Prolonged Duration Local Anesthesia by Combined Delivery of Capsaicin- and Tetrodotoxin-Loaded Liposomes

Abstract

Local anesthetics are commonly used in peripheral nerve blockade for the management of postoperative and chronic pain. However, single administrations of conventional local anesthetics often result in nerve blocks that are short compared to the duration of postoperative care, and are often associated with local toxicity or systemic side effects. Consequently, there is considerable interest in developing longer-lasting and safer local anesthetic formulations. Capsaicin, the active component of chili peppers, can produce long, sensory-selective peripheral nerve blockade, and its co-administration with tetrodotoxin (TTX), a site 1 sodium channel blocker, can achieve a synergistic effect on duration of nerve blocks. However, in sufficiently large amounts, capsaicin can be neurotoxic, and TTX can cause systemic toxicity. We evaluated whether co-delivery of small amounts of capsaicin and TTX, by their sustained release from liposomes, could achieve prolonged local anesthesia without local or systemic toxicity. We developed capsaicin- and TTX-loaded liposomes, and injected male Sprague-Dawley rats with free capsaicin, capsaicin liposomes, free TTX, TTX liposomes, and blank liposomes, singly or in combination. We used a modified hotplate test and a weight-bearing test to assess the duration of sensory and motor blocks, respectively. Finally, we examined tissues microscopically and assessed the animals’ rates of contralateral blockade, to determine local and systemic toxicity, respectively. The combination of capsaicin liposomes and TTX liposomes achieved a mean duration of sensory block of 18.2 (3.8) hours [mean (SD)], far longer than from capsaicin liposomes [0.4 (0.5) hours] (P < 0.001) or TTX liposomes [0.4 (0.7) hours] (P < 0.001) given separately, with or without the second drug in free solution. This combination caused minimal myotoxicity and muscle inflammation, and there were no changes in the percentage or diameter of unmyelinated axons. There was no detectable systemic toxicity. Our results indicate that capsaicin may be useful for its synergistic effects on other formulations even when used in very small, safe quantities. This work paves the way for the development of safer and more effective local anesthetics.