Author: Ashley Wellen, PharmD, PGY1 Community Pharmacy ResidentMentor: Michelle Jeon, PharmD, BCACP, Assistant Professor of Pharmacy Practice/Clinical Pharmacist - St. Louis College of Pharmacy/Walgreens Co.
Migraine is a disease that affects over 36 million Americans. The disabling disease affects almost three times as many women as men.1 Patients with episodic migraine may experience a few migraine days per month, and those with chronic migraine spend 15 or more days per month with debilitating pain and neurologic symptoms.2
A study published in 2018 that aimed to describe the prevalence of migraine in adults also described the socioeconomic burden of the disease.3 According to results, the following groups had a statistically significant higher burden of severe headache or migraine:
Migraine headache etiology and pathophysiology are not completely understood. The pain and associated symptoms a patient experiences are believed to occur through a combination of mechanisms including neural suppression and activation of subcortical structures of the trigeminal system. The activation of trigeminal sensory nerves leads to the release of vasoactive neuropeptides including calcitonin gene-related peptide (CGRP), neurokinin A, and substance P. The vasodilation caused by these neuropeptides leads to neurogenic inflammation. Continued nerve conduction relays information to the cortical pain centers and continued afferent input maintains the headache.4,5,6
Impact on Quality of Life
Individuals with migraine experience attacks that may last for several hours to days. Migraines can severely negatively affect quality of life for patients. Affected patients may not be able to participate in daily activities, engage with family and friends, or perform at work. Sunlight, smells, and weather may trigger, amplify and exaggerate symptoms of a migraine.
The Migraine Impact report published by Eli Lily presented data regarding the social burden associated with migraine headaches7. Findings included:
Migraine headaches have a significant impact on quality of life and overall well-being of those who are affected by the disease.
Prevention with Pharmacologic Agents
According to the American Academy of Neurology, about 38% of those with migraines need preventative therapy; however, only 3-13% use it.8 Migraine prevention is indicated for those patients with frequent or long lasting migraines; contraindications, adverse effects, failure, or overuse of acute therapies; or those with uncommon migraines. Goals of preventative therapy include reducing attack frequency, severity, and duration; improving responsiveness to treatment of acute attacks, improving function and reducing disability, and preventing progression of episodic to chronic migraines. The overall goal is to improve the patient’s quality of life from the debilitating disease.8,9
Preventative medications currently recommended by the American Academy of Neurology include agents from pharmacologic classes such as beta-blockers, antidepressants, antiepileptics, NSAIDs, and calcium channel blockers. Table 1 includes agents with labeled indications for migraine prevention. Other agents such as atenolol, amitriptyline, venlafaxine, verapamil, and NSAIDs, are commonly used off-label. Many of these agents have limited efficacy in migraine prevention as well as limited use in special populations. The agents with the highest level of evidence of use are described in Table 1 below. 8,9
Agents with Labeled Indications for Migraine Prevention
CGRP Antagonists for Migraine Prevention
AIMOVIG™ (erenumab), AJOVY™ (fremanezumab), and EMGALITY™ (galcanezumab) are CGRP antagonists that were approved by the FDA in 2018 for preventative migraine therapy. This is the first medication class primarily designed to prevent migraines.
MECHANISM CGRP antagonists are monoclonal antibodies that exert their action by blocking the action of CGRP ligands at the CGRP receptors. CGRP ligands have been discovered in high concentration in patients who experience migraine. By inhibiting ligand action at the CGRP receptor, the subsequent vasodilation and neuro inflammation that lead to migraine headache and pain are inhibited. Both AJOVY™ and EMGALITY™ bind to CGRP ligands and prevent their action at CGRP receptors. AIMOVIG™ has a slightly different mechanism, as it binds with high-affinity to the CGRP receptors and antagonizes their function.10
CLINICAL CONSIDERATIONS All CGRP antagonists are administered via subcutaneous injection. Most agents are administered monthly with the option of AJOVY™, which can be dosed every 3 months. Each pen is available as a standard dose; some regimens may require 2 to 3 consecutive injections to achieve the prescribed dose (Table 2). Hypersensitivity remains the only contraindication for all agents. Patients may continue to use triptans as acute therapy for migraine headaches as no drug interactions exist with CGRP antagonists.
* Administration of higher doses will require 2-3 consecutive subcutaneous injections.
EFFICACY All three agents were compared to placebo when determining efficacy in episodic and chronic migraine prevention. Outcomes of interest include reduction in number of migraine days per month (MMD), and achievement of a 50% reduction or more from baseline in mean migraine days (>/= 50% MMD responders). A statistically significant difference was found in all studies for all agents and their outcomes of reduction of MMD and >/= 50% MMD responders compared to placebo. Tables 3, 4, and 5 below list the trials for each CGRP antagonist and the previously mentioned outcomes.11-18
Table 3AIMOVIG™ (ERENUMAB)
Table 4EMGALITY™ (GALCANEZUMAB)
Table 5AJOVY™ (FREMANENZUMAB)
IMMUNOGENICITY Development of antibodies to the biologic agents was reported in clinical trials. Although the data did not demonstrate a significant impact on product efficacy, there is little data to make definitive conclusions at this point.
ADVERSE REACTIONS All agents have similarly shown to cause minimal adverse reactions. Those that occurred in 3% or more of patients were injection site reactions and constipation.
MONITORING Number of migraine days per month should be monitored to determine efficacy of the three agents. No safety-related monitoring is required.
SPECIAL POPULATIONS Data on efficacy and safety of these agents is limited for use in pregnant, lactating, or pediatric patients. Data is also limited regarding use in elderly; therefore, it is currently recommended to start with low doses in the elderly.
THERAPEUTIC POTENTIAL Currently, these therapies may be considered an alternative to the guideline recommended agents as no trials have compared CGRP antagonists to first line therapy options for migraine prevention. One study including AIMOVIG™ (erenumab) demonstrated its efficacy after patients had failed to experience improvement on at least 2 – 4 other agents.19 Although these agents are the first class to target pathophysiology specific to migraine headaches and are effective with minimal adverse effects, their cost hinders the decision to recommend CGRP antagonists as 1st line preventative treatment options. The subcutaneous route of administration also presents a disadvantage, however, pipeline oral CGRP antagonists are being evaluated in clinical trials.20 As several novel agents have offered new potential for more effective management of migraine, therapeutic options for the prevention of severe disease will likely continue to expand.