(254) Opioid overdose risk after oxycodone initiation during CYP3A4-inhibiting vs non-inhibiting calcium channel blocker therapy

Publication Number: 1244

Background: Oxycodone therapy is associated with a risk of opioid overdose. This risk may be increased by co-administering medications that inhibit the liver enzyme cytochrome P450 3A4 (CYP3A4), which is responsible for oxycodone metabolism.

Objectives: Compare opioid overdose risk in people initiating oxycodone while on CYP3A4-inhibiting calcium channel blocker (CCB) therapy (verapamil or diltiazem) vs CYP3A4 non-inhibiting CCB therapy (amlodipine).

Methods: The cohort included adults ≥18 years who newly initiated oxycodone while being treated with CYP3A4-inhibiting vs non-inhibiting CCB, identified in three United States health insurance claims databases (MarketScan, Medicare, Medicaid) from 2000-2020. The outcome of interest was defined as an emergency room visit or hospitalization for opioid overdose. Follow-up started on the day of oxycodone initiation, and ended at the time of opioid overdose, treatment discontinuation, switch of CCB group, end of insurance enrollment, day 365 of follow-up, or end of data, whichever occurred first. Propensity score (PS) matching weights (MW) were estimated within each database, and then used to balanced baseline covariates, including sociodemographics, comorbidities, prescription drug dispensings, and health services use baseline variables. Hazard ratios (HR) were estimated using Cox proportional hazards regressions. Analyses were conducted separately in each database and in pooled data with stratification by database. Sensitivity analyses included a 60-day intention-to-treat analysis, where discontinuation or switching of CCB therapy, or discontinuing oxycodone therapy, were ignored in censoring.

Results: The study cohort included 476,231 patients initiating oxycodone while on CYP3A4-inhibiting CCBs and 1587,672 patients initiating oxycodone while on CYP3A4 non-inhibiting CCB. Among those, 269 and 831 patients respectively had an opioid overdose in the pooled unweighted sample. In the pooled PS-MW weighted sample, the mean age was 61 years and 40% were female, with PS-MW weighted N=419,619.5 CYP3A4-inhibiting CCB co-exposed and 471,366.0 non-inhibiting CCB co-exposed. The opioid overdose incidence rates were 7.25 per 1,000 person-years (n=224) in the CYP3A4-inhibiting and 7.83 per 1,000 person-years (n=239) in the CYP3A4 non-inhibiting group over a median follow-up of 18 days in the weighted sample. The corresponding HR was 0.92 (95% CI: 0.79, 1.08). ITT 60-day analyses yielded similar results (HR=0.90; 95% CI: 0.78, 1.04). Results were consistent across databases.

Conclusions: We observed no clear evidence of an increased overdose risk with concomitant use of oxycodone and CYP3A4-inhibiting CCB therapy, as compared to non-inhibiting CCB therapy.