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This study introduces a pen device delivering tetrodotoxin (TTX), a potent neurotoxin targeting nerve voltage\u2010gated sodium channels, as a safe and effective topical anesthetic to treat severe chronic cutaneous pain. Chemical permeation enhancers, such as sodium dodecyl sulfate (SDS) and limonene (LIM), are incorporated to enhance TTX skin permeability. The device ensures precise TTX dosing down to the nanogram level, essential to avoid TTX overdose. In rats, the pen device treatment produces TTX\u2010dose\u2010dependent anesthetic effectiveness. An administration of 900\u00a0ng of TTX with SDS and LIM to the rat back skin produces a 393.25% increase (measurement limit) in the nociceptive skin pressure threshold, and the hypoalgesia lasts for 11.25\u00a0h, outperforming bupivacaine (28\u00a0\u00b5g), of which are 25.24% and under 1 h. Moreover, the pen device provides on\u2010demand therapy for multiple treatments, consistently achieving prolonged anesthesia over ten sessions (1 treatment per day) without noted toxicity. Furthermore, a single topical administration of 16\u00a0\u00b5g of TTX exhibits no TTX\u2010related toxicity in rats. The TTX delivery pen paves the way for clinical trials, offering a promising solution for severe cutaneous pain.<\/jats:p>","DOI":"10.1002\/adhm.202401549","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T07:16:29Z","timestamp":1740122189000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Tetrodotoxin Delivery Pen Safely Uses Potent Natural Neurotoxin to Manage Severe Cutaneous Pain"],"prefix":"10.1002","volume":"14","author":[{"given":"Yuhao","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Alabama  Tuscaloosa AL 35487 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Alabama  Tuscaloosa AL 35487 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay K.","family":"Banga","sequence":"additional","affiliation":[{"name":"Center for Drug Delivery Research Department of Pharmaceutical Sciences College of Pharmacy Mercer University  Atlanta GA 30341 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Wesselmann","sequence":"additional","affiliation":[{"name":"Departments of Anesthesiology and Perioperative Medicine\/Division of Pain Medicine Neurology and Psychology and Consortium for Neuroengineering and Brain\u2010Computer Interfaces The University of Alabama at Birmingham  Birmingham AL 35294 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5659-8580","authenticated-orcid":false,"given":"Chao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Alabama  Tuscaloosa AL 35487 USA"},{"name":"Center for Convergent Biosciences and Medicine University of Alabama  Tuscaloosa AL 35487 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2021.136233"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04777-z"},{"key":"e_1_2_10_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/exd.13991"},{"key":"e_1_2_10_2_3","doi-asserted-by":"publisher","DOI":"10.1007\/s11916-009-0033-x"},{"key":"e_1_2_10_3_1","first-page":"656","volume":"96","author":"Saguil A.","year":"2017","journal-title":"Am. 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