The effective and safe treatment of
pain is an unmet health-care need. Current medications used for
pain management are often only partially effective, carry dose-limiting adverse effects and are potentially addictive, highlighting the need for improved therapeutic agents. Most common
pain conditions originate in the periphery, where dorsal root ganglion and trigeminal ganglion neurons feed
pain information into the CNS. Voltage-gated
sodium (NaV) channels drive neuronal excitability and three subtypes - NaV1.7, NaV1.8 and NaV1.9 - are preferentially expressed in the peripheral nervous system, suggesting that their inhibition might treat
pain while avoiding central and cardiac adverse effects. Genetic and functional studies of human
pain disorders have identified NaV1.7, NaV1.8 and NaV1.9 as mediators of
pain and validated them as targets for
pain treatment. Consequently, multiple NaV1.7-specific and NaV1.8-specific blockers have undergone clinical trials, with others in preclinical development, and the targeting of NaV1.9, although hampered by technical constraints, might also be moving ahead. In this Review, we summarize the clinical and preclinical literature describing compounds that target peripheral NaV channels and discuss the challenges and future prospects for the field. Although the potential of peripheral NaV channel inhibition for the treatment of
pain has yet to be realized, this remains a promising strategy to achieve non-addictive
analgesia for multiple
pain conditions.