{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T01:44:54Z","timestamp":1792633494874,"version":"4.5.0"},"reference-count":27,"publisher":"American Medical Association (AMA)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n \n Cytochrome P450 2D6 (\n CYP2D6<\/jats:italic>\n ) bioactivates hydrocodone, tramadol, codeine, and oxycodone to active metabolites that primarily provide analgesic activity. Reduced\n CYP2D6<\/jats:italic>\n activity may be associated with poor pain control.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To evaluate associations of impaired\n CYP2D6<\/jats:italic>\n activity based on genotype or\n CYP2D6<\/jats:italic>\n inhibitors, alone and together, with analgesic activity of\n CYP2D6<\/jats:italic>\n -metabolized opioids among patients with pain.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n This retrospective national, community-based cohort study used electronic health records and genetics data from the All of Us Research Program. Participants included adults prescribed at least 1\n CYP2D6<\/jats:italic>\n -metabolized opioid for more than 7 days between January 1, 2014, and December 31, 2022, with whole-genome sequencing data available. Analysis groups were defined by\n CYP2D6<\/jats:italic>\n phenotype, which was determined based on\n CYP2D6<\/jats:italic>\n genotype or\n CYP2D6<\/jats:italic>\n inhibitor\u2013mediated phenoconversion. Statistical analysis was performed from July 1, 2023, to January 15, 2025.\n <\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n \n CYP2D6<\/jats:italic>\n -metabolized opioids, with or without concomitant\n CYP2D6<\/jats:italic>\n inhibitor exposure, based on prescription records and overlap with opioids.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n The primary outcome was occurrence of any pain-related emergency department (ED) visits during opioid treatment, up to 60 days after opioid initiation. The association between ED visits and\n CYP2D6<\/jats:italic>\n phenotype was assessed using inverse probability treatment weighting\u2013adjusted logistic regression. Additional analyses were conducted by drug and isolating\n CYP2D6<\/jats:italic>\n genotype and inhibitors.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 31\u202f669 patients (mean [SD] age, 51.2 [15.4] years; 66.5% women) prescribed\n CYP2D6<\/jats:italic>\n -metabolized opioids, 15\u202f960 had reduced\n CYP2D6<\/jats:italic>\n activity, and 15\u202f709 had normal or high\n CYP2D6<\/jats:italic>\n activity based on genotype and inhibitors. A higher percentage of patients with reduced\n CYP2D6<\/jats:italic>\n activity (hereafter referred to as phenotypic intermediate metabolizers [pIMs] or phenotypic poor metabolizers [pPMs]) had experienced pain-related ED visits compared with patients with normal or high\n CYP2D6<\/jats:italic>\n activity (phenotypic normal metabolizers [pNMs] and phenotypic ultrarapid metabolizers [pUMs]) (2.1% vs 1.8%; inverse probability\u2013weighted odds ratio, 1.19; 95% CI, 1.06-1.33). There were no significant differences in ED visits among\n CYP2D6<\/jats:italic>\n genotypic IMs or PMs vs NMs or UMs when testing all 4 drugs together. Among genotypic NMs, ED visits were more frequent among the individuals prescribed\n CYP2D6<\/jats:italic>\n inhibitors (inverse probability\u2013weighted odds ratio, 1.49; 95% CI, 1.32-1.68). In analyses by medication, drug interactions were important for all 4 medications, while genotype associations were significant only for hydrocodone, tramadol, and codeine.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n In this cohort study, reduced\n CYP2D6<\/jats:italic>\n activity was associated with increased ED visits among individuals treated with\n CYP2D6<\/jats:italic>\n -metabolized opioids. This finding suggests that incorporating data on\n CYP2D6<\/jats:italic>\n genotype and accounting for drug interactions in opioid prescribing may improve pain management and reduce ED visits.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.23543","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T15:00:17Z","timestamp":1753714817000},"page":"e2523543","source":"Crossref","is-referenced-by-count":18,"title":["CYP2D6<\/i>\n Phenotypes and Emergency Department Visits Among Patients Receiving Opioid Treatment"],"prefix":"10.1001","volume":"8","author":[{"given":"Noor A.","family":"Nahid","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville"},{"name":"Center for Pharmacogenomics and Precision Medicine, University of Florida College of Pharmacy, Gainesville"},{"name":"Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitrin W.","family":"McDonough","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville"},{"name":"Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Jung Jenny","family":"Wei","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville"},{"name":"Center for Pharmacogenomics and Precision Medicine, University of Florida College of Pharmacy, Gainesville"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip E.","family":"Empey","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Haddad","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger B.","family":"Fillingim","sequence":"additional","affiliation":[{"name":"Department of Community Dentistry and Behavioral Science, University of Florida, Gainesville"},{"name":"Pain Research and Intervention Center of Excellence, University of Florida, Gainesville"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville"},{"name":"Pain Research and Intervention Center of Excellence, University of Florida, Gainesville"},{"name":"Clinical and Translational Science Institute, The Ohio State University, Columbus"},{"name":"Department of Internal Medicine, The Ohio State University College of Medicine, Columbus"},{"name":"Department of Pharmaceutics & Pharmacology, The Ohio State University College of Pharmacy, Columbus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"issue":"4","key":"zoi250679r1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.1532","article-title":"The cost of pain.","volume":"2","author":"Smith","year":"2019","journal-title":"JAMA Netw 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