Perineural dexamethasone: neurotoxicity or neuroprotection? A systematic review of preclinical evidence

Background: Perineural dexamethasone is widely used as an adjuvant to local anesthetics in regional anesthesia to prolong analgesia. However, concerns persist regarding its potential neurotoxic effects, particularly when administered perineurally. This systematic review aims to synthesize preclinical evidence evaluating the neurotoxicity or neuroprotective properties of perineural dexamethasone. Methods: A systematic search of PubMed, CENTRAL, Scopus, and Embase was conducted through May 22, 2025. Eligible studies included in vivo or in vitro preclinical models assessing the neurotoxic or neuroprotective effects of perineural dexamethasone compared to control conditions. Risk of bias was assessed using the SYRCLE tool for in vivo studies and a narrative evaluation for in vitro studies. A total of 14 studies (11 in vivo, 3 in vitro) met inclusion criteria. Results: In vitro studies showed that dexamethasone alone was not neurotoxic at clinically relevant doses but could enhance cytotoxicity when combined with local anesthetics at higher concentrations. In vivo models generally demonstrated no significant long-term nerve inflammation, degeneration or demyelination, with some early protective effects observed in perineural dexamethasone groups. However, all in vivo studies were rated at high risk of bias. In nerve injury models, dexamethasone reduced apoptotic and inflammatory markers when administered immediately post-injury, with limited effect when delayed. Conclusions: Preclinical evidence supports the general safety of low-dose, preservative-free perineural dexamethasone. Nonetheless, high-dose use, additives, and application in patients with neuropathies may pose risks. Given the high risk of bias in existing studies and minimal added benefit over systemic administration, clinical caution is advised.