Optimal pharmacologic pain control has been a vexing problem in medicine. Dose-limiting adverse effects, opiate addiction, and lack of efficacy for neuropathic pain limit the utility of narcotic agents. Overall, a significant response to gold standard contemporary therapeutics approximates 50% in controlled clinical trials.2 In spinal surgery, a primary complaint of pain is often the driving force toward surgical intervention and complicates postoperative management. Currently, the pharmaceutical industry is investigating novel targets with alternative agents to achieve greater symptom reduction with fewer side effects.
Over the previous decade, the discovery of rare Mendelian disorders manifesting as an indifference to pain has led to the identification of a new pain transmission target. Dib-Hajj and colleagues1 and YP Golbderg, et al.2 review the identification and exploration of the Na(V)1.7 sodium channel in their respective articles. The identified mutation in humans, known as SCN9A, encodes for a specific voltage-gated sodium channel located in somatosensory and sympathetic ganglia named Na(V)1.7. Gain of function mutations causes severe neuropathic pain and leads to a condition known as erythromelagia. On the opposite end of the spectrum, loss of function mutations led to a congenital indifference to pain (CIP). This condition was first described by Dearborn in 1932, when he documented the life of a man working in the circus as a human pin cushion act.3 Other afflicted individuals have been employed as contortionists (Figure 1). Interestingly, patients with CIP display complete analgesia with preservation of all other sensory modalities and intact sympathetic function.
Patients with gain of function mutations of Na(V)1.7, such as those with inherited erythromelagia, present with a wide spectrum of attacks consisting of burning pain in the extremities, erythema, and elevated skin temperatures. Based on these patient populations, genetic, structural, and functional studies have provided insight into the role of Na(V)1.7 and the pathophysiology of pain transmission. Animal models have identified the amplification of pain transmission via Na(V)1.7 receptors at nerve endings and in the dorsal root ganglia. A small molecule Na(V)1.7 selective antagonist has been developed, and promising responses have been observed in these pain control models. Na(V)1.7 has not been identified in the central nervous system, providing solid logic for the minimal systemic side effects observed.
Convincing basic science data have propelled Na(V)1.7 small molecule antagonists into human clinical investigation. XEN402 (Xenon Pharmaceuticals) proved to be safe and well tolerated in a phase I trial of healthy volunteers. It also showed significant pain reduction in a small pilot randomized, doubled blinded study vs. placebo in a cohort of erythromelagia patients. Additional Na(V)1.7 agents are currently undergoing Phase I and II trials for patients with erythromelagia, trigeminal neuralgia, and post dental surgery pain, with results expected by the end of the year.
Na(V)1.7 has proven to be a major player in the transmission of human pain perception. The defined essential role in human pain signaling combined with the absence of cognitive, cardiac, motor, or other sensory abnormalities in humans that lack functional channels certainly make an attractive target for drug development. The theoretical properties of the novel small molecular Na(V)1.7 antagonists being investigated have the potential to improve quality of life, alter current medical practice across specialties, and alleviate the economic burden of pain.
1. Dib-Hajj SD, Yang Y, Black JA, Waxman SG. The Na(V)1.7 sodium channel: from molecule to man. Nat Rev Neurosci. 2013;14(1):49–62.
2. Goldberg YP, Pimstone SN, Namdari R, et al.. Human Mendelian pain disorders: a key to discovery and validation of novel analgesics. Clin Genet. 2012;82(4):367–373.
3. Dearborn G. A case of congenital pure analgesia. J Nerv Ment Dis. 1932:75:612–615.