Ouch! My Head Hurts.

photo by Cameron Whitman / iStock

Photo by Cameron Whitman / iStock

DESPITE EXCITEMENT over the years about one new migraine treatment after another, most sufferers have found little relief.  In the early 2000s came the discovery that laboratory-produced antibodies might prevent these excruciatingly painful experiences.

Since then so-called migraineurs have waited — patiently and painfully — as the new drugs made their way through FDA testing process, only recently arriving at Stage III trials, which are large human studies of safety and efficacy.  Now people are talking about widespread availability “later next year.”

Migraine headaches affect 10-12% of females and 6-8% of males, and are among the world’s most prevalent neurological conditions.  Migraines can be inherited, and some people are “superresponders,” such as someone who had a migraine every day from early childhood into her mid-20s.

The migraineur’s brain is like a car with a heightened alarm system that “goes off simply because you walked close to it,” says Mayo Clinic neurologist David Dodick.   Often more than headaches, migraine attacks  are complex events that cause brain activity to be “completely dysregulated,” Dutch neurologist Michel Ferrari told Science magazine.

Since the early 20th century, dilated veins and arteries in the brain have been blamed for migraines — in part because patients report throbbing blood vessels in their head during an attack.  Drugs introduced in the 1990s called triptans selectively constrict blood vessels in the brain and remain the most widely prescribed treatment.  While they can lessen the severity of headaches, they don’t reduce the overall number and, when taken frequently, can cause even worse headaches.  Other treatments include regular injections of botulinum toxin type A, and drugs such as beta-blockers, anticonvulsants and calcium-channel blockers.

Then came fMRIs (functional magnetic resonance imaging), which showed no relationship between abnormal blood flow in the brain and the pain of migraine attacks. What did occur was the release of a molecule called CGRP (calcitonin gene-related peptide), found in brain pathways that process pain and in brain regions that regulate blood flow.

“This is the most exciting thing we’ve seen so far,” said Swedish neurologist Lars Edvinsson, who studied blood taken from the jugular veins of people coming to the Emergency Room for severe migraines.   Besides expanding blood vessels, CGRP turned out to be a previously unknown pain-signaling neurotransmitter.

Rather than patterns of abnormal blood flow, it was rising levels of CGRP that triggered an attack.  In one study, CGRP injected into the blood of migraineurs produced migraine-like headaches whereas non-migraineurs had little reaction.

The first approach to treatment used compounds that block CGRP’s receptors, but these trials were stopped due to side effects.  The next step was antibodies, because they can be very specifically directed at substances causing problems.  Monoclonal antibodies created in the lab attacked CGRP and also mobilized the body’s own immune response.

Because these antibodies are too large to penetrate the blood-brain barrier and thus circulate only in the peripheral nervous system — their successful treatment of migraines led to the exciting discovery that neurological conditions could be treated from outside the brain, creating hope that other pain disorders like cluster headaches and fibromyalgia might also be treated this way.

“It is the only hope on the horizon, Cornell neurologist Joseph Safdieh told the New York Times.  For a subset of superresponders, just one injection of CGRP-blocking antibody stopped migraines entirely for six months.

Phase I and II trials on several thousand people over six-month periods have shown no significant side effects. Said corporate neuroscientist Corey Goodman: “I don’t think it’s too early to start talking about a cure for some patients suffering from this debilitating disease.”

Others are skeptical.  “If CGRP really is a fundamental mechanism, you would expect a much higher proportion of patients to be completely free of attacks,” says Ferrari.  Others point out that trials lasting longer than six months are needed to insure the safety of long-term use: because CGRP dilates arteries throughout the body to maintain blood supply to the heart and brain, blocking CGRP could amplify the effects of a minor stroke or cardiac incident.  Or it could cause high blood pressure that affects the kidneys or lungs.

Also, because other factors such as stress play a role in spurring migraines, some suspect these complex events could be symptoms of several different conditions.   Although one-quarter of migraine sufferers are male, female hormone fluctuations appear to play a role. Tennis player Serena Williams has blamed some losses on “menstrual migraines.”  And a medical editor who had terrible migraines before almost every deadline said hers ended entirely with menopause.

What gives sufferers the best hope is that four companies are currently competing to get the first monoclonal antibody drug onto the market.

— Mary Carpenter
Mary Carpenter is the well-being editor of MyLittleBird. Her most recent post was on the high costs of health care for women. 

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