CGRP Receptor Antagonists for the Prevention of Episodic Migraine

Migraine is a neurologic condition with a spectrum of disorders, which includes episodic and chronic migraines generally characterized by recurrent episodes of frequently unilateral throbbing headache that is worsened by activity and associated with at least 1 of the following symptoms: photophobia, phonophobia, nausea, or vomiting.1 Although the clinical presentation of episodic and chronic migraine overlap, they are differentiated by the symptom duration; episodic migraine is defined as fewer than 15 headache days per month, while chronic migraine is defined as 15 or more headache days per month lasting for more than 3 months.2 Migraine disorders significantly impact functional ability and were the sixth leading cause of years lived with disability globally, according to 2016 data.3 The economic burden of migraine can be significant, considering the cost of medications, hospital visits, and management of treatment side effects.4

The prevalence of self-reported migraine headaches varies among different populations in the United States; prevalence is generally higher among women than men and is higher among American Indians and Alaska Natives than other populations in the US.5 According to a study by the American Headache Society, the 1-year period prevalence of episodic migraine is approximately 3 times higher in women than in men (18% vs 6%, respectively), and prevalence peaks in those aged 25 to 55 years.4

While proper diagnosis of a specific migraine type enables appropriate and effective treatment, barriers to optimal management remain, including lack of appropriate medical consultation, inaccurate diagnostic evaluation, suboptimal management of acute attacks, and medication overuse.2 This article focuses on the use of calcitonin gene-related peptide (CGRP) antagonists for acute and preventive treatment of episodic migraine.

Challenges of Conventional Migraine Treatment and the Development of CGRP Antagonists

Migraine attacks, irrespective of the type, can be severe and disabling, requiring acute medication. Options for acute migraine treatment include analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) or migraine-specific agents, such as triptans and ergot derivatives. It is recommended to initiate therapy at the earliest onset of symptoms.1

Individuals who experience recurrent migraine attacks may benefit from preventive therapy. Several options have proven efficacy for the preventive treatment of episodic migraine, including propranolol, metoprolol, parenteral onabotulinumtoxinA, topiramate, valproate sodium, and candesartan. However, these agents are associated with poor adherence, especially with preventive oral migraine medications, because of excessive side effects or insufficient efficacy.4,6

Recent advances have focused on the role of CGRP in migraine headache, supported by studies showing that the level of CGRP increases during acute migraine attacks and subsequently normalizes following efficacious sumatriptan administration. Based on this finding, CGRP has become the focus of novel therapies for addressing migraine.7

Based on evidence from initial studies, monoclonal antibodies (mAbs) have been developed explicitly for the acute and preventive treatment of episodic and chronic migraine headaches. In randomized controlled trials (RCTs), they have shown efficacy in reducing monthly migraine days among patients experiencing episodic migraine.6 These trials have demonstrated the safety of mAbs, as there have been no safety concerns and the adverse event profile is considered similar to that of placebo.8

There are 2 types of CGRP inhibitors that have been investigated for acute and preventive treatment of episodic migraine9:

  • Anti-CGRP mAbs, which bind to the CGRP protein or its receptor and are administered as an intravenous (IV) or subcutaneous (SQ) injection; and
  • Small molecule CGRP receptor antagonists (gepants), which are administered orally.

In contrast to traditional migraine treatments such as NSAIDs or triptans, which have a short duration of action and undesirable side effects, CGRP antagonists have a longer duration of action. In addition, CGRP antagonists have a targeted effect exclusively in the peripheral portion of the trigeminovascular system known to be involved in migraine headaches and are associated with fewer side effects than traditional migraine treatments.4,8,10


CGRP mAbs have been demonstrated to be effective in the preventive treatment of episodic and chronic migraine.8 They have a relatively long half-life of 3 to 6 weeks that enables monthly or quarterly administration.9 There are 4 CGRP mAbs approved for preventive treatment of episodic migraine: erenumab, eptinezumab, fremanezumab, and galcanezumab (Table 1).11-14

Erenumab is a human immunoglobulin G (IgG)2 mAb that binds to the CGRP receptor, and clinical trials have supported its use as a preventive treatment for episodic migraine. A systematic review that analyzed 5 RCTs reported that 70 mg and 140 mg of erenumab reduced mean monthly migraine days and led to a ≥50% responder rate compared with placebo.15 Erenumab has been shown to be effective in reducing mean monthly migraine days in patients who had preventive therapy failures in the past, with the most significant improvement observed in patients receiving the larger dose (140 mg) of erenumab.16

Eptinezumab is a genetically engineered humanized IgG1 antibody that is administered via IV, selectively binding to the α and β forms of human CGRP.9 The approval of eptinezumab was supported by the PROMISE 1 ( identifier: NCT02559895) and PROMISE 2 ( identifier: NCT02974153) trials. These trials showed that 100-mg and 300-mg administrations of eptinezumab significantly reduced mean monthly migraine days compared with placebo.17,18 An integrated analysis of 5 clinical trials (including PROMISE 1, PROMISE 2, and the following 3 clinical trials: identifiers: NCT01772524, NCT02275117, and NCT02985398) showed that eptinezumab was safe and tolerable and that adverse events (AEs) were infrequent, with upper respiratory tract infection and nasopharyngitis being the most reported AEs.19

Studies examining the efficacy and safety of fremanezumab, an IgG2a mAb that binds to the CGRP ligand, show a reduction in migraine duration following treatment.9 In a study evaluating the efficacy of fremanezumab (225 mg monthly and 675 mg quarterly) compared with placebo for treating episodic migraine, the proportions of patients achieving at least a 50% reduction in the mean number of migraine days per month were 47.7% and 44.4% in the groups receiving monthly and quarterly fremanezumab, respectively, which was a significant reduction compared with placebo (27.9%).20

Galcanezumab is a humanized IgG4 mAb.9 In 2 randomized migraine studies involving 862 and 922 participants, patients assigned to treatment with galcanezumab reported improved daily function and decreased disability.21 In the EVOLVE 1 study ( identifier: NCT02614183), 120 mg and 240 mg of monthly galcanezumab resulted in a decrease of at least 50% in the average number of headache days in 20.5% and 19.2% of patients, respectively, compared with 8.9% in the group treated with placebo. The most common post-treatment emergent AE reported in this study was upper respiratory tract infection, but no serious AEs were considered by the investigator to be associated with galcanezumab.22

CGRP mAbs are indicated in adults who are unable to tolerate or who have an inadequate response to 2 or more oral preventive therapies administered for at least 8 weeks, and patients often experience a rapid onset of benefits with injectable CGRP mAbs. These agents should be continued only if there is a clinically meaningful improvement, and it is recommended that women who are pregnant, lactating, or trying to conceive avoid preventive pharmacotherapy for migraines due to the potential for AEs.4

Some patients treated with CGRP mAbs develop anti-drug antibodies (ADA), although neutralizing ADAs, which bind to and inhibit the pharmacologic activity of the biologic drug molecule, are slightly less common; despite this, immunogenicity-related AEs only rarely occur in patients treated with CGRP mAbs.23 For people who have refractory migraines despite using a CGRP mAb, adding onabotulinumtoxinA may potentially improve clinical outcomes.24

Gepants for Acute and Preventive Migraine Treatment

Gepants are small molecule oral agents that block the CGRP receptor. While clinical development on first-generation gepants was halted before approval due to concerns regarding hepatic side effects, new gepants that address hepatoxicity issues have shown positive results in terms of efficacy, tolerability, and safety.25 Current data suggest that frequent use of gepants may lead to fewer headaches, which contrasts with the increase in headache frequency, often called medication overuse headache or rebound, that is seen with the overuse of other acute treatments for migraine.10

The gepants approved by the US Food and Drug Administration (FDA) for the treatment of migraine are ubrogepant, atogepant, and rimegepant; ubrogepant is approved for acute treatment, atogepant is approved for preventive treatment, and rimegepant is approved for both preventive and acute treatment.26-28

In an RCT involving 1186 participants with at least a 1-year history of migraine and 2 to 8 migraine attacks of moderate or severe intensity per month, treatment with rimegepant resulted in a higher percentage of people experiencing pain relief and relief from their most bothersome symptom than placebo.29 Another study involving 1672 patients showed that treatment with ubrogepant resulted in a higher percentage of participants experiencing freedom from pain 2 hours after treatment compared with the placebo group.30 A systematic review of 7620 patients found that rimegepant and ubrogepant were associated with significant pain relief up to 1 week following treatment.31 A multicenter RCT found that 75 mg of rimegepant administered every other day resulted in fewer migraine days per month compared with placebo.32 A 12-week RCT of atogepant in adults with 4 to 14 migraine days per month found significant improvement in migraine-specific quality of life than did placebo.33 A similarly superior response was seen in a meta-analysis of 3 RCTs, which showed that atogepant significantly reduced monthly migraine days and monthly medication use days.34

Migraine medications that are not associated with medication overuse headache
Unlike other acute migraine medications, gepants are not associated with rebound headache from overuse.

Clinical Application of CGRP Antagonists for Migraine Prevention

Indications for the initiation of preventive treatment for individuals with frequent migraine are available in Table 2.4 The goal of preventive therapy is to reduce migraine attack frequency, severity, duration, and disability. In addition, preventive treatment aims to reduce the psychological burden, side effects, and overall cost of migraine treatment.

The criteria for initiating acute treatment with a gepant are as follows4:

  • The patient is at least 18 years old;
  • The patient has a diagnosis of International Classification of Headache Disorders (ICHD)-3 migraine with aura, migraine without aura, or chronic migraine; and
  • The patient meets 1 of the following conditions:
    • The patient has contraindications to or inability to tolerate triptans; or
    • The patient has inadequate response to 2 or more oral triptans, as determined by either a validated acute treatment patient-reported outcome questionnaire (Migraine Treatment Optimization Questionnaire [mTOQ], Migraine Assessment of Current Therapy [Migraine-ACT], Patient Perception of Migraine Questionnaire-Revised [PPMQ-R], Functional Impairment Scale [FIS], or Patient Global Impression of Change [PGIC]) or clinician attestation.

The criteria for initiating treatment with a CGRP mAb are as follows4:

  • The patient is at least 18 years old; and
  • The patient has 1 of the following diagnoses:
    • ICHD-3 migraine (4 to 7 monthly migraine days) with or without aura and both of the following conditions:
      • Inability to tolerate or inadequate response to an 8-week trial at a dose established to be potentially effective for 2 or more of the following: (1) topiramate, (2) divalproex sodium/valproate sodium, (3) a beta blocker (metoprolol, propranolol, timolol, atenolol, or nadolol), (4) a tricyclic antidepressant (amitriptyline or nortriptyline), (5) a serotonin-norepinephrine reuptake inhibitor (venlafaxine or duloxetine), and (6) other Level A or B treatments (established efficacy or probably effective) according to American Academy of Neurology (AAN) scheme for evidence classification; and
      • At least moderate disability (Migraine Disability Assessment [MIDAS] score ≥11 or Headache Impact Test [HIT]-6 score >50).
    • ICHD-3 migraine (8 to 14 monthly migraine days) with or without aura and the following condition:
      • Inability to tolerate or inadequate response to an 8-week trial at a dose established to be potentially effective for 2 or more of the following: (1) topiramate, (2) divalproex sodium/valproate sodium, (3) a beta blocker (metoprolol, propranolol, timolol, atenolol, or nadolol), (4) a tricyclic antidepressant (amitriptyline or nortriptyline), (5) a serotonin-norepinephrine reuptake inhibitor (venlafaxine or duloxetine), and (6) other Level A or B treatments (established efficacy or probably effective) according to AAN scheme for evidence classification.
    • ICHD-3 chronic migraine and either of the following conditions:
      • Inability to tolerate or inadequate response to an 8-week trial at a dose established to be potentially effective for 2 or more of the following: (1) topiramate, (2) divalproex sodium/valproate sodium, (3) a beta blocker (metoprolol, propranolol, timolol, atenolol, or nadolol), (4) a tricyclic antidepressant (amitriptyline or nortriptyline), (5) a serotonin-norepinephrine reuptake inhibitor (venlafaxine or duloxetine), and (6) other Level A or B treatments (established efficacy or probably effective) according to AAN scheme for evidence classification; or
      • Inability to tolerate or inadequate response to a minimum of 2 quarterly injections (6 months) of onabotulinumtoxinA.


1. Katsarava Z, Buse DC, Manack AN, Lipton RB. Defining the differences between episodic migraine and chronic migraine. Curr Pain Headache Rep. 2012;16(1):86-92. doi:10.1007/s11916-011-0233-z

2. Buse DC, Armand CE, Charleston L 4th, et al. Barriers to care in episodic and chronic migraine: results from the chronic migraine epidemiology and outcomes study. Headache. 2021;61(4):628-641. doi:10.1111/head.14103

3. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet. 2017;390(10100):1211-1259. doi:10.1016/S0140-6736(17)32154-2

4. Ailani J, Burch RC, Robbins MS; Board of Directors of the American Headache Society. The American Headache Society consensus statement: update on integrating new migraine treatments into clinical practice. Headache. 2021;61(7):1021-1039. doi:10.1111/head.14153

5. 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

6. Vandervorst F, Van Deun L, Van Dycke A, et al. CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs. J Headache Pain. 2021;22(1):128. doi:10.1186/s10194-021-01335-2

7. Deen M, Correnti E, Kamm K, et al. Blocking CGRP in migraine patients – a review of pros and cons. J Headache Pain. 2017;18(1):96. doi:10.1186/s10194-017-0807-1

8. Schoenen J, Manise M, Nonis R, Gérard P, Timmermans G. Monoclonal antibodies blocking CGRP transmission: an update on their added value in migraine prevention. Rev Neurol (Paris). 2020;176(10):788-803. doi:10.1016/j.neurol.2020.04.027

9. Dodick DW. CGRP ligand and receptor monoclonal antibodies for migraine prevention: evidence review and clinical implications. Cephalalgia. 2019;39(3):445-458. doi:10.1177/0333102418821662

10. Tepper D. Gepants. Headache. 2020;60(5):1037-1039. doi:10.1111/head.13791

11. AimovigTM. Prescribing information. Amgen, Inc; 2018. Accessed February 2, 2023.

12. Vyepti®. Prescribing information. Lundbeck Seattle BioPharmaceuticals, Inc; 2020. Accessed February 2, 2023.

13. AjovyTM. Prescribing information. Teva Pharmaceuticals USA, Inc; 2018. Accessed February 2, 2023.

14. EmgalityTM. Prescribing information. Eli Lilly & Co; 2018. Accessed February 2, 2023.

15. Zhu C, Guan J, Xiao H, Luo W, Tong R. Erenumab safety and efficacy in migraine: a systematic review and meta-analysis of randomized clinical trials. Medicine (Baltimore). 2019;98(52):e18483. doi:10.1097/MD.0000000000018483

16. Ashina M, Tepper S, Brandes JL, et al. Efficacy and safety of erenumab (AMG334) in chronic migraine patients with prior preventive treatment failure: a subgroup analysis of a randomized, double-blind, placebo-controlled study. Cephalalgia. 2018;38(10):1611-1621. doi:10.1177/0333102418788347

17. Ashina M, Saper J, Cady R, et al. Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia. 2020;40(3):241-254. doi:10.1177/0333102420905132

18. Silberstein S, Diamond M, Hindiyeh NA, et al. Eptinezumab for the prevention of chronic migraine: efficacy and safety through 24 weeks of treatment in the phase 3 PROMISE-2 (Prevention Of Migraine via Intravenous ALD403 Safety and Efficacy-2) study. J Headache Pain. 2020;21(1):120. doi:10.1186/s10194-020-01186-3

19. Smith TR, Spierings ELH, Cady R, et al. Safety and tolerability of eptinezumab in patients with migraine: a pooled analysis of 5 clinical trials. J Headache Pain. 2021;22(1):16. doi:10.1186/s10194-021-01227-5

20. 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

21. Ford JH, Ayer DW, Zhang Q, et al. Two randomized migraine studies of galcanezumab: effects on patient functioning and disability. Neurology. 2019;93(5):e508-e517. doi:10.1212/WNL.0000000000007856

22. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: The EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018;75(9):1080-1088. doi:10.1001/jamaneurol.2018.1212

23. Cohen JM, Ning X, Kessler Y, et al. Immunogenicity of biologic therapies for migraine: a review of current evidence. J Headache Pain. 2021;22(1):3. doi:10.1186/s10194-020-01211-5

24. Argyriou AA, Dermitzakis EV, Xiromerisiou G, Vikelis M. OnabotulinumtoxinA add-on to monoclonal anti-CGRP antibodies in treatment-refractory chronic migraine. Toxins (Basel). 2022;14(12):847. doi:10.3390/toxins14120847

25. Moreno-Ajona D, Villar-Martínez MD, Goadsby PJ. New generation gepants: migraine acute and preventive medications. J Clin Med. 2022;11(6):1656. doi:10.3390/jcm11061656

26. Ubrelvy®. Prescribing information. Allergan, Inc; 2019. Accessed February 4, 2023.

27. Qulipta. Prescribing information. Allergan, Inc; 2021. Accessed February 4, 2023.

28. Nurtec® ODT. Prescribing information. Biohaven Pharmaceuticals, Inc; 2020. Accessed February 4, 2023.

29. Lipton RB, Croop R, Stock EG, et al. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine. N Engl J Med. 2019;381(2):142-149. doi:10.1056/NEJMoa1811090

30. Dodick DW, Lipton RB, Ailani J, et al. Ubrogepant for the treatment of migraine. N Engl J Med. 2019;381(23):2230-2241. doi:10.1056/NEJMoa1813049

31. VanderPluym JH, Halker Singh RB, Urtecho M, et al. Acute treatments for episodic migraine in adults: a systematic review and meta-analysis. JAMA. 2021;325(23):2357-2369. doi:10.1001/jama.2021.7939

32. 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

33. 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

34. Tao X, Yan Z, Meng J, et al. The efficacy and safety of atogepant for the prophylactic treatment of migraine: evidence from randomized controlled trials. J Headache Pain. 2022;23(1):19. doi:10.1186/s10194-022-01391-2

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Reviewed March 2023