By: Samia Rahman Adity, PharmD Candidate c/o 2025
Migraine has been a throbbing topic of discussion and a serious public health concern in the United States (U.S.). As of 2018, headache was seen to be the fourth or fifth most common cause for patients to visit an emergency department.1 The National Institute of Neurological Disorder and Stroke (NINDS), characterizes migraine headaches as excruciating pain on one side of the head that is primarily caused by nerve fiber activation within the walls of the brain blood vessels into the meninges.2
Characteristics of a Migraine Attack
While incidences of migraine attacks are prevalent in both children and adults, adult females are more likely to be affected in comparison to males. The NINDS has affirmed migraine to be a genetic condition. However, it can also occur in people with other health conditions including those with epilepsy, bipolar disorder, depression, anxiety, and/or sleep disorder. Women are more prone to migraines due to a change in hormone levels during the start of the menstrual cycle or pregnancy.2
Migraine can be classified into two types – classic and common.2 Classic migraine is associated with aura, which includes neurological symptoms and visual disturbances. Other symptoms of having a classic migraine are increased sensitivity to light, sound, or noise; tingling sensation in the hands or face; abnormal numbness; and muscle weakness. Common migraine is aptly named, being the most prevalent form of migraine among patients; usually, the pain is experienced on one side of the head without any warning. Other symptoms of a common migraine attack include blurred vision, confusion, mood change, and fatigue.2
Treatment of Migraine
The clinical practice established has been using monotherapy with agents like Tylenol (acetaminophen) or nonsteroidal anti-inflammatory drugs (NSAIDs), or a combination of medications to treat the mild to moderate symptoms of migraine. Patients suffering from moderate to severe symptoms of migraine have benefited from the use of a combination of products such as 5-HT1B/1D receptor agonists (-triptans) and NSAIDs.2 Lasmiditan, a selective 5-HT1F receptor agonist is associated with fewer adverse events and can be used in patients with cardiovascular medical conditions such as arrhythmia, myocardial infarction, or simply if they are contraindicated to triptans.3
For status migranosus, which is a migraine attack lasting longer than 72 hours, agents like dihydroergotamine or valproate can be given intravenously, especially in cases where prophylaxis or other rescue therapies were not effective.3.4 However, this type of treatment is limited to the inpatient setting which is not going to be appropriate for every case of migraines.3,4 Additionally, oral forms of therapy may be associated with intolerable side effects like nausea or vomiting associated and can sometimes be considered too slow-acting to counter a migraine attack. These factors have contributed to the need for further research in intranasal dosage forms which would hopefully prove to have a faster onset of therapy and a more tolerable side effect profile.
Zavegepant 10mg nasal spray has been recently approved by the U.S. Food and Drug Administration for the treatment of acute migraine attacks. On March 10, 2023, a study conducted by Richard B Lipton et al. established the safety and efficacy of zavegepant 10mg in treating acute migraine attacks. This was a double-blinded, randomized, placebo-controlled, multicentered phase 3 clinical trial.3 Zavegepant is classified as a calcitonin gene-related peptide (CGRP) antagonist that inhibits the vasodilatory action of the CGRP and helps with pain and inflammation. The medication has been reported to have a longer half-life of 5 to 8 hours.4
The inclusion criteria of the study incorporated adults at least 18 years old with at least a 1-year history of migraine (with or without aura), had migraine attacks before the age of 50, had 2 to 8 moderate or severe migraine attacks per month or with less than 15 days of headache per month before screening.3 Participants receiving treatment or having symptoms of alcohol/drug abuse within the past 12 months were excluded from the study. Pregnant women were also excluded from the study.3
The study has been funded by Biohaven Pharmaceuticals. The investigation was initiated with a pool of 1978 patients, where 1405 patients were randomized.3 Among this population of patients, 703 patients were assigned the intranasal zavegepant and 702 patients were assigned a placebo.3 The acute treatment phase lasted for a total of 45 days. Participants were instructed to self-administer the nasal spray.3 The pain intensity was recorded using the electronic clinical outcome assessment (eCOA) immediately before dosing at 15, 30, 45, 60, and 90 minutes and at 2, 3, 4, 6, 8, 24, and 48 hours after dosing.3 The pain intensity was measured using a four-point scale where 0 is none, 1 is mild, 2 is moderate, and 3 is severe. Pain freedom from migraine was measured as 0 being “absent” and 1 being “present”.3
Statistical Significance of the Study
As mentioned in the study, 22.8% of the participants in the zavegepant group and 15.5% of the participants in the placebo-controlled group reported pain freedom after 2 hours of treatment.3 The relative risk was calculated to be approximately 1.4 which indicates the risk of having pain is greater in the placebo group compared to the treatment intervention. The risk difference was 8.8 which is statistically significant (95% confidence interval [CI] 4.5 to 13.1; p < 0.0001).3
In another study, the percentage of participants that reported pain freedom after 2 hours was higher in the treatment group: 22.5% of participants with zavegepant versus 15.5% of participants in the placebo group.4 The approximate relative risk was 1.45, also indicating that the risk of having pain is greater in the placebo group than in the treatment intervention (zavegepant). The alpha level for the study was set at 0.0167; the reported p-value for the experiment with zavegepant 10mg nasal spray has been reported to be 0.0113 which is less than 0.0167, indicating the data is statistically significant.4
Adverse Events
According to the study, a greater percentage of patients experienced adverse events in the zavegepant group (30%) in comparison to the placebo group (16%).3 Some of the common adverse events reported include dysgeusia (change in taste), nasal discomfort, nausea, vomiting, throat irritation, and an increase in blood creatinine phosphokinase (CPK) level. These side effects were well tolerated by the participants and there were no signs of hepatotoxicity due to the use of zavegepant.4
Conclusion
It can be concluded that zavegepant 10mg nasal spray is efficacious with a good tolerability profile. According to the study above, a greater percentage of patients had a normal functional ability at 30 minutes and 2 hours in the zavegepant group than those in the placebo group.4 However, the study was limited by the absence of data on long-term safety and consistency of treatment response. Additionally, the results and the discussions would have been more appropriate if the use of zavegepant had been compared with an active comparator. Despite these limitations, zavegepant is still considered a promising drug. However, no therapy is complete without a nonpharmacological treatment; hence, any combination of treatment with behavioral therapy, such as mindfulness, biofeedback, and cognitive behavioral therapy, is also useful in treating migraine attacks.5
References
- Burch R, Rizzoli P, Loder E. The Prevalence and Impact of Migraine and Severe Headache in the United States: Figures and Trends From Government Health Studies. Headache. 2018;58(4):496-505. doi:10.1111/head.13281
- Migraine. NIH National Institute of Neurological Disorders and Stroke. Published January 20, 2023. https://www.ninds.nih.gov/health-information/disorders/migraine
- Lasmiditan. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Last Updated June 01, 2023. Accessed June 19, 2023. http://online.lexi.com.
- Dihydroergotamine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Last Updated June 16, 2023. Accessed June 19, 2023. http://online.lexi.com.
- Valproic acid and derivatives. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Last Updated June 23, 2023. Accessed June 23, 2023. http://online.lexi.com.
- Lipton RB, Croop R, Stock DA, et al. Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial. Lancet Neurol. 2023;22(3):209-217. Doi:10.1016/S1474-4422(22)00517-8
- Croop R, Madonia J, Stock DA, et al. Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial. Headache. 2022;62(9):1153-1163. Doi:10.1111/head.14389
- Walter K. What Is Migraine?. JAMA. 2022;327(1):93. doi:10.1001/jama.2021.21857
