(ASPOT41) Clinical and Adverse Outcomes Associated with Concomitant Use of CYP2D6-metabolized Opioids with Antidepressants in Older Nursing Home Residents—A Retrospective Cohort Study

Background: Limited evidence exists on the safety of pharmacokinetic interactions of cytochrome P450 (CYP)2D6-metabolized opioids with antidepressants among older nursing home (NH) residents.

Objectives: To investigate the associations of concomitant use of CYP2D6-metabolized opioids and antidepressants with clinical outcomes and opioid-related adverse events (ORAEs).

Methods: This is a retrospective cohort study using a target trial emulation framework. The setting is a 100% Medicare nursing home (NH) sample linked to the Minimum Data Set (MDS) from 2010 to 2021. The study sample included long-term (>100 days) residents aged 65 years or older using CYP2D6-metabolized opioids between January 2011 and December 2021. Key exposure was initiating CYP2D6-inhibiting vs. CYP2D6-neutral antidepressants that overlapped with use of CYP2D6-metabolized opioids for ≥1 day. Cohort entry was defined as day 1 of opioid and antidepressant concomitant use. Residents were followed up from cohort entry until 1 year after baseline, Medicare disenrollment, death, NH discharge, or study end. Antidepressants that moderately or strongly inhibit CYP2D6 enzyme were classified as CYP2D6-inhibiting antidepressants; otherwise, as CYP-neutral antidepressants. Clinical outcome measures included 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. We used a separate Modified Poisson regression model to estimate a worsening clinical outcome from baseline and a Poisson or negative binomial model to estimate the incidence rate of an ORAE outcome. Analyses were adjusted for baseline covariates and censoring due to death via an inverse probability of treatment and censoring weighting.

Results: Data from 29,435 residents (mean [SD] age, 84.9 [8.9] years) were analyzed. Use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with a higher adjusted rate ratio of worsening pain (1.14; 95% confidence interval [CI], 1.10-1.18) and higher adjusted incidence rate ratios of pain-related hospitalization (1.39; 95% CI, 1.22-1.59]), pain-related ED visit (1.51; 95% CI, 1.27-1.79), and OUD (1.74; 95% CI, 1.21-2.49), with no difference in physical function, depression, and opioid overdose.

Conclusions: 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.