Chapter 1: The Struggle with Migraines

In the past year, a groundbreaking medication aimed at preventing migraines has been introduced, igniting hope for those suffering from these debilitating headaches.

The first severe migraine attack that Michelle Tracy faced occurred in August 2004 during her summer break between freshman and sophomore years at the University of Massachusetts Amherst. The pain radiated from her forehead to the base of her skull, intensifying throughout the day. Trapped in her parents' living room, every sound and light felt overwhelmingly harsh. "It was all too much," Tracy recalls. As dizziness set in and she began to vomit, her mother rushed her to the emergency room, where Tracy sobbed during the 20-minute drive.

At the hospital, a CAT scan and blood tests ruled out serious conditions like aneurysms or meningitis. The attending physician suspected a migraine, a condition defined by severe headaches lasting from four to 72 hours, often accompanied by nausea and heightened sensitivity to stimuli. Tracy was admitted overnight for IV fluids and medication, leaving the hospital the following day feeling dazed but improved. "I had no idea that was just the beginning," she reflects. This initial attack became a turning point, marking a clear division between her life before and after migraines.

Diagnosed with chronic migraine disorder shortly after her emergency visit, Tracy's condition is characterized by experiencing headaches on 15 or more days per month, lasting four hours or longer. While migraines are relatively common—affecting about 20% of women and 6% to 10% of men in the U.S.—the chronic form is less prevalent, impacting approximately 10% of those with migraines.

"You go through a cycle of trying different medications, never certain if they’ll help or worsen your condition," Tracy explains.

Over the next fifteen years, Tracy faced varying degrees of migraine severity, frequency, and duration, with episodes lasting from a few hours to three days. At times, her pain felt unrelenting. In her quest for relief, she experimented with numerous off-label treatments, including nerve blockers, Botox, anti-seizure medications, various blood pressure drugs, antidepressants, cannabis, and steroids. Unfortunately, most treatments either proved ineffective or their benefits dwindled over time, often accompanied by side effects such as anxiety, forgetfulness, tingling sensations, and insomnia. "It felt like an endless loop of trial and error," she admits. "You start questioning if it's worth the struggle." Ultimately, her condition forced her to take a leave of absence from school, and she graduated three years later than her peers. After college, as a preschool teacher, her migraines worsened again, leading to her dismissal in 2011 due to excessive absences.

In the summer of 2015, hope arrived when Tracy's neurologist informed her about a new targeted therapy specifically developed for migraines.

In May 2018, the first drug in this new category, Aimovig, gained approval from the U.S. Food and Drug Administration (FDA) for both episodic and chronic migraines. Manufactured by Amgen, Aimovig is a calcitonin gene-related peptide (CGRP) inhibitor that works by blocking a protein fragment involved in migraine formation, preventing the headache from developing.

Within a year, two additional CGRP inhibitors received FDA approval. These medications come in the form of self-administered monthly or quarterly injections, allowing patients to inject them into the upper arm, stomach, or thigh at home. Currently, about 200,000 people in the U.S. use Aimovig, with around 44,000 using AJOVY, another CGRP inhibitor. (Eli Lilly has not disclosed figures for its drug, Emgality, which has also been recently approved for acute cluster headache treatment.) For patients like Tracy, the approval of these new medications signifies a long-awaited evolution in migraine treatment options and an increasing recognition of the disorder's serious impact.

The introduction of CGRP inhibitors has been described as a "game changer" in the headache field, according to Dr. Juliana VanderPluym, a neurologist at the Mayo Clinic in Phoenix. Researchers have understood CGRP's involvement in migraines since the 1980s, but earlier treatments targeting this pathway were abandoned due to liver-related side effects. Today's CGRP inhibitors do not pose this risk, as they are not metabolized by the liver. Consequently, physicians had to rely on a mix of medications that offered varying relief, many of which came with significant side effects. A 2017 study found that 26% of episodic migraine patients and 53% of chronic migraine patients discontinued their preventative medications within three months, mainly due to ineffectiveness or intolerable side effects.

Christine Lagod, 66, has battled chronic migraines since her teenage years, learning to endure the pain. "A day without a headache became a rarity," she shares. It wasn't until she turned 30 that she consulted a neurologist, having tried countless home remedies. Since then, she's been prescribed at least four different drugs, including an anti-seizure medication that induced hallucinations. Ten years ago, a hysterectomy was suggested to alleviate her migraines, but that only exacerbated her condition. Now, she manages her symptoms with an estrogen patch, which carries its own risks.

Tracy received her first Aimovig injection on June 19 of last year and quickly felt relief. Prior to the injection, her migraines were so frequent that they merged into a continuous cycle of pain. By the following month, her headache days decreased to eight per month, a trend that continued into the summer. By October 2018, her migraines had reduced to just two to four per month, with many episodes being shorter and less intense. Remarkably, she experienced no side effects from Aimovig, a significant contrast to her past treatments.

Although some patients report mild gastrointestinal issues with the medication, overall side effects appear to be less severe compared to previous treatments, according to Dr. Matthew Robbins from the Weill Cornell Medicine Headache Program in New York. "One of the main advantages of these new medications is their tolerability," he states.

Researchers continue to monitor potential long-term side effects, such as CGRP inhibitors' influence on cardiovascular health, which could heighten risks of heart attacks, strokes, and pregnancy-related complications. While providers have not reported any such incidents yet, they remain vigilant as more patients use the drugs over extended periods. Concerns about unknown side effects have diminished as more long-term data becomes available. "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).

For migraine sufferers, CGRP inhibitors can be transformative, but they are not a definitive cure. "It's crucial for patients to understand that we don't have a cure for migraines; we have a targeted therapy," VanderPluym emphasizes. Even though Tracy has had an exceptionally positive response to Aimovig, she still uses triptans, a medication for acute migraines, at the onset of an attack.

Clinical trials have shown that those using CGRP inhibitors typically experience one to two and a half fewer migraine days each month compared to those receiving a placebo. While this average reduction is noteworthy, it obscures a more complex reality: nearly half of the participants receiving Aimovig saw at least a 50% decrease in their monthly headache days. However, this also implies that for many patients, the medication did not significantly reduce headache frequency.

Some individuals, like Tracy, experience dramatic relief, while others see more moderate improvements, and some find little to no benefit. A JAMA review of these medications suggests that while the average response rate may seem modest, the variability in migraine as a disorder complicates treatment outcomes. CGRP is one contributing factor, but likely not the sole neuropeptide involved in migraines.

Most insurance plans currently cover CGRP inhibitors for both episodic and chronic migraines, but patients usually must demonstrate that they have tried and failed alternative treatments to qualify for coverage. Those with episodic migraines may face additional hurdles in securing approval, as they are less likely to have a documented history of unsuccessful treatments. Fortunately, chronic migraine patients often have extensive medical records detailing their treatment failures. Tracy, who is on Medicaid, received approval for Aimovig shortly after its release. However, with an annual cost of nearly $7,000, these medications remain unaffordable for many without insurance or for those whose plans do not cover them.

The long-awaited arrival of CGRP inhibitors has made a significant impact on migraine care. "It's changed my practice," states Dr. Stewart Tepper, a professor of Neurology at the Geisel School of Medicine at Dartmouth.

Currently, acute migraine treatments differ from preventative therapies, as they are used to alleviate symptoms during an attack. However, this may soon change, with new CGRP-blocking pills for acute treatment nearing FDA approval, expected to launch by the end of the year. Both Allergan and Eli Lilly have submitted CGRP pills for review, while Biohaven is conducting late-stage trials for a similar treatment. Researchers are also exploring other neuropeptides related to migraines as potential targets for future therapies.

Nearly a year into her Aimovig treatment, Tracy has transitioned to freelance work, earning income through writing and speaking engagements. She has lost 50 pounds, which she attributes to her newfound ability to "get up and walk around." Just a year ago, her life revolved around her bed and couch; now, her world is expanding. Pain-free for most days, she has traveled extensively across the U.S., from her home in Amherst, Massachusetts, to Washington D.C., Providence, Rhode Island, San Antonio, Philadelphia, and Cincinnati, her family's hometown.

Recently, she has even contemplated returning to full-time work outside the home, considering going back to teaching, as she deeply misses her preschoolers. "The idea of building a life that includes a traditional 9-to-5 job is an exciting prospect for me," she says.

The first video, titled "November Headache Series: Update on Mechanisms of Migraine," provides insights into the underlying mechanisms that contribute to migraine development, highlighting recent research findings.

The second video, "Recent Developments in Migraine Treatment," discusses the latest advancements in migraine therapies, focusing on CGRP inhibitors and their impact on treatment strategies.