Clinical and Adverse Outcomes Associated with Concomitant Use of CYP2D6-Metabolized Opioids with Antidepressants in Older Nursing Home Residents

Limited evidence exists on the impact of pharmacokinetic interactions of cytochrome P450 (CYP)2D6-metabolized opioids with antidepressant medications among older nursing home (NH) residents. This study aimed to investigate the associations of concomitant use of CYP2D6-metabolized opioids and antidepressants with clinical outcomes and opioid-related adverse events (ORAEs). Using a 100% Medicare NH sample, we conducted a retrospective cohort study among 80,319 NH older (≥65 years) long-term (> 100 days) residents who initiated CYP2D6-metabolized opioids and antidepressants concurrently or initiated one drug class while already receiving the other. Key exposure was use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants for ≥30 days. Clinical outcomes were worsening pain, physical function, and depression from baseline to quarterly MDS assessments. ORAE outcomes included pain-related hospitalization and emergency department (ED) visit, opioid use disorder (OUD), and opioid overdose. Outcomes were measured during periods of concomitant use of opioid and antidepressant medications within 1 year after initiation of the study drug(s). We found that use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with a higher adjusted odds ratio of worsening pain (1.14; 95% CI, 1.08-1.19) and higher adjusted incidence rate ratios of pain-related hospitalization (1.39; 95% CI, 1.17-1.66]), pain-related ED visit (1.64; 95% CI, 1.28-2.10), and OUD (1.56; 95% CI, 1.28-1.89), with no difference in physical function, depression, and opioid overdose. In conclusion, use 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. Funding: R01AG073442.