A hybrid implementation-effectiveness randomized trial of CYP2D6-guided postoperative pain management

Abstract

Purpose: Cytochrome P450 2D6 ( CYP2D6) genotype-guided opioid prescribing is limited. The purpose of this type 2 hybrid implementation-effectiveness trial was to evaluate the feasibility of clinically implementing CYP2D6-guided post-surgical pain management and determine that such an approach did not worsen pain control. Methods: Adults undergoing total joint arthroplasty were randomized 2:1 to genotype-guided or usual pain management. For participants in the genotype-guided arm with a CYP2D6 poor (PM), intermediate (IM), or ultra-rapid metabolizer (UM) phenotype, recommendations were to avoid hydrocodone, tramadol, codeine, and oxycodone. The primary endpoints were feasibility metrics and opioid use; pain intensity was a secondary endpoint. Effectiveness outcomes were collected 2-weeks post-surgery. Results: Of 282 patients approached, 260 (92%) agreed to participate. In the genotype-guided arm, 20% had a high-risk (IM/PM/UM) phenotype, of whom 72% received an alternative opioid versus 0% of usual care participants (p<0.001). In an exploratory analysis, there was less opioid consumption (200 [104-280] vs. 230 [133-350] morphine milligram equivalents; p=0.047) and similar pain intensity (2.6 ± 0.8 vs. 2.5 ± 0.7; p=0.638) in the genotype-guided vs. usual care arm, respectively. Conclusion: Implementing CYP2D6 to guide post-operative pain management is feasible and may lead to lower opioid use without compromising pain control.

How to Integrate CYP2D6 Phenoconversion Into Clinical Pharmacogenetics: A Tutorial

“…The calculator was created in order to be used in the upcoming IGNITE II trials 20 . This automation replaces the manual process used in our previous chronic and acute pain trials and provides standardization among sites 17,19 . We recognized the value this calculator may have for the public and also created a beta version, called Propelling Clinical Pharmacogenomics into Practice (PROP).…”

“…Specifically, 5 of the 10 CYP2D6 inhibitors classified by the US Food and Drug Administration (FDA) as strong (i.e., bupropion, fluoxetine, and paroxetine) or moderate (i.e., duloxetine and mirabegron) are in the 2021 “Top 300 Drugs” list 15 . Recent studies from our group and others indicate that in the clinical settings where CYP2D6 genotype might be used, ~ 20–30% of individuals are also taking an enzyme inhibitor that leads to phenoconversion 16–19 . Integrating CYP2D6 phenoconversion into clinical practice is not yet standard of care as a majority of clinicians have limited knowledge of the drugs that might cause phenoconversion or, if knowledgeable, experience on how to integrate into practice, and no tool exists to facilitate integration.…”

Pharmacogenetics: A precision medicine approach to combatting the opioid epidemic

“…Drugs that inhibit CYP2D6, particularly antidepressants, are commonly prescribed to patients with chronic or acute pain. 41,42 In fact, data suggest that approximately 25% of those with chronic pain and 10% of those prescribed opioids for acute postsurgical pain are prescribed a moderate to strong CYP2D6 inhibitor, emphasizing the importance of accounting for phenoconversion. 42,43 An online calculator (https://rxgator.com/phenocalc-prop/) is freely available to assist clinicians with assigning phenotype based on genotype and concomitant use of CYP2D6 inhibitors.…”

“…41,42 In fact, data suggest that approximately 25% of those with chronic pain and 10% of those prescribed opioids for acute postsurgical pain are prescribed a moderate to strong CYP2D6 inhibitor, emphasizing the importance of accounting for phenoconversion. 42,43 An online calculator (https://rxgator.com/phenocalc-prop/) is freely available to assist clinicians with assigning phenotype based on genotype and concomitant use of CYP2D6 inhibitors. 44 Briefly, the clinician first enters the star alleles that make up the genotype and indicates whether there is an extra copy of either allele (ie, if allele multiplication is present).…”

“…If so, the calculator multiples the activity score by 0 for strong inhibitors and by 0.5 for moderate inhibitors, according to previous guidance and clinical studies, and provides a new activity score and phenotype that accounts for phenoconversion. 42,43…”