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

ABSTRACT: Voltage-gated sodium channels (Nav) play a fundamental role in generating action potentials in excitable cells including nociceptors. Certain Nav subtypes are enriched in nociceptors, and human genetic data link them to pain disorders meaning that Navs have long been key analgesic drug targets. Developing small molecules to reduce channel conductance in a subtype-specific manner has been challenging but the Nav1.8 channel blocker, suzetrigine, has finally reached the clinic. Alternative approaches to selectively targeting Nav isoforms include anti-NaV 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 Nav targeting analgesics.