R. Allan Purdy, MD, FRCPC
Dr. Purdy is Professor of Medicine (Neurology) at Dalhousie University, Halifax, Nova Scotia.
Although migraine has been with humans since antiquity, it is truly amazing that over the past 25 years and a bit longer there have been remarkable advances in our clinical understanding of migraine and its variations, along with sophisticated epidemiologic evidence and basic research into the neurobiological basis of migraine. These advances have brought this disorder/disease to the forefront as a serious neurologic condition deserving of attention. Migraine is a major cause of neurologic disability in the world. This fact has only been fully recognized in recent years.
From the 1980s through the 1990s, a series of events led to a seminal study of a medication that would truly alter the vector for migraine in the future. Studies coming out of Glaxo in the United Kingdom, under the direction of Pat Humphrey, OBE, DSc, PhD, led to the discovery of sumatriptan, the first truly designer medication for the treatment of acute migraine. The story of how this medication biologically affects the brain serotonin receptors on blood vessels and brain tissue to abort a migraine attack is well known today. Early observations on patients receiving subcutaneous sumatriptan clearly showed how powerful this agent was in shutting down the migraine attack. Patients having migraine in extremis, with severe throbbing headache, pallor, nausea and vomiting, appearing markedly distressed and ill, within minutes to an hour would return to a normal state. Nothing that preceded sumatriptan demonstrated such a remarkable clinical response in patients with headache.
In the past century, sumatriptan came to be one of the most important therapeutic advances in neurology. After its discovery, six other triptans entered the market over time. All of them had minor tweaks on the original molecule’s pharmacology and pharmacokinetics, including various modes of delivery with different results in subgroups of patients. Nevertheless, on balance, the triptans acted in a similar manner to produce similar outcomes. Today, many patients take triptans regularly for help with acute migraine attacks; however, other patients with migraine remain undiagnosed and undertreated and do not receive optimal care.
In the past 20 years, sophisticated laboratory and neuroimaging research allowed in-depth analysis of the migraine attack and spectrum of the migraine disorder. The brain areas that subserve the migraine attack have been mapped neuroanatomically throughout the nervous system, with input from the brainstem, hypothalamus, thalamus, and cortical structures. Cortical-initiated electrical events possibly trigger the trigeminal vascular system, and/or peripheral or central activation mechanisms produce the symptoms of migraine. The migraine story is not complete, but evidence clearly shows migraine to be a valid neurobiological disorder and disease. For some people with migraine, it is occasional aggravation, but for others it can be life-altering and, rarely, life-threatening.
In the past few years, new targets for migraine therapy have been pursued. A CGRP receptor antagonist (or “gepant”) showed benefit in early trials; however, because of potential hepatic side effects, other gepants and CGRP monoclonal antibodies have been studied in clinical trials.
Results of recent trials—one in episodic migraine and the other in chronic migraine—show that anti-CGRP monoclonal antibodies appear to be quite efficacious, have few side effects, and are well tolerated. Time will determine whether there are long-term consequences of their use, and what is the effectiveness of using these large molecules to treat migraine, but current results appear promising. Another triptan-like agent, a ditan, which activates receptors of serotonin without vasoconstrictor properties, has shown promise in acute migraine. Neuromodulation devices are also showing promise in migraine therapy and appear to be safe and well tolerated. Nonpharmacological therapies are more often utilized with benefits and help to avoid problems with medications and their side effects.
Increasing knowledge of migraine epidemiology has shown that there is a transition from acute to more frequent, and from high frequency to subsequent chronic migraine attacks. This transformation, or chronification, appears unique in patients with migraine. This process appears to be bidirectional and reversible in migraine. Whether migraine becomes chronic as a process over time or whether migraine is a chronic disease with episodic fluctuations is something to be further explored in research and clinical practice. Nevertheless, these concepts can only lead to better understanding and, hopefully, new therapeutic interventions that will reduce the frequency and severity of this unique neurologic disease.
As migraine progresses or evolves it can be associated with multiple comorbid disorders, including stroke, depression, seizures, and medication overuse. New preventive therapies in development can be modifications of medications for other neurologic conditions, such as the antiepileptic medications, for example. There are many other potential targets that will be explored for the management of migraine in this century. The future looks promising in that regard.
For decades, and now centuries, neurologists have been interested in migraine and related disorders. Sumatriptan jump-started the modern revolution and evolution of therapeutic options to manage migraine pharmacologically. Since its discovery and use in clinical medicine, the world of migraine has changed dramatically. As headache clinicians are being trained in the latest advances in migraine and other headache disorders, they are showing increasing interest and knowledge,which is provided by some of the most unique and relevant research involving the brain in the world. A cure for migraine may not be possible, but a better understanding and control of all of migraine’s myriad of symptoms is probably within reach in this century.