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

Shomorony, Andre BS*; Santamaria, Claudia M. MD*; Zhao, Chao PhD*; Rwei, Alina Y. PhD*; Mehta, Manisha MD*; Zurakowski, David MS, PhD; Kohane, Daniel S. MD, PhD*,†

doi: 10.1213/ANE.0000000000004108
Preclinical Pharmacology: Original Laboratory Research Report
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BACKGROUND: Capsaicin, the active component of chili peppers, can produce sensory-selective peripheral nerve blockade. Coadministration of capsaicin and tetrodotoxin, a site-1 sodium channel blocker, can achieve a synergistic effect on duration of nerve blocks. However, capsaicin can be neurotoxic, and tetrodotoxin can cause systemic toxicity. We evaluated whether codelivery of capsaicin and tetrodotoxin liposomes can achieve prolonged local anesthesia without local or systemic toxicity.

METHODS: Capsaicin- and tetrodotoxin-loaded liposomes were developed. Male Sprague-Dawley rats were injected at the sciatic nerve with free capsaicin, capsaicin liposomes, free tetrodotoxin, tetrodotoxin liposomes, and blank liposomes, singly or in combination. Sensory and motor nerve blocks were assessed by a modified hotplate test and a weight-bearing test, respectively. Local toxicity was assessed by histologic scoring of tissues at the injection sites and transmission electron microscopic examination of the sciatic nerves. Systemic toxicity was assessed by rates of contralateral nerve deficits and/or mortality.

RESULTS: The combination of capsaicin liposomes and tetrodotoxin liposomes achieved a mean duration of sensory block of 18.2 hours (3.8 hours) [mean (SD)], far longer than that from capsaicin liposomes [0.4 hours (0.5 hours)] (P < .001) or tetrodotoxin liposomes [0.4 hours (0.7 hours)] (P < .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 systemic toxicity.

CONCLUSIONS: The combination of encapsulated tetrodotoxin and capsaicin achieved marked prolongation of nerve block. This combination did not cause detectable local or systemic toxicity. Capsaicin may be useful for its synergistic effects on other formulations even when used in very small, safe quantities.

From the *Laboratory for Biomaterials and Drug Delivery, Division of Critical Care Medicine, Department of Anesthesiology, Boston Children’s Hospital, Boston, Massachusetts

Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts.

Published ahead of print 30 January 2019.

Accepted for publication January 30, 2019.

Funding: Supported by National Institutes of Health (GM073626).

Conflicts of Interest: See Disclosures at the end of the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Daniel S. Kohane, MD, PhD, Division of Critical Care Medicine, Department of Anesthesiology, Boston Children’s Hospital, 61 Binney St, Enders Bldg, Room 361, Boston, MA 02115. Address e-mail to daniel.kohane@childrens.harvard.edu.

Copyright © 2019 International Anesthesia Research Society
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