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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 \u201cnervous system disorders\u201d than transdermal (ROR 1.31; [95% CI, 1.12\u20131.41]) and oral transmucosal (1.30; [1.12\u20131.49]). Among central nervous system disorders, 50 brain lesions were identified, with no statistically significant difference observed. Nasal administration had a higher reporting frequency of \u201ccentral nervous system vascular disorders\u201d compared to transdermal (2.45; [1.14\u20135.24]), intravenous (2.53; [1.09\u20135.87]), and oral transmucosal routes (4.89; [1.54\u201315.51]). On the other hand, the intravenous had a higher disproportionate reporting of \u201cseizures\u201d compared to nasal (3.19; [1.17\u20138.69]), oral transmucosal (2.09; [1.31\u20133.32]), and transdermal routes (2.41; [1.96\u20132.96]). 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.<\/jats:p>","DOI":"10.1007\/s00210-026-05145-8","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T01:34:12Z","timestamp":1772156052000},"page":"11923-11937","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Safety profile of fentanyl with different routes of administration: a disproportionality analysis using the EudraVigilance database"],"prefix":"10.1007","volume":"399","author":[{"given":"Raffaella","family":"Di Napoli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Mascolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nunzia","family":"Balzano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Zinzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Maddalena","family":"Nicoletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Capuano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Gargano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"5145_CR1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/J.BJAN.2013.07.005","volume":"65","author":"YC Abut","year":"2015","unstructured":"Abut YC, Turkmen AZ, Midi A et al (2015) Neurotoxic effects of levobupivacaine and fentanyl on rat spinal cord. 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