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.
Keywords: Adverse events; Disproportionality analysis; Fentanyl; Opioid; Pain; Pharmacovigilance; Safety.
© 2026. The Author(s).