• Yu-Jung Jenny Wei, Almut G Winterstein, Siegfried Schmidt, Roger B Fillingim, Michael J Daniels, Steven T DeKosky, and Stephan Schmidt.
• Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio (Y.-J.J.W.).
• Ann. Intern. Med. 2024 Aug 1; 177 (8): 105810681058-1068.

BackgroundLimited evidence exists on the safety of pharmacokinetic interactions of cytochrome P450 (CYP) 2D6 (CYP2D6)-metabolized opioids with antidepressants among older nursing home (NH) residents.ObjectiveTo investigate the associations of concomitant use of CYP2D6-metabolized opioids and antidepressants with clinical outcomes and opioid-related adverse events (ORAEs).DesignRetrospective cohort study using a target trial emulation framework.Setting100% Medicare NH sample linked to Minimum Data Set (MDS) from 2010 to 2021.ParticipantsLong-term residents aged 65 years and older receiving CYP2D6-metabolized opioids with a disease indication for antidepressant use.InterventionInitiating CYP2D6-inhibiting versus CYP2D6-neutral antidepressants that overlapped with use of CYP2D6-metabolized opioids for 1 day or more.MeasurementsClinical outcomes were worsening pain, physical function, and depression from baseline to quarterly MDS assessments and were analyzed using modified Poisson regression models. The ORAE outcomes included counts of pain-related hospitalizations and emergency department (ED) visits, opioid use disorder (OUD), and opioid overdose and were analyzed with negative binomial or Poisson regression models. All models were adjusted for baseline covariates via inverse probability of treatment weighting.ResultsAmong 29 435 identified residents, use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with a higher adjusted rate ratio of worsening pain (1.13 [95% CI, 1.09 to 1.17]) and higher adjusted incidence rate ratios of pain-related hospitalization (1.37 [CI, 1.19 to 1.59]), pain-related ED visit (1.49 [CI, 1.24 to 1.80]), and OUD (1.93 [CI, 1.37 to 2.73]), with no difference in physical function, depression, and opioid overdose.LimitationFindings are generalizable to NH populations only.ConclusionUse of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with worsening pain and increased risk for most assessed ORAEs among older NH residents.Primary Funding SourceNational Institute on Aging.

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