Implementing a pragmatic clinical trial to tailor opioids for acute pain on behalf of the IGNITE ADOPT PGx investigators

Abstract

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

Trial registration: ClinicalTrials.gov NCT04445792.

Conflict of interest statement

The authors declared no competing interests for this work.

© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1

Trial design. *Primary outcomes will be compared between the subgroup of PMs and IMs in the intervention versus control arm. †IM, NM, and PM phenotypes are based on CYP2D6 genotype and use of moderate to strong CYP2D6 inhibitors. EHR, electronic health record; IM, intermediate metabolizer; NM, normal metabolizer; PM, poor metabolizer; UM, ultrarapid metabolizer.

FIGURE 2

CYP2D6 phenotype assignment and phenotype‐based opioid prescribing recommendations for participants in the intervention arm. *Based on CYP2D6 genotype and use of moderate or strong CYP2D6 inhibitors. Abiraterone, cinacalcet, duloxetine, and mirabegron are moderate inhibitors and reduce the activity score by 50%. Bupropion, fluoxetine, paroxetine, quinidine, and terbinafine are strong inhibitors that reduce the activity score to 0. †Phenotype definitions differs from Clinical Pharmacogenomic Implementation Consortium and Dutch Pharmacogenetics Working Group consensus definitions. Whereas sites detect copy number variation, they do not detect which allele is duplicated or multiplicated. This can result in a ranged phenotype. Given the potential for the IM and/or UM phenotype, recommendations consistent with these phenotypes are provided. In the case of copy number variation leading to ranged phenotypes, recommendations are provided to avoid hydrocodone, tramadol, or codeine for the IM to NM ranged phenotype and to avoid hydrocodone, tramadol, codeine, or oxycodone for the IM to UM and NM to UM ranged phenotypes. AS, activity score; IM, intermediate metabolizer; NM, normal metabolizer; PM, poor metabolizer; UM, ultra‐rapid metabolizer.

FIGURE 3

Example of an ADOPT PGx Consult Note. The note shown is for a CYP2D6 poor metabolizer as the result of taking a strong CYP2D6 inhibitor. Bulleted text are the required elements per the ADOPT PGx Clinical Decision Support Working Group Guidelines for consult notes. Consult note format and wording varied among sites, but all included these common elements. ADOPT PGx, A Depression and Opioid Pragmatic Trial in Pharmacogenetics; CPIC, Clinical Pharmacogenetics Implementation Consortium; FDA, US Food and Drug Administration; MRN, Medical Record Number.

FIGURE 4

Example of an ADOPT PGx Automated Alert. The alert shown is for a CYP2D6 poor metabolizer prescribed tramadol. A similar alert fires when hydrocodone or codeine is prescribed. Bulleted text are the required elements per the ADOPT PGx Clinical Decision Support Working Group Guidelines for automated alerts. ADOPT PGx, A Depression and Opioid Pragmatic Trial in Pharmacogenetics.