Diabetic Peripheral Neuropathy: Pathophysiology and New Insights into the Mechanism of Action of High-Concentration Topical Capsaicin.

Diabetic peripheral neuropathy (DPN) is a chronic, progressive complication of diabetes. Pain in DPN can be severe and detrimental to the patient's quality of life. In this review, we provide an update on the mechanism of action (MOA) of high-concentration capsaicin topical system (HCCTS) for treatment of painful DPN, with an emphasis on neuroregeneration. In diabetes, hyperglycemia and other metabolic imbalances lead to oxidative stress and inflammation, which result in degeneration of the axons of afferent neurons (particularly C and Aδ fibers) within the peripheral nervous system. Dysfunction of the microvasculature supporting the nerves further exacerbates neural damage. As a result, epidermal nerve fiber density (ENFD) diminishes, and physical and chemical changes to the remaining afferent fibers render them hypersensitive to painful stimuli and hyposensitive to normal stimuli. As the longest axons are usually damaged first, DPN normally begins in the feet, then legs, and finally the hands. HCCTS incorporates a matrix technology that forcibly diffuses a high concentration of capsaicin (a TRPV1 agonist) to the dermis and epidermis, targeting TRPV1 receptors that are upregulated in DPN and play a key role in pain generation. HCCTS activates TRPV1 receptors expressed on the neuron cell membrane and endoplasmic reticulum, leading to cytoplasmic calcium ion overload, and then a cascade of cellular events resulting in reversible neurolysis of these afferent terminals. After 1-3 months, the terminals regenerate with a "healthier" phenotype, increasing ENFD, resulting in vasodilation, which may lead to a microenvironment conducive to improved neuroregeneration. This MOA is supported by clinical evidence demonstrating that repeated HCCTS treatment provides cumulative benefits in pain and improvements in sensory function of the feet compared with baseline. If effects on sensory function are confirmed in large-scale clinical studies, HCCTS could help slow the progression of DPN to more severe forms of diabetic foot syndrome.