Within the last 3 decades there have been 3 revolutions in migraine therapeutics. The first occurred in the early 1990s, when injectable Imitrex was introduced in the US and triggered the Triptan Revolution. That seismic event opened the door to our recognizing migraine to be a biologic disorder that was eminently treatable if the right pharmacolgic key could be designed to fit the disorder’s biologic lock. It is hard to overestimate the impact made by the triptans on public and professional interest in the biology and treatment of migraine.

In the early 2000s a second and less heralded but nevertheless significant therapeutic revolution occurred with the simultaneous identification of chronic migraine, as a common and important variant of migraine and onabotulinumtoxinA (BotoxA) as an effective therapy for suppression of chronic migraine.

On the heels of the Botox Revolution came the identification of calcitonin gene-related peptide (CGRP) as an important component of the biologic circuitry that generates migraine, and shortly following this discovery came the introduction of the anti-CGRP monoclonal antibodies and gepants for migraine prevention (both episodic and chronic) and acute migraine treatment. 

To focus on chronic migraine specifically, despite the disorder’s high prevalence and disproportionate share of the adverse impact migraine imposes on the public health, prior to 2010 there existed no evidence-based therapy for its management. Courtesy of the BotoxA and CGRP Revolutions, by 2022 healthcare providers and their patients had available to them for treatment of chronic migraine no less than 6 evidence-based therapies of proven safety, high tolerability and clear effectiveness.

Now we are on the cusp of a fourth revolution in migraine therapeutics. There are about to commence large scale, multi-center studies investigating abobotulinumtoxinA (Dysport) as a potential alternative to BotoxA for suppression of chronic migraine; in addition, this neurotoxin is being evaluated for its utility in treating episodic migraine as well (BotoxA is not currently indicated for episodic migraine: ie, migraine with <15 days of headache per month). Pilot studies have indicated that prophylactic polytherapy – combining two evidence-based treatments – and specifically adding erenumab (Amovig) or atogepant (Qulipta) to BotoxA  potentially may be synergistic in suppressing chronic migraine. There is now a large scale, multi-center research study (UNCHAINED) now in progress that is examining the safety, tolerability and effectiveness of adding Qulipta to the treatment regimen of patients already receiving BotoxA.

Yet another component of this fourth revolution in migraine therapeutics may be the most interesting of all. Investigators have identified another protein target within the migraine circuitry that offers an entirely new way of attempting to reduce the activity of that circuit and thus reduce migraine burden. This protein, pituitary adenylate cyclase-activating polypeptide (PACAP) represents a therapeutic target distinct from CGRP. A neutralizing monoclonal antibody directed against PACAP and now being investigated in the migraine population may represent an effective alternative for the ~40% of migraine patients who require prevention therapy and fail to respond to the anti-CGRP drugs. In addition, PCAP may be especially abundant in the hypothalamus of the brain. The hypothalamus is believed by many to be the source of the prodromal symptoms experienced by so many migraineurs and, for some, as or more distressing than the headache of migraine. A therapy that inactivated or blocked PACAP theoretically could reduce or eliminate migraine prodrome, a feature which would make that therapy unique amongst the migraine preventatives.

It is - yet again - an exciting time to be involved in migraine research. Stay tuned for more. 

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