Methadone metabolism and cytochrome P450 polymorphisms: a systematic review and meta-analysis

Introduction: Confusion regarding methadone metabolism exists, hampering optimal clinical use. A systematic review was conducted to assess the impacts of cytochrome P450 (CYP) genetic polymorphisms on methadone outcomes. Methods: MEDLINE, EMBASE, Web of Science, PsycINFO, and CENTRAL were searched to identify studies reporting methadone dose-adjusted plasma concentrations, clearance, maintenance dose, or treatment response in relation to CYP polymorphisms in humans. ROBINS-I was used to evaluate risk of bias in included studies. Each outcome was synthesized for each CYP using the ratio of means or odds ratio as the effect size measure. Results: Ten, two, fourteen, and five studies were included in the meta-analyses of the concentration, clearance, dose, and treatment response, respectively. The CYP2B6 c.516 G>T variant was robustly associated with (S)-methadone concentrations (GT+TTvs.GG: ratio of means (RoM) 1.40, p < 0.01) and clearance (GT+TTvs.GG: RoM 0.65, p < 0.01) but less with (R)- or (R,S)-methadone. The CYP2B6 variant also affected methadone dose for opioid use disorder (GT+TTvs.GG: RoM 0.93, p = 0.04). CYP2C19, CYP2C9, CYP2D6, and CYP3A5 polymorphisms did not influence any of the assessed outcomes. Conclusions: CYP2B6 genetics had statistically significant impacts on (S)-methadone and less so on (R)-methadone exposure and clearance and was statistically significantly but not clinically meaningfully associated with dose requirements.