A REEXAMINATION OF TETRODOTOXIN FOR PROLONGED DURATION LOCAL-ANESTHESIA

Background: Highly potent toxins such as tetrodotoxin that block sodiu m channels with great specificity have been studied for many years and can provide prolonged blockade when coadministered with vasoconstrict ors or conventional local anesthetics. Their utility has been constrai ned, however, by systemic toxicity. The authors examined the efficacy of tetrodotoxin with and without epinephrine or bupivacaine for produc ing prolonged-duration sciatic nerve blockade in the rat, and they ass essed the degree of concomitant toxicity, Methods: Rats received percu taneous sciatic nerve blockade using tetrodotoxin with and without epi nephrine or bupivacaine. A subset received subcutaneous injections at the nuchal midline, Nociceptive, proprioceptive, and motor blockade we re quantified using contralateral leg responses as controls for system ic effects. Results: Tetrodotoxin without epinephrine produced sciatic nerve blockade, but with considerable toxicity at most effective dose s. Epinephrine reduced the median effective concentration of tetrodoto xin for nociception from 37.6 to 11.5 mu M and prolonged its duration, such that reversible blocks lasting >13 h were achieved. Epinephrine reduced measures of systemic distribution and increased the median let hal dose of tetrodotoxin from 40 to 53.6 nmole/kg, thus more than quad rupling the therapeutic index. Bupivacaine increased the local anesthe tic potency of tetrodotoxin, reduced its systemic toxicity, and, when coinjected subcutaneously, increased the median lethal dose from 43.7 to 47.7 nmole/kg, The addition of epinephrine did not further improve the effectiveness of the bupivacaine-tetrodotoxin combination. Conclus ion: Combinations of epinephrine or bupivacaine with tetrodotoxin or w ith other high-potency toxins active on sodium channels should be exam ined for the potential to provide clinically useful, prolonged nerve b lockade.