Migraine is a highly prevalent and debilitating condition affecting approximately 10%-15% of the population (Rev Neurol Aug 2023; Lancet 2012;380:2163-96). A migraine is a severe headache lasting up to 72 hours, accompanied by symptoms including nausea, vomiting, and hypersensitivity to light and sound. Women are twice as likely to experience migraine as men (Lancet 2012;380:2163-96).

Older theories that migraine was caused by vasodilation of meningeal arteries have been disproven by direct observation of vascular diameter using MRI (Lancet Neurol 2013;12:454-61). Current views classify migraine as a spectrum of diseases, ranging from acute severe headache to episodic clusters of headaches to chronic headache to “silent migraines” comprising migraine symptoms without accompanying headache (asamonitor.pub/44875me).

Research is slowly untangling the genetic, physiologic, and environmental factors responsible for the migraine spectrum of headaches. The most important observation over the past two decades is the identification of the fundamental role of calcitonin gene-related peptide (CGRP) in the onset of migraine. Two new classes of CGRP antagonists have emerged: direct antagonists (gepants) and monoclonal antibodies directed against either the CGRP protein or the CGRP receptor.

CGRP modulates cardiovascular hemostasis. As a result, migraine patients with cardiovascular disease, including Raynaud’s syndrome, should be carefully monitored for adverse effects when treated with CGRP antagonists for migraine. CGRP also modulates fetoplacental vascular tone. Thus, CGRP antagonism is contraindicated in women who are pregnant. The longer-lasting CGRP monoclonal antibodies (see below) are contraindicated in women planning to conceive. The FDA package inserts warn against the use of CGRP antagonists in breastfeeding women because the safety has not been established in infants. These concerns apply to the CGRP antagonists listed below and are not repeated for each new drug.

Gepants are CGRP antagonists (J Clin Med 2022;11:1656). Gepants have recently been found to be effective for treatment of acute migraines and migraine prophylaxis. Unlike triptans, gepants are not associated with overuse or rebound headaches (Drugs 2019;28:555-67). Recently introduced gepants include the following:

  • Zavegepant is a new nasal spray CGRP antagonist for acute migraine treatment in adults (asamonitor.pub/3OolO6u). It was approved by the FDA in July 2023. Clinical studies have shown pain relief in as little as 15 minutes after zavegepant administration. Common side effects include dizziness, dry mouth, and nausea.
  • Atogepant is an oral CGRP antagonist approved for migraine prophylaxis in adults (asamonitor.pub/43Ot41q). It is FDA-approved for patients with debilitating migraines and poor response to other preventatives. Clinical trials have shown that atogepant reduced mean monthly migraine days and improved function compared to placebo. Factors like liver and kidney function and medication interactions should be considered before prescribing atogepant. The drug is available in three strengths.
  • Rimegepant is a 75 mg orally disintegrating tablet CGRP antagonist used for abortive treatment of moderate to severe migraines in patients for whom triptans are contraindicated (asamonitor.pub/3E0230F). Rimegepant is also indicated for migraine prevention in prophylaxis. Common side effects include nausea, sleepiness, and dry mouth. For acute treatment, a single dose is taken. For preventive treatment, rimegepant is taken once every other day.
  • Ubrogepant is an oral CGRP antagonist used for acute migraine treatment (asamonitor.pub/3YohQ2r). Pain relief typically occurs 30 to 60 minutes after taking the medication. The dose can be repeated if needed.

Monoclonal antibodies directed against either the CGRP protein or the CGRP receptor are long-lasting preventive treatments for migraines (Neurotherapeutics 2022;19:922-30). They are typically administered monthly or quarterly. Side effects include injection site reactions. Rarely, they are associated with an increase in blood pressure. Drug interactions are typically not a concern with monoclonal antibody therapy.

“Migraines are a common debilitating condition that impose a substantial burden on individuals and society. While a cure for migraines remains elusive, recent advancements have broadened our therapeutic options with greater efficacy and less toxicity.”

  • Erenumab-aooe is a subcutaneously injected CGRP monoclonal antibody to the CGRP receptor. It is administered as a monthly injection. The “aooe” suggests that the inventor dropped an anvil on his or her toe while naming the molecule, but we could not find any explanation for this part of the name in the literature. Fortunately, it is generally called “erenumab” today. Erenumab was the first FDA-approved monoclonal CGRP antagonist. It is indicated for episodic and chronic migraine prophylaxis, with results starting within the first week (asamonitor.pub/3s09P80). It is administered monthly via subcutaneous injections using an auto-injector.
  • Fremanezumab is a subcutaneously injected monoclonal antibody to the CGRP protein. Fremanezumab is effective for prevention of episodic and chronic migraines (asamonitor.pub/3rVUd5c). Onset typically occurs within a week of the first injection.
  • Galcanezumab is a subcutaneously injected monoclonal antibody to the CGRP protein. Galcanezumab is indicated for prevention of episodic and chronic migraines, as well as episodic cluster headaches (asamonitor.pub/47iG02r). Galcanezumab is administered once a month via subcutaneous injections, with the first dose consisting of two injections, followed by monthly injections. Onset can be observed within a few days.
  • Eptinezumab is an intravenous monoclonal antibody to the CGRP protein. It is administered as an infusion every three months for prevention of episodic and chronic migraines (asamonitor.pub/3OnCivK).

Serotonin, also known as 5-hydroxytryptamine or simply 5-HT, is a well-studied neurotransmitter. The 5-HT receptor agonists, or triptans, are the current mainstays of treatment for migraine and cluster headaches (J Pain Res 2018;11:515-26). Lasmiditan is an agonist of the serotonin receptor. However, unlike the triptans, which are nonspecific, lasmiditan is an agonist of the 5-HT1F subtype (asamonitor.pub/47uW15y). As a result, lasmiditan acts on pain pathways without affecting blood vessels. It is considered an alternative for patients who do not tolerate triptans. Side effects include dizziness, fatigue, and tingling. Caution is advised regarding driving within eight hours due to potential dizziness.

Electrical neuromodulation uses electrical stimulation to alter pain perception. Familiar forms include transcutaneous electrical neurostimulation (TENS) and spinal stimulators. Two devices have demonstrated efficacy for migraine.

  • The Nerivio® armband device is used for the acute and preventive treatment of migraines in adults and adolescents. It attaches to the upper arm and is controlled via a smartphone app (Pain Manag 2022;12:267-81). Users can adjust the electrical intensity. The device includes a headache diary feature. Treatment sessions last 45 minutes, providing some pain relief. Side effects include warmth, numbness, muscle spasms, itching, tingling, and mild pain. Certain medical conditions and active implantable devices are contraindications for use.
  • The Relivion® MG headband device is used for the acute treatment of migraines (asamonitor.pub/47uQOuH). It targets the trigeminal and occipital nerve branches using electrical signals controlled through a smartphone. Treatment lasts 20 to 40 minutes, with relief varying. Side effects include tingling, skin irritation, dizziness, and sleepiness. It is contraindicated in individuals with certain medical conditions or implants. Relivion MG provides a convenient and adjustable approach to migraine relief, but multiple sessions may be needed for optimal results.

Migraines are a common debilitating condition that impose a substantial burden on individuals and society. While a cure for migraines remains elusive, recent advancements have broadened our therapeutic options with greater efficacy and less toxicity.