Methadone dose in heroin‐dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity

Abstract

AIMSMethadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients. METHODSEighty-one stable patients (60 men and 21 women, 43.7 ± 8.1 years old, 63.1 ± 50.9 mg day À1 methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes. RESULTSMethadone maintenance dose was correlated to the highest dose ever used (r 2 = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27-18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01-2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day À1 in neveraddict 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 (Spearman rank correlation coefficient [r s ] = 0.21, P = 0.06) but not with highest dose ever used (r s = 0.15, P = 0.18) or dosenormalized R,S-methadone trough concentrations (r s = À0.05, P = 0.64). WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Overall, 30-80% of patients on methadone maintenance treatment are still receiving doses that are too low to be effective and experience withdrawal symptoms or decreased methadone efficacy for part of the dosing interval and/or have persistent heroin use or dropouts because of relapses.• The role of several genetic polymorphisms, including the CYP2B6, CYP2C19, CYP2D6 and MDR1 genotypes, on steady-state concentrations of methadone enantiomers was also controversial in clinical studies.• These studies did not simultaneously address the influence of sociodemographic and clinical variables and concomitant medications on methadone maintenance treatment with a multivariate approach. Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose. CONCLUSIONSMethadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients.

Relevance of CYP2B6 and CYP2D6 genotypes to methadone pharmacokinetics and response in the OPAL study

“…In our study, the frequency of the CYP2B6 516T allele was 29%, which is almost identical to that reported by Crettol et al or Mouly et al The frequency of CYP2D6 PMs was slightly higher than the expected 5–10% but was within expected population variation regarding Confidence interval . It has already been reported that CYP2D6 PM status has no influence on methadone plasma level …”

“…In our study, we did not observe this clinical adjustment; we observed that the TT group had a lower dose administered, and the GT group a higher dose administered. Surprisingly, similar results were reported in the Mouly et al study . However, both studies included a small number of subjects, and these results need to be confirmed in a larger cohort.…”

“…The lack of correlation observed between methadone dose and CYP2D6 genetic polymorphism was not surprising as this enzyme may contribute only marginally to the methadone first‐pass effects, as compared with CYP2B6 …”

“…The influence of genetic polymorphisms on pharmacodynamic properties and treatment response has been less explored, and is not supported by much evidence . Moreover, the impact of genetic variations could be compounded by interactions between many environmental and individual factors …”

Risk Factors for Weight Gain during Methadone Maintenance Treatment

“…The correlation with earlier BMI may reflect the fact that patients' weight and height are just two of several factors that influence what constitutes an individual's adequate methadone dose [23][24]. It should be noted that a patient's methadone dose is determine by a physician, based mainly on clinical opioid withdrawal or intoxication signs and symptoms, as well as evidence of opioids in urine analyses, and only to a lesser extent on subjective reports of craving.…”