Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 Genotype and Methadone Therapy.

Document Type

Article

Publication Date

10-2024

Identifier

DOI: 10.1002/cpt.3338

Abstract

Methadone is a mu (μ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP). Genetic variation in the CYP2B6 gene has been investigated in the context of implications for methadone pharmacokinetics, dose, and clinical outcomes. Most CYP2B6 variants result in diminished or loss of CYP2B6 enzyme activity, which can lead to higher plasma methadone concentrations (affecting S- more than R-methadone). However, the data do not consistently indicate that CYP2B6-based metabolic variability has a clinically significant effect on methadone dose, efficacy, or QTc prolongation. Expert analysis of the published literature does not support a change from standard methadone prescribing based on CYP2B6 genotype (updates at www.cpicpgx.org).

Journal Title

Clinical pharmacology and therapeutics

Volume

116

Issue

4

First Page

932

Last Page

938

MeSH Keywords

Methadone; Humans; Cytochrome P-450 CYP2B6; Analgesics, Opioid; Opioid-Related Disorders; Genotype; Pharmacogenetics; Opiate Substitution Treatment; Pharmacogenomic Variants

Keywords

Methadone; Cytochrome P-450 CYP2B6; Opioid Analgesics; Opioid-Related Disorders; Genotype; Pharmacogenetics; Opiate Substitution Treatment; Pharmacogenomic Variants

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