• Sahadev A Shankarappa, Itay Sagie, Jonathan H Tsui, Homer H Chiang, Cristina Stefanescu, David Zurakowski, and Daniel S Kohane.
• Department of Anesthesiology, Perioperative and Pain Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
• Reg Anesth Pain Med. 2012 Sep 1; 37 (5): 483-9.

Background And ObjectivesQuaternary lidocaine derivatives (QLDs) have recently received much attention because of their potential application in prolonged or sensory-selective local anesthesia. However, associated tissue toxicity is an impeding factor that makes QLDs unfavorable for clinical use. Based on the proposed intracellular site of action, we hypothesized that nerve blocks obtained from lower concentrations of QLDs would be enhanced by the coapplication of extracellularly acting site 1 sodium-channel blocker, resulting in prolonged block duration but with minimal tissue toxicity.MethodsQuaternary lidocaine derivatives (QX-314 or QX-222), site 1 sodium-channel blockers (tetrodotoxin [30 μM] or saxitoxin [12.5 μM]), or both were injected in the vicinity of the sciatic nerve. Thermal nociceptive block was assessed using a modified hot plate test; motor block by a weight-bearing test. Tissue from the site of injection was harvested for histological assessment.ResultsCoapplication of 25 mM QX-314 or 100 mM QX-222 with site 1 sodium-channel blockers produced an 8- to 10- fold increase in the duration of nerve blocks (P < 0.05), compared with QLDs or site 1 blockers alone. Quaternary lidocaine derivatives elicited severe myotoxicity; this was not exacerbated by coinjection of the site 1 sodium-channel blockers.ConclusionsCoadministration of site 1 sodium-channel blockers and QLDs greatly prolongs the duration of peripheral nerve block without enhancing local tissue injury, but minimal myotoxicity still persists. It is not clear that the risks of QLDs are outweighed by the benefits in providing prolonged nerve blockade.

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