Applied Evidence

Migraine headache: When to consider these newer agents

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These agents are as effective as traditional acute and preventive treatments, cause fewer adverse effects, and can simplify regimens.


› Consider small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) for acute migraine treatment after treatment failure of at least 2 non-CGRP first-line therapies. A

› Consider anti-CGRP monoclonal antibodies or gepants for migraine prevention if traditional therapies have proven ineffective or are contraindicated or intolerable to the patient. A

› Add an anti-CGRP monoclonal antibody or gepant to existing preventive treatment if the patient continues to experience migraine. B

Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series



Migraine is a headache disorder that often causes unilateral pain, photophobia, phonophobia, nausea, and vomiting. More than 70% of office visits for migraine are made to primary care physicians.1 Recent data suggest migraine may be caused primarily by neuronal dysfunction and only secondarily by vasodilation.2 Although there are numerous classes of drugs used for migraine prevention and treatment, their success has been limited by inadequate efficacy, tolerability, and patient adherence.3 The discovery of pro-inflammatory markers such as calcitonin gene-related peptide (CGRP) has led to the development of new medications to prevent and treat migraine.4


Pathophysiology, Dx and triggers, indications for pharmacotherapy

Pathophysiology. A migraine is thought to be caused by cortical spreading depression (CSD), a depolarization of glial and neuronal cell membranes.5 This results in increased cortical excitability, central trigeminal-thalamic sensitization, and defective descending pain modulatory activity.6 The activation of the trigeminal sensory pathways, primarily the ophthalmic branch, sends nociceptive signals to second-order neurons mediated by the release of neurotransmitters, such as CGRPs.5 This activation explains in part the primary location for a migraine, which is around the eye and the neighboring cranial regions. The pain perceived by the patient is caused by these second-order neurons.

It has been theorized that gepants bind to calcitonin gene-related peptide receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.

Dx and triggers. In 2018, the International Headache Society revised its guidelines for the diagnosis of migraine.7 According to the 3rd edition of The International Classification of Headache Disorders (ICHD-3), the diagnosis of migraine is made when a patient has at least 5 headache attacks that last 4 to 72 hours and have at least 2 of the following characteristics: (1) unilateral location, (2) pulsating quality, (3) moderate-to-severe pain intensity, and (4) aggravated by or causing avoidance of routine physical activity.7 The headache attacks also should have (1) associated nausea or vomiting or (2) photophobia and phonophobia.7 The presence of atypical signs or symptoms as indicated by the SNNOOP10 mnemonic raises concerns for secondary headaches and the need for further investigation into the cause of the headache (TABLE 1).8 It is not possible to detect every secondary headache with standard neuroimaging, but the SNNOOP10 red flags can help determine when imaging may be indicated.8 Potential triggers for migraine can be found in TABLE 2.9

SNNOOP10 red flags for secondary headache disorder

Indications for pharmacotherapy. All patients receiving a diagnosis of migraine should be offered acute pharmacologic treatment. Consider preventive therapy anytime there are ≥ 4 headache days per month, debilitating attacks despite acute therapy, overuse of acute medication (> 2 d/wk), difficulty tolerating acute medication, patient preference, or presence of certain migraine subtypes.7,10

Migraine triggers

Acute treatments

Abortive therapies for migraine include analgesics such as nonsteroidal anti-­inflammatory drugs (NSAIDs) and acetaminophen, and ergot alkaloids, triptans, or small-molecule CGRP receptor antagonists (gepants). Prompt administration increases the chance of success with acute therapy. Medications with the highest levels of efficacy based on the 2015 guidelines from the American Headache Society (AHS) are given in TABLE 3.11 Lasmiditan (Reyvow) is not included in the 2015 guidelines, as it was approved after publication of the guidelines.

Non-CGRP migraine treatment first-line therapies
Non-CGRP migraine treatment first-line therapies

Non-CGRP first-line therapies

NSAIDs and acetaminophen. NSAIDs such as aspirin, diclofenac, ibuprofen, and naproxen have a high level of evidence to support their use as first-line treatments for mild-to-moderate migraine attacks. Trials consistently demonstrate their superiority to placebo in headache relief and complete pain relief at 2 hours. There is no recommendation for selecting one NSAID over another; however, consider their frequency of dosing and ­adverse effect profiles. The number needed to treat for complete pain relief at 2 hours ranges from 7 to 10 for most NSAIDs.11,12 In some placebo-controlled studies, acetaminophen was less effective than NSAIDs, but was safer because it did not cause gastric irritation or antiplatelet effects.12

Triptans inhibit 5-HT1B/1D receptors. Consider formulation, route of administration, cost, and pharmacokinetics when selecting a triptan. Patients who do not respond well to one triptan may respond favorably to another. A meta-analysis of the effectiveness of the 7 available agents found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.13 Lasmiditan is a selective serotonin receptor (5-HT1F) agonist that lacks vasoconstrictor activity. This is an option for patients with relative contraindications to triptans due to cardiovascular risk factors.10

Continue to: Second-line therapies


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