Nitroglycerine's Historic Role in Migraine 'Underappreciated'

Jim Kling

June 09, 2021

Apparent migraines experienced by 19th century factory workers remain relevant to clinical medicine today. Those workers were employed in the manufacture of nitroglycerine, and many became patients of a physician who in 1880 described them as experiencing headache with nausea, vomiting, and walking lightly on their toes. A majority of patients were women.

When researchers in the 1950s worked out how to use nitroglycerine to trigger migraine-like headaches, the chemical became an important experimental tool, Peter Goadsby, MD, PhD, said during a talk on the translational importance of nitroglycerine in headache medicine at the American Headache Society's 2021 annual meeting.

Some neurologists view nitroglycerine with skepticism, but that's not necessarily warranted, said Goadsby. "To me, it's underappreciated, but it has matured. If you were talking about this topic a decade ago, then the criticism would be that somehow that it's not migraine, or it's got nothing really to do with migraine," he said in an interview.

But varying lines of clinical and experimental research have strengthened the case that nitroglycerine-induced migraine is largely indistinguishable from natural-onset migraine, and that studies that use it can provide important insights into patient management. "If I said to a colleague, 'I've got this patient with headaches, and they've got nausea, and they're sensitive to light. And if they move their head about, it's worse,' that sounds like migraine, and that's what they'd say. The patients will tell you it's the same, and they have the same premonitory symptoms. They respond to the same medicines," said Goadsby.

The method is also one of the few available to study premonitory symptoms, since it is difficult to predict naturally-occurring migraines. Once the minimal dose of nitroglycerine dose to trigger an attack was worked out, researchers could use functional imaging to monitor what happens before and during the episode. To support this point, Goadsby cited a 2005 study in Brain by his own group. They used positron-emission tomography (PET) scans to conclude that lateralized brain dysfunction is associated with lateralized pain during migraine.

The premonitory stage is characterized by symptoms such as neck stiffness, cognitive impairment, mood alterations, and fatigue, as well as homeostatic symptoms such as sleepiness and polyuria. Other possible symptoms include photophobia, phonophobia, nausea, and cranial autonomic symptoms. These symptoms can be studied and established with the use of nitroglycerin trigger studies.

Goadsby pointed out that triggered episodes can also be used to test therapeutics. Calcitonin gene-related peptide receptor antagonists, 5-HT1F receptor agonists, and substance P/neurokinin 1 receptor antagonists have all been tested against nitroglycerine-induced migraines.

Other studies have used repeat exposures to nitroglycerine to better understand the effects of chronic migraines. Goadsby cited an example by researchers at the University of Illinois at Chicago led by Amynah Pradhan, PhD, which administered nitroglycerine repeatedly to mice and found that it led to acute mechanical hyperalgesia and basal hyperalgesia. The latter effect was dose dependent and persistent after nitroglycerine administration stopped. The phosphodiesterase inhibitor sildenafil, which can trigger migraines in humans, made the effect worse, suggesting that nitric oxide may be the mediator.

Another study from Pradhan's team looked used nitroglycerine to examine the delta opioid receptor (DOR) as a potential therapeutic target for migraine. In mice, they used nitroglycerine to induce migraines and then treated with the DOR agonist SNC80 and found that it alleviated symptoms in medical overuse headache, posttraumatic headache, opioid-induced hyperalgesia, and chronic migraine models, suggesting that the pathway could have broad activity against headache.

Another study used nitroglycerine to induce migraines in mice engineered to have distinct missense mutations in the casein kinase 1–delta (CK1-delta) gene that had been identified in two human families. That work revealed cellular, physiological, and behavioral changes that suggested potential roles of CK1-delta in migraine pathogenesis.

"We were very attracted to nitroglycerine as a model because it is such a reliable human migraine trigger," said Pradhan, associate professor of psychiatry at the University of Illinois at Chicago. She noted that the ability to study nitroglycerine-induced migraine in both mice and humans allows researchers to confirm symptom and physiologic parallels between preclinical and clinical research. "It's exciting to see parallel things happening, both clinically and preclinically, because I think that that helps move the field forward in terms of coming up with novel therapeutic targets and validating them," she said.

Goadsby has financial relationships with Amgen, Eli Lilly, Celgene, Gerson Lerhman, Guidepoint, Aeon Biopharma, Alder Biopharmaceutical, Allergan, Biohaven, Clexio, Electrocore, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Santara Therapeutics, Satsuma, Teva Pharmaceuticals, and WL Gore. Pradhan has no relevant financial disclosures.

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