Transcript Related Guidelines

New Developments in the Treatment of Acute Migraine: Gepants and Ditans

Stewart J. Tepper, MD · Dartmouth University


October 11, 2021

Editor’s Note: The US Food and Drug Administration has expanded the indication for rimegepant, the first calcitonin gene-related peptide receptor antagonist approved in 2020 for the acute treatment of migraine with or without aura in adults, to include prevention of episodic migraine in adults. The expanded indication was based on a phase 2/3 randomized study which found rimegepant to be effective for the preventive treatment of migraine.[1]

Additionally, the US Food and Drug Administration (FDA) has approved atogepant, the first once-daily novel calcitonin gene-related peptide (CGRP) receptor antagonist specifically developed for preventing episodic migraine in patients. The FDA approval was based partly on the results of the phase 3 ADVANCE trial.[2]

This transcript has been edited for clarity.

This is an exciting time in migraine treatment as new treatments roll off the FDA (Food and Drug Administration) approval list right and left. We have two new categories of acute medication treatment for migraine; they are the gepants and the ditans. Gepants are calcitonin gene-related peptide (CGRP) receptor antagonists. So, they are small molecules that block the CGRP receptor; they prevent the vasodilation that CGRP causes, which is associated with the migraine pain, and gepants are used acutely to terminate migraine.

The two gepants that are approved are ubrogepant and rimegepant. Ubrogepant comes in a 50- and 100-mg dose, and the maximum usage of ubrogepant in a 24-hour period is 200 mg.[3] So, it has some flexibility in dosing. Rimegepant comes as an orally dissolvable tablet that patients put on their tongue and it dissolves instantly. They have to swallow it. It does not have significant sublingual absorption, and it comes in a 75-mg dose, with only one dose allowed in a 24-hour period. So, they take one dose, and there’s no availability to rescue with a second rimegepant dose.[4,5]

Both ubrogepant and rimegepant result in pain freedom in about 20% of patients in 2 hours. So, kind of a gentle onset, and they are more similar than they are different. One of their hallmarks is tremendous tolerability. So, it would be very rare to have a patient have a side effect with a gepant.[6,7] So, they’re appropriate for patients with vascular disease, as they do not cause vasoconstriction, but prevent vasodilation,[8] and I recommend that patients take them very early in a migraine attack not only because of the slow rate of onset of pain relief but also because they have nothing to lose. They’re not going to have side effects when they take it. So early is better. 

The second group of medicines that have been approved for acute treatment are the ditans. There’s really only one, lasmiditan, and lasmiditan comes in a 50- and 100-mg dose, although the FDA has also approved a 200-mg dose in which the patient would take two of 100 mg.[9]

Ditans work as central serotonin 1F receptor agonists, and they interfere with the processing of the migraine centrally. Because they do that, patients can have central nervous system side effects, including drowsiness and dizziness.[10] The tolerability issue suggests beginning with a lower dose and then working up if patients tolerate it. Efficacy is higher with the higher dose, but so are the side effects. 

Because of the tolerability issues of central nervous system, somnolence, and dizziness and because the central penetration of lasmiditan can alter coordination, the FDA has stated that patients who take lasmiditan for the acute treatment of migraine should not drive for 8 hours after they take a dose. That makes it more likely to use it in the evening or on the weekends when somebody doesn’t need to drive or in a city where there’s mass transit where a patient doesn’t need to drive, but it limits the utility of using this kind of a medication at work. 

Also, lasmiditan—because of its central nervous system effects—is scheduled by the FDA, and it’s a Schedule V medication, similar to pregabalin. So, if you do have a patient who has an addiction or substance use problem, you probably would not want to use lasmiditan. On the other hand, lasmiditan has higher pain-free responses at 2 hours than gepants, so for efficacy, lasmiditan looks like it’s a faster medication for patients with quick time to peak intensity.[11] Lasmiditan is in a conventional tablet and not in an orally dissolvable tablet. But lasmiditan studies actually recruited patients with vascular disease, and because it works centrally, there are no effects on blood vessels, and it should be safe in patients with vascular disease.[12]

Both gepants and ditans then represent a new way to treat in patients who do not do well with triptans—whether efficacy or tolerability or safety or contraindications—or patients who have vascular disease and you need an acute medicine that does not cause vasoconstriction.


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