Risk of Opioid Overdose Associated With Concomitant Use of Oxycodone and Selective Serotonin Reuptake Inhibitors

Abstract

Importance: Some selective serotonin reuptake inhibitors (SSRIs) inhibit the enzymes responsible for the metabolism of oxycodone, a potent prescription opioid. The clinical consequences of this interaction on the risk of opioid overdose have not been elucidated.

Objective: To compare opioid overdose rates in patients initiating oxycodone while taking SSRIs that are potent inhibitors of the cytochrome-P450 2D6 enzyme (CYP2D6) vs SSRIs that are not.

Design, setting, and participants: This cohort study included adults who initiated oxycodone while receiving SSRI therapy between 2000 and 2020 whose data were included in 3 US health insurance databases.

Exposures: Use of SSRIs that strongly inhibit CYP2D6 enzyme (fluoxetine or paroxetine) vs use of other SSRIs at the time of oxycodone initiation.

Main outcomes and measures: Opioid overdose hospitalization or emergency department visit. Outcomes were assessed within 365 days of oxycodone initiation; in primary analyses, patients were followed up until the discontinuation of either oxycodone or their index SSRI group. Propensity score matching weights were used to adjust for confounding. Crude and weighted (adjusted) incidence rates and hazard ratios were estimated using Cox regression models, separately within each database and overall, stratifying on database.

Results: A total of 2 037 490 initiated oxycodone while taking SSRIs (1 475 114 [72.4%] women; mean [SD] age, 50.1 [15.3] years). Most (1 418 712 [69.6%]) were receiving other SSRIs at the time of oxycodone initiation. In the primary analysis, we observed 1035 overdose events (0.05% of the study cohort). The adjusted incidence rate of opioid overdose in those using inhibiting SSRIs at the time of oxycodone initiation (9.47 per 1000 person-years) was higher than in those using other SSRIs (7.66 per 1000 person-years), indicating a greater risk of overdose among patients using CYP2D6-inhibiting SSRIs (adjusted hazard ratio, 1.23; 95% CI, 1.06-1.31). Results were consistent across multiple subgroup and sensitivity analyses.

Conclusions and relevance: In this cohort study of US adults, initiating oxycodone in patients treated with paroxetine or fluoxetine was associated with a small increased risk of opioid overdose.

Figure 1.. Visual Depiction of the Study Design

Individuals taking selective serotonin reuptake inhibitors (SSRIs) with no oxycodone prescription in 180 days before their first oxycodone prescription were followed up from the day of oxycodone initiation. Patients were censored at the end of insurance enrollment, end of the database-specific study period, when switching to the other SSRI exposure group, when discontinuing either oxycodone or index SSRI exposure (defined as the end of days’ supply with no subsequent refilling within 14 days), or end of 1-year follow-up, whichever comes first. Rx indicates oxycodone prescription.

Figure 2.. Cohort Selection Process

CYP2D6 indicates cytochrome-P450 2D6; MAX, Medicaid Analytic eXtract; and SSRI, selective serotonin reuptake inhibitor. ^aMedicaid patients with incomplete capture of claims, which encompasses patients with managed care plans, restricted benefits, or benefits administered through a private plan, were excluded.

Figure 3.. Association Between Concomitant Exposure to Selective Serotonin Reuptake Inhibitors and Oxycodone and Opioid Overdose Among Subgroups

The vertical blue line shows the overall measure of association in all patients. aHR indicates adjusted hazard ratio; MME, morphine milligram equivalent.