Fig 4.

The site of action of topical capsaicin is in the skin, and pain relief is not mediated by transdermal systemic delivery. Owing to near insolubility in water, capsaicin is not readily absorbed into the microvasculature. When cutaneous nociceptors are hypersensitive and sometimes spontaneously active, localized defunctionalization of capsaicin-responsive nerve fibre terminals in the epidermis and dermis can reduce the afferent barrage which may drive pain syndromes. Inset shows how mitochondrial dysfunction leads to nerve terminal retraction.