Risk of Opioid Overdose Associated with Concurrent Use of Hydrocodone and CYP3A4-inhibiting Calcium Channel Blockers: A Population-based Cohort Study

Non-dihydropyridine calcium channel blockers (CCBs), including diltiazem and verapamil, inhibit cytochrome P450 3A4 (CYP3A4), an enzyme involved in the metabolism of hydrocodone, the most commonly used opioid in the United States (US). This study evaluated whether concomitant use of hydrocodone with CYP3A4-inhibiting CCBs increases the risk of opioid overdose compared to use of hydrocodone with amlodipine, a CCB that does not inhibit CYP3A4. Using three US databases (2000–2021), two cohorts were identified: (1) hydrocodone initiation while on CCB; and (2) CCB initiation while on hydrocodone. The outcome was hospitalization or emergency department visits for opioid overdose. Propensity score matching weights were applied to balance confounders, and Cox regression estimated hazard ratios (HRs), pooled using random-effects meta-analysis. In hydrocodone initiation cohort (mean age 61.2 years; 53.8% female), weighted incidence rates were 2.8 and 2.6 per 1,000 person-years, with a weighted HR of 1.07 (95% CI, 0.90–1.29). In CCB initiation cohort (mean age 55.2 years; 59.9% female), weighted incidence rates were 6.5 and 6.0, yielding an HR of 1.08 (95% CI, 0.88–1.32). The pooled HR was 1.07 (95% CI, 0.94–1.23). Concomitant use of hydrocodone with CYP3A4-inhibiting CCBs was not associated with an increased risk of opioid overdose relative to amlodipine.