Modulators of peripheral voltage-gated sodium channels for the treatment of neuropathic pain

Abstract

Pain is an important component of sensory response, signalling the potential for tissue damage resulting from conditions such as trauma, inflammation and disease. Although acute pain serves useful functions, the need to limit pain resulting from surgical intervention, as well as the desire to reduce or eliminate severe and chronic or pathological (neuropathic) pain, has proven difficult as a drug discovery endeavour. Traditionally, severe pain has been treated with compounds such as opioids that have many deleterious side effects, and to which tolerance and dependence develop. Opioids remain the most commonly prescribed medications for severe pain, and new opioids, including new formulations of older compounds, represent the majority of compounds currently under clinical evaluation. The search for new classes of pain medicines has been difficult as pain pathways involve many elements that are integral to normal neuronal function, the modulation of which can lead to deleterious side effects. Recent progress in the understanding of the neurobiology of pain and specifically the aetiology of chronic pain, as well as clinical experience with ion channel modulators, such as gabapentin, pregabalin, and ziconotide), has shown a number of ion channels to be important components of the neuronal plasticity that leads to chronic and, particularly, neuropathic pain. One family of ion channels, the voltage-gated sodium (Na⁺) channels (Na_v), appear to be of particular importance in both the normal transmission of sensory information from the periphery to central pain pathways and in the remodelling that occurs during severe chronic and neuropathic pain conditions. Some members of this gene family are specifically expressed at high levels in peripheral nociceptive neurons in sensory ganglia. Changes in expression of some Na_v channels occurs subsequent to injury in pain pathways, and gene knockdown or knockout of these Na_vs can result in elevations in pain threshold. Small molecule blockers of Na⁺ channels, although so far less than ideal in terms of their specificity and potency, have been shown to significantly alleviate pain in many animal models, including chronic nerve injury models of neuropathic pain. Reducing the Na⁺ current mediated by these channels following remodelling in pain pathways therefore appears to be a viable, effective mechanism for severe, chronic pain relief. Although highly channel-specific blockers have not yet been developed to the point of proof of concept in clinical trials, significant work has proceeded towards the discovery of Na_v channel blockers for pain. This paper will review some of the data in support of this hypothesis and review some of the recent patent filings in the area of peripheral sensory Na_v channel gene patents and modulators for pain therapy.

Keywords::

• Na_v
• pain therapy
• small molecule
• use-dependent
• voltage-dependent sodium channel