Isoform-selective voltage-gated Na+ channel modulators as next-generation analgesics

For many patients the current therapies for controlling chronic pain are inadequate. This has driven the search for analgesics with improved efficacy and side effect profiles. Some anticonvulsants have voltage-gated Na+ channels (VGSCs) as their molecular targets and are used to treat pain, but the efficacy seen is marginal and the drugs are generally poorly tolerated. The clinically used VGSC-modulating analgesics show no isoform selectivity, which probably limits their use. Thus, focus has fallen on VGSCs expressed selectively by primary afferent neurons and the search for isoform-selective drugs. In this review, we describe developments in our understanding of the biology of VGSCs, screening technologies and the pharmacological properties of VGSC modulators with promise as analgesics. Also highlighted are the challenges associated with targeting isoform-selective VGSCs.