Sertraline is associated with a lower risk of opioid overdose compared to other selective serotonin reuptake inhibitors in patients taking hydrocodone

1. Sertraline appears to be the safest selective serotonin reuptake inhibitor (SSRI) option for patients taking hydrocodone because it is associated with a lower risk of opioid overdose than other selective serotonin reuptake inhibitors.

Evidence Rating Level: 2 (Good) 

Hydrocodone is widely prescribed for pain and is often co-prescribed with selective serotonin reuptake inhibitors (SSRIs), raising concern for pharmacokinetic and pharmacodynamic interactions that may increase overdose risk. This target-trial emulated, population-based cohort study used four United States claims databases (2004–2022) to identify 1.49 million adults receiving hydrocodone who initiated sertraline, citalopram, escitalopram, fluoxetine, or paroxetine. Opioid overdose leading to hospitalization or emergency department visit was ascertained using validated diagnosis codes. Propensity score matching weights balanced 168 baseline covariates, and weighted Cox models estimated pairwise hazard ratios in on-treatment and 60-day intention-to-treat analyses. Over a median 28-day on-treatment follow-up, 1500 overdoses occurred; weighted incidence was 6.1 per 1000 person-years for sertraline versus 7.2–7.9 for other SSRIs. Compared with sertraline, overdose risk was higher with citalopram, escitalopram, fluoxetine, and paroxetine (hazard ratios 1.17–1.29), while risks were similar across non-sertraline SSRIs. Sensitivity and subgroup analyses, including alternate overdose definitions and high-risk strata (other opioid use, substance use disorders, concomitant central nervous system depressants), were consistent with the primary findings.

Click here to read this study in BMC Medicine

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