Integrated pharmacovigilance of fentanyl: multinational analysis reveals novel safety signals and demographic-specific risk profiles

Background This study aimed to characterize the comprehensive safety profile of fentanyl, including emerging and demographic-specific risks, by analyzing international pharmacovigilance data. Methods We conducted a retrospective analysis of fentanyl-associated adverse drug events (ADEs) from the FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report database (JADER) (2004–2025). Data integration was followed by rigorous cleaning, standardization using MedDRA v27.0, and multi-method disproportionality analysis (ROR, PRR, BCPNN, MGPS). Sensitivity analyses and time-to-onset modeling were performed to evaluate temporal risk dynamics. Results Among 76,903 reports, 396 significant signals were detected in FAERS and 95 in JADER. FAERS emphasized behavioral and device-related events (e.g., drug abuse [ROR = 31.3], administration errors [ROR = 71.08]), while JADER captured acute physiological events (e.g., respiratory depression [ROR = 57.41], neonatal respiratory failure [ROR = 212.77]). Novel signals included Kounis syndrome, application site injuries, and neonatal withdrawal. Gender disparities showed higher risks of administration errors and application site reactions in females, and misuse and overdose in males. Most events (51%) occurred within 1 month of treatment initiation. Conclusion Fentanyl’s risk profile varies significantly across regions and demographics, influenced by reporting biases and clinical use patterns. These findings advocate for global harmonization of surveillance practices and targeted risk mitigation strategies.