Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 Genotype and Methadone Therapy.
Katherine M RobinsonSeenae EumZeruesenay DestaRachel Fynvola TyndaleAndrea GaedigkRichard C CristCyrine E HaidarAlan L MyersCaroline Flora SamerAndrew Alexander SomogyiPablo ZubiaurOtito F IwuchukwuMichelle Whirl-CarrilloTeri E KleinKelly E CaudleRoseann S DonnellyEvan D KharaschPublished in: Clinical pharmacology and therapeutics (2024)
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).
Keyphrases
- chronic pain
- healthcare
- primary care
- stem cells
- randomized controlled trial
- emergency department
- pain management
- heart failure
- copy number
- young adults
- bone marrow
- spinal cord
- mesenchymal stem cells
- mass spectrometry
- liver failure
- dna methylation
- atomic force microscopy
- neuropathic pain
- genome wide
- case report
- transcription factor
- deep learning
- high speed
- quality improvement
- single molecule
- extracorporeal membrane oxygenation
- capillary electrophoresis
- acute respiratory distress syndrome
- mechanical ventilation