pain in the brain

The cause of migraine has eluded scientists for centuries. Now, a theory that blames one particular nerve has led to the development of drugs that prevent the attacks

The article is published with the approval of Scientific American Israel and the Ort Israel network

David Noonan

The 63-year-old man, who held the high position, was unable to perform his job. The migraine had disrupted his entire life as an adult, and now he was in the midst of another series of attacks. "I have but a short moment, in the morning, when I can read, write, or think," he wrote to a friend. After that he had to lock himself in a dark room until night. Thus, during his second term at the beginning of the spring of 1807, the President of the United States, Thomas Jefferson, was unable to function every afternoon because of the most common neurological problem in the world.
Jefferson, who was one of the authors of the American Declaration of Independence, never got over what he called his "periodic headaches", although the attacks apparently subsided after 1808. Two centuries later, 36 million Americans suffer from migraines and the same pains that afflicted the president. Similar to Jefferson, who tried to treat himself with an infusion of tree bark that contained quinine, today's patients also try a variety of treatments, from heart medications to yoga and medicinal herbs. The search continues because modern medicine, which has repeatedly failed in its attempts to discover the cause of migraine, has also failed to find a reliable cure.

These days a new chapter was written in the long and sometimes strange history of migraine. Neurologists believe they have identified an oversensitive nervous system that triggers the pain, and are in the final stages of testing drugs to calm the overactivity of these cells. These are the first drugs ever designed specifically to prevent crippling headaches before they start, and the drugs may be approved by the US Food and Drug Administration as early as 2016. If they live up to the expectations created by the studies so far, which included about 1,300 participants, millions of headaches may be avoided altogether.

"This completely changes our paradigm for treating migraine," says David Dudik, a neurologist at the Mayo Clinic Arizona campus and president of the International Headache Society. Although there are specific medications for migraine that stop the attacks after they have started, the "holy grail" for both patients and doctors is prevention.

Migraine attacks, which affect nearly 730 million people worldwide, usually last between 4 and 72 hours. In most patients, the migraines are irregular, and they bother them for 14 or fewer days every month. Chronic migraine sufferers, approximately 8% of all patients, experience 15 or more "headache days" each month. There are often preliminary symptoms of an attack: fatigue, mood swings, nausea, and more. 30% of migraine sufferers also experience visual disturbances called halos before the onset of the attack. The economic cost of migraine in the US, including direct medical costs and indirect costs such as lost work days, is estimated at approximately 17 billion dollars per year.

In the five thousand years since migraine symptoms were first recorded in Babylonian documents, treatment methods have reflected both our evolving understanding and our almost comical ignorance of the subject. In the Greco-Roman period, common treatments were bloodletting, drilling a hole in the skull or burning the shaved scalp with a bleached iron rod. The tenth century AD was perhaps the high point of the wrong treatments, when Ali Ibn Issa, who was also a talented ophthalmologist, recommended tying a dead mole to the head. In the 19th century, medicine with the help of electricity came into vogue, and migraine sufferers were electrified in a variety of devices, including the hydro-electric bath, which was actually an ordinary electrified bath.

At the beginning of the 20th century, doctors turned their attention to the role of blood vessels. This happened following the identification of strong pulsations in the patients' temporal arteries, the description of the migraine by the sufferers as throbbing pain, and the report of relief following pressure on the carotid arteries. For decades afterward, dilation of the blood vessels in the brain was thought to be the main cause of migraines.

This idea was further strengthened in the late 30s, with the publication of an article on the use of the substance ergotamine tartrate, an alkaloid that was known for its ability to constrict blood vessels. Despite the many side effects, including vomiting and addiction, this substance was able to stop migraine attacks in some patients.

But even if vasodilation was part of the mix, it wasn't the only thing going on in the brains of migraine sufferers, as the next wave of treatments proved. In the 70s, heart patients who also suffered from migraines began to tell their doctors that the beta-blocking drugs they took to slow the heart rate also reduced the frequency of migraine attacks. Even those who took medication for epilepsy and depression, or received cosmetic botox injections, reported relief from their headaches. Headache specialists began prescribing these "borrowed" drugs to migraine sufferers, and eventually the US Food and Drug Administration approved five of them for migraine treatment. Unfortunately, it is still not clear how exactly these drugs help, and besides, they have many side effects and only work in 45% of cases. According to Dodik, they may reduce hyperexcitation in the cerebral cortex and the pain transmission pathways in the brainstem.

Hypersensitive cells respond to normal lights, sounds and smells by releasing chemicals that transmit pain signals and cause migraines.
The first dedicated migraine medications, called triptans, appeared in the 90s. Richard Lipton, director of the Montefiore Headache Center in New York City, says that the triptans were developed based on the old idea, according to which the main cause of migraine is blood vessel dilation. The triptans were supposed to prevent this expansion. Ironically, later studies showed that these drugs actually disrupted the transmission of pain signals in the brain, while vasoconstriction was not essential. "But they work anyway," says Lipton. A review of 133 detailed studies on triptans showed that they relieved headaches within two hours, in 42% to 76% of sufferers. The triptans are taken after the onset of the attack, and they have become a reliable primary treatment for millions of people.

What triptans are unable to do is prevent migraine attacks from occurring in the first place, and this is what Peter Goadsby, director of the Headache Center at the University of California, San Francisco, has been dreaming of for thirty years. In the 80s, Goadsby focused on the trigeminal nerve, which had long been known to be the main pain pathway in the brain. He suspected that this is where the migraine works. Animal studies have suggested that the nerve branches that come out of the back of the brain and surround various parts of the face and head have overactive cells that may respond to normal lights, sounds, and smells by releasing chemicals that transmit pain signals and cause migraines. The increased sensitivity of these cells may be hereditary: 80% of sufferers have a family history of migraine.

Goadsby wrote his first paper on the subject in 1988, and other researchers (including Dodik) joined him. Their goal was to find a way to stop the pain signals. One of the chemicals found in high levels in the blood of people in the midst of a migraine attack is the peptide CGRP: a neurotransmitter that is released from one nerve cell and activates the next one in the neural pathway. It has been difficult for researchers to target CGRP and disrupt its action, because it is not easy to find a molecule that will affect it on the one hand, but on the other hand will not interfere with the action of other important chemicals.

Over time, biotech engineers' abilities to control and design proteins have improved, and several pharmaceutical companies have developed monoclonal antibodies to fight migraine. These artificial proteins bind tightly to CGRP molecules or their receptors in the trigeminal nerve cells, thereby preventing the cells from being activated. These new drugs are "like guided missiles," Dudik says. "They directly hit the target."

It is this specificity and the fact that scientists understand exactly how the drugs work that excite Dodik, Goadsby and others. In two studies conducted on the subject, which included a total of 380 people who suffered from acute migraine up to 14 days a month, as well as control groups that received a dummy drug (placebo), it was found that a single dose of a CGRP drug reduced the number of headache days by more than 60% (63 % in one study, and 66% in the other). Also, 16% of the patients did not suffer from a migraine at all for 12 weeks out of the 24 weeks of the experiment. Today, larger clinical studies are being conducted to confirm these findings. Meanwhile, the CGRP drugs prevent migraines better than the questionable heart or epilepsy drugs, and they have far fewer side effects. The drug is given monthly in a single injection.

Migraine experts are also looking at other treatments, including forehead and eyelid surgery to reduce pressure on the trigeminal nerve, as well as intracranial magnetic stimulation (TMS), which is a non-invasive way to influence nerve cell activity.

According to Lipton, he has had good results with TMS. He also referred patients to surgery, but he says "it was disappointing," and he does not recommend it. Goadsby sees surgery and high-tech treatments as an act of desperation. "They look to me like a call for help. If we understood migraine better, we would know better what we should do."

Although it now appears that the cause of migraine lies in the trigeminal nerve, according to Goadsby, the cause of the hypersensitivity of the cells is still shrouded in fog. "What is the nature of the hereditary factor when you inherit migraine from your parents? And why do you and I don't?" If researchers can decipher the genetics of migraine, perhaps Jefferson's "periodic headaches" will lose their painful grip.