My head doth ache, O Soppho! Take thy fillet, and bind the pain, or bring some bane to kill it. — Robert Herrick, "the Head-ake" (1648)*
Nearly 3,000 years before the English poet Robert Herrick evoked the torment of a crushing headache and the yearning of its sufferer for relief, scientists and philosophers had deliberated over the mysteries of a pounding cranium. Throughout human history, people have struggled in the throbbing grip of migraine — a particularly vicious form of headache. It only is recently, however, that researchers have begun to fathom the biological mechanisms of the complaint. With their increased knowledge, they now are better able to offer sufferers real hope for a cure.
Andrea Alsberg knows too well how migraines can hijack a person’s life. She was 28 years old when the first attack hit. Like most people, she had, over the years, dealt with off-and-on headaches, but this one was frighteningly different. “I was living in New York City and had just been to see a play,” she recalls. “Afterward, I went out with some friends, and suddenly I got this splitting headache — pain like never before in my life.”
When she got home, she took some over-the-counter pain meds and lay down for an hour. The headache, a directed, driving pain that took over the entire right side of her head, finally passed. This same approach worked with the next monster headache, which struck a few months later, and with the ones that came after that. But by the time Alsberg moved to Los Angeles, a few years later, the migraines had become more frequent. At the same time, the increasingly potent medications that doctors prescribed for her weren’t working.
“During one attack, my husband wasn’t home, and I was bathing our two little ones,” says Alsberg, who worked as a curator and later served as head of programming for the UCLA Film & Television Archive. “I leaned over to put them in the tub and had such an extreme wave of pain that I thought I was going to pass out.”
As often happens to migraine sufferers, Alsberg’s primary care physician soon ran out of treatment options. But instead of this being a dead end, it wound up opening a door. Her doctor referred her to Andrew Charles, MD ’86 (RES ’90, FEL ’92), a neurologist and professor at UCLA who is widely recognized as a leader in the field of migraine research. “Until that point, I had been alone in this,” Alsberg says. “And suddenly here was Dr. Charles, someone who understood every aspect of what I was going through and who gave me hope for the future.”
MIGRAINE IS A COMPLEX NEUROLOGICAL DISORDER in which headache is just one symptom among a web of symptoms. In addition to the crushing pain, which often throbs or pulsates, sufferers can experience nausea; dizziness; neck pain; sensitivity to light, smell or sound; visual disturbances; sensory hallucinations; mental confusion; depression; difficulty speaking; and acute exhaustion. With so many interlocking symptoms, it is not always easy to describe what a migraine actually feels like. Several years ago, the news and blog website Huffington Post asked followers on its social communities to try to put into words their experience of a migraine. “Like my brain is exploding, someone took a baseball bat and beat the base of my skull and neck with it, and there’s an ice pick jabbed into my right eye and temple,” one reader responded. “Every bright spot of light and every minor sound sets the entire back of my head on edge. The source of the noise or light becomes irritating and aggravating to me beyond anything else I ever experience,” wrote another. “Thunder and lightning inside of your head combined with a serious need to toss your cookies,” another reader wrote.
Despite centuries of inquiry, the physiological origins of the condition that lead to such excruciating descriptions have been elusive. Today, Dr. Charles is a leader in the effort to more fully understand and treat migraine. He holds the Meyer and Renee Luskin Chair in Migraine and Headache Studies, the only endowed chair in the U.S. that is dedicated to migraine, and he also serves as director of the UCLA Goldberg Migraine Program in the David Geffen School of Medicine at UCLA. As both an active researcher and a clinician who sees patients, he is a rarity in the field.
“One of the biggest challenges of migraine is that the whole field has long been filled with so many misconceptions,” Dr. Charles says. “Migraine is the third-most common of all disorders on the planet, and it is the second leading cause of time spent disabled over a lifetime, yet its mechanisms have been misunderstood, and its consequences have been greatly underestimated.”
In the U.S., about 100 million people suffer from chronic headache. Of those, close to 40 percent have migraine as defined by strict criteria, although it is likely that the actual percentage is much higher. The disorder, which is believed to have a genetic component, is three times as common in women as it is in men. According to the World Health Organization, as many as 20 percent of all women and 8 percent of all men worldwide suffer from migraine. That translates not just to several days per week or month spent in unrelieved pain, but also to a significant loss of quality of life and productivity.
“Tally up the time you spend disabled by this disorder over a lifetime, and it really is quite extraordinary,” Dr. Charles says. “Even for the luckiest individuals who have one migraine attack per month and lose just one day, over the course of 40 years, they have lost close to 500 days to a problem that they often aren’t bringing to the attention of a medical practitioner.” Patients who do discuss migraine with their family doctor often don’t get very far, Dr. Charles says. That is because, despite it being one of the most common of all medical disorders, the subject of headache, in all of its permutations, including migraine, merits just a few hours of lecture in medical school. Thanks in part to this information vacuum, migraine has become a common pathway for dependence on prescription opioids.
UNTIL QUITE RECENTLY, MIGRAINE WAS BELIEVED TO BE A VASCULAR DISORDER caused by the dilation and constriction of blood vessels in and around the brain. As a result, migraine treatments were for decades focused on vascular effects. Most current migraine therapies initially were licensed to treat other medical conditions, such as seizures, depression and high blood pressure. It was only by chance that they were discovered to offer benefits to migraine patients. Greater understanding of the basic mechanisms of migraine has led to major changes in the focus of the development of new therapies.
The search for answers goes back thousands of years. Migraine shows up in medical writings in ancient Egypt as early as 1200 BC. In 4000 BC, Hippocrates accurately described both the visual disturbances that often precede a migraine attack and the nausea that can accompany it. Attempts at a cure have included drilling holes into the skulls of sufferers in 7000 BC; acupuncture in ancient China; and blood-letting, hot irons and witchcraft during the Middle Ages. The first use of vasoconstrictors emerged in the 1920s in the form of ergotamine, a substance derived from fungi such as mushrooms. As is true of virtually all migraine treatments developed since the 20th century, the application of ergotamine for migraine was a secondary use; its original purpose was to lessen bleeding in childbirth.
Today’s seismic shift in migraine research is taking place, in part, thanks to the advent of sophisticated imaging technologies, advanced approaches for the analysis of genetic factors and the development of antibodies that can act with remarkable specificity on individual therapeutic targets. With these new tools, researchers can study migraine at the molecular and cellular levels, as well as visualize specific changes in the function of the nervous system that take place during a migraine attack. These studies are helping migraine to shed its status as a forgotten stepchild of medicine and become a disorder for which there are precise and targeted therapies.
In recent years, imaging studies have disproven the vascular theory of migraine, Dr. Charles says. Instead, scientists now see fluctuations in brain chemicals, as well as abnormal electrical activity in specific brain regions, as a likely cause. Another misconception that has been swept aside is that the throbbing nature of migraine pain is caused by the heartbeat, or vascular pulse. “What’s fascinating is that it turns out that the throb rate of a patient’s migraine pain is not the same as his or her vascular pulse,” Dr. Charles says. “So there has to be something else generating the throbbing nature of migraine other than the pulsation of a patient’s blood vessels.”
One possibility is that the pulsing pain mirrors the slow oscillations of brain activity itself. “That’s part of what we’re very interested in figuring out,” Dr. Charles says. “But it’s something we don’t have a clear understanding of just yet.”
What scans do show is that patients in the throes of a migraine are experiencing waves of abnormal activity that spread across the surface of the brain. There also is unusual stimulation of nerve centers deep within the brainstem. The ultimate treatment goal is a means to reduce, or even short-circuit, these abnormal patterns of brain activity before they can begin to cause symptoms.
In that regard, memantine, a drug used to treat moderate-to-severe confusion associated with Alzheimer’s disease, has shown promise. The drug inhibits the type of brain activity that researchers suspect to be a migraine trigger, and it has brought relief to some of the patients under Dr. Charles’s care. On the horizon are stimulation devices that would stop a budding migraine via an electrical or magnetic pulse sent to specific nerves or regions of the brain.
Another breakthrough that Dr. Charles believes has great potential is the use of monoclonal antibodies. These are laboratory-produced molecules designed to target or bind to precise sites within the body. In this case, the targets are certain peptides, or chains of amino acids, that are released during the earliest phases of a migraine attack. “The idea is that with traditional drugs, you basically are trying to target some sort of receptor or channel on a nerve cell or blood vessel, but it is rarely possible to design a drug that is 100 percent specific to the target. These off-target effects may lead to unwanted side effects,” Dr. Charles says. “With monoclonal antibodies, you are able to target mechanisms far more specifically. You can design antibodies that act as a sponge to soak up bad-acting molecules or to block a selected receptor or channel that is causing trouble.”
In fact, the Food and Drug Administration (FDA) this May approved erenumab-aooe, the first drug based on monoclonal antibodies to prevent migraines. And three other pharmaceutical companies are completing phase-3 clinical trials or awaiting FDA approval of similar medicines. Known as anti-CGRP (calcitonin gene-related peptide) drugs, all are compounds that target a specific protein in the brain that causes severe headache.
“The CGRP story is very exciting; we have been working on aspects of it in our laboratory here,” Dr. Charles says. “We are gearing up to deliver these new therapies to patients in our clinic, where quite a number of them are already asking about the treatment.”
The anti-CGRP therapies — the first treatments ever to be developed primarily and specifically for migraine — are intended to be preventive, Dr. Charles says. “We have seen remarkable results from the clinical trials, with a subset of patients for whom the response is a dramatic reduction in the number of migraine attacks,” he says. “A smaller percentage have shown complete remission, which is unlike what we’ve seen with other therapies.”
ADDITIONAL ADVANCES ARE TAKING PLACE IN DR. CHARLES’S LAB, where he and his colleagues are doing research with mice that have been genetically engineered to express human migraine genes. Other research takes place at UCLA’s imaging centers, where patients volunteer to have the course of their migraine attacks mapped or their anatomy characterized. Dr. Charles and his research team also collaborate on a variety of studies with other institutions.
Even as the science has advanced, lack of significant monetary support has hindered the development of new migraine therapies. “When it comes to the migraine field, there historically has been very little funding,” Dr. Charles says. It largely has been left to pharmaceutical companies to support research to bring new therapies forward. Today, that is changing, Dr. Charles says. “Thanks to philanthropy, we now are able to take control of the translation of basic science into new treatments.”
That effort is being significantly propelled by a gift from Wendy Goldberg, an author and philanthropist, and her husband Leonard Goldberg, an award-winning film and television producer and executive. The couple recently gave $10 million to support research at UCLA, with the bulk going to migraine research. It is the largest private donation ever to support migraine research.
Meanwhile, as these promising treatments progress from laboratory bench to bedside, Dr. Charles and his clinical staff work to help their migraine patients manage their conditions. New patients give a detailed oral history and fill out a medical questionnaire. They receive educational materials and undergo a physical exam. Based on the information gathered, Dr. Charles and his team formulate individualized treatment plans.
Migraine education is important. Dr. Charles and his staff teach patients to recognize migraine triggers like skipped meals, irregular caffeine intake, irregular sleep, changes in the weather, air travel and emotional or physical stress. Foods like chocolate, nuts, aged cheese, fermented foods, alcohol in general and red wine in particular can be problematic for migraine sufferers. Birth control pills and anti-depressants also can play a role in migraine. Ironically, so do over-the-counter pain medications, which can ease discomfort but then cause a “rebound” headache.
On patients’ to-do lists are aerobic exercise, which has been shown to reduce the frequency and severity of attacks. However, migraine patients often feel too unwell to exercise, which sets up a distressing Catch 22. Also included is a list of helpful vitamins and supplements such as Vitamin B2, magnesium, Coenzyme Q10 and melatonin.
This confluence of primary research with clinical care makes UCLA’s migraine program noteworthy, says Amy Gelfand, MD, assistant professor of pediatric neurology at UC San Francisco and director of the UCSF Pediatric Headache Program. Dr. Gelfand also is a leader in the field of migraine research; her recent breakthroughs include identifying a connection between migraine and colic in babies.
“The number of programs where people can get great clinical care and that also are doing original investigative research is small. Andy Charles’s program is one of the strongest in the field,” Dr. Gelfand says. “He and his group are moving the science forward and improving our understanding of migraine.”
Among the recent advances in how researchers think about migraine is the idea that headache pain is preceded by far subtler symptoms like irritability, foggy thinking or scent sensitivity. Learning to identify these early-warning signals allows patients to take medication at the earliest possible moment in a migraine attack, which is key to successful pain relief.
p>In UCLA’s Department of Neurology, Angel Moreno, NP, helps Dr. Charles’s patients work on this, as well as identifying drug-free alternatives for coping with migraine pain and symptoms. “I work with them on all aspects of their treatment — how they’re sleeping, what they’re eating, whether or not they’re exercising, what medications they are taking,” Moreno says. “We work on identifying their triggers and on how to avoid them in the future.”
Moreno teaches his patients about healing herbs and essential oils, showing them how, when and where on the body to use them. “For example, if someone has the migraine start in their temples or the back of their head, we may work with peppermint — a drop of it over the areas that are affected,” he says. “If it’s facial pain, I’ve found that frankincense rubbed over the area that’s affected can help.”
With precision health and targeted therapies coming into their own, Dr. Charles foresees a golden age of migraine research. “These are incredibly exciting times in migraine science and migraine therapy,” he says. “Now that we have powerful tools like monoclonal antibodies and functional imaging studies to visualize what’s happening in people’s brains at the various stages of an attack, we’re coming ever-closer to finding definitive therapies.”
For his patients, the potential for new cures is, indeed, exciting. Says Alsberg, Dr. Charles’s longtime patient, “He doesn’t have an answer for everyone. But the reason I love him is that he instills hope that someday there will be an answer.”
Veronique de Turenne is a freelance writer in Los Angeles.
*EDITOR’S NOTE: In “The Head-ake,” Robert Herrick — familiar to many readers for the line “Gather ye rosebuds while ye may” — conjures the torment of a sufferer in the throes of a headache, but it is, in fact, a metaphor for the pain of an aching heart. This does nothing to diminish the power of its evocation. Says Jonathan F.S. Post, PhD, Distinguished Research Professor in the UCLA Department of English: “The headache points to a real thing — pain — even if in the service of a greater thing — love; both are images of human suffering. It’s a wonderful little wisp of a poem that might go some distance to relaxing the reader and curing a headache.” Here is Herrick’s poem in total.*EDITOR’S NOTE: In “The Head-ake,” Robert Herrick — familiar to many readers for the line “Gather ye rosebuds while ye may” — conjures the torment of a sufferer in the throes of a headache, but it is, in fact, a metaphor for the pain of an aching heart. This does nothing to diminish the power of its evocation. Says Jonathan F.S. Post, PhD, Distinguished Research Professor in the UCLA Department of English: “The headache points to a real thing — pain — even if in the service of a greater thing — love; both are images of human suffering. It’s a wonderful little wisp of a poem that might go some distance to relaxing the reader and curing a headache.” Here is Herrick’s poem in total.
My head doth ache, O Sappho!
Take thy fillet, and bind the pain,
or bring some bane to kill it.
But less that part than my poor heart
now is sick; one kiss from thee
will counsel be and physic.