Background and Objectives: Clonidine, buprenorphine, dexamethasone, and midazolam (C, B, D, M) have been used to prolong perineural local anesthesia in the absence of data on the influence of these adjuvants on local anesthetic-induced neurotoxicity. Therefore, the impact of these adjuvants on ropivacaine (R)-induced death of isolated sensory neurons was assessed.
Methods: The trypan blue exclusion assay was used to assess death of sensory neurons isolated from adult male Sprague-Dawley rats. Drugs were applied, alone or in combination, for 2 or 24 hrs at 37°C.
Results: Neuronal viability was halved by 24-hr exposure to R (2.5 mg/mL), far exceeding the neurotoxicity of C, B, D, or M (at 2-100 times estimated clinical concentrations). Plain M at twice the estimated clinical concentration produced a small but significant increase in neurotoxicity at 24 hrs. After 2-hr exposure, high concentrations of B, C, and M increased the neurotoxicity of R; the combination of R + M killed more than 90% of neurons. Estimated clinical concentrations of C + B (plus 66 μg/mL D) had no influence on (i) R-induced neurotoxicity, (ii) the increased neurotoxicity associated with the combination of R + M, or (iii) the neurotoxicity associated with estimated clinical concentrations of M. There was increased neurotoxicity with 133 μg/mL D combined with R + C + B.
Conclusions: Results with R reaffirm the need to identify ways to mitigate local anesthetic-induced neurotoxicity. While having no protective effect on R-induced neurotoxicity in vitro, future research with adjuvants should address if the C + B + D combination can enable reducing R concentrations needed to achieve equianalgesia (and/or provide equal or superior duration, in preclinical in vivo models).
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This research is supported by National Institutes of Health grants DA025146, RR024153 (to B.A.W.), T32GM075770 (to J.W.I.), and NS063010 (to M.S.G.), as well as a special grant from the Office of the Senior Vice Chancellor for the Health Sciences, University of Pittsburgh. Dr. Williams received consulting fees from B.Braun USA (2010); B.Braun USA was not involved with the design or conduct of this study, and this article or its contents have not been made available to B.Braun USA before publication.
Exploratory data described herein were presented (abstract A-287) at the 2010 Annual Meeting of the American Society of Anesthesiologists, San Diego, CA.