Polydrug abuse: A review of opioid and benzodiazepine combination use

Methadone is widely used for the treatment of opioid dependence. Although in most countries the drug is administered as a racemic mixture of (R)- and (S)- methadone, (R)-methadone accounts for most, if not all, of the opioid effects. Methadone can be detected in the blood 15-45 minutes after oral administration, with peak plasma concentration at 2.5-4 hours. Methadone has a mean bioavailability of around 75% (range 36-100%). Methadone is highly bound to plasma proteins, in particular to alpha(1)-acid glycoprotein. Its mean free fraction is around 13%, with a 4-fold interindividual variation. Its volume of distribution is about 4 L/kg (range 2-13 L/kg). The elimination of methadone is mediated by biotransformation, followed by renal and faecal excretion. Total body clearance is about 0.095 L/min, with wide interindividual variation (range 0.02-2 L/min). Plasma concentrations of methadone decrease in a biexponential manner, with a mean value of around 22 hours (range 5-130 hours) for elimination half-life. For the active (R)-enantiomer, mean values of around 40 hours have been determined. Cytochrome P450 (CYP) 3A4 and to a lesser extent 2D6 are probably the main isoforms involved in methadone metabolism. Rifampicin (rifampin), phenobarbital, phenytoin, carbamazepine, nevirapine, and efavirenz decrease methadone blood concentrations, probably by induction of CYP3A4 activity, which can result in severe withdrawal symptoms. Inhibitors of CYP3A4, such as fluconazole, and of CYP2D6, such as paroxetine, increase methadone blood concentrations. There is an up to 17-fold interindividual variation of methadone blood concentration for a given dosage, and interindividual variability of CYP enzymes accounts for a large part of this variation. Since methadone probably also displays large interindividual variability in its pharmacodynamics, methadone treatment must be individually adapted to each patient. Because of the high morbidity and mortality associated with opioid dependence, it is of major importance that methadone is used at an effective dosage in maintenance treatment: at least 60 mg/day, but typically 80-100 mg/day. Recent studies also show that a subset of patients might benefit from methadone dosages larger than 100 mg/day, many of them because of high clearance. In clinical management, medical evaluation of objective signs and subjective symptoms is sufficient for dosage titration in most patients. However, therapeutic drug monitoring can be useful in particular situations. In the case of non-response trough plasma concentrations of 400 microg/L for (R,S)-methadone or 250 microg/L for (R)-methadone might be used as target values.

Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence.

Methadone is widely used for the treatment of opioid dependence. Although in most countries the drug is administered as a racemic mixture of (R)- and (S)methadone, (R)-methadone accounts for most, if not all, of the opioid effects. Methadone can be detected in the blood 15–45 minutes after oral administration, with peak plasma concentration at 2.5–4 hours. Methadone has a mean bioavailability of around 75% (range 36–100%). Methadone is highly bound to plasma proteins, in particular to α1-acid glycoprotein. Its mean free fraction is around

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Interindividual Variability of the Clinical Pharmacokinetics of Methadonefor the Treatment of Opioid Dependence

The use of cocaine by heroin-dependent individuals, or by patients in methadone or buprenorphine maintenance treatment, is substantial and has negative consequences on health, social adjustment and outcome of opioid-addiction treatment. The pharmacological reasons for cocaine use in opioid-dependent individuals, however, are poorly understood and little is known about the patterns of heroin and cocaine co-use. We reviewed anecdotal evidence suggesting that cocaine is co-used with opioid drugs in a variety of different patterns, to achieve different goals. Clinical and preclinical experimental evidence indicates that the simultaneous administration of cocaine and heroin (i.e. ‘speedball’) does not induce a novel set of subjective effects, nor is it more reinforcing than either drug alone, especially when the doses of heroin and cocaine are high. There is mixed evidence that the subjective effects of cocaine are enhanced in individuals dependent on opioids, although it is clear that cocaine can alleviate the severity of symptoms of withdrawal from opioids. We also reviewed preclinical studies investigating possible neurobiological interactions between opioids and cocaine, but the results of these studies have been difficult to interpret mainly because the neurochemical mechanisms mediating the motivational effects of cocaine are modified by dependence on, and withdrawal from, opioid drugs. Our analysis encourages further systematic investigation of cocaine use patterns among opioid-dependent individuals and in laboratory animals. Once clearly identified, pharmacological and neuroanatomical methods can be employed in self-administering laboratory animals to uncover the neurobiological correlates of specific patterns of co-use.

Understanding polydrug use: review of heroin and cocaine co-use

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. 1.Opioid-related disorders-drug therapy. 2.Opioid-related disorders-psychology. 3.Substance abuse-prevention and control. 4.

https://www.zora.uzh.ch/id/eprint/17408/1/opioid_dependence_guidelines.pdf

Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence

Naltrexone and placebo as adjuvant treatment of opioid dependence were compared in a double-blind, controlled clinical trial in 50 heroin addicts. The overall efficacy was assessed by the degree of treatment acceptance, percentage of relapse in heroin consumption, presence of side effects, and overall retention on naltrexone. A total of 50 patients of both sexes, aged from 18 to 30 years, who fulfilled DSM-III-R criteria for opioid dependence were included in the study. All patients completed detoxification with clonidine on an inpatient basis for 2 weeks and subsequently, on an out-patient basis, received oral naltrexone (350 mg per week) for a month. At the beginning of the second month patients were randomly allocated to treatment with naltrexone (28 patients) or placebo (22 patients) until a 6-month treatment period in a double-blind fashion had been completed. During the study period (1 year) all patients followed the same therapeutic schedule. Patients in both groups were comparable in terms of socio-demographic data and toxicological history. The efficacy of naltrexone was not superior to that of placebo as there were no significant differences in acceptance of treatment, retention rates, opioid and other drug consumption, drug compliance or side effects.

Follow-up after a six-month maintenance period on naltrexone versus placebo in heroin addicts.

The efficacy of a rapid detoxification schedule (8 to 10 days) with clonidine or methadone was evaluated in 30 patients addicted to heroin. The dose of study drug was preestablished according to the subject's weight and the amount of opioid consumption, and the total daily dose was reduced by approximately 15% during the study. All subjects completed the detoxification program and stayed in the hospital for at least 12 days. Clonidine and methadone therapies proved to be highly effective. There was a marked reduction in anxiety during opioid detoxification, although subjects' experiences differed according to the drug used. On the day of discharge, subjects who had received methadone still had attenuated withdrawal symptoms, whereas there were no such symptoms in the clonidine group. Muscular aching, flatulence, and daily drowsiness were more common among subjects in the methadone group, while subjects in the clonidine group had more sleep disturbances and weeping. Syncopal episodes and bradycardia occurred more frequently in the clonidine group.



Clinical Pharmacology and Therapeutics (1985) 38, 336–341; doi:10.1038/clpt.1985.182

Efficacy of clonidine and of methadone in the rapid detoxification of patients dependent on heroin.

Cocaine abuse among heroin addicts in Spain

We assessed the prevalence of consumption of buprenorphine and other drugs among heroin addicts under ambulatory treatment in two cross-sectional studies conducted in 1988 (188 subjects) and in 1990 (197 subjects). Patients were enrolled in one of three different programmes: methadone maintenance programme (MMP), antagonist maintenance programme (AMP) and drug-free programme (DFP). Information given by participants was compared with results of urine screening for drugs. Urine samples were tested using enzyme immunoassay for the detection of heroin, cocaine, dextropropoxyphene, cannabis and benzodiazepines, and radioimmunoassay for buprenorphine. Sixty-six percent of patients in 1988 and 71% of patients in 1990 reported having consumed buprenorphine at some time during their history of drug dependence (period prevalence) and 5.9% and 6.1%, respectively, tested positive to the drug (point prevalence). In over 70% of these patients consumption was by the intravenous route. Consumption of cannabis, cocaine and benzodiazepines was also very high in the study population. Overall, patients in the DFP group consumed the largest number of the drugs tested, while those in the AMP group consumed the smallest number. Abuse of buprenorphine could be more widespread than previously reported.

L. San

Papers

Follow-up after a six-month maintenance period on naltrexone versus placebo in heroin addicts.

Efficacy of clonidine and of methadone in the rapid detoxification of patients dependent on heroin.

Cocaine abuse among heroin addicts in Spain

Consumption of buprenorphine and other drugs among heroin addicts under ambulatory treatment: results from cross-sectional studies in 1988 and 1990.

Plasma methadone concentrations as an indicator of opioid withdrawal symptoms and heroin use in a methadone maintenance program