The New Science of Headaches

By Christine Gorman and Alice Park

For Henry Schipper, 49, of Venice, Calif., the first warning signs are mild and almost pleasant--a giddy light-headedness that evolves into what he describes as a "happy series of energetic moments." Then for about 15 minutes his eyes play tricks on him, and a wall of shimmering light obscures his field of vision. "There's no pain at that point," says Schipper, who produces documentaries for the History Channel. "But once the shimmer starts, the countdown begins."

If Schipper can't get to his medication quickly or if it doesn't kick in, he will experience a neurological event that 28 million Americans know all too well--the tidal wave of headaches known as a migraine. For Schipper the pain is sudden and sharp. "The front quarter of my head begins to pound and throb," he says. In extreme cases, he vomits violently every 20minutes. His senses of smell and hearing become agonizingly acute. "All I want to hear is gentle white noise at most and no movement, please. If there's a car alarm that goes off nearby, it's unbearable."

It was not that long ago that migraine sufferers like Schipper had no choice butto retreat to their darkened bedroom and wait, often for days, until the agony passed. Doctors could prescribe heavy-duty painkillers, but regular use often triggered even more painful episodes. Making matters worse, friends and co-workers tended to treat headache sufferers as the punch line of a bad joke, as if they were having headaches on purpose to avoid work or sex or some deeply repressed memory.

That bleak state of affairs is changing rapidly. Now physicians have at their disposal a growing arsenal of headache drugs--medications that can stop an accelerating migraine in its tracks, reduce the risk of recurrence or, in some cases, keep one from happening in the first place--but scientists are starting to uncover subtle defects in brain chemistry and electrophysiology that lead not just tomigraines but to all kinds of headaches. Indeed, many neurologists now believe that mostseverely disabling headaches are actually migraines in disguise and so are more likely to respond to migraine medications than to standard analgesics such asaspirin, ibuprofen or acetaminophen.

What it all adds up to is a revolutionary view of extreme headaches that treats them as serious, biologically based disorders on a par with epilepsy or Alzheimer's disease. "Before, patients got shipped around from doctor to doctor until eventually they wound up at a psychologist," says Dr. Joel Saper, director of the Michigan Head-Pain and Neurological Institute in Ann Arbor. Now their headaches are seen as the result of wayward circuits and molecules, not personality disorders.

The revolution in migraines was very much in evidence last week in London as more than 600 scientists from 32 countries gathered for the biennial symposium of the Migraine Trust (whose patron, the late Princess Margaret, suffered from migraines). A ripple of excitement followed reports of progress in blocking a key neuropeptide called cgrp (more on that later). But the biggest headlines came from a seemingly unlikely source, the anti-epilepsy drug topiramate. Dr. Stephen Silberstein of Thomas Jefferson University in Philadelphia presented a study of nearly 500 patients showing that topiramate significantly reduced both the occurrence and duration of migraines--offering hope that a whole class of existing antiseizure drugs could someday help migraine sufferers put an end to attacks before they occur.

Much remains to be determined. Researchers aren't sure whether they have identified all the pieces of the puzzle or if they know the order in which those pieces fall. "Does it all fit together in a cogent picture?" asks Dr. K. Michael Welch, a migraine researcher at the University of Kansas Medical Center in Kansas City. "I don't know. But we know a hell of a lot more than when I started in this field 25 years ago."

First, let's define a few terms. Doctors divide headaches into two broad categories: those that are self-contained (primary headaches) and those that result from another illness or accident (secondary headaches). The best treatment for a secondary headache depends on its origin. For example, an antibiotic may be prescribed for a headache caused by a bacterial infection.

The most common type of primary headache is the familiar tension headache, which is usually stress related. (Doctors now label it a tension-type headache to counter the idea that knotted muscles are the principal cause.) In most cases, a couple of aspirin and a good night's sleep are all that's required to get rid of one.

Not so the mercifully uncommon cluster headache, so named because an attack typically repeats itself, often daily, with each episode lasting anywhere from an hour to an hour and a half. Cluster headaches usually strike their victims, generally men, at fixed times of the year. The pain is so searing that they are also known as suicide headaches. Immediate treatment with oxygen and migraine drugs given intravenously can sometimes provide relief.

Somewhere between tension and cluster headaches are migraines. Typically, the pain from a migraine is a throbbing one, restricted to one side of the head, that gets worse with movement and lasts from four hours to three days. Migraines are usually accompanied by either nausea and vomiting, as they were for TV producer Schipper, or extreme sensitivity to both light and sound. By contrast, patients suffering from tension-type headaches may react badly to either light or sound but not both.

It is a mistake, however, to stick too rigidly to these definitions. "At one time people thought that migraine was a disorder all its own and that tension-type headache was totally separate," says Dr. Ninan Mathew, director of the Houston Headache Clinic. "Now we realize that headaches are not that clear cut." Indeed, Mathew says, nearly any recurring headache that is debilitating enough to keep you away from work or the things you enjoy is probably a migraine.

As far back as the 1600s, the prominent English physician Thomas Willis suggested that headaches are caused by a rapid increase in the flow of blood to the brain. He theorized that the suddenly bulging blood vessels put pressure on nearby nerves and that these in turn trigger the pain. A variation on Willis' idea became the favored explanation for the cause of migraines. (An important network of blood vessels at the base of the brain bears Willis' name.)

Two things have occurred in the past couple of decades to alter that view. First, several imaging techniques were developed that allowed doctors to study blood flow in the living brain. Second, scientists learned a great deal more about the nerve endings that are embedded in the dura mater, the fibrous outer covering of the brain. Armed with these tools and that information, researchers concluded that the order of events in a migraine is not as straightforward as they had been taught. The nerve endings in the dura mater appear to act first, releasing proteins that cause the blood vessels to open and prime the nerves to maintain a state of alert. In other words, swollen blood vessels are the result of a growing migraine, not its cause.

Tracing the pathway of the affected nerve endings deeper into the brain led researchers to the trigeminal nerve, a complex network of nerve fibers that ferries sensory signals from the face, jaws and top of the forehead to the brain. During the course of a migraine, scientists discovered, the trigeminal nerve practically floods the brain with pain signals. The more researchers learn about the trigeminal nerve, the more they believe that it is involved in all types of primary headaches, including tension and cluster headaches. The differences in the headache types seem to stem from what activates the trigeminal nerve and how it responds.

So much is happening all at once during a migraine that it has been hard to pinpoint what sets off the trigeminal nerve. Some scientists are focusing on a wave of electrical activity that spreads across the brain just before a migraine and triggers the aura--the shimmering light show experienced by 1 in 5 migraine patients. Others wonder wheth-er there is some kind of migraine generator buried deep within the brain stem. Even when researchers think they know the order in which different parts of the brain turn on during an attack, they can't always be sure if one section is initiating an action or anticipating the need to respond.

What seems clear, however, is that the brain of a migraineur (as sufferers are called) is primed to overreact to all sorts of stimuli that most people can easily tolerate. "The brain receives input from a wide variety of triggers--stress, hormones, falling barometric pressure, food, drink, sleep disturbances," says Dr.David Buchholz, a neurologist at the Johns Hopkins University School of Medicine in Baltimore, Md. "Each of us has hisown stack of triggers and his own personal threshold at which the migraine mechanism activates. The higher the trigger level climbs above the threshold, the more fully activated the migraine system--and the more pain."

In this view, people who are prone to migraine have a low threshold for activating the trigeminal nerve. Those who suffer only an occasional tension-type headache have a much higher threshold. Persistent treatment of acute attacks and prevention of additional ones may reset the brain's threshold point at a higher level.

Researchers are exploring the possibility that migraine sufferers are not just hypersensitive to various triggers but that their brains have lost some of their natural ability to suppress pain signals. To find out more, scientists are studying a part of the brain called the periaqueductal gray matter, which, says Dr. Welch in Kansas City, "switches off the pain response so that you can focus on the fight to survive. It's the reason why if you have a cut that you don't remember getting, it doesn't start to hurt until you actually look at it."

Each time a migraine occurs, Welch and others have found, the periaqueductal gray matter fills with oxygen, which triggers chemical reactions that deposit iron in that section of the brain. As the iron builds up, the brain's ability to block out pain decreases. That may explain why many migraineurs become more sensitive to pain with each episode.

If overly sensitive nerve cells are the problem, it makes sense to try to calm them down--and that's exactly what the first drug tailored to block an oncoming migraine was designed to do. Approved in the U.S. in 1993, sumatriptan mimics the action of a neurotransmitter called serotonin, which plays many roles in the brain, including regulation of mood and pain. In the case of migraines, the drug prevents nerve endings in the dura from releasing their stimulatory proteins. No proteins, no pain.

Sumatriptan's success launched a new class of drugs called triptans that provide most migraineurs substantial relief. Like the painkillers before them, the triptans deliver their best results when taken early in an attack. Unfortunately, their effect is often temporary (drug companies are working on longer-lasting versions). Also, the drugs can trigger certain cardiovascular side effects, which means they should not be used by patients who have an increased risk of heart attack or stroke.

Still, triptans have dramatically changed the lives of millions of migraine sufferers and opened up promising areas of research. Scientists have discovered that triptans, besides affecting serotonin pathways, also directly block one of the stimulatory proteins released by the nerve endings in the dura. New compounds that target this protein, dubbed cgrp, are being tested in Europe. One big problem, says Lars Edvinsson of Lund University in Sweden, "is that the drug can be given only intravenously. We need a cgrp blocker that works as a tablet."

Pain relief isn't the only reason to stop a migraine before it goes too far. When the illness goes untreated, there is some evidence "of a mechanism in the central nervous system that makes traditional medications less useful," says Dr. Michael Moskowitz, a neurologist at Harvard Medical School in Boston. How that resistance develops is the subject of intense investigation.

Ideally, you'd like to prevent a migraine from occurring in the first place. There is a lot you can do to help yourself. Identifying individual triggers--such as chocolate or fluorescent lights--and keeping away from them as much as possible is an obvious first step. You should also avoid relying too heavily on quick fixes. "People with severe migraine headaches can enter a cycle of taking medications on a daily or near daily basis," says Dr. Sonja Potrebic of the Pain Management Center at the University of California in San Francisco. "Initially it helps, but over time the headaches get worse." Painkillers that contain caffeine are the most common cause of such rebound headaches. Taking baby aspirin to prevent a heart attack does not seem to be a problem.

Many migraineurs swear by various nonpharmacological methods of keeping their headaches at bay, such as yoga, meditation and biofeedback. These techniques probably work best for patients whose headaches are triggered by stress or tense facial muscles. One of the surprises of the past couple of years is the effectiveness of botox, which is now being injected into facial muscles to temporarily erase wrinkles. Migraineurs have reported that botox seems to banish their headaches as well. Studies are under way to see if those observations hold up.

Lifestyle changes, however, are sometimes not enough to prevent migraines. In such cases, doctors may turn to beta-blockers, drugs that were designed to treat high blood pressure. Although these medications open up the blood vessels, which would seem counterproductive if you're trying to prevent a migraine, they also turn out to have a soothing effect on nerve cells.

Similarly, antidepressants have been used to help prevent migraines. "If antidepressants were discovered today and we didn't know they were antidepressants, we'd call them analgesics," says Dr. Seymour Diamond, director of the Diamond Headache Clinic in Chicago. Intriguingly, the pain-fighting effect of antidepressants takes just three to 10 days to kick in, less than half the time needed to alleviate depression. This suggests that depression and migraine are triggered by different, though related, neural pathways.

As helpful as beta-blockers, antidepressants and even anti-epilepsy drugs may be in preventing some migraines, they don't cure the condition. Eventually scientists hope to discover therapies that address the brain's overly sensitive circuits more directly. For what it's worth, getting older seems to soften the blow. Studies show that migraine attacks peak between the age of 35 and 45 and decline after that.

Meanwhile, it may be a process of trial and error for most migraineurs--and their physicians. Chances are, however, that more and more of them will, like Schipper, eventually hit on the combination of medications and lifestyle changes that works for them. In his case, careful attention to his triggers along with judicious use of a powerful painkiller has kept his headaches to a minimum. "It's a tricky thing to navigate a migraine," Schipper says. "You have to be adept at knowing your own patterns." But it can be done. And sometimes, knowing that relief is within reach is half the battle. --With reporting by Jeff Chu/London, Andrea Dorfman/New York, Harlene Ellin/Chicago and Jeffrey Ressner/Los Angeles

With reporting by Jeff Chu/London, Andrea Dorfman/New York, Harlene Ellin/Chicago and Jeffrey Ressner/Los Angeles