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Novel Migraine Prevention Medications Target New Pathway

18 Mar 2019 1:19 PM | Deleted user

Author:  Ashley Wellen, PharmD, PGY1 Community Pharmacy Resident
Mentor: Michelle Jeon, PharmD, BCACP, Assistant Professor of Pharmacy Practice/Clinical Pharmacist - St. Louis College of Pharmacy/Walgreens Co.


Migraine is a disease that affects over 36 million Americans. The disabling disease affects almost three times as many women as men.1 Patients with episodic migraine may experience a few migraine days per month, and those with chronic migraine spend 15 or more days per month with debilitating pain and neurologic symptoms.2  

A study published in 2018 that aimed to describe the prevalence of migraine in adults also described the socioeconomic burden of the disease.3 According to results, the following groups had a statistically significant higher burden of severe headache or migraine:

  • The highest prevalence on the basis of income was in those who lived below the poverty threshold of $11,670 per year for a single person in 2014 (21.7%).
  • In those under 65, prevalence was highest in those insured by Medicaid (26%), compared to those with private insurance (15.1%) or without any insurance (17.1%).3


Migraine headache etiology and pathophysiology are not completely understood. The pain and associated symptoms a patient experiences are believed to occur through a combination of mechanisms including neural suppression and activation of subcortical structures of the trigeminal system. The activation of trigeminal sensory nerves leads to the release of vasoactive neuropeptides including calcitonin gene-related peptide (CGRP), neurokinin A, and substance P. The vasodilation caused by these neuropeptides leads to neurogenic inflammation. Continued nerve conduction relays information to the cortical pain centers and continued afferent input maintains the headache.4,5,6

Impact on Quality of Life

Individuals with migraine experience attacks that may last for several hours to days. Migraines can severely negatively affect quality of life for patients. Affected patients may not be able to participate in daily activities, engage with family and friends, or perform at work. Sunlight, smells, and weather may trigger, amplify and exaggerate symptoms of a migraine.

The Migraine Impact report published by Eli Lily presented data regarding the social burden associated with migraine headaches7. Findings included:

  • 62% diagnosed with migraine agreed they try to hide the true impact of the headache at work or school.
  • 70% agreed to the statement “I’ve avoided making plans because of migraine.”
  • 55% with migraine agreed it had affected their career goals.7

Migraine headaches have a significant impact on quality of life and overall well-being of those who are affected by the disease.

Prevention with Pharmacologic Agents

According to the American Academy of Neurology, about 38% of those with migraines need preventative therapy; however, only 3-13% use it.8 Migraine prevention is indicated for those patients with frequent or long lasting migraines; contraindications, adverse effects, failure, or overuse of acute therapies; or those with uncommon migraines. Goals of preventative therapy include reducing attack frequency, severity, and duration; improving responsiveness to treatment of acute attacks, improving function and reducing disability, and preventing progression of episodic to chronic migraines. The overall goal is to improve the patient’s quality of life from the debilitating disease.8,9

Preventative medications currently recommended by the American Academy of Neurology include agents from pharmacologic classes such as beta-blockers, antidepressants, antiepileptics, NSAIDs, and calcium channel blockers. Table 1 includes agents with labeled indications for migraine prevention. Other agents such as atenolol, amitriptyline, venlafaxine, verapamil, and NSAIDs, are commonly used off-label. Many of these agents have limited efficacy in migraine prevention as well as limited use in special populations. The agents with the highest level of evidence of use are described in Table 1 below. 8,9

Table 1
Agents with Labeled Indications for Migraine Prevention

CGRP Antagonists for Migraine Prevention

AIMOVIG™ (erenumab), AJOVY™ (fremanezumab), and EMGALITY™ (galcanezumab) are CGRP antagonists that were approved by the FDA in 2018 for preventative migraine therapy. This is the first medication class primarily designed to prevent migraines.

MECHANISM    CGRP antagonists are monoclonal antibodies that exert their action by blocking the action of CGRP ligands at the CGRP receptors. CGRP ligands have been discovered in high concentration in patients who experience migraine. By inhibiting ligand action at the CGRP receptor, the subsequent vasodilation and neuro inflammation that lead to migraine headache and pain are inhibited. Both AJOVY™ and EMGALITY™ bind to CGRP ligands and prevent their action at CGRP receptors. AIMOVIG™ has a slightly different mechanism, as it binds with high-affinity to the CGRP receptors and antagonizes their function.10

CLINICAL CONSIDERATIONS    All CGRP antagonists are administered via subcutaneous injection. Most agents are administered monthly with the option of AJOVY™, which can be dosed every 3 months. Each pen is available as a standard dose; some regimens may require 2 to 3 consecutive injections to achieve the prescribed dose (Table 2). Hypersensitivity remains the only contraindication for all agents. Patients may continue to use triptans as acute therapy for migraine headaches as no drug interactions exist with CGRP antagonists.

Table 2
CGRP Antagonists

* Administration of higher doses will require 2-3 consecutive subcutaneous injections.

EFFICACY    All three agents were compared to placebo when determining efficacy in episodic and chronic migraine prevention. Outcomes of interest include reduction in number of migraine days per month (MMD), and achievement of a 50% reduction or more from baseline in mean migraine days (>/= 50% MMD responders). A statistically significant difference was found in all studies for all agents and their outcomes of reduction of MMD and >/= 50% MMD responders compared to placebo. Tables 3, 4, and 5 below list the trials for each CGRP antagonist and the previously mentioned outcomes.11-18 

Table 3

Table 4

Table 5

IMMUNOGENICITY Development of antibodies to the biologic agents was reported in clinical trials. Although the data did not demonstrate a significant impact on product efficacy, there is little data to make definitive conclusions at this point.

ADVERSE REACTIONS    All agents have similarly shown to cause minimal adverse reactions. Those that occurred in 3% or more of patients were injection site reactions and constipation.

MONITORING    Number of migraine days per month should be monitored to determine efficacy of the three agents. No safety-related monitoring is required.

SPECIAL POPULATIONS    Data on efficacy and safety of these agents is limited for use in pregnant, lactating, or pediatric patients. Data is also limited regarding use in elderly; therefore, it is currently recommended to start with low doses in the elderly.


  • Store in refrigerator in original container until ready to use.
  • May remain at room temperature for up to 7 days, discard after.
  • Do NOT shake.


  • Advantages of therapy with these agents include the minimal risk of adverse effects, and minimal monitoring requirements compared to the currently recommended medications for migraine prevention.
    • The therapy will reduce headache days per month by about 50% of days compared to no medication therapy for migraine prevention in a significant proportion of patients as results of studies have shown.
    • Adverse reactions occurred in a small proportion of participants enrolled in studies and were reported as mild.
    • There is no safety-related monitoring required with the new class of biologic agents.
    • Although the medications are administered via subcutaneous injection, they are dosed only once a month compared to currently recommended preventative oral agents which must be taken every day to achieve migraine prevention.
  • Disadvantages of the new agents include high cost, subcutaneous injection route, and limited data in special populations.
    • On average, CGRP antagonists cost $575 per month.
    • Data on safety in pregnancy would be valuable in determining if the medications have an advantage over other recommended classes, however, there is limited data at this time and use is not recommended.

THERAPEUTIC POTENTIAL    Currently, these therapies may be considered an alternative to the guideline recommended agents as no trials have compared CGRP antagonists to first line therapy options for migraine prevention. One study including AIMOVIG™ (erenumab) demonstrated its efficacy after patients had failed to experience improvement on at least 2 – 4 other agents.19 Although these agents are the first class to target pathophysiology specific to migraine headaches and are effective with minimal adverse effects, their cost hinders the decision to recommend CGRP antagonists as 1st line preventative treatment options. The subcutaneous route of administration also presents a disadvantage, however, pipeline oral CGRP antagonists are being evaluated in clinical trials.20 As several novel agents have offered new potential for more effective management of migraine, therapeutic options for the prevention of severe disease will likely continue to expand.


  1. Are You at Risk for Chronic Migraine? | The American Migraine Foundation. Info.americanmigrainefoundation.com. https://info.americanmigrainefoundation.com/are-you-at-risk-for-chronic-migraine?__hstc=12021355.1c76a0a110f54ade7719b03fdc2c19ba.1533826914624.1538749304730.1539638165880.17&__hssc=62189299.1.1551980429522&__hsfp=404373677&hsCtaTracking=34cc0fdf-2cc3-4bdb-8ec8-71fbbb2f6a0f%7C31afd483-7e65-4d30-8f5a-5083a73b4fc8. Published 2019. Accessed February 1, 2019.
  2. Headache Classification Committee of the International Headache Society. The international classification of headache disorders, 3rd ed. Cephalalgia 2013;33(9):629–808.
  3. 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: The Journal of Head and Face Pain. 2018;58(4):496-505. doi:10.1111/head.13281
  4. Bigal  ME, Ferrari  M, Silberstein  SD,  et al. Migraine in the triptan era: Lessons from epidemiology, pathophysiology, and clinical science. Headache 2009;49:S21–S33.
  5. Sprenger  T, Goadsby  PJ. Migraine pathogenesis and state of pharmacological treatment options. BMC Med2009;7(71):1–5.
  6. Noseda R, Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain. 2013;154(suppl 1):S44-S53. doi: 10.1016/j.pain.2013.07.021.
  7. Survey reveals many people with migraine live with pain nearly half of every month [news release]. Eli Lilly and Company: Indianapolis, IN; February 20, 2018. www.multivu.com/players/English/8259051-lilly-migraine-impact-report/. Accessed February 15, 2019.
  8. Silberstein  SD, Holland  S, Freitag  F,  et al. Evidence-based guideline update: Pharmacological treatment for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78:1337–1345. 
  9. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 55:754.
  10. Holland PR, Goadsby PJ. Targeted CGRP small molecule antagonists for acute migraine therapy. Neurotherapeutics. 2018;15(2):304-312. doi: 10.1007/s13311-018-0617-4.
  11. Dodick DW, Ashina M, Brandes JL, et al. ARISE: a phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia. 2018;38(6):1026-1037. doi: 10.1177/0333102418759786.
  12. Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377(22):2123-2132. doi: 10.1056/NEJMoa1705848.
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  14. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine. JAMA Neurol. 2018;75(9):1080-1088. doi: 10.1001/jamaneurol.2018.1212.
  15. Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalalgia. 2018;38(8):1442-1454. doi: 10.1177/0333102418779543.
  16. Detke HC, Goadsby PJ, Wang S, Friedman Di, Selzler KJ, Aurora SK. Galcanezumab in chronic migraine: the randomized, double-blind, placebo-controlled REGAIN study. Neurology. 2018; pii: 10.1212/WNL.0000000000006640. doi: 10.1212/WNL.0000000000006640.
  17. Dodick DW, Silberstein SD, Bigal ME, et al. Effect of fremanezumab compared with placebo
    for prevention of episodic migraine: a randomized clinical trial. JAMA. 2018;319(19):1999-2008.
    doi: 10.1001/jama.2018.4853.
  18. Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377(22):2113-2122. doi: 10.1056/NEJMoa1709038.
  19. Reuter U, Goadsby P, Lanteri-Minet M et al. Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study. The Lancet. 2018;392(10161):2280-2287. doi:10.1016/s0140-6736(18)32534-0.
  20. Biohaven announces robust clinical data with single dose rimegepant that defines acute and durable benefits to patients: the first oral CGRP receptor antagonist to deliver positive data on pain freedom and most bothersome symptom in two pivotal phase 3 trials in acute treatment of migraine [news release]. Biohaven Pharmaceuticals: Los Angeles, CA; April 22, 2018. www.biohavenpharma.com/investors/news-events/press-releases/04-23-2018.

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