{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T17:51:47Z","timestamp":1778867507177,"version":"3.51.4"},"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T00:00:00Z","timestamp":1681257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R35 GM131728"],"award-info":[{"award-number":["R35 GM131728"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>Benzonatate is an FDA-approved antitussive agent that resembles tetracaine, procaine, and cocaine in its chemical structure. Based on structural similarities to known local anesthetics and recent findings of benzonatate exerting local anesthetic-like effects on voltage-gated sodium channels <jats:italic>in vitro<\/jats:italic>, we hypothesized that benzonatate will act as a local anesthetic to yield peripheral nerve blockade.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Benzonatate was injected at the sciatic nerve of Sprague-Dawley rats. Sensory and motor blockade were assessed using a modified hot plate test and a weight-bearing test, respectively. Additionally, the effect of co-injection with tetrodotoxin and Tween 80 (a chemical permeation enhancer) was examined. Myotoxicity of benzonatate was assessed <jats:italic>in vivo<\/jats:italic> by histological analysis.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Benzonatate produced a concentration-dependent sensory and motor nerve blockade with no appreciable systemic effects. Co-injection with tetrodotoxin or Tween 80 produced prolongation of sensory nerve blockade. Histologic assessment showed significant inflammation and myotoxicity from benzonatate injection, even at low concentrations.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>This study demonstrates that benzonatate does act as a local anesthetic at the peripheral nerve, with sensory and motor nerve blockade. Benzonatate interacts with tetrodotoxin and Tween 80 to prolong nerve blockade. However, benzonatate causes significant myotoxicity, even at subtherapeutic concentrations.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0284401","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T17:35:34Z","timestamp":1681320934000},"page":"e0284401","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Benzonatate as a local anesthetic"],"prefix":"10.1371","volume":"18","author":[{"given":"Anna","family":"McGuire","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1407-6896","authenticated-orcid":true,"given":"Claire 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Kohane","year":"1998","journal-title":"Anesthesiology"},{"key":"pone.0284401.ref008","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1097\/AAP.0b013e3181e82df0","article-title":"Local anesthetic sciatic nerve block and nerve fiber damage in diabetic rats","volume":"35","author":"JS Kroin","year":"2010","journal-title":"Reg Anesth Pain Med"},{"key":"pone.0284401.ref009","doi-asserted-by":"crossref","first-page":"e0123459","DOI":"10.1371\/journal.pone.0123459","article-title":"Dexamethasone as adjuvant to bupivacaine prolongs the duration of thermal antinociception and prevents bupivacaine-induced rebound hyperalgesia via regional mechanism in a mouse sciatic nerve block model.","volume":"10","author":"K An","year":"2015","journal-title":"PLoS One."},{"key":"pone.0284401.ref010","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1097\/00000542-199504000-00026","article-title":"Neurologic evaluation of the rat during sciatic nerve block with lidocaine","volume":"82","author":"JG Thalhammer","year":"1995","journal-title":"Anesthesiology"},{"key":"pone.0284401.ref011","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/jbm.a.30654","article-title":"Biodegradable polymeric microspheres and nanospheres for drug delivery in the peritoneum","volume":"77","author":"DS Kohane","year":"2006","journal-title":"J Biomed Mater Res A"},{"key":"pone.0284401.ref012","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1016\/j.biomaterials.2014.02.015","article-title":"Multivesicular liposomal bupivacaine at the sciatic nerve.","volume":"35","author":"JB McAlvin","year":"2014","journal-title":"Biomaterials."},{"key":"pone.0284401.ref013","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1097\/ALN.0b013e31816c8a48","article-title":"Local myotoxicity from sustained release of bupivacaine from microparticles","volume":"108","author":"R Padera","year":"2008","journal-title":"Anesthesiology"},{"key":"pone.0284401.ref014","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1002\/mus.20618","article-title":"Tetrodotoxin for prolonged local anesthesia with minimal myotoxicity","volume":"34","author":"RF Padera","year":"2006","journal-title":"Muscle Nerve"},{"key":"pone.0284401.ref015","doi-asserted-by":"crossref","first-page":"713","DOI":"10.3109\/15563659809162620","article-title":"Benzonatate overdose associated with seizures and arrhythmias","volume":"36","author":"BI Crouch","year":"1998","journal-title":"J Toxicol Clin Toxicol"},{"key":"pone.0284401.ref016","first-page":"143","volume-title":"Miller\u2019s Basics of Anesthesia, Eighth Edition","author":"Charles B. Berde","year":"2023","edition":"8"},{"key":"pone.0284401.ref017","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1093\/jat\/bkx021","article-title":"Benzonatate Toxicity: Nothing to Cough At","volume":"41","author":"SC Bishop-Freeman","year":"2017","journal-title":"J Anal Toxicol"},{"key":"pone.0284401.ref018","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1213\/00000539-197607000-00025","article-title":"The local anesthetic activity of tetrodotoxin alone and in combination with vasoconstrictors and local anesthetics.","volume":"55","author":"HJ Adams","year":"1976","journal-title":"Anesth Analg"},{"key":"pone.0284401.ref019","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1097\/AAP.0b013e31826125b3","article-title":"Duration and local toxicity of sciatic nerve blockade with coinjected site 1 sodium-channel blockers and quaternary lidocaine derivatives","volume":"37","author":"SA Shankarappa","year":"2012","journal-title":"Reg Anesth Pain Med"},{"key":"pone.0284401.ref020","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1097\/00000542-199902000-00029","article-title":"Vanilloid receptor agonists potentiate the in vivo local anesthetic activity of percutaneously injected site 1 sodium channel blockers","volume":"90","author":"DS Kohane","year":"1999","journal-title":"Anesthesiology"},{"key":"pone.0284401.ref021","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.pain.2004.04.027","article-title":"Site 1 sodium channel blockers prolong the duration of sciatic nerve blockade from tricyclic antidepressants","volume":"110","author":"CS Barnet","year":"2004","journal-title":"Pain"},{"key":"pone.0284401.ref022","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1097\/00115550-200105000-00007","article-title":"Effects of adrenergic agonists and antagonists on tetrodotoxin-induced nerve block","volume":"26","author":"DS Kohane","year":"2001","journal-title":"Reg Anesth Pain Med"},{"key":"pone.0284401.ref023","doi-asserted-by":"crossref","first-page":"4688","DOI":"10.1073\/pnas.0501176102","article-title":"Design principles of chemical penetration enhancers for transdermal drug delivery","volume":"102","author":"P Karande","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0284401.ref024","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1213\/00000539-198010000-00003","article-title":"Myotoxicity of local anesthetics and regeneration of the damaged muscle fibers.","volume":"59","author":"AH Foster","year":"1980","journal-title":"Anesth Analg."},{"key":"pone.0284401.ref025","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s11095-019-2715-3","article-title":"The Duration of Nerve Block from Local Anesthetic Formulations in Male and Female Rats","volume":"36","author":"K Cullion","year":"2019","journal-title":"Pharm Res"},{"key":"pone.0284401.ref026","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.rapm.2004.02.008","article-title":"Local anesthetic myotoxicity","volume":"29","author":"W Zink","year":"2004","journal-title":"Reg Anesth Pain Med"},{"key":"pone.0284401.ref027","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1213\/01.ANE.0000155956.59842.0A","article-title":"The long term myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blocks.","volume":"101","author":"W Zink","year":"2005","journal-title":"Anesth Analg."},{"key":"pone.0284401.ref028","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1213\/01.ANE.0000184129.50312.C1","article-title":"Tissue injury from tricyclic antidepressants used as local anesthetics.","volume":"101","author":"CS Barnet","year":"2005","journal-title":"Anesth 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