Enhancing Post-Traumatic Pain Relief with Alternative Perineural Drugs

摘要

The primary objective of this proposal was to identify perineural drug combinations that enhance pain relief by producing longduration, sensory- specific nerve block with minimal toxicity. We assessed the efficacy of the adjuvants clonidine (C), buprenorphine (B), dexamethasone (D), and midazolam (M), alone and in combination with local anesthetics (LAs), in the block of peripheral nerve in vitro (Aim 1) and in vivo (Aim 2). Results of the first set of in vitro experiments indicated that M blocked C-fibers with greater potency and efficacy than A-fibers, consistent with a sensory-specific mode of action. C blocked A- and C-fibers, but only at concentrations greater than those associated with systemic side effects in vivo. D and B blocked neither C- nor A- fibers at clinically relevant concentrations. The combination of B, C and D had no influence on either LA- or Minduced nerve block. Further analysis of M effects indicated that peripheral nerve block and toxicity were due to a benzodiazepine receptor-independent increase in intracellular Ca2+. That increased axonal K+ conductance may be a viable way to increase LA potency was confirmed with several different classes of K+ channel opener in the isolated nerve preparation. Nevertheless, because the other adjuvants prolong LAinduced block in vivo, the failure to detect an influence of this drug combination on isolated nerves in vitro suggests that the drug interaction involves mechanisms extrinsic to peripheral nerve axons.