The Pain Gate
A rare disorder brings insights into the nature of pain.
by David Dobbs
Scientific American Mind, April/May 2007
________________________________

For most of the 140 years since it was named, the disorder known as Burning Man Syndrome has operated in near-total obscurity. Even today perhaps 200 to 500 people have it in all of North America, a few thousand worldwide. Until about three years ago, pretty much all medical knowledge about it was contained in its name, erythromelalgia, which translates as "painful red extremities." Few doctors knew of it, only a handful had seen it, and none knew what caused it or how to treat it. The few thousand people who had it at any given time suffered its torment -- searing heat in the feet and lower legs, sometimes the hands — without understanding why. Most thought they were completely alone.

Pam Costa, 42 now, lived her first decade this way. She is one of perhaps 30 or 40 people in the United States, and perhaps 200 to 500 worldwide, known to have an inherited form of the disease.

"In the crib I would pull myself up and hang my hands over the side and just scream," says Costa. "My first word, I'm told, was 'Hands,' because they were hot.

"Later, when I was in school -- I grew up in southern California, and it was hot -- my feet burned all the time. I frequently had to stick them in the toilet. I couldn't understand how other people could wear shoes and socks. And gym -- gym was torture. I remember once we had to run track. I ran as far as I could, until the burning was shooting all up my legs, and then I fell down. They sent me to the office for trying to get out of gym.

"No one had any idea what it was. I didn't even know it had a name."

In 1976, when she was 10 years old, Costa's family received a letter from a team of researchers at the University of Alabama. At the time, Pam was missing most of fifth grade. Walking to and around school inflamed her legs, and her hands hurt too much to hold a pen.

The researchers' letter shed some light on this. The university was assembling the pedigree of an Alabama family that had several members with something called erythromelalgia, or EM, a poorly understood disorder that in this case seemed to be hereditary. The family tree appeared to include Pam and her mother. Did either of them ever experience burning sensations in their feet or hands?

That letter, says Costa, "was just huge. It's not like it erased the problem. But I could start to grapple with it as a thing outside of me." With help from a remarkable sixth-grade teacher, Sally Jackson ("the first one," says Costa, "to notice I did A work when the weather was cool"), Costa began to confront and manage her condition instead of fleeing it. She brought ice packs to school, got released from gym to read, learned to recognize what she could and could not do, and learned she could make all As instead of mostly Ds. She went to college and then grad school, earning a Ph.D. in psychology; married; opened a practice; started teaching; and, 5 years ago, adopted a daughter. All, says Costa, made possible "by Sally Jackson, and by that letter 30 years ago." By naming and rationalizing her condition the letter made it finite. And the finite, however big and ugly, could be approached.

Costa never expected another insight with that sort of power. Yet 28 years later, in September 2004, one came. This one came via an email from the Erythromelalgia Association, a research-support group she had joined: A team of pain researchers at Yale, building on a Beijing team's discovery of a genetic mutation underlying inherited erythromelalgia, had not only confirmed that genetic basis but discovered what appeared to be EM's prime physiological mechanism: A defect in a sodium channel in pain-sensing neurons in the legs and arms -- a door, essentially, through which pain signals are sent to the brain -- was too quick to open and too slow to close. When this door was open, pain rushed through like fire. But it was a door, the research suggested, that might someday be shut.

*

Stephen Waxman, Yale Medical School chair of neurology and the head of the lab that published the sodium channel paper, is man who likes a bit of history. When the Beijing paper drew his attention to erythromelalgia — though Waxman sees a lot of patients, he had never seen an EM patient -- he soon took an opportunity to dig through the archives of the man who first named erythromelalgia, Silas Weir Mithchell. It proved an illuminating dig.

Mitchell, the son of a rich Philadelphia doctor, began his medical career "wanting," his own father said, "in nearly all the qualities that go to make a success in medicine." He ended it as one of the century's leading neurologists. The transition was due mainly to the Civil War, during which Mitchell directed a 400-bed military hospital for nervous injuries and diseases in Philadelphia. Among the hundreds of neurological problems he saw there were three that he first described and defined. One was erythromelalgia. The other two were phantom limb, which is the sensation of retaining one's amputated appendage, and causalgia, a burning pain that sets in near a wound site after the wound is repaired and seems to have healed.

Phantom limb and causalgia rise exclusively from trauma; erythromelalgia, not so. Yet Waxman, reading Mitchell's patient accounts and correspondence, could see why Mitchell would single out erythromelalgia as a separate but related entity. All three rise from mysterious mechanisms (phantom pain is still poorly understood today); all three today fall into the broad class of disorders known as peripheral neuropathies, in which numbness, poor function, or pain, usually in the limbs thus "periphery), rises not from active injury but from malfunctions in the sensory nerve fibers running from tissue to brain. Peripheral neuropathy can cause anything from numb toes to carpal tunnel syndrome to paralysis.

Most often it causes pain. The pain takes a bewildering variety -- shooting, burning, stabbing, electrical-like -- and usually affects feet or hands. Some patients, like Mitchell's soldier, develop neuropathies after injury or surgery. Many more suffer "secondary" neuropathies that accompany inflammatory, immunological, or other disorders such as hypertension, AIDs, cancer, diabetes, or multiple sclerosis. An estimated 50 million people in the United States alone have neuropathie. Some 10 to 20 million of them suffer pain.

"Virtually all chronic pain is neuropathic pain," says Waxman. "My dad had severe neuropathic pain from diabetes. Toward the end only opiates would help. Awful. "

Waxman and other resesarchers have tried for years to understand these pains, hoping to cure them and to reveal pain's fundamental mechanisms: If pain is a signal received, then study faulty signals. And what better signal to study than the exaggerated ones coming from neuropathies? Work as early as the 1950s showed that motor neurons damaged in trauma often emitted exaggerated signals weeks afterwards. Bt the 1980s, this malfunction was confirmed in sensory neurons, and this sort of sustained hyperexcitability, as if a relay switch were left on by accident, became the focal point of chronic pain research.

But a pain circuit holds many switches. Where was the open one? Sodium channels made the short list early. British physiologists Alan Lloyd Hodgkin and Andrew Huxley had established the existence and transmission role of sodium channels in 1954 by recording currents from the giant axon of an Atlantic squid. Subsequent research confirmed that sodium channels (along with calcium, potassium, and other ion channels) pass signals in many types of cells -- muscle, motor neuron, cardiac tissue. But sodium channels serve particularly vital roles in the nervous system: By releasing positively charged sodium ions through the walls of axon fibers, they create the electrical impulses -- the "action potentials"-- that start the electrochemical process by which neurons send signals.

By 1990, Waxman and many other researchers had produced a pile of studies suggesting that defects in sodium channels -- "channelopathies" -- might underlie neuropathic pain. But these studies, as Waxman lamented in a 1999 literature review, "did not answer the crucial questions: What type(s) of sodium channels produce the ... discharge associated with pain?" There were nine sodium channels altogether. Which were at fault?

Even as Waxman posed that question, his team was acquiring new tools of gene manipulation and observation that would help them answer it. Now they could examine an overexcited axon's various sodium channels and see which ones had genes that were behaving oddly -- building proteins (and thus setting off activity) when they should be dormant, for instance, or lying dormant when they should be busy. Over years of work they and others narrowed the field. To Waxman and his labmates (as well as some researchers elsewhere), the results increasingly implicated the seventh of the nine channels, Nav1.7. They just call it One Seven.

They got good at creating overexcitable One Sevens. But they couldn't find a way to block the activity of One Seven within complete pain systems, and that meant that they couldn't confirm its role by absence. (To confirm the role of a light switch, the easiest way is to flip it and turn off the light.) Another way to confirm its role would be to identify the particular gene underlying its odd behavior. Unfortunately, an injured neuron reacts by flipping switches on hundreds of genes, firing them up to build the proteins that send signals and repair things. They faced a needle-in-haystack situation.

"What we needed," says Waxman, "was a genetic change within the sodium channel -- presumably One Seven -- that we knew was isolated. In short, we needed a mutation.

" I actually said to the team, 'You know, sometimes rare genetic diseases can produce this sort of effect.' But ... well, they're rare. Most neurologists go through an entire career and never see a neuropathic problem that's genetic. None of us had ever seen one. No one in this state had. But that's what we needed. We needed a family."

*

One evening I was talking to Pam Costa when I had asked her if her condition had been worsening, as EM often does. She said it was. She had roughly doubled her pain medications in the last 5 years or so, and was now taking about 8 to 10 aspirin a day, another 6 to 8 naproxen and 90 milligrams of sustained-release morphine, and she still sometimes woke in so much pain her husband had to give a morphine injection. And the bad stretches seemed to get longer. She had recently had one go 17 days. "I had a friend who saw part of a shorter one," she said. "She asked me how I went 17 days. I get through it because I always tell myself that it'll end. And it always does."

"I should make it clear that I consider myself extraordinarily fortunate. I have two arms and legs, and they work. This has never stopped me from pursuing my goals. I have a fabulous family. I've worked with so many people who have suffered more."

At this point she paused. Over the phone, 3000 miles away, I could tell she was considering whether to continue.

"I have a young cousin," she said. "When Jacob [a pseudonym] was two he was in so much pain they started giving him morphine. At first they thought he had autism, because he couldn't seem to learn anything or relate to anyone. But a rheumatologist who examined him said he was in so much pain he just couldn't take anything in. I saw Jacob a year ago, when he was three. He was not walking.

"Jacob's mother is missing, probably an opiate addict. Too much pain. His grandmother committed suicide because of the pain. Jacob is being raised by his great-grandmother, who's in her eighties."

*

One of the many oddities of this story is that while Stephen Waxman knew about erythromelalgia, and even that it had an inherited form, he did not know of the University of Alabama study and so knew nothing of Pam Costa's family. Nor did anyone in his lab nor the many colleagues with whom he inquired about familial neuropathies. This can seem a bit strange - and it is. It reflects the weird obscurity that erythromelalgia retained until 2004. Despite 25 years of increasing recognition that most chronic pain rises from neuropathy, this singularly mysterious neuropathy never crossed the path of the pain research community.

"These people got sent everywhere else," says Waxman. "They got referred to dermatologists, vascular specialists, hematologists, cardiologists, rheumatologists -- everybody but neurologists."

This disconnect ended in March 2004, when Waxman spotted in the Journal of Medical Genetics a paper reporting "Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia." The authors, a team of dermatologists and geneticists in Beijing, had analyzed the genetic profiles of two relatives with inherited EM and ferreted out the faulty gene.

That was sharp work. But because the Beijing authors were dermatologists and geneticists, notes Waxman, "They did not know an important thing" -- specifically, that the sodium channel encoded by the mutation they had discovered operates almost exclusively in peripheral pain-sensing neurons. Dermatologists unaware of that would naturally try to find the channel doing its work in skin. But they would not. It was a neural-only channel.

The channel in question was Nav1.7. Waxman's lab most certainly knew where to look for it.

"In neuroscience," Waxman explained, "it's standard fare, if you find a mutation in an ion channel, to clone it into some fresh cells and see what effect the mutation has. Normally it would take a year of tough work to clone a channel like that. But as it happened, we had the construct right here on the shelf. It took us two months."

"It was as we expected. The mutations lowered One Seven's activation threshold. They created overactive channels that amplify and sustain.. When they're supposed to be quiet, they talk. When they're supposed to whisper, they scream."

They published the results in September 2004, and they and others have since confirmed and elaborated that certain mutations at SCN9A -- they've identified 7 so far -- create a malfunction at Nav1.7 that causes erythromelalgia. In December 2006, a Unviersity of Cambridge team reported an SCN9A mutation that created a complete lack of pain sensation. They found the mutation in the family of a 10-year-old street entertainer in Pakistan who wowed crowds by walking on hot coals and stabbing himself through the arm. He later died falling off a roof.

Waxman now knows scores of people with EM, including Pam Costa, who provided a blood sample, complete with a mutation at SCN9A, for one of his studies. More families have emerged. A couple times a month he gets an email from a patient he didn't know about. Most are wrenching. "Keeps us going," Waxman said, "when the experiments don't work."

"A lot of them ask," Waxman told me toward the end of our visit, 'When might you have a cure?' I don't mean to say they're impatient. They're not. They're remarkably generous-minded. But everyone needs to understand we're really still discerning fundamental biology here. And these things take a lot of time. If Merck or Abbott found on their shelves today a drug that quited One Seven in a lab assay, it could still take ten years. And this is pretty challenging biology."

On the plus side, notes Sulayman Dib-Hajj, Waxman's genetics specialist, Nav1.7 makes a pretty good drug target. It appears to do little besides sending pain, so dampening it may cause few side-effects. And "it expresses beautifully," says Dib-Hajj, generally responding to experimental manipulation in unambiguous ways.

"In the meantime," says Dib-Hajj, "I like to think that patients find it helpful to know a bit more about what they have. I mean, sometimes pain is in your head. But here it's not. It's in your sodium channels."

When I told Pam Costa about this, she laughed. "It's true!" she said. "I've always found it helps to think some particular physiological process was causing this. Now I have the process. I can visualize those sodium channels overacting, all those ions flowing through, and I think very hard about slowing those down."

__________

Update August 2007: Since the story was written and published, Waxman and other EM researchers have been contacted by other EM sufferers; he estimates there are probably several hundred heriditary cases in the U.S. and many thousands worldwide. He and others continue to make progress defining how sodium channel malfunctions and what variables drive EM's severity. For the latest scientific publications on EM, check this search in Google Scholar.