Multicenter study of OPRM1 A118G and promoter-region DNA methylation associations with opioid outcomes and chronic postsurgical pain after pediatric musculoskeletal surgery
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<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Introduction:</jats:title> <jats:p>Mu opioid receptor gene (<jats:italic toggle="yes">OPRM1</jats:italic>) variant rs1799971 introduces a CpG site, which may influence DNA methylation (DNAm) and opioid/pain outcomes.</jats:p> </jats:sec> <jats:sec> <jats:title>Objectives:</jats:title> <jats:p>In this nested analysis, we investigated both <jats:italic toggle="yes">OPRM1</jats:italic> A118G genotype and promoter/immediate downstream blood DNAm sequencing data for associations with opioid effects and chronic postsurgical pain (CPSP) in a surgical cohort.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>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; <jats:italic toggle="yes">P</jats:italic> = 0.03), Chr6:154039661-154039662 with acute integrated pain (β = −20.9, 95% CI, −40.70 to −1.10, <jats:italic toggle="yes">P</jats:italic> = 0.04), Chr6:154039520-154039521 (OR, 1.49; 95% CI, 1.09-2.03; <jats:italic toggle="yes">P</jats:italic> = 0.01), and Chr6:154039571-154039572 (OR, 1.47; 95% CI, 1.08-2.01; <jats:italic toggle="yes">P</jats:italic> = 0.02) with RD. Significant CpG sites were located in Repressed Polycomb chromatin states. Genotype was not associated with DNAm or outcomes.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>Our analyses support <jats:italic toggle="yes">OPRM1</jats:italic> 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.</jats:p> </jats:sec>
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Upton, BA, KN Krolick, X Zhang, V Pilipenko, LJ Martin, H Ji, S Glynn, K Barnett, et al. (n.d.). Multicenter study of OPRM1 A118G and promoter-region DNA methylation associations with opioid outcomes and chronic postsurgical pain after pediatric musculoskeletal surgery. PAIN Reports, 9. pp. e1201–e1201. 10.1097/pr9.0000000000001201 Retrieved from https://hdl.handle.net/10161/31585.
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Lisa Einhorn
Through my clinical expertise as a pediatric anesthesiologist and pain specialist, I am reminded every day of the challenges our pediatric patients and their families experience when undergoing a surgical procedure. Acute pain management in pediatrics is associated with numerous age-specific complexities, and unfortunately, many interventions that are easily accessible in adults remain out of reach for children due to lack of clinical knowledge and missing pharmacologic data. My research is focused on developing and analyzing innovative approaches to improve functional outcomes after pediatric surgery through interventional and observational clinical trials. As a physician-scientist, my goal is to advance our understanding of existing and novel analgesics to provide safe, effective, and personalized perioperative pain management in children and adolescents.
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