Acute treatment of migraine in adults

Authors: Todd J Schwedt, MD, MSCI, Ivan Garza, MD

Section Editor: Jerry W Swanson, MD, MHPE
Deputy Editor: Richard P Goddeau, Jr, DO, FAHA

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2024. | This topic last updated: Mar 25, 2024.

What's New

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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 episodic
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, calcitonin gene-related peptide (CGRP) antagonists,
lasmiditan, and dihydroergotamine. The selection of a specific agent depends on
patient-specific factors including the severity and character of symptoms, comorbid
conditions, and prior response to treatment ( algorithm 1). Noninvasive
neuromodulation devices are typically used for patients who do not respond to or
tolerate drug treatments and those who wish to avoid medications.

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.
For some patients, oral agents are less effective because of poor absorption
secondary to migraine-induced gastric stasis and vomiting.

General recommendations for the treatment of acute migraine include the following
[1-3]:
● Educate migraine sufferers about their condition and its treatment and
encourage them to participate in their own management.
● Use migraine-specific agents (eg, triptans, CGRP antagonists, lasmiditan,
dihydroergotamine) for 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 episodic 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 [4]. 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 attacks — For mild migraine attacks not associated with vomiting or severe
nausea, simple analgesics (NSAIDs, acetaminophen) or combination analgesics are
often tried first because they can be effective and are less expensive than migraine-
specific agents [5,6]. For attacks unresponsive to analgesics, we add a triptan. The
combined use of an NSAID with a triptan appears to be more effective than using
either drug class alone. When 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
'Triptans with NSAIDs' 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 [5,6]. For those
with contraindications to or who do not tolerate triptans, a calcitonin gene-related
peptide (CGRP) antagonist or lasmiditan may be effective. When complicated by
vomiting or severe nausea, severe migraine attacks can be treated with an antiemetic
drug or nonoral migraine-specific medications including subcutaneous sumatriptan,
nasal sumatriptan and zolmitriptan, parenteral dihydroergotamine, or nasal
zavegepant. (See 'Triptans' below and 'Triptans with NSAIDs' below and 'CGRP
antagonists' below and 'Lasmiditan' below and 'Antiemetics' below and 'Ergots'
below.)

Status migrainosus — For severe intractable migraine attacks, or status migrainosus

(ie, a debilitating attack lasting for more than 72 hours), patients may be treated with
a combination of intravenous fluids plus parenteral medications such as ketorolac and
a dopamine receptor blocker. Other parenteral medications such as valproate and/or
dihydroergotamine [7] may also be warranted depending on response to initial
therapy [8]. Treatment options are not based on high-quality evidence and medication
selection depends upon patient-level factors. (See 'Nonsteroidal anti-inflammatory
drugs' below and 'Prochlorperazine' below and 'Metoclopramide' below and 'Others'
below and 'Sodium valproate' below.)

Administration of parenteral dexamethasone is often used to prevent attack relapse.

(See 'Abortive therapy plus parenteral dexamethasone' below.)

Patients may require admission for persistent disabling symptoms despite the initial
treatment regimen or for weaning of medication overuse to monitor for withdrawal
symptoms [9-11]. (See 'Emergency settings' below and "Medication overuse
headache: Treatment and prognosis", section on 'Outpatient and inpatient settings'
and 'Antiemetics' below and 'Simple analgesics' below and 'Ergots' below.)

Variable attacks — Many patients with migraine have attacks that vary in severity,
time of onset, and association with vomiting and nausea [12]. 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 [13]. 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 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 [13-20]:
● Sumatriptan 6 mg subcutaneous injection (see 'Triptans' below)
● Antiemetics-dopamine receptor blockers (see 'Antiemetics' below):

• Prochlorperazine 10 mg intravenous (IV) or intramuscular (IM)

• Metoclopramide 10 mg IV
• Chlorpromazine 0.1 mg/kg (or 12.5 mg) single dose as a slow IV infusion
(maximum rate 1 mg/minute); maximum cumulative dose 25 mg
● Dihydroergotamine (1 mg IV) combined with metoclopramide (10 mg IV) (see
'Dihydroergotamine' below)
● Ketorolac 30 mg IV or 60 mg IM (lower doses may be warranted for patients ≥65
years old, <50 kg body weight, and those with kidney impairment) (see
'Nonsteroidal anti-inflammatory drugs' below)

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 and/or a
parenteral antiemetic (eg, prochlorperazine, metoclopramide, 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. (See 'Antiemetics' 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 dihydroergotamine should not be used as monotherapy.
Dihydroergotamine 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 suggest
adjunctive treatment with dexamethasone 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 [21,22],
despite available practice guidelines that recommend nonopioid medications as first-
line therapy for severe migraine [2], or recommend that opioids should not be used in
the acute treatment of migraine [23,24]. 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 [21,25].

Pregnancy — The treatment of migraine in pregnant patients differs somewhat from

the treatment of others because of concerns about adverse fetal drug effects. This
aspect of acute migraine care is reviewed separately. (See "Headache during
pregnancy and postpartum", section on 'Acute migraine treatment'.)

Avoidance of medication overuse — Medication overuse headache (MOH), also

called analgesic rebound headache, is a common disorder with significant morbidity.
Many 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. MOH
may be avoided with some CGRP antagonists, which are effective for preventive as
well as acute treatment of migraine [26-28]. 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 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".)

SIMPLE ANALGESICS

Some patients with migraine have an optimal response with simple analgesics,
including aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), and
acetaminophen ( table 1) [20].

Nonsteroidal anti-inflammatory drugs — NSAIDs with reported efficacy in

randomized placebo-controlled trials of migraine therapy include aspirin (900 to 1000
mg) [29,30], ibuprofen (400 to 600 mg) [31], naproxen sodium (275 to 825 mg) [32],
diclofenac (50 to 100 mg) [33], diclofenac epolamine (65 mg) [34], tolfenamic acid (200
mg) [35], celecoxib [36], and dexketoprofen (50 mg) [37,38]. Some of these studies are
limited by varying outcome measures and definitions of migraine.

A 2013 systematic review of eight randomized trials found that parenteral ketorolac
(30 mg intravenous [IV] or 60 mg intramuscular [IM]) was effective for acute migraine
in comparison with other agents, including intranasal sumatriptan, IV
prochlorperazine, IV chlorpromazine, and IV dihydroergotamine combined with
metoclopramide [39].

One trial showed powdered diclofenac potassium (50 mg) produced more rapid and
effective pain relief at two hours than tablets [40].

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

[41]. 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 [42].

Acetaminophen can be used in combination with NSAIDs. The combination of

acetaminophen-aspirin-caffeine was found to alleviate headaches in patients with
uncomplicated migraine in one report [43].

TRIPTANS

The serotonin 1b/1d agonists (triptans) are effective for the acute treatment of
migraine [20]. The triptans were developed specifically to treat migraine [1,2].
However, triptan responsiveness should not be considered diagnostic of migraine, as
other primary headaches and secondary headaches may also improve with triptan
treatment [44]. (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 [45]. 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 [46].

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, as a nasal powder, or orally. Zolmitriptan is
also available for both nasal and oral use. The others are available for oral use only,
including as pills and orally disintegrating tablets and/or films ( table 2).
A number of randomized controlled trials and systematic reviews have found all of the
triptans to be effective for the treatment of acute migraine [47]. 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) [48]. Pain relief was dose-
dependent, although the differences in most efficacy outcomes between the 40
and 80 mg doses were not statistically significant. 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 [49].
● Naratriptan – At least three randomized trials have found that naratriptan
significantly improves acute migraine relief compared with placebo [50-52]. 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 [51]. 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 [52]. One problem
with this study is that the 50 mg dose of sumatriptan used is often suboptimal
[53]. 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 multiple randomized placebo-controlled
studies [54]. 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 [55-58].

• Oral sumatriptan is given at 50 to 100 mg once. The most effective dose of

oral sumatriptan is 100 mg, while the 50 mg dose may provide the best
combination of efficacy and tolerability [58,59]. The dose (same strength as the
initial dose) may be repeated once after two hours if needed. The maximum
dose is 200 mg per 24 hours.

• Subcutaneous sumatriptan (6 mg) is more effective than oral sumatriptan,

but its use is associated with more adverse events [60]. Subcutaneous
sumatriptan has the fastest onset of action. For acute migraine, the usual initial
dose of subcutaneous sumatriptan is 6 mg. The dose may be repeated once if
needed after one hour. For patients who are intolerant of the 6 mg dose but
need a parental formulation (eg, due to protracted vomiting with migraine),
some experts try a lower initial/repeat dose (eg, 3 or 4 mg) [61]. Sumatriptan
for injection is commercially available in 3, 4, and 6 mg formulations. The
recommended maximum is 6 mg per dose and 12 mg per 24 hours. 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 [62]. 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.

• Intranasal spray sumatriptan (liquid) is given as one insufflation of 20 mg in

a single nostril. The dose may be repeated once after two hours if needed. The
maximum dose is 40 mg per 24 hours. Intranasal sumatriptan has fewer side
effects than the injectable formulation [60]. The most common side effect of
intranasal sumatriptan is an unpleasant taste.
 • Intranasal sumatriptan coformulated with DDM (a permeation enhancer for
more rapid absorption into the systemic circulation) is given as a single
insufflation of 10 mg in one nostril [63]. The maximum dose is 30 mg per 24
hours with individual doses separated by at least one hour. The most common
adverse reactions related to application were nasal discomfort, unpleasant
taste, and throat irritation.

• Nasal powder sumatriptan is given as a 22 mg dose using one 11 mg capsule

insufflated in each nostril with a breath-powered delivery device. The dose may
be repeated once after two hours if needed. The maximum dose is 44 mg per
24 hours. The most common adverse reactions are an abnormal or unpleasant
taste and nasal discomfort.
● Zolmitriptan – A number of randomized placebo-controlled trials and a
systematic review and meta-analysis [64] 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
[65]. 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 a triptan should be individualized; different

pharmacologic properties and delivery routes may help guide the choice ( table 2).
Patients who do not respond well to one triptan may respond to another [66].

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 [67]. 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 [68]. 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
[69].

Factors predicting response — Prompt treatment of migraine attacks is considered

important to successful acute therapy [53,70,71], 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 [72]. 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) [72]. 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 [73]. 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 nonallodynic attacks [74]. The
authors concluded that patients who develop allodynia, which takes one to four hours
to establish [75], 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 [76]. A systematic review of observational studies found no association
between triptan use and the risk of vasoocclusive cardiovascular events, though only
four relevant studies were identified [77]. 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 [78]. However, in this cohort, triptans were prescribed to those at less risk of
these events.
● Dosing frequency – All triptans should be limited to no more than 10 days of use
per month to avoid medication overuse headache. (See "Medication overuse
headache: Etiology, clinical features, and diagnosis", section on 'Triptans'.)
● High cardiovascular risk profile – Based on limited evidence, triptans should be
avoided in patients with ischemic stroke, ischemic heart disease, Prinzmetal's
angina, and uncontrolled hypertension [79]. In a Danish case-crossover study of
more than 429,000 individuals, new use of a triptan within the preceding two
weeks was associated with an elevated risk of stroke or myocardial infarction [80].
This association was strongest among individuals age <60 years and those with a
history of hypertension, diabetes mellitus, and prior myocardial infarction.
However, overall event rates were low, occurring in only 28 patients following
triptan initiation.
 ● Migraine subtypes – Triptans are avoided in patients with hemiplegic migraine
or migraine with brainstem aura due to the theoretical risk of cerebral
vasoconstriction. (See "Hemiplegic migraine", section on 'Medications generally
avoided' and "Migraine with brainstem aura", section on 'Medications to avoid'.)
● Drug interactions – Combination with monoamine oxidase inhibitors is relatively
contraindicated with triptans because of the risk of serotonin syndrome. Triptans
should not be used within 24 hours of the use of ergotamine preparations or a
different triptan medication [81]. (See "Serotonin syndrome (serotonin toxicity)".)

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) [82]. 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 [83-86]. 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.

For additional information on triptan drug interactions, refer to individual drug

monographs or the drug interactions program included within UpToDate.

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 [87]. 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 formulation of sumatriptan succinate 85 mg and
naproxen sodium 500 mg in a single tablet (Treximet) [88]. 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 randomized placebo-controlled 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) [89]. Even at 30 minutes, there was a
statistically significant pain-free response with combination sumatriptan plus
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) [90].
ANTIEMETICS

Intravenous (IV) metoclopramide and IV or intramuscular (IM) prochlorperazine can

be used along with other agents or 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 25
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.

Other antiemetic medications can cause dose-dependent prolongation of the QT

interval on electrocardiogram (ECG), which can lead to a life-threatening cardiac
arrhythmia, including torsades de pointes. These include haloperidol,
chlorpromazine, droperidol, and ondansetron. They may be used for patients when
migraine symptoms are unresponsive to antiemetics that do not prolong the QT
interval. They should be avoided in patients with congenital long QT syndrome, those
with persistent corrected QT interval (QTc) >500 milliseconds on ECG, and with other
risk factors for acquired long QT syndrome ( table 3). (See "Acquired long QT
syndrome: Definitions, pathophysiology, and causes", section on 'Risk factors for
drug-induced long QT syndrome'.)

In contrast with IV or IM preparations, oral antiemetics should not be considered as

monotherapy in acute migraine [1,2].

Prochlorperazine — In controlled trials, IV prochlorperazine appears to be as

effective or more effective than IV metoclopramide or subcutaneous sumatriptan, and
more effective than hydromorphone or placebo in the acute treatment of migraine
[14,16,19,91,92]. In most of these trials, diphenhydramine was used as adjunct
treatment to prevent akathisia and dystonic reactions, and the possibility of migraine
benefit from diphenhydramine cannot be completely discounted.

In one randomized controlled trial evaluated that 127 adults who presented to the
emergency department for the treatment of migraine, the combination of IV
prochlorperazine (10 mg) and IV diphenhydramine (25 mg) was more effective than IV
hydromorphone (1 mg) for achieving sustained headache relief, defined as a
reduction to a level of mild or no headache within two hours of medication
administration and without relapse or need for rescue mediation for 48 hours [92].

In another 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 [93]. A high dropout 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 [14,16,19,94]. One meta-
analysis, published in 2004, reviewed 13 clinical trials [94]. Study methods varied
considerably, and the quality of the included studies was generally poor. The following
observations were made [94]:
● 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.
● Metoclopramide was less effective than chlorpromazine and prochlorperazine in
relieving pain and nausea, although differences were not always statistically
significant.
● One trial found that metoclopramide treatment was not statistically different than
sumatriptan for rates of complete resolution of migraine or significant reduction
in pain or nausea.

Oral metoclopramide may be effective when combined with other treatments. (See
'Use in adjunctive therapy' below.)
Others — Chlorpromazine, ondansetron or granisetron, 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 [19]. Adverse effects with these agents
may include rebound headache, akathisia, and arrythmia from QT-segment
prolongation on ECG ( table 3). If these medications are used, ECG should be
obtained at baseline and at two to three hours after dosing [95], and patients should
be monitored for clinical symptoms suggestive of QT-segment prolongation. (See
"Acquired long QT syndrome: Clinical manifestations, diagnosis, and management",
section on 'Precautions for any patient starting QT-prolonging drugs'.)
● Chlorpromazine – Although data are limited, IV chlorpromazine appears to be
effective in the acute treatment of migraine [14,16,19]. In one of the larger clinical
trials that assessed chlorpromazine treatment in the emergency department, 128
patients with migraine were assigned 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 [96]. 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.
● Ondansetron and granisetron – Treatment of acute migraine using ondansetron
or granisetron has not been rigorously evaluated, although there are reports
describing their use [97]. However, both ondansetron and granisetron have been
associated with a relatively high incidence of headache as an adverse effect [98-
100]. Several guidelines recommend against the use of intravenous granisetron
for acute migraine [2,19].
● Droperidol – 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 [101]. 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 [14,16].
● Haloperidol – A placebo-controlled trial of 40 hospitalized patients found that
haloperidol (5 mg IV) was effective for migraine pain relief [102]. 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 [103]. 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 [104]. 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.

CGRP ANTAGONISTS

Pharmacologic modulation of calcitonin-gene related peptide (CGRP) activity appears

to mediate trigeminovascular pain transmission in migraine (see "Pathophysiology,
clinical manifestations, and diagnosis of migraine in adults"). Several CGRP
antagonists have been developed for acute and preventive treatment of migraine
headache. Monoclonal antibodies directed against the CGRP receptor or ligand are
given by periodic injection for migraine prevention. Small-molecule CGRP antagonists
(also termed "gepants") are oral or intranasal medications with specific agents
formulated for acute treatment, and others for migraine prevention.
CGRP antagonists are often used for patients with either insufficient response or
contraindication (eg, coronary artery disease) to treatment with triptans and/or
antiemetics. Options for acute migraine include:
● Ubrogepant – Ubrogepant is given as a single oral tablet at either 50 or 100 mg.
The dose may be repeated in two hours with a maximum daily dose of 200 mg.

Multiple clinical trials have shown ubrogepant is effective for acute migraine [105-
107]. One trial randomly assigned adult patients with episodic migraine in a 1:1:1
ratio to one tablet of ubrogepant 100 mg, ubrogepant 50 mg, or placebo taken
within four hours of a single migraine attack; an optional second dose or the
patient's own rescue medication was permitted 2 to 48 hours after the first dose
[106]. With efficacy data for 1327 patients, the proportion with pain freedom at
two hours after treatment was greater for those assigned to the 100 mg and 50
mg doses of ubrogepant compared with placebo (21.2, 19.2, and 11.8 percent,
respectively). Also, the proportion who reported absence of their most
bothersome migraine-associated symptom (ie, photophobia, phonophobia, or
nausea) at two hours after treatment was greater for those assigned to
ubrogepant 100 and 50 mg compared with placebo (37.7, 38.6, and 27.8 percent).
The most common adverse events were nausea, somnolence, and dry mouth.

Ubrogepant may also be effective at preventing onset of acute headache when

taken during migraine prodrome. In a trial of 477 patients with migraine who
were treated at onset of prodromal symptoms and prior to headache, the
proportion of patients who remained free of moderate to severe headache at 24
hours was higher in patients who received ubrogepant than those who received
placebo (46 versus 29 percent) [107]. Enrolled patients had migraines that
consisted of prodromal symptoms (eg, photophobia, fatigue, neck pain) occurring
one to six hours before headache onset in at least 75 percent of attacks. Adverse
rates were low in the trial and included nausea, fatigue, dizziness, and
somnolence.

Ubrogepant received US Food and Drug Administration (FDA) approval for the
treatment of acute migraine in adults in December 2019 [108].
● Rimegepant – Rimegepant is given at 75 mg as a single oral dose.
 Clinical trial evidence supports the efficacy of rimegepant for acute migraine
treatment. In a clinical trial of 1466 patients with migraine, patients who received
rimegepant were likelier to be pain free at two hours than those who received
placebo (21 versus 11 percent) and had higher rates of freedom from most
bothersome migraine symptom (35 versus 27 percent) [109]. Nausea and lower
urinary tract infections were common adverse effects. Similar results were
reported in another trial of 1186 patients with migraine [110]. Rimegepant
received US FDA approval for acute migraine treatment in February 2020 [111].

Rimegepant has also been found to be effective in some patients who did not
respond previously to a triptan [112]. Rimegepant is also approved by the US FDA
for migraine prevention when given at a dose of 75 mg once every other day. (See
"Preventive treatment of episodic migraine in adults", section on 'CGRP
antagonists'.)
● Zavegepant – Zavegepant is given at 10 mg intranasally as a single spray.

In a trial of 1405 adult patients with migraine, those assigned to zavegepant 10

mg were likelier to be pain free at two hours than patients assigned to placebo
(24 versus 15 percent; risk difference 9 percent, 95% CI 4.5-13.1) [113]. In
addition, resolution of the most bothersome acute symptom (eg, photophobia,
nausea) was more common with zavegepant (40 versus 31 percent). Adverse
events were transient and mild and included dysgeusia and nasal discomfort.
Nasal administration of a CGRP-receptor antagonist provides rapid absorption
and effect and may be preferred for patients with nausea and/or vomiting who
are unable to tolerate oral options. Zavegepant was approved for acute migraine
by the US FDA in 2023 [114].

The safety of using a CGRP antagonist within two to four hours of a triptan or
ergotamine agent is not well established. Additional long-term data on CGRP
antagonists are needed to better define safety and tolerability.

Several other CGRP antagonists are approved for migraine prevention, as discussed
separately. (See "Preventive treatment of episodic migraine in adults", section on
'CGRP antagonists'.)
LASMIDITAN

Lasmiditan is a selective serotonin 1F receptor agonist that lacks vasoconstrictor

activity and therefore can be used for patients with relative contraindications to
triptans due to cardiovascular risk factors [115].

In a randomized trial of over 2200 patients with episodic migraine, the proportion
who were headache pain-free at two hours was greater with lasmiditan 200 mg (32
versus 15 percent with placebo; absolute risk difference [ARD] 17 percent; odds ratio
[OR] 2.6, 95% CI 2.0-3.6) and lasmiditan 100 mg (28 versus 15 percent; ARD 13
percent; OR 2.2, 95% CI 1.6-3.0) [116]. In a 2021 meta-analysis including five trials and
more than 7000 patients, resolution of pain at two hours likelier with lasmiditan than
placebo (relative risk [RR] 1.95, 95% CI 1.3-3.0) [117]. Lasmiditan was also effective for
treating acute migraine in another randomized placebo-controlled trial of 2310
patients [118].

In October 2019, the US Food and Drug Administration (FDA) approved lasmiditan oral
tablets for the acute treatment of migraine in adults [119]. The initial dose of
lasmiditan is 50 or 100 mg; there is no benefit with taking a second dose for the same
migraine attack. With subsequent attacks, the dose may be increased to 100 or 200
mg as needed, but no more than one dose should be taken in 24 hours [120].

The most common adverse event associated with lasmiditan is dizziness; other
relatively frequent adverse events are paresthesia, somnolence, fatigue, and nausea
[116,118]. Dizziness with lasmiditan is dose-dependent and largely mild to moderate
in severity, with a median duration of 1.5 to 2 hours [121]. The drug may cause driving
impairment, and patients should not drive a motor vehicle, operate machinery, or
engage in potentially hazardous activities for at least eight hours after each dose of
lasmiditan [120].

ERGOTS

A variety of ergotamine preparations, alone and in combination with caffeine and

other analgesics, have been used for the abortive treatment of migraine [122]. Both
ergotamine and dihydroergotamine bind to 5HT 1b/d receptors, just as triptans do. As
the evidence reviewed below suggests, parenteral dihydroergotamine is effective for
acute migraine, while the effectiveness of ergotamine is uncertain.

Dihydroergotamine — Dihydroergotamine is an alpha-adrenergic agonist that is a

weaker arterial vasoconstrictor and more potent venoconstrictor than ergotamine
tartrate. It is also a potent 5-HT 1b/1d receptor agonist. Dihydroergotamine has fewer
side effects than ergotamine [7]. It is available for intravenous (IV), intramuscular (IM),
subcutaneous, and intranasal use. Dihydroergotamine 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 dihydroergotamine 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 dihydroergotamine (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 IV or IM
dihydroergotamine therapy for acute migraine in adults [123]. The quality of the
included studies was variable, and most had relatively small sample sizes. The
following observations were reported:
● In two studies, dihydroergotamine alone (without an antiemetic) was less
effective on most outcome measures than sumatriptan [124,125], and in one
study was less effective on some (but not all) outcome measures than
chlorpromazine [126].
● In eight studies, the combination of parenteral dihydroergotamine 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 dihydroergotamine 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 dihydroergotamine combined with an antiemetic was
superior to other agents combined with the same antiemetic, suggesting that
dihydroergotamine does have independent efficacy for migraine [126].

Self-administered intranasal dihydroergotamine has been found, in placebo-

controlled trials, to be efficacious for the treatment of migraine symptoms [127,128].
In one trial of over 300 patients with migraine, for example, 27 percent of patients
who administered 2 mg of intranasal dihydroergotamine had resolution of their
headache within 30 minutes [129]. 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.

A delivery system targeting the upper nasal cavity may improve systemic availability
of dihydroergotamine. In an open-label study of 360 patients with migraine, 52
percent of patients reported resolution of the most bothersome migraine symptom
and 66 percent reported pain relief at two hours when using dihydroergotamine
mesylate delivered to the upper nasal cavity [128]. The most common treatment-
related adverse effects were nasal congestion (15 percent), nausea (7 percent), and
nasal discomfort (5 percent).

Subcutaneous dihydroergotamine 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 dihydroergotamine 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 [124]. Headache relief occurred in 86 and 83 percent by four
hours, respectively, a difference that was not statistically significant. However,
dihydroergotamine 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).

Dihydroergotamine should not be used within 24 hours of triptans or other ergot-like

agents. Dihydroergotamine is contraindicated in patients with hypertension or
ischemic heart disease, and in pregnancy. Dihydroergotamine should not be used in
combination with peripheral and central vasoconstrictors or with potent inhibitors of
CYP3A4 (including protease inhibitors, azole antifungals, and some macrolide
antibiotics) and in patients with hemiplegic migraine or migraine with brainstem aura.

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) [130], and most placebo-controlled
trials of oral ergotamine alone have failed to show efficacy in the relief of migraine
[131]. 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 [132,133]. 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 [134].

Ergotamine should not be used within 24 hours of triptans or other ergot-like agents.
Ergots should be avoided in patients with coronary artery disease because they cause
sustained coronary artery constriction [135], peripheral vascular disease,
hypertension, and liver or kidney 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 [136].
They also should not be used in patients who have hemiplegic migraine, migraine
with brainstem aura, and 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 [132]. 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

For patients who present to the emergency department with severe or prolonged
migraine, we suggest adjunctive intravenous (IV) dexamethasone along with an
abortive agent to reduce the risk of early headache recurrence. However, frequent use
of adjunctive dexamethasone for headache increases the risk of glucocorticoid
toxicity and should be avoided.

In a meta-analysis of seven randomized trials conducted in emergency departments

or headache clinics, parenteral treatment with dexamethasone was found to reduce
the rate of early headache recurrence when added to standard acute migraine
therapy [137]. All patients (n = 738) received standard abortive migraine headache
treatment and were also randomly assigned to treatment with either a single IV or
intramuscular (IM) dose of dexamethasone 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. There were no
significant differences regarding adverse events between the dexamethasone and
placebo groups. However, dexamethasone provided no additional benefit for
immediate relief of headache. Similar results were found in a second meta-analysis
and a systematic review [138,139].

We suggest using dexamethasone as a single IV dose of 4 mg. Initial trials reported

benefit with single doses of IV dexamethasone at a range of 8 to 24 mg [137,138].
However, treatment benefits were similar whether trials used doses less than 15 mg
or higher doses [137]. Subsequent trial data have found similar benefit with low
dexamethasone dosing. In a 2023 trial of 209 patients with moderate to severe
migraine presenting to the emergency department treated with metoclopramide and
dexamethasone, the rates of sustained relief at 48 hours were similar whether
patients were assigned to a single dose of dexamethasone at 4 or 16 mg (34 versus 41
percent, absolute difference 7 percent, 95% CI -6 to 20 percent) [140]. Similar results
for low- and high-dose dexamethasone groups were also found in the rate of
immediate headache relief as well as the subsequent number of headache days and
rates of headache medication use in the week following discharge. Adverse effects in
both groups were rare.

Adjunctive treatment with oral glucocorticoids for acute migraine was not beneficial
for prevention of recurrent headache in a small trial [141].

SODIUM VALPROATE

Limited data suggest that intravenous (IV) sodium valproate may be effective for
acute migraine treatment. In a small trial of 99 adults with migraine without aura
presenting acutely to an emergency department, patients who were given a single
dose of IV sodium valproate at 800 mg were likelier to report pain relief by two hours
than those who received 800 mg of ibuprofen [142]. Similar benefit was found in small
studies when sodium valproate was compared with sumatriptan and dexamethasone
[143,144]. However, other studies have suggested only short-term benefit with higher
rates of rescue therapy with sodium valproate than antiemetics and analgesics
[18,145].

Intravenous valproate is preferred over oral formulations for acute migraine

treatment because it is faster acting. The typical dose is 500 to 1000 mg over 5 to 10
minutes (up to 10 mg/kg each minute). Adverse effects with valproate include nausea,
vomiting, and tremor. Valproate for migraine treatment is contraindicated in pregnant
patients due to an elevated risk of teratogenicity.

NEUROMODULATION

Limited data from small randomized controlled trials suggest benefit of various forms
of neuromodulation for the treatment of acute migraine pain. These treatments
stimulate the central or peripheral nervous system with an electrical current or a
magnetic field [146]. They are options for patients who prefer nonpharmacologic
treatments or who have an inadequate response, inability to tolerate, or
contraindications to drug treatments for migraine.

Transcutaneous supraorbital nerve stimulation — Transcutaneous supraorbital

nerve stimulation can reduce migraine pain intensity, as shown in the ACME trial,
which randomly assigned 109 subjects having an acute migraine attack of at least
three hours duration to a one-hour treatment session with external trigeminal nerve
stimulation or sham stimulation [147]. Pain was assessed using a visual analog scale,
ranging from 0 (no pain) to 10 (maximum pain). The mean reduction in pain intensity
at one hour was greater for the true stimulation group compared with the sham
group (-3.46 versus -1.78). There were five minor adverse events and no serious
adverse events in the true stimulation group.

The supraorbital transcutaneous trigeminal nerve stimulator device used in this trial is
approved for marketing in the United States, Canada, Europe, and several additional
countries. The evidence pertaining to migraine prevention is reviewed separately. (See
"Preventive treatment of episodic migraine in adults", section on 'Neuromodulation'.)

Remote electrical neuromodulation — Data from several trials suggest that a device
applying nonpainful electrical skin stimulation can reduce acute migraine pain [148-
150]. The stimulating device, controlled with a smartphone, consists of an armband
with rubber electrodes and a power source. The armband is applied, and stimulation
started as soon as possible after the onset of a migraine attack. In a sham-controlled
crossover pilot trial of 71 patients, the proportion of responders was higher with
active stimulation compared with sham stimulation [148].

A later trial of 252 adults with episodic migraine tested randomized patients in a 1:1
ratio to receive 30 to 45 minutes of active stimulation (frequency 100 to 120 Hz, pulse
width 400 microseconds, and output current up to 40 mA adjusted by the patient) or
sham stimulation (pulse frequency approximately 0.08 Hz, modulated pulse width 40
to 550 microseconds) [149]. Sham stimulation was designed to produce a sensation
similar to active stimulation but with a frequency too low to induce pain inhibition. At
two hours after treatment, more patients assigned to active stimulation were pain-
free (37 percent, versus 18 percent with sham, absolute risk difference [ARD] 19
percent) or had pain relief, defined as an improvement from severe or moderate pain
to mild or none, or from mild pain to none (67 versus 39 percent, ARD 28 percent).
Mild device-associated adverse events occurred in approximately 4 percent and
included a warm sensation, arm or hand numbness, redness, itching, tingling, muscle
spasm, arm pain, shoulder pain, and neck pain. There were no serious adverse events.
The remote electrical neuromodulation device used in this trial is approved for
marketing in the United States.

Transcranial 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 [151]. 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 the United States. The
TMS device may prove to be useful as a second-line intervention for those who have
migraine 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 [152].

Noninvasive vagus nerve stimulation — Noninvasive vagus nerve stimulation

(nVNS) may be beneficial for the acute treatment of episodic migraine. The PRESTO
trial randomly assigned over 240 participants to treatment with a proprietary nVNS
device or a sham device [153]. Subjects were instructed to self-administer stimulation
for 120 seconds each to right and left sides of the neck within 20 minutes from the
onset of migraine pain, and to repeat stimulation, if not pain-free, at 15 minutes and
120 minutes. More patients achieved pain freedom with nVNS compared with sham,
but the difference was not significant at 120 minutes (30 versus 20 percent). The most
common adverse effects in the nVNS group were discomfort at the application site
and nasopharyngitis. The nVNS device used in this trial is approved for marketing in
the United States and European Union.

PERIPHERAL NERVE BLOCKS

Nerve blocks targeting the occipital nerve, sphenopalatine ganglion, and trigeminal
nerve are options for the acute treatment of migraine in patients who have severe
and prolonged migraine attacks, and in patients who are refractory to or have
contraindications to standard migraine treatments [154,155]. The most important
contraindications to peripheral nerve blocks include known allergy to a local
anesthetic, open skull defect, and overlying skin infection; pregnancy is a relative
contraindication. (See "Headache during pregnancy and postpartum".)

Evidence of efficacy is limited mainly to small, low-quality trials.

● Occipital nerve blocks – A sham-controlled trial enrolled patients with migraine
from the emergency department who had persistent headache one hour or more
after treatment with intravenous metoclopramide [156]. The primary outcome of
headache freedom at 30 minutes was achieved by 4 of 13 (31 percent) treated
with bilateral greater occipital nerve blocks, and none of 15 patients (0 percent)
who received sham therapy. There were no differences in adverse effects
between the treatment groups.
● Sphenopalatine ganglion blocks – Commercially available intranasal devices
supposedly facilitate blockade of the sphenopalatine ganglion (SPG) by topical
application and passive diffusion of local anesthetic. However, anatomic research
has shown that the SPG is not as close to the nasal mucosa as previously believed,
raising doubt that SPG blockade can be accomplished through intranasal
application of local anesthetic [157].

Nevertheless, limited data suggest benefit of SPG blocks for treatment of acute
migraine. One early trial randomly assigned patients in a 2:1 ratio to intranasal 4
percent lidocaine or saline placebo; a 50 percent reduction in headache intensity
at 15 minutes was achieved by 29 patients (55 percent) treated with lidocaine
compared with 6 patients (21 percent) who received placebo [158]. A later
parallel-arm, randomized pilot trial enrolled patients with chronic migraine and
randomly assigned them in a 2:1 ratio to repetitive SPG blocks twice weekly for six
weeks with either 0.5 percent bupivacaine or saline. With efficacy data for 38
patients, pain rating scores were lower at 15 minutes, 30 minutes, and 24 hours
postprocedure for patients treated with bupivacaine compared with those treated
 with saline [159]. However, patients treated bupivacaine had only a marginal
absolute reduction in average pain intensity (1 to 1.5 units on the numerical
rating scale) compared with placebo.

OPIOIDS AND BARBITURATES

Opioids and barbiturates should not be used for the treatment of migraine, except as
a last resort [160]:
● Opioids generally are not as effective as migraine-specific medications for acute
migraine treatment [16,17,23]. In addition, the use of opioids is complicated by
their potential for tolerance, dependence, addiction, and overdose [15,20].
● There is no high-quality evidence supporting the efficacy of barbiturates (ie,
butalbital-containing compounds) for acute migraine treatment [5,20].
● 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".)

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 and other primary headache disorders".)

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.)
● Basics topics (see "Patient education: Migraine in adults (The Basics)")
● Beyond the Basics topics (see "Patient education: Migraine in adults (Beyond the
Basics)" and "Patient education: Headache treatment in adults (Beyond the
Basics)")

SUMMARY AND RECOMMENDATIONS

● Approach to treatment – Abortive treatments are usually more effective if they
are given early in the course of the migraine attack; a large single dose tends to
work better than repetitive small doses. For patients who present with significant
nausea or vomiting, a nonoral (eg, intravenous [IV], intramuscular [IM], or
subcutaneous) agent may be preferred. Adjunctive preventive medications may
be warranted when headaches are frequent or unresponsive to acute therapies to
reduce the risk of medication overuse headache. (See 'Approach to treatment'
above.)

The selection of a specific agent depends on patient-specific factors including the

severity and character of symptoms, comorbid conditions, and prior response to
treatment ( algorithm 1).
● Patients with mild migraine attacks – For patients with mild migraine attacks
without vomiting or severe nausea, we suggest initial treatment with nonopioid
analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs) and/or
acetaminophen ( table 1), rather than migraine-specific agents (Grade 2C). (See
'Mild attacks' above and 'Simple analgesics' above.)

For patients unresponsive to nonopioid analgesics, we add a triptan ( table 2).

The combined use of an NSAID with a triptan is more effective than either agent
 alone. (See 'Triptans with NSAIDs' above and 'Antiemetics' above and 'Simple
analgesics' above.)
● Patients with moderate to severe migraine attacks – For patients with
moderate to severe migraine attacks, we suggest treatment with a triptan with or
without a nonopioid analgesic (eg, naproxen sodium) ( table 1), rather than
other migraine-specific agents (Grade 2C). Several triptans are available in a
variety of formulations ( table 2). All the triptans are effective for the acute
treatment of migraine and the combined use of a triptan and a nonopioid
analgesic appears to be more effective than using either class alone. (See
'Moderate to severe attacks' above and 'Triptans' above and 'Triptans with
NSAIDs' above.)

When attacks are associated with severe nausea or vomiting, we add an

antiemetic and/or switch to a nonoral migraine-specific medication.

Alternative options include calcitonin gene-related peptide (CGRP) antagonists,

lasmiditan, an antiemetic drug, and dihydroergotamine. (See 'CGRP antagonists'
above and 'Lasmiditan' above and 'Antiemetics' above and 'Ergots' above.)
● Patients with severe migraine attacks in an emergency department – For
patients with refractory migraine attacks who present to the hospital emergency
department (ED), we suggest combination treatment that includes (Grade 2C)
(see 'Emergency settings' above):

• Subcutaneous sumatriptan 6 mg and/or a parenteral antiemetic agent. (See

'Triptans' above and 'Antiemetics' above.)
• Adjunctive diphenhydramine 25 mg, if IV metoclopramide or prochlorperazine
are used, to prevent akathisia and other dystonic reactions. (See 'Antiemetics'
above.)
• Adjunctive dexamethasone 4 mg (IV or IM) to reduce the risk of early headache
recurrence. (See 'Abortive therapy plus parenteral dexamethasone' above.)

Alternative options include IV dihydroergotamine (DHE 45) combined with IV

metoclopramide (for patients who have not receive a triptan within 24 hours), IV
sodium valproate, or IM/IV ketorolac. (See 'Dihydroergotamine' above and
'Sodium valproate' above and 'Simple analgesics' above.)
 ● Status migrainosus – For patients with status migrainosus (ie, a debilitating
attack lasting for more than 72 hours), we suggest a combination of intravenous
fluids plus parenteral medications, including ketorolac and a dopamine receptor
blocker (eg, prochlorperazine, metoclopramide, chlorpromazine) (Grade 2C).
Other options include valproate and/or dihydroergotamine; some patients may
require admission for persistent disabling symptoms. (See 'Status migrainosus'
above.)

ACKNOWLEDGMENTS

The editorial staff at UpToDate acknowledge Ashraf Sabahat, MD, Zahid H Bajwa, MD,
and Jonathan H Smith, MD, who contributed to earlier versions of this topic review.
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