1E-02 - Risk of Opioid Overdose Associated with Concurrent Use of Hydrocodone and CYP3A4-inhibiting Calcium Channel Blockers

Background: Non-dihydropyridine calcium channel blockers (CCB), such as diltiazem and verapamil, inhibit a key liver enzyme, cytochrome P450 3A4 (CYP3A4), involved in the metabolism of hydrocodone. The impact of this interaction on the risk of opioid overdose has not been elucidated.

Objectives: To evaluate the relative incidence of opioid overdose among patients who concomitantly use hydrocodone and CYP3A4-inhibiting CCB (diltiazem or verapamil) vs hydrocodone and amlodipine.

Methods: We conducted a population-based cohort study using three United States databases with data from 2000 to 2021. Two separate cohorts were identified: (1) patients initiating hydrocodone while on a CYP3A4-inhibiting CCB versus those initiating hydrocodone while on amlodipine (hydrocodone initiation cohort), and (2) patients initiating a CYP3A4-inhibiting CCB while on hydrocodone vs those initiating amlodipine while on hydrocodone (CCB initiation cohort). The index date was defined as the initiation date of hydrocodone or CCB, depending on the cohort. The outcome was hospitalization or emergency department visits for opioid overdose. Patients were followed from the index date until the first occurrence of the outcome, insurance disenrollment, end of available data, death, CCB switch, or discontinuation of hydrocodone or CCB. Propensity score matching weights were applied to balance confounders. Cox proportional hazards regression models, stratified by database, were used to estimate cohort-specific hazard ratios (HR) with 95% confidence intervals (CI). Results from the two cohorts were pooled using random-effects meta-analysis.

Results: The hydrocodone initiation cohort (mean age 61.2 years, 53.8% female) included 1,011,683 individuals on diltiazem/verapamil and 3,252,732 individuals on amlodipine. Weighted incidence rates (IRs) were 2.8 and 2.6 per 1,000 person-years for the diltiazem/verapamil and amlodipine groups, respectively, corresponding to a weighted HR of 1.07 (95% CI, 0.90–1.29). In the CCB initiation cohort (mean age 55.2 years, 59.9% female), 142,463 individuals initiated diltiazem/verapamil, and 538,056 initiated amlodipine while on hydrocodone. Weighted IRs were 6.5 and 6.0 per 1,000 person-years for the diltiazem/verapamil and amlodipine groups, respectively, yielding a weighted HR of 1.08 (95% CI, 0.88–1.32). Pooling effect estimates from the two cohorts yielded a weighted HR of 1.07 (95% CI, 0.94–1.23). Results were consistent across subgroup and sensitivity analyses.

Conclusions: Concomitant use of hydrocodone with CYP3A4-inhibiting CCBs did not lead to a higher incidence of opioid overdose compared with concomitant use of hydrocodone and amlodipine. The overall incidence of opioid overdose was low.