Migraine Headache Treatment & Management

Migraine treatment involves acute (abortive) and preventive (prophylactic) therapy. Patients with frequent attacks usually require both. Measures directed toward reducing migraine triggers are also generally advisable.

Acute treatment aims to reverse, or at least stop, the progression of a headache that has started. Preventive treatment, which is given even in the absence of a headache, aims to reduce the frequency and severity of the migraine attack, make acute attacks more responsive to abortive therapy, and perhaps also improve the patient's quality of life. An overview of migraine treatment is shown in the image below.

Migraineurs should be screened for cardiovascular risk factors, which, if present, should be aggressively treated. Migraineurs with aura should also be counseled on the increased risk of stroke with smoking and oral contraceptive use.

A neurologist, neuro-ophthalmologist, and/or neurosurgeon should be consulted as deemed clinically appropriate for the treatment of patients with migraine.

Emergency medical services personnel should transport patients in a way that minimizes visual and auditory stimulation. Once in the emergency department (ED), most patients should not receive opiate analgesics until a thorough neurologic examination can be completed by the responsible physician.

While the emergency physician must be able to identify patients with serious headache etiology, note that more than 90% of patients who present to the ED because of headache have migraine, tension, or mixed-type benign headache. Therefore, providing symptomatic relief should be a priority. Rest in a darkened, quiet room is helpful. Some patients find cool compresses to painful areas helpful.

Migraine-specific medications and analgesia are key elements of ED care. Although narcotics remain the most frequently administered medication for patients with migraine and for ED patients with headache, evidence suggests that they are potentially ineffective, and their use may lead to more prolonged ED stays. ^{[80, 81]}

Friedman et al found that nearly three quarters of ED patients with migraine or other primary headache reported headache recurrence within 48 hours of ED discharge; in this study, naproxen 500 mg and oral sumatriptan 100 mg provided comparable relief of post-ED recurrent migraine. ^[82]

Hospital admission for migraine may be indicated for the following:

• Treatment of severe nausea, vomiting, and subsequent dehydration

• Treatment of severe, refractory migraine pain (ie, status migrainosus)

• Detoxification from overuse of combination analgesics, ergots, or opioids

Patients should avoid factors that precipitate a migraine attack (eg, lack of sleep, fatigue, stress, certain foods, use of vasodilators). Encourage patients to use a daily diary to document the headaches. This is an effective and inexpensive tool to follow the course of the disease.

Patients may need to discontinue any medications that exacerbate their headaches. If an oral contraceptive is suspected to be a trigger, the patient may be advised to modify, change, or discontinue its use for a trial period. ^[83] Similarly, when hormone replacement therapy is a suspected trigger, patients should reduce dosages, if possible. If headaches persist, consider discontinuing hormone therapy.

Biofeedback, cognitive-behavioral therapy, and relaxation therapy are frequently effective against migraine headaches and may be used adjunctively with pharmacologic treatments. Occipital nerve stimulators may be helpful in patients whose headaches are refractory to other forms of treatment.

In December 2013, the FDA approved the Cerena Transcranial Magnetic Stimulator (Cerena TMS), the first device to relieve pain caused by migraine headache with aura for use in patients aged 18 years and older. Users hold the device with both hands to the back of the head and press a button to release a pulse of magnetic energy that stimulates the occipital cortex. The recommended daily usage of the device is not to exceed one treatment in 24 hours. ^{[84, 85]}

Approval for the Cerena TMS was based on a randomized study of 201 patients with moderate to strong migraine headaches, in which 39% of the patients using the device were pain-free 2 hours following its use, relative to 22% of control patients (therapeutic gain: 17%). ^{[86, 87]} At 24 hours, nearly 34% of patients treated with the device were pain-free, compared with 10% of the control group.

Contraindications and precautions regarding the use of the Cerena TMS include the following: ^{[84, 85]}

• Do not use for patients with any metal in the head, neck, or upper body that is attracted by a magnet

• Do not use for patients with an active implanted medical device (eg, pacemaker, deep brain stimulator)

• Do not use for patients with suspected/diagnosed epilepsy or who have a personal or family history of seizures

Trials of nonpharmacologic management have produced average reduction in migraines of 40–50%, closely paralleling results obtained in trials of preventive drugs; however, the evidence base for nonpharmacologic and pharmacologic prevention remains limited. A 16-month randomized, placebo-controlled trial by Holryod et al found that the combination of beta-blocker therapy and behavioral management improved outcomes in patients with frequent migraines, while neither intervention was effective by itself. ^[88]

In January 2018, the FDA approved a vagus nerve stimulator (vNS) for the treatment of migraine pain in adults. The hand-held, noninvasive device was previously approved for treating episodic cluster headache pain. The prescription-only device is placed over the vagus nerve in the neck and releases a mild electrical stimulation to the nerve's afferent fibers. Approval was based on the Prospective Study of vNS for the Acute Treatment of Migraine (PRESTO) of 243 patients with episodic migraine. Significantly more patients in the nVNS group were pain free at 30 minutes (12.7%) compared to those who received sham treatment (4.2%). ^[89]

Another noninvasive neuromodulation device for the relief of acute migraine pain was approved by the FDA in May 2019. The device is worn on the upper arm and uses smartphone-controlled electronic pulses to relieve migraine through conditioned pain modulation. It is approved for acute migraine with or without aura in adults who do not have chronic migraine. ^[90]

Numerous abortive medications are used for migraine. The choice for an individual patient depends on the severity of the attacks, associated symptoms such as nausea and vomiting, comorbid problems, and the patient's treatment response. A stratified approach based on the patient's therapeutic needs has been advanced (see Table 1, below), as has a stepped-care approach.

Table 1. Abortive Medication Stratification by Headache Severity (Open Table in a new window)

Simple analgesics alone or in combination with other compounds have provided relief for mild to moderately severe headaches and sometimes even for severe headaches. ^[91] Acute treatment is most effective when given within 15 minutes of pain onset and when pain is mild. ^[92]

Analgesics used in migraine include acetaminophen, NSAIDs, and narcotic analgesics (eg, oxycodone, morphine sulfate). Propoxyphene (Darvon) was formerly used; however, propoxyphene products were withdrawn from the United States market in 2010, because this agent can cause prolonged PR interval, widened QRS complex, and prolonged QT interval at therapeutic doses. For more information, see MedWatch safety information, from the US Food and Drug Administration (FDA).

For more severe pain, 5-hydroxytryptamine–1 (5-HT1) agonists (triptans) and/or opioid analgesics are used, either alone or in combination with dopamine antagonists (eg, prochlorperazine [Compazine]). The use of abortive medications must be limited to 2–3 days a week to prevent development of a rebound headache phenomenon.

Intravenous metoclopramide is recognized as an effective therapy for acute migraine, but the optimal dosing has not been established. A study by Friedman et al determined that 20 or 40 mg of metoclopramide is no better in the treatment of acute migraine than 10 mg of the drug. ^[93]

A systematic review by Taggart et al found that ketorolac is an effective alternative agent for the relief of acute migraine headache in the ED. Ketorolac provides pain relief similar to that with meperidine (with less potential for addiction) and is more effective than sumatriptan; however, it may not be as effective as metoclopramide/phenothiazine agents. Side-effect profiles were similar with ketorolac and these other agents. ^[94]

Triptans and ergot alkaloids

The 2 categories of migraine-specific oral medications are triptans and ergot alkaloids. The specific ergot alkaloids include ergotamine and dihydroergotamine (DHE). ^[95] The specific triptans include the following: ^[96]

• Sumatriptan

• Rizatriptan

• Zolmitriptan

• Naratriptan

• Almotriptan

• Eletriptan

• Frovatriptan

Although the triptans share a common mechanism of action, they differ in the available routes of administration, onset of action, and duration of action. Routes of administration include oral, intranasal, subcutaneous, and intramuscular. Transdermal patches have proved effective for the delivery of sumatriptan, and one such product has received FDA approval. ^[97] The sumatriptan iontophoretic transdermal system (Zecuity, NuPathe Inc) was approved by the FDA in January 2013 for the acute treatment of migraine with or without aura in adults. The single-use patch also treats migraine-related nausea. In phase 3 trials involving 800 patients, the patches safely and effectively relieved migraine pain, migraine-related nausea, sonophobia, and photophobia within 2 hours of activation. ^[97]

The FDA approved a low-dose intranasal sumatriptan powder for migraine in January 2016. The product consists of 22 mg of sumatriptan powder and is the first breath-powered intranasal medication delivery system to treat migraines. Approval was based on data from phase 2 and phase 3 trials, reference data on the use of sumatriptan, and safety data from more than 300 patients. ^{[98, 99]}

All the triptans are most effective when taken early during a migraine and all may be repeated in 2 hours as needed, with a maximum of 2 doses daily. While different formulations of a specific triptan may be used in the same 24-hour period, only 1 triptan may be used during this time frame.

The longer-acting triptans (eg, frovatriptan, naratriptan) may be used continuously for several days (mini-prophylaxis) to treat menstrual migraine. Triptans should not be used more than 3 days weekly, to avoid transformed migraine and medication overuse headache.

The effectiveness and tolerability of triptans varies among patients. Lack of response or side effects experienced with one triptan does not predict the response to another.

The safety of triptans is well established, and the risk of de novo coronary vasospasm from triptan use is exceedingly rare. However, triptans should not be taken by patients with known or suspected coronary artery disease, as they may increase risk of myocardial ischemia, infarction, or other cardiac or cerebrovascular events.

The dose of rizatriptan must be reduced to 5 mg in patients taking propranolol. Sumatriptan, zolmitriptan, and rizatriptan are primarily metabolized by monoamine oxidase (MAO) and should be avoided in patients taking MAO-A inhibitors.

The first combination product of a triptan and an NSAID, Treximet, was approved by the FDA in 2008. Treximet contains sumatriptan and naproxen sodium. In 2 randomized, double-blind, multicenter, parallel-group trials, a significantly greater percentage of patients remained pain free for 24 hours postdose after a single dose of Treximet (25% and 23%) than after use of placebo (8% and 7%) or either sumatriptan (16% and 14%) or naproxen sodium (10%) alone. ^[100]

Patients with severe headaches need subcutaneous, intravenous, or oral formulations of an ergot alkaloid or triptan. Do not administer vasoconstrictors, such as ergots or triptans, to patients with known complicated migraine; treat their acute attacks with one of the other available agents, such as NSAIDs or prochlorperazine.

Ditans

In October 2019, the FDA approved lasmiditan for treatment of acute migraine with or without aura. Lasmiditan is the first of a new drug class, serotonin 5-HT1F receptor agonists (ie, ditans). Ditans do not elicit a vasoconstrictive effect, whereas triptans cause vasoconstriction via agonistic action at 5-HT1B/1D receptors. Lasmiditan’s approval was based on two phase 3 studies, SAMURAI and SPARTAN, as well as an open label GLADIATOR trial totaling nearly 4000 patients. Collectively, the trials found the percentage of patients that were free of migraine pain at 2 hours postdose ranged from 28.2% to 38.8% compared with placebo of 15.3% to 21.3% (p < 0.001-0.003). ^{[101, 102, 103]}

CGRP antagonists

Zavegepant intranasal (Zavzpret) is the first intranasal CGRP antagonist approved for adults to treat acute migraine with or without aura. Onset of action is rapid (approximately 15 minutes) and significantly more individuals remained pain free at 2 hours after treatment compared with placebo (P < 0.0001). ^[104]  

Ubrogepant (Ubrelvy) is the first drug in the class of oral calcitonin gene-related peptide (CGRP) antagonists approved for the acute treatment of migraine. Rimegepant (Nurtec ODT) is another oral CGRP antagonist approved in February 2020 for acute treatment.

Approval of ubrogepant was based on 2 randomized, double-blind, placebo-controlled trials (ACHIEVE I and ACHIEVE II). In total, 1439 adults with a history of migraine, with and without aura, received ubrogepant to treat an ongoing migraine. The percentage of participants who had freedom from pain at 2 hours in the ACHIEVE I study was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P = 0.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P < 0.001). ^[105]  The ACHIEVE II trial had similar results of 14.3% in the placebo group and 21.8% in the 50-mg ubrogepant group (p = 0.01). ^[106]

Rimegepant approval was supported by a phase 3 trial (n = 1186) of patients with moderate-to-severe migraines with a frequency of 2-8 attacks per month. The percentage of patients who were pain-free 2 hours after receiving rimegepant was 19.6% compared with and 12% in the placebo group (P < 0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after rimegepant was 37.6% compared with 25.2% for placebo (P < 0.001). ^[107]  A corroborating study (n = 1811) showed similar results. ^[108]  

Rimegepant was also approved for preventive treatment of episodic migraine in June 2021. The efficacy was demonstrated in a randomized, double-blind, placebo-controlled trial of a different oral dosage form of rimegepant. There was statistically significant 4.3-day reduction from baseline in monthly migraine days, compared with a 3.5-day reduction in the placebo group (n = 348; p = 0.01). Also, the percentage of patients who achieved at least a 50% reduction from baseline in moderate-to-severe monthly migraine days during Weeks 9 through 12 was 49.1% in the rimegepant group compared to the placebo group. ^[109]

Treatment of nausea and vomiting

Antiemetics (eg, chlorperazine, promethazine) are used to treat the emesis associated with acute migraine attacks. Patients with severe nausea and vomiting at the onset of an attack may respond best to intravenous prochlorperazine. These patients may be dehydrated, and adequate hydration is necessary.

Antiemetics are commonly combined with diphenhydramine to minimize the risk of akathisia. This combination of drugs has been found to be superior to subcutaneous sumatriptan when given intravenously in emergency patients. ^[110]

The following may be considered indications for prophylactic migraine therapy:

• Frequency of migraine attacks is greater than 2 per month

• Duration of individual attacks is longer than 24 hours

• The headaches cause major disruptions in the patient’s lifestyle, with significant disability that lasts 3 or more days

• Abortive therapy fails or is overused

• Symptomatic medications are contraindicated or ineffective

• Use of abortive medications more than twice a week

• Migraine variants such as hemiplegic migraine or rare headache attacks producing profound disruption or risk of permanent neurologic injury ^[5]

The goals of preventive therapy are as follows:

• Reduce attack frequency, severity, and/or duration

• Improve responsiveness to acute attacks

• Reduce disability

Currently, the major prophylactic medications for migraine work via one of the following mechanisms:

• 5-HT2 antagonism - Methysergide

• Regulation of voltage-gated ion channels - Calcium channel blockers

• Modulation of central neurotransmitters - Beta blockers, tricyclic antidepressants

• Enhancing gamma-aminobutyric acid-ergic (GABAergic) inhibition - Valproic acid, gabapentin

• Prevention of acetylcholine from presynaptic membrane – Botulinum toxin

• Calcitonin gene-related peptide (CGRP) inhibitors – Atogepant, eptinezumab, erenumab, fremanezumab, galcanezumab

Another notable mechanism is alteration of neuronal oxidative metabolism by riboflavin and reduction of neuronal hyperexcitability by magnesium replacement.

As with abortive medications, the selection of a preventive medication must take into consideration comorbid conditions and the side-effect profile (see Tables 2 and 3, below). Most preventive medications have modest efficacies and have therapeutic gains of less than 50% when compared with placebo. The latency between initiation of therapy and onset of positive treatment response can be quite prolonged. Furthermore, the scientific basis for using most of these medications is wanting.

Table 2. Preventive Drugs for Migraine (Open Table in a new window)

Table 3. Preventive Medication for Comorbid Conditions (Open Table in a new window)

Propranolol, timolol, methysergide, valproic acid, and topiramate (Topamax) have been approved by the FDA for migraine prophylaxis. However, a 2009 report suggested that long-term topiramate use in pediatric patients can cause metabolic acidosis and hypokalemia; the risk was deemed mild but statistically significant. ^[111]

Misra et al reported that in migraineurs with allodynia, prophylactic therapy with divalproex and amitriptyline were equally effective in relieving allodynia. In study patients, the presence of allodynia was related to the duration, severity, and frequency of migraine and to female gender. ^[112]

The NSAID naproxen sodium has also been used for prophylaxis. In controlled clinical trials, naproxen sodium demonstrated better efficacy than placebo and similar efficacy to propranolol. However, this agent should be reserved for short-term use, such as for menstrual migraines. ^[113] Tolfenamic acid has also been tried for migraine prophylaxis, but its clinical efficacy is not as good as that of beta blockers, valproate, or methysergide.

Of note, an open pilot study reported that quetiapine is effective for migraine prophylaxis in patients with migraine refractory to treatment with standard therapies (eg, atenolol, nortriptyline, flunarizine). The authors stated that controlled studies would be necessary to confirm their observations. ^[114]

Classes of prophylactic drugs

The classes of medications that are effective for migraine prevention include:

• Antiepileptics

• Antidepressants

• Antihypertensives

• Botulinum toxin

• Calcitonin gene-related peptide (CGRP) inhibitors

Antiepileptics, antidepressants, and antihypertensives may be considered initially since they are more affordable. For any of these initial prophylactic agents, prophylaxis should not be considered a failure until it has been given at the maximum tolerable dose for at least 30 days.

Antiepileptics

Antiepileptics are generally well tolerated. The main adverse effects of topiramate are weight loss and dysesthesia. ^[115] Valproic acid (Depakote) is useful as a first-line agent. It is a good mood stabilizer and can benefit patients with concomitant mood swings. However, it can cause weight gain, hair loss, and polycystic ovary disease; therefore, it may not be ideal for young female patients who have a tendency to gain weight.

Valproic acid also carries substantial risks in pregnancy; it may be best suited for women who have had tubal ligation and who cannot tolerate calcium channel blockers because of dizziness. Data for other antiepileptics (eg, gabapentin, ^[116] lamotrigine, oxcarbazepine) are limited in migraine.

Topiramate is approved in the US for migraine prophylaxis in adults and adolescents aged 12 years or older. The safety and effectiveness of topiramate in preventing migraine headaches in adolescents were established in a clinical trial of 103 participants. Frequency of migraine decreased by approximately 72% in treated patients, compared with 44% in participants receiving placebo. ^{[117, 118]}

Antidepressants

Tricyclic antidepressants are good second-line alternatives because of their adverse-effect profile and efficacy. Head-to-head comparisons of agents in this class have not been conducted, but amitriptyline and nortriptyline are commonly used.

Although selective serotonin reuptake inhibitors (SSRIs) are widely used, data regarding their efficacy in migraine prevention are lacking; consequently, SSRIs are not recommended for migraine prevention. However, limited data do support the use of serotonin/norepinephrine reuptake inhibitors (SNRIs) such as duloxetine (Cymbalta) and venlafaxine (Effexor) for migraine prevention.

Antihypertensives

Antihypertensives such as beta blockers should be tailored if the patient is young and anxious. Moreover, they may not be the ideal choice for elderly patients or patients with depression, thyroid problems, or diabetes. Calcium channel blockers are another possible choice of treatment. Angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril) and angiotensin-receptor blockers (eg, candesartan) ^[119] have also been shown to be effective for migraine prevention. ^[120]

Botulinum toxin

Botulinum toxin A (onabotulinumtoxinA; BOTOX®) may be beneficial in patients with intractable, chronic migraine that has failed to respond to at least 3 conventional preventive medications. The injections are administered to the scalp and temple. They may reduce the frequency and severity of migraine attacks after 2-3 months of injections.

The injections are expensive and must be administered every 2-3 months to maintain their effectiveness. The most appropriate duration of prophylactic therapy has not been determined. In most patients who are receiving prophylaxis, therapy must be continued for at least 3-6 months.

Multiple trials of onabotulinumtoxinA for migraine prevention have been conducted, with mixed results. ^[121] A review by Schulte-Mattler and Martinez-Castrillo found no evidence of a beneficial effect from botulinum toxin. These authors do not recommend the widespread use of botulinum toxin therapy in headaches. ^[122]

More recently, however, 2 multicenter, placebo-controlled trials included in the Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program found onabotulinumtoxinA to be effective for headache prophylaxis in adults with chronic migraine. Nearly 1400 patients were included in the results. Secondary benefits included significantly reduced headache-related disability and improved functioning, vitality, and overall health-related quality of life. ^[123]

In 2016, the American Academy of Neurology updated its 2008 guidelines on using botulinum toxin for brain disorders. Botulinum toxin A is now recommended for the management of chronic migraine, defined as attacks lasting 4 or more hours on at least 15 days each month for 3 months. Botulinum toxin A is not recommended for less frequent, "episodic" migraine. ^[124]

Calcitonin gene-related peptide inhibitors

Inhibiting the calcitonin gene-related peptide (CGRP) pathway is a new method to prevent migraines. CGRP is a potent vasodilator and is a key neuropeptide that is central to migraine pathophysiology. CGRP concentrations decrease following administration of triptans when treating a migraine attack. Three monoclonal antibodies that bind to the CGRP receptor were approved in the United States in 2018 (ie, erenumab, fremanezumab, galcanezumab). The first IV CGRP monoclonal antibody, eptinezumab, was approved for migraine prophylaxis in 2020. 

The first CGRP inhibitor approved by the FDA for migraine prophylaxis was erenumab (Aimovig) in May 2018. Approval was based on findings from the LIBERTY, ARISE, and STRIVE clinical trials. ^{[125, 126, 127]}

The LIBERTY trial studied difficult-to-treat patients (n=246) with episodic migraine who had failed 2 to 4 previous treatment. Patients treated with erenumab 140 mg had about a 3-fold higher odds of having their migraine days cut by half or more compared with placebo. ^[125]

In the ARISE trial, 577 adults with episodic migraine were randomized to placebo or 70 mg erenumab (570 were included in efficacy analysis). Patients receiving erenumab experienced -2.9 days change in monthly migraine days, compared with -1.8 days for placebo (p < 0.001). A ≥50% reduction in monthly migraine days was achieved by 39.7% (erenumab) and 29.5% (placebo) of (p = 0.010). Migraine-specific medication treatment days were reduced by -1.2 (erenumab) and -0.6 (placebo) days, a treatment difference of -0.6 (p = 0.002). ^[126]

The STRIVE clinical trial compared erenumab doses of 70-mg (n=317) or 140-mg (n=319) to placebo (n=319). The mean number of migraine days per month at baseline was 8.3 in the overall population; by months 4 through 6, the number of days was reduced by 3.2 in the 70-mg erenumab group and by 3.7 in the 140-mg erenumab group, as compared with 1.8 days in the placebo group (P< 0.001 for each dose vs. placebo). ^[127]

Two additional CGRP inhibitors, fremanezumab (Ajovy) and galcanezumab (Emgality), were approved in September 2018.

Approval of fremanezumab was based on the HALO study. Fremanezumab was administered monthly or quarterly and compared with matching placebo. The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab-quarterly group, 41% in the fremanezumab-monthly group, and 18% in the placebo group (P< 0.001 for both comparisons with placebo). ^[128]

Approval of galcanezumab was based on the EVOLVE clinical trials. Mean monthly migraine headache days were reduced by 4.3-4.7 and 4.2-4.6 days by galcanezumab 120 and 240 mg, respectively, and 2.3-2.8 days by placebo (both P < 0.001). ^{[129, 130]}

Eptinezumab (Vyepti) was approved in February 2020 for preventive treatment of migraine in adults. It is administered IV every 3 months. Approval was supported by two phase 3 trials, PROMISE-1 (n = 665) and PROMISE-2 (n = 1072). Percent of responders with at least 50% reduction of monthly migraine days (MMD) from baseline was higher with eptinezumab (100 mg or 300 mg IV every 3 months) compared with placebo (0.001). The trials also showed a higher percentage of patients achieved a 75% reduction in MMD compared with placebo. ^{[131, 132]}  

In September 2021, the FDA approved atogepant (Qulipta), an oral CGRP receptor antagonist indicated for preventive treatment of episodic migraine in adults. Drug approval was based on the ADVANCE phase 3 trial. Patients received once-daily atogepant or placebo. Among 873 participants who were included in the efficacy analysis; 214 received atogepant 10 mg, 223 received atogepant 30 mg, 222 received atogepant 60 mg, and 214 were in the placebo group. Mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the 4 groups. Changes from baseline over 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo (P < 0.001 for all comparisons with placebo). ^[133]  

Devices

In March 2014, the FDA approved the first device for the preventive treatment of migraine headaches for adults, a transcutaneous electrical nerve stimulation (TENS) device that is worn for 20 minutes a day. The device fits across the forehead and over the ears and stimulates the trigeminal nerve with a self-adhesive electrode in the center of the forehead. Approval was based on a study of 67 migraine patients in which the device reduced the number of migraine days per month and medication use, and on a patient satisfaction study of 2313 device users, in which more than 53% of patients were satisfied with the device. ^[134]

Walling et al looked into developing a non-invasive treatment for medically refractory chronic migraine. Their work has shown some evidence that pulsed focused ultrasound in a rodent headache model of cutaneous allodynia may provide therapeutic option for patients suffering from chronic migraines. ^[135]

Approximately 40% of all migraine attacks do not respond to a given triptan or any other substance. If all else fails, an intractable migraine attack (status migrainosus), that is, an attack lasting longer than 72 hours, should be addressed in an urgent care or emergency department. In rare cases, patients may need to be hospitalized for a short period and may need to be treated with intravenous valproate or dihydroergotamine (intravenously/subcutaneously/intramuscularly) for a few days. ^[136]

Abortive therapy for menstrual migraine is the same as for nonmenstrual migraine. Patients with frequent and severe attacks may benefit from short-term, perimenstrual use of preventive agents (eg, frovatriptan ^[137] ). Patients with menstrual and nonmenstrual migraine who are receiving continuous preventive therapy and experiencing breakthrough menstrual migraine headaches may benefit from perimenstrual elevation of the dose of the preventive medication.

Patients who do not respond to standard preventive measures may benefit from hormonal therapy. Perimenstrual estrogen supplementation with estradiol (0.5 mg orally twice a day, or a 1-mg transdermal patch) may be beneficial. A study by De Leo et al of oral contraceptive use in women with menstrual migraine without aura found that a regimen of 24 ethinyl estradiol/drospirenone pills and 4 inert pills was more effective than a regimen of 21 active pills and 7 inert pills. ^[138]

Interest in the use of complementary and alternative medicine (CAM) by headache patients is widespread. A 2002 survey showed that more than 85% of headache patients use CAM therapies and 60% felt they provided some relief. ^[139] Overall, more than 70% of patients who use CAM do not tell their doctors about it.

Some CAM techniques have good scientific evidence of benefit and have been proven by studies to be effective in preventing migraine. Biofeedback and behavioral therapy should be part of the standard of care for a difficult migraine patient.

Good studies have demonstrated the effectiveness of the herb butterbur (Petasites hybridus) in preventing migraines. ^[140] A guideline from the American Academy of Neurology and the American Headache Society (AAN/AHS) recommends offering butterbur to patients with migraine to reduce the frequency and severity of migraine attacks (level A recommendation). ^[113] Patients on butterbur require monitoring of liver enzymes.

The AAN/AHS found moderate evidence of effectiveness for riboflavin (vitamin B2), magnesium, and feverfew. A 3-month, randomized, controlled trial of high-dose riboflavin (400 mg) found that riboflavin was superior to placebo in reducing attack frequency and headache days. ^[141]

A randomized, controlled trial of coenzyme Q10 (CoQ10) documented that CoQ10 is effective and well tolerated for migraine prophylaxis. ^[142] Results of a trial in children and adolescents suggested that prophylaxis with CoQ10 may lead to earlier improvement in headache severity than does placebo-based prophylaxis, but the trial found no long-term difference in headache outcomes between the CoQ10 and placebo groups. ^[143]

Melatonin has also been used for migraine prevention. Alstadhaug et al conducted a randomized, controlled, 8-week trial of prolonged-release melatonin (2 mg 1 hour before bedtime) in adult patients experiencing 2-7 migraine attacks per month. Although the investigators found that in the melatonin group the average attack frequency fell from 4.2 to 2.8 per month, this result was not significantly superior statistically to the reduction seen with placebo. ^[137]

A variety of other CAM techniques are not bolstered by solid scientific data, but they may be perceived to be of benefit to patients. ^[144] Techniques that some patients use for headache relief include the following:

• Body work - Eg, chiropractic, massage, and craniosacral therapy ^[145] )

• Nutritional/herbal supplements - Eg, vitamins and herbs

• Yoga ^[146]

• Acupressure and acupuncture ^[147]

• Biofeedback ^{[148, 149]}

Overall, scientific evidence on the efficacy of these modalities is lacking, partly due to the poor design and/or poor quality of the studies performed to date.

Mindfulness-based stress reduction and home meditation have been studied as a method to reduce the pain and improve health-related quality of life in patients with chronic pain syndromes. While this method proved effective for chronic arthritis patients, it was not deemed effective in patients with chronic headache/migraine or fibromyalgia. ^[150]

The advantages of CAM therapies are that many of these remedies have no adverse effects, they advocate a self-help technique that is attractive to patients, and they offer a holistic approach. The practitioners often spend significant time with their patients, and that in itself makes the patient feel as if he or she has been given careful attention.

The disadvantages of CAM therapies include the lack of standardization of either the practice or the dispensing of the therapies and techniques. In addition, for many of these modalities, no standard format exists to ensure that practitioners are adequately trained in the techniques they use.

Surgical therapy for migraine is highly controversial. In a study of 60 patients, Dirnberger and Becker reported that corrugator muscle resection produced total relief of migraine in 28.3% of patients, essential improvement in 40%, and minimal or no change in 31.7%. The more severe their migraine, however, the less likely patients were to experience improvement. In addition, 11 patients who had a very favorable short-term response experienced a gradual return of their headaches to preoperative intensity within about 4 weeks postoperatively. ^[151]

The significance of diet as a migraine trigger is controversial. ^[152] Nevertheless, individual patients often can identify these triggers. Common dietary triggers include the following:

• Alcohol - Particularly wine and beer

• Caffeine overuse or caffeine withdrawal

• Chocolate

• Aspartame - eg, NutraSweet and Equal

• Monosodium glutamate (MSG) - May be found in Asian food, canned soup, frozen or processed foods, and the seasoning product Accent

• Fruits - Citrus fruits, bananas, avocados, and dried fruit

• Nuts - Peanuts, soy nuts, and soy sauce

Tyramine, a biogenic amine that accumulates in food as it ages, may provoke migraine. Sources include the following:

• Dairy - Aged cheese

• Meat - Bacon, sausage, luncheon meat, deli meat, pepperoni, and smoked or cured meat

• Pickled foods

• Heavily yeasted breads - Eg, sourdough

• Vinegars - Especially wine vinegar

• Some types of beans

Nutraceuticals shown to be effective in randomized clinical trials include the aforementioned vitamin B2, CoQ-10, magnesium, and butterbur (Petadolex). ^[153]

One study of exercise for migraine prevention (40 minutes 3 times weekly for 3 months) reported a mean attack reduction of 0.93 during the final month of treatment, which was not significantly different from the reductions achieved in the control groups using topiramate or a relaxation program. ^[154] However, most studies of aerobic exercise in migraine patients have not found a significant reduction of headache attacks or headache duration, although regular exercise has been shown to reduce pain intensity in many patients. ^[155]

Tonabersat is a novel benzopyran compound that markedly reduces cortical spreading depression (CSD) and CSD-associated events by inhibiting gap-junction communication between neurons and satellite glial cells in the trigeminal ganglion. ^[156] In a randomized, double-blind, placebo-controlled crossover trial, preventive therapy with tonabersat reduced the frequency of aura attacks with or without headache but had no efficacy on non-aura attacks. ^[15]

The pipeline of future compounds for the treatment of acute migraine headaches also includes the following medications:

• Transient receptor potential vanilloid type 1 antagonists

• Prostaglandin E receptor 4 receptor antagonists

• Serotonin 5HT1(F) receptor agonists

• Nitric oxide synthase inhibitors

The immediate future of preventive treatment for migraine headaches will likely involve glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonists and gap-junction blockers. ^[157]

It is worth mentioning here that so far there is insufficient evidence to support the use of intranasal lidocaine in acute management of primary headaches and requires further research. ^[158]