Status of peripheral sodium channel blockers for non-addictive pain treatment

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 (Na_V) channels drive neuronal excitability and three subtypes - Na_V1.7, Na_V1.8 and Na_V1.9 - 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 Na_V1.7, Na_V1.8 and Na_V1.9 as mediators of pain and validated them as targets for pain treatment. Consequently, multiple Na_V1.7-specific and Na_V1.8-specific blockers have undergone clinical trials, with others in preclinical development, and the targeting of Na_V1.9, 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 Na_V channels and discuss the challenges and future prospects for the field. Although the potential of peripheral Na_V 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.