Tetrodotoxin Delivery Pen Safely Uses Potent Natural Neurotoxin to Manage Severe Cutaneous Pain

Abstract Clinically available therapies often inadequately address severe chronic cutaneous pain due to short anesthetic duration, insufficient intensity, or side effects. This study introduces a pen device delivering tetrodotoxin (TTX), a potent neurotoxin targeting nerve voltage‐gated 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‐dose‐dependent anesthetic effectiveness. An administration of 900 ng 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 h, outperforming bupivacaine (28 µg), of which are 25.24% and under 1 h. Moreover, the pen device provides on‐demand 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 µg of TTX exhibits no TTX‐related toxicity in rats. The TTX delivery pen paves the way for clinical trials, offering a promising solution for severe cutaneous pain.