by Diksha Mohanty, MD, and Steven Lippmann, MD

Dr. Mohanty is a Neurology Resident Physician, and Dr. Lippmann is a Psychiatry Emeritus Professor at the University of Louisville School of Medicine in Louisville, Kentucky.

FUNDING: No funding was provided for this study.

DISCLOSURES: The author has no conflicts of interest relevant to the content of this article.

ABSTRACT: Migraine headaches remain a significant medical concern; lots of people are adversely affected. Many existing pharmacotherapies have disappointing results. The pathophysiology is related to calcitonin gene-related peptide (CGRP) pathways. There is hope for better efficacy from the now-available CGRP inhibitor drugs made available to patients suffering these cephalgias.

Keywords: Migraine, headache, chronic migraine, episodic migraine, calcitonin-gene related peptide, CGRP inhibitor, gepants, erenumab, monoclonal antibody

Innov Clin Neurosci. 2020;17(4–6):39–40

Migraine headaches are major contributors to disease and disability, affecting about 12 percent of the American population.1 The economic burden of migraine headaches, including direct and indirect costs, was estimated at $36 billion in 2016.2 They are often described as unilateral, paroxysmal headaches of moderate-to-severe degree, sometimes aggravated by movements, lights, and sounds. They evidence a three-fold greater preponderance among female individuals.3 Genetic and environmental factors contribute to their predisposition. Migraines can be episodic or chronic. By definition, chronic migraine describes patients who report headaches 15 or more days in a month (of which, most headache days meet criteria for migraine).4 Cephalalgia classified as migraine, but occurring less frequently, is the episodic variant.

Pathophysiology 

Migraines often present with complex phenomena, such as autonomic dysfunction, tactile, visual, and/or auditory manifestations. They might be preceded by premonitory symptoms called “aura” that herald the onset of pain, even three days ahead of time.5 A migraine complex is comprised of four stages: prodrome, aura, headache, and postdrome. The pathophysiology remains unclear. Imaging studies suggest causality by activation of central nervous system areas that control physiologic functions, rather than the previously believed vascular etiology.6 A cascade of inflammatory pathways triggered by a “cortical spreading depression” results in pain.1 The glutamate, dopamine, serotonin, and gamma-aminobutyric acid neurotransmitter systems are implicated in the pathology of migraine headaches.7

Current Pharmacotherapies 

Migraine therapy is classified into preventive, abortive, and biofeedback. Existing treatments are often deficient in pain relief, induce adverse effects, and yield the probability of medication-overuse headaches.5 Acute interventions are classified as migraine-specific medication and nonspecific analgesic therapy. They include ergotamine derivatives, triptans, nonsteroidal anti-inflammatory drugs, anti-emetic medications, acetaminophen, neuromodulation using devices, and combination therapies.

Ergot alkaloids are the oldest medicines in the migraine-specific category, but they are poorly tolerated. Triptans (5-HT1B/1D agonists) are a better tolerated group. However, ergots and triptans provide inadequate pain relief and are rarely prescribed for people with cardiovascular diseases.5 A big risk associated with these acutely acting drugs is medication-overuse headaches, that potentially occurs due to receptor down-regulation in the pharmaceutical response pathway.5

CGRP Inhibitors 

A new class of drugs to treat patients with frequent, episodic, and/or chronic migraine headaches acts by antagonism of the calcitonin gene-related peptide (CGRP) pathway. This is the first category of pharmaceuticals developed as targeted therapy for migraine prevention. Discovered 35 years ago, CGRP is a neuropeptide located centrally and peripherally in the nervous system, with a role in pain modulation.8 Animal research and human studies reveal that CGRP is released during migraines, and exogenous administration might provoke migraine symptoms. There is evidence that CGRP levels were lowered by exposure to triptans.9,10 CGRP exists in two isoforms, α and β, with the ability to cause dilation of cerebral arteries and degranulation of mast cells, predominantly in the trigeminal vascular network, and possibly leading to nociception.11–13 Due to a large molecular size, CGRP inhibitors are administered parenterally. They do not cross the blood–brain barrier, nor undergo hepatic metabolism.

Within this class, monoclonal antibodies exert their effect by antagonism of the CGRP molecule (eptinezumab, galcanezumab, and fremanezumab) or the CGRP receptor (erenumab). Prescribing them for people can diminish migraine frequency, headache days, and medication usage.8,14 These therapies effectively attenuate migraines with or without aura, episodic variants, chronic versions, and medication-overuse headaches.

Erenumab (AMG 334), marketed as Aimovig, is approved as an antimigraine treatment. Fremazenumab and galcanezumab are available as well. Erenumab is the first human monoclonal antibody that produces high-affinity, competitive, and reversible inhibition at the receptor-level. It is prescribed at 70mg subcutaneous in monthly injections. Phase 3 clinical trials, such as PROMISE-1 (eptinezumab), REGAIN, EVOLVE-1, EVOLVE-2 (galcanezumab), and ARISE and STRIVE (erenumab), document the efficacy of this drug class in several migraine variants.15

Adversities 

Older classes of CGRP antagonists, known as gepants, are smaller in molecular size and are for oral dosing. Major adversities included hepatotoxicity and transaminitis; lesser side effects include sensory abnormalities, such as paresthesia, headache, visual disturbances, and/or xerostomia, leading to drug discontinuation.9 Despite cardiac and/or hepatic concerns, the newer CGRP antagonists are evidenced as safer and better tolerated. Upper respiratory and urinary tract infections, fatigue, arthralgia, and injection-site pain are reported. No central nervous system toxicity has been described, possibly due to limited blood–brain barrier passage. The long-term role of nonselective CGRP blockade in effects such as pituitary gland dysfunction, ischemic events, hypertension, gastrointestinal disturbances are currently being researched.

Conclusion 

Prescribing the CGRP inhibitor drugs might improve the quality of life for patients with migraine headaches. Hopefully, they will be a positive influence in the lives of migraine-afflicted people and could prove to be an excellent, safe anti-migraine pharmacotherapy.

References

  1. Urits I, Jones M, Gress K, et al. CGRP antagonists for the treatment of chronic migraines: a comprehensive review. Curr Pain Headache Rep. 2019;23(5):23–29.
  2. Bonafede M, Sapra S, Shah N, et al. Direct and indirect healthcare resource utilization and costs among migraine patients in the United States. Headache. 2018;58(5):700–714.
  3. James S, Abate D, Abate K, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2018;392(10159):1789–1858.
  4. ICHD-3 Site. Migraine with Aura. The international classification of headache disorders 3rd edition. 2019. https://www.ichd-3.org/1-migraine/1-2-migraine-with-aura/. Accessed December 19, 2019.
  5. van Hoogstraten W, MaassenVanDenBrink A. The need for new acutely acting antimigraine drugs: moving safely outside acute medication overuse. J Headache Pain. 2019;20(1):54.
  6. Iyengar S, Johnson K, Ossipov M, Aurora S. CGRP and the trigeminal system in migraine. J Oral Facial Pain Headache. 2019;59(5):659–681.
  7. Pomes L, Guglielmetti M, Bertamino E, et al. Optimising migraine treatment: from drug-drug interactions to personalized medicine. J Headache Pain. 2019;20(1):56.
  8. Hershey A. (2017). CGRP—the next frontier for migraine. N Engl J Med. 2017;377(22):2190–2191.
  9. 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.
  10. Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. J Oral Facial Pain Headache. 2017;57(1):47–55.
  11. Ashina H, Schytz H, Ashina M. CGRP in human models of primary headaches. Cephalalgia. 2016;38(2):1–8.
  12. Israel H, Neeb L, Reuter U. CGRP monoclonal antibodies for the preventative treatment of migraine. Curr Pain Headache Rep. 2018;22(5):38.
  13. Hay D, Walker C. CGRP and its receptors. J Oral Facial Pain Headache. 2017;57(4):625–636.
  14. Goadsby P, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377(22):
    2123–2132.
  15. Raffaelli B, Reuter U. The biology of monoclonal antibodies: focus on calcitonin gene-related peptide for prophylactic migraine therapy. Neurotherapeutics. 2018;15(2):324–335.