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Evolution of Acute and Preventive Treatment of Migraine

Robert G. Kaniecki, MD

Director, UPMC Headache Center
Chief, Headache Division
Director, Headache Fellowship Training Program
Assistant Director, Neurology Residency Training Program
Associate Professor of Neurology
University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania


Robert G. Kaniecki, MD, has no relevant conflicts of interest to disclose.


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Released: March 26, 2020

Acute Migraine Treatment
My first year in the practice of headache medicine was momentous, for it was in 1992 that sumatriptan was approved for acute migraine. Following the launch of the subcutaneous formulation of sumatriptan in 1993, 6 additional triptan compounds were soon approved and marketed for the acute treatment of migraine.

The impact on headache management was historic. We were no longer treating migraine with nonspecific analgesics, antiemetics, and “dirty” serotonin agonists like ergotamine, but instead had relatively cranio-selective, “cleaner” migraine-specific acute therapies.

Finally, the rewards of scientific insights into migraine pathophysiology were being translated into options providing tremendous benefit to our patients. Within the decade, the central role of calcitonin gene-related peptide (CGRP) in migraine pathogenesis became more apparent. Small-molecule CGRP antagonists were synthesized and shown to be effective in acute migraine, but liver toxicity issues temporarily stalled their development.

Preventive Migraine Treatment
Fast forward to 2018, a full 25 years later, and a second seismic shift in migraine therapeutics occurred. This one, however, was set to change the landscape of migraine prevention.

Before that year, similar to the previous situation with acute migraine treatment, the medications used in migraine prevention were nonspecific and often “dirty.” Beta-adrenergic blockers (propranolol, timolol) and the serotonin antagonist methysergide were first to receive FDA approval, followed by 2 antiepileptic agents (valproic acid, topiramate) and then, for chronic migraine, onabotulinum toxin A.

None was specific for migraine, none was developed for migraine, and benefits were typically noted serendipitously. The oral agents all carried baggage of limited efficacy and poor tolerability. Fatigue, exercise intolerance, depression, and sexual dysfunction were seen with the beta-blockers; weight gain, hair loss, and tremor with valproic acid; and cognitive impairment, paresthesias, and nausea with topiramate. Onabotulinum toxin was typically better tolerated and perhaps was more effective in the chronic migraine population, but efficacy in episodic migraine was not demonstrated.

Then, in 2018, investments into earlier research into CGRP finally paid dividends with the release of the first migraine-specific preventive medications. Erenumab, fremanezumab, and galcanezumab received FDA approval in 2018, and eptinezumab in 2020. All are monoclonal antibodies. Erenumab targets the CGRP receptor, and the others target the CGRP ligand. The first 3 are delivered subcutaneously on a monthly basis, whereas eptinezumab is given intravenously and quarterly.

Unlike small molecule–direct CGRP antagonists, these antibodies are processed through the reticuloendothelial system and have shown no hepatotoxicity.

Benefits in clinical trials for these agents were impressive and consistent. They were shown to be effective in episodic and chronic migraine, in migraine with and without aura, in migraine accompanied with and without medication overuse, and in migraine failing previous preventive medications. Every primary endpoint in every migraine trial was met for every drug, and benefits were sometimes realized within the first week.

Most adverse events were mild and infrequent. No significant drug–drug interactions or safety issues were noted.

Although more expensive than the nonspecific agents, cost-effectiveness was demonstrated. Due to these cost considerations most insurance providers require failure of 2-3 of the oral agents before approval, but I have found the extra paperwork to be well worth it.

Your Thoughts?
I would like to hear your opinion and learn of your experiences. Are your patients achieving success with these drugs? Are they “as good as they sound”? Answer the polling question and leave a comment in the discussion section.

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