Reviewing pharmacogenetics to advance precision medicine for opioids

Leen Magarbeh; Ilona Gorbovskaya; Bernard Le Foll; Reuven Jhirad; Daniel J Müller

doi:10.1016/j.biopha.2021.112060

Reviewing pharmacogenetics to advance precision medicine for opioids

Biomed Pharmacother. 2021 Oct:142:112060. doi: 10.1016/j.biopha.2021.112060. Epub 2021 Sep 12.

Authors

Leen Magarbeh¹, Ilona Gorbovskaya², Bernard Le Foll³, Reuven Jhirad⁴, Daniel J Müller⁵

Affiliations

¹ Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health, Toronto, ON, Canada.
² Institute of Medical Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health, Toronto, ON, Canada.
³ Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Family and Community Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health, Toronto, ON, Canada; Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Acute Care Program, Centre for Addiction and Mental Health, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
⁴ Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; Office of the Chief Coroner and Ontario Forensic Pathology Service, Toronto, ON, Canada.
⁵ Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Institute of Medical Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health, Toronto, ON, Canada. Electronic address: daniel.mueller@camh.ca.

PMID: 34523422
DOI: 10.1016/j.biopha.2021.112060

Abstract

Background: Adequate opioid prescribing is critical for therapeutic success of pain management. Despite the widespread use of opioids, optimized opioid therapy remains unresolved with risk of accidental lethal overdosing. With the emergence of accumulating evidence linking genetic variation to opioid response, pharmacogenetic based treatment recommendations have been proposed.

Objective: The aim of this review is to evaluate pharmacogenetic evidence and provide an overview on genes involved in the pharmacokinetics and pharmacodynamics of opioids.

Methods: For this review, a systematic literature search of published articles was used in PubMed®, with no language restriction and between the time period of January 2000 to December 2020. We reviewed randomized clinical studies, study cohorts and case reports that investigated the influence of genetic variants on selected opioid pharmacokinetics and pharmacodynamics. In addition, we reviewed current CPIC clinical recommendations for pharmacogenetic testing.

Results: Results of this review indicate consistent evidence supporting the association between selected genetic variants of CYP2D6 for opioid metabolism. CPIC guidelines include recommendations that indicate the avoidance of tramadol use, in addition to codeine, in CYP2D6 poor metabolizers and ultrarapid metabolizers, and to monitor intermediate metabolizers for less-than-optimal response. While there is consistent evidence for OPRM1 suggesting increased postoperative morphine dosing requirements in A118G G-allele carriers, the clinical relevance remains limited.

Conclusion: There is emerging evidence of clinical relevance of CYP2D6 and, to a lesser extent, OPRM1 polymorphism in personalized opioid drug dosing. As a result, first clinics have started to implement pharmacogenetic guidelines for CYP2D6 and codeine.

Keywords: Cytochrome P450; OPRM1; Opioids; Pharmacogenetics; Precision medicine.

Publication types

Systematic Review

MeSH terms

Analgesics, Opioid / administration & dosage*
Analgesics, Opioid / pharmacokinetics
Analgesics, Opioid / pharmacology
Animals
Cytochrome P-450 CYP2D6 / genetics
Dose-Response Relationship, Drug
Humans
Pain / drug therapy
Pharmacogenetics*
Precision Medicine / methods*
Randomized Controlled Trials as Topic
Receptors, Opioid, mu / genetics

Substances

Analgesics, Opioid
OPRM1 protein, human
Receptors, Opioid, mu
Cytochrome P-450 CYP2D6