Pharmacological reviews
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Acute nociceptive, inflammatory, and neuropathic pain all depend to some degree on the peripheral activation of primary sensory afferent neurons. The localized peripheral administration of drugs, such as by topical application, can potentially optimize drug concentrations at the site of origin of the pain, while leading to lower systemic levels and fewer adverse systemic effects, fewer drug interactions, and no need to titrate doses into a therapeutic range compared with systemic administration. Primary sensory afferent neurons can be activated by a range of inflammatory mediators such as prostanoids, bradykinin, ATP, histamine, and serotonin, and inhibiting their actions represents a strategy for the development of analgesics. ⋯ There are preclinical data supporting the potential for development of local formulations of adenosine agonists, cannabinoid agonists, cholinergic ligands, cytokine antagonists, bradykinin antagonists, ATP antagonists, biogenic amine antagonists, neuropeptide antagonists, and agents that alter the availability of nerve growth factor. Given that activation of sensory neurons involves multiple mediators, combinations of agents targeting different mechanisms may be particularly useful. Topical analgesics represent a promising area for future drug development.