The New War Against Migraines

It flattens you out, the woman says, describing the pain that seems to lie, throbbing, just inside the skull, so that she can feel her blood vessels pulse and tingle with every heartbeat. She is 42 and has had migraines with virtually every menstrual period since puberty, and usually several other times a month as well. The pain announces itself with an aura of spectacular visual effects, ""like 20 sparklers'' flashing across her field of vision, and can last for up to three days. She has had acupuncture therapy, massage therapy, relaxation therapy and hormonal therapy to try to induce early menopause. At Chicago's Diamond Headache Clinic she is checking off the drugs that have been prescribed for her over the years, on a form that lists about 180 different products. Antidepressants, including Elavil and Zoloft. Nausea medications--Compazine and Decadron. Antihistamines, decongestants and, of course, painkillers. ""Fiorinal, plain, and also with codeine. I'm up to around 10 a day on those. And I've been on morphine for the last three months,'' the woman says matter-of-factly. Karen Frizelis, a nurse practitioner, writes down all the meds in a long column. ""Thirty to 50 is typical,'' Frizelis remarks. ""My personal record was a patient with over a hundred.''

Patients come to this clinic, one of the oldest and largest of its kind, at the end of a long line of family doctors, neurologists, even chiropractors, all baffled by the unique affliction known as migraine--that is, if they recognize it in the first place. Of an estimated 25 million American ""migraineurs,'' only about half even know what they have; the rest are being treated, ineffectively, for something else, or not being treated at all.

Yet 1998 was actually a banner year for migraine awareness, starting with the Super Bowl, when Denver Broncos running back Terrell Davis forgot to take his migraine medication until 10 minutes before game time and sat out the second quarter with a 300-pound head-ache. (He recovered over half time.) More important, researchers are starting to unlock the mystery of what goes on inside the head of a migraine sufferer. Drug companies are using that information to pioneer new treatments that attack even the most intractable migraines, and that work many times faster than existing drugs, with fewer side effects. In ways undreamed of when Dr. Seymour Diamond started his clinic 35 years ago, doctors are starting to make a difference in the lives of what he calls ""probably the most misunderstood, misdiagnosed and mistreated group of patients in modern medicine.''

Migraine is not just a name for an unusually painful headache; it is a specific diagnosis, involving pain that begins on one side of the head, often accompanied by nausea and sensitivity to light and sounds. The National Headache Foundation distinguishes 21 kinds of head pain, from the commonplace ""tension'' headache (chart), usually caused by emotional stress, to those resulting from hangovers, aneurysms and tumors. Migraines have traditionally been considered ""vascular'' headaches, in which the blood vessels surrounding the brain become dilated and press against the adjacent nerves. Caffeine-withdrawal headaches are of this kind; caffeine constricts the blood vessels, and when people suddenly stop taking it, the arteries expand in a rebound effect. Another is the relatively rare ""cluster'' headache, which neurologists consider the most severe sustained pain human beings regularly experience. Migraine is preceded, in about 15 percent of patients, by an ""aura'': typically, visual disturbances, such as flashing lights or blind spots, numbness or weakness on one side of the body or slurred speech--all signals to head for bed, close the curtains and pull up the covers.

It can strike almost any time, although the hormonal changes around menstruation and ovulation often seem to set off migraines in women, who are three times as likely to get migraines as men are. Migraines can occur in children as young as 2--Elizabeth Pirsch, an Alexandria, Va., lawyer, remembers at the age of 6 ""begging my mother to cut off my head'' to stop a headache--and the incidence seems to peak among people in their mid-20s through middle age, trailing off after about 55.

Migraineurs tend to develop theories about what sets off their headaches, often something they ate or drank, such as chocolate, cheese, red wine, nuts, yeast, corn, cane sugar, dairy products, wheat or, in summary, just about anything. Some patients attribute their migraines to too little sleep, hunger or excess humidity, while others swear the culprit is too much sleep, overeating or dryness. But researchers who have tried to induce migraines in patients this way almost always fail. ""There's very little science, if any, demonstrating all these trigger factors really are important,'' says Michel Ferrari, a neurologist at Leiden University in the Netherlands, adding that the research has mostly just resulted in creating ""patients who refuse to do anything or eat anything, and they still get headaches.''

The debate over triggers, though, only serves to underline the subjective nature of migraine, which for a long time kept neurologists from taking it seriously. All pain is subjective and self-reported, naturally, but there are ways to test patients for conditions such as angina or rheumatoid arthritis. There is no blood test for migraine, and although it runs in families, a specific gene has been found for only one very rare type (familial hemiplegic migraine, marked by weakness on one side of the body during attacks). Migraine does show up on a PET scan--but only if the patient can be rushed into a machine just as she's having an attack. Doctors often fail to diagnose migraine in patients who don't experience an aura--which is most of them.

Historically, the medical profession tended to regard migraine as just another curse of womanhood at best, and a hysterical artifact at worst. ""I was taught as a medical student that migraine is a disease of rich women who have nothing better to worry about than their headaches,'' says Richard Lipton of Albert Einstein College of Medicine in the Bronx, N.Y., a leading authority on the epidemiology of migraine. It turns out that rich women don't actually get more migraines than anyone else, but they alone could spend the day in bed recovering. The notion that migraine is a suspiciously self-generated complaint is enormously offensive to migraineurs, none more so than Pirsch, the lawyer who has suffered from migraines for almost all her 43 years. She wasn't diagnosed until 10 years ago, though; before that, doctors told her, variously, that she had sinus problems, that she needed more sleep or that she needed a boyfriend. Not long ago, one of her pharmacists warned her against staying on painkillers for too long. Why didn't she just get her headaches cured? the druggist suggested. Infuriated, Pirsch responded: ""Do you think I'm doing this for attention? That I like waking up in agony every morning, missing four months of work a year? You want me to be cured? Then tell me what to do!''

She may never be cured; it's not clear that anyone ever has been. On the other hand, the fact that she was even able to get up and walk to the drugstore is a tribute to a remarkable new drug: Imitrex, or sumatriptan, one of the first fruits of research into what really happens during a migraine attack.

One thing doctors know happens: blood vessels dilate in the membrane that surrounds the brain. A generation ago they assumed that this was the precipitating event in migraine. Treatment, therefore, relied on reversing the dilation with drugs that caused the vessels to constrict, notably compounds derived from the rye fungus ergot. In 1997 Novartis figured out how to deliver the ergot derivative DHE in the form of a nasal spray, which is one of the fastest ways to get a substance to the brain. It was that drug, known as Migranal, that put Davis back into last year's Super Bowl.

But ergot drugs have side effects that many patients cannot tolerate. Not every patient even responds to them, and those who do sometimes become habituated, and wake up every day with a ""rebound'' headache almost as bad as the migraine it's replacing. And from the theoretical standpoint, the original vascular theory of migraines--which supposed that some substance circulating in the blood was causing the vessels to dilate--contained some inconsistencies. Why, wondered Michael Moskowitz, a neurologist at Massachusetts General Hospital, should a blood-borne problem show up on only one side of the head?

Over 20 years, Moskowitz and his associates traced the complex relationship between the cerebral arteries and the peripheral nerves of the face and head--anatomically, the ophthalmic division of the trigeminal nerve, which runs from a spot near the center of the skull up and over the eyes and toward the forehead. The cause is a mystery--""It may be a series of disorders that produce the same symptoms,'' says Temple University neurologist Stephen Silberstein--but something, perhaps a signal from the brain stem, activates the pain sensors in the trigeminal system. ""When these fibers are activated, they release protein fragments called neuropeptides,'' explains Mass General neurologist Michael Cutrer. Those substances, in turn, cause the blood vessels to dilate--and as they expand, they irritate the nerves further. ""Over a few hours,'' Cutrer says, ""the threshold is lowered so things that wouldn't cause pain ordinarily--even the faint pulsing of the heartbeat in the vessels--now do.'' It is that feedback cycle--nerve activation causing vasodilation, the expanded arteries irritating the nerves--that keeps a migraine going for as long as 72 hours.

In similar fashion, Cutrer has helped overturn what had been conventional thinking about the telltale auras. Under the vascular hypothesis, the arteries were believed to contract briefly before dilating, reducing the flow of blood to the brain and causing transient sensory and motor-control disturbances. By finding migraineurs among the employees at Mass General willing to be rushed into an MRI machine at the first sign of an aura--his first subject was himself--Cutrer showed that the aura also originated in the nervous system. In fact, it resembles a well-known cerebral event, first demonstrated in rats, known as a spreading depression of the cortex--a wave of decreased neural activity that moves like a shadow across the brain's surface. Intriguingly, the sequence of disturbances in migraine aura--from visual to tactile to language--also follows the topography of the brain. The same experiments also suggested that the pain of migraine does not originate with vasodilation; blood flow doesn't increase until hours after the aura has passed and the headache has begun.

Of more immediate significance, there was now a road map for how to design better drugs. Moskowitz and other researchers found receptors on the trigeminal nerve, designated 5HT, which served to shut down the inflammation and the transmission of pain. Serotonin, the neurotransmitter implicated in almost everything that happens in the brain, binds to these receptors; an injection of serotonin into the bloodstream will stop a migraine cold, although it is far too powerful for people to casually administer to themselves. (In addition, the ergot-based compounds that doctors had been using to treat migraine bind to the 5HT sites, which explains why they worked for some patients.) What was needed, clearly, were synthetic compounds that would bind specifically to the receptors implicated in migraine. These were the triptans. Sumatriptan, or Imitrex, introduced in 1993 and still by far the most widely used, was prescribed more than 6 million times in 1997, despite costing $14 a pill--and three times that in injectable form. ""This changed the whole face of treating migraine,'' says Dr. Alan Rapoport, director of the New England Center for Headache in Stamford, Conn. Two hours after taking 50 milligrams of sumatriptan orally, 61 percent of patients have improved significantly and 31 percent are pain-free. Taken by nasal spray or injected under the skin, it works even faster.

Imitrex was followed in the last year by Zomig, Amerge and Maxalt, and more are on the way. The new triptans work essentially the same way as Imitrex but have various advantages: they get to the brain faster or they last longer. (All triptans, though, are cleared from the body in a few hours, and the migraine sometimes returns.) Some patients use more than one of them--injectable Imitrex for a devastating migraine, say, and Zomig for the merely incapacitating. A new compound being tested by Eli Lilly binds to a different subset of the 5HT receptors, eliminating some of the side effects of the other triptans--tightness in the chest and occasional difficulty breathing.

Meanwhile, Imitrex has been a boon to someone like Pirsch, whose daily routine now is to wake up between 2 and 6 a.m. with a monumental headache, swallow a couple of painkillers and amino acids to boost her serotonin, wash down a massive dose of B vitamins with juice, shoot herself with a syringe full of Imitrex, pack her head in ice and go back to bed for a few hours before getting up for work. That way, she says, she can count on getting to the office an average of four days a week.

But every patient is different, and there are those for whom the triptans, for whatever reason, just don't work. Many of them are among the 2,000 new patients who come each year to Diamond's clinic, sometimes staying for as long as two weeks in its dimly lit inpatient rooms on a hushed, carpeted floor of Columbus Hospital. Seven or 8 percent turn out to have an underlying organic disease, such as a tumor or cervical arthritis; up to 5 percent resist treatment for psychological reasons, although Diamond says hardly anyone actually says, ""Not tonight, dear, I have a headache.'' The rest, he says, can be helped.

By the time patients come here, they've usually tried the ergots, the triptans and anything else they've read about, seen on television or picked up at the health-food store, such as St. John's wort and feverfew, a relative of the daisy flower. That describes Deborah Stevens, a soft-spoken 36-year-old from Huntsville, Ala., who checked into the Diamond clinic in early December. A former Air Force officer and engineer, she'd seen six neurologists in the last four years, had been on disability since 1996 and for several months had been surviving on narcotic painkillers. ""I used to be a private pilot; I worked on the space shuttle,'' she says quietly. ""Now I just get headaches.'' Her treatment over the next two weeks consisted of nine intravenous infusions of DHE, an ergot-based drug that enabled her to be taken off narcotics, followed by biofeedback training to reduce stress. Then a variety of pain relievers, looking for the combination that worked best; she was sent home, finally, with a calcium blocker, an antidepressant, an analgesic, a muscle relaxant and an anti-inflammatory, and she got through Christmas OK and was feeling pretty good heading into New Year's. ""Right now,'' she said last week, ""I'm doing pretty good. I'd like to go back to some of the fun things in my life.'' For someone like her, whose highest aspiration a few months ago was just to get out of bed, that's a pretty good measure of progress--and how far we still have to go.


Migraines occur in three times as many women as men, and they often happen during hormonal fluctuations, such as periods or ovulation. But hormones' role still isn't fully understood.


In life, patients say, migraines can be triggered by emotional stress, the weather, lack of sleep and a long list of foods. But it doesn't happen in the laboratory, so researchers are skeptical.


Overall, 18% of women and 6% of men get migraines. The 30s and 40s are peak years.


Doctors classify headaches into three main types. The worst, cluster headache, is also the rarest; tension-type headache is more familiar. But an estimated 25 million people get migraines, complicated combinations of intense pain and neurological symptoms like visual problems, nausea, vomiting and sensitivity to light and sound. Researchers haven't yet figured out the basic causes of migraines, but the last few years have seen a new understanding of its mechanisms and powerful new drugs for treatment.

The Pain Is All in Your Head. . .And It's Not Leaving

For decades, doctors thought migraines were psychological, or could be traced back to uncontrolled constriction and dilation of blood vessels around the brain. New theories paint a far more complex picture. Follow the numbers below for the latest ideas:

1 About 15 percent of people with migraines have a stage called an aura. Researchers think a wave of activity spreads across the cortex, causing visual hallucinations like flashes or blind spots.

2 Whether they have an aura or not, sufferers' pain begins when a signal from the brain--possibly the brain stem--turns on a branch of the trigeminal nerve leading to the face and forehead.

3 Trigeminal-nerve endings at blood vessels in the outer lining of the brain respond to the activation signal by releasing protein fragments called neuropeptides, a type of chemical signal.

4 These neuropeprides cause the blood vessels to enlarge; the nerve endings become inflamed. Blood pulsing in the vessels furthers the inflammation, prolonging pain in a kind of feedback loop.

Most people feel the pain behind or around one eye, always on the same side of the head. It feels like a pulsing dagger or pressure, and may get worse with each heartbeat. The pain can last for hours or days, and then vanish.

It can last for hours or come and go and feel like a dull, steady muscle ache on both sides or the front of the head. Treatment involves painkillers like aspirin or muscle relaxants.

Occurring daily for weeks, then disappearing for months, this type of headache pulses around the eye, temple and cheek. One eye tears; the nose runs. Inhaled oxygen and triptan migraine drugs work.


In addition to gender and age, there are other predictors of migraine prevalence:

VARIABLE WOMEN MEN Race and ethnicity Black 16.2% 7.2 White 20.4 8.6 Asian-American 9.2 4.8 Other 19.6 11.4 Household income Less than $10,000 20.8% 7.4% $10,000-$19,999 17.8 6.8 $20,000-$29,999 17.9 5.9 $30,000-$45,000 16.3 5.8 More than $45,000 16.3 5.3 Education Below 12th grade 21.2% 8.4% Completed HS 19.2 8.4 Post-HS 21.4 10.5 College degree 18.0 5.9 Postgraduate 16.3 8.5 Urban vs. rural population Less than 50,000 19.7% 6.2% 50,000-500,000 17.6 5.8 More than 500,000 16.4 6.0