Published in Br J Clin Pharmacol. 2014 Dec 30.
Authors: Mouly S et
AIMS:
Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic & genotype variables on methadone maintenance dose requirement in opioid-dependent responder patients.
METHODS:
Eighty-one stable patients (60 men/21 women, 43.7±8.1 years, 63.1±50.9 mg/day methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history, liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms determination of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes.
RESULTS:
Methadone maintenance dose was correlated to the highest dose ever used (r2 =0.57, P<0.0001). Fractioned methadone intake (OR 4.87, 95%CI 1.27-18.6, P=0.02), body weight (OR 1.57, 95%CI 1.01-2.44, P=0.04), history of cocaine dependence (80 versus 44 mg/day in never-addict patients, P=0.005) and ethnicity (Asian>Caucasian>African, P=0.04) were independently associated with high dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (rs =0.21, P=0.06) but not with highest dose ever used (rs =0.15, P=0.18) nor dose-normalized R,S-methadone trough concentrations (rs =-0.05, P=0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphism explored was predictive of the methadone maintenance dose.
CONCLUSION:
Methadone maintenance dose was predicted by sociodemographic & clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients.
Leave a Reply
You must be logged in to post a comment.