The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.
This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.
The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.
This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.
CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.
This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.
This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.
Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.
The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.
This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.
A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.
Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.