Association of initiating CYP2D6-metabolized opioids with risks of adverse outcomes in older adults receiving antidepressants: A retrospective cohort study

Background: 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. Methods and findings: 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]; P