Duren M. Ready, MD, FAHS

Migraine is a chronic condition with episodic attacks of disabling pain and associated symptoms. Chronicity represents an innate sensitivity that may modulate but not resolve over time. This innate sensitivity has been described as a hypersensitive nervous system that is poorly tolerant of change. The “migraine brain” perceives sensory input at a lower threshold and retains that input, often leading to pain sensitization. The hypersensitive nervous system predisposes susceptible patients to disabling painful attacks. The Global Burden of Disease Study 2016 identified migraine as the leading cause of neurological disability in people under the age of 50 and the second leading cause of worldwide disability (based on years lived with disability).

 With 39 million Americans with migraine and a prevalence peaking between 18 and 55 years of age, there is a high economic cost with diminished productivity due to absenteeism and presentism.

The most visible aspects of migraine are painful attacks and associated symptoms. Acute pharmacological treatment is a necessary component for effective migraine management, with 98% of people with migraine reporting using at least 1 acute medication during an attack.

 Failure to resolve an attack may prolong the activation of the pain processing network, leading to central sensitization with hyperalgesia (observed clinically as cutaneous allodynia, a marker for intrac- tability and progression).

 Inadequate acute treatment is associated with a 2-fold risk of progression to chronic migraine.

 Various research results have shown that 55% of patients received insufficient relief from prior acute migraine treatments,

 40% of were dissatisfied with how fast relief came,

 and about half required a second medication dose.

 In addition, adverse events (AEs) were reported by 43% of patients within 24 hours of dosing,

 and pain and associated symptom recurrence occurred within 24 hours in 17% to 40%.

Prescription and over-the-counter medications are often used for acute migraine treatment. One pharmacy data survey of 138,004 migraineurs enrolled in 10 health plans showed
substantial medication use, including triptans (38%), short-acting opioids (50%), long-acting opioids (4%), and butalbital compounds (10%, averaging 10 monthly doses).

An Italian study found that only 25% of patients were initially offered a triptan.12 When there was an inadequate triptan response, a problematic medication was commonly added (opiate, 54%; nonsteroidal anti-inflammatory drug (NSAID), 24%; butalbital, 18%) or the triptan changed for one (opiate, 50%; butalbital, 25%; NSAID, 25%).

It is also important to note that among the estimated 31 million adults in the United States with migraine, 2.6 million have a triptan cardiovascular contraindication. Thus, it is not surprising that almost 80% of those patients appear willing to try another acute medication.

 The current treatment landscape suggests that acute migraine treatment should be based on a patient’s unmet needs and prior and present treatments.

Why a “Migraine Toolbox?” Migraine is a heterogenous condition and as such there are no “one-size-fits-all” options. Accordingly, optimal outcomes are likely to require different options, hence multiple tools. Similar to what might be kept for home repair, a good migraine tool kit will contain a variety of instruments to help restore order, returning the system to baseline. Patients with episodic headaches may require only a few tools, whereas the patient with chronic 

migraine is likely to require a more substantial armamentarium of medications and devices. By analyzing headache patterns, degree of sensitization, contraindications, tolerance to adverse effects, and affordability, physicians can help build individualized tool kits and give patients the expertise to treat their pain when and where they need it.

Addressing migraine complexity with a framework

Migraine is complex, and such systems require a framework that allow mapping (structuring acquired knowledge in a way that directs appropriate action). The Managing Migraine book series presents a framework that bases treatment needs on migraine attack frequency.

Education is primary at all stages. Essential patient information for acute migraine should include recognizing when an attack is coming; treating mild pain (preferably with a migraine-specific medication

; and recognizing that the goal is pain freedom. Different attacks may require different interventions, and with more frequent attacks, the acute treatments may not work as well or may require more aggressive interventions (

Essential provider knowledge includes reviewing patient diaries and providing feedback for optimization, having available appropriate interventions, and recognizing that the presence of allodynia requires more aggressive treatment.

Education creates expectations for actions and results. Patient actions may include setting goals for treatment outcomes, keeping a diary, and active (not passive) participation in care. These activities are associated with better outcomes. When patients are not getting the results they would like, ask them why? If they say they don’t know, that means they don’t know enough about their condition and more education is required.

Optimal acute migraine treatment is a “one and done” approach with the application of minimal necessary tools. This requires recognizing the severity of the attack and determining the most appropriate intervention. Prior acute migraine treatment was often based on stepped care. Stratified care has demonstrated both a higher mean effectiveness and lower mean cost than stepped care, as well as a higher patient satisfaction rate.

The American Headache Society’s acute migraine treatment goals

 call for rapid and consistent pain freedom with restored function, limited recurrence, and limited need for repeat dosing or rescue medications, as well as a reduction in health care resource utilization, with minimal or no AEs.

To measure progress toward the acute treatment goal, physicians can use the Migraine Treatment Optimization Questionnaire (M-TOQ). This 6-item clinical tool is designed to assess and optimize acute treatment

 and has demonstrated excellent psychometric properties in a wide range of treatment option optimization distribution.

Optimized acute treatment increases self-efficacy and internal locus of control.

 The M-TOQ can identify weak links in acute migraine care. The best outcomes are associated with increasing patient engagement; thus, as migraine complexity increases, so does the need for patient engagement.

Adherence to an appropriate plan is associated with the best clinical outcomes.

 Feedback addressing weak links in patient decision-making (choosing when to treat, time to treat, and what to treat with) regarding their acute migraine treatment plan is essential. Common barriers to acute migraine treatment may include distinguishing between migraine and other headache types early in the attack; no available medication while in mild pain; role conflicts (work and home obligations); and social influence (stigma).

 Negative factors affecting optimization include chronic migraine, cutaneous allodynia, depression, NSAID use, ergot use, and no migraine prophylaxis.

After increasing knowledge about the why and how of migraine management, the focus shifts to tool acquisition. These tools include 

a migraine diary, in addition to pharmacological, nonpharmacological, and, potentially, behavioral interventions.

The migraine diary (paper or electronic) is an essential tool. A patient’s recall may be influenced by the most recent attack or past experiences, and spontaneous recall often overestimates attack severity. The diary should at least allow for the recording of the date, time, treatment used, and response. Several smart phone app–based diaries are available, including Migraine Buddy, Migraine Monitor, and N1-Headache. A recent app, BonTriage Headache Compass, is a new addition that uses artificial intelligence to develop a diagnosis and improve self-monitoring.

Patients are more likely to achieve acute migraine resolution when the type of attack is recognized. Is it a mild, moderate, or severe attack? Is it secondary to a prolonged provocation (such as menses or altitude)? Is it associated with nausea or vomiting, suggesting the need for a parenteral intervention? An accurate diary can be invaluable in helping to recognize attack pattern and response. Unfortunately, it is most helpful in identifying suboptimal responses.

Since the early 1990s, triptans have been the leading evidence-based acute therapy for migraines. Triptans are 5HT1B/1D receptor agonists, and one of their many actions is to inhibit calcitonin gene-related peptide (CGRP) release.

 As all triptans are generic, they are afford- able for most patients.

 Results from a recent meta-analysis of trip- tans showed that they produced pain relief (moderate or severe pain reduced to mild or no pain) in 43% to 76% of patients, 2-hour pain freedom (moderate or severe pain to no pain) in 15% to 50% of patients, and sustained 24-hour pain freedom in 29% to 50% of patients.24 These findings are consistent with the Canadian Headache Society guidelines, which gave a strong recommendation for triptans, NSAIDs, ASA, and acetaminophen but did not recommend ergots for routine use in acute migraine management.

 Parental triptans (SQ or IN) were superior to oral formulations.

 Recent guidance from the UK’s National Institute for Health and Care Excellence recommends combining an oral triptan with an aspirin or acetaminophen.

Concerns arose with triptan use when the FDA placed a black box warning regarding the concomitant use of triptans and several antidepressants (principally the SSRIs and SNRIs). The American Headache Society’s position paper on the FDA action

 recommended physician vigilance due to the seriousness of serotonin syndrome but concluded that current evidence does not support limiting triptan use in monotherapy or with SSRIs or SNRIs over serotonin syndrome concerns, noting that the risk is a theoretical and not a practical one.

 Cardiovascular risks regarding triptan 5HT1B vasoconstriction have also created concerns. A 2004 consensus panel reviewing the data concluded that the chest symptoms occurring with triptan use are generally nonserious and are not explained by ischemia.

 The incidence of triptan-induced serious cardiovascular AEs in clinical trials and clinical practice appears to be extremely low, and absent contraindications, the cardiovascular risk‐benefit profile of triptans favors their use. However, the panel pointed out that most of the triptan data were derived from patients without known coronary artery disease.

Three new acute pharmacological migraine treatments have recently become available —lasmiditan (Reyvow; Eli Lilly and Company), ubrogepant (Ubrelvy; AbbVie), and rimegepant (Nurtec ODT; Biohaven). These new medications have demonstrated therapeutic gain over placebo, with good safety and tolerability, and can be used by people who could not use triptans.

Lasmiditan (ditan), a 5HT1F receptor agonist, does not affect the 5-HT1B receptor that mediates vasoconstriction and as such has no cardiovascular contraindications. Long-term safety was demonstrated in the GLADIATOR trial (NCT02565186) that included data from 814 patients observed over a medium duration of 288 days.

 The most frequent AE was dizziness (18.6%), followed by somnolence (8.5%), paresthesia (6.8%), fatigue (5.5%), and nausea (4.7%).30 Lasmiditan is thought to cross the blood-brain barrier, and this likely accounts for some of the central adverse effects. Notably, lasmiditan is a Schedule V medication and has an 8-hour post-dose driving prohibition.

As elevated CGRP levels became associated with an acute migraine attack, blocking CGRP became an attractive target. It is expressed in neurons in both the central and peripheral nervous systems and is widely dispersed throughout the nervous system.

 Newly released ubrogepant and rimegepant (gepants) are attractive options for individuals who cannot use triptans for medical reasons such as uncontrolled hypertension or coronary artery disease and for those who do not tolerate or respond to triptans.

 Gepants have been tested in patients with coronary artery disease and showed good tolerability with no 24 EKG changes.

Ubrogepant’s pivotal trials demonstrated pain freedom in 20.5% of patients in the 50-mg group and 21.2% in the 100-mg group, representing a therapeutic gain of approximately 8% over placebo.

 The secondary end point of pain relief was achieved by 61.7% in the 50-mg group and 61.7% in the 100-mg group, a therapeutic gain of 13% over placebo. There was also superior relief for most bothersome symptom. In those patients who did not achieve pain freedom and elected to redose, pain freedom was achieved in 54.7% in the 50-mg group and 51.6% in the 100-mg group, representing a therapeutic gain of 21% and 18% over placebo, respectively.

The pivotal phase 3 trial evaluating 75-mg rimegepant showed a 2-hour pain freedom achieved in 21.2% of patients and pain relief in 59.3%, representing a therapeutic gain of 10.3% and 16% over placebo, respectively.

 The investigators also recorded a sustained pain response between 2 to 24 hours in 47.8% of patients and 2 to 48 hours in 42.7% of patients. Notably, 85.2 % of the participants did not use a rescue medication within 24 hours of dosing versus 70.8% in the placebo arm, and 38.1% of patients taking rimegepant thought they were able to resume functioning within 2 hours versus 25.8% in the placebo arm.

Although it is exciting to have additional entries in the acute migraine tool kit, these newer medications should not be seen as replacements for current medications but instead as options for patients in whom current medications are contraindicated or ineffective. There are foreseeable scenarios in which a patient may have 2 different triptans, an NSAID, and a ditan or gepant in their tool kit.

Neuromodulation devices offer an alternative option for individuals interested in effective nonpharmacological interventions. Currently, 4 devices are FDA-approved for migraine: supraorbital stimulation (Cefaly), transcranial magnetic stimulation (eNeura), noninvasive vagus nerve stimulation (gammaCore), and remote electrical neuro- modulation (Nerivio). The low adverse effect profile makes neuromodulation attractive in pregnancy and in other vulnerable groups.

 Notably, all of the devices are contraindicated in individuals with other implanted devices, such as pacemakers or cochlear implants. Unfortunately, commercial insurance does not cover these devices well, although their cost may be applied toward an insurance deductible in many cases or paid for by a flexible spending account. Veterans Affairs also appears to be offering some coverage for the Cefaly and gammaCore devices.

Some additional patient-specific tools that may help patients manage acute migraine include migraine sunglasses, pressure-relieving earplugs, and cooling wraps or cold caps, though evidence supporting these therapies is scarce to limited. Many patients suffer from photo- phobia, which can be a trigger or most bothersome symptom. FL-41– tinted sunglasses can help with this trigger or provide symptom relief. The FL-41 tint can be placed on prescription glasses by most optometrists, but nonprescription versions can be purchased over the internet through reliable vendors. Additionally, some patients are very sensitive to barometric pressure changes. When using WeatherX earplugs with the associated app, patients are notified of impending pressure changes, allowing them the opportunity to proactively place 

their earplugs and prevent a pressure-associated headache. Lastly, cold caps or cooling wraps can be a useful tool for many patients who are not tolerant of pharmacological solutions or who need additional adjunctive relief.

Even though therapeutic gain may be small with some of our treatment options, due to the nature of migraine, having multiple tools to treat acute attacks is necessary as not every patient will respond to the same treatment for every attack. Thus, using a combination of pharmacology, neuromodulation, and nonpharmacological tools may provide the best kit for patients to manage migraine.

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Plagued by a long history of under- and inadequate treatment, clinicians have more options than ever to craft a personalized, effective plan for their patients.

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