CYP2D6 Metabolizer Phenotype and New Persistent Opioid Use After Spine Surgery

Study Design Retrospective Cohort Study. Objectives To determine whether cytochrome P450 2D6 (CYP2D6) metabolizer phenotype is associated with new persistent opioid use after cervical, thoracic, or lumbar spine surgery among opioid-naive adults. Methods Adults with whole-genome sequencing data who underwent cervical, thoracic, or lumbar fusion or decompression between May 2018 and January 1, 2025, were identified in the All of Us Research Program. Participants had 365 days of baseline observation, 180 days of postoperative follow-up, and no opioid fills from 365 to 30 days before surgery. CYP2D6 phenotype was categorized as poor, intermediate, normal, or ultrarapid metabolizer. New persistent opioid use required a perioperative opioid fill and another fill 90 to 180 days postoperatively. Associations were estimated using Firth-penalized logistic regression adjusted for ancestry principal components and clinical covariates. Results Among 3,820 participants, 460 (12.0%) developed new persistent opioid use. The overall association across CYP2D6 phenotypes was significant (χ 2 = 15.30; P = .002). Compared with normal metabolizers, adjusted odds ratios were 1.48 (95% CI, 1.00–2.18) for poor, 1.05 (95% CI, 0.85–1.30) for intermediate, and 1.50 (95% CI, 0.89–2.54) for ultrarapid metabolizers. Poor metabolizers receiving hydrocodone had higher odds of persistent use (OR, 2.15; 95% CI, 1.07–4.32). Conclusions CYP2D6 phenotype was associated with new persistent opioid use after spine surgery, with higher risk estimates at the metabolic extremes. Extreme-phenotype estimates were reportable only in European-ancestry participants, so risk in other ancestry groups remains unknown. Medication-specific replication in larger, ancestry-diverse cohorts is needed before clinical implementation.