been made is breaking down. In fact, one could argue that coercive suppression of cultivation in areas where there are no other viable sources of income is leading to greater instability—and thereby establishing preconditions for increased cultivation. One needs only to look at recent insurgency penetration in a number of districts in Nangarhar to see what appears to be the failure of success.

Some of the narratives analysts use to justify an aggressive approach to opium poppy reduction, including the „nuclear option“ of aerial chemical spraying, are built on „faith-based“ policy and questionable data. Several years ago, for instance, a US military commander mentioned that the percentage of the insurgency funded by the opium trade was likely between 20 and 40 percent, although an „international expert“ had said that the percentage could reach 60 percent; within weeks, much of the media had discarded the caveats so that 60 percent became the number of record. In some counterinsurgency circles, the belief that only 10 percent of the population is directly engaged in cultivation legitimates coercive measures on the grounds that even the harshest approach will not alienate the majority of the population. Yet the figure is based on a flawed methodology, and it ignores both the multiplier effect of the created wealth as well as bonds of solidarity, by which communities will band together to resist outside threats to life and livelihoods.

Such arguments also tend to shift from year to year. In 2007, UNODC proclaimed that „opium cultivation is no longer associated with poverty—quite the opposite.“ But by 2009 it was saying that „opium remains a major source of income in one of the world’s poorest and most unstable countries. Farmers may grow it to stave off poverty…. Eradicate poverty, not just poppies.“

The past two years have brought a welcome respite from the eradication debate, in part because of the Obama administration’s focus on the interdiction of traffickers rather than the destruction of crops, and in part because the military has sensibly recognized that obliterating Afghan rural livelihoods does not win hearts and minds. Still, there are forces that remain committed to a more aggressive eradication strategy, and they may be revived if the number of hectares heads upward in key provinces. If this year’s opium figures show an increase in cultivation, brace yourself for lurid headlines, Congressional delegations and calls to abandon a failed policy.

Rather than constantly alternating between back-slapping and hand-wringing, in the discussion over counternarcotics we should keep in mind that the transition away from opium is a long-term process and that the annual ups and downs are somewhat irrelevant. We must recognize that one size will not fit all areas, and that we can’t simply view drugs as a „bad“ to be stomped out while ignoring the role they play at all levels of the political economy. Ironically, aspects of the opium economy have contributed to stability and development by generating financial flows that have, in turn, been used to fund other licit economic activities, while counternarcotics policies have destabilized areas by forcing households deeper into poverty and by undermining political arrangements.

Above all else, acknowledging that drugs are a part of the rural economy and social structure in the distressed environment of a country wracked by decades of war and violence will allow us to focus on governance, security and economic growth—which will facilitate a slow but steady transition out of opium rather than spending on stovepiped, single-season interventions.


SHAN STATE, 13 January 2011 (IRIN) – Poverty and lucrative profits make poppy cultivation increasingly attractive to farmers who would otherwise produce legal crops to feed their families and make a living, say experts.

„More of the rural poor continue to be drawn into participating in the illicit drug trade as a last means of finding money to feed their families,“ Jason Eligh, Country Representative for the UN Office on Drugs and Crime (UNODC) Myanmar, told IRIN.

Shan State, 400km north of the capital, Yangon, between Myanmar, Laos and Thailand, produces more than 90 percent of all opium in Myanmar, an estimated 35,000 tons in 2010, according to UNODC.

UNODC is the only international agency directly involved in supporting different crops in poppy cultivation areas, with three agriculture projects in southern Shan State trying to reach 100,000 people. However, much more needs to be done to stop farmers from reverting to opium production, said Eligh.

„UNODC wants to see a strong alternative development response, one that includes market access, community mobilization, access to credit, improved technology and better overall infrastructure in rural areas.“

Cash crop

In 2010, a higher proportion of farmers‘ income came from poppies than in previous years, reversing a trend of steady decline in the past six years.

Between 2003 and 2009, the proportion of total household income from poppies fell from 70 to 20 percent, according to a December 2010 UNODC report.

In 2010, however, high prices paid for poppy in Myanmar and low food security throughout the country meant income from the seed contributed to 43 percent of total household income in Shan State, the report stated. About a quarter of the state’s population was involved, estimate aid agencies.

Though prices at source (farm-gate) for poppy fell marginally in 2010 from 2009, opium overall remained lucrative at US$305 per kilo. Poppy farmers can earn 13 times more money cultivating poppies than rice, making poppies the cash crop of choice for most, based on the UNODC report.

Farmers forced out of poppy cultivation are having problems growing other food to survive. „I grow enough vegetables to keep my family going, but that is all,“ U Tin Kyi told IRIN.

U Tin Kyi grew poppy seeds to supplement his income until authorities destroyed his fields two years ago. Like many of his neighbours in this hilltop village, U Tin Kyi has little extra income. „The fuel cost to get to the market outweighs any profit I would make from selling vegetables,“ he told IRIN.

Eradication efforts

Poppy cultivation continued to rise in Myanmar in 2010, despite an official 15-year drug elimination plan developed in the late 1990s. In 2009, the authorities initiated the final five-year phase of this plan.

Government figures claim 8,268 hectares of poppy-cultivating land were eradicated in 2010, a 102 percent increase on the previous year.

But other groups calculate that Myanmar’s poppy cultivation area and yield actually increased during this period.

„In 2010 we estimate that there [was] 20 percent more area under opium poppy cultivation, a 46 percent increase in average opium yield, and a 17 percent increase in the number of households involved in domestic opium poppy cultivation,“ said Eligh of UNODC.

In northern Shan State, in 2008, government figures showed 25 percent of poppy fields were destroyed, but a 2010 report by Palaung Women’s Organization (PWO), an NGO based in Mae Sot along the Thai-Myanmar border, stated only 11 percent of poppy fields had been eradicated.

Government anti-drug teams were only destroying easily visible poppy fields and filing false eradication data to the police headquarters, the report said. At the same time, farmers were forced to pay taxes to continue growing poppies.

In Mantong village in northern Shan State, PWO estimated the government collected approximately $37,000 in poppy taxes in 2008.


Methadone Detoxification


  • The physical process of detoxification is, in itself, relatively easy to achieve.
  • Long-term abstinence from opiate use is much harder to achieve.
  • Most opiate users will undergo detoxification many times before they achieve lasting periods opiate free.
  • Prescribed medication to assist in these detoxes will probably be a feature on more than one occasion.
  • Lofexidine is a useful non-opiate treatment for both community and in-patient rapid detoxification.
  • It is important that services respond to the requests for help in a therapeutic way that reduces drug-related harm and helps the client move on and learn from their experiences.
  • Drug users who become abstinent are vulnerable to relapse.
  • Drug services should offer full support for at least 6 months following detox.

Methadone detoxification is a complex area dealt with in various sections throughout this book.

This section deals with the practical issues around prescribing and the rate of detox, the anxieties for clients about detox and the alternatives to methadone in detox.

This section should be read in conjunction with:

  • Section 2 – where there is a discussion of the research into methadone detoxification
  • Section 4 – where withdrawal symptoms are discussed
  • Section 7 – where there is discussion of the different detox durations and their indications and contra-indications
  • Section 11 – where there is discussion of detoxification which does not end in lasting abstinence.

People reducing from methadone are often anxious and afraid of the withdrawal syndrome and relapse.

Relapse following detox is an often neglected area because drug services and drug users tend to concentrate on the withdrawal syndrome and process of detoxification.

Effective follow up is vital in ensuring that detoxification is more than a reducing dose of methadone mirrored by a concurrent rise in heroin (or other depressant drug) use or a prelude to a short period of abstinence followed by relapse that the prescriber is unaware of.

Information for clients on the issues around detoxification and residential rehabilitation is available in the Detox Handbook and the Rehab Handbook – also available from ISDD (address on back cover).

Reasons for detoxing
In an ideal world people would detox from a stabilising dose of methadone or illicit drugs when they, and their prescriber, agreed that they were ready and able to do so without significant risk of early relapse. However people may want to detox when either they or their prescriber do not feel they are ready because:

  • Service prescribing policy dictates the regime on offer
  • They have a new job
  • They are moving to a new area
  • Of changes in their relationship
  • Attitudes of staff involved in methadone prescribing
  • Unrealistic staff beliefs about client’s ability to achieve abstinence
  • Unrealistic client beliefs about their ability to achieve abstinence
  • Stigma associated with having a methadone prescription
  • Dislike of practical aspects of a regime, such as the collection frequency
  • Change of drug of choice e.g. methadone to benzodiazepines or alcohol
  • Exclusion from a prescribing programme
  • Imminent or actual prison sentence.

These are discussed below.

Attitudes of staff
Opiate users are sensitive to the attitudes of the staff they come into contact with and sometimes choose not to seek, or to terminate treatment because of the attitudes and behaviour of staff.

This can probably be best avoided by offering services that are:

  • Client centred
  • Empowering
  • Flexible in their treatment approaches
  • Not seen to subscribe rigidly to any duration of methadone treatment
  • Non-judgmental and respectful
  • Staffed by people who are well trained and receive good supervision.

Following these principles also means that, having discussed the options, if a client decides to detoxify against advice the staff should still offer their full support and encouragement during and after the detox. They should also endeavour to discuss possible outcomes in a way that does not set the client up to fail but allows the making of contingency plans that can be brought into play if the detox does not work.

Unrealistic staff beliefs about a client’s ability to detox
It is easy for workers to fall into the trap of prematurely believing that people can achieve abstinence and encourage the client to detox. Often the client will continue down this road because they do not want to upset the worker and this can continue afterwards, with the client not wishing to re-refer themselves to a prescribing service for fear of admonishment from, or upsetting, the people who helped them before.

Cushman and Dole87 found that of a group of methadone maintenance clients who were assessed as ‚rehabilitated‘ and detoxed with the anticipation of success, some asked to be returned to maintenance during the detox and 25% returned to maintenance after detox (mainly because of protracted withdrawals).

Therefore support, encouragement and optimism should always be tempered by continual reassessment and meaningful negotiation.

Unrealistic client beliefs about their ability to detox
Clients too can be unrealistically optimistic about their ability to get off opiates. Often people will present after many years of heavy opiate use, adamant that in a few weeks they will be able to get themselves together and detox successfully.88

This belief sometimes stems from concentrating on the physical aspects of opiate withdrawal. If past experience of relapse during or after opiate detox has been that the withdrawal symptoms were the main factor causing relapse, this can reinforce the belief that if the physical symptoms of withdrawal can be reduced to tolerable levels by a methadone detox, abstinence will be easily achieved.

Another factor can be the flawed but understandable and apparently logical conclusion that ‚if all my problems are heroin-related then if I give up heroin all my problems will go away‘. The experience of many is that the compulsive behavioural aspects of their drug taking and the social and emotional difficulties that they experience once opiate-free add a previously ignored and difficult-to-overcome dimension to their drug use.

Stigma associated with having a methadone prescription
Many people on a maintenance methadone prescribing programme say ‚the act of having to take an opiate every day is a reminder that I’m a junkie‘.

For the relatives and friends of people on methadone it can be perceived as being ‚as bad as heroin‘ – regardless of any associated lifestyle improvements that have been achieved. Indeed associated improvements often serve only to increase the pressure on the person to detox as the perception is that they do not need the methadone anymore.

Heroin users are often dismissive of those on methadone and street myths of the terrible long-term health consequences of methadone treatment still abound. So the person receiving methadone often feels stigmatised from all sides.

Heroin users who feel the need to seek help for the first time also feel this and may request a methadone detox so that they can rationalise their request as one for a short-lived intervention that does not involve long-term methadone treatment.

Dislike of practical aspects of a regime, such as the collection frequency
Avoidance of longer-term treatment may also include factors such as a desire not to have to:

  • Collect methadone daily from a drug service or pharmacy.
  • Attend a drug service on a regular basis
  • Engage in a counselling relationship
  • See other drug users when collecting the prescription and/or methadone

It is important for the worker involved to have an awareness of these issues if they are factors in a request for methadone detoxification.

Change of drug of choice
Sometimes poly drug users change their drug of choice in a cyclical way from, say, heroin to benzodiazepines to alcohol to amphetamines and back to heroin; or simply switch from heroin to, say, alcohol and back again.

They may ask for a detox at the end of the opiate part of the cycle – either as a new referral as a heroin user or following a period on methadone. In these cases treatment may or may not be appropriate, but if commenced should be carefully monitored.

Clients going to prison
Clients who have a prison sentence coming up present drug services with a dilemma. On the one hand premature detox may lead to relapse with risk behaviour prior to prison. On the other hand arriving at a prison where detox facilities are poor or non-existent in full methadone withdrawal is likely to result in illicit heroin use. The sharing of injecting equipment in prison is much more prevalent than in the community. The best that can be done is to:

  • Offer as much support as possible
  • Help them make informed choices
  • Inform them of the risks of intravenous drug use in prison
  • Appropriately influence the pre-sentence report.

Blind or open reductions?
There is no evidence to suggest that knowing or not knowing the frequency or size of dose reductions is more effective in helping people detox using methadone.

The answer for most people who attend prescribing and dispensing services that are flexible enough to offer both, is to consider the pros and cons of each approach in conjunction with the prescribing staff, and to make an informed decision for themselves as to which is the most appropriate regime. Generally a key factor is the level of control that a person feels they have over their lives. Anyone who feels in control is unlikely to opt for blind dose reductions.

The arguments for and against blind and open reductions are set out below.

Arguments for blind dose reductions Arguments against blind dose reductions
Reduced anxiety around the day of dose reduction Possible constant anxiety about when reductions are going to happen
Objective self assessment of withdrawal symptoms Constant anxiety about and experience of withdrawal symptoms
Concentration on issues around coping rather than drug dose Client not taking responsibility for the dose reductions or their response to them
Reduced anxiety about passing psychologically important doses e.g. 20mg,10mg, 5mg Inability to ‚take credit‘ for success so far

Arguments for open dose reductions Arguments against open dose reductions
Client takes responsibility for the dose reductions and their response to them Increased anxiety and expectations of withdrawal symptoms at times of dose reductions
Ability to plan life around reductions Weeks of concentration on drug dose as the major factor in determining ability to function is not always helpful preparation for a drug-free life
The rate of reduction can be negotiated once detox has started Client is more able to identify psychologically significant doses at which to stop – which can weaken resolve

Setting the appropriate rate of detox
Almost everyone undergoing methadone detoxification will experience withdrawal symptoms, and for many these will be serious enough to be a major contributing factor in either relapse to heroin use or a request for methadone maintenance – even if all other preconditions for a successful detox are in place.87

For people detoxing following a period on methadone maintenance, faster detoxes are associated with higher drop-out rates and slower detoxes are associated with lower drop-out rates.89

In general detoxes consist of gradual reductions of 5mg or 10mg in the daily dose to a given level, usually 20-30mg (depending on the starting dose and the client), and then become more gradual, either in terms of time between reductions and/or size of daily dose reduction.

Negotiation between worker and client is an important component of any detoxification. A negotiated detoxification in which the client is able to take responsibility for coping with the dose reductions is likely to reduce the risk of concurrent illicit opiate use and be a better foundation for continued abstinence afterwards.

Prescribers without specialist experience who agree to a short-term programme without support from a specialist service should seek support if their patient is unable to detox successfully at the agreed rate.

Detox regime suggestions

Long-term detox regimes are seldom the optimum treatment option, to read an additional piece on long-term detox written for this online edition of the book, please click here.

All the regimes below are for methadone mixture 1mg/1mL. All detox regimes are a plan only and should be subject to regular, i.e. weekly or fortnightly, review against the treatment aims.

The definitions, indications and contra-indications for each of the regimes below are given in Section 7 – Treatment aims and choices. It is important that detox regimes are only entered into with clear treatment aims and following a thorough assessment that has established that these aims are achievable.

The very low doses (i.e. less than 5mg) suggested in the following regimes are of little physiological value as they are unlikely to make much difference to the level of physical withdrawal. However withdrawal symptoms can also be aggravated by anxiety and where low dose prescribing at the end of a detox reduces anxiety it is likely to reduce subjectively experienced withdrawals.

Where a client has high levels of anxiety about making the final reductions they are often afraid of being drug free and of the changes this will bring. It is therefore important that low dose prescribing is coupled with counselling.

Short-term detoxification: decreasing doses over one month or less Two week detoxification regime

  • 20mg for 3 days
  • 15mg for 4 days
  • 10mg for 3 days
  • 5mg for 4 days

This regime has the advantage that it is easy to prescribe as there is a dose drop at the end of each week.

An alternative starting slightly higher could be:

  • 25mg for 3 days
  • 20mg for 3 days
  • 15mg for 3 days
  • 10mg for 3 days
  • 5mg for 2 days

For people who need more methadone to stabilise or who are detoxing from an existing methadone prescription there are two main choices. Either reduce the dose prior to the final detox or reduce the dose by 25%-50% each day until 20mg is reached and then complete the programme as above. However it must be recognised that these large early reductions will probably result in intense withdrawal symptoms.

If required, ‚holding‘ on a given dose on one or two occasions during the detox may increase the client’s sense of control and decrease their anxiety. Delays in the rate of reduction should usually be accompanied by an increase in psychological support.

Longer-term detoxification: decreasing doses over 1-6 months

1 month detoxification regime

From a starting dose of 40mg:

  • 40mg for 4 days
  • 35mg for 3 days
  • 30mg for 4 days
  • 25mg for 3 days
  • 20mg for 4 days
  • 15mg for 3 days
  • 10mg for 4 days
  • 5mg for 3 days

From a starting dose of 25mg:

  • 25 mg for 4 days
  • 20mg for 3 days
  • 15mg for 4 days
  • 10mg for 3 days
  • 8mg for 4 days
  • 6mg for 3 days
  • 4mg for 4 days
  • 2mg for 3 days

4 month detoxification regime
Following initial stabilisation, and a period in which the client remains heroin free, the daily dose can be reduced by 5mg or 10mg every week or fortnight until 30mg is reached.

The rate of reduction in the daily dose is then reduced to 5mg every week or fortnight until 10-15mg is reached. At this point daily dose reductions can be reduced to 2 or 2.5mg every week or fortnight.

A typical 4 month regime using these principles from a starting dose of 45mg would be:

  • 45mg for 14 days
  • 35mg for 14 days

  • 30mg for 14 days
  • 25mg for 14 days

  • 20mg for 14 days
  • 15mg for 14 days

  • 10mg for 14 days
  • 7mg for 14 days

6 month detoxification regime
A 6 month detox regime using the same principles as the 1-5 month detox, from a start of 60mg might be:

  • 60mg for 14 days
  • 50mg for 14 days

  • 40mg for 14 days
  • 30mg for 14 days

  • 25mg for 14 days
  • 20mg for 14 days

  • 15mg for 14 days
  • 10mg for 14 days

  • 8mg for 14 days
  • 6mg for 14 days

  • 4mg for 14 days
  • 2mg for 14 days

Detoxification following exclusion from a methadone prescribing programme
Sometimes methadone prescriptions are stopped. The reasons for doing this are discussed in Section 10: Practical issues in methadone prescribing – Terminating treatment.

The client should be aware of exactly what the rate of detox will be before the prescription is terminated. Abrupt cessation of opiates is not fatal in people who are otherwise healthy. The rate of reduction therefore usually seeks to strike a balance between continuance of the prescribing programme under a new guise, and a rate of reduction which gives the individual little chance of achieving abstinence if they want to.

A regime such as the following is commonly used:

  • 10mg reduction in the daily dose every day until the patient is receiving 30mgs daily

and then:

  • 5mg reduction in the daily dose each day with 2 days on 5mg at the end.

However any of the above regimes could be employed.

Client expectations of anxiety are one of the best indicators of the intensity of withdrawal symptoms and there can be little doubt that the two are closely linked.

As with all anxiety-provoking situations, levels of anxiety during and after methadone detoxification can be reduced through information being given to the client about what they can expect to happen and why it is happening, and the opportunity being given to discuss the issues that are raised.

Emotions such as anger and depression can trigger withdrawal symptoms in people who are stabilised on methadone – this is known as ‚pseudo withdrawal syndrome‘. If clients become more aware of these feelings during a detox then this too will increase the severity of their withdrawal symptoms. Counselling during and after the detox can help deal with these emotions and reduce the physical consequences.

Abstinence phobia
S M Hall in 1979 described abstinence phobia as an exaggerated response to comparatively mild withdrawal symptoms.90

Indeed many clients become very anxious as soon as dose reductions begin and feel unable to continue with the detoxification. Hall suggested that previous actual or observed traumatic experience of withdrawal symptoms may be the cause of this fear. Unfortunately her attempts to use standard cognitive behavioural therapy in a controlled trial – which has been shown to be effective in other anxiety disorders – were unsuccessful.

This being the case, choices for clients who demonstrate high levels of anxiety during detox are limited as they are unlikely to achieve abstinence without considerable support. Slowing the rate of reduction and increasing support is the first line response. Following this in-patient detoxification or residential rehabilitation might be options.

If the anxiety cannot be resolved, and relapse is the outcome of all attempts at detox, the most appropriate response may be methadone maintenance.

Alternatives to methadone in detoxification

This is similar in its action to lofexidine (see below), the major difference being its more powerful hypotensive action which contra-indicates its use in anything other than an in-patient setting. Clonidine has never had a product licence for opiate detoxification.

Lofexidine (BritLofex)
Lofexidine hydrochloride is now fully licensed in the UK for management of the symptoms caused by withdrawal. Lofexidine is not an opiate and does not stimulate opiate receptors and therefore does not have the psychoactive effect nor the dependency potential of opiates.

It works by inhibiting the release of noradrenaline. Noradrenaline is a key chemical transmitter that acts on the nervous system, the action of which has been suppressed by opiates: see Section 4: The physiology and pharmacology of methadone.

As lofexidine is not an opiate, increasing the dose too quickly, or beyond the recommended maximum, will not necessarily reduce withdrawal symptoms but it will increase the risk of side effects such as hypotension (low blood pressure). This should be made very clear to patients who are self administering their lofexidine tablets.

The safety of lofexidine in pregnancy has not yet been established.

Lofexidine is unlikely to:

  • Completely eliminate withdrawal symptoms (the extent to which it reduces withdrawal symptoms varies)
  • Greatly affect the insomnia associated with opiate withdrawal
  • Stop cravings for opiates
  • Reduce anxiety
  • Be effective if used in the absence of careful assessment and support during and after treatment.

The effect of these factors can be reduced by:

  • Giving the client full information about what to expect
  • Using low-dose prescribed night sedation for a defined period (lofexidine may potentiate the action of anxiolytics and hypnotics)
  • Offering support and counselling during and after the detox.

Side effects
Hypotension (low blood pressure) is the principle possible side effect that can occur during treatment with lofexidine. Although this could prohibit its use for some clients and may result in discontinuation of treatment in others, in practice there is rarely a clinically significant reduction in blood pressure.

Blood pressure should be monitored, especially while the dose is increasing. For in-patients if the standing systolic BP has dropped by more than 30 mmHg (and is associated with symptoms of dizziness and light-headedness or over-sedation) the next dose of lofexidine should be withheld until the systolic BP is less than 30mmHg below the baseline.

Sedation is more likely to occur in clients concurrently prescribed (or taking) benzodiazepines and/or other central nervous system depressants.

Lofexidine is safe for community use in patients who are:

  • Able to control their use of the drug
  • Unlikely to use illicit drugs concurrently
  • Willing to comply with the regime
  • In regular contact with the prescriber/drug worker.

A typical 10 day out-patient lofexidine regime
Reduce the methadone dose to 15mg daily and ask the patient to take their last dose in the evening.

The following morning (detox day 1) begin the following regime:

Day of detox Maximum number of tablets to be taken in the morning Maximum number of tablets to be taken at lunch time Maximum number of tablets to be taken at 6pm Maximum number of tablets to be taken at night
Day 1 2 0 0 2
Day 2 2 0 2 2
Day 3 2 2 2 2
Day 4 3 2 2 3
Day 5 3 3 3 3
Day 6 3 1 2 3
Day 7 2 0 2 3
Day 8 2 0 1 2
Day 9 1 0 0 1
Day 10 0 0 0 1


  • The action of lofexidine is reduced by tricyclic antidepressants and they should not, therefore, be prescribed concurrently.
  • Patients may determine their own dose, titrated against withdrawal symptoms, up to the maximum doses shown.
  • Blood pressure and pulse should be monitored regularly, especially while the dose is increasing.
  • The maximum dose phase i.e. ‚Day 5‘ may be continued for up to 6 days prior to beginning the ‚Day 6-10‘ reduction regime if withdrawals remain severe or if there has been additional illicit drug use.

The patient must be told:

  • To omit or take less than the maximum dose if giddiness is a problem
  • That once the maximum dose is reached taking more tablets will only increase the side effects and will not further diminish the withdrawal symptoms
  • That the worst withdrawal symptoms will be experienced on days 1-5
  • That there may be an immediate drop in tolerance to opiates – so if they relapse, the risk of overdose will be high.

In an attempt to reduce the severity of withdrawal symptoms some services switch detoxifying clients from methadone to dihydrocodeine for the final part of the process – usually when the daily methadone dose reaches around 15mg.

The rationale for this is that dihydrocodeine is:

  • A shorter-acting drug that may interfere with natural endorphin production less than methadone, thus reducing the severity of long-term withdrawals
  • A relatively weak opiate (30mg of dihydrocodeine = 3mg of methadone)
  • Easy to reduce slowly without practical difficulties, especially if the 10mg/5mL elixir is used.

There have been no controlled trials comparing subjective experience of withdrawals when detoxing on methadone, heroin or dihydrocodeine, but some clinicians have found the switch helpful, particularly if the anxiety of withdrawal is focused on the problems of coming off methadone.

However the treatment can have drawbacks. The experience of a ‚high‘ on dihydrocodeine can be greater than with methadone and thus clients can attempt unsustainable methadone dose reductions in pursuit of the ‚reward‘ of a ‚better drug‘.

Switching drug can also detract from the other psychological causes of withdrawal symptoms, neglect of which is unlikely to be therapeutic.

The product licence for dihydrocodeine does not include treatment of opiate dependence.

Methadone v heroin in detoxification
There is a commonly held belief amongst drug users that the withdrawal symptoms are worse and more prolonged when coming off methadone than heroin.

Given that methadone is a longer-acting drug this is probably true. However the experience of withdrawal is probably exacerbated by factors which are different with regard to most methadone detoxes as opposed to most illicit heroin detoxes.

Most illicit heroin withdrawal symptoms are:

  • Part of a fluctuating drug-using pattern and associated with shortages of heroin
  • Result in only a few days‘ abstinence
  • Self-medicated, to some extent, with benzodiazepines, alcohol or other drugs
  • Not part of a planned attempt to become drug free.

Most methadone withdrawal symptoms are:

  • A planned part of a clear intention to become drug free
  • At the end of a planned detox with an intention to give up drug use
  • Experienced without the relieving effects of concurrent drug use.

These factors probably all increase the stress associated with methadone dose reductions and serve to increase the subjective experience of withdrawal symptoms. Discussion of these issues with the client will probably serve to reduce the severity of the withdrawal experience.

Follow up/relapse prevention
People who have been using opiates for some time and who detoxify using methadone often benefit from support and assistance for some time afterwards. Plans and support mechanisms for the period after the detox should be in place before it commences.

Risk of relapse is always high as there are many potential causes of relapse including:

  • Protracted withdrawal symptoms
  • Insomnia
  • Environmental cues
  • Contact with current users
  • Stress
  • Anxiety
  • Low self esteem
  • Depression.

The person who has succeeded in getting off opiates will need help to resist these cues to relapse. Often clients are reluctant to return to prescribing services for follow-up support and there are often few services for those that do.

Support that would help and could be provided by drug services includes:

  • ‚Coming off/staying off‘ therapeutic groups
  • Relapse prevention training
  • Individual counselling
  • Self help groups
  • Life skills instruction, assertiveness, etc.
  • Naltrexone treatment.

Support that could be suggested/facilitated by drug services includes:

  • Careers advice
  • Further education
  • Narcotics Anonymous meetings
  • Vocational training.


A wonderful Source:

(lsw) Künstliches Heroin auf Rezept ist für viele Schwerstabhängige der letzte Weg aus dem Sumpf. Doch wann es eine flächendeckende Versorgung gibt, ist unklarer denn je. Nicht selten fehlt es einfach an Patienten mit den notwendigen Voraussetzungen.

Bund und Land sind mittlerweile willig, die Krankenkassen signalisieren Einverständnis – und doch läuft die Diamorphin-Abgabe für Schwerstabhängige in Baden-Württemberg nur schleppend an. Das unternehmerische Risiko, das eine neue Abgabestelle für künstliches Heroin birgt, ist oft zu groß. Nach Angaben des Gesundheitsministeriums steht die Stadt Stuttgart in den Startlöchern. Der Gemeinderat hat sich Ende November berichten lassen, wie die gesetzlichen Voraussetzungen für eine Abgabestelle sind. Doch: „Vor 2012 wird es sicher nichts“, schätzt Hans Gros, Suchthilfeplaner der Landeshauptstadt.

Hohe Auflagen

Bevor der Gemeinderat grünes Licht geben könne, müsse die Finanzierung stehen. Und danach dauere es sicher noch ein Jahr. Dabei würde Suchtmediziner Andreas Zsolnai, der die Anlaufstelle betreiben soll, am liebsten bald loslegen. Die rechtlichen Vorgaben seien erfüllt, auch Kooperationspartner habe er schon. „Doch wegen der Auflagen und des hohen Personalschlüssels ist das betriebswirtschaftliche Risiko so hoch, dass ein einzelner Arzt wie ich das nicht schultern kann.“

Bis sich die Abgabestelle trägt, braucht es nach Schätzung der Fachleute rund 50 Patienten. Sie müssen unter anderem mindestens 23 Jahre alt und seit fünf Jahren abhängig sein. Voraussetzung sind zudem zwei gescheiterte Therapieversuche, etwa mit Methadon. Die hohen Hürden führen dazu, dass laut Gesundheitsministerium von den rund 9000 Schwerstabhängigen im Land nur etwa 200 bis 300 die Voraussetzungen für die Diamorphin-Behandlung erfüllen.


Eine Anlaufstelle in Stuttgart könne sich durchaus tragen, sagt Zsolnai. Wie lange es aber dauere, bis die notwendigen Patienten auch in die Praxis kommen, könne er nicht schätzen. „Irgendjemand müsste für die Anfangszeit grade stehen. Es bräuchte vielleicht ein fünfjähriges Modellprojekt.“ Für die Räume gibt es ebenfalls enge Vorgaben – aus Sicherheitsgründen. Zsolnais derzeitige Praxis im Gesundheitsamt wäre zu klein. In seinen Augen drängt die Zeit, weil jederzeit Kooperationspartner abspringen könnten. „Wenn es nicht innerhalb des nächsten Jahres festgezurrt wird, besteht die Gefahr, dass es im Sande verläuft.“

Als mögliche Standorte für die Diamorphin-Zentren waren im Sommer auch noch Mannheim, Freiburg, Heilbronn, Tübingen, Singen, Ulm und Ravensburg im Spiel. Doch sieht es vielerorts nicht rosig aus. „Viele dieser Anlaufstellen werden sich wohl nicht realisieren lassen“, sagt Joachim Holzapfel, Leiter des Suchthilfezentrums in Karlsruhe. Meist fehlten Patienten.



Hundreds of drug users from Iran are turning up in Afghanistan’s western Nimroz province, with some claiming they were dumped there as undesirables by police from their own country.

Afghan officials worry that Tehran is exporting its social problems, although Iranian diplomats say there is no such policy. Others say that at least some drug users congregate in Afghanistan because narcotics are so freely available there and there are none of the draconian punishments meted out by the Iranian authorities.

Reza, 27, told how he was detained as a drug user in his home city of Zahedan in Iran’s Sistan-Baluchestan province, and was then included among a group of Afghan refugees who were being deported.

“I have documents showing I’m an Iranian national,” he told IWPR. “When I apply to government offices in Nimroz, they tell me to go to the border and ask the Iranian frontier officers to let me cross over. But when I go there, Iranian border officials abuse me and refuse to let me enter my own country.”

Reza says he sleeps in religious shrines in Zaranj, the main provincial town in Nimroz, and survives on the food he gathers from rubbish piles. He recently helped bury a friend. aged 40 and like him from Zahedan, who he says died “for lack of drugs”.

“Other addicts buried him between two graves,” he said.

Another man, Hossein, 38, said he was detained after family members in Iran’s Zabol province went to the police to complain about his chronic addiction problem.

He too said he was packed off across the border as part of a group of deported Afghan nationals. When he showed Afghan police his Iranian ID, they made efforts to send him home, but guards on the other side of the border would not admit him.

Mohammad Anwar Muradi, the head of the provincial counter-narcotics department, said ten to 15 Iranian drug users were entering Nimroz every week.

“There are currently about 2,000 drug addicts in Nimroz province, 80 per cent of them Afghans and Iranians deported from Iran,” he said. “It isn’t yet clear why Iranian border officials are deporting their own nationals to Afghanistan.”

The provincial police chief Hajji Musa Rasuli says his men have detained around 40 Iranian nationals in the region in the past two months, but have yet to pinpoint those living in Zaranj. His officers have tried to send ten drug users back home in recent weeks but Iranian frontier guards would not let them in.

Hajji Najibullah Alami, chief of staff in the provincial governor’s office, said the matter had been raised with Iranian officials, but no satisfactory response had been received.

An Iranian diplomat at the consulate in Herat, speaking on condition of anonymity, flatly denied that his country was expelling its own citizens. He suggested that individuals claiming to be Iranian nationals were in fact Afghans who had been properly deported, and were now seeking a way back into Iran.

“Anyone who has documents can enter Iran and will be assisted by Iranian border officers,” he said.

Residents of Nimroz province say many Iranians come and go voluntarily to enjoy the free market in heroin and other drugs.

“There’s no rigorous control in border areas, so Iranians come over from the other side, buy drugs and go back,” restaurant owner Hajji Sultan said.

He went on to voice a belief that appears to be widespread and was even articulated by some of the officials interviewed for this article, “Iran is deliberately deporting its addicts to Afghanistan in order to spread lethal diseases among Afghans.”

The Afghan government is struggling to provide drug treatment centres for the expanding number of users, and health officials in Nimroz say they do not have the resources to admit Iranian nationals as well. The country’s counter-narcotics minister, Zarar Ahmad Moqbel, recently said there was capacity to treat just one per cent of the estimated one million addicts.

Dr Nur Ahmad, the provincial health chief for Nimroz province, said no clinics existed to run medical checks on individuals – whether returning Afghan refugees or Iranians – as they entered the country.

“Initial assessments indicate that 50 per cent of addicts in Nimroz province are using needles, which increases the incidence of diseases like HIV/AIDS and hepatitis,” he said.

Zia Ahmadi is an IWPR-trained journalist reporting from western Afghanistan.