Advances in the Prevention and Acute Treatment of Migraine
Author: Christine Zink, MD
Migraine is a widespread neurologic problem. It affects 1 billion people worldwide and almost 40 million people in the United States.1 The primary care clinician needs to understand the management options for preventing and acutely treating migraine. In this article, learn about the epidemiology of migraine, the pathophysiologic mechanisms behind migraine pain, options for the prevention and acute treatment of migraine, and the newest FDA-approved agents. Here are the key takeaways:
- Approximately 12% of the population suffers from migraine, and many who would benefit from preventive treatment do not receive the care they need.
- More than four headaches per month or headaches lasting longer than 12 hours are generally reasonable thresholds for initiating preventive therapy.
- The pathophysiology of migraine is complex. Currently, the dominant theory is that the disorder causes pain through a cascade of events that lead to recurrent inappropriate activation of the trigeminocervical pain system.
- Half of patients will respond to first-line migraine medications, including beta-blockers, antidepressants, and anticonvulsants.
- CGRP antagonists are the newest agents recommended for difficult-to-treat patients with migraine.
- Rimegepant and atogepant are the most recent FDA-approved CGRP antagonists that offer easy administration and reduce migraine days by approximately four days per month.
- Triptans and ergots are staples in migraine treatment, and recent approvals have led to easy formulations that can be administered at home.
- Clinicians have historically avoided triptans in patients with cardiovascular disease. However, a large systematic review did not show evidence of cardiovascular complications in patients who used triptans to treat migraine.
- Treatment decisions should be based on individual patient characteristics, comorbid conditions, side effects, and cost.
Approximately 12% of the population suffers from migraine, and it is more prevalent in women than men.1 Most people with migraine experience acute attacks once or twice a month, lasting between 4 to 72 hours, but millions of people have chronic daily migraine.1 There are a variety of medications to prevent and treat migraine, however, most people with migraines are either never diagnosed or do not seek medical care for their pain.1 For those who seek care and would benefit from preventive treatment, clinicians often overlook prescribing it.1
Migraine management can be divided into preventative and acute treatment. There are no strict guidelines that dictate when a patient should be managed with preventive therapy. However, specialists feel that more than four headaches per month or headaches lasting longer than 12 hours are generally reasonable thresholds for initiating preventive therapy.2 The goal is to reduce the frequency, severity, and duration of acute migraine attacks to improve overall function and quality of life.
Previously, migraine headache was thought to be a neurovascular problem. However, the pathophysiology of migraine is complex. Currently, the dominant theory is that the disorder causes pain through a cascade of events that lead to recurrent inappropriate activation of the trigeminocervical pain system.3 Several neurotransmitters are implicated in the pathophysiology of migraine, including serotonin, nitric oxide, pituitary adenylate cyclase-activating polypeptide, and calcitonin gene-related peptide (CGRP).2 CGRP is the prominent neurotransmitter involved in signaling through the trigeminal ganglion to neurons in the trigeminocervical complex.3
Several classes of medications are used as preventive therapy for migraine, some of which act on these neurotransmitters. They include beta-blockers, antidepressants, anticonvulsants, and CGRP antagonists.2 Specialists recommend initial preventive treatment with either amitriptyline, venlafaxine, metoprolol, propranolol, or topiramate.2 Half of patients will respond to these medications.2 The choice of agent depends on individual patient characteristics, comorbid conditions, side effects, and medication costs.
However, recent attention has focused on the modulation of CGRP, and CGRP antagonists are the newest agents recommended for difficult-to-treat patients with migraine. The first CGRP receptor antagonist was developed in 2000. However, none of the agents were FDA approved until 2018.4 CGRP antagonists are monoclonal antibodies directed against the CGRP receptor or ligand, or they are small-molecule CGRP antagonists called “gepants.” The first FDA-approved CGRP receptor antagonist was erenumab, a monoclonal antibody.2-4 Since that time, other monoclonal antibodies, fremanezumab, galcanezumab, and eptinezumab, have also been approved.2,4
The first-generation gepants did not work well because of poor oral bioavailability and hepatotoxicity. However, these small-molecule antagonists have been revisited over the last few years, and they are effective without hepatotoxicity. Rimegepant was approved for migraine prevention in May 2021. More recently, atogepant was approved in October 2021.2 Similar to the monoclonal antibodies, these agents are effective compared to placebo, but compared to the monoclonal antibodies—which require intravenous infusion or subcutaneous injection— rimegepant and atogepant are administered orally. Furthermore, rimegepant is available as an orally disintegrating tablet.
The FDA approved once-daily oral atogepant from the phase 3 ADVANCE trial,5,6 and they approved rimegepant from a different phase 3 study.7,8 In ADVANCE, 873 patients were assigned to receive three different doses of atogepant (10, 30, or 60 mg) versus placebo.5,6 In the rimegepant trial, 747 patients were treated with either rimegepant 75 mg or placebo.7,8 After 12 weeks of study treatment in both trials, there was a significant reduction in the number of migraine days per month, approximately four days in all treatment groups.5-8
Similar to preventive therapy, clinicians have a large armamentarium of treatment options for acute migraine pain. The treatment modality can depend on the severity of the migraine attack, previous and current migraine treatments, associated symptoms, and the treatment setting.9 Some people will respond well to simple analgesics like nonsteroidal anti-inflammatory drugs and acetaminophen. Intravenous antiemetics like metoclopramide and prochlorperazine are also effective for acute migraine pain since they are dopamine receptor antagonists.9 Some CGRP antagonists are FDA approved for both preventive and acute treatment of migraine pain. In particular, rimegepant was approved in February 2020, and ubrogepant was approved in December 2019.9 Both CGRP antagonists can be used for at-home treatment.
The more traditional acute migraine treatments are the triptans and ergots. Triptans are serotonin agonists (5-HT1B and 5-HT-1D) that inhibit the release of vasoactive peptides, promote vasoconstriction, and block pain pathways in the brainstem.9 The available agents include sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan. There are several delivery options, particularly with sumatriptan, which is available orally, subcutaneously, or as an intranasal spray or powder.
Ergotamine and dihydroergotamine are alpha-adrenergic agonists and serotonin-receptor agonists similar to triptans.9 These medications have not been shown to be more effective than the triptans and are best utilized in combination with an antiemetic.9 Additionally, until recently, dihydroergotamine has only been available as an injectable form. Still, the ergots provide yet another alternative treatment option.
A new easy-to-use at-home formulation of dihydroergotamine was approved in September 2021.10 This formulation is a nasal spray that offers rapid relief of symptoms since it bypasses metabolism by the gastrointestinal tract. The FDA approved the formulation of the long-term migraine treatment based on the STOP 301 trial.11 The study was conducted to assess the safety and tolerability of the intranasal formulation, and no new safety signals were identified in the 360 participants.11 Approximately 36% of patients experienced an adverse event, and the most common were nasal congestion, nausea, nasal discomfort, and abnormal taste.11
Potential Complications and Concerns
Clinicians have had concerns about using triptans or ergots in people with cardiovascular disease. Ergots should be avoided in these patients because their use has led to coronary artery constriction, peripheral vascular disease, hypertension, and hepatic or renal disease.9 However, a large systematic review did not show evidence of cardiovascular complications in patients who used triptans for migraine treatment.12 In any case, lasmiditan is a selective serotonin receptor (5-HT-1F) agonist approved for acute migraine that can be used to replace triptans and ergots in people with cardiovascular disease.9
While the newer migraine treatments offer great promise, notably if other treatments have failed, it is essential to consider how they compare to current therapies and what the medication costs are. In general, the CGRP antagonists have not been shown to be superior to current preventive treatments.3 In addition, their use can be prohibitive because they are costly. For acute migraine treatment, there are many effective options, and treatment decisions should be based on individual patient characteristics, comorbid conditions, side effects, treatment setting, and cost.
Overall, there are many new treatment options to consider for the prevention and acute treatment of migraine. Bucklan, et al. gives an excellent review of the new CGRP antagonists if you are interested in reading more.
Gain additional insights into advances in acute migraine treatment and migraine prevention in primary care at Pri-Med. Learn more about non-opioid pain management for potential options when treating patients with chronic migraine pain. These courses are available for free and provide pharmacology continuing medical education credit.
1. Migraine Research Foundation. Migraine facts.. Accessed November 10, 2021. https://migraineresearchfoundation.org/about-migraine/migraine-facts/
2. Schwedt TJ, Garza I. Preventive treatment of episodic migraine in adults. UpToDate. Updated October 19, 2021. Accessed November 11, 2021.
3. Bucklan J, Ahmed Z. CGRP antagonists for decreasing migraine frequency: new options, long overdue. Cleve Clin J Med. 2020 Apr;87(4):211-218. doi: 10.3949/ccjm.87a.19048.
4. Moreno-Ajona D, Pérez-Rodríguez A, Goadsby PJ. Small-molecule CGRP receptor antagonists: a new approach to the acute and preventive treatment of migraine. Medicine in Drug Discovery. 2020(7):3-9.
5. Ailani J, Lipton RB, Goadsby PJ, et al. Atogepant for the preventive treatment of migraine. N Engl J Med. 2021;385(8):695-706. doi: 10.1056/NEJMoa2035908.
6. Abbvie. New England Journal of Medicine Publishes 12-Week Results from Study Evaluating Atogepant for the Preventive Treatment of Migraine. Updated August 18, 2021. Accessed November 13, 2021. https://news.abbvie.com/news/press-releases/new-england-journal-medicine-publishes-12-week-results-from-study-evaluating-atogepant-for-preventive-treatment-migraine.htm
7. Croop R, Lipton RB, Kudrow D, et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet. 2021;397(10268):51-60. doi: 10.1016/S0140-6736(20)32544-7.
8. American Headache Society. NURTEC® ODT (rimegepant) receives additional approval for preventive treatment for adult patients with episodic migraine. Updated June 1, 2021. Accessed November 13, 2021. https://americanheadachesociety.org/news/nurtec-odt-rimegepant-receives-additional-approval-for-preventive-treatment-for-adult-patients-with-episodic-migraine/
9. Schwedt TJ, Garza I. Acute treatment of migraine in adults. UpToDate. Updated October 20, 2021. Accessed November 12, 2021. https://www.uptodate.com/contents/acute-treatment-of-migraine-in-adults
10. American Headache Society. Dihydroergotamine mesylate nasal spray receives FDA approval for the acute treatment of migraine in adults. Updated September 9, 2021. Accessed November 12, 2021. https://americanheadachesociety.org/news/dihydroergotamine-mesylate-nasal-spray-receives-fda-approval-for-the-acute-treatment-of-migraine-in-adults/
11. Smith TR, Winner P, Aurora SK, et al. STOP 301: A Phase 3, open-label study of safety, tolerability, and exploratory efficacy of INP104, Precision Olfactory Delivery (POD® ) of dihydroergotamine mesylate, over 24/52 weeks in acute treatment of migraine attacks in adult patients. Headache. 2021;61(8):1214-1226. doi: 10.1111/head.14184. https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14184
12. Roberto G, Raschi E, Piccinni C, et al. Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine: systematic review of observational studies. Cephalalgia. 2015;35(2):118-31. doi: 10.1177/0333102414550416.