American Headache Society Position Statement Calcitonin Gene-Related Peptide (CGRP) Inhibitors should now be considered a first-line option for migraine prevention (2)

American Headache Society Position Statement: Calcitonin Gene-Related Peptide (CGRP) Inhibitors should now be considered a first-line option for migraine prevention

Calcitonin gene-related peptide (CGRP) inhibitors are the first drugs developed for migraine prevention. All other agents used to prevent migraine prior to 2018, were originally developed for the management of other conditions and include antidepressants, antihypertensives, antiseizure medications and more. CGRP inhibitors block the effect of CGRP, a small protein, that is highly prevalent in the sensory nerves supplying the head and the neck and is involved in the transmission of pain.1

There are two types of CGRP inhibitors:

  • CGRP monoclonal antibodies (MABs), which are used for migraine prevention:
    • Erenumab (Aimovig)
    • Fremanezumab (Ajovy)
    • Galcanezumab (Emgality)
    • Eptinezumab (Vyepti)
  • CGRP receptor antagonists (gepants), which are used both as abortive and/or preventive migraine medications
    • Rimegepant (Nurtec): Acute or preventive treatment of episodic migraineUbrogepant (Ubrelvy): Acute treatmentAtogepant (Qulipta): Preventive treatment
    • Zavegepant (Zavzpret): Acute treatment

Although the CGRP inhibitors have had a transformational impact on migraine management in the last 5 years, they were not considered first-line treatments in the United States until recently. As of March 11, 2024, the American Headache Society provided a position statement update:

“The CGRP targeting therapies are a first-line option for migraine prevention. Initiation of these therapies should not require trial and failure of non-specific migraine preventive medication approaches.”2

Previously, indications for the initiation of CGRP inhibitors for migraine prevention included the inability to tolerate two or more of the standard preventive medications (listed below) due to side effects or an inadequate response to an 8-week trial at a dose established to be potentially effective.3

  1. Topiramate
  2. Divalproex sodium/valproate sodium
  3. Beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol
  4. Tricyclic antidepressant: amitriptyline, nortriptyline
  5. Serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine
  6. Other Level A or B treatments (established efficacy or probably effective) according to AAN scheme for classification of evidence.

For people with chronic migraine, a minimum of two quarterly injections of onabotulinumtoxinA (BOTOX) was an alternative to two standard oral prevention medications.3

As evident from the table below, candesartan; monoclonal antibodies targeting CGRP or its receptor including erenumab, fremanezumab, galcanezumab, or eptinezumab; small-molecules targeting the CGRP receptor (“gepants”) including atogepant and rimegepant were added as first line treatment options.2

Updated recommendations for migraine prevention.2

  1. Diagnosis of episodic migraine with or without aura (4–14 MMDs) based upon ICHD-3 with at least moderate disability (MIDAS score ≥11 or HIT-6 score >50). Treatments to consider include:
    1. Topiramate
    2. Divalproex sodium/valproate sodium
    3. Beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol
    4. Candesartan
    5. Tricyclic antidepressant: amitriptyline, nortriptyline
    6. Serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine
    7. Other Level A or B treatments (established efficacy or probably effective) according to AAN scheme for classification of evidence
    8. Monoclonal antibodies targeting CGRP or its receptor including erenumab, fremanezumab, galcanezumab, or eptinezumab
    9. Small-molecules targeting the CGRP receptor (“gepants”) including atogepant and rimegepant
  2. Diagnosis of chronic migraine with or without aura (≥15 MHDs) based upon ICHD-3. Treatments to consider include:
    1. Topiramate
    2. Divalproex sodium/valproate sodium
    3. Beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol
    4. Candesartan
    5. Tricyclic antidepressant: amitriptyline, nortriptyline
    6. Serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine
    7. Other Level A or B treatments (established efficacy or probably effective) according to AAN scheme for classification of evidence
    8. OnabotulinumtoxinA
    9. Monoclonal antibodies targeting CGRP or its receptor including erenumab, fremanezumab, galcanezumab, or eptinezumab
    10. Small-molecules targeting the CGRP receptor (“gepants”) including atogepant

Abbreviations: AAN, American Academy of Neurology; CGRP, calcitonin gene-related peptide; HIT-6, six-item Headache Impact Test; ICHD-3, International Classification of Headache Disorders, third edition; MMDs/MHDs, monthly migraine/headache days; MIDAS, Migraine Disability Assessment.

Since older preventive medications were developed for indications other than migraine, the choice of treatments was often based upon comorbid conditions, including insomnia, obesity, hypertension, and depression.2

Although the older and newer preventive medications have similar efficacies, the CGRP monoclonal antibodies often have better tolerability and fewer side effects than the antidepressants, antihypertensives, and antiseizure medications.4,5

There has been one published head-to-head clinical trial that compares erenumab (Aimovig) to topiramate (Topamax).6

The study found:

  • 55.4% of the patients on erenumab achieved a greater than 50% reduction in monthly migraine days (MMD) versus 31.2% of the patients on topiramate.6
  • 10.6% discontinued erenumab due to adverse events compared to 38.9% in the topiramate group.6

In addition, commercial insurance claims data has shown adherence to the 14 oral standard-of-care medications to be 26-29% at 6 months and 17-20% at 12 months in people with chronic migraine.7 Other claims data demonstrated a higher adherence to galcanezumab (Emgality) compared to oral standard-of-care preventive medications.8

There is one recent clinical trial that compares onabotulinumtoxinA (BOTOX) to CGRP monoclonal antibodies in patients with chronic migraine at 6 and 12 months.9

The study found:

  • At 12 months, the reduction of headache days for Anti-CGRP monoclonal antibodies was 11.9 days compared to 7.6 days for onabotulinumtoxinA.9
  • At 6 and 12 months, there was a higher reduction in MIDAS scores and use of monthly acute medications for people using Anti-CGRP monoclonal antibodies compared to onabotulinumtoxinA.9

It is important to mention that participants with comorbid conditions are excluded from many clinical trials. However, in clinical practice providers see migraine patients who have comorbid conditions such as hypertension, insomnia, obesity, anxiety, depression, and epilepsy. The co-morbid condition often affects the choice of a first-line therapy.

CGRP inhibitors are significantly more expensive on an annual basis than most of the older therapies that have generic equivalents available. This expense is a primary consideration in clinical decision-making for many patients.3 For example, the annual cost of preventive therapy with generic propranolol (Inderal) is $1,400, in comparison with up to $10,000 for 12 doses of monthly galcanezumab (Emgality) injections.4

Although CGRP inhibitors are now a first-line treatment, an insurance plan may or may not cover certain medications. CGRP inhibitors are brand-name medications and may be covered as tier 3, with a copay as high as $300-600 a month. For prescription assistance in the US, visit: Financial Assistance Guides and needymeds.org/.10

Insurance plans will still require prior authorization if a medication is tier 2 or 3. It is the expectation that moving the CGRP inhibitors to the first line should reduce barriers to treatment. The American Headache Society encourages insurers and providers to consider not only the direct cost of the medication but also the increased risk of chronification of migraine and resulting substantial costs to the individual and society when optimal treatment is delayed.3 “Access to care should be modifiable based on medical need and individual circumstances.”3

For more information on support for prior authorizations, view How to Get Prior Authorizations for Migraine Medications Approved.

  • If a patient does not report any relief after an adequate trial of one CGRP inhibitor, it is reasonable to offer another CGRP inhibitor. While these medications are from the same class of drugs they are not identical.
  • Females of reproductive age should be counseled on the use of contraception, as these medications have not been studied in pregnant women. Patients should be educated about the long half-life of CGRP monoclonal antibodies and should be advised to avoid pregnancy for 6 months from the last dose of the medication. Gepants should be stopped 5-7 days before conception. Encourage patients to enroll in Migraine Pregnancy Registry at 1-833-464-4724.
  • If a provider is not familiar with CGRP inhibitors, they should read the product insert or reach out to a medical science liaison for help. Contact information can be found on the manufacturer’s website. Medical science liaisons are extremely helpful and knowledgeable professionals who are often pharmacists, neuroscientists, biochemists, nurse practitioners, etc.

It is important for providers treating migraine patients to spend time on proper headache education. Patients need to understand that migraine is a chronic neurologic disease characterized by recurrent episodic attacks and the successful treatment includes a combination of acute therapies and preventive strategies to reduce the frequency of attacks.11 Although no medication is a cure for all, many patients may find freedom from pain and significantly improved quality of life and health outcomes using CGRP inhibitors.

Patients who have a good response to CGRP inhibitors may:

CGRP-targeting therapies should now be considered a first-line treatment option for migraine prevention without requiring prior failure of other migraine preventive classes. Hopefully, the new American Headache Society position statement update will help many providers, including those in primary care, manage migraine as a chronic condition by utilizing migraine-specific treatments to reduce the number of monthly migraine days for their patients.

“The basis for this focused AHS position statement is:3

  1. There is solid human evidence that establishes CGRP as a fundamental mechanism of migraine and therefore establishes CGRP-targeting therapies as “migraine-specific” in contrast to all the other established therapies.
  2. The cumulative evidence for the efficacy, safety, and tolerability of CGRP-targeting therapies is significantly greater than that for any established migraine preventive therapy. The remarkable tolerability of the CGRP-targeting therapies is a particularly positive feature.
  3. Nearly all CGRP-targeting therapies are FDA-approved for the preventive treatment of both episodic and chronic migraine, which simplifies decision-making in patients who may spontaneously transition back and forth between episodic and chronic migraine.
  4. There are multiple categories of evidence supporting the use of CGRP-targeting therapies that do not exist for other migraine preventive therapies, including: responder rates, efficacy in patients with multiple prior treatment failures, efficacy in those with acute medication overuse, and those who do and do not have aura.
  5. There is one head-to-head study demonstrating the superiority of a CGRP-targeting therapy (erenumab) over an established migraine preventive therapy (topiramate). In addition, multiple studies indicating the efficacy of CGRP-targeting migraine preventive therapies in those who have previously failed multiple other established treatments provide indirect evidence of the superiority of CGRP-targeting therapies for some patients.
  6. Acknowledging CGRP-targeting therapies as first-line approaches will increase the likelihood that their efficacy and safety will be more thoroughly evaluated in understudied populations, particularly youth.
  7. Cost considerations regarding migraine therapies should include not only the direct cost of the treatments, but also the indirect costs of healthcare utilization and acute therapies, as well as socioeconomic costs for those who are disabled by the disease.”

“The CGRP-targeting migraine therapies are a first-line option for migraine prevention. Initiation of these therapies should not require trial and failure of non-specific migraine preventive medication approaches.3

  1. Drugs.com. (2023). CGRP inhibitors. https://www.drugs.com/drug-class/cgrp-inhibitors.html
  2. Charles, A. C., Digre, K. B., Goadsby, P. J., Robbins, M. S., Hershey, A., & American Headache Society. (2024). Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update. Headache, 10.1111/head.14692. Advance online publication. https://doi.org/10.1111/head.14692. Retrieved from https://headachejournal.onlinelibrary.wiley.com/doi/full/10.1111/head.14692
  3. Ailani, J., Burch, R. C., Robbins, M. S., & Board of Directors of the American Headache Society (2021). The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache, 61(7), 1021–1039. https://doi.org/10.1111/head.14153
  4. Moskatel, L.S., Zhang, N. The role of step therapy in the treatment of migraine. Current pain and headache reports (27), 571–577 (2023). https://doi.org/10.1007/s11916-023-01155-w
  5. Vandervorst, F., Van Deun, L., Van Dycke, A., Paemeleire, K., Reuter, U., Schoenen, J., & Versijpt, J. (2021). CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs. The journal of headache and pain, 22(1), 128. https://doi.org/10.1186/s10194-021-01335-2
  6. Reuter, U., Ehrlich, M., Gendolla, A., Heinze, A., Klatt, J., Wen, S., Hours-Zesiger, P., Nickisch, J., Sieder, C., Hentschke, C., & Maier-Peuschel, M. (2022). Erenumab versus topiramate for the prevention of migraine – a randomised, double-blind, active-controlled phase 4 trial. Cephalalgia : an international journal of headache, 42(2), 108–118. https://doi.org/10.1177/03331024211053571
  7. Hepp, Z., Dodick, D. W., Varon, S. F., Gillard, P., Hansen, R. N., & Devine, E. B. (2015). Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia : an international journal of headache, 35(6), 478–488. https://doi.org/10.1177/0333102414547138
  8. Varnado, O. J., Manjelievskaia, J., Ye, W., Perry, A., Schuh, K., & Wenzel, R. (2022). Treatment Patterns for Calcitonin Gene-Related Peptide Monoclonal Antibodies Including Galcanezumab versus Conventional Preventive Treatments for Migraine: A Retrospective US Claims Study. Patient preference and adherence, 16, 821–839. https://doi.org/10.2147/PPA.S346660
  9. Grazzi, L., Giossi, R., Montisano, D.A. et al. Real-world effectiveness of Anti-CGRP monoclonal antibodies compared to OnabotulinumtoxinA (RAMO) in chronic migraine: a retrospective, observational, multicenter, cohort study. J Headache Pain 25, 14 (2024). https://doi.org/10.1186/s10194-024-01721-6
  10. Coalition for Headache and Migraine Patients.(2024). Financial Assistance Guides. https://headachemigraine.org/migraine-financial-assistance-guides/
  11. Robbins, M. S., Victorio, M.C., Bailey, M., Cook, C., Garza, I., Huff, S., Ready, M., Schuster, N., Seidenwurm, D., Seng, E., Szperka, C., Lee, E., Villanueva, R. (2021, January). Quality improvement in neurology: Headache quality measurement set. Headache, 61(1). https://doi.org/10.1111/head.13988

Author

Vera Gibb, DNP, APRN, FNP-C, AQH, CCTP is a Family Nurse Practitioner in primary care and an Assistant Professor, Graduate Studies Department, School of Nursing, of The University of Texas Medical Branch (UTMB) at Galveston. She holds additional certifications in headache medicine, clinical trauma, and interprofessional education. Vera Gibb serves on the Board of Directors of Coalition for Headache and Migraine Patients (CHAMP) and the Advisory Board of The First Contact – Headache in Primary Care Program of the American Headache Society. She’s actively involved in improving headache education for current and future providers across different healthcare disciplines.

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