Effects of Topical Capsaicin on Cutaneous Innervation: Implications for Pain Management

Changes in cutaneous innervation are a hallmark of neuropathic pain syndromes. Although in few cases the density of cutaneous innervation increases in painful areas, for the most part the density of nociceptive sensory nerve endings decreases and the degree of deinnervation seems to correlate with the severity of pain. In combination with tests for nociceptor function, immunostaining for protein gene product 9.5 (PGP 9.5) is commonly used as diagnostic tool to indicate these pathophysiological changes in cutaneous innervation. However, sole reliance on PGP 9.5 may underestimate the presence of regenerating sensory nerve terminals or fail to capture changes in the expression of proteins such as ion channels or receptors. Topical capsaicin consistently reduces intra-epidermal nerve fiber density assayed via PGP 9.5, and also increases thresholds for activation of some thermoreceptors. The mechanism of action involves a highly localized insult to cutaneous nociceptors mediated by activation of TRPV1 and calcium overload, and perhaps even a direct toxicity to mitochondria. It is possible that topical capsaicin and lidocaine share an ability to reduce cutaneous innervation by inducing localized toxicity in mitochondria-rich nociceptive terminals. Overall, the high local concentrations of drugs and even excipients delivered by topical analgesics into the skin may be able to activate secondary pharmacodynamic processes. Optimizing topical formulations of capsaicin or other analgesics to maximize pain relief with the fewest adverse effects is not a simple matter of varying drug concentration, and it is highly questionable whether 'bioequivalence' could ever be based simply upon equivalent cutaneous drug delivery.