Multicenter study of OPRM1 A118G and promoter-region DNA methylation associations with opioid outcomes and chronic postsurgical pain after pediatric musculoskeletal surgery

Abstract Introduction: Mu opioid receptor gene ( OPRM1 ) variant rs1799971 introduces a CpG site, which may influence DNA methylation (DNAm) and opioid/pain outcomes. Objectives: In this nested analysis, we investigated both OPRM1 A118G genotype and promoter/immediate downstream blood DNAm sequencing data for associations with opioid effects and chronic postsurgical pain (CPSP) in a surgical cohort. Methods: Prospectively recruited opioid naïve patients undergoing Nuss procedure or spinal fusion with rs1799971 genotypes (Illumina arrays), DNAm (next generation enzymatic methylation sequencing at Chr6:154,039,209-154,039,803) and outcomes—opioid analgesia (integrated opioid use + pain over postoperative days 0 and 1 normalized to surgery type), safety—respiratory depression (RD) in high opioid use groups, and CPSP (Numerical Rating Scale >3/10 2-12 months postsurgery)—were included. Linear and logistic regression were performed to test genetic and epigenetic associations, adjusted for sociodemographics, cell types, and analgesics. Results: In this cohort (N = 112; 15.3 ± 2.0 years, 50% female, 83% White, 55% had CPSP, 13% had RD), DNAm at Chr6:154039216-154039217 was associated with CPSP (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.00-1.57; P = 0.03), Chr6:154039661-154039662 with acute integrated pain (β = −20.9, 95% CI, −40.70 to −1.10, P = 0.04), Chr6:154039520-154039521 (OR, 1.49; 95% CI, 1.09-2.03; P = 0.01), and Chr6:154039571-154039572 (OR, 1.47; 95% CI, 1.08-2.01; P = 0.02) with RD. Significant CpG sites were located in Repressed Polycomb chromatin states. Genotype was not associated with DNAm or outcomes. Conclusion: Our analyses support OPRM1 DNAm as predictors of acute and chronic pain/opioid outcomes in children after painful surgery. Study limitations included absent GG genotype, low sequencing coverage, and lack of correction for multiple testing.