Duration of Concurrent Oxycodone and Selective Serotonin Reuptake Inhibitors Use and the Risk of Opioid Overdose

Concurrent use of oxycodone and strong cytochrome P450 2D6 (CYP2D6)-inhibiting selective serotonin reuptake inhibitors (SSRIs), specifically paroxetine and fluoxetine, is associated with the risk of opioid overdose.

This study assessed the association between the duration of concurrent oxycodone and CYP2D6-inhibiting SSRI use and overdose risk.

A retrospective cohort study conducted using the Merative MarketScan claims database from January 1, 2017, to December 31, 2019. Adults aged ≥18 years with private insurance who initiated both oxycodone and SSRIs were included. Patients were grouped as (1) oxycodone with other SSRIs (reference); (2) oxycodone with paroxetine or fluoxetine with <14 days of overlap; and (3) oxycodone with paroxetine or fluoxetine with ≥14 days of overlap. The primary outcome was opioid overdose. Cox proportional hazards models estimated adjusted hazard ratios (HRs), adjusting for demographics, comorbidities, and prior medication use.

A total of 97 446 patients met inclusion criteria (mean age 46.4 years; 73.6% female). Among these, 26 967 (27.7%) used oxycodone with CYP2D6-inhibiting SSRIs; 86% of them had <14 days of overlapping therapy. The risk of overdose increased with longer durations of overlapping oxycodone and CYP2D6-inhibiting SSRI use. Compared with patients using other SSRIs, the adjusted HR for opioid overdose was 0.98 (95% CI, 0.65-1.01) for <14 days of concurrent use, and 1.24 (95% CI, 1.03-1.50) for ≥14 days.

Prolonged concurrent use (≥14 days) of oxycodone with paroxetine or fluoxetine was associated with an increased risk of opioid overdose compared with use with other SSRIs.