Abstract
Oxycodone is a widely used opioid for the management of chronic pain. Analgesic effects observed following the administration of oxycodone are mediated mostly by agonistic effects on the μ-opioid receptor. Wide inter-subject variability observed in oxycodone efficacy could be explained by polymorphisms in the gene coding for the μ-opioid receptor (OPRM1). In humans, oxycodone is converted into several metabolites, particularly into oxymorphone, an active metabolite with potent μ-opioid receptor agonist activity. The CYP2D6 enzyme is principally responsible for the conversion of oxycodone to oxymorphone. The CYP2D6 gene is highly polymorphic with encoded protein activities, ranging from non-functioning to high-functioning enzymes. Several pharmacogenetic studies have shown the importance of CYP2D6-mediated conversion of oxycodone to oxymorphone for analgesic efficacy. Pharmacogenetic testing could optimize oxycodone therapy and help achieve adequate pain control, avoiding harmful side effects. However, the most recent Clinical Pharmacogenetics Implementation Consortium guidelines fell short of recommending pharmacogenomic testing for oxycodone treatment. In this review, we (1) analyze pharmacogenomic and drug-interaction studies to delineate the association between CYP2D6 activity and oxycodone efficacy, (2) review evidence from CYP3A4 drug-interaction studies to untangle the nature of oxycodone metabolism and its efficacy, (3) report on the current knowledge linking the efficacy of oxycodone to OPRM1 variants, and (4) discuss the potential role of CYP2D6 brain expression on the local formation of oxymorphone. In conclusion, we opine that pharmacogenetic testing, especially for CYP2D6 with considerations of phenoconversion due to concomitant drug administration, should be appraised to improve oxycodone efficacy.
Highlights
Drug overdose deaths involving prescription opioids rose from 3442 in 1999 to 14,139 in 2019, reaching a peak of 17,209 deaths in 2017 [1]
The role of genetic polymorphisms associated with proteins involved in the pharmacokinetics and pharmacodynamics of oxycodone was reviewed by the Clinical Pharmacogenetics Implementation
Our systematic analysis of the current knowledge pertaining to the contribution of oxymorphone to oxycodone efficacy for pain management and the relevance of CYP2D6 and OPMR1 genetic polymorphisms lead us to the following deductions: (1)
Summary
Drug overdose deaths involving prescription opioids (natural and semi-synthetic opioids and methadone) rose from 3442 in 1999 to 14,139 in 2019, reaching a peak of 17,209 deaths in 2017 [1]. Oxycodone is a semi-synthetic opioid used for pain management, accounting for approximately 17 million prescriptions in 2018 [2]. The role of genetic polymorphisms associated with proteins involved in the pharmacokinetics and pharmacodynamics of oxycodone was reviewed by the Clinical Pharmacogenetics Implementation. Some study results have clearly demonstrated and supported the value of genetic testing, though others have not found clinical value in genetic testing to improve pain management with oxycodone. This is especially the case for Pharmaceutics 2021, 13, 1466. This review uses the Quality of Evidence per GRADE Criteria for each section presented [6], and evidence supporting the role of relevant pharmacokinetics, pharmacodynamics, and pharmacogenomics information for pain management with oxycodone is discussed. This review aims to explain why discrepancies exist between results from fundamental research and some clinical studies
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