Abstract
The discovery and development of effective analgesics is greatly lagging behind the steadily rising prevalence of chronic pain. Currently prescribed analgesics for chronic pain are lacking in efficacy mainly due to their narrowly-targeted mechanism of action. Driving neuronal hyperexcitability that underlies symptoms of chronic pain are multiple non-neuronal processes, among which are tissue hypoxia and oxidative stress. Here we demonstrate the design, synthesis, and activity of new multi-component bi-functional analgesic crystalline solids, co-crystals, and salts, based on pairing of vasodilatory anti-hypoxic drugs pentoxifylline, clonidine and linsidomine with antioxidant nutraceuticals protocatechuic acid, α-lipoic acid, and caffeic acid. After validation, chemical and structural characterization of these novel salts and co-crystals, topical formulations of the products were tested in a rat model of complex regional pain syndrome. Analgesic effects achieved with the salts and co-crystal exceeded the efficacy and/or potency of constituent compounds indicating that more effective, advanced analgesics can readily be developed by careful pairing of compounds that simultaneously target multiple neural and non-neural processes driving chronic pain.
Highlights
Chronic pain is a highly prevalent, expensive to treat condition that causes physical disability and psychological debilitation to nearly 22% of the general population [1]
In a rat model of complex regional pain syndrome (CRPS), we demonstrate the augmentation of analgesic efficacy and/or potency achieved by co-crystallization and salt formation between pentx, clon, and lin and the nutraceutical antioxidants Hpca, Hala, and Hcafa
A rat model of CRPS was prepared by inducing prolonged hind paw ischemia and subsequent reperfusion, previously described by Coderre et al as chronic post-ischemia pain (CPIP) [32]
Summary
Chronic pain is a highly prevalent, expensive to treat condition that causes physical disability and psychological debilitation to nearly 22% of the general population [1]. One reason for the limited efficacy exhibited by most analgesics in clinical use is their narrowly directed mechanism of action that impacts a limited aspect of the disease process [5]. This can be circumvented by the introduction of broader-purposed multi-component analgesics. The past decade has witnessed the rapid development of designs and uses of advanced multi-component pharmaceutical solids. These are often based on association of an active pharmaceutical ingredient (API) with additional counter molecules in order to provide a novel and unique crystalline material whose structure and physicochemical properties are distinct from those of pure component solid forms [6]. In a rat model of CRPS, we demonstrate the augmentation of analgesic efficacy and/or potency achieved by co-crystallization and salt formation between pentx, clon, and lin and the nutraceutical antioxidants Hpca, Hala, and Hcafa
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