"Byline: Christine Gorman And Alice Park With reporting by Jeff Chu and Kate Noble/London, Andrea Dorfman/New York, Harlene Ellin/Chicago and Jeffrey Ressner/Los Angeles Publication: Time International Edition: TIME Atlantic Issue: December 23, 2002 Vol. 160 No. 26 Publication Date: 12-23-2002 Page: 50+ Section: Health

HOW WE HURT

The first step in treating a headache is to determine what kind you have

MIGRAINE This type lasts from four hours to three days, with pulsing pain on one side of the head, nausea and sensitivity to light and sound

TENSION Diffuse, viselike pressure throughout the head. Attacks last from 30 minutes to a week

CLUSTER Also known as suicide headaches, these are the most painful kind. They occur in groups--as often as eight times a day--and are experienced as a searing pressure in one eye

OTHER Any number of medical conditions, from viral infection to brain tumor, can cause a headache. Treating the disease usually relieves the pain

PIPELINE OF PAIN

Using sophisticated images of the brain taken during the onset of a migraine attack, scientists have traced the path of a headache from the initial triggers to the final, throbbing outcome. While some of the details are still in doubt, the main outline is clear

1 Incoming

Any number of triggers can provide the spark that starts the process. In most people, it takes a combination of several factors, building up over time, to reach an individual's neurological threshold. These factors can be internal (hormonal changes, stress, lack of sleep) or external (changes in weather, diet, allergens) or both

2 Control Center

Most migraine triggers are funneled to the hypothalamus, one of the brain's main processing hubs, responsible for regulating hormones, sleep and hunger. Migraine symptoms such as nausea and vomiting are initiated by signals sent from the hypothalamus to the migraine generator

3 Migraine Generator

The hypothalamus fires signals to an area of the upper brain stem that contains the trigeminal nerve, a massive network of nerve fibers with tendrils that branch out to cover the entire brain like a helmet. Activating this nerve starts the migraine rolling

4 Pain

The throbbing pain of a headache is caused by the swelling of blood vessels in the outer covering of the brain-the dura-which has embedded blood vessels and pain-sensitive nerve fibers

Once the nerves are activated, they release compounds that awaken pain receptors and cause blood vessels to swell even more

5 Auras

In some migraine patients, visual cues and other sensory input generate a pulse of electrical activity that travels through the brain like a wave. The crest of this wave can garble the signals reaching the optic nerve. Result: many sufferers see visions of jagged lines and bright shining lights shortly before the pain sets in

Sources: Dr. Ninan Mathew, Houston Headache Clinic; Dr. David Buchholz, Johns Hopkins University School of Medicine

HOW TO COPE

Learning to live with headaches--or better still how to live headache-free--is a three-stage process. First identify your triggers and find ways to avoid them. Then determine the treatments that work best to relieve your pain. Finally, discover how to keep from getting headaches in the first place.

TRIGGERS

Everybody has his own list of headache triggers and his own breaking point. For migraineurs, the threshold is particularly low. The most common factors:

HORMONES Menses, stress

FOOD Caffeine, alcohol, nitrites (in hot dogs, for example)

ENVIRONMENT Allergies, shifting weather or changes in barometric pressure

SLEEP Too little or too much of it, crossing too many time zones

TREATMENT

Once an attack starts, over-the-counter analgesics are generally not strong enough to dull the pain. Triptans are the most popular prescription drugs. These target the brain chemicals that launch the migraine and bring relief within an hour for three out of four sufferers. Ergotamine and dihyroergotamine (DHE) are doubly effective. They block the inflammation of nerve cells that activate pain receptors while discouraging nerves from sending pain signals. Other antimigraine medications include corticosteroids, which calm inflamed pain nerves in the brain, and blood-pressure-lowering drugs such as beta-blockers.

PREVENTION

MEDICATION Besides lowering blood pressure, beta-blockers can help prevent migraines from getting started, as can drugs that relax muscles and calm hypersensitive nerves--including antiseizure drugs and even botox.

ALTERNATIVE STRATEGIES Because stress is a major trigger, many misgraine sufferers have cut down on attacks by reducing their stress level. Yoga, meditation and biofeedback can decrease stress-hormone levels and keep them low.

Three times as many women as men suffer from migraines. Men are five times as likely to have cluster headaches

Allowing migraines to go untreated is not only extremely painful but may make future attacks harder to control
 

For Astri Walseth, a 57-year-old teacher in Arendal, Norway, the first warning signs usually start with a "small something" in the back of her neck, which then creeps up behind her ear. "When I feel this, I know that a migraine is on its way," Walseth says. From that moment on, it may take anywhere from one to 12 hours before the really excruciating pain grabs the side of her head and won't let go for three or four days. And there's no way to predict when the migraines will strike. They can be triggered by almost anything: the smell of paint or perfume, the flickering pattern of sunshine and shade along a tree-lined road, or even sex. "That is one of the worst," Walseth says. "And it's such a shame because I have a lovely husband."

It was not that long ago that migraine sufferers like Walseth had no choice but to 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. And scientists are starting to uncover subtle defects in brain chemistry and electrophysiology that lead not just to migraines but to all kinds of headaches. Indeed, many neurologists now believe that most severely disabling headaches are actually migraines in disguise and so are more likely to respond to migraine medications than to standard analgesics such as aspirin, ibuprofen or paracetamol.

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 recently 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 a presentation by Dr. Stephen Silberstein of Thomas Jefferson University in Philadelphia, which showed that the antiepilepsy drug topiramate significantly reduced both the occurrence and duration of migraines. But the real excitement came with new research into methods of blocking a key neuropeptide called calcitonin gene-related peptide, or CGRP (more on that later).

In order to use these newly available drugs, patients must consult healthcare professionals first--and many headache sufferers don't. "The most common treatments are over-the-counter analgesics," says Anne MacGregor, director of the City of London Migraine Clinic, "because around 50% of people with migraine never go to see their doctor."

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. Overindulgence at the office Christmas party calls for rest, fluids and cheap remorse; a headache caused by a bacterial infection would be treated with an antibiotic.

The most common type of primary headache is known as the tension headache, which is essentially two different conditions. One arises from muscular tension, as when you get a stiff neck from driving. This condition responds to ordinary painkillers or massaging the affected muscle. The other sort is more the result of emotional tension or stress-related depression. "People will be very vague about the symptoms," says MacGregor. "They will describe it as a band around or a weight on top of the head. That type of headache responds to treating the underlying emotional problems."

This treatment doesn't work for the mercifully uncommon cluster headache, so named because an attack typically repeats itself, often daily, with each episode lasting from an hour to 90 minutes. 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, or extreme sensitivity to both light and sound. By contrast, patients suffering from tension 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 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.

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 one in five migraine patients. Others wonder whether 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, Maryland. "Each of us has his own 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 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. K. Michael Welch, a migraine researcher at the University of Kansas Medical Center, "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. 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. "CGRP is one of the areas that are very interesting," says Troels Jensen, professor of neurology at Denmark's Aarhus University. "When CGRP is released there is a dilatation of the vessel. Many headache sufferers have this dilatation and pulsating type of sensation. If you can prevent the release of CGRP you have an indirect pain-inhibiting effect." But 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.

Since migraine is so much more common in women than men, researchers like MacGregor are looking into a possible link with female hormones. An extensive study showed that falling levels of estrogen in the lead up to menstruation triggered an attack. But MacGregor also found that women on hormone replacement therapy, who had high levels of estrogen, tended to experience migraine with aura. Her conclusion: "The hypothalamus, the part of the brain that is responsible for controlling the menstrual cycle, is also implicated in migraine."

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. At the City of London Clinic, MacGregor starts treatments by asking migraineurs to keep diaries of their attacks. "People are best able to control a problem if they understand why it is happening," she says.

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. "Used in low doses, antidepressive drugs can be very effective in migraine," says MacGregor. "We use them to try to break the cycle of the problem, while we try to uncover whatever else may be going on." But drugs should be used sparingly. "If you prescribe a whole lot of medication to someone who is not into taking prescribed drugs, you are not helping," she says. "Managing migraine is a case of tailoring the management to the needs of the individual."

As helpful as beta-blockers, antidepressants and even antiepilepsy 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 eventually hit on the combination of medications and lifestyle changes that works for them. For Walseth the triptan Relpax has brought some relief. "I used to have between 15 and 18 days a month with migraine, " she says. "Now I have a maximum of 10 days." It's far from a cure, but at least it makes daily life more bearable.

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