A Narrative Review of the Metabolic Assessment of Patients on Methadone: An Alternative to Pharmacokinetically Blind Prescribing.

Abstract

With the increase in fentanyl use, methadone remains one of the standards of care for opioid use disorder and may confer some advantages over buprenorphine. Yet the wide range of patient metabolism makes individual prescribing unpredictable. Induction and subsequent dose adjustments have historically been guided using a "start low and go slow" approach to minimize the risk of overdose, with individual metabolic differences unassessed. However, heroin's replacement by fentanyl in the illegal market has resulted in unprecedented levels of physical dependence necessitating higher doses and more rapid inductions. Methadone metabolism is unpredictable, largely due to phenotypic and genotypic variability of cytochrome P450 enzyme activity. Early research found a 17-fold variation in serum level for a given dose, corroborated recently by finding an equally wide range of individual metabolic speeds. Little work has been done documenting how this variability affects clinical response. Dosing practices have remained "pharmacokinetically blind" to a patient's capacity to metabolize a medication with a narrow therapeutic window and potentially serious consequences of underdosing or overdosing. Serum-based measures of methadone can provide objective information on individual metabolism. These tests include trough levels, peak levels, a methadone/metabolite ratio, and a peak/trough ratio. Genetic testing for variant alleles that alter metabolism (pharmacokinetics) or alter mu receptor activity (pharmacodynamics) can identify patients whose ability to metabolize methadone is either impaired or augmented. This review discusses the laboratory tools available to guide safe induction protocols and subsequent prescribing.