Abstract

Chronic pain affects approximately 20% of the American population, with significant effects on quality of life and an enormous economic burden in terms of lost productivity. While advances have been made, treatments are still constrained by addiction liability, tolerance, and reduced efficacy, especially for neuropathic pain. Voltage-gated sodium channels (VGSCs), most importantly the NaV-1.7, NaV-1.8, and NaV-1.9 subtypes that are present on nociceptors, have emerged as promising therapeutic targets for selective chronic pain treatment. These channels play a significant role in neuronal stimulation and pain conduction. Activation of these specific VGSC subtypes may grant selective analgesia without the undesirable side effects of more diffusely acting pain modulation. Meanwhile, novel advances in gene therapies, including antisense oligonucleotides, CRISPR-based epigenetic control, small interfering RNAs, and nanomedicine delivery devices, have enabled novel prospects for treating chronic pain at the molecular genesis level. This review is focused on novel VGSC-targeted therapeutic approaches that are emerging, and we evaluate traditional pharmacologic regimens, gene-based methods, and natural products that affect VGSC function. The role of new delivery systems and long-term pain modulation by gene expression alteration in dorsal root ganglia is also discussed. By integrating data from both preclinical and clinical studies, this review assesses efficacy, mechanism of actions, and safety profiles of the treatments with considerations of translational matters such as bioavailability, long-term safety, and regulatory hurdles. Lastly, this review shows the potential of VGSC-targeted treatments in revolutionizing chronic pain management, with optimistic new options to opioid treatments.

Keywords

chronic pain, voltage-gated sodium channels, modulation, pharmacogenetics, CRISPR, quercitin