<i>L</i>-Methadone and <i>D,L</i>-Methadonein Methadone Maintenance Treatment: A Comparison of Therapeutic Effectiveness and Plasma Concentrations

Abstract

The clinical effectiveness of l-methadone maintenance treatment (LMMT) carried out using d,l-methadone or l-methadone have been compared with ambulatory heroin-dependent subjects. A total of 40 heroin-dependent subjects, previously maintained on l-methadone in Frankfurt am Main, were divided into two groups under randomised double-blind conditions and received either an equivalent dose of l-methadone as d,l-methadone or remained on the previous l-methadone treatment. Requests for a change in the dose of d,l-methadone and l-methadone were recorded, urine samples for determination of illicit drug use were collected and the individual level of opiate craving was determined over a 22-day observation period. There was no significant difference between the two groups in the number requests for a dose change (dose increase <10%). However, there was a significant increase in heroin use in the group which continued to receive l-methadone. Although there was less variability in opiate craving in the group receiving d,l-methadone, the mean intensity of opiate craving did not differ between the two groups. The mean l-methadone dose:l-methadone plasma concentration ratio, an index of the bioavailability of l-methadone in individual subjects, showed no significant change when the treatment was changed to d,l-methadone. The mean d-methadone:l-methadone plasma concentration ratio was 1.17. There was no significant difference between these ratios for day 15 and day 22. The mean l-methadone:EDDP plasma concentration ratio in the l-methadone group was 22.2 and the d,l-methadone:EDDP plasma concentration ratio was 18.4 . The plasma EDDP concentration in the d,l-methadone group increased 3-fold after starting treatment with d,l-methadone. These findings suggest that d,l-methadone can be used in methadone maintenance treatment of heroin-dependent subjects but that further studies are required to evaluate pharmacokinetic interactions between methadone enantiomers.

Subjective and physiological responses among racemic‐methadone maintenance patients in relation to relative (S)‐ vs. (R)‐methadone exposure

“…To this extent, it would be expected that the use of (R)‐methadone alone instead of rac‐ methadone for maintenance treatment would yield improved treatment outcomes. Although previous comparisons of clinical efficacy and acceptability for rac‐ and (R)‐methadone have found no significant differences [13–16, 24], interpretation of these findings is complicated by several factors. These studies generally failed to account for variation in methadone dose or enantiomeric ratio, featured few measures of subjective effects (e.g.…”

“…Although (R)‐methadone is believed to account for most if not all of the therapeutic effects of methadone maintenance treatment (e.g. suppression of opioid withdrawal and cravings), rac‐ methadone is normally used due to its lower production cost and evidence that it produces similar therapeutic outcomes when compared with (R)‐methadone alone [13–16].…”

Hepatitis C Virus Infection Influences the S-Methadone Metabolite Plasma Concentration

“…Methadone is a racemic mixture with unique characteristics in comprising an R - and S -methadone enantiomer. R -methadone (or l-isomer) is a 10-fold more potent agonist of the μ-opioid receptor [25] and has a 50-fold higher analgesic potency [26] than S -methadone. R -methadone thus seems to be the major stereoisomer involved in pain relief and the prevention of opioid withdrawal.…”

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Substance Use and Related Disorders. Part 2: Opioid dependence

“…No randomized studies have compared the efficacy of the two methadone isoforms, and few studies have addressed the impact of switching from one form to the other (Judson et al 1976;Scherbaum et al 1996;de Vos et al 1998;Soyka et al 2009). Single-dose studies (Kristensen et al 1996;Boulton et al 2001) and studies under steady-state conditions (Kreek et al 1979;Nakamura et al 1982) suggest that ( R -) methadone has a longer elimination half-life than ( S -) methadone.…”