Safety of clonidine and dexmedetomidine in peripheral nerve blocks: a systematic review of preclinical evidence

Background: Perineural α2-adrenergic receptor agonists, particularly clonidine and dexmedetomidine, can be used to prolong peripheral nerve block duration. Although clinical studies suggest enhanced analgesia, concerns remain regarding their neurotoxicity or neuroprotective potential, especially in compromised nerves. We aimed to synthesise preclinical evidence on the safety of these agents. Methods: A systematic search of PubMed, CENTRAL, Embase, and Scopus was conducted up to July 13, 2025, supplemented by reference screening and large language model queries. Preclinical in vivo and in vitro studies examining perineural clonidine or dexmedetomidine were included. Outcomes assessed included indicators of neurotoxicity (e.g. apoptosis, demyelination, axonal degeneration) and neuroprotection (e.g. anti-inflammatory effects, neuronal preservation). Risk of bias was evaluated using the SYRCLE tool and narrative assessment. Results: Twenty-five studies (19 in vivo, six in vitro) were included. High-dose α2-agonists can induce direct toxicity in vitro, but no evidence of neurotoxicity has been demonstrated in vivo, even at doses exceeding those used clinically. Conversely, α2-agonists have been shown to reduce apoptosis, axonal degeneration, and inflammation compared with untreated groups, although such protective effects are observed at clinically relevant concentrations only after intraneural injection. In contrast, in models with pre-existing nerve injury, α2-agonists have been associated with exacerbated demyelination and inflammation. Conclusions: Preclinical evidence suggests that perineural α2-adrenergic receptor agonists are safe at clinically relevant doses on healthy nerves. While they probably do not offer a clinically significant neuroprotective effect at therapeutic doses (≤2 μg kg−1), they can increase neurotoxicity in compromised nerves. These data should not be directly extrapolated to clinical practice. Careful patient and dose selection and further high-quality preclinical and clinical studies are warranted.