Migraine Pharmacotherapy and Novel Agents

Migraine Pharmacotherapy and Novel Agents
Anna K Hanson, PharmD, Essentia Health

Background: The landscape of migraine pharmacotherapy has been shifting in recent years due to development of agents targeted specifically at the condition’s underlying pathophysiology. In light of these emerging therapies, the American Headache Society (AHS) published a consensus statement in December 2018 to provide guidance on preventive and acute treatment of migraine. The goal of this article is to summarize current recommendations and highlight recently approved agents since the publication of these guidelines.

Evidence and Discussion: The AHS Consensus Statement summarizes first-line oral therapies for the prevention of migraines as antiepileptic drugs (valproic acid, topiramate), select beta-blockers (metoprolol, propranolol, timolol), and frovatriptan (specifically for menstrual migraine). General recommendations for these oral agents are to start at low dose, titrate slowly, and allow an adequate trial of at least eight weeks at an effective dose. First-line agents for the acute treatment of migraines include NSAIDs, nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations for mild-to-moderate attacks. Triptans or dihydroergotamines are recommended for moderate-to-severe attacks or mild-to-moderate attacks that do not respond to other first-line therapies. It is generally recommended that patients limit treatment to an average of two headache days per week to avoid medication overuse.

Medications targeting calcitonin gene-related peptide (CGRP) are an exciting development as the first class of medications specifically designed for the preventive treatment of migraines. This class of medications targets the vasoactive peptide CGRP which is involved in a signaling cascade that perpetuates cranial vasodilation, neurogenic inflammation, and release of toxic substances from mast cells. Designed as monoclonal antibodies, these agents either act by antagonizing the CGRP receptor or binding the CGRP ligand to prevent action at its receptor.Currently approved for both episodic and chronic migraine prevention, erenumab (Aimovig®) and galcanezumab (Emgality®) are administered subcutaneously once monthly while fremanezumab (Ajovy®) is administered either once monthly or quarterly. Eptinezumab is another CGRP-targeted agent pending FDA approval, which is given by intravenous infusion. According to the AHS guidelines, the lack of need for dose titration and rapid onset of efficacy for these injectable therapies are notable differences when compared to oral agents. To assess therapeutic benefit, AHS recommends a three-month trial for the monthly injections and six-month trial if administered quarterly. Due to limited drug interactions, the CGRP-targeted agents may be used alone or in combination with other preventive treatments. The most common adverse event with these agents is injection site reactions. Due to the high cost associated with these agents, the AHS has developed indications for initiation which involve criteria of previous treatment failures and severity of disease.

In October and December 2019, the FDA approved two novel oral agents for the acute treatment of migraine with or without aura in adults, lasmiditan (Reyvow®) and ubrogepant (Ubrelvy®), respectively. Lasmiditan is a first-in-class selective serotonin (5-HT1F) receptor agonist, while ubrogepant is the first oral CGRP receptor antagonist approved by the FDA. According to publications by Dodick et al. on ubrogepant and Wietecha et al. on lasmiditan, both agents were found in phase III clinical trials to have improved pain freedom and absence of most bothersome symptoms at two hours as compared to placebo. These results were statistically significant across all studied doses of the two agents. The most common adverse events of lasmiditan included dizziness, fatigue, somnolence, nausea, vomiting, and paresthesia. The most common adverse events of ubrogepant included nausea, somnolence, and dry mouth. Given their lack of vasoconstrictive properties, these agents may be beneficial in those with cardiovascular contraindications to triptans. Rimegepant (Nurtec ODT®) is another oral CGRP-targeted agent for acute treatment of migraine which recently received approval from the FDA on February 27th, 2020.

In addition to pharmacotherapy, the AHS emphasizes the benefit of other treatment modalities  for treatment or prevention such as neuromodulation, cognitive behavioral therapy (CBT), and optimized biobehavioral therapies focused on avoidance of triggers and adequate nutrition, exercise, and hydration.

Clinical Impact: Emerging treatments with novel mechanisms for both the preventive and acute treatment of migraine provide promising new strategies. Knowledge of novel therapies and comprehensive review of individualized medication histories, disease severity, and non-pharmacological strategies will be crucial to optimize drug selection and achieve cost-effectiveness.


  1.  American Headache Society position statement on integrating new migraine treatments into clinical practice. JHeadache Pain. 2019;59:1‐18. doi:10.1111/head.13456.

  2. U.S. Food & Drug Administration. New drug class employs novel mechanism for migraine treatment and prevention.https://www.fda.gov/drugs/news-events-human-drugs/new-drug-class-employs-novel-mechanism-migraine-treatment-and-prevention. Updated January 29, 2019. Accessed February 9, 2020.

  3. American Headache Society. FDA approves acute migraine treatment for adults.https://americanheadachesociety.org/news/fda-approves-lasmiditan/. Published October 21, 2019. Accessed February 9, 2020.

  4. Dodick DW, Lipton RB, Ailani J, et al. Ubrogepant for the treatment of migraine. N Engl J Med. 2019;381:2230-41. doi:10.1056/NEJMoa1813049.

  5. Wietecha LA, Kuca B, Asafu-Adjei J, Aurora SK. Phase 3 studies (SAMURAI, SPARTAN) of lasmiditan compared to placebo for acute treatment of migraine. Neurology. 2018;90 (S50.008).

  6.  American Headache Society. Ubrogepant, first oral CGRP receptor antagonist or gepant, approved by FDA.https://americanheadachesociety.org/news/Ubrogepant+Approved+by+FDA. Published December 24, 2019. Accessed February 9, 2020.