The effects of racemic d,l-methadone and l-methadone in substituted patients—a randomized controlled study

doi:10.1016/j.drugalcdep.2005.04.007

Drug and Alcohol Dependence

Volume 80, Issue 2, 1 November 2005, Pages 267-271

https://doi.org/10.1016/j.drugalcdep.2005.04.007 Get rights and content

Abstract

Aims:

To test the hypothesis that switching from l-methadone to d,l-methadone is associated with more frequent withdrawal symptoms and side-effects than switching from d,l-methadone to l-methadone.

Design:

Stratified, randomized 2 × 2 crossover study design over a time-period of 8 weeks. At study entry, every second patient was switched from the pre-study substance to the other medication, after 4 weeks all patients were subject to a (re-)switch.

Setting:

The study was conducted as a multi-centre trial in three methadone maintenance therapy (MMT) clinics.

Participants:

Seventy-five patients previously treated with either d,l-methadone or l-methadone for at least 1 year took part in the study.

Measurements:

Intra-individual changes in withdrawal symptoms (Short Opiate Withdrawal Scale, SOWS) and side-effects were defined as primary outcome criteria. Secondary outcome measures included necessity for methadone dose adjustment.

Findings:

Complete data were available for 68 patients (91%). Sample strata were unbalanced at baseline: 15 patients (22%) were treated with l-methadone and 43 with d,l-methadone (78%). Thirty-five patients were randomized into the group treated with l-methadone and 33 into the group treated with d,l-methadone during the first 4 weeks. There were no significant differences in intra-individual change of withdrawal symptoms and side-effects between groups after crossover. However, patients treated with levomethadone tended to feel less withdrawal symptoms than patients treated with d,l-methadone.

Conclusions:

d,l-methadone and l-methadone can safely be replaced by each other on a 2:1 ratio. Withdrawal symptoms or side-effects due to conversion are of transient nature only.

Introduction

Maintenance treatment of opioid dependence with methadone is the most widely used approach. Methadone maintenance therapy (MMT) was introduced in Germany in 1988 (Verthein et al., 1998). Initially, levomethadone (l-methadone, l-Polamidon^®) was the only drug approved for this indication, d,l-methadone was not approved until 1994. The rationale for using racemic methadone is that direct treatment costs are lower compared to l-methadone. As of December 2003, there were 56,000 patients in maintenance treatment in Germany of whom 70% were treated with d,l-methadone, 16% with l-methadone, 12% with buprenorphine and 1.6% with codeine.

l-Methadone is regarded as the active component in MMT. Compared to d,l-methadone, l-methadone shows a 10-fold higher affinity to μ₁-receptors with treatment satisfaction corresponding to l-methadone plasma concentration (Hiltunen et al., 1999). As to analgetic efficacy, l-methadone is 50 times more potent than d-methadone (Scott et al., 1948). With respect to pharmacokinetics some studies showed a slower elimination for l-methadone compared to d,l-methadone (e.g. Kristensen et al., 1996). Plasma levels of l-methadone and d-methadone do not only differ inter-individually, but also intra-individually. The average plasma concentration ratio between l-methadone and d-methadone varies in different studies from 0.8 to 2.0, also when switching between both substitutes (Eap et al., 1996, Hiltunen et al., 1999). Considering the pharmacodynamic and kinetic data, the recommended l-methadone/d,l-methadone conversion factor of 1:2 may not necessarily meet pharmacological requirements (Jage, 1989, Scott et al., 1948).

Double-blind studies comparing the effects of l- and d,l-methadone showed either no differences between both substitutes (Judson et al., 1976), the need for increased dosages of racemic methadone (Scherbaum et al., 1996), or increased illicit heroin use in patients treated by l-methadone (de Vos et al., 1998). A naturalistic study showed that after switching from l-methadone to d,l-methadone 58% of patients felt worse (mainly subjective feeling of decreased efficacy), 11% felt better and 31% did not realize any changes (Ulmer, 1995).

The present study was conducted to explore clinically relevant differences between l-methadone and d,l-methadone for treatment with either substance or switching from one to the other. It was hypothesized that switching from l-methadone to racemic d,l-methadone is associated with more withdrawal symptoms and opioid side-effects when compared to switching from d,l-methadone to l-methadone.

Section snippets

Methods

The study was conducted in three MMT clinics in Hamburg, Germany. The study followed a double-blind, stratified, randomized 2 × 2 crossover design covering a time period of 8 weeks. Inclusion criteria comprised a minimum of 1 year stable substitution with either d,l-methadone (R-stratum) or l-methadone (L-stratum), contact to the clinic physician at least once weekly, 18 years or older and written informed consent. Patients were excluded in case of a change of MMT (substance or clinic) during the

Sample characteristics

Seventy-five patients participated in the study, seven patients were excluded due to missing data (drop-outs). Drop-outs were on average 5 years younger, 1 year longer in MMT and had a higher frequency of participation in concomitant psychosocial care than completers (Table 1). The remaining study population (completers, n = 68 and 91% of the total included) was predominantly male, on average 39 years old, started heroin use on average 16 years before entering the study and the mean dose

Discussion

This study with a double-blind, stratified, randomized 2 × 2 crossover design meant to explore withdrawal symptoms and side-effects when converting from l-methadone to d,l-methadone and vice versa. Seventy-five patients took part in the study, 68 patients (91%) were included in the final analysis. Compared to all MMT patients in Hamburg, the study population is characterized by a higher percentage of males and slight advantages concerning vocational and living situation (Martens et al., 2003).

Acknowledgements

The authors wish to thank the patients and the teams of the participating clinics in Hamburg. This study was supported by an unrestricted educational grant from Aventis.

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Short communicationThe effects of racemic d,l-methadone and l-methadone in substituted patients—a randomized controlled study

Abstract

Aims:

Design:

Setting:

Participants:

Measurements:

Findings:

Conclusions:

Introduction

Section snippets

Methods

Sample characteristics

Discussion

Acknowledgements

Addict. Behav.

Int. J. Drug Policy

Replacement of (R)-methadone by a double dose of (R, S)-methadone in addicts: interindividual variability of the (R)/(S) ratios and evidence of adaptive changes in methadone pharmacokinetics

Eur. J. Clin. Pharmacol.

Rated well-being in relation to plasma concentrations of l- and d-methadone in satisfied and dissatisfied patients on methadone maintenance treatment

Psychopharmacology

Methadon–pharmakokinetik und pharmakodynamik eines opiates. [Pharmacokinetics and pharmacodynamics of an opiate]

Anästhesist

Side effects of levomethadone and racemic methadone in a maintenance program

Clin. Pharmacol. Ther.

Short communication
The effects of racemic d,l-methadone and l-methadone in substituted patients—a randomized controlled study