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Neurotoxicity of Adjuvants Used in Perineural Anesthesia and Analgesia in Comparison With Ropivacaine
  1. Brian A. Williams, MD, MBA*,,,
  2. Karen A. Hough, AS, CVT, RLAT*,,
  3. Becky Y. K. Tsui, MPH*,
  4. James W. Ibinson, MD, PhD*,,,
  5. Michael S. Gold, PhD*, and
  6. G. F. Gebhart, PhD*,
  1. From the *University of Pittsburgh School of Medicine Department of Anesthesiology and
  2. Center for Pain Research, and
  3. VA Pittsburgh Health System, Pittsburgh, PA.
  1. Address correspondence to: Brian A. Williams, MD, MBA, W-1403 BST-WR, Department of Anesthesiology, Center for Pain Research, University of Pittsburgh, Pittsburgh, PA 15261 (e-mail: williamsba{at}


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.