Sodium channel blockers in the treatment of neuropathic pain

Abstract

Chronic pain is a global unmet medical need because of complex and incompletely understood underlying pathophysiological mechanisms and because treatment is mostly ineffective and can be addictive. Genetic and functional studies have linked mutations in voltage-gated sodium channels NaV1.7, NaV1.8 and Nav1.9 and pain syndromes. Studies of several families with Nav1.7 mutations uncovered different pain profiles in affected members of the same family. Using patient-specific iPSC-based differentiated sensory neurons, modulatory genetic factors that explain inter-individual variability of pain have begun to emerge. The robust genetic validation of Nav1.7 as a key factor in human pain disorders has led to intensive efforts for the development of novel isoform-specific drugs which are being tested in clinical studies. Importantly, a subset of mutations in Nav1.7 have been shown to respond to existing drugs which act in a novel mode of action, shifting channel activation in a deploarized direction, in addition to the classical state- and use-dependent inhibition. This new mode of action has now been shown to extend to a corresponding mutation in another sodium channel, Nav1.8. These studies show how monogenic pain disorders have advanced our understanding of the pathophysiology of chronic pain and show proof-of-principle studies implementing a precision medicine approach to treat pain.