Use of CYP2D6 Inhibitors with CYP2D6 Opioids: Association with Emergency Department Visits for Pain

Hydrocodone, tramadol, codeine, and oxycodone are commonly prescribed opioids that rely on activation by cytochrome P450 2D6 (CYP2D6). CYP2D6 inhibitors can significantly decrease CYP2D6 activity, leading to reduced generation of active metabolites, and impairing pain control. To understand this impact, we assessed emergency department (ED) visits in patients initiating these CYP2D6-dependent opioids while on CYP2D6-inhibitor antidepressants vs. antidepressants that do not inhibit CYP2D6. This retrospective cohort study included adult patients prescribed CYP2D6-dependent opioids utilizing electronic health records data from the University of Florida Health (2015-2021). The association between ED visits and inhibitor exposure was tested using multivariable logistic regression. The primary analysis had 12,118 patients (72% female; mean (SD) age, 55 (13.4)) in the hydrocodone/tramadol/codeine cohort and 5,547 patients (64% female; mean (SD) age, 53.6 (14.2)) in the oxycodone cohort. Hydrocodone/tramadol/codeine-treated patients exposed to CYP2D6-inhibitor antidepressants (n = 7,043) had a higher crude rate of pain-related ED visits than those taking other antidepressants (n = 5,075) (3.28% vs. 1.87%), with an adjusted odds ratio (aOR) of 1.75 (95% CI: 1.36 to 2.24). Similarly, in the oxycodone cohort, CYP2D6-inhibitor antidepressant-exposed individuals (n = 3,206) had a higher crude rate of ED visits than individuals exposed to other antidepressants (n = 2,341) (5.02% vs. 3.37%), with aOR of 1.70 (95% CI: 1.27-2.27). Similar findings were observed in secondary and sensitivity analyses. Our findings suggest patients with concomitant use of hydrocodone/tramadol/codeine or oxycodone and CYP2D6 inhibitors have more frequent ED visits for pain, which may be due to inadequate pain control.