New understanding of migraines may lead to more effective treatments

April 26, 2000

Hypersensitive skin reveals clues about mechanism of migraine pain The painfully sensitive skin that accompanies many migraines has revealed a new understanding of the debilitating headaches. The latest findings from Boston researchers are the first human test of a migraine model that may explain why current medications are ineffective in many cases and suggests a new target for the next generation of migraine drugs.

Beth Israel Deaconess researchers documented extreme skin sensitivity in 79 percent of migraine sufferers who were tested several hours after their headache pain began. The other 21 percent of people with migraines showed no increase in skin sensitivity. The study of 42 people is published in the May issue of the Annals of Neurology.

"Patients tell us they can't brush their hair, wear earrings or eyeglasses, or shave their beards because it's so painful," says first author Rami Burstein Ph.D., a pain researcher in the Beth Israel Deaconess anesthesiology department. "The immediate implication of this finding, and the understanding of the neuronal mechanism behind it, is that patients need to treat their migraines as soon as the pain starts." Burstein is also an associate professor at Harvard Medical School.

Migraines affect an estimated 25 million Americans, mostly women. There is no known cure for migraine disease, only treatments for the symptoms, and the treatments are ineffective in many cases. In addition to the throbbing pain in the head or around the eyes, migraine symptoms can include flashing lights, zigzag lines, or temporary vision loss; speech difficulty; tingling of the face or hands; and nausea. Although hypersensitive skin may not come as a surprise to some patients and experienced doctors, this is believed to be the first time these symptoms have been documented in rigorous testing.

"This is the most important paper on headache in a long time," says Stephen Silberstein, M.D., professor of neurology at Thomas Jefferson University in Philadephia and director of the Jefferson Headache Center. "It's a logical approach to the problem of headaches, beginning with a laboratory model, validating it in the clinic and suggesting therapeutic options."

Researchers surprised by some findings

The study verifies in humans for the first time a migraine model proposed by Burstein and his colleagues four years ago in the journal Nature. Experimental headaches in rats had suggested the underlying mechanism of the throbbing, pounding sensation of migraines. Pain signals from blood vessels inside the head made the nerves hypersensitive, converting routine blood pulsing into throbbing pain during a migraine.

Further animal studies also predicted increased skin sensitivity in people, especially around the eyes on the side of the head where the migraine occurs. The same pain signals that sensitize the nerve also sensitize spinal cord neurons at the base of the skull. There, where other nerves connect, the sensitized neurons distort normal sensory signals from skin around the eyes and send a message of pain up to the brain.

In the latest study, researchers were surprised to find that some people in the study reported skin sensitivity at other places on their faces or heads, not just around their eyes, and 42 percent of migraineurs with hypersensitive skin reported sensitivity all over their bodies.

It's possible that hypersensitive neurons in the spinal cord at the base of the skull may sensitize yet another set of neurons, these ones in the thalamus. This may explain why tight clothes, jewelry, a shower, and even the weight of a blanket become painful and irritating. In turn, the thalamus may misinterpret normal signals from other parts of the body as painful. Burstein and his colleagues will return to the animal model to test the idea.

The researchers caution that the prevalence of increased skin sensitivity documented among patients at a pain center may be higher than among migraine sufferers in a general population.

"This study breaks new ground in this field," says Michael Moskowitz M.D., professor of neurology at Harvard Medical School and Massachusetts General Hospital. "It provides the first explanation of certain migraine symptoms not previously understood."

Lessons for doctors, patients

Currently approved migraine medications act on the blood vessels and the pain fibers that carry the initial pain signals, not at the level of the spinal cord where the sensitization is taking place, Burstein says. For people with skin sensitivity, the study suggests that current migraine medications are most effective if taken immediately at the onset of a migraine attack. Then, they can prevent the distorted signals from being sent to the brain. Unfortunately, the cost of medications, the uncertainty of early migraine warning signs, and the onset of migraines during sleep may discourage effective use of current medications for some people.

Future directions

The study suggests a target for a new generation of migraine drugs that would prevent hypersensitivity of the spinal cord neurons at the base of the skull. Burstein and his colleagues continue to work on understanding the molecular basis of changes in the properties of the neurons in hopes of eventually preventing changes or reversing the sensitization.
The research was funded by grants from the National Institutes of Dental and Craniofacial Research and the National Institutes of Neurological Disorder and Stroke. Other funding came from the Education Fund of the Department of Anesthesia and Critical Care at Beth Israel Deaconess Medical Center; the Goldfarb family of Hartford, Conn.; and the Boston Foundation.

Co-authors on the paper published in the Annals of Neurology include: David Yarnitsky, M.D., chief of neurology, Rambam Medical Center, Israel, a specialist in sensory testing in humans; Itay Goor-Aryeh, M.D., director of invasive pain medicine, BIDMC Pain Clinic; Bernard Ransil, Ph.D., M.D., biostatistician in the BIDMC neurology department; and Zahid Bajwa, M.D., head of the BIDMC headache clinic, whose patients participated in the study.

Beth Israel Deaconess Medical Center is a major independent teaching hospital for Harvard Medical School and is the third largest recipient of NIH funds among independent teaching hospitals.

VISUALS: An illustration will be available early Wednesday, April 26, at Study participants will be available to media at 10 am Thursday, April 27. Please call 617-975-6150 to make arrangements.

Beth Israel Deaconess Medical Center

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