Migraine Acute Therapies

Introduction

Migraine may be best conceptualized as a chronic neurologic disorder, punctuated by recurrent attacks of headache and other related symptoms. Migraine management includes acute and preventive therapies, in addition to mitigation of lifestyle and environmental factors. The goals of acute treatment are to provide reliable and effective symptom relief, as quickly as possible, with minimal side effects so affected individuals can resume daily activities without symptom recurrence.¹ Both pharmacologic and nonpharmacologic interventions exist that must be tailored to the individual. Once patients are provided with an acute treatment regimen, counseling on when and how often to use treatments is required to avoid over- or underuse of therapies. We review an approach to acute migraine management including available pharmacologic and nonpharmacologic acute migraine therapies and those on the horizon.

Eligibility and Access for Care

All patients with migraine should be offered acute therapies, tailored to the individual patient. Migraine is among the most common neurologic disorders, affecting approximately 12% of the population,² and is the 7th highest cause of years lost due to disability.³ Despite the prevalence and impact of migraine on affected people’s lives, there are barriers to obtaining appropriate migraine management, including acute therapies. Barriers identified include:

1. consulting a prescribing health care professional;

2. receiving a migraine diagnosis; and

3. using migraine-specific/other appropriate acute treatment.⁴

Only 26.3% of persons with episodic migraine and less than 5% with chronic migraine receive appropriate acute migraine treatment.^4,5 Undertreatment is in part due to the fact that 50% to 60% of affected individuals do not seek treatment for a number of reasons (eg, health insurance status⁴ or misattribution, most commonly to stress or sinus disease).⁶ Even physicians misattribute migraine as sinus headaches or tension-type headaches.⁷ (See also Migraine Mimics in this issue.)

Choosing Among the Acute Treatments

Factors to consider when choosing acute migraine therapy are listed in Table 1.

Avoiding Medication Overuse

When prescribing pharmacologic acute treatment for migraine, education is essential to reduce the risk of medication overuse headache (MOH)—a secondary headache, which is a complication of frequent migraine attacks. Diagnosis of MOH is operational and based on headache frequency (≥ 15 days per month for > 3 months) and number of days per month that specific medications are used. Use of triptans, ergot alkaloids, combination analgesics, or opioids on 10 or more days per month meets criteria for MOH. For simple analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), use on 15 or more days per month meets criteria for MOH. Finally, use of more than a single class of medications, for example a triptan and an NSAID, on 10 or more days per month also meets criteria for MOH.¹⁵

All acute treatments do not have equal risk for MOH. Opiates and barbiturates have a twofold higher risk of MOH compared with simple analgesics and triptans. Medication overuse is a significant risk factor for the development of chronic migraine. If MOH is suspected, withdrawal of overused medications is associated with a decline in both pain intensity and headache frequency in 42% to 92% of patients, although the relapse rate is high, up to 41%.^16-19 Initiation of migraine preventive therapy at the same time as withdrawal of overused acute treatment is supported by some studies and thought to reduce the relapse rate.²⁰ Primary prevention, however, is the best treatment for MOH, with education at initiation of pharmacologic acute treatments. It is important to give clear parameters for when and how often to use acute treatments. For anyone with more than 1 attack per week, initiating preventive treatment should be considered. This is essential for persons having frequent attacks because on one hand they are instructed to take acute medications as close to attack onset as possible for maximum effect, and on the other, are then told to limit the numbers of days they do so. Both initiating prevention and providing nonpharmacologic approaches to treat more mild attacks are key in these clinical scenarios.

Available Options

Evidence-based guidelines from the American Headache Society²¹ give level A recommendations for 5 different classes of medications and 1 combination; see Table 2 for administrative routes and doses. Note that acetaminophen 1,000 mg has a level A recommendation only for nondisabling attacks and that only 1 opioid (ie, butorphanol) is recommended with guidelines emphasizin that it is generally not used because of the risk of dependence, addiction, and MOH.

Stratified Approach to Acute Treatment

There are several different ways to advise patients regarding migraine acute treatment, including stratified care, step care within an attack, and step care across attacks.²²

Step Care Within an Attack. In step care within an attack, people are advised to start with a nonspecific simple analgesic then add a migraine-specific treatment (eg, DHE or a triptan) a few hours later if the initial medication does not provide relief. The disadvantage to this plan is that patients may have a longer period of suffering and a delay to obtaining headache freedom if the initial treatment is not effective. Furthermore, triptans might not be as effective if taken later in an attack.^23,24

Step Care Across Attacks. It could be argued that most people who seek medical help for migraine have already tried step care across attacks. With this approach, individuals try the same nonspecific simple analgesic for several different migraine attacks, and then consult with a physician for different treatment options if those treatments do not help.

Stratified Care. Research suggests that stratified care is better than either step care option, particularly if an individual is able to assess at the onset of a migraine whether it will be responsive to a nonspecific treatment (eg, an NSAID) or not. With stratified care, patients have the option to start with either a nonspecific analgesic or a triptan, based on their perception of which drug will be most effective for a given migraine attack. In a single randomized, controlled study comparing both step care approaches with stratified care, participants who were randomized to stratified care had better headache response at 2 hours and less attack-related disability.²² These data, along with findings that stratified care is associated with reduced direct healthcare costs and costs per aborted migraine attack,²⁵ have led to the recommendation that patients be advised to use a stratified care approach.⁹

In a stratified approach, selection of initial acute treatment is based on features of a specific attack (eg, pain intensity, migraine-associated disability, or presence of associated symptoms including nausea and vomiting).⁹ For milder attacks, an NSAID or acetaminophen are advised so that triptans can be reserved for onset of more severe attacks. Triptans can be taken alone or in combination with an NSAID, and individuals have the option to add an antiemetic as appropriate. If the attack is not completely aborted, patients can take a second dose of the initial medication, and if that is not effective, then try a medication from a different class. Some may benefit from having a rescue medication available, in the event their migraine persists despite acute treatment options. This rescue medication might be a steroid or even an opioid, provided they are used extremely infrequently and as a last resort to avoid the emergency room or urgent care. If patients are experiencing a migraine attack that does not respond to these measures and seek urgent medical care, a combination of various intravenous medications can be administered. Details of parenteral treatment of status migraine are beyond the scope of this article.

Emerging Acute Treatments

Triptans are serotonin agonists that bind 5-hydroxytryptamine 1B/1D (5HT_1B/1D) receptors and have a risk of vasoconstriction; therefore triptans are contraindicated in patients with a history of heart attack, stroke, hemiplegic migraine, or other vascular risk factors including uncontrolled hypertension.^26-30 This has left many individuals who have both migraine and vascular disease without migraine-specific therapy. Additionally, although triptans are the most commonly prescribed acute medications for migraine,³¹ approximately 30% to 40% of individuals with migraine do not find triptans to be beneficial.³² Fortunately there are emerging novel acute treatments for migraine that so far, are not contraindicated in people who also have cardiovascular disease or risk factors.

Lasmiditan

Lasmiditan is a serotonin antagonist that binds the 5HT_1F receptor and is being closely studied for acute migraine treatment. In a recently completed randomized double-blind placebo-controlled phase 3 trial, 1,856 participants with episodic migraine were randomly assigned to receive lasmiditan 200 mg or 100 mg, or placebo to treat their next migraine attack within 4 hours of headache onset. Most participants (77.9%) also had at least 1 vascular risk factor. Of those treated with 200 mg or 100 mg of lasmiditan, 32.2% and 28.2% had freedom from pain after 2 hours compared with 15.3% of those who received placebo (P < .001 for both comparisons). Freedom from most bothersome symptom (MBS) at 2 hours was achieved by 40.7% and 40.9% of those who received 200 mg or 100 mg of lasmitidan, respectively, vs only 29.5% of those who received placebo (P < .001 for both comparisons). Lasmiditan was relatively well tolerated, with no serious treatment-emergent adverse events (TEAE) and no adverse events leading to study discontinuation. The most common TEAE was dizziness (16.3% and 12.5% with lasmiditan 200 mg or 100 mg, respectively, vs 3.4% with placebo), followed by paresthesias, somnolence, nausea, fatigue, and lethargy. These TEAEs were felt to be mild to moderate and self-limited, and likely related to the fact that lasmiditan acts centrally. The incidence of cardiovascular TEAEs was also low, with palpitations in 3 patients (0.5%) who received 200 mg of lasmiditan and 2 patients (0.2%) who received 100 mg of lasmiditan, and bradycardia in 2 patients (0.3%) and 1 patient (0.2%) who received 200 mg and 100 mg of lasmiditan, respectively. These findings support lasmiditan as a promising emerging acute treatment option for migraine without significant vascular risks.^33,34

-Gepants

Calcitonin gene-related peptide (CGRP) plays a key role in migraine, and there are 3 monoclonal antibody CGRP antagonists approved for preventive treatment. Small molecule CGRP antagonists are being evaluated for the acute treatment of migraine. These oral medications, referred to as -gepants, are felt to be safe in those with vascular disease. Although several of the initial -gepants developed were associated with hepatotoxicity,³⁵ ubrogepant, rimegepant, and atogepant have not been associated with liver problems and remain in clinical development because they have shown positive results for acute migraine treatment. In trials, the -gepants show an approximately 20% pain-free rate at 2 hours and no serious TEAEs including vascular or hepatotoxic TEAEs.^36,37 A new drug application for ubrogepant is under review by the Food and Drug Administration (FDA).

Neuromodulation for Acute Treatment

Noninvasive neuromodulation for acute treatment of migraine has several advantages including high tolerability, minimal contraindications, no risk of MOH, and potential efficacy. Several options have been studied over the last several years and due to low risk, high safety, and promising results in clinical trials, 3 noninvasive neuromodulation devices have received FDA clearance and are available for clinical use (See Neuromodulation Therapies for Headache in this issue). Unfortunately, cost and insurance coverage for these devices does pose a barrier to access, but it is hoped that additional studies will bolster insurance approval.

Conclusion

Migraine can be a highly disabling disease especially for individuals with frequent, poorly treated attacks. Every patient with migraine needs an acute treatment regimen. Appropriate acute treatment of migraine is important for improvement of daily function, reduced migraine-associated disability, and to reduce the risk of disease progression and transformation to chronic migraine. Fortunately, there are several options available and more in development that range from pharmacotherapy to noninvasive neuromodulation. The choice of a single or combination of acute treatment options for a specific person depends on attack characteristics, frequency of attacks, outcomes of prior therapeutic trials, medical comorbidities, and individual preference. In addition, education is essential to ensure individuals know how and when to use acute treatment options with an emphasis on clear parameters for the frequency of use to practice primary prevention of MOH.