Managing Migraine: From Acute Treatment to CGRPs

Drug Topics JournalDrug Topics February 2022
Volume 166
Issue 02

Less than 5% of people with migraine have received an accurate diagnosis for this disabling—and painful—disease.

More than 37 million men, women, and children across the United States are affected by migraine. This translates to 1 in every 4 households, with higher rates of migraine among women: Roughly 3 of every 4 people living with migraine are women.1,2

“Because migraine has many different triggers, it is important to address prevention from multiple angles,” said Sara Crystal, MD, a neurologist and headache specialist and medical director of Cove, a digital health program that provides patients with expert care for migraine. “In addition to pharmacologic therapies, many nonpharmacologic treatments have been found to be effective for migraine.”

Nonpharmacologic Treatments

Crystal keeps the “SEEDS” mnemonic in mind when providing lifestyle recommendations: Patients should be encouraged to practice good sleep hygiene (prioritizing both quantity and quality of sleep), exercise 30 to 60 minutes 3 to 5 times per week, eat regular healthy meals, diary their migraine attacks on a calendar or in an app, and modulate stress through mindfulness, cognitive behavioral therapy, and biofeedback.2,3

For some, a supplement regimen that includes magnesium, riboflavin (vitamin B2), and coenzyme Q10 may be effective. And according to a study published in BMJ,4 a diet high in omega-3 fatty acids can reduce migraine frequency. “[T]he study group that increased dietary omega-3, and reduced omega-6, had the greatest benefit—on average, a 4-day reduction in migraine frequency,” Crystal said.

Another dietary supplement of interest is feverfew, which may help reduce migraine frequency and symptoms, and should be avoided during pregnancy.5 Patients who ask about butterbur should be cautioned that the American Academy of Neurology stopped recommending butterbur in 2015 because of a risk of liver toxicity. Some butterbur products contain pyrrolizidine alkaloids that can damage the liver and lungs and impact blood circulation, as well as potentially cause cancer. Patients should use a butterbur product that is certified as pyrrolizidine alkaloid free.6

Methods like relaxation training, thermal biofeedback combined with relaxation training, electromyographic biofeedback, and cognitive behavioral therapy may also help migraine, according to the United States Headache Consortium.

Preventive Prescriptions

When nonprescription measures aren’t enough, preventive treatment with prescription medications may be necessary.

When choosing preventive treatment for her patients, Crystal explained, “the most important [goal] is to establish realistic expectations.” Crystal teaches her patients that complete elimination of headaches is unlikely. “The goal of preventive therapy is a 50% reduction in migraine/headache days per month, in addition to decreasing the severity and duration of attacks and overall disability,” she said. Crystal cautions patients that it can take weeks to months to notice improvements from oral preventive drugs. “The migraine-specific anti–[calcitonin gene-related peptide] medications demonstrate faster onset, though,” she said.

Crystal turns to preventive medication in patients with 4 or more migraine days per month, or 2 or more migraine days if the headaches are disabling and don’t respond to acute treatments.

There are 3 classes of nonspecific migraine preventives; these medications were developed for other conditions and found to be effective for migraine prevention: blood pressure medications, antiseizure medications, and antidepressants.

“When choosing a preventive, we take into account the patient’s comorbidities and other medications, as well as [adverse] effects. A β-blocker may be a good choice for someone with hypertension and migraine, while a tricyclic antidepressant might be avoided in someone trying to lose weight,” Crystal explained. Her rule of thumb in terms of dosing is to start low and go slow. She starts the patient on a low dose and titrates slowly to the dose that is effective for the patient with minimal adverse effects.

These first-line prescription preventives include β-blockers
(propranolol, metoprolol, and timolol), anticonvulsants (divalproex and topiramate). Antidepressants venlafaxine and amitriptyline are classified as “probably effective”; amitriptyline received this classification due to the adverse effect profile.7 Each of these drugs has been recommended by the American Headache Society and the American Academy of Neurology and are backed by high-quality evidence and established efficacy.
Botox is another effective migraine preventive, but only for those with chronic migraine; it is not effective for episodic migraine.

Migraine-Specific Preventive Therapies

Calcitonin gene-related peptide (CGRP) antagonists are the first class of drugs developed exclusively for migraine prevention. CGRP is a neuropeptide in the nervous system released during migraine attacks, causing blood vessel dilation, inflammation, and migraine pain. CGRP inhibitors can reduce migraine frequency, number of headache days, and medication usage.8
Parenteral CGRP inhibitors are monoclonal antibodies and must be injected because of their large molecular size. Erenumab (Aimovig) works by binding to the CGRP receptor so that CGRP cannot attach to it. Fremanezumab (Ajovy), galcanezumab (Emgality), and eptinezumab (Vyepti) all bind to the CGRP molecule, preventing it from binding to the receptor.8

Gepants are a class of CGRP antagonists that are smaller in molecular size and are dosed orally. They work by binding to CGRP receptors.9 These oral CGRP inhibitors include atogepant (Qulipta), rimegepant (Nurtec ODT), and ubrogepant (Ubrelvy). Both atogepant9 and rimegepant10 are indicated for the preventive treatment of episodic migraine in adults; rimegepant is also indicated for acute treatment of migraine with or without aura. Atogepant adverse effects include nausea, constipation, and fatigue, while common rimegepant adverse effects are nausea, abdominal pain, and indigestion. Ubrogepant is indicated for the acute treatment of migraine with or without aura in adults. Unlike atogepant and rimegepant, it is not indicated for preventive treatment of migraine. The most common adverse effects are nausea, drowsiness, and dry mouth. 11

Options for Acute Treatment

“While not all patients need a prescription migraine preventive treatment, all patients should be offered a migraine-specific acute treatment,” Crystal said of her view on acute treatment. “By the time someone is seeking care, they no doubt have tried over-the-counter medications and found them ineffective.”

Triptans are generally considered first-line treatment in patients without contraindications, with the caveat that patients with uncontrolled hypertension, cardiovascular disease or risk factors, cerebrovascular disease or stroke, or ischemia should not take triptans because of their effects on vessel constriction. They should be used cautiously in patients over 50 years—because of cardiovascular risk factors—and in patients with Raynaud phenomenon.

There are 7 triptans currently available: naratriptan (Amerge), almotriptan (Axert), frovatriptan (Frova), sumatriptan (Imitrex), rizatriptan (Maxalt), eletriptan (Relpax), and zolmitriptan (Zomig). Patients who experience significant nausea or vomiting, or who do not respond to oral triptans, may benefit from non-oral triptans, including nasal sprays and injectables. In her practice, Crystal assesses response to the acute medication after 2 attacks. If the drug is ineffective, she considers another class of medication or route of delivery.

The risk of serotonin syndrome is minimal, said Crystal, referring to a 2018 study published in JAMA Neurology.1 While serotonin syndrome is an important counseling point, the study concluded that “patients with coexisting affective disorders and migraine need not forgo management of one condition to treat the other.”12

For acute prevention, the gepant class of drugs has several advantages over triptans. These small molecule CGRP receptor antagonists have “better tolerability/[adverse] effect profiles, and they do not cause vasoconstriction, so they should be safer in patients with stable cardiovascular disease,” Crystal said, but cautioned that there are drug interactions to consider: Rimegepant should not be administered concomitantly with strong cytochrome P450 (CYP) 3A4 inhibitors, strong and moderate CYP3A inducers, or inhibitors of P-gp or BCRP; ubrogepant should not be administered with strong CYP3A4 inducers; and lasmiditan (Reyvow),13
a serotonin (5-HT) 1F receptor agonist, should be used with caution in patients taking medications that lower heart rate and should not be used concomitantly with drugs that are P-gp or BCRP substrates.
There are also several noninvasive neuromodulation devices on the market that can offer a “nonmedication option and can be used in conjunction with medications,” said Crystal.

Karen Berger, PharmD, is a graduate of the University of Pittsburgh School of Pharmacy. Her experience includes chain and independent pharmacy, as well as medical writing and reviewing.


  1. The facts about migraine. American Migraine Foundation. March 28, 2019. Accessed January 13, 2022.
  2. Migraine. Office on Women’s Health. Updated April 1, 2019. Accessed January 13, 2022.
  3. Migraine. Medline Plus. Accessed January 13, 2022.
  4. Burch R. Dietary omega 3 fatty acids for migraine. BMJ. 2021;374:n1535. doi:10.1136/bmj.n1535
  5. Feverfew. National Center for Complementary and Integrative Health. Updated December 2020. Accessed January 13, 2022.
  6. Butterbur. National Center for Complementary and Integrative Health. Updated July 2020. Accessed January 13, 2022.
  7. Ha H, Gonzalez A. Migraine headache prophylaxis. Am Fam Physician. 2019;99(1):17-24.
  8. Mohanty D, Lippman S. CGRP inhibitors for migraine. Innov Clin Neurosci. 2020;17(4-6):39-40.
  9. Qulipta- atogepant tablet. DailyMed. Updated October 12, 2021. Accessed January 13, 2022.
  10. Nurtec ODT- rimegepant sulfate tablet, orally disintegrating. DailyMed. Updated December 20, 2021. Accessed January 13, 2022.
  11. Ubrelvy- ubrogepant tablet. DailyMed. Updated March 1, 2021. Accessed January 13, 2022.
  12. Orlova Y, Rizzoli P, Loder E. Association of coprescription of triptan antimigraine drugs and selective serotonin reuptake inhibitor or selective norepinephrine reuptake inhibitor antidepressants with serotonin syndrome. JAMA Neurol. 2018;75(5):566-572. doi:10.1001/jamaneurol.2017.5144
  13. Reyvow- lasmiditan tablet. DailyMed. Updated August 24, 2021. Accessed December 29, 2021.
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