Migraine Headaches

Introduction

The current International Classification of Headache Disorders (ICHD-3) divides migraine into two major types: migraine without aura and migraine with aura. Migraine without aura – formerly also known as common migraine or hemicrania simplex – is described in the ICHD-3 as a recurrent headache disorder which manifests in attacks that last 4-72 hours. Migraine with aura is described as characterized by transient focal neurological symptoms that typically precede or sometimes accompany the headache. Typical characteristics of migraine headache are:

• Unilateral location
• Pulsating quality
• Moderate or severe intensity
• Aggravation by routine physical activity
• Associated with nausea
• Photophobia and/or phonophobia.

The pathogenesis of migraine was once thought to be due to primary vascular events, in which intracerebral vasoconstriction produced aura and reactive vasodilation would cause head pain. However, during the past two decades, research that focused on the physiologic causes of migraine has revealed a neurovascular etiology that includes neurochemical imbalances, the trigeminal system and meningeal blood vessels (Figure 3-1). The neurovascular theory thus proposes that migraine attacks are generated in the brain rather than in the vasculature. Briefly, first-order trigeminovascular neurons are inappropriately activated and sensitized, sending a nociceptive transmission to the brainstem, which activates second-order neurons. Third-order neurons in the thalamus are activated next, and the signals transmitted from there to the cortex, which contributes to the feeling of pain (Figure 3-1). The threshold for the initiation of cortical excitation is lowered due to neuronal hyperexcitability. Additionally, the trigeminovascular pathway parasympathetically (via the salivatory nucleus and the sphenopalatine ganglion) causes dilation of intracranial arteries (Figure 3-2). Although the details of the mechanism are unclear, it is understood that the dilation is effected by several signaling molecules, including pituitary adenylate cyclase–activating peptide (PACAP), vasoactive intestinal polypeptide and calcitonin gene-related peptide (CGRP); this last molecule is the target of several novel anti-migraine agents (see the Treatmentsection below).

Research has revealed parasympathetic influence in the production of peripheral and central sensitization during migraine through activating and/or sensitizing intracranial nociceptors. Once the migraine attack has started, central neurons can disperse information about the pain process without the need for further external stimuli. The head pain and other symptoms of migraine can be attributed to the trigeminal nerves which innervate intracranial and extracranial tissues. Studies have demonstrated that migraine pain radiates across the neural pathway, and the throbbing pain of migraine occurs early in the attack. This stage is followed by central sensitization and cutaneous allodynia within the referred pain area and finally extracephalic allodynia (Figure 3-2). Central sensitization is responsible for secondary hyperalgesia and allodynia in acute and chronic pain states.

In the past two decades, cutaneous allodynia was identified as a symptom of migraine, involving the scalp, face and extremities. This recognition can have significant implications in the treatment of migraine attacks. The definition of cutaneous allodynia is pain resulting from the application of a non-noxious stimulus (e.g., heat, cold, pressure) to normal skin. The symptoms of cutaneous allodynia may be described as discomfort on one side or both sides while shaving, combing the hair, or wearing glasses, contact lenses, earrings, or tight clothing. Because of its frequent occurrence in migraine attacks, the presence of cutaneous allodynia should be determined during the clinical evaluation of the migraine patient. Recognition of this manifestation of central sensitization will influence the choice of treatment, such as early intervention with the triptans. It will also impact on headache recurrence, consistency of response to triptans and development of chronicity of migraine.

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Diagnosis and Classification

Migraine is diagnosed based on the criteria defined in the ICHD-3. In general, a diagnosis of migraine requires at least two attacks for migraine with aura and five attacks without aura. There is a high heterogeneity of clinical features between patients and even between distinct attacks in a single patient.

As mentioned above, the two main types of migraine are migraine without aura and migraine with aura. The ICHD-3 diagnostic criteria for migraine without aura are shown in Table 3-1. Aura is a term that describes several symptoms that precede or occur together with the headache. These symptoms gradually develop over 5 to 20 minutes and usually last <60 minutes. Aura is most commonly visual – the classic type of visual aura is scintillating scotoma, which begins as a flickering light near the center of the visual field that may enlarge and block vision. Other types of sensory aura (e.g., paresthesia, facial numbness) may also occur, as may other symptoms, including language dysfunction and motor symptoms. In rare cases, hemiparesis may occur.

The ICHD-3 divides migraine with aura into migraine with typical aura (with or without headache), migraine with brainstem aura, hemiplegic migraine and retinal migraine – the diagnostic criteria for these subtypes are shown in Table 3-2. Approximately 5% of patients with migraine have chronic migraine, defined by ICHD-3 as headache that occurs on ≥15 days per month (and has migraine features ≥8 of those days) for more than three months. Although the term “chronic” is used to describe this disorder, it is better thought of as high-frequency migraine, as it may or may not persist for a very long time. The ICHD-3 diagnostic criteria for chronic migraine are shown in Table 3-3.

The ICHD-3 classification also includes several complications of migraine, including:

• Status migrainosus
• Persistent aura without infarction
• Migrainous infarction
• Migraine aura-triggered seizure.

Status migrainosus is a debilitating and unremitting attack of migraine that lasts for more than 72 hours. Persistent aura without infarction is defined as symptoms of aura which persist for at least one week without neuroimaging evidence of an infarction; with evidence of brain ischemia, the complication is considered a migrainous infarction. Finally, as the name suggests migraine aura-triggered seizure is defined as an epileptic seizure during an attack of migraine with aura, or within one hour after the attack.

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Clinical Features

Although not as common as tension-type headache, migraine affects ~15% of the global population and is highly morbid, being the second most common cause of disability worldwide. Up to 70% of migraine sufferers have a positive family history of migraine headaches. There is a gender preponderance in migraine with approximately 75% of migraine sufferers being female.

The onset of migraine usually starts during adolescence and the early 20s. Migraine tends to diminish in the fifth and sixth decades.

Headache triggers include:

• Stress
• Fatigue
• Oversleeping
• Fasting or missing a meal
• Vasoactive substances in foods
• Caffeine
• Alcohol
• Menses
• Changes in barometric pressure
• Changes in altitude.

Medications that may precipitate migraine include:

• Reserpine
• Nitrates
• Indomethacin
• Oral contraceptives
• Postmenopausal hormones.

Personality features of migraine patients are a topic of debate; perfectionism, rigidity, compulsiveness and neuroticism may be more common among patients with migraine. Migraine patients tend to build environments too complex to handle.

Migraines are usually unilateral headaches but may occur bilaterally or switch sides. They are recurring headaches with a median frequency of 1.5 attacks per month; about a quarter of patients have weekly attacks and chronic migraine is comparatively rare (5%). The typical duration of attack is 4 to 24 hours, although some attacks are more prolonged (up to 3 days).

Severity of pain varies from moderate to incapacitating. The pain is often described as throbbing or pulsating. Associated symptoms include:

• Nausea
• Vomiting
• Photophobia and/or phonophobia
• Facial pallor
• Vertigo
• Tinnitus
• Irritability.

The course of a migraine attack is today understood to include four distinct phases – prodrome, aura, headache and postdrome (Figure 3-3). Importantly, none of the phases are necessary for the diagnosis of migraine. For example, migraine without aura is more common than migraine with aura and even the headache phase may be missing, as in the ICHD-3 designation of “migraine with typical aura without headache.”

The first, prodrome phase occurs in ~80% of patients with migraine, and is characterized by specific symptoms occurring before headache onset (in migraine without aura) or aural symptoms (in migraine with aura). Prodromal symptoms – also called premonitory symptoms – typically occur 2-48 hours before the headache attack. Prodromal symptoms may include (in order of frequency):

• Scotomata (blind spots)
• Teichopsia (fortification spectrum)
• Photopsia (sparks or flashes of light)
• Visual and auditory hallucinations.

Other premonitory symptoms may precede an attack of migraine with or without aura. These symptoms include:

• Bursts of energy
• Fatigue
• Nausea
• Extreme hunger
• Speech dysfunction
• Cognitive impairment
• Nervousness.

The second phase – aura – occurs in about one third of patients with migraine, and as previously described in the Diagnosis and Classification section above, is characterized by transient focal neurological symptoms. Aural symptoms typically occur 5 to 60 minutes before the onset of headache pain.

The third phase – headache – lasts between 4 and 72 hours (or 2 and 72 hours in pediatric patients), and is characterized by 1) pain that is typically severe, unilateral, throbbing and aggravated with physical activity, and 2) at least 1 associated symptom (nausea, vomiting, photophobia, phonophobia).

The fourth phase – postdrome, also known as the recovery phase – is the final phase of a migraine attack. Like the other phases, the postdrome is characterized by specific symptoms which may occur a few hours up to 2 days following the headache phase. Postdromal symptoms occur in approximately 80% of patients with migraine, and may include:

• Asthenia (physical weakness)
• Fatigue
• Somnolence
• Cognitive dysfunction.

The time between migraine attacks is called the interictal period, and is by definition not a phase of a migraine attack. During the interictal period, patients are largely symptom-free. However, the brains of patients with migraine display several structural differences compared to brains of people without migraine, including decreased gray matter in pain processing regions, increased gray matter in the somatosensory cortex, and increased white matter lesions. Such structural differences are associated with functional differences, including enhanced nociceptive processing. Together, these anatomical and functional abnormalities are likely contributors to migraine-associated cortical hyperexcitability.

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Treatment

Migraine treatment can be divided into four types:

• General treatment measures
• Pharmacologic management:
  • Acute (abortive) therapy
  • Pain-relief measures
  • Prophylactic therapy.

General Treatment Measures

General treatment measures include:

• Maintain a regular sleeping schedule: Migraine attacks may be precipitated by fatigue or oversleeping. On weekends, holidays and during vacations, patients should awaken at the same time each day.
• Maintain a regular meal schedule: Migraine attacks may be triggered by missing a meal or fasting. Meals should be consumed at the same time daily, and the patient should eat breakfast at a regular time each day to avoid the weekend or holiday headache.
• Diet: Migraine patients may benefit from a tyramine-restricted diet and should avoid most foods containing vasoactive substances (Table 3-4). Migraine sufferers should also limit intake of caffeine-containing substances.
• Coping strategies: Stress may be impossible to avoid, but the patient may learn to handle stress and also to practice relaxation methods. The patient should learn to identify specific stressors and avoid these triggers. Progressive relaxation and breathing exercises may be of particular help.

The severity, frequency and impact on the patient’s daily life will influence the type of therapy to be selected. A proposed general 10-step approach to manage migraine is shown in Figure 3-4.

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Acute Therapy

For those patients with less than two headaches per month, acute therapy may be selected (Table 3-5). In the modern era, acute therapy options for migraine include:

• Nonsteroidal anti-inflammatory agents (NSAIDs), including cyclooxygenase-2 (COX2) inhibitors
• Triptans
• Gepants
• Lasmiditan.

The first-line option for acute migraine treatment are NSAIDs (typically acetylsalicylic acid, ibuprofen or diclofenac potassium). If 3 or more consecutive migraine attacks happen with insufficient response to a NSAID, triptans (with or without naproxen) are the second-line agents. Finally, if 3 or more consecutive attacks occur with triptan and naproxen therapy, gepants or lasmiditan should be considered.

Migraine attacks are caused by a simultaneous dysfunction of multiple functions in diverse anatomic sites in the central and peripheral nervous systems, accounting for the within- and inter-patient variability in attacks. Some of these sites and functions are shown in Figure 3-5, and represent potential therapeutic targets.

During the past four decades, research has suggested a relationship between serotonin (5-HT) and migraine. One theory proposes that migraine attacks are triggered by the release of 5-HT from the platelets. Another theory indicates that the release of 5-HT from perivascular terminals of putative serotonergic nerve fibers initiates an acute attack. Another precipitating event has been suggested—systemic metabolic changes in 5-HT metabolism. It is known that serotoninergic drugs, such as reserpine, can provoke a migraine attack. Sterile neurogenic inflammation has been suggested as the cause of migraine pain. Stimulation of the trigeminal ganglion in the rat results in the release of substance P and calcitonin-generated peptide, which produces neurogenic plasma extravasation, an event which can be blocked by the 5-HT₁ agonists.

Agents recognized as 5-HT agonists, such as triptans, ergotamine and DHE, have demonstrated efficacy in aborting migraine attacks and have variable affinity for the 5-HT_1A, 5-HT_1B, 5-HT_1D and 5-HT_1F receptors. Their antimigraine effect is exerted by a receptor-mediated neural pathway in both the central nervous system and the trigeminal nerve, where they block neurogenic inflammation. A novel 5-HT_1F receptor agonist, lasmiditan, has demonstrated therapeutic effect for acute treatment of migraine. Although the details of its mechanism of action are unknown, lasmiditan is highly lipophilic and crosses the blood-brain barrier affectively.

Repeated daily doses over an extended interval of any of these 5-HT receptor agonists may cause a rebound phenomenon. This should be distinguished by the clinician from a headache recurrence, which may present from 2 to 12 hours after one dose of the agent.

The origins of migraine, however, may be centered in the brain. A “spreading depression” has been shown to transverse the cortex to the brain stem in migraine attacks. Magnetoencephalographic studies have demonstrated brain stem activity in patients suffering from migraine attacks as opposed to nonmigraine pain. The trigeminal nerve and other cervical nerves are now thought to stimulate the vascular reaction of migraine described above (see Figure 3-1). The role of CGRP in migraine has been studied since the 1990s. This 37-amino acid neuropeptide is expressed in many discrete regions of the central and peripheral nervous system, including regions that regulate the cardiovascular system. In the context of migraine, CGRP also mediates neurogenic inflammation and modulates nociception. The levels of CGRP appear to be elevated in the jugular outflow of blood during a migraine attack, and have been detected in the serum and saliva during attacks. Finally, CGRP levels were shown to be reduced by triptans.

Thus, all available evidence points to an important role of this signaling peptide in migraine pathophysiology. Gepants – small molecules that target the CGRP receptor and thus inhibit the binding of CGRP and downstream signaling – have been developed in the last two decades and several have recently received FDA approval for the treatment of acute migraine. Monoclonal antibodies (mAbs) that target CGRP signaling have also recently been developed; however, since anti-CGRP mAbs have a half life of ~1 month, they are used for migraine prevention, while gepants, with a half life of hours, are typically used for acute treatment of migraine attacks.

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Nonsteroidal Anti-Inflammatory Agents

The NSAIDs are the preferred first-line option for migraine abortive therapy. These agents stabilize proteins and inhibit the formation of active prostaglandins from their precursors, inhibiting inflammation through their effects on:

• Chemotaxis
• Phagocytosis
• Lysosomal enzyme release
• Kinin generation.

Available NSAIDs include:

• Ibuprofen
• Diclofenac potassium
• Aspirin
• Naproxen sodium (appropriate as an add-on to triptans for second-line treatment).

COX₂ Inhibitors

Because of the efficacy of the NSAIDs in migraine abortive therapy, the use of a COX₂ inhibitor may be indicated. The NSAID-induced inhibition of COX₂ and COX₁ appears to correlate with clinical efficacy and toxicity, respectively. An NSAID with greater COX₂ selectivity offers the possibility of fewer adverse effects. For migraine abortive therapy, we have used celecoxib.

Some COX₂ inhibitors have been linked to possible increased cardiac disturbances.

Triptans

The triptans are selective agents of 5-HT–like receptors, which are believed to be membranal “trigger” proteins with which 5-HT must interact to produce its various actions. These actions include dilation of certain cranial arteries or arteriovenous anastomoses by neurogenic dural plasma extravasation, or both mechanisms, which in turn will trigger a migraine. Triptans block these phenomena and have demonstrated efficacy in migraine abortive therapy. The chemical structures of the triptans are shown in Figure 3-6.

Research on central sensitization and cutaneous allodynia has influenced treatment options in migraine. Data have indicated that migraine agents used to prevent central sensitization can decrease the pain, although it cannot reverse it. Focus should be on administering treatment early after the onset of migraine pain with the goal of preventing intracranial hypersensitivity and the resultant cutaneous allodynia. The triptans have been noted to be effective in aborting migraine pain prior to the onset of central sensitization but are less effective once allodynia has been established.

Triptans are appropriate as second-line therapy (after NSAIDs) for patients with episodic or intermittent migraine, both with and without aura, regardless of attack severity. These agents are not appropriate for patients with daily headaches.

Studies have involved over 236 million triptan doses worldwide, which included treating more than 88,000 patients with 300,000 migraine attacks and 2000 healthy volunteers. We now also benefit from over three decades of experience with the triptans, and it has been demonstrated that triptans are well tolerated and have an acceptable risk-benefit ratio. Significant cardiovascular and cerebrovascular events are rare but have been observed. Used appropriately, including adhering to the prescribing recommendations, triptans are essential to the treatment of migraine. The clinical pharmacology of the available triptans is shown in Table 3-6.

Each of the triptans has been evaluated in studies in which headache response was defined as reduction of pain from severe or moderately severe to mild or no headache. Table 3-7 lists the response rates to the available triptans based on the clinical trials submitted to the Food and Drug Administration (FDA) for approval of the medications. Patients were instructed to treat a moderate to severe migraine headache. In most studies, associated symptoms (nausea, photophobia and phonophobia) were assessed at baseline and 2 hours after triptan administration. The estimated probability of the patient taking a second dose or other medication for migraine over the 24 hours following the initial dose of a triptan is shown in Figure 3-7. The significance of early treatment with the triptans has been demonstrated in research on the association of these agents with cutaneous allodynia. Migraine attacks have been consistently effectively managed when the triptan treatment was initiated as early as possible in an attack and cutaneous allodynia has not been established. It has been suggested that the patient should be educated to identify the signs of skin hypersensitivity, a hallmark of cutaneous allodynia.

As stated in the previous section, repeated doses of these agents on consecutive days may produce a rebound phenomenon and the triptans should not be used as a daily medication. If a patient is experiencing a 2-day headache, use of the triptan on consecutive days would be permissible. However, the triptans should be limited to twice-weekly use. The triptans should not be used in patients with concomitant ischemic heart disease, Prinzmetal’s angina, or basilar or hemiplegic migraine. Although no data are available, concomitant use of a triptan with a monoamine oxidase inhibitor (MAOI) is permissible but should be undertaken cautiously. Also, for a patient with a known sensitivity to one triptan, he or she should not be switched to another triptan.

Limitations of some triptans include the presentation of chest symptoms (which may or may not indicate cardiac ischemia due to vasoconstriction of coronary arteries), recurrence of the headache within 24 hours after initial successful treatment of an attack and in a small number of patients, abuse of the agent possibly due to a rebound phenomenon.

The triptans should not be prescribed for patients with uncontrolled hypertension since these agents may cause increases in blood pressure. The triptans should never be used concomitantly with ergotamine preparations.

For patients with risk factors predictive of coronary artery disease, initial exposure to a triptan is best undertaken in a clinician’s office or emergency department. This allows for careful observation of those individuals with a high potential for unrecognized coronary disease, such as postmenopausal women and men over age 40. Risk factors for coronary artery disease include:

• Hypertension
• Hypercholesterolemia
• Obesity
• Diabetes
• Smoking
• Strong family history.

An electrocardiogram (ECG) should be performed in patients presenting with symptoms consistent with angina in order to rule out ischemic changes.

Because the triptans are migraine-specific, these agents can be effective in the headache phase of the migraine attack and can relieve the associated symptoms such as nausea, photophobia and phonophobia. Although the triptans are similar, each is slightly different; thus if one triptan does not work, the patient should try using another of these drugs. Before determining its efficacy, each triptan should be tried for at least three different episodes.

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Sumatriptan

The subcutaneous form of sumatriptan (Imitrex) was the first triptan introduced in 1991. In controlled clinical trials involving over 1000 patients experiencing moderate or severe migraine pain, onset of relief after parenteral sumatriptan administration started as early as 10 minutes postdose. Headache relief was achieved in 70% of patients within 1 hour of a single 6-mg subcutaneous dose of sumatriptan.

In three randomized, double-blind, placebo-controlled studies of oral sumatriptan, results in headache response, as well as relief of associated symptoms, were assessed up to 4 hours after dosing. In all three trials, the percentage of patients achieving headache response 2 to 4 hours after receiving oral sumatriptan was significantly greater than in the placebo group. In one of the three studies, a significantly greater response was demonstrated at 2 hours postdose in the 50-mg (50% to 61%) and 100-mg (56% to 62%) groups when compared with the 25-mg group (52%). The placebo group at 2 hours ranged from 17% to 27%. No statistical significance was noted between the 50-mg and 100-mg groups. At 4 hours postdose, the range for 25 mg was 65% to 70%, 50 mg was 68% to 78%, 100 mg was 71% to 79% and placebo was 19% to 38%. In those patients complaining of nausea, photophobia and phonophobia at baseline, a lower incidence of these symptoms was noted at 2 hours postdose of sumatriptan.

In five studies utilizing the market formulation and recommended dosing regimen of sumatriptan nasal spray, the percentage of patients achieving headache response 2 hours postdose was significantly greater than in the placebo group. In all studies, doses of 10 mg and 20 mg were compared with placebo. In the 10-mg group, the response rate ranged from 43% to 46%; in the 20-mg groups, the rate range was 55% to 64%; and in the placebo groups, the range was 25% to 36%. There was a significantly higher response in the 20-mg groups as compared with lower-dose groups of 5 mg (45% to 49%) and 10 mg. For migraine-associated symptoms that were present at baseline, there was a lower incidence 2 hours following administration of sumatriptan nasal spray.

Certain precautions are observed with sumatriptan because it is the only triptan available for parenteral administration. Because of its potential to cause coronary vasospasm, sumatriptan should never be administered intravenously. Also, it should not be given subcutaneously in patients with:

• Ischemic heart disease (or presenting with symptoms or signs consistent with ischemic heart disease)
• Prior history of myocardial infarction
• Documented silent ischemia
• Prinzmetal’s angina.

Adverse events reported by ≥2% of patients taking oral sumatriptan compared with placebo are listed in Table 3-8. In the controlled clinical trials, sumatriptan oral tablets and nasal spray were well-tolerated. Side effects were mild and transient over all doses and did not produce prolonged effects.

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Sumatriptan/Naproxen Combination

Multiple pathogenic processes occur in migraine. A combination agent containing sumatriptan 85 mg/naproxen sodium 500 mg (Treximet) is available which targets multiple migraine mechanisms. Studies have demonstrated its efficacy over monotherapy with either agent.

In a study involving two replicate, randomized, double-blind, multicenter trials by Brandes and colleagues, the combined agent was compared with placebo, monotherapy with sumatriptan 85 mg and monotherapy with naproxen sodium 500 mg. This investigation demonstrated that in the acute treatment of migraine, the combined agent achieved superior efficacy to sumatriptan alone, naproxen sodium alone and placebo. In patients with headache relief at 2 hours, sumatriptan/naproxen sodium was superior to sumatriptan alone (65% vs 55%). For patients achieving 2 to 24 hours of sustained pain-free results, sumatriptan/naproxen sodium was superior to monotherapy with sumatriptan (25% and 16%). Versus sumatriptan alone, sumatriptan/naproxen sodium was superior for patients who required no rescue medications (78% vs 68%).

At 2 hours, sumatriptan/naproxen sodium was more effective than placebo in the absence of photophobia (58% vs 34%; P <0.001) and in the absence of phonophobia (61% vs 38%; P <0.001). There were no significant differences in sumatriptan/naproxen sodium vs placebo in the absence of nausea at 2 hours.

In another study, the use of the single combination agent sumatriptan/naproxen sodium was investigated for efficacy in early intervention of an acute migraine attack. The single agent, containing sumatriptan 85 mg with naproxen sodium 500 mg, was utilized in one of two identically designed, randomized, double-blind, parallel groups that were placebo-controlled. The subjects used the agent or placebo for a single migraine attack within 1 hour of the onset of head pain and while the pain was mild. The study involved 576 and 535 migraine sufferers in an intent-to-treat analysis. At 2 hours, 52% and 51% of the patients treated with active drug reported they were pain-free. In contrast, 17% and 15% of the placebo treated patients (P <0.0001) reported being pain-free. The significant pain-free responses were reported as early as 30 minutes and were maintained at 1 hour. The pain-free response was sustained from 2 to 24 hours.

Also, frequent migraine-associated symptoms, such as nausea, photophobia and phonophobia, were reported at significantly lower rates at 2 and 4 hours after treatment with sumatriptan/naproxen sodium. Other symptoms (sinus pain/pressure and neck pain/discomfort), which are associated with migraine to a lesser degree, also occurred at lower rates. Side effects, such as nausea and dizziness, were not significant. The authors concluded that the combination agent of sumatriptan/naproxen sodium was effective and well-tolerated in the early intervention therapy of acute migraine.

In one review, the authors noted that the combination of sumatriptan and naproxen sodium in a single agent is clinically advantageous due to a sustained pain-free response to the therapy.

Naratriptan

Naratriptan (Amerge) was evaluated in six randomized, double-blind, placebo-controlled studies. Four of these studies involved the recommended dosing regimen and were conducted as outpatient trials; three of the studies involved adult patients. Headache response was assessed up to 4 hours after dosing. When naratriptan was used in recommended dosage regimens in outpatients, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients on naratriptan 1.0 mg (42%) and 2.5 mg (48%) as compared with those using placebo (31%). In all studies, the responses to naratriptan 2.5 mg were greater than the responses to 1 mg. For patients with associated symptoms at baseline, there was a decreased incidence of these symptoms 4 hours following administration of naratriptan 1 mg and 2.5 mg compared with placebo.

There is no evidence that naratriptan 5 mg provides a better response than the 2.5-mg dose. In at least 2% of patients in the placebo-controlled studies, the same adverse events were reported and are listed in Table 3-9. Naratriptan was generally well-tolerated. Most side effects were mild and transient.

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Rizatriptan

The efficacy of rizatriptan (Maxalt) was demonstrated in four multicenter, randomized, placebo-controlled studies. In all studies, the percentage of patients achieving headache response 2 hours after administration of either 5-mg (60% to 62%) or 10-mg (67% to 77%) rizatriptan was significantly higher compared with those receiving placebo (23% to 40%). Migraine-associated symptoms were also lower at 2 hours in the rizatriptan groups compared with placebo.

Rizatriptan is also available in an orally disintegrating tablet (Maxalt-MLT). Two multicenter, randomized, placebo-controlled trials of Maxalt-MLT were undertaken in designs similar to those for Maxalt. When compared with placebo (28% to 47%), Maxalt-MLT in 5-mg (59% to 66%) or 10-mg (66% to 74%) doses was significantly more efficacious. Maxalt-MLT also significantly decreased the associated symptoms at 2 hours postdose compared with placebo.

Adverse events that were reported after a single dose of rizatriptan are listed in Table 3-10. Rizatriptan was generally well-tolerated, and the side effects were mild in intensity and transient. There is evidence that rizatriptan 10 mg may provide a greater effect than the 5-mg dose. There is a higher incidence of side effects with the 10-mg dose.

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Zolmitriptan

In five randomized, double-blind, placebo-controlled studies of zolmitriptan (Zomig), the 1-mg and the 2.5-mg doses were used in two trials and the 5-mg dose in four trials. All studies used the marketed formulation. Headache response was evaluated at 1, 2 and, in some studies, 4 hours after dosing. From baseline, associated symptoms were assessed. Headache response at 2 hours postdose was significantly greater in the zolmitriptan groups than the placebo groups. In the 1.0-mg group, the efficacy range was 27% to 50%; for 2.5-mg, the range was 62% to 65%; for 5-mg, the range was 59% to 67%; and the placebo range was 16% to 44%. No statistically significant difference was noted between the 2.5-mg and the 5-mg groups at 2 hours postdose. The associated symptoms were significantly decreased at 2 hours in the zolmitriptan groups as compared with placebo.

Zolmitriptan is also available as an orally disintegrating tablet (Zomig-ZMT). Its efficacy was evaluated in a randomized, placebo-controlled trial in a design similar to those of Zomig. At 2 hours following Zomig-ZMT 2.5 mg, 63% demonstrated headache response compared with 22% in the placebo group. Adverse events are listed in Table 3-11. Most of these events were mild and transient and did not produce long-lasting effects.

Zolmitriptan is also available for intranasal administration in a 5-mg dose.

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Almotriptan

Almotriptan (Axert) was evaluated in three multicenter, randomized, double-blind, placebo-controlled trials. Headache response was assessed 2 hours postdose. In patients receiving almotriptan 6.25 mg or 12.5 mg, the headache response was significantly higher than those in the placebo group. The response rate for 6.25 mg was approximately 55%; for 12.5 mg, the response rate was 57% to 65%; and for placebo, 33% to 40%. A higher percentage of relief was noted by the 12.5-mg group than the 6.25-mg group. Doses over 12.5 mg did not produce significantly better response.

The adverse avents that occurred in ≥2% of patients taking almotriptan are listed in Table 3-12. These events were mild and transient and did not lead to prolonged symptoms.

Research has demonstrated that almotriptan 12.5 mg was more effective than placebo and well tolerated in migraine patients who responded poorly to sumatriptan in the treatment of previous migraine attacks. Almotriptan provided better rates of sustained pain-free states and complete relief when compared with placebo. This study reiterated that if one triptan does not work for an individual patient, a trial with another triptan is indicated.

In another study, almotriptan 12.5 mg was evaluated with regard to its effect on pain intensity vs time of administration. The patients were instructed to use the study drug at earliest onset of headache pain (within 1 hour) vs treating the headache pain when the intensity was moderate or severe. Treating the headache early significantly decreased attack duration. Both types of treatment were more beneficial when treating mild to moderate pain than with severe pain intensity.

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Frovatriptan

The efficacy of frovatriptan (Frova) was evaluated in five randomized, double-blind, placebo-controlled outpatient trials. In two of these studies, patients were randomized to receive doses of frovatriptan ranging from 0.5 mg to 40 mg. The approved dose (2.5 mg) was evaluated in three studies. In all five placebo-controlled studies, headache response at 2 hours postdose was significantly higher in the frova­triptan group (37% to 46%) than in the placebo group (21% to 27%). Higher doses of frovatriptan (5 mg to 40 mg) showed no added efficacy but did increase the incidence of adverse events. Frovatriptan has the longest half-life of the available triptans, which may have a role in aborting prolonged migraine attacks.

The migraine-associated symptoms present at baseline decreased in the frovatriptan group as compared with placebo. Adverse events are listed in Table 3-13. The majority of side effects were mild or moderate and transient. The recommended dose is 2.5 mg orally with fluids. The total daily dose should not exceed three tablets.

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Eletriptan

Eletriptan (Relpax) has been evaluated in eight randomized, double-blind, placebo-controlled studies. In each of these studies, the 40-mg dose was assessed, and two studies included a 20-mg dose. Seven of the studies involved adult patients, and one study assessed the efficacy of eletriptan in adolescents. The percentage of patients achieving headache response in the seven adult studies was significantly greater than that with placebo. For the 40-mg dose, the response ranged from 53.9% to 65%. In the two studies with a 20-mg dose, the response was 47.3% to 54.3%. In the placebo group, the response ranged from 19% to 31.3%.

The most commonly reported adverse effects with eletriptan are listed in Table 3-14. Across all doses, eletriptan was generally well-tolerated, with side effects mild and transient. In clinical trials, if two doses of eletriptan were taken during 24 hours, the incidence of adverse events did not increase. In controlled clinical trials, a single dose of eletriptan 20 mg or 40 mg was effective. The maximum recommended single dose of eletriptan is 40 mg.

A study was undertaken to determine the efficacy of eletriptan in patients switching from barbiturate-containing analgesics, and specifically analgesics combined with butalbital. Eletriptan demonstrated improved efficacy at the 2-hour headache response rate, and an improved functional response rate at 2 hours. Patients reported few adverse effects, and the use of a triptan, unlike analgesics combined with barbiturates, is not associated with psychological and physical dependence.

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Gepants

Gepants are a class of small molecules that target the CGRP receptor and prevent the aberrant CGRP signaling that triggers vasodilation and contributes to migraine attacks. Of the four available gepants, three – ubrogepant, rimegepant and zavegepant – are a useful option for third-line acute migraine therapy. Atogepant is used in migraine prevention (see the prophylactic therapy section below).

Ubrogepant

The first gepant to receive FDA approval (December 2019), ubrogepant (Ubrelvy) is currently indicated for acute treatment of migraine with or without aura in adults. Ubrogepant is available in two tablet formulations: 50 mg and 100 mg. The recommended dose is 50 mg or 100 mg, followed if needed by another dose 2 hours or more after the first dose; the maximum 24-hour dose should not exceed 200 mg. The use of ubrogepant with concomitant strong CYP3A4 inhibitors is contraindicated.

The efficacy of ubrogepant for the acute treatment of migraine was tested in two phase 3, double-blind, multi-center clinical trials.

The first trial randomized (1:1:1) patients to one dose of ubrogepant 50 mg (n = 423 assessed for efficacy), ubrogepant 100 mg (n = 448 assessed for efficacy), or placebo (n = 456 assessed for efficacy) for the treatment of a single migraine attack. An optional second dose or rescue medication was allowed 2 to 48 hours after the first dose. Significantly more patients achieved the co-primary endpoint of freedom from pain 2 hours after treatment in the ubrogepant 50 mg (19.2%; P = 0.002) and 100 mg (21.2%; P <0.001) groups compared to the placebo group (11.8%). The other co-primary endpoint – absence of the most bothersome symptom (MBS) at 2 hours after treatment – was also achieved by significantly more patients in the ubrogepant 50 mg (38.6%; P = 0.002) and 100 mg (37.7%; P = 0.002) groups than in the placebo group (27.8%).

The second trial (ACHIEVE II) had a similar design, with identical co-primary endpoints. Patients were randomized (1:1:1) to treat a single migraine attack with either ubrogepant 50 mg (n = 464 assessed for efficacy), ubrogepant 25 mg (n = 435 assessed for efficacy), or placebo (n = 456 assessed for efficacy), with an optional second dose allowed 2 to 48 hours after the initial dose. A significantly greater proportion of patients in the ubrogepant 50 mg (21.8%; P = 0.01) and 25 mg (20.7%; P = 0.03) groups achieved freedom from pain 2 hours after treatment compared to those in the placebo group (14.3%). However, only ubrogepant 50 mg significantly increased the proportion of patients who achieved absence of the MBS (38.9%; P = 0.01) compared to the placebo (27.4%); the proportion in the ubrogepant 25 mg group was not significantly different (34.1%; P = 0.07).

Ubrogepant demonstrated a good safety profile in clinical trials. The most common adverse events in the first trial were nausea (ubrogepant 100 mg: 4.1%; ubrogepant 50 mg: 1.7%; placebo: 1.6%), somnolence (ubrogepant 100 mg: 2.5%; ubrogepant 50 mg: 0.6%; placebo: 0.8%) and dry mouth (ubrogepant 100 mg: 2.1%; ubrogepant 50 mg: 0.6%; placebo: 0.4%). In ACHIEVE II, the most common treatment-related adverse events were nausea (ubrogepant 50 mg: 1.8%; ubrogepant 25 mg: 1.9%; placebo: 1.8%) and dizziness (ubrogepant 50 mg: 1.4%; ubrogepant 25 mg: 1.7%; placebo: 1.2%).

Rimegepant

Rimegepant (Nurtec) was first approved by the FDA in February 2020 for the acute treatment of migraine.It is currently indicated in adult patients for both acute treatment of migraine with or without aura and for preventive treatment of episodic migraine (see the section on prophylactic treatment below). Rimegepant is available in the form of orally disintegrating tablets (ODT); each ODT contains 75 mg of rimegepant. The recommended dosage for acute migraine is 75 mg (one ODT) as needed. The maximum dose in a 24-hour period is 75 mg.

The efficacy of rimegepant for the acute treatment of migraine was assessed in a multicenter, double-blind trial which randomized (1:1) patients to receive either rimegepant 75 mg (n = 669 patients assessed for efficacy) or placebo (n = 682) to treat a single moderate or severe migraine event. Treatment with rimegepant resulted in a significantly higher proportion of patients who achieved freedom from pain (21% vs 11% with placebo; P <0.0001) or freedom from the MBS (35% vs 27% with placebo; P = 0.0009) two hours after taking the dose, which were the co-primary endpoints of the trial.

Rimegepant was generally safe and well tolerated in the acute treatment trial. The most common adverse events were nausea (rimegepant 2% vs placebo 0.4%), urinary tract infection (1% vs 0.6%) and dizziness (both groups ~1%).

Zavegepant

Zavegepant (Zavzpret) is the most recent gepant, receiving FDA approval in March 2023. Zavegepant is currently indicated for the acute treatment of migraine with or without aura in adults. Unlike the other gepants which are administered orally, zavegepant is available as a nasal spray; each device contains 10 mg of zavegepant and administers the entire dose in a single spray. The recommended dose of zavegepant is 10 mg once daily, which is also the maximum recommended dose.

The efficacy of zavegepant for the acute treatment of migraine was tested in two randomized, double-blind, multicenter trials of similar design. Eligible patients (adults with ≥1 year history of migraine with or without aura) were randomly assigned to either placebo or zavegepant and instructed to self-treat a single moderate or severe migraine attack. The co-primary endpoints in both trials were freedom from pain and freedom from MBS 2 hours after treatment.

In the first trial, patients were randomized (1:1) to either the placebo (n = 646) or zavegepant 10 mg (n = 623). Zavegepant was superior to the placebo with respect to both the proportion of patients who achieved freedom from pain (24% vs 15%; P <0.0001) and freedom from the MBS (40% vs 31%; P = 0.0012).

The second trial randomized patients (1:1:1:1) to either the placebo (n = 401) or one of three zavegepant doses: 5 mg (n = 387), 10 mg (n = 391), or 20 mg (n = 402). Compared to the placebo, significantly more patients in the zavegepant 20 mg group achieved freedom from pain (23.1% vs 15.5%; P = 0.0055) and freedom from the MBS (42.5% vs 33.7%; P = 0.0094). This was also the case for the zavegepant 10 mg group, for both freedom from pain (22.5% vs 15.5%; P = 0.0113) and freedom from the MBS (41.9% vs 33.7%; P = 0.0155), but not the zavegepant 5 mg group (freedom from pain: 19.6% vs 15.5%; P = 0.1214; freedom from the MBS: 39.0% vs 33.7%; P = 0.1162).

Zavegepant spray showed a good overall safety profile in clinical trials. The most common adverse events in the two studies were taste disorders (zavegepant 18% vs placebo 4%), nausea (4% vs 1%), nasal discomfort (3% vs 1%) and vomiting (2% vs 1%).

Ditans

Ditans are a class of small molecules which are selective agonists of the 5-HT_1F receptors. This selectivity gives ditans an advantage over triptans because the 5-HT_1F receptor is not expressed in human coronary arteries; ditans are therefore not associated with cardiovascular adverse events. The first – and thus far, the only – ditan to receive FDA approval is lasmiditan. Together with the gepants, lasmiditan represents a third-line treatment option for the abortive treatment of migraine in patients who did not respond to first-line (NSAID) or second-line (triptan) therapy.

Lasmiditan

Lasmiditan (Reyvow) received FDA approval for the treatment of migraine in October 2019. Lasmiditan is currently indicated for the acute treatment of migraine with or without aura in adult patients; the prescribing information specifically states that it is not indicated for migraine prevention. Lasmiditan is available in the form of tablets in two dosage forms – 50 mg and 100 mg. The recommended dosage is 50, 100, or 200 mg to treat a single migraine attack. No more than one dose should be taken in any 24-hour period and patients should wait at least 8 hours after taking a dose before driving or operating machinery.

The efficacy of lasmiditan for the acute treatment of migraine was tested in two randomized, double-blind, multi-center trials.

The first trial randomized (1:1:1) adult patients to treat a single migraine attack with a placebo (n = 524), lasmiditan 100 mg (n = 503), or lasmiditan 200 mg (n = 518). The primary endpoint was the proportion of patients free of headache pain 2 hours after taking the study drug; this was achieved by 15.3% of patients in the placebo group and significantly more patients in the lasmiditan 100 mg (28.2%; P <0.001) and 200 mg (32.3%; P <0.001) groups.

The second trial had a similar design, also assessing the proportion of headache-free patients 2 hours after treatment as the primary endpoint. Eligible adult patients were randomized (1:1:1:1) to one of four treatment groups: placebo (n = 540), lasmiditan 50 mg (n = 556), lasmiditan 100 mg (n = 532), or lasmiditan 200 mg (n = 528). The proportion of patients who achieved the primary endpoint was significantly greater in the lasmiditan 50 mg (28.6%; P = 0.003), 100 mg (31.4%; P <0.001) and 200 mg (38.8%; P <0.001) groups than in the placebo group (21.3%).

Lasmiditan demonstrated good safety and tolerability in the two clinical trials. The most common adverse events in the two trials that were more common with lasmiditan than with the placebo included dizziness (9%, 15%, 17% and 3% with lasmiditan 50 mg, 100 mg, 200 mg and placebo, respectively), fatigue (4%, 5%, 6%, 1%), paresthesia (3%, 7%, 9%, 2%), sedation (6%, 6%, 7%, 2%), nausea and/or vomiting (3%, 4%, 4%, 2%) and muscle weakness (1%, 1%, 2%, 0%). Because lasmiditan may cause adverse events that impair wakefulness and attention, patients should not drive or operate machinery for a minimum of 8 hours after taking lasmiditan, even if they are feeling well.

Other Agents

A number of other, older agents, now largely fallen out of favor due to the availability of triptans, gepants and lasmiditan, are still available as fall-back options for the acute treatment of migraine.

Ergotamine Tartrate Preparations

Ergotamine tartrate preparations are vasoconstrictors that have been used in migraine abortive therapy for over 50 years, but their use has declined dramatically in recent years due to the availability of agents with a better safety profile. These agents are available for oral administration in combination with caffeine (Cafergot). Ergotamine is also available for sublingual administration (Ergomar). It is no longer available in the United States in the parenteral or rectal form. An adequate dose should be taken as early as possible in the attack to achieve a maximum response.

To prevent ergotamine rebound headaches or ergotism, care should be taken to remain within the limits of recommended dosage. Ergotamine tartrate should not be used in patients with:

• Cerebrovascular disease
• Cardiovascular disease
• Peripheral vascular disease
• Severe hypertension
• Ischemic heart disease
• Sepsis
• Renal disease
• Hepatic disease
• Pregnancy.

Ergotamine should be used cautiously in patients with:

• Peptic ulcer
• Recent infection.

Dihydroergotamine Mesylate

Dihydroergotamine mesylate (DHE 45) has also been used safely and effectively in the abortive therapy of migraine for over 50 years; however, it has also largely been displaced in the migraine treatment armamentarium by more novel agents. In addition to the 5-HT_1D receptor, DHE is also potent at a number of other biogenic amine receptors. Unlike ergotamine tartrate, DHE is associated with less nausea and is more of a venoconstrictor than an arterial vasoconstrictor. DHE can also be used to help “detox” patients who are ergotamine-dependent.

Dihydroergotamine is available in 1 mg/mL ampules for parenteral administration (intramuscular [IM], subcutaneous, intravenous [IV]). Onset of action occurs within 15 to 30 minutes after IM injection and continues for 3 to 4 hours. Given IV, DHE produces less nausea than ergotamine. In patients with intractable migraine, DHE given in repetitive IV doses has been successful. DHE 0.5 mg given IV push, over 2 to 3 minutes, in combination with an antiemetic (such as metoclopramide 10 mg) and repeated every 8 hours for 3 days has shown efficacy in the treatment of intractable migraine. Ondansetron 8 mg may also be used with DHE.

simplest route, it may not be indicated in the 70% of patients with migraine who experience associated nausea and vomiting.

Intranasal DHE (Migranal)

A more acceptable form of administration, intranasal DHE, is also approved. For those patients using oral preparations of 5-HT receptor agonists and requiring increasing doses or who are considered treatment failures with the 5-HT receptor agonists, DHE nasal spray may be a viable alternative.

Due to its vasoconstrictive properties, DHE is contraindicated in patients with:

• Peripheral vascular disease
• Coronary heart disease
• Severe hypertension
• Impaired hepatic or renal function
• Sepsis
• Pregnancy
• Hypersensitivity.

Isometheptene Mucate

In patients who cannot tolerate ergotamine or in whom these drugs are contraindicated, isometheptene mucate may be effective. Similar to ergotamine, isometheptene has cerebral vasoconstrictive actions.

Phenothiazines

The phenothiazines have been used effectively in the emergency department setting for the abortive treatment of acute migraine. Their efficacy is attributed to their antinauseant and sedative effects. In addition, their dopaminergic and adrenergic actions may provide specific mechanisms for aborting migraine. The phenothiazines used in migraine abortive therapy include:

• Chlorpromazine
• Prochlorperazine.

Intranasal Lidocaine

One report has suggested the use of intranasal lidocaine as a viable agent for the abortive treatment of an acute migraine attack. A 50% reduction in headache was noted by 55% of patients treated with lidocaine. Relapse was common and occurred early after treatment, but in this author’s clinical experience, this treatment has particularly demonstrated significant benefit.

Pain Relief

Complete resolution of the attack may not be achieved by abortive therapy, and analgesics may be indicated. These agents include:

• Aspirin
• Acetaminophen
• Ibuprofen
• Naproxen sodium
• Ketoprofen
• Combination agent of aspirin, acetaminophen and caffeine
• COX₂ inhibitors
• Narcotic analgesics
• Antiemetics
• Transnasal butorphanol
• Cold packs.

Aspirin, Acetaminophen and Caffeine

A combination of aspirin, acetaminophen and caffeine (Excedrin Migraine) was the first over-the-counter (OTC) preparation to receive approval for this indication. This combination agent is suggested for the acute treatment of mild-to-moderate headache without associated vomiting and disability.

OTC NSAID preparations have also been approved for relief of migraine pain and include Advil Migraine and Motrin Migraine.

Overconsumption of these analgesics, particularly OTC analgesics containing caffeine, can produce serious side effects. Withdrawal from caffeine-containing drugs may trigger the caffeine-withdrawal headache. These drugs should be avoided in patients with frequent migraine attacks.

NSAIDs/COX₂ Inhibitors

Celecoxib has been used effectively for migraine pain relief. The most common side effects are GI symptoms (ie, dyspepsia, abdominal pain). In a small study of patients previously responsive to indomethacin, a COX₂ inhibitor was effective in decreasing or abolishing the pain of an acute attack.

A parenteral form of NSAID is available: Ketorolac (Toradol) is advantageous since it offers a parenteral analgesic that:

• Is non-narcotic
• Is nonhabituating
• Has a low side effect profile.

Ketorolac is administered in doses of 60 mg IM.

Narcotic Analgesics

The use of narcotic analgesics, preferably administered parenterally, is acknowledged to be effective for pain relief. As with other pain syndromes, these drugs should not be used in patients with frequently occurring migraine attacks. Narcotic analgesics used in relief of acute attacks include:

• Codeine
• Meperidine
• Methadone.

Antiemetics

Antiemetics are typically used parenterally or rectally due to the associated symptoms of nausea and vomiting. The phenothiazines are also useful for their sedative action in relieving the symptom complex present in an acute migraine attack. These drugs include:

• Promethazine (Phenergan)
• Chlorpromazine
• Prochlorperazine.

Some antiemetics have little sedative effect, including:

• Metoclopramide (Reglan)
• Ondansetron.

Metoclopramide, a 5-HT₃ receptor agonist, has been shown to enhance the absorption of oral medications and has been used effectively in combination with DHE IV. Metoclopramide will occasionally cause nervousness and tremor. Ondansetron is a serotonin 5-HT₃ receptor antagonist with effects on both peripheral and central nerves. It is well tolerated with few side effects, which include dizziness and constipation.

Transnasal Butorphanol

Transnasal butorphanol is a synthetic mixed agonist-antagonist opioid analgesic that was initially available for parenteral administration. Its quick absorption via the transnasal route is enhanced by its lipophilic nature. The highly vascular nature of the nasal mucosa renders it conducive to rapid intake and absorption of agents via the transnasal route. Caution should be exercised with its use in any patient with daily headache since habituation can occur.

Cold Packs

Cold packs have been used for many years by migraine patients. The use of ice bags or commercially manufactured ice packs, along with pressure, may reduce the pulsating pain associated with acute migraine attacks.

Prophylactic Therapy

Advances in migraine prophylactic (preventive) therapy have progressed at a slower pace than those associated with acute migraine therapy. The introduction of agents that block CGRP – gepants and CGRP receptor-directed mAbs – represents a major recent advance in prophylactic therapy.

For those patients experiencing more than two migraine attacks per month, prophylactic therapy may be considered. Prophylactic therapy is also indicated for patients complaining of attacks lasting for several days per week or of a degree of severity that critically impacts on the patient’s daily life. Several agents have been used successfully in migraine prophylaxis (Table 3-15):

• β-Blockers
• Anticonvulsants
• Angiotensin II-receptor blockers
• Calcium channel blockers
• Antidepressants
• Botulinum toxin
• CGRP inhibitors
• NSAIDs.

Beta Blockers

Beta blockers (β-blockers) have been used successfully in the preventive treatment of migraine headaches, and several are now considered a first-line option for prophylaxis. It is suggested that those β-blockers that do not possess intrinsic sympathomimetic activity (ISA) are more effective than those β-blocking agents that do possess ISA. β-blockers that are used in migraine prophylaxis include:

• Atenolol
• Bisoprolol
• Metoprolol
• Nadolol
• Propranolol.

Propranolol is the agent of choice in migraine prophylaxis and is FDA-approved for this indication. It is especially useful in migraine patients with concomitant:

• Hypertension
• Angina pectoris
• Thyrotoxicosis.

Propranolol is contraindicated in patients with:

• Asthma
• Chronic obstructive lung disease
• Congestive heart failure
• Atrioventricular conduction disturbances.

This drug should be avoided in patients who are receiving concomitant therapy with:

• Insulin
• Oral hypoglycemics
• MAOIs.

The usual dosage is 20 mg to 40 mg four times per day. A long-acting form of propranolol is available for once-a-day administration (80-160 mg). This preparation enhances patient compliance.

In selecting the appropriate β-blocker for migraine prophylaxis, it should be noted that the nonselective β-blockers have been used more successfully in migraine therapy than the cardioselective β-blockers. Also, if the patient has been refractory to two or more β-blockers, treatment with another β-blocker should not be attempted.

Nadolol, a nonselective β-blocker that is devoid of ISA, has demonstrated efficacy in migraine. Atenolol, bisoprolol and metoprolol are cardioselective β-blockers that have been used effectively in migraine. These drugs may be used for migraine patients with concomitant asthma.

Anticonvulsants

Although a number of anticonvulsants or antiepileptic drugs have been tried in treating headache, only two have proven to be consistently effective and well-tolerated through multiple clinical trials. One of these – topiramate – is considered a first-line option for the prophylactic treatment of migraine, while the other – divalproex sodium – can be a useful second-line option. These agents are believed to act to reduce the brain’s sensitivity for the development of migraine as well as stabilizing neural pain pathways in the brain stem.

Divalproex sodium (Depakote) has been used for over 30 years in migraine treatment. It is available as a direct-release tablet and as an extended-release formulation to improve compliance and reduce adverse events. Typically, the direct-release form is given twice per day, although a once-daily dose at bedtime has been used successfully with potentially better tolerability. The dosage is 250 mg to 750 mg twice daily. The extended-release formulation is taken once a day, usually at doses of 500 mg to 1500 mg at bedtime. Each extended-release tablet delivers about 87% of the divalproex dose. The most common side effects are tiredness, nausea, weight gain, tremor and hair loss.

Bedtime dosing and the use of 50-mg supplements of zinc and selenium appear to reduce the risk of hair loss as well as reduce the incidence of weight gain and daytime tiredness. Tremor may require dose reduction. Divalproex sodium increases the risk of spinal cord abnormalities in pregnancy. It should not be used in women contemplating pregnancy nor in those not utilizing contraception. Folic acid 4 mg per day may be taken by women to reduce the incidence of birth defects in general, although this has not been proven to be effective in the case of valproic acid exposure. In addition to prevention of migraine headache, divalproex sodium has been demonstrated to be an effective compound for preventive treatment of cluster headache and chronic daily headache.

In 2004, topiramate (Topamax) was approved by the FDA for the prevention of migraine in adults. In several large, controlled studies, topiramate demonstrated efficacy in migraine prophylaxis and was generally well tolerated. The ideal dose of topiramate for migraine prevention is 100 mg per day in divided doses. At this dose, migraine attacks were reduced by two in patients experiencing three to 12 attacks per month. Other factors were also improved at this dose, including days per month with migraine and decreased use of acute treatments. The efficacy was decreased with the 50-mg dosage, and significant adverse effects were reported at the 200-mg dose. The most commonly reported side effect, paresthesias, appears to be dose-related. Less frequent effects included cognitive dysfunction and weight loss, possibly due to decreased appetite and taste perversion. There is some data to suggest fetal toxicity in animal studies, and an increased risk of oral clefts in human babies exposed to topiramate in utero has been observed in pregnancy registries.

Starting dose is usually 25 mg per day, increasing by 25-mg increments up to 100 mg per day. Increasing potassium in the diet has reportedly reduced the incidence of paresthesias.

The impact of topiramate on health-related quality of life (HRQoL) was reviewed in a study by Diamond and associates. The Migraine-Specific Questionnaire (MSQ, version 2.1) was employed to determine the effect of topiramate 100 mg per day on both functionality and HRQoL. Three domains of the MSQ were assessed, including role restriction (the degree to which performance of daily activities is limited by migraine), role prevention (the degree to which performance of daily activities is interrupted by migraine), and emotional function (feelings of frustration and helplessness due to migraine). The results of the double-blinded, placebo-controlled, 26-week trial revealed that topiramate at the 100-mg daily dose significantly improved all three domains of the MSQ as compared with treatment with placebo. The HRQoL was significantly improved in patients for up to 6 months following treatment with topiramate.

The typical daily dose of topiramate in migraine is between 50 mg/day and 200 mg/day, with a target dose of 100 mg/day. As with divalproex sodium, it is recommended for twice daily dosing. The initial dose of topiramate is 25 mg once daily for a week and should be tapered upwards in 25 mg/week increments until a target dose of 100 mg/day or the most effective target dose is reached. Appropriate dosing and titration is important when initiating patients on topiramate therapy.

The most common side effects of topiramate compared with placebo as reported in the 100-mg dose trials are:

• Paresthesia
• Loss of appetite
• Diarrhea
• Weight loss
• Taste perversion.

Paresthesia was common but rarely led to discontinuation. It appears that increasing potassium in the diet or by additives may reduce the paresthesia. Cognitive changes have been observed in patients taking topiramate, with increased rates in the higher doses.

Patients on migraine preventive therapy should be given an adequate trial, based on drug tolerability, for up to 3 months before considering alternative therapies. Topiramate typically shows efficacy within the first month, with some patients demonstrating efficacy even earlier. Several small studies have suggested topiramate may be effective in the preventive treatment of cluster headache, trigeminal neuralgia and chronic migraine.

Angiotensin II-Receptor Blocker

The angiotensin receptor blocker candesartan, primarily used for the treatment of hypertension and heart failure, also has demonstrated efficacy for the preventive treatment of migraine – together with β-blockers and topiramate, it is an appropriate first-line option. In a 2014 head-to-head trial of candesartan and propranolol, the two agents were mutually non-inferior and superior to the placebo both with regard to number of monthly migraine days (candesartan: 2.95, propranolol: 2.91, placebo: 3.53) and proportion of responders (candesartan: 43%, propranolol: 40%, placebo: 23%). Candesartan is administered orally, at a daily dose of 16-32 mg and is contraindicated for concomitant administration with aliskiren.

Calcium Channel Blockers

Considering that the pathogenesis of migraine is partially vascular in etiology, the use of the calcium channel blockers with their suggested role in intracranial vasoconstriction may be appropriate for preventive therapy. The calcium channel blockers that have been used effectively in migraine include:

• Flunarizine
• Nimodipine
• Verapamil.

These agents have not received approval for the indication of migraine treatment. Research continues concerning their use in migraine therapy.

A 2019 systematic review and meta-analysis revealed that flunarizine reduces headache frequency by 0.4 attacks per 4 weeks, compared to the placebo and that its overall prophylactic efficacy is similar to propranolol.

Nimodipine has the highest marked selectivity for cerebral vasculature. The relative high cost of this drug has thwarted its popular prescribing.

Verapamil also has antiplatelet effects that add to its efficacy in migraine. This calcium channel blocker is noted for its long-term effects in decreasing the frequency, severity, and duration of migraine. The most commonly reported side effect associated with verapamil is constipation.

Two other calcium channel blockers have been investigated for use in migraine prophylaxis, but the results were not clinically significant:

• Diltiazem
• Nifedipine.

Antidepressants

Several antidepressants have been investigated in the past few decades for use in migraine prophylaxis. The efficacy of these drugs is believed to be independent of their antidepressant actions and may be due to possible analgesic effects. Antidepressants that have been used in migraine prophylaxis include:

• Tricyclic antidepressants (amitriptyline)
• MAOIs.

Although no robust evidence of its efficacy yet exists, oral amitriptyline at a daily dose of 10-100 mg, taken at night, is used in clinical practice and represent a good second-line option for the preventive treatment of migraine.

These drugs are discussed in Tension-Type Headaches/Coexisting Migraine and Tension-Type Headaches.

Anti-CGRP Agents

Anti-CGRP agents (i.e., drugs that block the interaction between the CGRP peptide and its receptor) are a relatively novel addition to the anti-migraine armamentarium. These drugs can be divided into two classes – mAbs against either the CGRP peptide (galcanezumab, fremanezumab, eptinezumab) or the CGRP receptor (erenumab) and small molecule inhibitors of the CGRP receptor (the gepants). The anti-CGRP mAbs are all approved by the FDA for the prophylactic treatment of migraine and represent effective third-line options. While most gepants are used in acute migraine therapy, two – rimegepant and atogepant – are also indicated for the preventive treatment of migraine, with atogepant being approved only for prophylaxis.

Rimegepant

Rimegepant (Nurtec) received FDA approval for the preventive treatment of episodic migraine in May 2021. Rimegepant is available as orally disintegrating tablets, each containing 75 mg of the active substance. The recommended dosage for the prevention of episodic migraine is 75 mg every other day. The maximum 24-hour dose is 75 mg.

The efficacy of rimegepant for the prevention of episodic migraine was tested in a multicenter, double-blind trial, in which patients with a history of migraine lasting at least one year were randomized (1:1) to receive either rimegepant 75 mg (n = 348 patients assessed for efficacy) or placebo (n = 347) every other day for 12 weeks. Patients underwent a 4-week observation period before initiating treatment. The primary endpoint of change in the mean number of migraine days from the 4-week observation period to weeks 9-12 was -4.3 days in the rimegepant group and -3.5 days in the placebo group (P = 0.0099), demonstrating the superiority of rimegepant.

In clinical trials for migraine prevention, rimegepant was generally safe and well tolerated. The most common adverse events were nasopharyngitis (rimegepant 4% vs placebo 2%), nausea (3% vs 1%), urinary tract infection (both groups ~2%), and upper respiratory tract infection (2% vs 3%).

Atogepant

Atogepant (Qulipta) received FDA approval in September 2021. Atogepant is currently approved for the preventative treatment of migraine in adults. It is available in tablet form in three dosage strengths: 10 mg, 30 mg and 60 mg. The recommended dose of atogepant is 10 mg, 30 mg, or 60 mg once daily for the prevention of episodic migraine, and 60 mg once daily for the prevention of chronic migraine.

The efficacy of atogepant for the preventative treatment of migraine was established in three randomized, double-blind, multicenter trials; two trials for episodic migraine and one trial for chronic migraine.

The two episodic treatment trials had a similar design, enrolling patients with a history of migraine of 1 year or longer, with 4-14 monthly migraine days (MMDs). The treatment phase lasted 12 weeks, and the primary endpoint was the mean change from baseline in the number of MMDs.

In the first trial, patients were randomized (1:1:1:1) to receive atogepant 10 mg (n = 214), 30 mg (n = 223), 60 mg (n = 222), or a matching placebo (n = 214) once daily. Atogepant demonstrated superiority over the placebo at all three doses, with a mean change from baseline of -2.5, -3.7, -3.9, and -4.2 days for the placebo, atogepant 10 mg, atogepant 30 mg and atogepant 60 mg, respectively (P <0.0001 for all comparisons).

The second trial randomized (2:1:2:2:1:1) patients to the placebo (n = 178) or one of the following five atogepant groups: 10 mg once daily (n = 92), 30 mg once daily (n = 182), 60 mg once daily (n = 177), 30 mg twice daily (n = 79), or 60 mg twice daily (n = 87). The mean change from baseline in MMDs was -2.9 days in the placebo group. All five atogepant groups were superior to the placebo, showing the following MMD changes from baseline: 10 mg once daily, -4.0 days (P = 0.024); 30 mg once daily (-3.8 days; P = 0.039), 60 mg once daily (-3.6 days; P = 0.039), 30 mg twice daily (-4.2 days; P = 0.0034), and 60 mg twice daily (-4.1 days; P = 0.0031).

The third trial of atogepant tested its efficacy in patients with a history of chronic migraine (defined per the ICHD-3 criteria). Eligible patients were randomized (1:1) to either the placebo (n = 259) or atogepant 60 mg once daily (n = 262), for a treatment course of 12 weeks. Like in the episodic migraine trials, the primary efficacy endpoint was mean change in the number of MMDs. Patients in the atogepant group demonstrated a significantly greater change from baseline in MMDs (-6.9 days; P <0.001) compared to those who received the placebo (-5.1), demonstrating the superiority of atogepant for the prevention of chronic migraine.

Overall, atogepant was well tolerated and exhibited a good safety profile in the three trials described above. The most common adverse events were nausea (placebo, atogepant 10 mg, atogepant 30 mg, and atogepant 60 mg: 3%, 5%, 6%, and 9%, respectively), constipation (2%, 6%, 6%, 8%), fatigue/somnolence (4%, 4%, 4%, 5%), decreased appetite (<1%, 2%, 1%, 3%), and dizziness (2%, 2%, 2%, 3%).

Erenumab

Erenumab (Aimovig) is a human IgG2 mAb that binds to and inhibits the activity of the CGRP receptor. First approved by the FDA in May 2018, it is currently indicated for the preventive treatment of migraine in adults. Erenumab is self-administered subcutaneously (SC), and is available in the form of a pre-filled syringe or autoinjector, with two dosage strengths: 70 mg and 140 mg. The recommended dosage is one 70-mg injection per month; a once-monthly injection of 140 mg may be beneficial for some patients.

The efficacy of erenumab for the preventive treatment of migraine was assessed in three randomized, double-blind, multi-center studies: two in patients with episodic migraine (defined as 4-14 MMDs) and one in patients with chronic migraine (defined as >15 monthly headache days with ≥8 MMDs).

The first trial randomized (1:1:1) adults with episodic migraine to receive the placebo (n = 319), erenumab 70 mg (n = 317), or erenumab 140 mg (n = 319) once monthly by SC injection, and assessed the mean change in the number of MMDs from baseline to months 4-6 as the primary endpoint. At months 4-6, the reduction in MMDs was significantly greater in both the erenumab 70 mg group (-3.2 days; P <0.001) and the erenumab 140 mg group (-3.7 days; P <0.001), compared to the placebo group (-1.8 days).

In the second trial, adults with episodic migraine were randomized (1:1) to either placebo (n = 288) or erenumab 70 mg (n = 282) once per month by SC injection. The primary endpoint was the mean change in MMDs at week 12. Erenumab treatment resulted in a mean MMD reduction of -2.9 days, significantly more than the placebo (-1.8 days; P <0.001).

The third trial assessed the efficacy of erenumab in adults with chronic migraine. Eligible patients were randomized (3:2:2) to placebo (n = 281), erenumab 70 mg (n = 188), or erenumab 140 mg (n = 187) every 4 weeks by SC injection. The primary endpoint was the mean change from baseline in MMDs during week 9-12. Compared to the placebo (-4.2 days) both erenumab 70 mg (-6.6 days) and 140 mg (-6.6 days) significantly reduced the number of MMDs (P <0.0001 for both).

Data from these three trials indicated that erenumab is well tolerated and has a favorable safety profile. In the first three months in clinical trials, the most common adverse events that were at least 2% more common with erenumab than with placebo included injection site reactions (6%, 5%, and 3% for erenumab 70 mg, 140 mg, and placebo, respectively), constipation (1%, 3%, and 1%) and cramps or muscle spasms (<1%, 2%, <1%).

Galcanezumab

Galcanezumab (Emgality) is a humanized IgG4 mAb which targets the CGRP ligand. It received initial FDA approval in September 2018 for the preventive treatment of migraine in adults, for which it is still indicated. It is also approved for the treatment of episodic cluster headache. Galcanezumab is administered by SC injection, typically by the patient. It is available in the form of a single-dose pre-filled 120 mg pen or 120 mg or 100 mg single-dose, pre-filled syringe. The recommended dose is 240 mg as an initial loading dose, followed by 120 mg once per month.

The efficacy of galcanezumab for the preventive treatment of migraine was tested in three randomized, double-blind, multi-center studies, of which two were in patients with episodic migraine and one was in patients with chronic migraine.

The first episodic migraine trial (EVOLVE-1) randomized (2:1:1) eligible adults to receive the placebo (n = 425), galcanezumab 120 mg (n = 210), or galcanezumab 240 mg (n = 208) once per month by SC injection; patients in the galcanezumab 120 mg group received a loading dose of 240 mg initially. The primary efficacy outcome was the change from baseline in the number of MMDs in the 6-month treatment period. Galcanezumab demonstrated superiority to the placebo (-2.8 days) at both the 120 mg (-4.7 days; P <0.001) and the 240 mg (-4.6 days; P <0.001) monthly dose.

The second episodic migraine trial (EVOLVE-2) had a similar design to EVOLVE-1, with the same primary endpoint. Eligible patients were randomized in a 2:1:1 ratio to placebo (n = 461), galcanezumab 120 mg (n = 231), or galcanezumab 240 mg (n = 223) once monthly by SC injection, with a first (loading) dose of 240 mg in the galcanezumab 120 mg group. Compared to the placebo group (-2.3 days), both the 120 mg (-4.3 days; P <0.001) and the 240 mg (-4.2 days; P <0.001) galcanezumab groups showed a significantly greater reduction from baseline in MMDs.

The third efficacy trial of galcanezumab, REGAIN, was performed in patients with chronic migraine. Although the patient population was different, the trial design of REGAIN was similar to the EVOLVE trials, with eligible patients randomized 2:1:1 to receive the placebo (n = 558) or galcanezumab at either the 120 mg (n = 278) or the 240 mg (n = 277) dose every month by SC injection. The primary endpoint was the mean change in MMDs in the three-month double-blind period. This was significantly greater with both galcanezumab 120 mg (-4.8 days; P <0.001) and 240 mg (-4.6 days; P <0.001) compared to the placebo (-2.7 days).

Overall, galcanezumab was safe and well tolerated in the clinical trials described above. The most common adverse event that was more common in the galcanezumab group by at least 2% compared to the placebo was injection site reactions (18% with galcanezumab 120 mg vs 13% with placebo; combined data from all three studies).

Fremanezumab

Fremanezumab (Ajovy) is a fully humanized IgG2Δa/kappa mAb that binds the CGRP ligand. Fremanezumab was initially approved by the FDA in September 2018, and is currently indicated for the preventive treatment of migraine in adults. Intended for SC self-injection, fremanezumab is available in the form of a pre-filled, single-dose (225 mg) syringe or autoinjector. The recommended dose of fremanezumab is 225 mg once monthly or 675 mg (three consecutive injections) once every three months.

Two randomized, double-blind, multi-center trials assessed the efficacy of fremanezumab for the preventative treatment of migraine – one each in patients with episodic and chronic migraine.

In the episodic migraine trial, eligible adult patients were randomized (1:1:1) to placebo (n = 290), fremanezumab 225 mg (n = 287), or fremanezumab 675 mg (n = 288). Patients in the placebo and fremanezumab 225 mg groups received a SC injection of the treatment they were randomized to once per month, while those in the fremanezumab 675 mg group received 675 mg of fremanezumab at baseline followed by monthly placebo injections. The primary endpoint was the change from baseline in the number of MMDs during the 12-week treatment period. Fremanezumab proved superior to the placebo (mean change in MMDs: -2.2 days) at both the 225 mg monthly dose (-3.7 days; P <0.001) and the single initial 675 mg dose (-3.5 days; P <0.001).

The chronic migraine trial had a very similar trial design, with the key difference that the primary endpoint was the change from baseline in the number of monthly headache days (MHDs), not MMDs, during the 12-week treatment period. Eligible adult patients were randomized (1:1:1) to placebo once monthly (n = 371), fremanezumab 225 mg once monthly (n = 375), or a single dose of fremanezumab 675 mg followed by monthly placebo (n = 375). The mean change in MHDs was significantly greater in both the fremanezumab 225 mg once monthly (-4.6 days; P <0.001) and the fremanezumab 675 mg quarterly (-4.3 days; P <0.001) group, compared to the placebo (-2.5 days).

Fremanezumab demonstrated a favorable safety profile in the two clinical trials. The most common adverse reaction occurring at least 2% more frequently in the fremanezumab groups than in the placebo groups was injection site reactions (43% in the monthly fremanezumab group, 45% in the quarterly fremanezumab group, and 38% in the monthly placebo group).

Eptinezumab

Eptinezumab (Vyepti) is a humanized IgG1 mAb that binds to the CGRP ligand. It received FDA approval in February 2020 for the preventive treatment of migraine in adults, and is currently approved for the same indication. Eptinezumab is administered by a healthcare provider as an intravenous (IV) infusion; it is available in single-dose (100 mg) vials. The recommended dosage is 100 mg every 3 months, although some patients may benefit from a 300 mg dose given every 3 months.

The efficacy of eptinezumab was tested in two randomized, double-blind, multi-center trials: one each for the preventive treatment of episodic migraine (PROMISE-1) and chronic migraine (PROMISE-2).Both trials were placebo-controlled, and had the same the primary endpoint of change from baseline in MMDs over weeks 1-12.

The PROMISE-1 trial randomized (1:1:1:1) eligible patients to receive placebo (n = 222), eptinezumab 30 mg (n = 223), 100 mg (n = 221), or 300 mg (n = 222) every 3 months by IV infusion. Although eptinezumab failed to achieve a statistically significant response at the 30 mg dose (according to the testing hierarchy), both the 100 mg (-3.9 days; P <0.0182) and the 300 mg (-4.3 days; P <0.0001) dose significantly improved the number of MMDs compared to the placebo (-3.2 days).

In PROMISE-2, eligible patients were randomized (1:1:1) to either placebo (n = 366), eptinezumab 100 mg (n = 356), or eptinezumab 300 mg (n = 350) given by IV infusion every 3 months. The number of MMDs was significantly reduced with both eptinezumab 100 mg (-7.7 mg) and eptinezumab 300 mg (-8.2 mg) compared to the placebo (-5.6 days).

Eptinezumab demonstrated a good overall safety profile in the PROMISE trials. The most common adverse reactions that were at least 2% more common with eptinezumab than with placebo were nasopharyngitis (6%, 8%, and 6% for eptinezumab 100 mg, 300 mg, and placebo, respectively) and hypersensitivity reactions (1%, 2%, and 0%).

Botulinum toxin

Botulinum toxin A (onabotulinumtoxinA) has been used for treatment of chronic migraine and chronic daily headaches. A 2018 Cochrane review concluded that onabotulinumtoxinA injection may reduce the number of MMDs by 2 compared to the placebo.

NSAIDs/COX₂ Inhibitors

The NSAIDs have been successfully used in migraine prophylaxis due to their effects on the prostaglandins and inhibition of inflammation. Several NSAIDs have been effective agents in migraine prophylaxis:

• Naproxen
• Aspirin
• Ketoprofen
• Tolmetin sodium
• Fenoprofen calcium.

Celecoxib is a COX₂ inhibitor that may cause less GI problems than other NSAIDs. In randomized, double-blind, multicenter studies, celecoxib demonstrated superiority over placebo in improving pain and inflammation in chronic pain disorders. It has a relatively safe side effect profile. Although some data are available, its efficacy has not been established for acute pain relief. For prophylactic therapy, celecoxib dosage is 100 mg to 200 mg twice daily.

Some COX₂ inhibitors have been linked to possible increased cardiac disturbances.

Cyproheptadine

Cyproheptadine is an antihistamine with mild-to-moderate antiserotonin activity. Cyproheptadine has been used successfully in childhood migraine although it has not demonstrated significant effects in adults with migraine. The usual dose for children is 4 mg at bedtime, and for adults, the dosage is 4 mg four times per day up to 32 mg per day. This drug has not received approval for this indication.

Biofeedback

The use of biofeedback in migraine treatment has offered an excellent adjunct to pharmacologic therapy and can be used in those patients unable to use medications. Biofeedback training traces its origins to the discipline of self-awareness. By using a monitoring device, the patient is taught to control autonomic functions that previously were considered strictly involuntary actions, including:

• Blood flow
• Blood pressure
• Pulse.

The training is achieved through the reinforcement of the correct response to a conditioned stimulus. Biofeedback training utilizes:

• Relaxation methods
• Imagery
• Self-hypnotic phrases.

The use of biofeedback training in headache therapy is focused on two types of biofeedback:

• Temperature training
• Muscle-relaxation electromyographic (EMG) training.

Temperature training focuses on the patient increasing the local peripheral temperature of the hand and, thereby, redirecting blood flow to that area. Autogenic phrases (Table 3-16) which focus on warmth and relaxation are practiced while the patient’s finger temperature is being monitored. Patients may also focus on warm images, such as sitting by a fire or on a beach, holding a hot cup of tea, etc. By utilizing these techniques at the first sign of a headache, it is hoped that the patient can abort the acute attack or, at least, decrease the severity and duration of the migraine headache.

Muscle-relaxation training involves the use of an EMG monitor that measures muscle tension over a particular area, such as the:

• Forehead
• Neck
• Shoulder.

Tension is measured via a high-pitched tone, which increases as the muscles tense and decreases as the tension is reduced. To achieve this decrease in tension, a set of progressive relaxation exercises are employed (Table 3-17). Patients are encouraged to practice these exercises at least twice daily to help them identify which muscles are being tensed at times of stress or during a headache. The use of EMG biofeedback at the time of an acute migraine hopefully will decrease the severity of the headache and possibly prevent attacks from occurring.

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Neurostimulation

Neurostimulation is another option for patients who cannot tolerate or who do not respond to pharmacological therapy. Neurostimulation manipulates the neural pathways involved in migraine through the application of electrical or magnetic impulses, with the goal of reducing pain. Both invasive and non-invasive methods of neurostimulation have been developed in recent decades, and neurostimulatory devices can be used both for acute and preventive treatment of migraine, for example by blocking the pathways responsible for attack generation (acute treatment) and by desensitizing them long-term (prophylaxis).

Neuromodulatory modalities that have been developed and FDA approved for the treatment of migraine include external trigeminal nerve stimulation (approved for both acute and preventive treatment), vagus nerve stimulation (approved for acute treatment), transcranial magnetic stimulation (approved for both acute and preventive treatment) and remote electrical neuromodulation (approved for acute treatment).

External trigeminal nerve stimulation (e-TNS) is applied via a supraorbital nerve stimulator worn on the forehead and currently marketed as the Cefaly device. In the ACME trial, the Cefaly device demonstrated efficacy in acute migraine treatment by reducing the pain intensity from baseline to a significantly greater level (-59%) compared to the sham device (-30%; P <0.0001) at 1 hour after attack onset. In a trial of its efficacy in the preventive treatment of migraine, daily use of the Cefaly device was shown to be superior to the sham device, significantly reducing the number of migraine days in third month of treatment compared to the 1-month run-in period (from 6.94 to 4.88; P = 0.023); the number remained the same in the sham group (from 6.54 to 6.22; P = 0.608).

Non-invasive vagus nerve stimulation (nVNS) is currently available in the form of a handheld device (the gammaCore) which is applied to the neck and delivers a low-voltage electrical signal to deliver neurostimulation to the cervical vagus. Its use in acute migraine treatment is supported by data from the PRESTO trial, which showed that nVNS delivered by the gammaCore device resulted in a higher proportion of patients that achieved freedom from pain compared to the sham device at both 30 minutes (12.7% vs 4.2%; P = 0.012) and 60 minutes after attack onset (21.0% vs 10.0%; P = 0.023).

Transcranial magnetic stimulation (TMS) is currently available in the form of the Cerena device, a handheld device that delivers individual magnetic pulses to the brain. Cerena was tested for use in acute migraine treatment, where in one trial it demonstrated superior pain-free response rates (39%) compared to the sham device (22%; P =0.0179). An open-label, observational trial has suggested a benefit for TMS in the preventative treatment of migraine.

Finally, remote electrical neuromodulation (REN) uses a wireless device (the Nerivio device) to deliver transcutaneous electrical stimulation in the upper arm; this induces endogenous analgesic activity and inhibits migraine pain. In the pivotal trial of the Nerivio device, active REN demonstrated superiority in achieving pain relief (66.7%) compared to sham REN (38.8%; P <0.0001).