Migraine is at once one of the most common diseases in the world, and one of the most misunderstood. The word migraine comes from the Greek hemikrania, meaning half-skull, a reference to the severe, one-sided head pain that characterizes the condition. But migraine is much more than a headache. Previously believed to originate in blood vessels inside the skull, migraine is now recognized to be a disease of the brain. There, disturbances in delicately balanced neuronal systems lead to episodes of throbbing head pain, accompanied by sickening sensitivity to light, sound, and movement. People with migraine (migraineurs) experience attacks monthly, weekly or even daily, and attacks may increase in frequency over time.
Migraine attacks last for several hours to several days, and often include nausea and vomiting. “That is time when migraineurs cannot work or function,” said Messoud Ashina, a neurologist and professor at the Rigshospitalet, University of Copenhagen in Denmark. “Basically, for each attack, you take 2 or 3 days out of your calendar.”
That lost time hurts doubly, because migraine often coincides with the prime productive years of life, between the ages of 20 and 55. And migraine is exceedingly common—nearly half of women and one-fifth of men experience a migraine attack at some point in their lives, and one-fifth of women report migraine in any one year. According to data from the World Health Organization, migraine is the sixth leading cause of disability in the world.
Now, based on research started 30 years ago, a new crop of experimental medicines are in the works that appear to efficiently and effectively prevent migraines. If the drugs pass the final stage of testing—and they are expected to do so—they could potentially revolutionize the treatment of recurrent migraines, by targeting the unique biological basis of the disease.
Starts and stops
The story begins in 1985, at a scientific meeting in Sweden. Lars Edvinsson of the University of Lund had been working on an interesting new neuropeptide, a small protein released by nerve cells to communicate with neighboring cells and tissues. The peptide, named calcitonin gene-related peptide (CGRP), was found in the trigeminal nerves, whose branches innervate the face and head and are believed to be the source of migraine pain. Work at the time suggested that CGRP, released by trigeminal nerves, was mainly involved in regulating blood flow through cranial arteries that supply the brain.
Also at the meeting, a young Australian neurologist named Peter Goadsby became intrigued by the idea that CGRP might play a role in migraine. In the light of a long June evening, Goadsby, who is now a migraine clinician and researcher at King’s College London, and Edvinsson planned out a series of experiments to explore that question. Several years of work in both animals and people culminated in a study of CGRP in the blood of migraineurs, revealing that levels of the peptide are elevated during migraine attacks.
“Once we found that CGRP was the positive marker, the hypothesis was that if you blocked that, you would control the migraine attack,” explained Goadsby. In support of that idea, they found that triptans, a class of drugs that are used today to treat migraine, reduced CGRP levels at the same time the medications resolved headache. Later, other researchers found that giving CGRP to migraineurs could trigger a migraine attack, pinpointing the neuropeptide as a definitive cause of migraine.
Several pharmaceutical companies picked up the CGRP lead and ran with it, developing drugs that inhibited CGRP’s actions by interfering with its binding site on cells, the so-called CGRP receptor. After extensive testing in thousands of migraineurs, the results looked “fantastic,” said Rami Burstein, a professor of anesthesia and neuroscience at Harvard Medical School. “It was clear that this molecular target would be effective in the treatment of migraine,” Burstein said.
Then, at almost the last moment, several participants in the clinical trials showed signs of liver damage. After years of work and millions of dollars spent, the safety of the treatment could not be ensured, and in July 2011, the drug maker Merck dropped the project. Several other companies working on similar treatments followed suit.
The sudden and unexpected failure was a shock and a loss to both the pharmaceutical industry and to the migraine community. But it left the clear message that targeting CGRP, if it could be done safely, had enormous potential for headache treatment.
The setback did not last long, as several companies quickly embarked on a new and potentially safer way to block CGRP. The new approach uses antibodies, proteins borrowed from the immune system that could attach to and neutralize either CGRP, or its receptor. Antibody therapies are given by injection each month or every few months, which makes them suitable for prevention, though not for acute treatment of ongoing migraine episodes.
Today, four companies are racing to complete testing and apply for marketing approval of the new antibody-based medicines. The results of clinical trials have been trickling out over the past year, at meetings and in journal publications, and they are consistent. Four antibodies, three to CGRP and one to its receptor, have been given to patients with frequent migraine, defined as 8-11 headache days per month. One antibody was also tested in people with chronic migraine (more than 15 headache days per month). All of the antibodies decreased headache frequency by at least half in half or more of the people tested, with a small proportion of patients (ten to twenty percent) getting total relief. But not everyone responded—CGRP may not work for all people, and it will be important to understand if some migraineurs have other causes to their pain.
Because they are natural products of the immune system, antibodies are relatively non-toxic. So far no serious side effects have been seen with the CGRP treatments, but more time will be needed to draw any conclusion about long-term safety.
The introduction of CGRP antibodies would mark a “seismic change” in migraine treatment, Goadsby said. For the first time, migraine patients would have a drug specifically developed to treat migraine, he said. Existing drugs, in contrast, have mostly been borrowed from other diseases. But many questions remain. On the clinical side, doctors want to understand which patients are most likely to benefit from CGRP-targeted treatment. On the neurobiology front, little is known about the details of CGRP’s actions in migraine: Where is CGRP released? Where are its receptors? How does it work to cause not only pain, but also other symptoms of migraine?
These are good questions to have, said Goadsby. “It’s a very good example of how drug development leads to new questions which academia can push forward on. It’s a kind of virtuous cycle,” he said, that will ultimately lead to better treatments.
Andrew Russo, a neuroscientist at the University of Iowa, would like to know more about how CGRP causes migraine, and he has some mice that might help.
As Russo explains, CGRP acts to modulate neurotransmission, fine-tuning the chemical communication that occurs in the nervous system. In general, CGRP seems to turn up the volume on chatter passing from one neuron to another.
In migraineurs, “CGRP could be increasing the shouting across sensory synapses, so that input that is not normally interpreted as painful now gets interpreted as painful,” said Russo. He compares it to listening to a concert—at normal volume, the music is pleasant and fine, but if it gets turned up too loud, it becomes unpleasant or even painful.
Light is the classical example—sensitivity to light, or photophobia, is diagnostic of migraine, and differentiates it from other headache conditions. Throughout the brain, there are many target sites where CGRP might heighten sensory perception or alter sensory processing to cause light, but also sound, smells and even touch to go from pleasant or unoffending to painful during a migraine attack.
If you give a mouse a migraine
A few years ago, Russo started to think there must be some way to use mice to figure out exactly how CGRP was acting in migraine. The problem was that people had been injecting CGRP into rats and mice for 20 years, and no one had ever reported anything like migraine behavior. But then, in 2002, Jes Olesen and colleagues at the University of Copenhagen showed that if you inject CGRP into healthy human volunteers, it caused at most a mild headache. Giving the same dose to a migraineur caused a full-blown migraine attack.
That work says there is something fundamentally different about how migraineurs respond to CGRP. “It seemed to me the most likely reason was they were more sensitive to CGRP,” Russo said. Using genetic engineering, Russo was able to replicate this state in mice, by increasing the number of CGRP receptors on cells, so that CGRP became much more effective at cranking up the volume of neuronal signals.
That raised a key question—how can you tell if a mouse has a migraine? The short answer is, you really can’t. But Russo figured he could look for signs of other behaviors related to migraine, like light sensitivity.
To do that, Russo got a cardboard box, cut a small hole in it, put his mice inside, and watched how the animals acted. The CGRP receptor mice scampered in and out, spending about half the time in the dark box, and half outside in the light, like normal mice. But after Russo injected the mice with CGRP, they spent much more time in the dark, and of that time, spent more time laying still. This was reminiscent of the behavior of migraineurs, who often seek to lie down in a dark room because light and movement aggravate their pain.
Russo’s group has also found that the mice are more sensitive to touch. “Touch that was not painful, once you give them CGRP, becomes painful,” he explained. That phenomenon, known as allodynia, is present in many migraineurs. The mice may even show signs of spontaneous pain when given CGRP—Russo is working on measuring changes in facial expressions, and in particular eye squinting, that the mice do even in the dark, and that may be signs of headache.
Russo wants to be clear about one thing—“We do not know if our mice have a migraine or not and we may never know that.” That’s because at present the only way to know if a person—or a mouse—has a headache is to ask them. “Our mice obviously can’t tell us they have a headache but they show behavior that’s consistent with migraine symptoms.”
Brain on the verge
While boosting CGRP receptor levels seems to predispose mice to display migraine-like behaviors, researchers only have theories about what makes people more or less prone to migraine attacks. Genes are clearly important—children of a migraineur have an increased chance of having migraine themselves. In the last two decades, researchers have identified genes for inherited migraine disorders that strike a few unlucky families, and genes that contribute to the risk of the common kinds of migraine that affect millions of people. The results point to several potential causes for migraine, including an inherited state of neuronal hyperexcitability in the brain, which interacts with environmental triggers to initiate attacks.
Back in 1996, Michel Ferrari and colleagues at Leiden University Medical Center in the Netherlands discovered the very first migraine gene. Working with families suffering from generations of neurological disease, researchers subsequently uncovered mutations in three different genes that cause a rare form of severe migraine. All three genes direct the production of ion channels, proteins that regulate the excitability of neurons. When one of the genes, CACNA1A, was mutated in mice, the animals displayed classic features of migraine, including signs of photophobia and head pain that responded to triptans. At the neuronal level, the mice were more responsive to stimuli and showed a much lower threshold for triggering of cortical spreading depression (CSD), a pattern of brain activity linked to the initiation of migraines in people. And, female mice were more susceptible to CSD, mimicking the increased susceptibility of women to migraine.
The results are intriguing, but how they will translate to people is not clear yet, says Arn van den Maagdenberg, a geneticist also at Leiden University who created the mutant mice. Together with Ferrari, van den Maagdenberg leads the EuroHeadPain research initiative, which brings together collaborators from 11 different European institutions to pursue multidisciplinary research on markers and mechanisms of migraine.
Van den Maagdenberg points out that the CACNA1A gene is not in fact mutated in people with common forms of migraine. Nonetheless, these kinds of studies give researchers a “foot in the door,” he said, to build and test hypotheses about the causes of, and possible cures for, migraine.
One hypothesis is that neuronal hyperexcitability in the migraine brain leads to a higher production of CGRP in response to migraine triggers. Van den Maagdenberg says there is some evidence for this in the mice, but more studies will be needed to cement the connection.
The work of Ferrari and van den Maagdenberg, Goadsby, and a host of other researchers has fueled an important shift in the perception of migraine among physicians and patients.
Arne May, a neurologist at the University of Hamburg in Germany, said that when he started in the field 25 years ago, migraine was not taken seriously. “It was completely accepted that migraine was a psychogenic disorder of women. There were a lot of jokes about migraine,” he said.
Twenty years ago, May and his colleagues were among the first to use magnetic resonance imaging (MRI) to analyze brain activity during headache attacks. They identified a small spot in the brainstem that became active in migraine, but not other types of headaches. Finding that unique migraine signature in the brain “was hugely important,” May said. “For the first time we could say, this is a disease, and we can show you where in the brain the motor for the disease is,” he said.
Whether through imaging, genetics, or animal studies, research that advances understanding of migraine as a biologically based, neurological disease is vitally important to finding new treatments, said Goadsby. Yet the fact is that migraine research is chronically underfunded, considering the number of people with the disease, and its cost to society. In the United States, the National Institutes of Health spends about $20 million annually for migraine research, or less than one dollar for each of the 36 million Americans with migraine. There is no national strategy for headache research.
“It’s terrible to see people totally disabled from migraine, when if we can get the right treatment, they can function normally. We are not talking about prolonging someone’s life for 6 months, we’re talking about taking a 35-year-old and making him or her fully functional,” said Goadsby. “Migraineurs ought to be pushing the government quite hard for their fair share of the research cake.”
Pat McCaffrey is a freelance science writer in Boston, MA, US.