{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T17:54:57Z","timestamp":1784310897837,"version":"3.55.0"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG073442"],"award-info":[{"award-number":["R01AG073442"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>The safety of pharmacokinetic opioid-antidepressant interactions may be affected by the sequence in which the drug is initiated. Previous literature showed that initiation of cytochrome P450 (CYP) 2D6-inhibiting versus CYP2D6-neutral antidepressants concomitantly with existing CYP2D6-metabolized opioids (i.e., antidepressant-triggered interaction) was associated with heightened risks of adverse outcomes (e.g., worsening pain). However, little is known about whether and to what extent the risks exist when CYP2D6-metabolized opioids are initiated on existing antidepressants (i.e., opioid-triggered interaction), a more common pattern of concomitant use of these two drugs. The study aims to examine the association of initiation of CYP2D6-metabolized opioids with risks of adverse outcomes among older nursing home residents who already received antidepressants.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and findings<\/jats:title>\n<jats:p>We conducted a retrospective cohort study using a 100% Medicare nursing home sample linked to Medicare claims and Minimum Data Set (MDS) assessments from January 1, 2010, to December 31, 2021. Participants included long-term care residents 65 years of age or older who initiated CYP2D6-metabolized opioids while already receiving antidepressants for at least 30 days. The key exposure was the use of CYP2D6-inhibiting (versus CYP2D6-neutral) antidepressants concomitantly with CYP2D6-metabolized opioids, with day 1 of antidepressant-opioid concomitant use designated as cohort entry. Patients were followed from cohort entry until the end of 1 year, nursing home discharge, death, or study end (12\/31\/2021). Seven adverse outcomes included worsening pain, physical function, and depression, and counts of pain-related hospitalizations and emergency department (ED) visits, opioid use disorder (OUD), and opioid overdose (OD). We identified 127,200 older nursing home long-term residents who initiated CYP2D6-metabolized opioids while already receiving antidepressants (mean [SD] age, 84.4 [8.7] years). After covariate adjustment via inverse probability of treatment weighting, use of CYP2D6-inhibiting (versus CYP2D6-neutral) antidepressants concomitantly with CYP2D6-metabolized opioids was associated with a higher risk of worsening pain (relative risk:1.04 [95% CI, 1.02, 1.06]; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001; risk difference (RD): 1.1% [95% CI, 0.6%, 1.6%]) and a higher incidence rate of pain-related hospitalizations (incidence rate ratio [IRR]:1.13 [95% CI, 1.04, 1.22]; <jats:italic>P<\/jats:italic>\u2009=\u20090.003; RD: 1.21 [95% CI, 0.39, 1.89] per 1,000 patient-years) and pain-related ED visits (IRR\u2009=\u20091.17 [95% CI, 1.07, 1.29]; <jats:italic>P<\/jats:italic>\u2009=\u20090.003; RD: 0.85 [95% CI, 0.29, 1.41] per 1,000 patient-years), with no difference in physical function, depression, OUD, and OD. Main study limitations included unmeasured confounding and limited generalizability.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>This cohort study of older nursing home residents showed that initiation of CYP2D6-metabolized opioids on existing CYP2D6-inhibiting (versus CYP2D6-neutral) antidepressants was associated with increased risk of worsening pain, pain-related hospitalizations, and pain-related ED visits, although the relative and absolute risks are small to moderate. Clinicians should be aware of potential worsening pain and hospital and ED visits due to pain among patients who used CYP2D6-metabolizing opioids concomitantly with antidepressants, particularly those with CYP2D6-inhibiting antidepressants.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pmed.1004620","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T17:40:42Z","timestamp":1748886042000},"page":"e1004620","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Association of initiating CYP2D6-metabolized opioids with risks of adverse outcomes in older adults receiving antidepressants: A retrospective cohort study"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8861-6907","authenticated-orcid":true,"given":"Yu-Jung 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