CYP2D6 phenotype and post-surgical pain control with hydrocodone and oxycodone

Background Hydrocodone and oxycodone are widely used for acute postoperative pain and are metabolized by CYP2D6 to more potent agonists. The clinical impact of CYP2D6 metabolizer status on hydrocodone and oxycodone analgesic response remains uncertain. This secondary analysis of A Depression and Opioid Pragmatic Trial in Pharmacogenetics (ADOPT PGx) evaluated associations between CYP2D6 phenotype and postoperative pain and opioid consumption among patients taking hydrocodone or oxycodone. Methods This analysis included participants from the ADOPT PGx Acute Pain Trial (NCT05966129). Among patients who consumed hydrocodone or oxycodone postoperatively, analyses were conducted separately by drug, comparing outcomes between poor (PM) vs. normal (NM) and intermediate (IM) vs. normal CYP2D6 metabolizers, with phenotypes predicted by genotype and concomitant CYP2D6 inhibitor use. A positive control analysis was performed among tramadol users. Outcomes were cumulative opioid use (morphine milligram equivalents) and composite Patient-Reported Outcomes Measurement Information System® pain intensity scores at 10 days post-surgery. Regression models adjusted for demographics, surgery type, trial site, and non-opioid analgesic use; P -values were corrected for multiple comparisons. Results The cohort primarily underwent orthopedic procedures and concomitant non-opioid analgesic use was common across hydrocodone, oxycodone, and tramadol cohorts, with 88%–100% of patients receiving at least one non-opioid analgesic or nerve block. Among hydrocodone users, predicted CYP2D6 phenotype was not associated with postoperative hydrocodone consumption (PM vs. NM: mean ratio [MR] = 1.12, 95% CI 0.92–1.36, P = 0.262) or pain intensity (PM vs. NM: odds ratio [OR] = 1.13, 95% CI 0.66–1.92, P = 0.668). Among oxycodone users, CYP2D6 phenotype was not associated with postoperative oxycodone consumption (PM vs. NM: MR = 1.02, 95% CI 0.79–1.34, P = 0.880) or pain intensity (PM vs. NM: OR = 0.84, 95% CI 0.47–1.51, P = 0.568). Similarly, in the positive control tramadol cohort, CYP2D6 phenotype was not associated with tramadol consumption (PM vs. NM: MR = 1.02, 95% CI 0.79–1.32, P = 0.847) or pain intensity (PM vs. NM: OR = 1.43, 95% CI 0.66–3.00, P = 0.668). Conclusion Predicted CYP2D6 metabolizer status was not associated with postoperative pain control or opioid use in patients taking hydrocodone, oxycodone, or positive-control tramadol, suggesting that multimodal analgesic use may have weakened pharmacogenetic effects. These findings suggest that CYP2D6 phenotype associations with hydrocodone or oxycodone analgesic response, if present, are attenuated in multimodal postoperative pain management.