Treatment of Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker.
|
| Abstract |
Mutations in the SCN9A gene leading to deficiency of its protein product, Na(v)1.7, cause congenital indifference to pain (CIP). CIP is characterized by the absence of the ability to sense pain associated with noxious stimuli. In contrast, the opposite phenotype to CIP, inherited erythromelalgia (IEM), is a disorder of spontaneous pain caused by missense mutations resulting in gain-of-function in Na(v)1.7 that promote neuronal hyperexcitability. The primary aim of this study was to demonstrate that Na(v)1.7 antagonism could alleviate the pain of IEM, thereby demonstrating the utility of this opposite phenotype model as a tool for rapid proof-of-concept for novel analgesics. An exploratory, randomized, double-blind, 2-period crossover study was conducted in 4 SCN9A mutation-proven IEM patients. In each treatment period (2days), separated by a 2-day washout period, patients were orally administered XEN402 (400mg twice daily) or matching placebo. In 3 patients, pain was induced by heat or exercise during each treatment arm. A fourth patient, in constant severe pain, required no induction. Patient-reported outcomes of pain intensity and/or relief were recorded, and the time taken to induce pain was measured. The ability to induce pain in IEM patients was significantly attenuated by XEN402 compared with placebo. XEN402 increased the time to maximal pain induction and significantly reduced the amount of pain (42% less) after induction (P=.014). This pilot study showed that XEN402 blocks Na(v)1.7-mediated pain associated with IEM, thereby demonstrating target engagement in humans and underscoring the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept.
|
|---|---|
| Authors | Yigal Paul Goldberg, Nicola Price, Rostam Namdari, Charles Jay Cohen, Mieke H Lamers, Conrad Winters, James Price, Clint E Young, Henry Verschoof, Robin Sherrington, Simon Neil Pimstone, Michael Reuben Hayden |
| Journal | Pain (Pain) Vol. 153 Issue 1 Pg. 80-85 (Jan 2012) ISSN: 1872-6623 [Electronic] United States |
| PMID | 22035805 (Publication Type: Journal Article, Randomized Controlled Trial) |
| Copyright | Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!