Development and Applications of Opioids Alternatives for Pain Management

This dissertation explores alternative pain management strategies to opioids, focusing on tetrodotoxin (TTX) and capsaicin as novel anesthetics. Acute post-surgical pain typically lasts 5-7 days, while long-term pain management can span up to 12 weeks. Opioids are commonly used but are linked to serious side effects, including addiction, nausea, cognitive impairment, and fatal overdoses. TTX is a site-1 sodium channel blocker, nearly 1000 times more potent than conventional amino-amide and amino-ester local anesthetics, and it lacks the myotoxicity and nerve toxicity often associated with these anesthetics. However, its systemic distribution can cause fatal diaphragm paralysis. To limit this, drug delivery systems were developed to refine the release kinetics of TTX. Initially, a hydration-induced void-containing hydrogel system was created to encapsulate TTX physically. Following a simple hydration process between the polymer and the TTX solution, TTX was successfully encapsulated in voids shielded by densely packed polymer, achieving 100% encapsulation efficiency. These injectable hydrogels can be stored for several months without compromising drug encapsulation and release properties. A single injection of the hydrogel/TTX formulation produced a sciatic nerve block lasting up to 10 hours.Despite progress, the duration of nerve blockade remains insufficient for clinical needs. The physical encapsulation method limits TTX dosage due to unstable release kinetics. Therefore, polymer-TTX conjugates were developed by chemically conjugating TTX to the polymer backbone and releasing it through ester bond hydrolysis. This increased the TTX dosage nearly 40-fold, prolonging the nerve blockade to more than three days.Finally, a galacturonic acid-capsaicin prodrug was developed. Capsaicin, the active component of chili peppers, selectively targets the transient receptor potential vanilloid-1 (TRPV1) receptor to block nociceptive signaling without affecting motor nerves. The prodrug utilized facilitated transport by glucose transporters across the perineurium, eliminating the side effects typically caused by capsaicin, such as burning pain, seizures, and respiratory depression. A single injection at the sciatic nerves of rats resulted in nociceptive-selective nerve blockade lasting 10 days with minimal tissue toxicity or side effects.This research aims to address the limitations of traditional pain management methods and pave the way for safer, more effective pain management solutions that could benefit patients suffering from postoperative pain.