The first significant attack Michelle Tracy experienced took place in August 2004. It was the summer between her freshman and sophomore year at The University of Massachusetts Amherst. The pain, which radiated from the left side of her forehead to the base of her skull in throbbing waves, began early in the day. As the minutes and hours ticked by, the pain swelled into an excruciating force.
Her parents’ living room, where she was riding out the episode, became nightmarishly amplified. Everything was too bright, too noisy, too smelly. “It was all too much,” says Tracy. She grew dizzy. When she began vomiting uncontrollably, her mom drove her to the emergency room. Tracy sobbed the entire 20-minute ride there.
At the hospital, a CAT scan and blood tests ruled out an aneurysm or meningitis. Given her symptoms, the attending physician on duty suspected Tracy was having a migraine — a headache that lasts between four and 72 hours, is severe enough to impact a person’s daily routine, and is accompanied by symptoms such as nausea and sensory sensitivity. Tracy was admitted to the hospital overnight and given saline fluid and a cocktail of medication administered via IV for the nausea and pain; she left the hospital the next day feeling loopy, but better. “I didn’t realize that was the beginning,” she says. In retrospect, this first attack “was a demarcation,” Tracy says. There was life before the migraine attacks, and then there was life after.
Chronic migraine disorder, which a neurologist diagnosed Tracy with shortly after her initial ER visit, is defined as having 15 or more days with a headache that lasts four hours or more, in a given month. While migraine attacks are common — an estimated 20% of women and 6% to 10% of men in the U.S. suffer from them — the chronic form of the condition is more rare, afflicting an estimated 10% of people with migraine.
“You go through this trial and error with medication. You never know, ‘Is this going to help? Is it not going to help?’”
Over the next decade and a half, Tracy dealt with migraine attack symptoms that fluctuated in their severity, frequency, and length — lasting anywhere from a couple hours to three days (a common experience for people with migraine disorder). At times, her pain was near-constant. To quell it, she tried dozens of medications that are used off-label to treat migraine, including nerve blockers, Botox injections, anti-seizure medications, an array of blood pressure drugs and antidepressants, cannabis, steroids, and much more. None of them worked particularly well for her, and even when there was a benefit, the effects usually faded over time. There were also side effects like anxiety, forgetfulness, a tingling in her arms and legs, and insomnia. “You go through this trial and error with medication,” Tracy says. “You never know, ‘Is this going to help? Is it not going to help? Or is it going to make things worse?’ You start to have this loop in your head: ‘Is this worth it?’” Her migraine disorder got so bad she took a leave of absence from school, graduating three years after her freshman-year classmates. After college, she worked as a preschool teacher but the attacks worsened again; in 2011, she was let go for missing too much work.
Then, in the summer of 2015, Tracy’s neurologist told her that a new targeted therapy for migraine — the first developed specifically to treat the condition — was being developed.
In May 2018, the first drug in this class, Aimovig, was approved by the U.S. Food and Drug Administration (FDA) for episodic and chronic migraine. Brought to market by the pharmaceutical company Amgen, Aimovig is a calcitonin gene-related peptide (CGRP) inhibitor. It prevents migraines by stopping a protein fragment called CGRP — which is involved in the formation of migraine attacks — from binding to CGRP receptors in the brain, effectively blocking the migraine from developing.
Within the calendar year, two more CGRP inhibitors, one from the pharmaceutical company Teva and the other from Eli Lilly, were also approved by the FDA. All come in the form of monthly or quarterly injections that can be self-administered at home into the upper arm, stomach, or thigh. Today, 200,000 people in the U.S. are taking Aimovig and an estimated 44,000 are taking AJOVY, Teva’s CGRP inhibitor. (Eli Lilly declined to provide a figure for its drug, Emgality, which was also recently approved for the acute treatment of cluster headaches.) For people like Tracy, the approval of these medications marks a long-awaited shift in available treatments for the disorder, and a growing acknowledgement that migraine disorders are real, debilitating, and in dire need of more innovative therapies.
The launch of CGRP inhibitors was also “a big deal in the headache world,” says Dr. Juliana VanderPluym, a neurologist at the Mayo Clinic in Phoenix. Researchers have known about CGRP’s role in the development of migraines since the 1980s. But the first wave of treatments targeting them were ultimately shelved because they caused liver problems in people taking them. (Today’s CGRPinhibitors don’t cause this issue because they aren’t metabolized by the liver.) So, as Tracy experienced, doctors relied on a patchwork of borrowed medicines that also happened to show a benefit for migraine, including antidepressants, blood pressure medication, and anti-seizure drugs — most of which came with significant side effects. A 2017 study found that over the course of three months, 26% of people with episodic migraine and 53% of people with chronic migraine discontinued or switched their preventative treatment, with the majority doing so because they said the drugs didn’t work or they couldn’t tolerate the side effects.
Christine Lagod, 66, has experienced chronic migraines since she was a teenager. She taught herself to push through the pain. “It got to the point where a day without a headache was unusual,” she says. She didn’t see a neurologist until she was 30, by which point she’d exhausted every home remedy she could think of (aspirin, caffeine, ice). Since then, she’s been prescribed at least four different drugs including an anti-seizure drug that made her hallucinate. Most invasively, about 10 years ago, her neurologist recommended she get a hysterectomy, as the drop in estrogen levels before menstruation has been associated with migraine attacks. Instead, the procedure had the opposite effect: the attacks got worse. To course correct, she wears an estrogen patch. It comes with its own side effects, including an elevated risk of breast cancer.
Tracy’s first injection of Aimovig was on June 19 of last year, and she says the relief came fast. Before the injection, her migraines were so frequent that she says they blended into a single unending block of pain. By the next month, her headache days were down to eight days a month, a reduction that continued into the summer. By October 2018, Tracy says she was only experiencing two to four headaches a month. The attacks, when they do occur, are generally shorter — some last less than two hours — and milder; she can sometimes go weeks without pain. And unlike other therapies Tracy has tried, she has no side effects.
There are reports of people who take the drugs experiencing constipation, stomach pain, and other gastrointestinal issues, but in general, side effects appear to be relatively mild, says Dr. Matthew Robbins, a neurologist at the Weill Cornell Medicine Headache Program in New York. “So far, a major advantage of these medications, relative to older treatments, is their tolerability.”
Possible long-term side effects — such as CGRP inhibitor’s impact on cardiovascular health, which could increase the risk of heart attack and stroke and pregnancy-related conditions such as preeclampsia — remain on researchers’ radar, due to the role CGRP plays in regulating blood pressure and wound healing. While the providers I spoke with say they haven’t heard reports of any of these conditions yet, they remain on alert should any emerge as people take the drug over longer periods of time. It’s possible long-term adverse effects could have been missed due to the relatively short duration of the three to six month trials. But one year in, experts are feeling tentatively confident.
“Now that these products have been on the market for a while, we have longer-term data that lessen concerns around unknown side effects,” says Dr. David Rind, chief medical officer of the Institute for Clinical and Economic Review (ICER), a nonprofit that evaluates the cost-effectiveness of new therapies.
For people who experience migraine attacks, CGRPinhibitors can be life-changing. But even then, they are not a cure. “That’s important for patients to understand,” VanderPluym says. “We don’t have a cure for migraine, we have a targeted therapy for migraine.” While Tracy has responded miraculously well to the drug, she still takes triptanes, a medicine for acute migraine, when she feels an attack coming on.
In clinical trials, people taking CGRPinhibitors experienced an average of one to two and a half fewer migraine days a month than people who received a placebo. This relatively modest decrease masks a more complicated picture: In clinical trials, 48% of people with recurrent migraines who received a monthly dose of Aimovig experienced at least a 50% reduction in monthly migraine days. While impressive, it also means for more patients than not, the drug was unable to reduce their headache days by half.
In other words, some patients, like Tracy, responded dramatically. Some experienced a more tempered, if still significant, decrease, while others saw little to no benefit. In a JAMA review of the class of drugs, the authors note that while it’s tempting to blame the modest average response rate on the therapies themselves, “it is more likely that migraine is a heterogeneous disorder.” CGRP is one cause of migraine, but it’s likely not the only neuropeptide responsible.
So far, most insurance plans are covering CGRP inhibitors for both episodic and chronic migraine, but to be approved for coverage, people generally have to show that they have tried and failed other migraine treatments. People with episodic migraines — which means they experience 14 headache days or fewer per month — could have a more difficult time getting approval, possibly because they are less likely to have tried and failed several treatments. Fortunately — and unfortunately — people with chronic migraine often have a long, documented medical history of failed previous treatments. Tracy, who is on Medicaid, was approved for Aimovig soon after the drug’s launch. But at just under $7,000 a year, Amovig and its competitors are cost prohibitive for those without insurance, or whose insurance won’t cover them.
CGRP inhibitors were a long time coming, and while they don’t work for everyone, they’ve had a significant impact. “It’s changed my practice,” says Dr. Stewart Tepper, a professor of Neurology at the Geisel School of Medicine at Dartmouth.
This is still the case for acute migraine treatments, which, unlike preventative therapies, are taken at an attack’s onset to mitigate symptoms. But likely not for much longer. New medications for the acute treatment of migraine, in the form of CGRP-blocking pills, are working their way towards FDA approval, with the first expected to launch by the end of the year. Allergan and Eli Lilly have submitted CGRP pills for the agency to review, and the pharmaceutical company Biohaven has a similar treatment in late-stage clinical trials. Researchers are also investigating other neuropeptides associated with migraine as alternative targets for future therapeutics.
Tracy has been on Aimovig for almost a year now; she’s working in a freelance capacity, making money through writing and speaking projects. She has lost 50 pounds, a side effect, she suspects, of being able to able to “get up and walk around.” A year ago, her life was primarily confined to the bed and the couch. Today, it’s limits continue to expand. Pain-free most days, she’s traveled across the country from her home in Amherst, Massachusetts to Washington D.C., Providence, Rhode Island, San Antonio, Philadelphia, and Cincinnati, where her family is from.
Recently, she began thinking about getting a full-time job outside the home, even considering going back to teaching since she misses her preschoolers. “Building a life that also includes a 9-to-5, so to speak, is an exciting prospect for me,” she says.