The current state of acute treatment for migraine in adults in the United States

ABSTRACT

Migraine is a common and disabling disorder with substantial personal, social, and economic burden that affects 37 million people in the United States. Risk factors for migraine include age, sex, and genetics. The goal of acute treatment of migraine attacks is to stop the pain and associated symptoms of the migraine attack and return the patient to normal function.

The acute treatment landscape for migraine has recently expanded beyond the standard nonsteroidal anti-inflammatory drugs, analgesics, triptans, ergotamines, and combination therapies, to include neuromodulation devices, and recently approved calcitonin gene-related peptide receptor antagonists and a serotonin (5-HT_1F) receptor agonist. Unmet acute treatment needs still exist due to lack of efficacy, unwanted side effects, or contraindication to treatment. Effective treatment of migraine requires the clinician to assess the patient, make an accurate diagnosis, and then offer appropriate therapy based on the patient’s medical history, comorbidities, and preferences, as well as published clinical evidence. The objective of this narrative review is to familiarize primary care clinicians with the variety of acute treatment options available in the United States today based on clinical trial findings, meta-analyses, evidence-based guidelines, and professional society consensus statements.

KEYWORDS:

• Migraine disorders/pathophysiology
• migraine disorders/therapy
• quality of life
• headache-related disability
• unmet need
• prevalence
• epidemiology

1. Introduction

Migraine is a common neurologic disease characterized by recurring attacks of head pain associated with sensitivity to light and sound, nausea, and/or vomiting [1,2]. Worldwide, migraine prevalence is approximately 12% [3]. In the United States, it is estimated that 37 million people, approximately 15% of the population [4,5], have migraine. During midlife, episodic migraine attacks are three times more common in women [6]. The likelihood for migraine is highest between 25 and 55 years of age, the prime working years, and typically declines in frequency later in life, but not for all patients with migraine [5,7].

1.1. Burden of migraine

This lifelong disorder is the second leading cause of time lost to disability [8], after low back pain, in high- and middle-income countries. Migraine is a common cause of emergency department visits [9,10]. More than one-half of all healthcare facility visits for migraine occur in a primary care setting [9].

Indirect costs of migraine include missed workdays (absenteeism) and decreased productivity while at work (presenteeism). More than one-half of the workdays lost to headache are a result of migraine [11,12]. In the United States, 113 million workdays are lost each year as a result of migraine attacks at a cost to employers of 13 USD billion [13]. People with chronic migraine spend approximately one-quarter of their workdays working at 50% capacity or less [14]. Overall, the economic burden of migraine in the United States is more than 56 USD billion per year [15]. This burden is aggravated in populations with low socioeconomic status, which have people more likely to be unemployed or underemployed in jobs with no sick days or without health insurance [9].

The personal burden of migraine weighs not only on people with migraine, but also on family and friends. Anxiety and fear of experiencing an attack during an activity can contribute to an individual deciding to not participate in social and family activities [16]. Approximately one-half (48%) of people with migraine who have adolescent or younger children, and 77% of those with chronic migraine, report missing important celebrations such as weddings or birthdays, or enjoying them less, because of migraine attacks [17]. Parenting is affected by migraine as well. Approximately one-half (44%) of parents with migraine say that at least once a month they are unable to help their children with homework or talk with their children about important topics. In many cases, the spouse has to take over parenting duties including preparing meals and carpooling.

Migraine also causes stress in couples’ relationships. More than one-half of people with migraine and their spouses report disrupted time alone as a couple and reduced enjoyment of the time they are together [17]. One study reported that migraine can even affect a couple’s decision whether to have children [16].

1.2. Risk factors, common triggers, and comorbidities

Risk factors for migraine include age, sex, and genetics [18,19]. Genetic factors may account for about 50% of a person’s risk of migraine [19]. Common triggers for migraine attacks include stressful life events, caffeine use, acute medication overuse, changes in sleep patterns, certain foods, weather changes, and female hormonal changes [20,21]. Common comorbidities include depression, bipolar disorder, anxiety, obesity, chronic pain, fibromyalgia, and hypertension [6,22].

1.3. Diagnosis of migraine

Migraine attacks are characterized by recurrent attacks of moderate-to-severe head pain that may be unilateral or bilateral, pulsating, and aggravated by routine physical activity. The headache phase during a migraine attack can last from 4 to 72 h and can be accompanied by nausea and/or vomiting and/or photophobia and phonophobia [2]. Some people experience a premonitory phase up to 72 h before the onset of headache which may include changes in mood, irritability, fatigue, food cravings, thirst, repetitive yawning, stiff neck, and phonophobia.

The two major subtypes are migraine with aura and without aura. Migraine with aura includes neurological disturbances characterized by visual symptoms such as seeing spots, lines, or gray patches; sensory symptoms including tingling or numbness; or difficulty speaking that usually precede the headache and last for up to an hour [2]. Aura usually begins with visual and then sensory symptoms followed by difficulty speaking or understanding language. Sensory aura is most commonly unilateral affecting the face and arm, and less commonly in the trunk and leg. About one-third of people with migraine experience aura before or during the attack. Migraine without aura does not include the above symptoms, although migraine attacks of both types may be accompanied by photo- or phonophobia, nausea, and/or vomiting.

The International Classification of Headache Disorders 3rd edition (ICHD-3) distinguishes chronic migraine as having headache on 15 or more days per month (with 8 or more headache days fulfilling migraine criteria) over a period of more than three months, while episodic migraine is characterized as having fewer than 15 headache days per month for a period of more than three months [2].

When a patient presents with a headache in a primary care office, the physician needs to gather the patient’s history of headache in order to make an accurate diagnosis.

Three simple questions, known as the ID Migraine Screener [23], can help with the diagnosis of the headache. In this validated screener, the healthcare provider asks

1. Does light bother you a lot more when you have a headache?

2. Does a headache limit you from working, studying, or doing what you need?

3. Do you feel nauseated or sick to your stomach when you have a headache?

2. Acute treatments for migraine

Significant expansion in the understanding of migraine pathophysiology has occurred over the last 20+ years. Knowledge of central and peripheral neural pathways, neuropeptides, and neurotransmitters has led to innovation in the treatment of migraine after decades of little change. In the last year, three new acute treatments for migraine as well as multiple neuromodulation devices were approved in the United States.

As the treatment landscape evolves, clinicians rely on resources such as guidelines and position statements for treatment decision-making. Given the rapid increase in treatment options over a short period of time, it is challenging for guidelines to keep up with the pace of innovation. For example, the American Academy of Neurology (AAN) published its most recent evidence-based treatment guidelines for migraine in 2000 [24]. In 2015, the American Headache Society (AHS) published an updated evidence assessment of research on acute therapies for migraine published between 1998 and 2013 [25]. Most recently, the AHS published a 2018 position statement [1] on integrating new migraine treatments into clinical practice, prior to the approval of the three novel acute treatments. These publications report that several therapies are effective for the acute treatment of migraine, but the publications lack important information on novel acute treatments to aid clinicians with treatment decision-making.

When making decisions regarding acute treatment for migraine, a healthcare provider must consider a given therapy’s efficacy and safety. Efficacy is now determined by the treatment’s ability to deliver pain freedom at 2 h. Historically, the efficacy of acute treatment in clinical trials was evaluated using four co-primary endpoints: pain relief (reduction in pain from moderate-to-severe to mild-or-none), and reduction of photophobia, phonophobia, and nausea at 2 h. In 2018, the FDA updated acute treatment trial guidelines to require pain freedom and freedom from the most bothersome symptom (MBS) at 2 h[26]. The MBS is determined by each patient among the choices of photophobia, phonophobia, or nausea. This new efficacy requirement aligns with recommendations of scientific experts in the international and American headache societies [27], and important acute treatment attributes identified by patients [26]. It is important for healthcare providers to understand the new pain freedom and MBS freedom standard when discussing treatment expectations with their patients with migraine [28,29]. Additionally, a healthcare provider must also be mindful of the potential for side effects and interactions with concomitant medications when considering acute therapies, emphasizing the need for individualization of treatment plans.

Categories of medications currently approved in the United States for acute treatment of migraine include triptans, ergotamines, nonsteroidal anti-inflammatory drugs (NSAIDs), ditans, gepants, analgesics, and combination therapies (Table 1). Neuromodulation devices have also been approved for acute treatment of migraine.

Table 1. Acute treatments for migraine

Medication	Formulation	Estimated Cost (US Dollars) Generic/Branded
First-line treatments
Acetaminophen (Tylenol)	325 mg	$2/$10 for 30 tablets
NSAIDs
Aspirin	325 mg	$3/$3 for 30 tablets
Diclofenac potassium (Cambia)	50 mg	$19 for 60 tablets/$534 for 9 packets
Ibuprofen (Advil)	200 mg	$7/$10 for 100 tablets
Naproxen sodium (Anaprox)	500 mg	$3/$8 for 30 tablets
Triptans
Almotriptan (Axert)	12.5 mg	$108/$514 for 12 tablets
Eletriptan (Relpax)	40 mg	$27/$367 for 6 tablets
Frovatriptan (Frova)	2.5 mg	$100/$876 for 9 tablets
Naratriptan (Amerge)	2.5 mg	$20/$511 for 9 tablets
Rizatriptan (Maxalt)	10 mg	$13/$333 for 9 tablets
Sumatriptan (Imitrex)	100 mg	$12/$605 for 9 tablets
Zolmitriptan (Zomig)	5 mg	$26/$1,156 for 9 tablets
Ergotamines
Dihydroergotamine mesylate (D.H.E. 45), injectable	1 mg/mL	$48/$1,169 for 1 ampule
Dihydroergotamine mesylate (Migranal) nasal spray	4 mg/mL	$1,243/$3,779 for 8 vials
Combined regimens
Acetaminophen/aspirin/ Caffeine	Acetaminophen 250 mg/aspirin 250 mg/caffeine 65 mg	$5/$6 for 24 tablets
Sumatriptan/naproxen (Treximet)	Sumatriptan 85 mg/naproxen 500 mg	$132/$1056 for 9 tablets
Second-line treatments
Antiemetics
Chlorpromazine	25 mg	$37 for 30 tablets (generic only)
Metoclopramide (Reglan)	10 mg	$5/$113 for 30 tablets
Prochlorperazine	10 mg	$9 for 30 tablets (generic only)
Promethazine	25 mg	$10 for 30 tablets (generic only)
Novel Acute Treatments
Ubrogepant (Ubrelvy)	50 mg	$847 for 10 tablets (brand only)
Lasmiditan (REYVOW)	100 mg	$640 for 8 tablets (brand only)
Rimegepant (NURTEC ODT)	75 mg	$847 for 8 tablets (brand only)

Source for treatments is Marmura et al. 2015.

Prices listed on 16 April 2020 at www.cvs.com for over-the-counter medications, and goodrx.com for prescription medications.

2.1. Triptans

Triptans (potent 5-HT_1B/1D receptor agonists) are considered first-line treatment for moderate-to-severe migraine attacks [1]. Triptans specifically target the 5-HT_1B and 5-HT_1D receptor subtypes (some triptans also have an affinity for the 5-HT_1F receptor subtype) [30]. Triptans were specifically developed for the acute treatment of migraine based on their ability to induce vasoconstriction through their agonism of the 5-HT_1B receptor, at a time when migraine was believed to be a vascular disorder. Because of their vasoconstrictive properties, triptans are contraindicated in patients with cerebrovascular and cardiovascular disease.

The AHS Evidence Assessment of Acute Treatment for Migraine (2015) reports level A evidence for all seven of the available triptans and a sumatriptan/naproxen combination, meaning they are ‘effective’ for the acute treatment of migraine [25]. Comparative efficacy of the triptans has been assessed in meta-analyses. Table 2 provides rates of 2-h pain freedom as reported by Cameron et al. [31]. This same meta-analysis found that eletriptan and rizatriptan had the largest effect on 24-h sustained pain freedom among monotherapies at 33% and 24%, respectively. Sumatriptan is the most extensively studied triptan [30] and is the only triptan available in a subcutaneous injectable formulation. In some patients, an injection of sumatriptan provides an onset of headache pain relief in as little as 10 minutes [32].

Table 2. Efficacy of triptans for pain freedom at 2 hours

Triptan, standard dose	Pain Freedom at 2 Hours (%)
Almotriptan, 12.5 mg	25
Eletriptan, 40 mg	39
Frovatriptan, 2.5 mg	35
Naratriptan, 2.5 mg	18
Rizatriptan, 10 mg	37
Sumatriptan, 50 mg	28
Zolmitriptan, 2.5 mg	27

Proportions of study participants reporting pain freedom at 2 h is based on meta-analysis performed by Cameron et al., 2015.

Despite the acute treatment efficacy reported in clinical trials, triptans are associated with insufficient tolerability, increased effect latency, and decreased adherence (26% to 29% at 6 months) [33], which underscores the need for novel acute treatment options.

Triptans are associated with fatigue, dizziness, chest discomfort, somnolence, and nausea [30] (Table 3). For example, among study participants taking oral sumatriptan, 76% reported heavy arms and 50% reported chest pressure [34].

Table 3. Potential adverse events of acute treatments for migraine

Medication	Most Common Adverse Events
Acetaminophen	Nausea, vomiting, headache, and insomnia
NSAIDs	NSAIDs have a black box warning regarding cardiovascular, and gastrointestinal risk
Aspirin	Gastrointestinal events including dyspepsia, hepatic enzyme elevation, hepatitis, and Reye’s Syndrome
Diclofenac	Gastrointestinal events including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), and vomiting Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tinnitus
Ibuprofen	Nausea, epigastric pain, heartburn, diarrhea, abdominal distress, nausea and vomiting, indigestion, constipation, abdominal cramps or pain, fullness of GI tract (bloating and flatulence)
Naproxen	Dyspepsia, abdominal pain, nausea, headache, rash, ecchymosis, and edema
Triptans
Almotriptan	Nausea, dry mouth, and paresthesia
Eletriptan	Asthenia, nausea, dizziness, and somnolence
Frovatriptan	Dizziness, headache (other than a migraine headache), paresthesia, dry mouth, dyspepsia, fatigue, feeling hot or cold, chest pain, skeletal pain, and flushing
Naratriptan	Paresthesias, nausea, dizziness, drowsiness, malaise/fatigue, throat/neck symptoms
Rizatriptan	Asthenia/fatigue, somnolence, pain/pressure sensation and dizziness
Sumatriptan	Paresthesia, warm/cold sensation, chest pain/tightness/pressure and/or heaviness, neck pain/pressure/tightness/heaviness, vertigo, malaise/fatigue
Zolmitriptan	Neck/throat/jaw pain/tightness/pressure, dizziness, paresthesia, asthenia, somnolence, warm/cold sensation, nausea, heaviness sensation, and dry mouth
Ergotamines
Dihydroergotamine mesylate	Rhinitis, nausea, altered sense of taste, application site reactions, dizziness, vomiting
Combined regimens
Acetaminophen/aspirin/caffeine	Nausea, vomiting, headache, insomnia Gastrointestinal events including dyspepsia, hepatic enzyme elevation, hepatitis, and Reye’s Syndrome Nervousness, irritability, sleeplessness, and, rapid heartbeat
Sumatriptan/naproxen	Dizziness, somnolence, paresthesia, nausea, dyspepsia, dry mouth, chest discomfort/chest pain, neck/throat/jaw, pain/tightness/pressure
Antiemetics
Chlorpromazine	Drowsiness, dizziness, dry mouth, blurred vision, fatigue, nausea, constipation, and trouble sleeping
Metoclopramide	Restlessness, drowsiness, fatigue, and lassitude
Prochlorperazine	Drowsiness, dizziness, amenorrhea, blurred vision, skin reactions, and hypotension
Promethazine	Drowsiness, dermatitis, photosensitivity, urticaria, dry mouth, asthma, nasal stuffiness, hyperexcitability, and abnormal movement
Serotonin (5-HT)1F receptor agonists
Lasmiditan	Dizziness, fatigue, paresthesia, and sedation
CGRP receptor antagonists
Rimegepant	Nausea and hypersensitivity reactions
Ubrogepant	Nausea, somnolence, and dry mouth

The presentation of the most common adverse events is based on the prescribing information for each product.

Although the incidence of serious cardiovascular events with triptans is very low, according to the 2004 Consensus Statement: Cardiovascular Safety Profile of Triptans (5-HT1B/1D Agonists) in the Acute Treatment of Migraine, triptans are still contraindicated in people with cerebrovascular and cardiovascular disease.

2.2. Ergotamines

Ergot is one of the oldest treatments for migraine, dating back to the middle ages. However, poor tolerability because of nausea, vomiting, and cardiovascular effects drove researchers to create a synthetic modification, dihydroergotamine mesylate (DHE) that has been in use for the treatment of migraine since 1946. Because of its poor oral bioavailability DHE is administered in a dose of 1 mg/mL intravenously or by subcutaneous/intramuscular injection or 2 mg/0.5 mL via nasal spray [35]. Both injectable and nasal DHE are suitable to treat moderate-to-severe migraine attack and less severe migraine when nonopiate medications fail, according to the AAN guidelines of 2000.

According to the American Headache Society Evidence Assessment of Migraine Pharmacotherapies, no recent high-quality studies have been published for injected DHE [25]. In clinical trials with DHE nasal spray, 30% to 61% of participants reported a reduction in headache severity to mild or no pain in 2 h, compared to 20% to 33% for placebo. The most common side effects associated with DHE nasal spray were rhinitis, altered sense of taste, application site reactions, dizziness, nausea, and vomiting [36]. Because nausea and vomiting are common side-effects of DHE, coadministration of an antiemetic is recommended [37]. DHE should be used with caution, or avoided entirely, in patients with cardiovascular disease including coronary artery disease, peripheral vascular disease, and uncontrolled hypertension [1].

2.3. NSAIDs and non-opiate analgesics

Oral NSAIDs are appropriate first-line treatment for mild-to-moderate migraine [1]. Aspirin, ibuprofen, and naproxen sodium are considered to have proven clinical benefits, and diclofenac and naproxen have shown moderate clinical benefits [24].

As reported in 2 trials [25] published after the AAN guidelines, aspirin in a 900- to 1000-mg dose was effective in providing headache relief at 2 h for 48% to 52% of participants, compared to 19% to 34% for placebo. Pain freedom at 2 h was 14% compared to 5% for placebo in one of the two studies [38].

Ibuprofen may also be used for the treatment of migraine attacks. A dose of 400 mg is indicated for mild-to-moderate pain. However, in a study comparing 200- and 400-mg doses for mild-to-moderate migraine headaches, a similar proportion of participants in each treatment group (42% for 200 mg vs. 41% for 400 mg) experienced headache relief at 2 h [39]. Among participants with severe headache in the same study, the 400-mg dose was superior to placebo for headache relief (41% vs. 28%), while the 200-mg dose showed no significant difference compared to placebo.

A powdered formulation of diclofenac for reconstitution into oral solution is approved for the acute treatment of migraine. In people with moderate-to-severe migraine, pain freedom at 2 h was reported by 25% of study participants receiving diclofenac oral solution 50 mg, compared to 10% to 12% of participants receiving placebo [40].

Although effective, NSAIDs such as aspirin or ibuprofen come with gastrointestinal risk, such as ulcers, bleeding, or perforation in the stomach or intestine [30,41] (Table 3). Acetaminophen is associated with hepatotoxicity when used at high doses [42].

NSAIDs are also associated with an increased risk of cardiovascular events. A meta-analysis of 639 randomized trials found that high doses of traditional NSAIDs diclofenac and ibuprofen had vascular risks similar to that of COX-2 inhibitors, which increased the risk of major cardiovascular events by about one-third [43]. The increased risk was similar for people who were already at risk of cardiovascular events as well as those who were not. Naproxen did not, however, seem to increase the risk of major cardiovascular events, although the authors said that this result should be interpreted with caution. A separate meta-analysis of pooled data from 446,763 individuals found that ibuprofen, diclofenac, and naproxen used for 1 to 7 days increased the risk of acute myocardial infarction as early as the first week of use [44]. All non-aspirin NSAIDs are now required to carry a black-box warning in their labeling to indicate that there is an increased risk of MI, stroke, and other serious cardiovascular thrombotic events.

2.4. Combination therapies

Acetaminophen alone is not recommended for acute treatment of migraine except for migraine during pregnancy [24]. However, a combination of acetaminophen, aspirin, and caffeine can have clinical benefit. In a placebo-controlled study of acetaminophen, aspirin, and caffeine, pain freedom at 2 h was achieved by 21% of participants who took the combination and 7% of those given placebo [45]. In another placebo-controlled study, a combination of acetaminophen, aspirin, and caffeine was superior to ibuprofen and placebo in delivering pain freedom at 2 h [46].

Sumatriptan/naproxen sodium is another effective combination therapy. Two large studies have compared a combination of sumatriptan 85 mg/naproxen 500 mg with sumatriptan 100 mg alone and naproxen sodium 500 mg alone. In the first study, 34% of participants were headache-free at 2 hours with the combination therapy, compared to 25% for sumatriptan monotherapy, 15% for naproxen sodium monotherapy, and 9% for placebo. In the second study, 30% of participants reported pain freedom at 2 h with the combination therapy, compared to 23% for sumatriptan monotherapy, 16% for naproxen sodium monotherapy, and 10% for placebo [25].

Although historical guidelines recommended the use of opioid analgesics or opioid combinations for rescue therapy, current guidelines and recommendations do not support the use of opioids for acute treatment of migraine [10,47].

2.5. Recently approved acute treatments – gepants and ditan

Over the last two decades, the hypothesis that vasodilation is the cause of migraine has receded as a result of magnetic resonance angiography that showed that migraine headache pain was not accompanied by extracranial arterial dilatation [48,49]. Consequently, migraine pain research has moved toward nonvascular theories involving other processes and targets [34]. Emerging acute treatments that do not cause vasoconstriction may have a role in treating people who do not favorably respond to triptans or those with cerebro- or cardiovascular contraindications to triptans [50,51].

Two new classes of acute treatment for migraine that do not cause vasoconstriction, calcitonin gene-related peptide (CGRP) receptor antagonists (gepants), and 5-HT_1 F receptor agonists (ditans) have demonstrated efficacy [49]. CGRP is a neuropeptide released from peripheral trigeminal perivascular nerve fibers as a result of trigeminal nerve activation. CGRP is involved in migraine pathophysiology and causes vasodilation, neurogenic inflammation, and pain signal transmission [52]. 5-HT_1 F receptors are located in many areas of the central and peripheral nervous systems including the trigeminovascular pathway [53]. 5-HT_1F receptor agonism leads to inhibition of neurotransmitter and neuropeptide release [54], including CGRP, and inhibition of pain signaling [53]. These new classes represent promising options for primary care clinicians and their patients [50]. However, data are limited to clinical trials and broader clinical experience will help inform on their safety profiles.

Rimegepant, a CGRP receptor antagonist in orally disintegrating tablet form approved in 2020, has shown efficacy in the acute treatment of migraine in adults in a pair of phase 3 studies [55,56]. In these studies, 20% to 21% of participants taking rimegepant reported pain freedom at 2 h compared to 11% to 12% in the placebo arm. The most common adverse events in these studies were nasopharyngitis, nausea, and urinary tract infection (Table 3).

Ubrogepant is an orally administered CGRP receptor antagonist approved in December 2019 for the acute treatment of migraine with and without aura in adults. In a pair of phase 3 studies, 19% to 21% in the 50-mg dose arm achieved pain freedom at 2 h, compared to 12% to 14% for placebo [57,58]. In one study, 21% in the 100-mg dose group achieved pain freedom at 2 h compared to 12% for placebo [58]. The most common adverse events in these studies were nausea, somnolence, dry mouth, and upper respiratory tract infection (Table 3).

Lasmiditan is a selective serotonin (5-HT_1F) receptor agonist (ditan) that was approved in 2019 by the FDA for the acute treatment of migraine with and without aura in adults. The vasoconstrictive effects of triptans have been attributed to their 5-HT_1B agonist activity. Lasmiditan has a high affinity for 5-HT_1 F receptors and no appreciable affinity for 5-HT_1B receptors. In phase 3 clinical trials, the proportion of participants who were pain free at 2 h was 29% for 50 mg, 28% to 31% for 100 mg, and 32% to 39% for 200 mg versus 15% to 21% for placebo [59,60]. The most common adverse reactions (≥2% and >placebo) were dizziness, fatigue, paresthesia, and sedation and were mostly mild-to-moderate in severity (Table 3). The central nervous system adverse events are believed to be more common with lasmiditan due to its central penetrance [61].

2.6. Antiemetics

Oral antiemetics such as metoclopramide or prochlorperazine can be used as adjuncts to analgesics to treat nausea associated with migraine attacks and may contribute to headache pain relief [24,62]. Administration of an antiemetic can also help counter gastroparesis, which impairs the bioavailability of oral treatments early in a migraine attack [63].

In clinical trials, 5% to 14% of participants reported pain freedom at 2 h after taking a combination of aspirin and metoclopramide [62]. A meta-analysis that included three studies that compared parenteral metoclopramide, chlorpromazine, and prochlorperazine suggested that metoclopramide was less effective in relieving pain and nausea [64]. Use of dopamine antagonists (e.g. metoclopramide) carry a risk of extrapyramidal adverse effects [30].

2.7. Medication overuse headache

Excessive use of medications for acute treatment of migraine can lead to medication overuse headaches (MOH), a situation where short-acting acute medications used over the course of time exacerbate underlying headache patterns and lead to more frequent and more intense attacks. Approximately one-half of people with more than 15 headache days per month have MOH [65]. Triptans, when used for 10 or more days a month, can lead to MOH. People who take analgesics daily or weekly are at increased risk for MOH, whether they take the analgesic for headache or for pain elsewhere [66]. Among all medications used for acute treatment of migraine, barbiturates, and opiates are the most likely inducers of MOH, followed by triptans, acetaminophen, and NSAIDs [66]. Using NSAIDs or simple analgesics for 15 or more days a month can lead to MOH, while using triptans, ergotamines, opioids, and combination analgesics for as few as 10 days per month can lead to MOH [2,65]. The lasmiditan prescribing information warns of the possibility of MOH [67]; however, studies with continuous dosing are not available to provide information about the likelihood of MOH with lasmiditan. Treating MOH requires withdrawal of the overused medication, and consideration for a bridge therapy and concurrent preventive therapy.

2.8. Neuromodulation devices

Several noninvasive devices designed to stimulate the nervous system with an electric current or magnetic field have been approved to treat and prevent migraine (Table 4). These include three types of devices approved for acute or preventive treatment of migraine: a single-pulse transcranial magnetic stimulator (TMS) [68], a transcutaneous supraorbital stimulator (tSNS) [69], and a noninvasive vagus nerve stimulator (nVNS) [70]. These devices apply electrical or magnetic stimulation to pain pathways, which is believed to modify neurotransmitters, disrupt cortical spreading depression, and/or modulate pain transmission [71]. Additionally, a remote electrical trigeminal nerve stimulation (REN) device is approved for the acute treatment of migraine [72]. The REN device is unique in that it provides conditioned stimulation to the peripheral nerves at the upper arm to inhibit pain in remote body regions.

Table 4. Noninvasive neuromodulation devices approved in the US

Device	Technology	Approved Use
SpringTMS® by eNeura	Transcranial Magnetic Stimulation	Acute or prevention in adolescents (12 years or older) and adults
Cefaly® Acute by Cefaly Technology Cefaly® Prevent Cefaly® Dual	Transcranial Neural Stimulation	Acute in adults with migraine or prevention in adults with episodic migraine
gammaCore Sapphire™ by electroCore	Vagus Nerve Stimulation	Acute or prevention in adults with migraine
Nerivio™ by Theranica	Remote Electrical Neuromodulation	Acute treatment in adults with episodic migraine

This table is based on information gathered from the device manufacturers and the FDA at www.eneura.com, www.cefaly.us, www.gammacore.com, theranica.com/nerivio/, and www.fda.gov/medical-devices/510k-clearances.

The FDA standards for approval of noninvasive devices is less rigorous than for medications. They must show evidence of efficacy and safety, but the studies tend to be smaller and may or may not include a sham (placebo) device [71]. Candidates for these therapies include patients not suited for or unwilling to use pharmacotherapy [1]. In addition, these treatments can be used as an adjunct to pharmacotherapy.

2.9. Treatment decision-making

Migraine is often managed in the primary care setting. In the United States, 14% of people with episodic migraine and 26% of people with chronic migraine visit their primary care physician at least once every three months [73]. Comparatively, visits to a neurologist or headache specialist were 3% for patients with episodic migraine and 14% for patients with chronic migraine. Thus, it is important for clinicians in the primary care setting to be familiar with the efficacy and safety profiles of acute treatments for migraine so that appropriate treatments can be offered to patients.

Ideally, effective acute treatment of migraine results in the complete elimination of headache pain and associated migraine symptoms, with a tolerable safety profile [1]. With increasing treatment options designed to target pathophysiologic mechanisms of migraine, treatment selection may become individualized to the patient and result in improved treatment efficacy, tolerability, and patient satisfaction [74].

Conversely, suboptimal or less effective treatment can lead to pain for a longer amount of time; chronification of migraine; more likelihood to have another attack; and increased risk for MOH [75]. It is important to consider the role of preventive therapy when a patient is consistently experiencing a suboptimal response to acute treatment or is requiring frequent use of their acute treatment.

It is also important to counsel patients on behavioral therapies, migraine disease education, and lifestyle modifications that can contribute to the management of migraine. Lifestyle modifications include following a healthy diet, getting adequate and restorative sleep, and regular exercise appropriate for the individual patient. The benefit of cognitive behavioral therapy, biofeedback, and relaxation therapy has been demonstrated in numerous studies to be an effective tool for the management of a migraine attack [1]. Advocacy organizations for people with migraine in the United States offer online resources for migraine education and behavioral strategies for migraine management (e.g. American Migraine Foundation [AmericanMigraineFoundation.org], Migraine Again [MigraineAgain.com], National Headache Foundation [Headaches.org]).

2.10. When to refer to a specialist

Most people with migraine can be treated in a primary care setting. However, sometimes a patient may need to be referred to a neurologist or other specialist in order to rule out other serious disorders. Comorbidities such as anxiety or depression may also require referral to a specialist [76].

According to the American Migraine Foundation [77], referral to a neurologist or headache specialist may be appropriate in the following cases:

• The patient is dissatisfied with the treatment regimen and has intolerable side effects

• Headaches often return after treatment

• The patient is pregnant, nursing, or trying to get pregnant and experiencing frequent or severe headache

• The patient experiences headache on 15 or more days per month

• The patient has recently experienced a headache that is significantly different from other headaches or one described as the ‘worst headache of your life’

3. Conclusion

Migraine is a common and disabling disorder with a substantial personal, social, and economic burden. Effective acute treatment requires the clinician to assess the patient, make a positive diagnosis, and then offer individualized therapy based on the patient’s medical history, comorbidities, and preferences as well as published clinical evidence. The mainstays for acute treatment of migraine include NSAIDs and analgesics, triptans, ergotamines, and combination therapies. There still exists an unmet need for acute treatment options because current therapies are not always effective, may have unwanted side effects, or are contraindicated for people with cerebro- or cardiovascular disease. Recently approved therapies including oral CGRP receptor antagonists, a 5-HT_1 F receptor agonist, and neuromodulation devices may help address this unmet need because they do not induce vasoconstriction. It is also important to counsel patients on lifestyle modifications and behavioral strategies that can aid with the management of migraine. For primary care clinicians, treating migraine requires keeping abreast of current guidance and keeping an open mind to the variety of treatment options.

Declaration of interest

W. Cooper has served as consultant or advisor to Alder Biopharmaceuticals, Amgen, Biohaven, Eli Lilly and Company, Theranica Bioelectronics, and Teva Pharmaceuticals. E. Doty, H. Hochstetler, and A. Hake are employees of Eli Lilly and Company and own stock in the company. V. Martin has served as speaker for Amgen, a consultant for Alder Biopharmaceuticals and Theranica Bioelectronics, and speaker and consultant for Allergan, Biohaven, Eli Lilly and Company, and Teva Pharmaceuticals.

A reviewer on this manuscript has disclosed that they have received consulting, speaking fees and travel grants from Allergan, Amgen, Bayer, Biogen, Cefaly, Genesis Pharma, GlaxoSmithKline, ElectroCore, Eli Lilly, Merck-Serono, Merz, Mylan, Novartis, Roche, Sanofi- Genzyme, Specifar and Teva. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Acknowledgments

Kent Steinriede, MS, CMPP, of Syneos Health, Morrisville, NC, provided writing and editing assistance Angela Lorio, ELS, of Syneos Health, provided editing services. Their services were funded by Eli Lilly and Company.