Objective. To identify and characterize methadone-related drug interactions, as well as factors accounting for the variability in manifesting these interactions clinically.
Design. Systematic review of the primary literature.
Methods. Over 200 articles, reports of clinical trials, and case reports were reviewed. Studies and case reports were included if they revealed either quantitative or qualitative methods to identify, evaluate severity of, or compare methadone-related drug interactions.
Results of Data Synthesis. The evidence base associated with methadone drug interactions is underdeveloped in general, as the majority of references found were case reports or case series. Most of the studies and reports focused on inpatients receiving methadone maintenance treatment (MMT) that were between 20 and 60 years of age, taking 200 mg/day of methadone or less. Evidence supporting the involvement of lesser known cytochrome P450 enzymes such as 2B6 is emerging, which may partially explain the inconsistencies previously found in studies looking specifically at 3A4 in vitro and in vivo. Genetic variability may play a role in the pharmacokinetics and pharmacodynamics of many medications, including methadone.
Conclusions. Drug interactions associated with methadone and their clinical significance are still poorly understood in general. Many tertiary drug information references and review articles report interactions associated with methadone in a general sense, much of which is theoretical and not verified by case reports, much less well-designed clinical trials. The majority of drug interaction reports that do exist were performed in the MMT population, which may differ significantly from chronic pain or cancer pain populations.