Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment

Abstract

Methadone is a 50:50 mixture of two enantiomers and ( R)-methadone accounts for the majority of its opioid effect. The aim of this study was to determine whether a blood concentration of ( R)-methadone can be associated with therapeutic response in addict patients in methadone maintenance treatment. Trough plasma concentrations of ( R)-, ( S)- and ( R, S)-methadone were measured in 180 patients in maintenance treatment. Therapeutic response was defined by the absence of illicit opiate or cocaine in urine samples collected during a 2-month period prior to blood sampling. A large interindividual variability of ( R)-methadone concentration-to-dose-to-weight ratios was found (mean, S.D., median, range: 112, 54, 100, 19–316 ng×kg/ml×mg). With regard to the consumption of illicit opiate (but not of cocaine), a therapeutic response was associated with ( R)- (at 250 ng/ml) and ( R, S)-methadone (at 400 ng/ml) but not with ( S)-methadone concentrations. A higher specificity was calculated for ( R)- than for ( R, S)-methadone, as the number of non-responders above this threshold divided by the total number of non-responders was higher for ( R, S)-methadone (19%) than for ( R)-methadone (7%). The results support the use of therapeutic drug monitoring of ( R)-methadone in cases of continued intake of illicit opiates. Due to the variability of methadone concentration-to-dose-to-weight ratios, theoretical doses of racemic methadone could be as small as 55 mg/day and as large as 921 mg/day to produce a plasma ( R)-methadone concentration of 250 ng/ml in a 70-kg patient. This demonstrates the importance of individualizing methadone treatment.