{"doi":"10.1001/jamanetworkopen.2025.23543","title":"<i>CYP2D6</i> Phenotypes and Emergency Department Visits Among Patients Receiving Opioid Treatment","abstract":"Importance: Cytochrome P450 2D6 (CYP2D6) bioactivates hydrocodone, tramadol, codeine, and oxycodone to active metabolites that primarily provide analgesic activity. Reduced CYP2D6 activity may be associated with poor pain control. Objective: To evaluate associations of impaired CYP2D6 activity based on genotype or CYP2D6 inhibitors, alone and together, with analgesic activity of CYP2D6-metabolized opioids among patients with pain. Design, Setting, and Participants: 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 CYP2D6-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 CYP2D6 phenotype, which was determined based on CYP2D6 genotype or CYP2D6 inhibitor-mediated phenoconversion. Statistical analysis was performed from July 1, 2023, to January 15, 2025. Exposures: CYP2D6-metabolized opioids, with or without concomitant CYP2D6 inhibitor exposure, based on prescription records and overlap with opioids. Main Outcomes and Measures: 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 CYP2D6 phenotype was assessed using inverse probability treatment weighting-adjusted logistic regression. Additional analyses were conducted by drug and isolating CYP2D6 genotype and inhibitors. Results: Among 31 669 patients (mean [SD] age, 51.2 [15.4] years; 66.5% women) prescribed CYP2D6-metabolized opioids, 15 960 had reduced CYP2D6 activity, and 15 709 had normal or high CYP2D6 activity based on genotype and inhibitors. A higher percentage of patients with reduced CYP2D6 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 CYP2D6 activity (phenotypic normal metabolizers [pNMs] and phenotypic ultrarapid metabolizers [pUMs]) (2.1% vs 1.8%; inverse probability-weighted odds ratio, 1.19; 95% CI, 1.06-1.33). There were no significant differences in ED visits among CYP2D6 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 CYP2D6 inhibitors (inverse probability-weighted 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. Conclusions and Relevance: In this cohort study, reduced CYP2D6 activity was associated with increased ED visits among individuals treated with CYP2D6-metabolized opioids. This finding suggests that incorporating data on CYP2D6 genotype and accounting for drug interactions in opioid prescribing may improve pain management and reduce ED visits.","journal":"JAMA Network Open","year":2025,"id":514836,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.961,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":635221,"name":"Caitrin W. McDonough","orcid":"0000-0001-6393-7288","position":1,"is_corresponding":false},{"id":687629,"name":"Yu‐Jung Jenny Wei","orcid":"0000-0001-8861-6907","position":2,"is_corresponding":false},{"id":388359,"name":"Yan Gong","orcid":"0000-0002-8218-1620","position":3,"is_corresponding":false},{"id":456304,"name":"Philip E. Empey","orcid":"0000-0001-7474-2339","position":4,"is_corresponding":false},{"id":1037096,"name":"Andrew Haddad","orcid":"0009-0003-4279-9367","position":5,"is_corresponding":false},{"id":301592,"name":"Roger B. Fillingim","orcid":"0000-0002-7699-8183","position":6,"is_corresponding":false},{"id":235377,"name":"Julie A. Johnson","orcid":"0000-0001-9847-1932","position":7,"is_corresponding":false},{"id":858242,"name":"Noor A. Nahid","orcid":null,"position":0,"is_corresponding":true}],"reference_count":23,"raw_metadata":null,"created_at":"2026-07-19T02:48:34.431522Z","pmid":"40720122","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}