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

FRANÇAIS :
La méthadone est un mélange racémique 50/50 de deux énantiomères mais c'est la R-méthadone qui possède la majorité des effets opioïdes. La concentration sanguine en R-méthadone influence-t-elle l'efficacité thérapeutique chez le patient en traitement de maintenance ? Pour éclaircir cette question, on mesure les concentrations en R, S et (R,S) méthadone dans le plasma de 180 patients. La réponse thérapeutique est définie comme l'absence d'opiacés illicites ou de cocaïne dans les urines collectées durant deux mois avant le prélèvement sanguin. On observe alors une grande variabilité individuelle de la concentration en R-méthadone en fonction du poids. Une bonne réponse thérapeutique est associée à 250 ng/ml de R-méthadone et 400 ng/ml de (R,S)-méthadone. Il importe donc de mesurer la proportion de R-méthadone et d'adapter la dose de méthadone à chaque individu soigné, entre 55mg/j et 92 mg/j pour obtenir une concentration sanguine en R-méthadone proche de 250ng/ml chez une personne de 70kg.
ENGLISH :
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-close-to-weight ratios was found (mean, S.D., median, range: 112, 54, 100, 19-316 ng x kg/ml x 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. (Author's abstract.)