1E-03 - Opioid Overdose Associated With Concomitant Use of Hydrocodone And Selective Serotonin Reuptake Inhibitors

Background: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and various pain-related conditions, often in combination with opioids. This combination has raised concerns about increased risk of opioid overdose, however, the comparative impact of individual SSRIs on the risk of opioid overdose is unknown.

Objectives: To evaluate the comparative risk of opioid overdose among patients initiating SSRIs while concomitantly using hydrocodone.

Methods: We conducted a population-based cohort study using public and commercial health insurance claims data from the United States (US), from 2004 to 2022. The study included patients who initiated SSRIs (sertraline, citalopram, escitalopram, fluoxetine, or paroxetine) while on hydrocodone, and had at least 6 months of data prior to SSRI initiation (index date) The outcome was hospitalization or emergency department visits due to opioid overdose. Patients were assigned to a treatment group based on the SSRI initiated and followed from SSRI initiation until the occurrence of the outcome, switch to a different SSRI, discontinuation of SSRI or hydrocodone, end of insurance coverage, death, or end of the data, whichever came first (on-treatment analysis). Propensity score matching weights were used to adjust for confounders within each database and pooled to create the overall population cohort. Comparisons were performed for all possible combinations of the five SSRIs using a weighted Cox proportional hazards model, stratified by data source. Sensitivity analyses included a 60-day intention-to-treat analysis and alternative outcome definitions.

Results: We identified 1,486,137 patients (mean age: 46.9 years; 73.7% female) who initiated an SSRI while taking hydrocodone. Among them, 23.4% initiated citalopram, 20.9% escitalopram, 17.4% fluoxetine, 11.1% paroxetine, and 27.1% sertraline. In the on-treatment analysis, during a mean follow-up of 52.8 days, 1,500 outcomes were identified. Weighted incidence rates of opioid overdose ranged from 6.1 (for sertraline) to 7.9 (for fluoxetine) per 1,000 person-years across individual SSRIs. Compared to sertraline, the weighted HRs were 1.20 (95% CI, 1.02–1.42) for citalopram, 1.19 (95% CI, 1.00–1.41) for escitalopram, 1.29 (95% CI, 1.09–1.54) for fluoxetine, and 1.17 (95% CI, 0.95–1.42) for paroxetine. Comparisons between SSRIs other than sertraline showed similar risks of overdose. Results were consistent across sensitivity analyses.

Conclusions: In this cohort study using US data, initiating sertraline with hydrocodone was associated with a lower risk of opioid overdose compared to citalopram, escitalopram, paroxetine, or fluoxetine. No substantial risk differences were observed across SSRIs other than sertraline.