Like a game of medical Mad Libs, you likely hear the word “migraine” and immediately think headache. But migraine is far more than just a headache. It is a complex neurological disorder that affects many parts of the brain, including those that process pain, emotion, senses, and thoughts.<sup?1 Its symptoms, which may vary widely from person to person, can include nausea, vomiting, dizziness, diarrhea, and extreme sensitivity to light, smells, or sounds.2
At its root, explains Michael Cutrer, MD, a neurologist and division chair of headache at the Mayo Clinic, is excess excitability in the brain’s early-warning system, which normally detects stimuli that might pose a threat to the brain or upper spinal cord.
This system “does a very good job of getting our attention, to try to protect us from real or threatened injury,” says Dr. Cutrer, who himself is a migraineur—a person who suffers from migraines. However, “those of us who have migraine have inherited or acquired things in our life that make the threshold for activation of that system so low that things in the environment that really represent no threat to the brain can turn it on in an inappropriate way,” he adds.
He likens it to a first-generation car alarm, which would blast into crisis mode if a pedestrian simply passed by the vehicle. What causes this neural excitability in any individual person remains unclear, though migraine has a known genetic component; it tends to run in families, and researchers estimate that up to 60 percent of the risk for developing migraines comes from inherited genetic factors.3
The Hormone Connection
Each migraine attack has four potential stages (see sidebar “The Four Stages of a Migraine Attack”) and can cause significant distress and disability in those afflicted. Around 12 percent of Americans age 12 years or older experience migraine sporadically (called episodic migraine).4 Almost 1 percent—about 2 million people—live with chronic migraine,5 defined as at least 15 headache days per month for at least three months, of which eight days of each month meet the criteria for migraine. Of these chronic migraineurs, only a minority ever receive a proper diagnosis.6
Despite the relative rarity of migraine among health conditions, in 2012 the World Health Organization ranked migraine as the eighth-leading cause of worldwide disability, due to its severe impact on patients’ lives.7 The majority of people living with this burden are women: migraine is three times more common in women than men.8 Researchers have found strong links between female hormones and migraine. For example, migraine onset often begins in puberty, the frequency of attacks associates with the menstrual cycle in more than half of female migraineurs, and this frequency can change during pregnancy, breastfeeding, and menopause.3,9
For now, how normal hormonal fluctuations trigger the brain’s pain system is not fully understood, though researchers know that estrogen and progesterone affect the nervous system.10 Why only some women are susceptible to these fluctuations as a migraine trigger and if this knowledge can be translated into new treatments for migraine remain topics under study.
Medications for Migraine Management
Available drug therapies for migraine fall into two categories: acute medications, which can decrease the length of an attack or sometimes stop a migraine from progressing once its early signs are felt, and preventive medications, which are taken daily with the goal of reducing the number of migraine days per month.
Drugs used for the acute treatment of migraine range from over-the-counter painkillers to a class of drugs called triptans, which were developed specifically to treat migraine pain. One problem with acute medications, explains Dr. Cutrer, is that when taken regularly—more than about two days per week—they can either lose their effectiveness or actually exacerbate the migraines, a condition called medication-overuse headache.
Migraineurs passing this threshold for overuse may try preventive medication. Preventive medications are started at a low dose, which is then slowly increased to minimize the potential development of side effects.2 This means that it can take a while for a patient to know if a drug has the desired effect, explains Dr. Cutrer. In his clinic this process can take up to six weeks per drug.
For some patients the side effects of a drug end up outweighing its benefits, or the drugs simply don’t work or stop working over time. But for other patients, the drugs can provide a “reset” button, giving the hyped-up pain receptors a chance to stop overreacting and restabilize, says Dr. Cutrer. A minority of these patients can eventually even have their doses lowered or stop taking the preventives for a while and manage an occasional attack with acute medications.
A Potential Short Circuit
Because both acute and preventive drugs for migraine come with side effects, many migraineurs are interested in non-pharmacologic treatments for the disorder. One technology that shows promise is noninvasive neuromodulation—the use of devices that produce electrical or magnetic fields to calm hyperactive neurons in the brain.
One of these devices, called single-pulse transcranial magnetic stimulation (sTMS), has been tested as an acute treatment for patients who have migraine with aura. When held against the back of the head, the sTMS device delivers two closely spaced magnetic pulses that are thought to short-circuit the cause of aura—a neural phenomenon called cortical spreading depression, explains Richard Lipton, MD, a professor of neurology at Albert Einstein College of Medicine, who led the clinical trial. “So the idea was, we short-circuit cortical spreading depression, we reduce the length of aura and also eliminate headache.”
In the clinical trial, 39 percent of patients who used sTMS as soon as possible after the onset of the aura were pain-free two hours later compared with 22 percent who used a sham device.11 No side effects related to the device were reported, and it received US Food and Drug Administration (FDA) approval for the acute treatment of migraine with aura in 2013.
Interestingly, adds Dr. Lipton, other studies now suggest that sTMS also works for migraine without aura and that when used more frequently may help with prevention. But “how it works in those other cases is not at all well understood,” he says.
Another noninvasive device, called a transcutaneous electrical nerve stimulation (TENS) device, received FDA approval for migraine prevention in 2014. In a randomized trial, three months of use of the device, which delivers electrical current through the skin of the forehead to the nerves of the pain system, reduced the number of headache days per month by 26 percent, but use of a sham device did not.12
Avoiding True Triggers
A side-effect-free way that people with migraines can help manage the disorder is by identifying and limiting their exposure to the environmental factors that trigger the brain’s alarm system. Some common migraine triggers, like the drop in barometric pressure before a rainstorm, can’t be avoided, says Dr. Curter. But others, like certain foods and disrupted sleep patterns, can.
“Trigger management is very important, but the challenge is that there are huge individual differences in which triggers matter,” says Dr. Lipton. He has seen patients come into his clinic with drastic weight loss because they’ve tried to avoid every food listed as a potential migraine trigger without knowing if any really affect them personally, “and there’s nothing left to eat.” True trigger identification, he says, requires that patients keep a migraine diary and look at multiple attacks over time.
Dr. Lipton is excited about the new generation of online diary tools, such as Curelator Headache (curelator.com), which he recommends to his patients. These tools let migraineurs use a smartphone or tablet to track exposures and symptoms in real time and generate reports of potential triggers that they can then discuss with their doctor.
“It’s one of those areas of medicine where rationalization and individualization is particularly important,” says Dr. Lipton. “And the better we get at identifying individual triggers, the better able we’ll be to give people individualized advice on trigger avoidance.”
Moving toward Personalized Medicine
While an increasing number of genes that contribute to migraine risk continue to be identified, Dr. Cutrer thinks the real breakthroughs will come when researchers develop a complete understanding of what drives migraine on a molecular level and can use that knowledge to develop truly targeted treatments.
“The ideal situation would be for us to figure out what the total number of molecular processes are that, when altered, make someone susceptible to having their environment turn on this pain system falsely, and then we treat people based on testing them to find out what their [individual] migraine drivers are,” he says.
This type of completely personalized medicine may be decades away, but the first treatments based on targeting the molecular drivers of migraine are now making their way into the clinic. Monoclonal antibodies, which are designed to destroy specific proteins or their receptors within the body, have been developed for migraine. These antibodies target a protein called calcitonin gene-related peptide (CGRP) or its receptor, which helps transmit pain signals during migraine attacks.
In early clinical trials of migraine prevention, the anti-CGRP antibodies significantly reduced the number of migraine days per month compared with a placebo.13 And although long-term follow-up to track side effects is needed, so far they seem to be free of many of the toxicities that prevent some patients from taking migraine preventives, says Dr. Lipton.
“The CGRP monoclonal antibodies are the first real ‘designer drugs’ for migraine, which were developed to target a mechanism that we believe is specifically involved in the biology of migraine,” he concludes. “I think they’re the most exciting thing happening in headache medicine today.”
Botox for Migraine?
The new kid on the block in terms of preventive treatment for chronic migraine is botulinum neurotoxin, best known in the United States by one of its brand names, Botox®. For more information about the use of botulinum neurotoxin in the treatment of chronic migraine and other health conditions, see the article “Beyond Botox” in the fall 2015 issue of Women magazine, available online at awomanshealth.com/beyond-botox.
The Four Stages of a Migraine Attack
- Prodrome: the warning signs of a migraine, which vary but can include either fatigue or bursts of energy, yawning, frequent urination, and mood changes.
- Aura: nervous system symptoms that can be visual (such as flashes of light or blind spots) or involve other senses (such as tingling and numbness).
- Headache: the attack phase, which can also include nausea, vomiting, and sensitivity to light, sounds, and smells.
- Postdrome: the migraine “hangover,” which can include residual low-grade headache and continued sight, sound, and smell sensitivity.
Not all migraine attacks include all four stages. Only about 25 percent of migraineurs will ever experience aura. Some migraines even skip the headache phase, a phenomenon called acephalgic or silent migraine.
Migraine runs in Samantha Semlitz’s family. Several aunts had it. Her father developed it later in life. Her grandmother suffered from vestibular migraine, with which patients experience debilitating vertigo. And Samantha, now 27, has had migraines for as long as she can remember—and even before that.
Her parents tell her that her episodes started with bouts of unprovoked nausea and vomiting, a condition called abdominal migraine; but by the time she was four, they had progressed to debilitating headaches. “My parents say that I used to describe it like there was a headband on my head, and I would try to take it off, but there was no headband,” she recounts.
By the time Samantha was nine, she was getting two or three migraines per week. During the summer before seventh grade, they became daily. “I was still going to school, but I wasn’t very functional,” she says. After a weeks-long hospitalization during her junior year in high school, she and her family ended up flying to the Michigan Headache & Neurological Institute, a visit that she says “probably saved my life.” There she learned how to manage chronic pain, control her triggers, and generally live with migraine.
Samantha’s parents were so moved by the suffering they saw on that visit that they founded the Migraine Research Foundation to raise funds to expand research into the biology of migraine. Samantha went on to college and then graduate school in education. While in graduate school, she found a neurologist who prescribed a medication that, while rarely used to treat migraines, finally reduced her headache frequency. She still gets migraines about 12 days of each month, but they don’t stop her from doing her job as a special-education teacher in New York.
“Teaching actually happens to be fantastic for me because if I’m distracted, I’m not focusing on my pain,” she says. Sometimes she wears dark glasses in the classroom, but her students themselves all use tools like noise-reducing headsets to help them feel comfortable: “All of my students have so many accommodations, they just get that the teacher has accommodations, too.”
When talking to other migraineurs, Samantha always stresses working with a specialist who is board-certified in migraine. “Don’t leave it to your primary care practitioner, especially if [the migraines are] more than once a month, because if they’re mistreated, they can get worse,” she concludes.
- Burstein R, Noseda R, Borsook D. Migraine: Multiple processes, complex pathophysiology. The Journal of Neuroscience. 2015;35(17):6619-29. doi: 10.1523/JNEUROSCI.0373-15.2015.
- Weatherall MW. The diagnosis and treatment of chronic migraine. Therapeutic Advances in Chronic Disease. 2015;6(3):115-23. doi: 10.1177/2040622315579627.
- Ferrari MD, Klever RR, Terwindt GM, Ayata C, van den Maagdenberg AM. Migraine pathophysiology: Lessons from mouse models and human genetics. The Lancet Neurology. 2015;14(1):65-80. doi: 10.1016/S1474-4422(14)70220-0.
- Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-49.
- Buse DC, Manack AN, Fanning KM, et al. Chronic migraine prevalence, disability, and sociodemographic factors: Results from the American Migraine Prevalence and Prevention Study. Headache. 2012;52(10):1456-70.doi: 10.1111/j.1526- 4610.2012.02223.x.
- Diener HC, Solbach K, Holle D, Gaul C. Integrated care for chronic migraine patients: Epidemiology, burden, diagnosis and treatment options. Clinical Medicine. 2015;15(4):344-50. doi: 10.7861/clinmedicine.15-4-344.
- Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990- 2010: A systematic analysis for the Global Burden of Disease Study 2010. The Lancet. 2012;380(9859):2163-96. doi: 10.1016/S0140- 6736(12)61729-2.
- Bigal ME, Lipton RB. The epidemiology, burden, and comorbidities of migraine. Neurologic Clinics. 2009;27(2):321-34. doi: 10.1016/j.ncl.2008.11.011.
- Macgregor EA. Menstrual migraine: Therapeutic approaches. Therapeutic Advances in Neurological Disorders. 2009;2(5):327- 36. doi: 10.1177/1756285609335537.
- Macgregor EA. Menstrual migraine: A clinical review. The Journal of Family Planning and Reproductive Health Care. 2007;33(1):36-47.
- Lipton RB, Dodick DW, Silberstein SD, et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: A randomised, double-blind, parallel-group, sham-controlled trial. The Lancet Neurology. 2010;9(4):373-80. doi: 10.1016/ S1474-4422(10)70054-5.
- Schoenen J, Vandersmissen B, Jeangette S, et al. Migraine prevention with a supraorbital transcutaneous stimulator: A randomized controlled trial. Neurology. 2013;80(8):697-704. doi: 10.1212/WNL.0b013e3182825055.
- Diener HC, Charles A, Goadsby PJ, Holle D. New therapeutic approaches for the prevention and treatment of migraine. The Lancet Neurology. 2015;14(10):1010-22. doi: 10.1016/S1474-4422(15)00198-2.