By Annette M. Boyle
NEW HAVEN, CT — Researchers at the West Haven VAMC and Yale University are moving closer to a new class of pain medications devoid of side effects and may have uncovered a critical factor in determining which patients with chronic pain will respond to specific drugs.
In a study published in Nature Communications, the researchers used sophisticated atomic modeling techniques to find the mutations on sodium channel Nav1.7 that determined whether the anti-seizure medication carbamazepine would provide pain relief for patients with inherited erythromelagia (IEM), a rare pain syndrome that is generally unresponsive to pharmacotherapy. 1
“Neuropathic pain is a large unmet medical need for veterans, military service members and the general population,” noted Stephen Waxman, MD, senior author of the paper and director of the Neurorehabilitation Research Center at the West Haven VAMC and professor of neurology at the Yale School of Medicine. Existing medications provide only partial relief for most patients with IEM and have undesirable side effects that make long-term use challenging.
“Sodium channels make nerve cells special by enabling them to generate electrical impulses, essentially creating molecular batteries,” Waxman said. “It’s been a Holy Grail of pain research to find sodium channels that produce nerve impulses in peripheral pain receptors, but not in the brain. If such channels existed, we should be able to turn them off without affecting brain function.”
Existing treatments that act on sodium channels, such as phenytoin, are nonselective, and can cause multiple side effects that include double vision, confusion and somnolence. Thus they cannot be safely used at dosages that would mute pain-signaling nerve cells.
About 10 years ago, Waxman and his colleagues launched a worldwide search for families with a history of inherited pain.
“We had a lot of evidence that Nav 1.7, 1.8 and 1.9 were involved in pain, based on cultured cells and research animals, but had not established the role in humans,” Waxman told U.S. Medicine. All three isoforms are preferentially expressed in peripheral neurons. “We reasoned that, if we could find families with inherited pain syndromes, we might see specific genetic mutations in one or more of these channels.”
Inherited pain syndromes are quite rare and the one that ultimately came to the lab’s attention, IEM or “Man on Fire Syndrome,” causes patients to experience excruciating burning, scalding pain in the feet and hands in response to mild warmth. Symptoms typically appear in childhood or adolescence and, in advanced disease, may occur spontaneously multiple times a day or continuously. The syndrome is caused by mutations in the SCN9A gene that make the Nav1.7 channel overactive.
“Having demonstrated that Nav1.7 plays a key role in IEM, which is a rare but highly informative disease, we’ve gone on to show that other mutations in Nav1.7 cause other, more common disorders, such as painful peripheral neuropathy (PPN),” Waxman said.
He and his coworkers recently also found mutations of Nav1.8 also are associated with painful neuropathies.
New Generation of Pain Medications
Several biotech and pharmaceutical companies have focused attention on developing sodium channel blockers that affect only Nav1.7. The goal of this work is the development of new pain medications that do not have central side effects such as double vision, confusion and somnolence. This path is especially promising as a lack of Nav1.7, as seen in families with another rare disorder, congenital insensitivity to pain (CIP), does not correlate with any serious cognitive, cardiac or motor deficits or complications. The first drugs of this type are currently entering clinical trials.
In addition, Waxman and his team have found that some families have certain polymorphisms in sodium channel genes that give their sodium channels an increased sensitivity to existing sodium channel blockers. Most families with IEM do not respond to treatment with existing medications. However, one family with IEM found relief from the burning sensation with carbamazepine.
The researchers found that the genetic variant in this family, which substitutes one single amino acid within the Nav1.7 with an incorrect, “imposter” amino acid, accounted for the heightened response to carbamazepine. In individuals with erythromelalgia who have this Nav1.7-V400M mutation, the drug normalizes the hyperexcitability of the dorsal root ganglion neurons.
In the most recent study, the researchers created a three-dimensional model of the Nav1.7 channel and studied mutations associated with erythromelagia at the atomic level. They searched for other mutations within the maze of atoms that make up the channel that were located close the imposter amino acid in the Nav1.7-V400M mutation and that were thermodyanically coupled, or worked in tandem, with it. Using powerful computational techniques, they identified a second mutation (Nav1.7-S214T) that also responds to carbamazepine at the cellular level.
“By studying variations in these sodium channels, perhaps we will be able to deliver first-time-around genomically specific therapies. If there’s enough variation, we may be able to harness polymorphisms clinically and provide effective, genomically guided personalized pain treatment,” Waxman said.
“We’re also looking at more common causes of pain, where we don’t have mutations. If we get an injury to our peripheral nerves, for instance, our traumatized nerve cells make too many Nav1.7 sodium channels. These play an important role in burn injuries as well,” Waxman noted. “It’s possible that by developing ways to modulate Nav1.7 with small molecule blockers, we can mitigate many forms of pain.”
If effective Nav1.7-selective compounds can be developed, “we will have a new generation of pain medications that are much more effective, with very few central nervous system side effects and minimal or no potential for abuse or addiction,” Waxman said. “I see no reason why these drugs would not be usable long term, but, as with any new medication, they will need to be studied very carefully.”
1. Yang Y, Dib-Hajj SD, Zhang J, Zhang Y, Tyrrell L, Estacion M, Waxman SG. Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Na(V)1.7 mutant channel. Nat Commun. 2012;3:1186. doi: 10.1038/ncomms2184.PubMed PMID: 23149731; PubMed Central PMCID: PMC3530897.