Individual Treatment Possible For ‘Man On Fire Syndrome’

Yale researchers are developing a strategy that may lead to personalized pain therapy for patients who suffer from inherited erythromelalgia, or “Man on Fire Syndrome.” The researchers are also developing a strategy that will predict which chronic pain patients will respond to treatment.

With more than a quarter of Americans suffering from chronic pain, nearly 40 percent do not find effective relief from existing drugs. The Yale researchers’ study, then, may finally provide hope to those who have previously been unable to find a way to cope with their pain.

The study, which was published Tuesday in Nature Communications, used sophisticated atomic modeling techniques to search for mutations that cause the rare, and previously untreatable, disease.

“Man on Fire Syndrome” is a disease of small nerves and blood vessels that causes severe pain in response to heat, exertion, pressure, or stress. Dr. Stephen Waxman, a neuroscientist at Yale and the West Haven Veterans Affair Hospital said that people who suffer from the disease “feel excruciating, scalding pain while putting on shoes or putting on a sweater.”

“They will keep their feet on ice to the point of getting gangrene, just to relieve the sensation,” he said.

Under Waxman’s leadership, Yale has become a leader in identifying the sodium channel Nav1.7 at the base nerve cells as the regulator of several forms of chronic pain. People who suffer from inherited erythromelalgia have a defect in this channel that allows too many sodium ions to enter the C-fibers of the spinal cord, which then causes an increase in the sensitivity of the nerves.

People whose Nav1.7 channels are completely defective suffer from the opposite of “Man on Fire Syndrome,” called congenital indifference to pain. These people feel no pain at all, and there are reports of being able to walk on hot coals without pain.

The researchers were intrigued when it was reported that the anti-seizure medicine carbamazepine relieved pain in members of a family suffering from “Man on Fire Syndrome” by working on the Nav1.7 sodium channel.

The Yale team conducted an exhaustive genetic analysis and found that a specific variant in the sodium channel — a difference of a single amino acid among 1,800 — explained why the family responded to carbamazepine. They then developed a 3D structural model of the Nav1.7 channel and looked at different erythromelagia mutations at the atomic level.

The researchers found a second mutation that was sensitive to carbamazepine treatment. In theory, chronic pain patients with this mutation should respond to treatment with carbamazepine.

The current drug therapies for pain include medicines like morphine, aspirin, and ibuprofen. While these decrease the sensation of pain, they also interact with other tissues and cause side effects. But since the Nav1.7 channel does not appear to be present in large quantities outside of the C-fibers, drugs that target it may lead to a new class of pain treatments that have fewer side effects.