Published in Br J Clin Pharmacol. 2014 Dec 30.
Authors: Mouly S et
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.
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.
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.
Methadone maintenance dose was predicted by sociodemographic & clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients.
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