Serotonin syndrome risk with concomitant opioid and serotonergic antidepressant use: a multinational pharmacovigilance study

Background: The concurrent use of serotonergic antidepressants (SSRIs, SNRIs) and opioid analgesics is frequent in the perioperative setting. While this combination carries a known risk of serotonin syndrome, large-scale epidemiological evidence remains scarce. Methods: We performed a multinational pharmacovigilance study using data from the US FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report database (JADER) from Q1 2004 to Q2 2025. Disproportionality analyses, including Reporting Odds Ratio (ROR) with a multi-algorithm framework, were employed to quantify signals for serotonin syndrome and other adverse events. We further characterized clinical profiles and conducted gender-stratified and time-to-onset analyses. Results: Opioids (e.g., tramadol, fentanyl, oxycodone) were consistently among the top drugs associated with serotonin syndrome reports. Concomitant SSRI/SNRI-opioid use showed exceptionally strong signals for serotonin syndrome (SSRI-opioid ROR 95.94, 95% CI 88.9-103.53; SNRI-opioid ROR 57.68, 95% CI 52.32-63.59). SSRI-opioid combinations were uniquely associated with cardiac disorders (ROR 1.87, 95% CI 1.77-1.98), whereas SNRI-opioid use was linked to drug withdrawal syndrome. Gender-stratified analysis indicated a higher reporting proportion for serotonin syndrome in males prescribed SSRI-opioids. Notably, up to 30% of adverse events occurred more than 300 days after therapy initiation, indicating a persistent risk. Conclusion: This study provides robust multinational evidence that concomitant serotonergic antidepressant and opioid use is strongly associated with a high risk of serotonin syndrome and distinct adverse event profiles. These findings highlight the urgent need for systematic preoperative medication review, tailored perioperative monitoring, and sustained clinical vigilance.