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INTRODUCTION — Migraine is a common episodic disorder, the hallmark of which is a disabling headache generally associated with nausea, and/or light and sound sensitivity. The acute treatment of migraine in adults is reviewed here. Preventive treatment of migraine in adults is discussed separately. (See "Preventive treatment of migraine in adults".)
The pathophysiology, clinical manifestations, and diagnosis of the migraine are also discussed separately. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)
APPROACH TO TREATMENT — The abortive (symptomatic) therapy of migraine ranges from the use of simple analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen to triptans, antiemetics, or the less commonly used dihydroergotamine. Abortive treatments are usually more effective if they are given early in the course of the headache; a large single dose tends to work better than repetitive small doses. Many oral agents are ineffective because of poor absorption secondary to migraine-induced gastric stasis.
General recommendations for the treatment of acute migraine include the following [1,2]:
●Educate migraine sufferers about their condition and its treatment and encourage them to participate in their own management
●Use migraine specific agents (eg, triptans, dihydroergotamine) in patients with more severe migraine and in those whose headaches respond poorly to NSAIDs or combination analgesics
●Select a nonoral route of administration for patients whose migraines present early with significant nausea or vomiting
●Consider a self-administered rescue medication for patients with severe migraines that do not respond well to other treatments
●Guard against medication overuse headache by educating patients about risk and using prophylactic medications in patients with frequent headaches (see "Medication overuse headache: Etiology, clinical features, and diagnosis" and "Preventive treatment of migraine in adults")
The early use of migraine-specific medications for severe attacks provided the best outcomes in a randomized, controlled trial of 835 adults with migraine that compared these strategies . One group (step care within attacks) received aspirin (800 to 1000 mg) plus metoclopramide (20 mg) as initial therapy for all attacks; patients not responding to treatment after two hours in each attack escalated treatment to zolmitriptan (2.5 mg). A second group (step care across attacks) received initial treatment with aspirin (800 to 1000 mg) plus metoclopramide (10 mg); patients not responding in at least two of the first three attacks switched to zolmitriptan (2.5 mg) for the next three attacks. In a third group (stratified care), patients with mild headaches were treated with aspirin plus metoclopramide, while those with more severe headaches were treated with zolmitriptan. The latter two groups had significantly better outcomes than the first group as measured by headache response and disability time, although patients in the stratified group had the greatest number of adverse events.
The pharmacologic approach to migraine is directed mainly by the severity of the attacks, the presence of associated nausea and vomiting, the treatment setting (outpatient or medical care facility), and patient-specific factors, such as the presence of vascular risk factors and drug preference.
Mild to moderate attacks — For mild to moderate migraine attacks not associated with vomiting or severe nausea, simple analgesics (NSAIDs, acetaminophen) or combination analgesics are first choice agents because they are effective, less expensive, and less likely to cause adverse effects than migraine-specific agents such as triptans or ergots [4,5]. When mild to moderate attacks are associated with severe nausea or vomiting, an oral or rectal antiemetic drug can be used in conjunction with simple or combination analgesics. (See 'Simple analgesics' below and 'Triptans' below and 'Antiemetics' below.)
Moderate to severe attacks — For moderate to severe migraine attacks not associated with vomiting or severe nausea, oral migraine-specific agents are first-line, including oral triptans and the combination of sumatriptan-naproxen [4,5]. When complicated by vomiting or severe nausea, severe migraine attacks can be treated with nonoral migraine-specific medications including subcutaneous sumatriptan, nasal sumatriptan and zolmitriptan, nonoral antiemetic agents, and parenteral dihydroergotamine. (See 'Triptans' below and 'Ergots' below and 'Antiemetics' below.)
Variable attacks — Many patients with migraine have attacks that vary in severity, time of onset, and association with vomiting and nausea . These patients may require two or more options for self-management of acute migraine, including oral medications for mild to moderate attacks and nonoral medications (eg, subcutaneous or nasal triptans) for more severe attacks or those associated with vomiting or severe nausea.
Emergency settings — Patients who present with migraine in emergency settings generally have unusually severe attacks, and in many cases their customary acute migraine treatment has failed to provide relief . The treatment of migraine attacks in the emergency department or other urgent care settings follows the same principles as treatment in nonurgent settings outlined above (see 'Mild to moderate attacks' above and 'Moderate to severe attacks' above), with the obvious difference that parenteral medications are more readily available. The following are reasonable options, with evidence of efficacy from randomized trials [7-14]:
●Antiemetics/Dopamine receptor blockers (see 'Antiemetics' below):
•Metoclopramide 10 mg intravenous (IV)
•Prochlorperazine 10 mg IV or intramuscular (IM)
•Chlorpromazine 0.1 to 1 mg/kg IV
For patients who present to the hospital emergency department with severe migraine, particularly if the migraine is accompanied by severe nausea or vomiting, we suggest initial treatment with either subcutaneous sumatriptan or a parenteral antiemetic (ie, metoclopramide, prochlorperazine, or chlorpromazine) at the doses listed above. When giving parenteral antiemetics for migraine, we suggest adjunct use of diphenhydramine (12.5 to 25 mg IV every hour up to two doses) to prevent akathisia and other dystonic reactions. A more aggressive alternative option, based upon the results of one clinical trial, is high-dose metoclopramide (20 mg IV every 30 minutes up to four doses) given with diphenhydramine. (See 'Metoclopramide' below.)
Dihydroergotamine (DHE 45) 1 mg IV combined with metoclopramide 10 mg IV is also a reasonable alternative for treatment of intractable severe migraine in the emergency department, and it can be used if metoclopramide monotherapy is ineffective. Parenteral DHE 45 should not be used as monotherapy. DHE 45 is contraindicated in patients with ischemic vascular disease involving cardiac, cerebrovascular, or peripheral circulations. (See 'Dihydroergotamine' below.)
For patients who are treated in the emergency department or clinic for migraine headache with one of the standard migraine abortive therapies, we recommend adjunctive treatment with dexamethasone (10 to 25 mg IV or IM) to reduce the risk of early headache recurrence. (See 'Abortive therapy plus parenteral dexamethasone' below.)
Overuse of opioid medications for acute headache in hospital emergency departments appears to be widespread in the United States and Canada [15,16], despite available practice guidelines that recommend nonopioid medications as first-line therapy for severe migraine , or recommend that opioids should not be used in the acute treatment of migraine [17,18]. Patients treated with opioids as first-line therapy are significantly more likely to return to the emergency department with a headache within seven days of the original visit [15,19].
Pregnancy — The treatment of migraine in pregnant women differs somewhat from the treatment in nonpregnant women because of concerns about adverse fetal drug effects. This aspect of acute migraine care is reviewed separately. (See "Headache in pregnant and postpartum women", section on 'Treatment of acute migraine'.)
Avoidance of medication overuse — Medication overuse headache (MOH), also called analgesic rebound headache, is a common disorder with significant morbidity. All acute symptomatic medications used to treat headaches have the potential for causing MOH. However, the degree of risk differs depending upon the specific medication or class of medications. Based upon the literature and clinical experience, the risk for MOH appears to be highest with opioids, butalbital-containing combination analgesics, and aspirin/acetaminophen/caffeine combinations. The risk with triptans is considered intermediate by some experts but high by others. The risk is lowest with NSAIDs, which may even be protective against the development of chronic migraine for patients who have less than 10 headache days per month.(See "Medication overuse headache: Etiology, clinical features, and diagnosis", section on 'Causal medications'.)
In order to prevent the development of medication overuse headache (MOH), most acute medications should be limited to less than 10 days per month (or less than 15 days per month for aspirin, acetaminophen, and NSAIDS), and preventive therapies should be used as the mainstay in patients with frequent headaches. (See "Medication overuse headache: Etiology, clinical features, and diagnosis".)
Nonsteroidal anti-inflammatory drugs — NSAIDs with reported efficacy in randomized, placebo-controlled trials of migraine therapy include aspirin (650 to 1000 mg) , ibuprofen (400 to 1200 mg) , naproxen (750 to 1250 mg) , diclofenac (50 to 100 mg) , diclofenac epolamine (65 mg) , tolfenamic acid (200 mg) , and dexketoprofen (50 mg) [26,27] Some of these studies are limited by varying outcome measures and definitions of migraine, but all NSAIDs may be beneficial in patients who have migraine, with or without aura.
A 2013 systematic review of eight randomized trials found that parenteral ketorolac (30 mg intravenous or 60 mg intramuscular) was effective for acute migraine in comparison with other agents, including intranasal sumatriptan, IV prochlorperazine, IV chlorpromazine, and IV dihydroergotamine combined with metoclopramide . However, no placebo-controlled trials were identified.
Although the data are limited, benefit may be seen with indomethacin as abortive therapy for migraine. It is a potent NSAID that is also available in suppository form, which may be helpful for nauseated patients. Indomethacin suppositories contain 50 mg of the drug; the suppositories may be cut into halves or thirds for patients with recurrent attacks.
There are no studies comparing the relative efficacy of different NSAIDs. If one NSAID is ineffective, a different drug may be tried. (See "NSAIDs: Therapeutic use and variability of response in adults".)
Acetaminophen — Acetaminophen is an effective abortive agent in some patients . This was illustrated in a population-based randomized, placebo-controlled trial of 289 patients with self-reported migraine, which found acetaminophen at a dose of 1000 mg to be highly effective for treating pain, functional disability, photophobia, and phonophobia, although the study excluded patients with severe symptoms requiring bed rest or associated with vomiting more than 20 percent of the time .
Acetaminophen can be used in combination with NSAIDs. The combination of acetaminophen-aspirin-caffeine (Excedrin, 2 extra strength tablets) was found to alleviate headaches in patients with uncomplicated migraine in one report .
TRIPTANS — The serotonin 1b/1d agonists (triptans) are effective for the acute treatment of migraine , as detailed in the sections below. The triptans are considered to be "specific" therapies for acute migraine since, in contrast to analgesics, they act at the pathophysiologic mechanism of the headache [1,2]. However, triptan responsiveness should not be considered diagnostic of migraine, as secondary headaches may also improve with triptan treatment . (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)
All of the triptans inhibit the release of vasoactive peptides, promote vasoconstriction, and block pain pathways in the brainstem . Triptans inhibit transmission in the trigeminal nucleus caudalis, thereby blocking afferent input to second order neurons; this effect is probably mediated by reducing the levels of calcitonin gene related peptide (CGRP). (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)
Triptans may also activate 5-HT 1b/1d receptors in descending brainstem pain modulating pathways and thereby inhibit dural nociception .
Preparations and efficacy — The available triptans include sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan. Sumatriptan can be given as a subcutaneous injection (usually administered by autoinjector in the thigh), as a nasal spray, or orally. Zolmitriptan is also available for both nasal and oral use. The others are available for oral use only.
A number of randomized, controlled trials and systematic reviews have found all of the triptans to be effective for the treatment of acute migraine . The range of findings is illustrated by the following reports:
●Eletriptan — In a meta-analysis of six randomized, controlled trials of eletriptan involving 3224 patients, eletriptan at doses of 20, 40, and 80 mg was significantly better than placebo for all main outcomes (including headache response at one and two hours and sustained relief over 24 hours) . Pain relief was dose dependent, with the 80 mg dose providing statistically significant greater pain relief than 40 mg at two and 24 hours. The drug was well tolerated and caused no major harm. The incidence of minor side effects was also dose related, but all adverse effects were transient and reversible. Eletriptan is not available in 80 mg tablets in the United States, and 40 mg is recommended for most patients .
●Naratriptan — At least three randomized trials have found that naratriptan significantly improves acute migraine relief compared with placebo [38-40]. In one of the studies, a dose of 2.5 mg was most effective in producing headache relief at four hours, with an adverse event rate similar to placebo . Adverse events did not appear to be dose related.
In a second study, patients who did not respond to sumatriptan 50 mg with a first attack had a significantly superior response to naratriptan 2.5 mg compared with placebo during a second migraine attack one week later, suggesting that patients who do not respond to one triptan may respond to another . One problem with this study is that the 50 mg dose of sumatriptan used is often suboptimal . On the other hand, it is worthwhile to try another triptan if the response is not optimal.
●Rizatriptan — The efficacy of rizatriptan for acute migraine has been demonstrated in a systematic review of seven randomized, placebo-controlled studies involving 3528 patients . Significant benefit of rizatriptan compared with placebo was shown for both the 5 and 10 mg dose of rizatriptan for all five main efficacy outcomes (ranging from relief at 1 to 24 hours). The 10 mg dose was more effective than 5 mg. The most common adverse effects were dizziness, asthenia/fatigue, nausea, and somnolence; in one study these effects were dose dependent .
●Sumatriptan — The subcutaneous, oral, and intranasal preparations of sumatriptan have proven efficacy in randomized, placebo-controlled trials of acute migraine therapy, as established in systematic reviews and meta-analyses [44-47], and the transdermal formulation was also effective in a single placebo-controlled trial . Subcutaneous sumatriptan (6 mg) is more effective than oral sumatriptan (100 mg), but its use is associated with more adverse events . Subcutaneous sumatriptan has the fastest onset of action. Intranasal sumatriptan (typically one insufflation of sumatriptan 20 mg, repeated at two hours if necessary) has fewer side effects than the injectable formulation . In one trial of subcutaneous sumatriptan in 639 patients, administration of a second dose of the drug 60 minutes after the first in those who did not respond well initially provided little additional benefit . The most effective dose of oral sumatriptan is 100 mg, while the 50 mg dose may provide the best combination of efficacy and tolerability [47,51].
Common side effects of subcutaneous sumatriptan include an injection site reaction, chest pressure or heaviness, flushing, weakness, drowsiness, dizziness, malaise, a feeling of warmth, and paresthesias. Most of these reactions occur soon after the injection and resolve spontaneously within 30 minutes. The most common side effect of intranasal sumatriptan is an unpleasant taste.
●Zolmitriptan — A number of randomized, placebo-controlled trials and a systematic review and meta-analysis  have proven the efficacy of zolmitriptan as acute migraine therapy. As an example, one trial of 1000 patients with migraine compared four doses of zolmitriptan (1, 2.5, 5, and 10 mg) with placebo . There was a dose-response relationship in terms of both efficacy and adverse effects; 2.5 mg appeared to be the optimal starting dose. The most common side effects included nausea, dizziness, somnolence, paresthesia, fatigue, and tightness in the throat or chest. The incidence of unpleasant taste is lower with intranasal zolmitriptan, as compared with that reported in trials of intranasal sumatriptan.
Choice of triptan — The choice of serotonin agonist should be individualized; different pharmacologic properties and delivery routes may help guide the choice. Patients who do not respond well to one triptan may respond to another .
Relatively few trials have compared the triptans head to head, making it difficult to decide whether to use one versus another. A meta-analysis of 53 clinical trials of the oral serotonin agonists that included over 24,000 patients concluded that all of the available oral drugs are effective and well tolerated . The highest likelihood of consistent success was found with rizatriptan (10 mg), eletriptan (80 mg), and almotriptan (12.5 mg). The findings of a subsequent network meta-analysis suggested that eletriptan was the most likely of all the triptans to produce short-term and sustained benefit . These data and clinical experience suggest that sumatriptan, rizatriptan, eletriptan, almotriptan and zolmitriptan are very similar orally, while naratriptan and frovatriptan are slower in onset and have lower efficacy.
Sumatriptan offers the most options for routes of drug delivery, with subcutaneous sumatriptan offering the fastest onset of action. The dose of rizatriptan must be adjusted downward in patients who take propranolol, since propranolol increases rizatriptan levels by 70 percent. Naratriptan and frovatriptan have the slowest onset of action among the triptans, and may have the lowest propensity to cause side effects .
Factors predicting response — Prompt treatment of migraine attacks is considered important to successful acute therapy [41,58,59], but few rigorous studies have examined the factors that may influence the probability of a good response to triptan therapy.
●In a randomized, placebo-controlled trial that evaluated 403 patients with migraine, almotriptan 12.5 mg was effective whether started when headache was early and mild, or started when headache was moderate to severe . When treatment was initiated while headache intensity was mild and within one hour of onset, a significantly greater proportion of patients were pain-free at two hours with almotriptan than with placebo (49 versus 25 percent) . Similarly, when treatment was started when headache intensity was moderate to severe, almotriptan remained significantly better than placebo on the same outcome measure (40 versus 15 percent).
●Another study analyzed a database of 130,000 migraine attacks in 28,000 patients with migraine . Pretreatment pain severity was the strongest predictor of both headache relief (defined as mild or no pain) and pain-free response two hours after taking sumatriptan, with lower baseline severity predicting a better response. The resistance of severe pain to triptan therapy found in this study may be due to the development of central sensitization during the attack, which is thought to counteract analgesic and triptan therapy. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)
In patients susceptible to cutaneous allodynia (the perception of pain produced by innocuous stimulation of normal skin), limited data suggest that triptans are less effective once allodynia is established during migraine attacks. In a study of 31 patients, triptan treatment resulted in complete pain relief by two hours in only 15 percent of 34 allodynic attacks versus 97 percent of 27 non-allodynic attacks . The authors concluded that patients who develop allodynia, which takes one to four hours to establish , should take triptans as early as possible in a migraine attack. Conversely, patients who never develop allodynia can benefit from triptan therapy at any time during an attack. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)
Limitations to use — Triptans have proven to be safe and effective for most patients with migraine . A systematic review of observational studies found no association between triptan use and the risk of cardiovascular events, though only four relevant studies were identified . Similarly, in a cohort study of 63,575 patients with migraine, 13,664 of whom were treated with a triptan, there was no association between triptan prescription and stroke, other cardiovascular events, or death . However, in this cohort, triptans were prescribed to those at less risk of these events.
Based on limited evidence, it is still recommended that triptans be avoided in patients with hemiplegic migraine, basilar migraine, ischemic stroke, ischemic heart disease, Prinzmetal's angina, uncontrolled hypertension, and pregnancy .
Combination with monoamine oxidase inhibitors is contraindicated with triptans other than eletriptan, frovatriptan, and naratriptan. Triptans should not be used within 24 hours of the use of ergotamine preparations or a different triptan medication .
Eletriptan is primarily metabolized by cytochrome P-450 enzyme CYP3A4. Therefore, eletriptan should not be used within at least 72 hours of treatment with other drugs that are potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir.
Concerns have been raised about the development of a serotonin syndrome (see "Serotonin syndrome (serotonin toxicity)") in patients who use triptans in combination with a selective serotonin reuptake inhibitor (SSRI) or a selective serotonin-norepinephrine reuptake inhibitor (SNRI) . However, the added risk of serotonin syndrome posed by the combined use of a triptan with an SSRI or SNRI appears to be very low to nonexistent [70-72]. Thus, many headache experts suggest that triptans in combination with SSRIs or SNRIs can be used in most cases where both are needed as long as the risks and benefits are discussed, and patients are monitored for symptoms of serotonin syndrome. The combination should be discontinued if such symptoms arise.
TRIPTANS WITH NSAIDS — The combined use of a triptan and a nonsteroidal anti-inflammatory drug (NSAID) to treat acute migraine appears to be more effective than using either drug class alone. The best-studied combination is sumatriptan with naproxen. A systematic review and meta-analysis, updated in 2016, found that the combination of sumatriptan and naproxen was more effective than either agent alone for the treatment of acute migraine headache . Among the largest of the included studies were two randomized placebo-controlled trials of similar design, involving a total of nearly 3000 patients, which evaluated a proprietary formulation of sumatriptan succinate 85 mg and naproxen sodium 500 mg in a single tablet (Treximet) . The following observations were reported:
●At two hours after dosing, the combination of sumatriptan and naproxen was more effective than placebo or sumatriptan alone for headache relief (defined as reduction of pain from moderate or severe intensity to mild intensity or no pain without use of rescue medication)
●Sumatriptan and naproxen was more effective than sumatriptan monotherapy and naproxen monotherapy for sustained pain-free response (defined as initially moderate or severe pain reduced to no pain from 2 through 24 hours after dosing without use of rescue medication)
●The combined agent was well tolerated; dizziness, somnolence, paresthesia, and nausea were the most common side effects
In two placebo-controlled randomized trials with more than 1000 patients that tested early treatment (within one hour of migraine onset when the pain was mild), a pain-free response at two hours was significantly more frequent in patients assigned to the combination sumatriptan and naproxen 85/500 mg (approximately 50 percent, versus approximately 16 percent with placebo) . Even at 30 minutes, there was a statistically significant pain-free response with combination sumatriptan plus naproxen.
Since the propriety medication is quite expensive, an alternative is to use generic naproxen sodium 550 mg tablet or capsule and a triptan together. Naproxen sodium is more rapidly absorbed than naproxen.
Whether the results of the trials testing sumatriptan with naproxen are generalizable to other triptan/NSAID combinations is uncertain. However, a double-blind controlled trial of 279 patients found that the combination of frovatriptan (2.5 mg) and dexketoprofen (25 mg or 37.5 mg) was more effective than frovatriptan alone for treating migraine attacks, as measured by the proportion of subjects who were pain-free at two hours (51 percent for frovatriptan with either dose of dexketoprofen, versus 29 percent for frovatriptan alone) .
ANTIEMETICS — Intravenous (IV) metoclopramide, and IV or intramuscular (IM) chlorpromazine and prochlorperazine can be used as monotherapy for acute migraine headache. These medications act as antiemetics mainly because they are dopamine receptor antagonists. In addition, they are effective for reducing migraine headache pain. The benefit of these agents for migraine has been demonstrated in randomized placebo-controlled trials as will be discussed below. Intravenous diphenhydramine (12.5 to 20 mg every hour for two hours) is sometimes given with these drugs to prevent akathisia and acute dystonic reactions, which are the main side effects of this class of medications.
Of note, most of these drugs (ie, chlorpromazine, prochlorperazine, droperidol, and diphenhydramine) are associated with a risk of QT interval prolongation and torsades de pointes. Risk factors for medication-induced torsades de pointes include high drug concentrations, concurrent use of other drugs (table 1) that can prolong the QT interval or that slow drug metabolism due to inhibition of cytochrome P450 enzymes, concurrent intake of grapefruit juice, baseline QT prolongation or T wave lability, development of marked QT prolongation or T wave changes during therapy, bradycardia, electrolyte disturbances (particularly hypokalemia and hypomagnesemia), impaired hepatic and/or renal function, underlying heart disease, recent conversion from atrial fibrillation, and female sex. Therefore, alternatives to QT prolonging drugs should be considered in patients with the above risk factors, particularly if the patient is already taking a QT prolonging drug. Patients with these risk factors who are treated with antiemetics for acute migraine should be monitored before and for several hours after their administration. The duration of QT interval monitoring depends upon the duration of treatment with the QT prolonging drug and the drug half-life. (See "Acquired long QT syndrome", section on 'Monitoring'.)
In contrast to intravenous or intramuscular preparations, oral antiemetics should not be considered as monotherapy in acute migraine [1,2]. However, oral metoclopramide has the benefit over prochlorperazine and chlorpromazine of a prokinetic effect on gastric emptying.
As an example, one of the larger clinical trials that assessed chlorpromazine treatment in the emergency department randomly assigned 128 patients with migraine to chlorpromazine 0.1 mg/kg IV or placebo. Chlorpromazine treatment was associated with significant improvement in pain, nausea, photophobia, phonophobia, and need for rescue medication at 60 minutes compared with placebo . Benefit extended to both migraine with aura and migraine without aura. The number needed to treat (NNT) to enable one patient to achieve significant improvement at 60 minutes was two. In addition, chlorpromazine-treated patients had a significantly reduced rate of headache recurrence at 24 hours. Drowsiness and postural hypotension were seen more frequently with chlorpromazine treatment than with placebo.
Prochlorperazine — In controlled trials, IV prochlorperazine appears to be as effective or more effective than IV metoclopramide or subcutaneous sumatriptan, and more effective than placebo in the acute treatment of migraine [8,10,78].
In a double-blind randomized controlled trial that evaluated the emergency department treatment of migraine in 66 patients, the combination of IV prochlorperazine (10 mg) and IV diphenhydramine (12.5 mg) was significantly more effective than subcutaneous sumatriptan (6 mg) for the reduction of pain intensity at 80 minutes or time of discharge . Diphenhydramine was used with prochlorperazine to prevent akathisia and dystonic reactions. However, the possibility of migraine benefit from diphenhydramine cannot be completely discounted. A high drop-out rate upon attempted telephone contact at 72 hours precluded meaningful assessment of headache recurrence, although none of the enrolled patients returned to the emergency department with complaint of headache.
Metoclopramide — IV metoclopramide is effective for acute migraine treatment, as demonstrated in systematic reviews and meta-analyses [8,10,80]. One meta-analysis, published in 2004, reviewed 13 clinical trials . Study methods varied considerably, and the quality of the included studies was generally poor. The following observations were made :
●In pooled data from three studies, metoclopramide was more likely to provide headache pain reduction than placebo (odds ratio (OR) 2.84; 95% CI 1.05-7.68).
●The NNT to enable one patient to achieve significant reduction in pain with metoclopramide was four.
In a subsequent randomized controlled trial that evaluated emergency department treatment of migraine in 78 patients, aggressive metoclopramide (20 mg IV every 30 minutes up to four times) treatment provided similar relief of headache pain as sumatriptan (6 mg SC dosed once) treatment . Diphenhydramine (25 mg IV every hour up to two times) was used with metoclopramide to prevent akathisia and dystonic reactions, and no such side effects occurred in this study. Another randomized controlled trial from the same investigators found that diphenhydramine did not improve migraine outcomes when added to metoclopramide .
Others — Droperidol and haloperidol appear to be effective for the acute treatment of migraine but are not considered first-line agents because the evidence is mainly from lower-quality randomized trials and because rates of adverse effects are high .
●In a randomized controlled trial of over 300 patients, droperidol (2.75 mg, 5.5 mg, and 8.25 mg IM) was superior to placebo for the treatment of acute migraine attacks . However, these doses were associated with high rates of adverse events including akathisia and asthenia. Systematic reviews of randomized controlled trials have found that the effectiveness of parenteral droperidol (IV or IM) for acute migraine relief was equal to or better than prochlorperazine [8,10].
●A placebo-controlled trial of 40 hospitalized patients found that haloperidol (5 mg IV) was effective for migraine pain relief . Adverse effects, mainly sedation and akathisia, occurred in 80 percent of patients who received haloperidol. Another trial randomly assigned 64 adults presenting to the emergency department with acute migraine to treatment with either haloperidol 5 mg IV or metoclopramide 10 mg IV . There was no difference in pain relief between the treatment groups, but the incidence of restlessness (akathisia) was higher in the haloperidol group (43 versus 10 percent).
Use in adjunctive therapy — Antiemetics are commonly used as adjunctive therapy to treat migraine. As an example, nonsteroidal anti-inflammatory drugs (NSAIDs) can be combined with metoclopramide to decrease nausea and vomiting. The efficacy of this approach was illustrated in a randomized trial of 421 patients with migraine that compared oral lysine acetylsalicylate (equivalent to 900 mg of aspirin) plus oral metoclopramide (10 mg) with oral sumatriptan (100 mg) or placebo . Headache intensity decreased in 57, 53, and 24 percent of patients, respectively. Thus, in patients who will not use suppositories, or who are having difficulty tolerating oral analgesics, an analgesic plus metoclopramide is a reasonable, relatively low-cost alternative.
ERGOTS — A variety of ergotamine preparations, alone and in combination with caffeine and other analgesics, have been used for the abortive treatment of migraine . Both ergotamine and dihydroergotamine (DHE 45) bind to 5HT 1b/d receptors, just as triptans do. As the evidence reviewed below suggests, parenteral DHE is effective for acute migraine, while the effectiveness of ergotamine is uncertain.
Dihydroergotamine — Dihydroergotamine (DHE 45) is an alpha-adrenergic blocker that is a weaker arterial vasoconstrictor and more potent venoconstrictor than ergotamine tartrate. It is also a potent 5-HT 1b/1d receptor agonist. DHE 45 has fewer side effects than ergotamine; it does not cause the development of physical dependence or rebound headaches . It is available for intravenous, intramuscular, subcutaneous, and intranasal use. DHE 45 is often used in combination with an antiemetic drug, and this is always the case when it is given by intravenous administration.
The use of intravenous DHE for the treatment of chronic intractable migraine headache or status migrainosus (a debilitating migraine attack lasting for >72 hours) is discussed separately. (See "Medication overuse headache: Treatment and prognosis", section on 'Dihydroergotamine'.)
Parenteral DHE 45 administered with an antiemetic appears to be effective for acute migraine. This conclusion is supported by the findings of a systematic review that analyzed 11 randomized controlled trials of intravenous (IV) or intramuscular (IM) DHE 45 therapy for acute migraine in adults . The quality of the included studies was variable, and most had relatively small sample sizes. The following observations were reported:
●In two studies, DHE 45 alone (without an antiemetic) was less effective on most outcome measures than sumatriptan [90,91], and in one study was less effective on some (but not all) outcome measures than chlorpromazine .
●In eight studies, the combination of parenteral DHE 45 with an antiemetic (most commonly metoclopramide) was as effective as or more effective than meperidine, valproate, or ketorolac in relieving migraine headache and preventing relapses.
Whether DHE contributed additional benefit when used with an antiemetic in these studies is uncertain, since the antiemetic metoclopramide is known to be effective for migraine when used alone (see 'Metoclopramide' above). However, in several studies DHE combined with an antiemetic was superior to other agents combined with the same antiemetic, suggesting that DHE 45 does have independent efficacy for migraine .
Self-administered intranasal DHE 45 has been found, in placebo-controlled trials, to be efficacious for the treatment of migraine symptoms . In one trial of over 300 patients with migraine, for example, 27 percent of patients who administered 2 mg of intranasal DHE 45 had resolution of their headache within 30 minutes . By four hours after treatment, 70 percent of the headaches were resolved and returned within 24 hours in only 14 percent. No serious adverse effects of treatment were observed.
Subcutaneous DHE 45 may be slightly more effective than the intranasal preparation, but it has the disadvantage that it does not come in a preloaded syringe. Nevertheless, patients can be taught to self-inject this agent. One study randomly assigned 295 patients with acute migraine (with or without aura) to receive 1 mg of subcutaneous DHE 45 or 6 mg of subcutaneous sumatriptan succinate; a second injection of the same drug was used in two hours if patients did not experience initial relief . Headache relief occurred in 86 and 83 percent by four hours, respectively, a difference that was not statistically significant. However, DHE 45 was more likely to produce relief by 24 hours (90 versus 77 percent) and was associated with a lower incidence of recurrence in the 24 hours after therapy (18 versus 45 percent).
Similar to the triptans, DHE 45 is contraindicated in patients with hypertension or ischemic heart disease, in combination with MAO inhibitors, and in older adults.
Ergotamine — It is unclear if it is the ergotamine itself or the other ingredients in the combination drugs that provide the most effect. There are two observations that question the efficacy of ergotamine alone: oral and rectal ergotamine have a very poor bioavailability (2 and 5 percent, respectively) , and most placebo-controlled trials of oral ergotamine alone have failed to show efficacy in the relief of migraine . One controlled trial found that rectal suppositories containing ergotamine (2 mg) plus caffeine (100 mg) were as effective as sumatriptan (25 mg) suppositories for migraine headache relief [97,98]. However, there were more side effects among patients treated with ergotamine.
Ergotamine tartrate may be associated with significant side effects, and may worsen the nausea and vomiting associated with migraine. In addition, vascular occlusion and rebound headaches have been reported with oral doses exceeding 6 tablets per 24 hours or 10 tablets per week. Years of use also may be associated with valvular heart disease . In addition, ergotamine may worsen the nausea and vomiting associated with migraine.
Ergots should be avoided in patients with coronary artery disease because they cause sustained coronary artery constriction , peripheral vascular disease, hypertension, and hepatic or renal disease. In addition, ergotamine overuse has been associated with an increased risk of cerebrovascular, cardiovascular, and peripheral ischemic complications, particularly among those using cardiovascular drugs . They also should not be used in patients who have migraine with prolonged aura because they may reduce cerebral blood flow.
A European consensus panel reviewed the use of ergotamine for the acute treatment of migraine and concluded that ergotamine is the drug of choice in relatively few patients with migraine because of issues of efficacy and side effects . Suitable candidates may be those with prolonged duration of attacks (eg, greater than 48 hours) and possibly frequent headache recurrence.
ABORTIVE THERAPY PLUS PARENTERAL DEXAMETHASONE — When added to standard acute migraine therapy, parenteral treatment with dexamethasone reduces the rate of early headache recurrence. Supporting evidence comes from a meta-analysis of seven randomized trials conducted in emergency departments or headache clinics . All patients (n = 738) received standard abortive migraine headache treatment, and were also randomly assigned to treatment with either a single dose of dexamethasone (intravenous or intramuscular, 10 to 25 mg) or placebo.
●In the pooled results, dexamethasone was significantly more effective than placebo for reducing migraine recurrence from 24 to 72 hours after treatment (relative risk 0.74, 95% CI 0.6-0.9). The number needed to treat to prevent one recurrent headache was nine.
●Dexamethasone provided no additional benefit for immediate relief of headache.
●There were no significant differences regarding adverse events between the dexamethasone and placebo groups.
A second meta-analysis  and a systematic review  also concluded that adjunctive parenteral dexamethasone is effective for reducing the rate of migraine recurrence. Adjunctive treatment of acute migraine with oral prednisone was not beneficial for prevention of recurrent headache in a small trial .
Given these data, we recommend adjunctive treatment with a single dose of parenteral dexamethasone (10 to 25 mg) to reduce the risk of early headache recurrence for patients who are treated with standard abortive therapy for migraine headache in the emergency department or clinic. However, frequent use of adjunctive dexamethasone for headache increases the risk of glucocorticoid toxicity and should be avoided.
OPIOIDS AND BARBITURATES — Opioids and barbiturates should not be used for the treatment of migraine, except as a last resort :
●Opioids generally are not as effective as migraine-specific medications for acute migraine treatment [10,11,17]. In addition, the use of opioids is complicated by their potential for tolerance, dependence, addiction, and overdose [9,14].
●There is no high-quality evidence supporting the efficacy of barbiturates (ie, butalbital-containing compounds) for acute migraine treatment [4,14].
●The use of opioids and butalbital is associated with an increased risk for the development of chronic migraine and medication overuse headache. (See "Chronic migraine" and "Medication overuse headache: Etiology, clinical features, and diagnosis".)
TRANSCUTANEOUS MAGNETIC STIMULATION — The efficacy of single-pulse transcranial magnetic stimulation (TMS) was demonstrated in a sham-controlled trial of 201 adults with episodic migraine with aura . The analysis was based upon 164 patients who treated at least one attack of migraine during the aura phase. Pain freedom at two hours post-treatment was significantly greater with the TMS device compared with sham stimulation (39 versus 22 percent, absolute risk reduction 17 percent, 95% CI 3-31 percent). Furthermore, significance for a sustained pain-free response was maintained at both 24 and 48 hours. There were no serious adverse events related to use of the device.
The portable TMS device is available in the United Kingdom and selected centers in the United States, but more data are needed to confirm the benefit of this treatment for episodic migraine. The TMS device may prove to be useful as a second-line intervention for those who have episodic migraine with aura that does not respond to first-line therapy with triptans or other agents discussed above or who are unable to take these agents because of contraindications or intolerance. TMS should not be used to treat migraine for patients who have epilepsy, since there is theoretical concern that TMS could trigger seizures .
INVESTIGATIONAL AGENTS — A number of novel drugs are under investigation for the treatment of migraine, including calcitonin-gene related peptide receptor antagonists and serotonin 1F receptor agonists.
CGRP receptor antagonists — Pharmacologic modulation of calcitonin-gene related peptide (CGRP) activity offers the promise of future treatment options for acute migraine attacks. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)
A number of randomized trials suggested that the investigational CGRP receptor antagonists telcagepant (MK-0974) and olcegepant (BIBN 4096 BS) were beneficial for acute migraine attacks [109-112]. However, development of telcagepant was stopped due to concerns regarding hepatotoxicity, and development of olcegepant was halted because of poor oral bioavailability . It remains unclear whether other orally bioavailable CGRP receptor antagonists still in development will be hampered by liver toxicity.
Lasmiditan — Lasmiditan, a selective serotonin 1F receptor agonist that lacks vasoconstrictor activity, was effective for treating migraine in a preliminary randomized placebo-controlled trial . However, lasmiditan had a relatively high rate of serious adverse events, particularly at higher doses; the most common were dizziness, fatigue, vertigo, paresthesia, and somnolence. Further study is needed to determine whether lasmiditan is tolerable at effective doses.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Migraine".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Migraine headaches in adults (Beyond the Basics)" and "Patient education: Headache treatment in adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●There is high-quality evidence from placebo-controlled randomized trials that the following drugs are effective for the treatment of acute migraine attacks:
●For adults with mild to moderate migraine attacks not associated with vomiting or severe nausea, we suggest initial treatment with simple analgesics, including NSAIDs or acetaminophen, rather than other migraine-specific agents (Grade 2C). (See 'Mild to moderate attacks' above and 'Simple analgesics' above.)
●For adult outpatients with moderate to severe migraine attacks, we suggest treatment with a triptan or the combination of sumatriptan-naproxen, rather than other migraine-specific agents (Grade 2C). There are no efficacy data that definitively support use of one triptan versus another; different pharmacologic properties and delivery routes may help guide the choice. Patients who do not respond well to one triptan may respond to a different triptan. (See 'Moderate to severe attacks' above and 'Triptans' above and 'Triptans with NSAIDs' above.)
●Abortive treatments for migraine are usually more effective if they are given early in the course of the headache; a large single dose tends to work better than repetitive small doses. Triptan treatment, in particular, should be given at the first sign of pain in patients susceptible to cutaneous allodynia. (See 'Factors predicting response' above.)
●Many oral agents are ineffective in migraine because of poor absorption secondary to migraine-induced gastric stasis. Therefore, a non-oral route of administration should be selected for patients whose migraines present early with significant nausea or vomiting. (See 'Approach to treatment' above.)
●For patients who present to the hospital emergency department with moderate to severe migraine, particularly if the migraine is accompanied by vomiting or significant nausea, we suggest initial treatment with either subcutaneous sumatriptan 6 mg or a parenteral antiemetic agent rather than other migraine-specific drugs (Grade 2C); reasonable antiemetic choices are intravenous (IV) metoclopramide (10 mg) or prochlorperazine (10 mg). When giving IV metoclopramide or prochlorperazine for migraine, we suggest adjunct use of diphenhydramine (12.5 to 20 mg IV every hour up to two doses) to prevent akathisia and other dystonic reactions (Grade 2C). (See 'Emergency settings' above and 'Antiemetics' above.)
•A more aggressive alternative option, based upon the results of one clinical trial, is high-dose metoclopramide (20 mg IV every 30 minutes up to four doses) given with diphenhydramine. (See 'Metoclopramide' above.)
•IV dihydroergotamine (DHE 45) 1 mg combined with intravenous (IV) metoclopramide 10 mg is also a reasonable alternative for treatment of intractable severe migraine in the emergency department, and it can be used if metoclopramide monotherapy is ineffective. Parenteral DHE 45 should not be used as monotherapy. DHE 45 is contraindicated in patients with ischemic vascular disease involving cardiac, cerebrovascular, or peripheral circulations. (See 'Dihydroergotamine' above.)
●For patients who are treated in the emergency department or clinic for migraine headache with one of the standard abortive therapies discussed above, we recommend adjunctive treatment with IV or intramuscular dexamethasone (10 to 25 mg) to reduce the risk of early headache recurrence (Grade 1B). (See 'Abortive therapy plus parenteral dexamethasone' above.)
●Sublingual, oral, or rectal ergotamine is the drug of choice in relatively few patients with migraine because of uncertain efficacy and risk of serious side effects. Suitable candidates may be those with prolonged duration of attacks (eg, greater than 48 hours) and possibly frequent headache recurrence. (See 'Ergotamine' above.)
●Prophylactic headache treatment is indicated if the headaches are frequent, long lasting, or account for a significant amount of total disability. This topic is discussed separately. (See "Preventive treatment of migraine in adults".)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Ashraf Sabahat, MD, who contributed to an earlier version of this topic review.
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