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PubMed2006

Pharmacokinetic interaction between voriconazole and methadone at steady state in patients on methadone therapy.

This trial was aimed to estimate the pharmacokinetic interaction between voriconazole and methadone at steady state in male patients on methadone therapy and to characterize the safety and tolerability profile during the coadministration. Twenty-three patients on individualized methadone therapy (30 to 100 mg once daily) were enrolled into this randomized, patient- and investigator-blind, placebo-controlled, parallel-group study. Methadone pharmacokinetic samples were collected from patients receiving methadone alone as the baseline before they were randomized to coadminister either 200 mg voriconazole twice daily (BID) (400-mg BID loading doses on the first day) (n = 16) or matching placebo (n = 7) for the next 5 days. Pharmacokinetic samples for methadone and voriconazole were collected on the last day of voriconazole dosing. The safety data were collected throughout the study. Voriconazole increased the steady-state exposure of pharmacologically active enantiomer (R)-methadone: the mean area under the concentration-time curve from 0 to 24 h (AUC(0-24)) was increased by 47.2% (90% confidence intervals [CI]: 37.7%, 57.4%), and the mean peak concentration (C(max)) was increased by 30.7% (90% CI: 22.2%, 39.8%). The magnitude of increase in (S)-methadone exposure was greater than that of (R)-methadone: the AUC(0-24) was increased by 103.4% (90% CI: 85.0%, 123.6%), and the C(max) was increased by 65.4% (90% CI: 52.6%, 79.2%). Methadone appeared to have no effect on the steady-state voriconazole pharmacokinetics compared to the historical data for voriconazole alone. Methadone patients receiving voriconazole showed no signs or symptoms of significant opioid withdrawal or overdose. Coadministration of 200 mg voriconazole BID with methadone was generally safe and well tolerated. Nevertheless, caution should be exercised when voriconazole is coadministered with methadone due to the increase in (R)-methadone exposure, which in turn may require a dose reduction of methadone.

Adult↗

PubMed2001

Outcomes after methadone maintenance and methadone reduction treatments: two-year follow-up results from the National Treatment Outcome Research Study.

This paper provides a detailed analysis of the 2-year outcomes for 351 drug misusers allocated on an intention-to-treat basis to methadone maintenance or methadone reduction treatments. Both groups showed substantial reductions in their use of illicit drugs and in other outcome areas. However, whereas most methadone maintenance patients received maintenance, only about one third of those allocated to methadone reduction received methadone reduction, and many actually received a form of methadone maintenance. Reduction patients were more likely to receive low doses of methadone, and were less likely to remain in treatment. For maintenance patients, higher doses and retention in treatment were both associated with improvements in illicit heroin use at 2 years. For the reduction patients, the more rapidly the methadone was reduced, the worse the heroin use outcomes. For patients in both treatment conditions, reductions in heroin use were associated with improvements in other outcome areas. The more severely dependent patients showed better outcomes in methadone maintenance. Methadone reduction treatment processes were associated with poor outcomes, and many patients who were allocated to methadone reduction treatment did not receive reduction treatment as intended. This calls into question the appropriateness of either the initial treatment planning process or the treatment delivery process, or both. A clearer distinction should be made between methadone maintenance and methadone reduction. Treatment goals should be made explicit both to the patient and to the clinical staff at the start of treatment. We suggest the need for a reappraisal of the goals and procedures of methadone reduction treatment.

Chi-Square Distribution↗

PubMed1979

Pharmacokinetics of methadone during maintenance therapy: pulse labeling with deuterated methadone in the steady state.

A technique is presented for study of steady state kinetics of methadone using pulse labeling with deuterated methadone (d3) and mass fragmentography to measure both unlabeled and labeled methadone in blood. Seven subjects maintained on methadone for at least 10 months were admitted to a closed metabolic ward. The daily dose of unlabeled methadone (d0) was substituted by one dose of methoadone-d3 and plasma levels of methadone-d0 and methadone-d3 were followed for 48 h using a precise (SD +/- 5%) and sensitive (30 pmol/ml) mass fragmentographic technique. Plasma half-lives (T1/2) for both methadone-do and methadone-d3 were calculated from samples obtained 8--24 H following the dose of methadone-d3. The t1/2 of oral methadone-d3 was shorter (22 +/- 2 h) than that of methadone-d0 (52 +/- 20 h). The same pattern was observed after intravenous administration. The results indicate multiple pools of methadone in the body.

Administration, Oral↗

PubMed1984

Diazepam and methadone interactions in methadone maintenance.

Survey study data and high rates of diazepam use/abuse in methadone maintenance suggest that acute administration of diazepam with daily methadone doses may enhance methadone effects. Acute subjective and physiologic effects of single oral doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150%, and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose) were assessed under double-blind conditions. The subjects were five adult male patients on methadone maintenance with histories of diazepam abuse who were receiving 50 to 60 mg methadone a day. Physiologic measures were continuously monitored for 30 min before and for 2 hr after dosing. Pupil diameter and subjective responses were measured 15 min before dosing and 15, 30, 45, 60, 90, and 120 min after dosing. Methadone induced dose-dependent increases in pupil constriction and scores on a subjective opioid effects rating scale, but diazepam had no significant effect on either. The combination of methadone at 150% of the maintenance dose with 40 mg diazepam induced increases in these measures greater than those induced by either drug dose alone. Drug combinations, however, were more frequently identified as being benzodiazepine/barbiturate-like than as methadone-like. Thus although the subjective effects of the drug combination are distinguishable from those of methadone alone, diazepam with methadone in methadone maintenance appears to increase some physiologic and subjective opioid effects that may be related to the relatively great use/abuse of diazepam in this population.

Administration, Oral↗

PubMed2004

Nevirapine significantly reduces the levels of racemic methadone and (R)-methadone in human immunodeficiency virus-infected patients.

Methadone is metabolized by various isoforms of the cytochrome P450 family, which can be induced by many drugs, including nevirapine. The objective of the present study was to determine the effects of coadministration of nevirapine and methadone on the dose-adjusted areas under the concentration-time curves (AUCs) of racemic and (R)-methadone. Twenty-five human immunodeficiency virus-infected subjects taking stable single daily doses of racemic methadone or (R)-methadone were included in this prospective, single-crossover trial. At the baseline, nevirapine was either started as part of a new regimen containing two nucleoside reverse transcriptase inhibitors (NRTIs) or added to an ongoing NRTI regimen. Patients could increase their methadone doses if withdrawal symptoms developed. Twelve-hour pharmacokinetic profiles were obtained before and 28 days after the start of nevirapine treatment. The total concentrations of methadone and its inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), in serum were determined by liquid chromatography-tandem mass spectrometry. Among the 20 evaluable patients, coadministration of nevirapine significantly decreased the mean dose-adjusted AUC of methadone by 41%. AUC reductions were similar for patients taking racemic methadone (37%; n = 11) and (R)-methadone (44%; n = 9). AUC changes ranged from mild increases in three patients to decreases of up to 70%. Fourteen of 20 patients required additional methadone due to withdrawal symptoms. However, the median dose increase was only 15%, which was less than that which would have been expected from the pharmacokinetic data. The AUC of EDDP increased significantly, by 35%. Methadone dose adjustments are justified when methadone is coadministered with nevirapine. Due to extensive variability, the adjustments must be tailored to the individual patient's needs.

Adult↗

PubMed1985

Altered methadone pharmacokinetics in methadone-maintained pregnant women.

We studied the influence of human pregnancy on the maternal disposition and effects of methadone. Nine healthy pregnant women who had been on p.o. methadone maintenance for at least 2 months were studied between 20 and 34 weeks of gestation (phase I), 35 and 40 weeks (phase II), 1 to 4 weeks post partum (phase III) and 8 to 9 weeks post partum (phase IV). Two subjects who breast-fed their infants had plasma and breast milk samples collected simultaneously. With or without normalization for dose and body weight, trough plasma concentrations of methadone were significantly lower and total or unbound methadone clearances greater during pregnancy than after delivery. Plasma protein binding of methadone was lower during pregnancy but the difference was only statistically significant between phases I and IV. The greater ratios of urinary excretion of the major metabolites to total and unbound methadone areas under the curve during pregnancy suggests that methadone metabolism was enhanced. The ratios of concentrations of methadone in milk to plasma were constant in two subjects, 0.32 +/- 0.06 and 0.61 +/- 0.07, respectively. Some of the women reported symptoms of methadone withdrawal during pregnancy, even when the daily methadone dose did not change. Because of the lower plasma methadone concentrations, increased methadone doses may be required during pregnancy to achieve methadone maintenance.

Adult↗

PubMedDate not supplied

Effect of methadone dose on the biliary excretion of methadone metabolites in the rat.

The effect of three different doses of 14C-methadone (0.08, 1.0 and 2.5 mg/kg) on the biliary excretion of methadone metabolites was studied in the rat. After administration of the 0.08- and 1.0-mg/kg doses of 14C-methadone there was no difference in the percentage of administered 14C excreted into bile with time. However, after the 2.5-mg/kg dose a significant increase was observed in the percentage of administered 14C excreted into bile. Analysis of bile samples showed that this increase was due to increases in the biliary excretion of two of the major metabolites of methadone. Several mechanisms could be responsible for this disproportionate increase in biliary excretion of methadone metabolites after high doses of methadone. It was found that the effect of high methadone dose on the biliary excretion of its metabolites was nearly eliminated when studied in phenobarbital (PB)-pretreated rats. Pretreatment of rats with PB increases the biliary excretion of methadone metabolites, primarily by increasing rates of methadone metabolism. The lack of additivity of the effect of the high dose of methadone and PB pretreatment on the biliary excretion of methadone metabolites suggests that a high dose of methadone also stimulates methadone metabolism, which results in the observed increased percentage of the administered dose excreted into bile.

Animals↗

PubMed2002

Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence.

BACKGROUND: Methadone maintenance was the first widely used form of opioid replacement therapy developed to treat heroin dependence, and it remains the best-researched treatment for this problem. Despite the widespread use of methadone in maintenance treatment for opioid dependence in many countries, it is a controversial treatment whose effectiveness has been disputed. OBJECTIVES: To evaluate the effects of methadone maintenance treatment (MMT) compared with treatments that did not involve opioid replacement therapy (i.e., detoxification, offer of drug-free rehabilitation, placebo medication, wait-list controls) for opioid dependence. SEARCH STRATEGY: We searched all the following databases up to 2001: Cochrane Drugs and Alcohol Review Group Register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE, Current Contents, Psychlit, CORK [www. state.vt.su/adap/cork], Alcohol and Drug Council of Australia (ADCA) [www.adca.org.au], Australian Drug Foundation (ADF-VIC) [www.adf.org.au], Centre for Education and Information on Drugs and Alcohol (CEIDA) [www.ceida.net.au], Australian Bibliographic Network (ABN), and Library of Congress databases, available NIDA monographs and the College on Problems of Drug Dependence Inc. proceedings, the reference lists of all identified studies and published reviews; authors of identified RCTs were asked about other published or unpublished relevant RCTs. SELECTION CRITERIA: All randomised controlled clinical trials of methadone maintenance therapy compared with either placebo maintenance or other non-pharmacological therapy for the treatment of opioid dependence. DATA COLLECTION AND ANALYSIS: Reviewers evaluated the papers separately and independently, rating methodological quality of concealment of allocation, data were extracted independently for meta-analysis and double-entered. MAIN RESULTS: Six studies met the criteria for inclusion in this review, all were randomised clinical trials, two were double-blind. There were a total number of 954 participants. The method of concealment of allocation was inadequate in one study, not clearly described in four studies, but adequate in a sixth study. Based on the meta-analysis, methadone appeared statistically significantly more effective than non-pharmacological approaches in retaining patient in treatment (3 RCTs, RR=3.05; 95%CI: 1.75-5.35) and in the suppression of heroin use (3 RCTs, RR=0.32; 95%CI: 0.23-0.44), but not statistically in criminal activity (3 RCTs, RR=0.39; 95%CI: 0.12-1.25). REVIEWER'S CONCLUSIONS: Methadone is an effective maintenance therapy intervention for the treatment of heroin dependence as it retains patients in treatment and decreases heroin use better than treatments that do not utilise opioid replacement therapy. It does not show a statistically significant superior effect on criminal activity.

Humans↗

PubMed1995

Effects of buprenorphine and methadone in methadone-maintained subjects.

Buprenorphine, a partial mu opioid agonist, is an experimental medication under development for the treatment of opioid dependence as an alternative to methadone maintenance. The present study examined the relationship between level of opioid physical dependence and response to buprenorphine administration as part of a program to develop procedures for transferring patients from methadone to buprenorphine treatment. This laboratory study characterized the agonist and antagonist effects of acute doses of buprenorphine and methadone in subjects maintained on either 30 (n = 7) or 60 (n = 6) mg/day oral methadone. Test doses of placebo [sl. and PO), methadone (15, 30, and 60 mg PO) and buprenorphine (2, 4, and 8 mg sl.) were administered to volunteers residing on a closed residential unit. Subjective, physiological, observer-rated, and cognitive/psychomotor measures were collected for 6.5 h after test doses. Test doses of methadone, but not buprenorphine, constricted pupils and produced dose-related increases on subjective report measures reflecting opioid agonist drug effects. Agonist effects of methadone were more prominent in the 30 mg than in the 60 mg methadone maintenance condition. Buprenorphine, but not methadone, precipitated opioid withdrawal signs and symptoms that were more prominent in the 60 mg than in the 30 mg methadone maintenance condition. These findings suggest that abrupt transition from methadone to buprenorphine may produce patient discomfort that is positively related to both methadone maintenance dose and buprenorphine transition dose.

Administration, Oral↗

PubMed2004

(S)-(+)-methadone is more immunosuppressive than the potent analgesic (R)-(--)-methadone.

Methadone is a widely used synthetic opioid which is administered as a racemic mixture of (R)-(--)- and (S)-(+)-enantiomers, with only (R)-(--)-methadone possessing mu opioid receptor agonist activity. Methadone inhibits numerous immune functions in vitro at concentrations above 10 microM in a nonstereoselective and naloxone-insensitive fashion, suggesting the presence of nonclassical opioid receptors on immune cells. No in vivo data on the effects of methadone's enantiomers on immune function are available. Therefore, the stereoselectivity of methadone's analgesia (hot plate latency) in vivo and immune suppression ex vivo (splenocyte proliferation) was investigated in groups of Balb/c mice. Significant analgesia was observed in animals that received racemic methadone (P=0.0012, 52% MPE) and (R)-(--)-methadone (P=0.0002, 70% MPE) when compared to saline-treated controls, while (S)-(+)-methadone was devoid of any such effect (-4% MPE). In vivo (R)-(--)- and racemic methadone caused significant inhibition (P<0.001, greater than -70%) of basal proliferation compared to saline control. In stark contrast to analgesia, in vivo (S)-(+)-methadone caused significantly greater inhibition of basal proliferation (P<0.001, -130%) than (R)-(--)- and racemic methadone. The immune suppression caused by methadone is not purely a classical opioid response but involves nonclassical opioid receptors located at the central level, which have yet to be characterised. Moreover, the dose at which immune suppression occurred could be achieved clinically.

Analgesics, Opioid↗

PubMed2004

Methadone implants for methadone maintenance treatment. In vitro and in vivo animal studies.

Methadone implant formulations elaborated with polylactide-co-glycolide (PLGA) and polylactic acid (PLA) for 1 week and 1 month release duration, respectively, were evaluated in vitro and in vivo. One-week implants prepared with methadone clorhydrate, methadone clorhydrate/methadone base blend or methadone base were tested in vitro. Results showed that the methadone release rate decreased as the methadone base increased. The best release profile was achieve when the methadone base implants, made by compression of a 50:50 PLGA (12 kDa) and methadone base mix, were coated with PLA (30 kDa). For 1-month implants, the methadone base load was increased to 65% and PLA of 30 kDa was used as a matrix component. In this case the implants were coated with the same polymer. Deconvolution methods could not be used for in vivo release estimation because an increase in methadone clearance was observed with methadone clorhydrate solution multiple-dose treatment. Therefore the amount of drug remaining within the implants was evaluated and the deconvolution was only used to establish the release profile range. The upper limit was estimated applying the absorption-disposition function obtained after multiple-dose administrations while the lower curve was estimated using the single-dose function. Methadone serum levels were maintained around 200 ng/ml during 1 week and approximately 5 weeks with the optimised implants. In vivo-in vitro correlations were always very good with slopes near 1.

Animals↗

PubMed2007

Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients: a cross-sectional study.

AIMS: To determine and evaluate QTc intervals in electrocardiograms (ECGs) of former heroin addicts, currently in methadone maintenance treatment (MMT), as previous reports suggest that methadone may prolong QTc intervals, thus possibly increasing the risk for Torsade de pointes (TdP). DESIGN: Cross-sectional study. SETTING: Between January 2003 and September 2004, patients on a steady dose of methadone for at least 2 weeks were studied. PARTICIPANTS: This study is a subset of 153 patients, of whom 151 patients participated in a study of high methadone doses and serum levels. A total of 138 patients in MMT for a minimum of 100 days up to 10.7 years, receiving 40-290 mg/day methadone dose, participated. MEASUREMENTS: Patients had an ECG at the time when blood was drawn for determination of serum methadone levels at around 24 hours after the last oral methadone dose. Corrected-QT intervals (QTc) were calculated using the Bazett formula. FINDINGS: Of 138 patients studied, 98 (71%) were male. Mean QTc interval was 418.3 +/- 32.8 milliseconds (ms). Mean methadone dose was 170.9 +/- 50.3 mg/day and mean serum methadone level was 708.2 +/- 363.1 ng/ml. Methadone dose and serum levels did not correlate with QTc. Three patients had QTc intervals above 500 ms ('prolonged'). After 2 +/- 0.4 years of follow-up, two patients died; they were two of three patients with very prolonged QTc. Causes of death were not attributed to cardiac origin. An additional 19 patients had QTc intervals of between 450 and 499 ms ('possibly prolonged'). None of these QTc > or = 450 ms patients had any cardiac problems. Methadone doses of all 22 patients were > 120 mg/day. CONCLUSIONS: Methadone maintenance is generally safe; however, the possible toxicity of high dose (> 120 mg/day) should be monitored for QTc.

Adolescent↗

PubMed2004

Population pharmacokinetics of (R)-, (S)- and rac-methadone in methadone maintenance patients.

AIM: To construct a population pharmacokinetic model for methadone enantiomers in the setting of methadone maintenance treatment for opioid dependence. METHODS: A population pharmacokinetic model was developed using P-Pharm software for rac-, (R)- and (S)-methadone using data (8-13 plasma samples per subject) obtained from 59 methadone maintenance patients during one interdosing interval at steady state. The patients were randomly assigned to either a development (n = 38) or a validation dataset (n = 21). The model was refined by inclusion of all subjects to construct a final basic model, which was used to construct a covariate model. RESULTS: A population-based two-compartment open model with first-order absorption and lag time was developed and validated for all analytes. The population geometric mean (coefficient of variation) of maximum a posteriori probability Bayesian estimated values for clearance, terminal half-life and volume of distribution at steady-state of the active (R)-enantiomer were 8.7 (42%) l h(-1), 51 (45%) h and 597 (45%) l, respectively. For all analytes, the volume of the central compartment was decreased with increasing plasma alpha(1)-acid glycoprotein concentration and was lower in females, while the delay in absorption was longer at higher doses. No covariates were identified for apparent oral clearance. The apparent oral clearance of (R)-methadone (geometric mean ratio; 95% confidence interval) was 105% (99, 110), that of (S)-methadone (P = 0.19), while (R)-methadone V(c)/F (154%; 151, 157), V(dss) /F (173%; 164, 183), t(1/2beta) (162%; 153, 172) and mean residence time (166%; 156, 176) were significantly greater (P < 0.0001) than for (S)-methadone. The population pharmacokinetic models were able to predict accurately oral clearance values from limited (one or two samples) blood sampling protocols. CONCLUSIONS: The substantial stereoselectivity in methadone disposition reinforces the potential for misinterpretation of racemic methadone disposition data. The marked interindividual variability in (R)-methadone clearance, with no covariates identified, highlights the need for alternative methods to determine an individual's metabolic clearance. The ability to predict (R)-methadone clearance from one to two blood samples at steady state may prove clinically useful if a drug-drug interaction or poor adherence are suspected and guide the prescriber in deciding if a client's request for a dose increase is warranted or whether an alternative opioid would be more appropriate.

Adult↗

PubMed1997

Methadone-related overdose deaths in South Australia, 1984-1994. How safe is methadone prescribing?

OBJECTIVE: To assess the safety of prescribing of methadone tablets and syrup in South Australia by investigating overdose deaths of patients using prescribed methadone and non-patients using illegally obtained methadone. DESIGN: Surveillance study of deaths related to methadone overdose, 1984-1994. DATA SOURCES: Coroner's Office and the Therapeutic Goods Section of the South Australian Health Commission. RESULTS: Per capita prescription of methadone tablets for chronic pain in South Australia was the highest in Australia in 1994. A large increase in deaths, due mainly to methadone tablets prescribed for chronic pain, occurred in 1993-1994. Illegal diversion of methadone to non-patients was responsible for half of the deaths during these two years. Deaths from overdoses of methadone syrup prescribed in maintenance therapy for drug dependence declined from 1984 to 1994. The relative risk for patient deaths due to methadone tablets versus methadone syrup was estimated to be 7.29 (95% confidence limits, 2.15-31.48). Psychotropic drug combinations were present in 86% of deaths. CONCLUSION: The methadone syrup program for drug dependence remains relatively safe. Our data raise concerns about prescribing methadone tablets for chronic pain. Better prescriber education and accountability, patient assessment and supervision and advice to patients about concurrent use of alcohol and benzodiazepines are needed.

Adult↗

PubMed1995

Subjective and objective symptoms in relation to plasma methadone concentration in methadone patients.

Two rating scales, which were originally developed for measurements of objective and subjective signs of opiate withdrawal, were used to evaluate potential estimates (correlates) of methadone effects in relation to plasma methadone concentrations. Patients participating in our regular methadone maintenance treatment project were studied during 24 h after the intake of the daily methadone dose. Methadone concentrations in plasma were compared to the subjective (estimated by the patients) and objective (estimated by the investigator) signs of the drug effects before, and 2.5, 5, 9 and 24 h after intake of methadone. Some new items possibly related to rising methadone concentrations were added to the subjective scale. Results indicated that, for subjective ratings, the majority of the items investigated corresponded well with the plasma methadone concentrations. The most significant associations were found for the following items: low psychomotor speed, alertness, running nose, yawning and anxiety. For objective ratings, only the items rhinorrhea, piloerection and signs of anxiety were significantly associated with the methadone concentrations. These rating scales may, together with plasma methadone determinations, be of considerable value when making dose adjustments for methadone maintenance patients. Further work is, however, needed to establish concentration-effect relationships.

Adult↗

PubMed1999

Induction of antibodies to methadone during methadone maintenance treatment of heroin addicts and its possible clinical implications.

By means of two different types of enzyme-linked immunosorbent assay (ELISA) techniques, antibodies to methadone were detected in blood plasma of heroin addicts on methadone maintenance treatment. In 11-15% of cases immunoglobulin (Ig) M antibodies were detected, while IgG antibodies were observed in 33-40%. At least two types of antibodies to methadone were induced-antibodies with high affinity to methadone and low-affinity antibodies more specific for morphine than for methadone. The methadone antibody-positive group of patients had a significantly higher plasma methadone concentration--440 ng/ml, than the antibody-negative group--250 ng/ml (P < 0.005) despite almost the same mean therapeutic doses of methadone. Of patients with all types of antibodies to methadone 52% were human immunodeficiency virus (HIV)-positive, whereas in the group without antibodies, HIV-positive reactions were observed in 10.5% only (P < 0.002). Alternatively, 87.5% of HIV-positive patients had antibodies to methadone, a fact which should be taken into consideration during methadone dose adjustment.

Adult↗

PubMed2003

Cessation of methadone maintenance treatment using buprenorphine: transfer from methadone to buprenorphine and subsequent buprenorphine reductions.

BACKGROUND: Buprenorphine is used in the treatment of opioid dependence. Due to its pharmacology, the transfer from methadone to buprenorphine may precipitate withdrawal symptoms. METHODS: Methadone maintained patients with clinical indicators of stability who were seeking withdrawal from methadone were recruited from three Australian states. Patients on methadone doses between 30 and 40 mg were randomised to transfer to buprenorphine by a fixed dose (transfer at 30 mg methadone) or by a variable dose induction (transfer when 'uncomfortable'). A third group of patients with methadone doses less than 30 mg were transferred to buprenorphine at their entry methadone dose. Fifty-one patients were inducted onto buprenorphine using the same dosing protocol with the first dose of 4 mg buprenorphine. Following stabilisation on buprenorphine, patients gradually reduced the buprenorphine dose to 0 mg. Withdrawal severity and drug use was monitored. RESULTS: There were no significant difference between the transfer at 30 mg and transfer when 'uncomfortable' dosing protocols in severity of withdrawal on transfer from methadone to buprenorphine. Those on doses less than 30 mg reported significantly less withdrawal discomfort at transfer. All but one patient stabilised on buprenorphine. Thirty-eight of the 51 patients inducted onto buprenorphine reached 0 mg. CONCLUSIONS: Transfer from methadone to buprenorphine can safely occur from doses of around 30 mg of methadone. Buprenorphine dose reductions were well tolerated. Thirty-one percent of patients were not using heroin or methadone at 1-month follow-up.

Adult↗

PubMed2000

The effect of sertraline on methadone plasma levels in methadone-maintenance patients.

The authors examine methadone plasma levels in 31 depressed methadone-maintained opiate addicts enrolled in a 12-week placebo-controlled, double-blind study of sertraline. Between baseline and week 6, patients on sertraline showed a mean increase in methadone plasma level/dose (P/D) ratio of 26% (SD = 43%, range -32% to +118%), while patients on placebo showed a mean decrease of 16% (SD = 27%, range -62% to +50%). This difference was significant (p < 0.02). The sertraline and placebo groups did not differ in reported side effects or methadone dose adjustments. Between weeks 6 and 12, methadone P/D in the sertraline group decreased back towards baseline, and the treatment groups did not differ significantly at week 12. The results suggest sertraline may produce a modest increase in methadone serum levels over the first six weeks of treatment. Depression and anxiety disorders are common in methadone-maintained patients. Serotonin uptake inhibitors are attractive choices for treatment due to their low toxicity and low abuse potential, but these agents variously inhibit isoenzymes responsible for the metabolism of methadone. Clinicians treating depressed or anxious methadone patients with second-generation antidepressants should monitor for clinical signs of increased or decreased methadone levels and consider monitoring serum methadone levels.

Adult↗