Editorial  |   September 2020
Rational Drug Design for Pain Medicine: A New Nav1.7 Inhibitor
Author Notes
  • From the Department of Neurology and Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, Connecticut; and the Neurorehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut.
  • This editorial accompanies the article on p. 611.
    This editorial accompanies the article on p. 611.×
  • Accepted for publication June 9, 2020. Published online first on July 23, 2020.
    Accepted for publication June 9, 2020. Published online first on July 23, 2020.×
  • Address correspondence to Dr. Waxman: stephen.waxman@yale.edu
Article Information
Editorial / Pain Medicine / Pharmacology
Editorial   |   September 2020
Rational Drug Design for Pain Medicine: A New Nav1.7 Inhibitor
Anesthesiology 9 2020, Vol.133, 497-499. doi:https://doi.org/10.1097/ALN.0000000000003447
Anesthesiology 9 2020, Vol.133, 497-499. doi:https://doi.org/10.1097/ALN.0000000000003447
The ability to silence pain messages at their source in the periphery, without dampening neuronal activity elsewhere within the nervous system, is a holy grail of pain research that has focused interest on “peripheral” ion channels as potential therapeutic targets. Sodium channel Nav1.7 has emerged as a key target in this search, due to its preferential expression in pain-signaling neurons within dorsal root, trigeminal, and other sensory ganglia, and its role as a threshold channel that sets the gain and regulates the excitability of these cells.1  Molecular genetic validation has further propelled interest in Nav1.7 as a pain target: gain-of-function mutations of Nav1.7 produce nociceptor hyperexcitability that underlies severe pain in disorders such as inherited erythromelalgia, which is now regarded as a human genetic model of neuropathic pain2  while loss-of-function mutations produce a syndrome of profound insensitivity to pain.3,4  It is no surprise, then, that Nav1.7 has attracted substantial interest as a molecular target for pain and itch. However, while studies within the academic and biopharmaceutical sector have begun to identify subtype-selective inhibitors that block the activity of Nav1.7 while leaving other Nav channel subtypes intact and have yielded positive results in studies in animal models of pain and in some early human studies, Nav1.7 blockers have not yet entered the clinical arena. This reflects, in part, general challenges inherent in clinical studies on pain (subjective readouts such as Numerical Ratings Scores that can vary, for example, depending on level of stress or expectancy; lack of biomarkers; large placebo response) and the fact that, for at least some clinical trials, the patient population studied was, at least at a molecular level, heterogeneous.