Safety profile of fentanyl with different routes of administration: a disproportionality analysis using the EudraVigilance database

Abstract Fentanyl is associated with significant respiratory, cardiovascular, and neurological adverse events (AEs). This study aimed to describe the safety of fentanyl administered through different routes of administration, with a focus on brain lesions. Safety data related to fentanyl were extracted from the EudraVigilance database up to March 7, 2024. Descriptive and disproportionality analyses were performed. A total of 6,441 cases were classifiable for the administration route. The transdermal route (80.9%) was the most reported route. Most cases were from adults and females. Overall, 92.8% of AEs were serious. The intravenous route had a higher disproportionate reporting of “nervous system disorders” than transdermal (ROR 1.31; 95% CI, 1.12–1.41) and oral transmucosal (1.30; 1.12–1.49). Among central nervous system disorders, 50 brain lesions were identified, with no statistically significant difference observed. Nasal administration had a higher reporting frequency of “central nervous system vascular disorders” compared to transdermal (2.45; 1.14–5.24), intravenous (2.53; 1.09–5.87), and oral transmucosal routes (4.89; 1.54–15.51). On the other hand, the intravenous had a higher disproportionate reporting of “seizures” compared to nasal (3.19; 1.17–8.69), oral transmucosal (2.09; 1.31–3.32), and transdermal routes (2.41; 1.96–2.96). The study provides a comprehensive safety profile of fentanyl across different administration routes, highlighting a higher disproportionate reporting of central neurologic and cardiovascular AEs with nasal and intravenous routes.