Once again, management of migraine prevention and acute treatments with calcitonin gene-related peptides (CGRP) receptor antagonists dominated the 2022 American Headache Society (AHS) Annual Scientific Meeting, held from June 9 to 12 in Denver, Colorado, and virtually. Highlighted here are research findings on a combination of CGRP antagonists and onabotulinumtoxinA to treat breakthrough migraines, preventive medication for patients who have failed other treatments, whether high-fat meals affect the pharmacokinetics of atogepant, and use of vagal nerve stimulation to treat visual snow associated with migraines

Ubrogepant Plus OnabotulinumtoxinA Effective for Breakthrough Migraine

Real world evidence supports the efficacy of ubrogepant combined with onabotulinumtoxinA to treat breakthrough migraine attacks.1 Ubrogepant acts as an antagonist to receptors for calcitonin gene-related peptides (CGRP) which, when released in the brain, contribute to inflammation and the development of migraines.

To study the effectiveness of this combination, researchers conducted the prospective, observational, COURAGE study of ubrogepant in treating breakthrough migraine in 122 patients currently undergoing preventative treatment with onabotulinumtoxinA. The study included patients who experienced 3 or more migraine attacks in the last 30 days and who used either 50 mg or 100 mg of ubrogepant to acutely treat breakthrough migraine. Patients reported a median of 9 breakthrough migraine attacks during the 30-day period. The researchers assessed meaningful pain relief and return to normal functioning 2 and 4 hours after ubrogepant treatment. Data was collected via the Migraine Buddy app.

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During the first breakthrough migraine attack, 53.3% and 76.2% of patients reported meaningful pain relief at 2 and 4 hours following ubrogepant dosing, respectively. Similarly, 25.4% and 45.9% of patients reported return to normal functioning at 2 and 4 hours after taking ubrogepant, respectively. Cumulatively, over the first 10 breakthrough migraine attacks, meaningful pain relief occurred in 44.8% and 72.9% of patients at 2 and 4 hours after taking ubrogepant, respectively. Additionally, 30.1% and 52.1% of patients returned to normal functioning at 2 and 4 hours following ubrogepant treatment.

“These findings support the real-world effectiveness of ubrogepant as an acute treatment in combination with onabotulinumtoxinA, providing evidence for a common treatment pattern,” the researchers concluded. “These results also demonstrate the feasibility of using a novel, app-based design to evaluate the real-world effectiveness of migraine treatment.”

Eptinezumab Prevents Migraine in Patients With Prior Treatment Failures

Patients who have failed prior migraine treatments may benefit from the anti-CGRP agent eptinezumab. In phase 3 trials, eptinezumab significantly reduced monthly migraine days (MMD) up to week 24 compared with placebo among patients with episodic or chronic migraine who had 2 to 4 prior treatment failures.2 The agent also demonstrated safety, tolerability, and efficacy for preventing migraine.

The DELIVER study was a phase 3b, multicenter, parallel-group, double-blind, randomized clinical trial of eptinezumab. Patients (N=891) with episodic or chronic migraine who had 2 to 4 preventative treatment failures in the past 10 years were randomized to receive 100 mg (n=299) or 300 mg (n=294) eptinezumab or placebo (n=298) intravenous infusions administered every 12 weeks. The study included a 28 to 30-day screening period, 24-week placebo-controlled period, and 48-week dose-blinded extension period. The primary endpoint was change in MMD during the placebo-controlled period. A total of 865 patients completed the placebo-controlled portion of the trial.

Eptinezumab significantly reduced MMD at 12 weeks from baseline among the 100 mg (mean difference, [MD], -4.8) and 300 mg (MD, -5.3) groups compared with the placebo group (MD, -2.1; P <.0001).

Between weeks 13 and 24, a 50% or greater reduction in MMD was maintained among 42.1% of the low-dose and 49.5% of the high-dose eptinezumab cohorts compared with 13.1% of the placebo group (P <.0001). A 75% or greater reduction in MMD was maintained among 15.7%, 18.8%, and 2.0% among the respective groups (P <.0001).

Eptinezumab was also associated with significant decreases on the Headache Impact Test (HIT-6) at week 12 compared with baseline among recipients who took 100 mg (mean difference, -6.9) and 300 mg (MD, -6.9) compared with those in the placebo group (MD, -3.1; P <.0001).

Treatment-emergent adverse event (42.5% vs 40.8% vs 39.9%) and serious adverse event (1.7% vs 2.4% vs 1.3%) rates were similar among the low- and high-dose eptinezumab and placebo cohorts, respectively.

The researchers concluded that “eptinezumab robustly decreased MMDs and improved responder rates” across weeks 1 to 12 and weeks 13 to 24 compared with placebo. The safety and tolerability profile was comparable to that observed previously, they said.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

Do High-Fat Meals Affect the Pharmacokinetics of Atogepant for Episodic Migraine?

Consuming a high-fat meal had an insignificant effect on the pharmacokinetics of immediate-release atogepant tablets.3 Atogepant, an oral CGRP receptor antagonist, is approved for the prevention of episodic migraine in adults.

Researchers conducted a single-center, open-label, 2-period, randomized crossover study in which 20 healthy adults took a single 60-mg dose of atogepant to investigate how a high-fat meal impacts systemic exposure to the drug, and thus, potentially, its efficacy.

During the first period of the study, some of the participants took atogepant after fasting overnight, while the others consumed a high-fat meal 30 minutes prior to taking the medication. Following a 7-day washout period, the study participants received the opposite treatment regimen during the second period of the study.

The researchers obtained plasma samples prior to dosing and up to 48 hours following dosing at specified time intervals to determine atogepant plasma concentrations and various pharmacokinetic parameters, including maximum plasma concentration (Cmax) and the area under the curve (AUC).

A high-fat meal decreased maximum atogepant concentration levels by 22% and decreased the AUC by 18%. No serious adverse events or deaths occurred during the trial, indicating that a single dose of 60 mg of atogepant was safe and tolerated well under both fed and fasted states.

A high-fat meal did cause a mild food effect on the pharmacokinetics of atogepant; however, the researchers determined that this small food effect did not make a significant difference on the efficacy of the drug.

Since “atogepant [is] a preventive treatment for migraine with a wide effective dose range of 10 to 60 mg/day, the mild food effect on its [pharmacokinetics] is not considered clinically relevant,” the researchers concluded.

Noninvasive Vagal Nerve Stimulation: a Potential Treatment for Visual Snow?

A small study of patients with visual snow (VS) treated with noninvasive vagal nerve stimulation (nVNS) had mixed results.4

Visual snow presents as continuous tiny dots or pixelations in the entire visual field accompanied by 2 or more symptoms of palinopsia, enhanced entopic phenomena, photophobia, or nyctalopia. Currently, no validated tools are available for quantifying VS symptomology or associated disability nor are there established treatments.

Researchers at the Mayo Clinic studied the theory of cortical hyperexcitability as a mechanism for VS, making nVNS a potential treatment. In this retrospective case series, 3 patients trialed nVNS by performing a pair of 2-minute stimulations 3 times per day using a gammaCore™ device for 10 to 12 weeks. To evaluate VS symptoms, patients recorded specific symptoms on an 11-point scale for a total score of 60 points. The patients also recorded the number of days they experienced VS symptoms and headache.

The patients included a 67-year-old man (patient 1), 38-year-old woman (patient 2), and 48-year-old man (patient 3). All patients reported constant VS symptoms. Patients 2 and 3 had no obvious inciting VS event whereas patient 1 awoke from anesthesia with VS. Patients 1 and 3 had episodic migraine and migraine with visual aura, respectively.

In an attempt to reduce VS symptoms, patient 1 had used benzodiazepines, serotonin reuptake inhibitors, tricyclic antidepressants, anticonvulsants, diuretics, magnesium, effervescent tablets, and pulse transcranial magnetic stimulation; patient 2 had used amitriptyline.

During the nVNS treatment, total VS symptoms scale score decreased from 40 to 37 points in patient 1, 40 to 20 points in patient 2, and 41 to 27 points in patient 3.

Patients 1 and 2, who reported a 3- and 20-point change in their VS symptoms, respectively, rated their change in symptoms as “better, and a definite improvement that has made a real and worthwhile difference.” Conversely, patient 3 who reported a 14-point change, also reported “no change” to their symptoms, however, the patient’s reaction to treatment may have been confounded by a depressive episode not related to the nVNS device.

The patients reported transient neck tightness during nVNS use.

These data were limited by the small sample size and nVNS should be evaluated among a larger cohort to corroborate findings.

Response to nVNS was mixed, the study authors concluded. “Our symptom scale score helped to standardize recording of VS symptoms but changes in the overall symptom scale score did not consistently match the global impression of change,” the researchers stated. The overall decrease in reported VS symptoms likely indicated that nVNS should be investigated further.


1. Lipton RB, Engstrom E, Serrano D, et al. Real-world effectiveness of ubrogepant for the acute treatment of migraine in combination with onabotulinumtoxinA preventive: Results from the COURAGE study. Presented at: AHS 2022 Annual Scientific Meeting; June 9-12, 2022; Denver, Colorado. Poster 190.

2. Ashina M, Lanteri-Minet M Pozo-Rosich P, et al.  Efficacy and safety of eptinezumab for migraine prevention in patients with 2 to 4 prior preventive treatment failures. Presented at: AHS 2022 Annual Scientific Meeting; June 9-12, 2022; Denver, Colorado. Poster 164.

3. Boinpally R, Trugman JM. Effect of high fat meal on the pharmacokinetics of an immediate release atogepant tablet. Presented at: AHS 2022 Annual Scientific Meeting; June 9-12, 2022; Denver, Colorado. Poster 118.

4. Arca KN, VanderPluym J. Noninvasive vagus nerve stimulation for the treatment of visual snow. Presented at: AHS 2022 Annual Scientific Meeting; June 9-12, 2022; Denver, Colorado. Poster 183.