Ann Pharmacother

CYP2D6-inhibiting SSRIs linked to increased risk of opioid overdose with oxycodone

October 17, 2025

Study details: This retrospective cohort study analyzed U.S. insurance claims (MarketScan, 2017–2019) for 97,446 adults (mean age, 46.4 years; 73.6% female) who initiated both oxycodone and an SSRI. Patients were grouped by SSRI type and duration of overlap: (1) oxycodone with other SSRIs (reference), (2) oxycodone with paroxetine/fluoxetine for <14 days, and (3) oxycodone with paroxetine/fluoxetine for ≥14 days. Primary outcome was opioid overdose, assessed using adjusted Cox proportional hazards models.

Results: Prolonged concurrent use (≥14 days) of oxycodone with paroxetine or fluoxetine was associated with a significantly increased risk of opioid overdose (adjusted hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.03–1.50) compared with other SSRIs. Shorter overlap (<14 days) didn’t increase risk (HR, 0.98; 95% CI, 0.65–1.01). Most patients (86%) had <14 days of overlap.

Clinical impact: Clinicians should be cautious when prescribing oxycodone with CYP2D6-inhibiting SSRIs (paroxetine, fluoxetine) for durations ≥14 days, as this combination may increase overdose risk. Consider alternative SSRIs or minimizing overlap duration to mitigate this risk.

Source:

Okeke C, et al. (2025, October 8). Ann Pharmacother. Duration of Concurrent Oxycodone and Selective Serotonin Reuptake Inhibitors Use and the Risk of Opioid Overdose. https://pubmed.ncbi.nlm.nih.gov/41063462/