Duration and local toxicity of sciatic nerve blockade with coinjected site 1 sodium-channel blockers and quaternary lidocaine derivatives.
OBJECTIVE
Quaternary 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.


METHODS
Quaternary 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.


RESULTS
Coapplication 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.


CONCLUSIONS
Coadministration 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.
Department of Anesthesiology, Perioperative and Pain Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
Sahadev A
SA
Shankarappa
Itay
I
Sagie
Jonathan H
JH
Tsui
Homer H
HH
Chiang
Cristina
C
Stefanescu
David
D
Zurakowski
Daniel S
DS
Kohane
D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D004359:Drug Therapy, Combination; D008012:Lidocaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D009407:Nerve Block / Q000379:methods*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects* / Q000473:pathology; D026941:Sodium Channel Blockers / Q000008:administration & dosage* / Q000633:toxicity; D013997:Time Factors
D000779:Anesthetics, Local; D026941:Sodium Channel Blockers; C006072:QX-222; C012647:QX-314; D008012:Lidocaine