Dr. Messoud Ashina is a Professor of Neurology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. He is Director of the Human Migraine Research Unit at the Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup. He serves an associate editor for Cephalalgia, Journal of Headache and Pain, and Brain.
Dr. Faisal Mohammad Amin is an Associate Professor, Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, University of Copenhagen, Denmark. He is an associate editor for Headache Medicine and is President of the Danish Headache Society.
Dr. Ashina reports that he has received fees and grants from and/or has served as a principal trial investigator for AbbVie, Amgen, Eli Lilly, Lundbeck Pharmaceuticals, Lundbeck Foundation, Novartis, Novo Nordisk Foundation, and Teva.
Dr. Amin reports that he has worked as a consultant, speaker, and/or primary investigator Eli Lilly, Lundbeck, Novartis, and Teva. Both authors have reported that they have no ownership interest nor own any stocks in a pharmaceutical company.
Since the time of the Neanderthals, humankind has looked for ways to rid the brain of migraine headache. There is evidence that trepanation –removing a portion of bone from the skull–was performed on Neolithic skulls. Did it work for that poor individual? We will never know.
What is known is that the often circuitous hunt for effective treatments has taken centuries. And while this search led to the successful introduction of calcitonin gene-related peptides (CGRPs) a few years ago, the search is nowhere near finished, as efforts to pinpoint the source of migraine continue, as does the search for other possible therapies.
The nearly 39 million people with migraine in the United States would be grateful; they often experience a perplexing, frustrating, and unsatisfactory search for a pain-free existence. Migraine is estimated to cost more than $20 million per year in direct medical expenses and lost productivity in the United States. People with migraine, meanwhile, face the prospect of significant disability. More than 8 in every 10 participants in the American Migraine Study had at least some headache-related disability. More than half said their pain has caused severe impairment.
The search to find relief for these patients is focused on understanding the pathophysiology of migraine. Approaches include in vitro application of mediators, direct electrical stimulation of trigeminal neurons in vivo, administration of vasoactive substances in vivo, and introduction of exogenous pain-inducing substances in vivo. In 2021, investigators at AstraZeneca and the University of Arizona College of Medicine described their development of an injury-free murine model to be used to study migraine-like pain. Animal research has led to a few interventional studies involving new and existing medications.
How the field has evolved from using a chisel to make a cranial hole to using magnetic resonance imaging and other technologies to examine the trigeminovascular system’s role in the pathophysiology of migraine headache is a tale worth telling.
From crocodiles to nitroglycerin to allergies
The search for an effective remedy for migraine has proved to be torturously slow. In addition to trepanation, another procedure thought to have been used during prehistoric times involved a religious ritual whereby a clay crocodile was attached tightly with a strip of linen to an individual’s head. Though the gods were credited if the headache pain receded, relief likely came from the resulting compression on the scalp. Centuries later, in the Middle Ages, treatments included soaking bandages in drugs and then applying them to the head or mixing elixirs with vinegar (which opened scalp pores) and opium (which traveled into the scalp through the open pores ).
The Persian scholar Ibn Sina (980-1032), also known as Avicenna, postulated that the pain could emanate from the bones that comprise the skull or within the parenchyma or from veins and arteries outside the cranium. The medicinal plants he investigated for the treatment of migraine have components that resonate today: antineuroinflammatory agents, analgesics, and even cyclooxegenase-2 inhibitors .
Six hundred years later, English physician Thomas Willis discussed how the vascular system perpetrated migraine, and in the next century, Erasmus Darwin, Charles’ grandfather, proposed that individuals with migraine be spun around so that blood from the head would be forced down toward the feet. In the 1800s, English physician Edward Liveing abandoned vascular theory, instead proposing that migraine resulted from discharges of the central nervous system.
British neurologist William Gowers thought migraine could be a derangement of neurons, but ultimately wrote in his Manual of Diseases (p. 852) that, “When all has been that can be, mystery still envelops the mechanism of migraine.” Gowers advocated continuous treatment with drugs to minimize the frequency of attacks, as well as treating the attacks themselves. His preferred treatments were nitroglycerin in alcohol, combined with other agents, as well as marijuana. His choice of nitroglycerin is an interesting one, given that modern medicine considers nitroglycerin an important neurochemical in migraine initiation.
The concept of neuronal involvement retained support into the 20th century, solidified by German physician Paul Ehrlich’s Nobel Prize–winning work involving immunology and brain receptors. In the 1920s, thoughts turned to allergy as the source of migraine, as an association between migraine, asthma, and urticaria emerged, but this connection was eventually proved to be incidental, not causal.
In the 1930s, the vascular theory again was vogue -- aided by studies performed by US physician Harold G. Wolff . His work, the first to assess headache in a laboratory setting, along with observations about changes in vasculature and evolving treatment , appeared to support the vascular nature of headache. In the 1940s and 1950s, psychosomatic disorders crept into the mix of possible causes. Some categorized migraine as a so-called stress disease.
Puzzles and irony
In 1979, Moskowitz and colleagues introduced a new hypothesis focused on the importance of the neuropeptide-containing trigeminal nerve . CGRP is stored in vesicles in sensory nerve terminals, where it is released along with the vasodilating peptide, substance P, when the trigeminal nerve is activated.
At about the same time, researchers in England were working on a discovery with ancestral roots going back hundreds of years. In the 18th century, scientists learned that rye ergot was a constrictor of blood vessels. In time, ergot became ergotamine and hence more valuable because it could reduce vascular headaches. But the adverse effects , prominent in those with cardiovascular disease, kept researchers in the lab.
So, while Moskowitz and colleagues were focused on CGRPs, Humphrey et al were focused on a receptor they found in cranial blood vessels that came to be called serotonin (5-HT 1B). An agonist soon followed. In 1991, sumatriptan became available in Europe, and 2 years later, it was available in the United S tates. But sumatriptan is for acute care treatment, not a preventive therapy. It was Moskowitz’s work that led to studies demonstrating that antisera could neutralize CGRP and substance P.
For those with chronic migraine, preventive therapy was exactly what they needed because, while the triptans helped, they were insufficient for many. In a 2-year longitudinal analysis conducted in Italy involving 82,446 individuals prescribed at least 1 triptan, 31,515 had an unmet medical need in migraine (3.1 per 1000 patients).
In February 2022, a team of researchers published the results of a genome-wide association study involving over 100,000 cases. The results were 125 risk loci linked to migraine within the vascular and central nervous systems, thereby firmly establishing that the pathophysiology of migraine exists in neurovascular mechanisms.
The fact that it has taken technology to prove that migraine exists and that it is organically rooted is obviously satisfying but also frustrating. For centuries, people with migraine were considered to have caused their own illness or were exaggerating the pain.
In March 2022, a large German population -based study found that people with migraine still struggled with bias, stigma, and undermedication. Fifty-four percent said they were not seeing a physician for their migraine, and 33% said they had not received information on medication overuse risks.
With captured images of what happens inside the brains of these patients during an attack, now the focus can be on helping them and not questioning the validity of their reported symptoms.
Coming next month, a discussion about migraine therapies.