Selective targeting of voltage-gated sodium channels to achieve analgesia: current status and future directions

Abstract Voltage-gated sodium channels (Na v ) play a fundamental role in generating action potentials in excitable cells including nociceptors. Certain Na v subtypes are enriched in nociceptors, and human genetic data link them to pain disorders meaning that Na v s have long been key analgesic drug targets. Developing small molecules to reduce channel conductance in a subtype-specific manner has been challenging but the Na v 1.8 channel blocker, suzetrigine, has finally reached the clinic. Alternative approaches to selectively targeting Na v isoforms include anti-Na V aptamers and oligonucleotides, RNA editing, subtype-specific antibodies, and targeted protein degradation. Our hope, therefore, is that the recent approval of suzetrigine for acute pain will be but the first of a series of novel Na v targeting analgesics.