CRPS-1 is a chronic pain condition of the limbs that follows sugery, trauma or minor injuries. CRPS-1 affected limbs exhibit peripheral tissue ischemia/hypoxia and oxidative stress. Current analgesics for CRPS-1 have poor efficacy and a myriad of systemic side effects. 

Clonidine, linsidomine and pentoxifylline are drugs that enhance microvascular flow by modulating sympathetic vasoconstriction and nitric oxide mediated vasodilation. α-lipoic acid, caffeic acid and protocatechuic acid are antioxidant nutraceuticals that scavenge reactive oxygen species and alleviate oxidative stress.

Nutraceutical salts/co-crystals of clonidine, linsidomine and pentoxifylline were synthesized mechanochemically using liquid-assisted grinding and products validated with crystallographic and spectroscopic techniques. The chronic post-ischemic pain (CPIP) model of CRPS-1 was generated by inducing 3-hour long ischemia of the rat hind paw followed by reperfusion. Ointment formulation of the salts/co-crystals, using a polyethylene-glycol-base system, was prepared and applied on the hind paws of CPIP rats. The baseline and post-treatment levels of mechanical allodynia in the rats were measured by an up-down paw withdrawal threshold procedure using von Frey filaments.

Our results show that topical formulations that simultaneously target tissue ischemia/hypoxia and oxidative stress can effectively relieve mechanical allodynia in CRPS-1.