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We performed high\u2010throughput screening for clinically relevant DDIs with methadone or buprenorphine by combining pharmacoepidemiologic and pharmacokinetic approaches. We conducted pharmacoepidemiologic screening via a series of self\u2010controlled case series studies (SCCS) in Optum claims data from 2000 to 2019. We included persons 18\u2009years or older who experienced an outcome of interest during target drug treatment. Exposures were all overlapping medications (i.e., the candidate precipitants) during target drug treatment. Outcomes were opioid overdose, non\u2010overdose adverse effects, and cardiac arrest. We used conditional Poisson regression to calculate rate ratios, accounting for multiple comparisons with semi\u2010Bayes shrinkage. We explored the impact of key study design choices in analyses that varied the exposure definitions of the target drugs and the candidate precipitant drugs. Pharmacokinetic screening was conducted by incorporating published data on CYP enzyme metabolism into an equation\u2010based static model. In SCCS analysis, 1,432 events were included from 248,069 new users of methadone or buprenorphine. In the primary analysis, statistically significant DDIs included gabapentinoids with either methadone or buprenorphine; baclofen with methadone; and benzodiazepines with methadone. In sensitivity analysis, additional statistically significant DDIs included methocarbamol, quetiapine, or simvastatin with methadone. Pharmacokinetic screening identified two moderate\u2010to\u2010strong potential DDIs (clonidine and fluconazole with buprenorphine). The combination of clonidine and buprenorphine was also associated with a significantly increased risk of opioid overdose in pharmacoepidemiologic screening. These DDI signals may be the most important targets for future confirmation studies.<\/jats:p>","DOI":"10.1002\/cpt.2717","type":"journal-article","created":{"date-parts":[[2022,7,26]],"date-time":"2022-07-26T20:44:53Z","timestamp":1658868293000},"page":"1120-1129","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Identifying Clinically Relevant Drug\u2013Drug Interactions With Methadone and Buprenorphine: A Translational Approach to Signal Detection"],"prefix":"10.1111","volume":"112","author":[{"given":"Todd A.","family":"Miano","sequence":"first","affiliation":[{"name":"Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania 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M.","family":"Brensinger","sequence":"additional","affiliation":[{"name":"Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5150-5995","authenticated-orcid":false,"given":"Emily K.","family":"Acton","sequence":"additional","affiliation":[{"name":"Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania 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Informatics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Psychiatry, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha E.","family":"Soprano","sequence":"additional","affiliation":[{"name":"Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3589-764X","authenticated-orcid":false,"given":"Thanh Phuong Pham","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Translational Center of Excellence for Neuroepidemiology and Neurology Outcomes Research, Department of Neurology, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Woody","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elmer","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Neuman","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care, Perelman School of 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Pharmacology and Translational Therapeutics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,20]]},"reference":[{"key":"e_1_2_10_1_1","unstructured":"The ASAM National Practice Guideline for the Treatment of Opioid Use Disorder \u2013 2020.Focused Update<https:\/\/www.asam.org\/Quality\u2010Science\/quality\/2020\u2010national\u2010practice\u2010guideline>. 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