Jessica Ailani, MD, director of the MedStar Georgetown Headache Center, had been treating a woman for several years with Botox injections, a standard treatment to relieve frequent, debilitating migraine. The patient, a health care researcher, was doing okay but not great, so she asked if any other options might work better.
Ailani decided to try galcanezumab, a new medication in a class called calcitonin gene-related peptide (CGRP) inhibitors. A few visits later, the woman reported publishing three scientific papers in the past seven months — more than her output for the previous eight years.
“She said, that’s the difference — the cognitive clarity, being myself, being able to function. I can make a commitment because I know I’m going to feel good,” Ailani recalls. “She said I’m back to that person I was 20 years ago.”
For decades, science provided no major breakthroughs to migraine sufferers. But now research at teaching hospitals and elsewhere is finally offering hope to patients like Ailani’s, who sometimes experienced limited or even no success with earlier methods. A new type of drug approved by the Food and Drug Administration in recent years blocks a pain pathway associated with migraine. In addition, new devices use electrical or magnetic pulses to quell migraine-related brain activity. And work continues as researchers seek more answers to aid the 38 million migraine sufferers in the United States.
“Gone is the day that we just use treatment options that were approved for other indications for our migraine patients…. We are now in an era where we understand what is happening in migraine inside of the brain.”
Amaal J. Starling, MD, Mayo Clinic
Importantly, the new discoveries are the first treatments designed specifically for migraine. Previous drugs had been developed for conditions such as epilepsy or high blood pressure and recruited into the battle against migraine.
“Gone is the day that we just use treatment options that were approved for other indications for our migraine patients in clinical trials and find that they might be effective,” says Amaal J. Starling, MD, a neurologist at the Mayo Clinic in Arizona. “We are now in an era where we understand what is happening in migraine inside of the brain. Based on our understanding, we’re designing treatment options.”
These new treatments “all are testament to the fact that if you dig at it enough and start to understand what’s important in the disease, you can actually target a therapy to that,” says Peter Goadsby, MD, a professor of neurology at the University of California, San Francisco, School of Medicine. “It’s a really exciting time to be in neurology broadly and particularly in headache medicine — to have people whose lives have been blighted by the problem where it’s just turned around. They come back and their lives have been transformed. The look on their faces is priceless.”
The burden of migraine
Migraine is not just about headaches. Attacks can include symptoms such as throbbing pain, nausea, vomiting, and acute sensitivity to light and sound. They may be preceded by aura — nerve-related symptoms such as flashes of light, blind spots, difficulty speaking, and tingling in the face, arms, or legs. Migraine may last four hours or three days. Attacks may occur rarely or several times a week.
According to the American Migraine Foundation, 1 in 5 U.S. women have migraine. So do 1 in 16 men and 1 in 11 children. Because migraine is common and debilitating, the burden on personal wellness and economic productivity is staggering. In 2016 the combination of medical costs and lost productivity due to migraine in the United States totaled $36 billion, according to a study published in the American Journal of Managed Care.
“There are so many people who are brilliant and successful who have had to walk away from work because this disease has completely destroyed them.”
Jessica Ailani, MD, MedStar Georgetown
“It takes careers away from people,” says Ailani. “You know, they could have been a teacher and now they’re an assistant. They could have been a professor and now they’re the janitor in the hallway. There are so many people who are brilliant and successful who have had to walk away from work because this disease has completely destroyed them.”
For a long time, researchers didn’t know how migraine worked. “The understanding used to be that migraine was a blood vessel disorder — they dilated and they constricted,” says Stephen Silberstein, MD, director of the Jefferson Headache Center of Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia. “But now we know that blood vessels are innocent bystanders.” Instead, Silberstein explains, it’s primarily a disorder of the trigeminal nerve and its connections. That nerve wraps around the eyes, forehead, and mouth, and among other roles, affects sensation in a person’s face.
Thirty years ago, Goadsby did some of the earliest work establishing that abnormal nerve activity preceding migraine released a flood of proteins called CGRPs, which produced pain in some people with migraine as the compound latched on to a neural receptor. This CGRP activity could be measured by increased concentrations of the peptide in the blood. In fact, administering CGRP could induce migraine in many patients. Understanding this CGRP pathway opened the door to new migraine treatments.
Locking out CGRPs
The newest drugs for migraine block the effect of CGRP by preventing it from grabbing its neural receptor. Some of these drugs latch onto the CGRP. Others lock onto the receptor. Both block the action of CGRP.
These drugs fall into two additional categories.
First are several small-molecule compounds known as gepants. “They compete with CGRP to jump on the receptor,” Goadsby explains. “They have a half-life that’s measured in hours. If you take a gepants, the effect of it is gone tomorrow.” FDA approval of several gepants is pending.
“The major thing I have seen — and we have data — is that these drugs often work when other drugs have failed. That’s the game changer.”
Stephen Silberstein, MD, Sidney Kimmel Medical College
Second are monoclonal antibodies, a collection of large proteins. “They live in the body for weeks, up to a month, and they either latch onto the antibody or latch onto the CGRP or the CGRP receptor,” says Goadsby. Three monoclonal antibodies won FDA approval last year, and a fourth is being reviewed.
“The major thing I have seen — and we have data — is that these drugs often work when other drugs have failed,” says Silberstein. “That’s the game changer. They’re an alternative.” For example, one CGRP study with patients who were unsuccessfully treated in the past found that 30% had their monthly migraine days cut in half.
For “super-responders,” perhaps 20% of migraine patients, CGRP inhibitors can be life-changing, notes Starling. Unfortunately, they don’t work for everyone, suggesting a different pathway is at work in those patients.
One potential option is lasmiditan, recently approved by the FDA for acute migraine treatment. It targets a second pathway that plays a role in migraine, the serotonin 5-HT1F receptor. It works much like triptans, a much older class of drugs. Because it is more specific to the pathway relevant to migraine, it doesn’t constrict blood vessels, as the old drug does, so it can possibly be used for patients with coronary artery disease, a history of stroke, or uncontrolled high blood pressure.
Says Ailani, “We need more things like this. We need to figure out those other pathways and how do we shut these switches off so we make people feel like the person they were supposed to be.”
Pulsing devices to the rescue
Also new in migraine treatment are neuromodulators, devices that use electrical or magnetic pulses to calm an electrical wave associated with migraine called cortical spreading depression.
“When a migraine attack starts there is this abnormal electrical activity that travels over the brain surface area,” Starling explains. “And so the theory was, if we have a device that stops cortical spreading depression, then maybe we can stop a migraine attack once it has already started.”
The FDA recently cleared several devices for treatment of acute migraine and prevention of migraine. One, the single-pulse transcranial magnetic stimulation device, is roughly the size and shape of a binocular case. Starling demonstrates by holding it to the back of her head with both hands and pressing two buttons. The device makes a sharp click as it sends a magnetic pulse into the scalp. Other than the noise, there’s no physical sensation, she says.
Starling has been recommending the device for daily use to reduce the frequency of migraine —“four pulses in the morning, four pulses at night — and they could also use it as needed,” she says.
Such devices have several advantages over other treatments. They are noninvasive and seem to have minimal side effects, if any. They can be used whenever needed without contraindications for other drugs or medical conditions such as autoimmune conditions, heart disease, or pregnancy.
There’s a big drawback, though: The devices are pricey, even to rent, and not usually covered by insurance.
Starling says neuromodulation has success similar to CGRP inhibitors. “In general it is effective in about 50% of patients,” she says. “And in that 50% of patients, it has at least a 50% reduction in migraine days.”
Patients often ask Starling why no one treatment will work for every person. “The thing is, migraine is a genetic disease. We have identified about 40 genes that have associations with migraine. And everybody has a little bit of a different combination of these different gene mutations,” she explains.
“Everybody’s migraine is different, and so not one treatment option is going to be effective for everyone,” Starling notes. “I dream about the day where I can do a genetic analysis on somebody and then I can say, based on your genetic analysis this is the treatment option that’s going to work for you.”
Other treatments are being investigated, such as the anesthetic ketamine, which has been proven effective in treating persistent depression. “It may act as a neuromodulator,” says Silberstein. Treating patients with ketamine for four to five days can appear to break a cycle of chronic migraine, he says. Ketamine for migraine is now being tested in a pilot study.
There’s also evidence that some new treatments work synergistically with older treatments, such as Botox injections, says Silberstein. In particular, he says, adding antibodies to Botox treatment appears more effective than antibodies alone.
Among the standard treatments that can improve the effectiveness of any new drug or device are lifestyle changes. A study currently underway at Vanderbilt University Medical Center is exploring the effects of lifestyle modifications, such as avoiding certain foods and improving sleep, on one type of migraine.
“Adequate sleep is important,” says Silberstein. “If you don’t get it you need to find out why.” Sleep apnea is “a major aggravating factor for migraine and health in general,” he says. “That’s one thing that’s frequently missed and easily corrected.”
Regular exercise and relaxation techniques such as yoga and meditation can help stave off migraine attacks, he says. “You can’t avoid stress, but you can handle it better. No matter what, these are good things to do.”
Although Silberstein believes “diet is overblown” as a remedy, migraine sufferers should limit monosodium glutamate and the nitrites and nitrates found in processed meats. Otherwise, he says, “Healthy eating. Don’t get drunk. Don’t starve. Don’t withdraw from caffeine.”
Diets that are low-fat, plant-based, and high in omega 3 fatty acids have been shown to reduce the pain of migraine, according to the Physicians Committee for Responsible Medicine. Elimination diets are useful in identifying foods that may trigger migraine in patients, says the PCRM. Also, carrying too little weight is associated with greater risk of migraine, and carrying excess weight is even more problematic.
As scientists continue to seek additional answers to what works well for migraine, it’s important that patients who are suffering see their doctors, even if treatments in the past produced little or no success, experts note.
“Things are very different right now,” says Ailani. “It’s an exciting time in our field. I think that this is a great time to see patients who have headaches because we have so much to offer them.”