Review Article

Acute Migraine
Address correspondence to
Dr Werner J. Becker, Foothills
Hospital, Division of Neurology,
12th Floor, 1403 29th Street NW,

Treatment Calgary, AB, T2N 2T9, Canada,

[email protected].
Relationship Disclosure:
Werner J. Becker, MD Dr Becker has served on the
medical advisory boards of
Allergan, Inc; Amgen Inc;
electroCore Medical LLC; and
ABSTRACT Tribute Pharmaceuticals
Canada, Inc, and the clinical
Purpose of Review: This article provides a systematic, evidence-based approach to trial steering committee of
acute medication choices for the patient with migraine. St. Jude Medical, Inc. He
Recent Findings: Recent clinical trials, meta-analyses, and practice guidelines have has received personal
compensation for speaking
confirmed that four nonsteroidal anti-inflammatory drugs (NSAIDs) with random- engagements from Allergan,
ized controlled trial evidence for efficacy in migraine (ibuprofen, naproxen sodium, Inc; EMD Serono, Inc; Teva
diclofenac potassium, and acetylsalicylic acid) and seven triptans (sumatriptan, rizatriptan, Pharmaceutical Industries Ltd;
and Tribute Pharmaceuticals
eletriptan, zolmitriptan, almotriptan, frovatriptan, and naratriptan) are appropriate medi- Canada, Inc, and for the
cations for acute migraine treatment. Dihydroergotamine (DHE) is also suitable for development of educational
selected patients. materials for Allergan, Inc.
Unlabeled Use of
Summary: NSAIDs and triptans are the mainstays of acute migraine therapy, and Products/Investigational
antiemetic drugs can be added as necessary. Opioids and combination analgesics Use Disclosure:
containing opioids should not be used routinely. Patient-specific clinical features should Dr Becker discusses the
unlabeled/investigational
help guide the selection of an acute medication for an individual patient. Acute use of butalbital, codeine,
medications can be organized into four treatment strategies for use in various clinical dexamethasone, dexketoprofen,
settings. The acetaminophen-NSAID strategy is suitable for patients with attacks of dimenhydrinate, domperidone,
ketorolac, metoclopramide,
mild to moderate severity. The triptan strategy is suitable for patients with severe morphine, oxycodone,
attacks and for those with attacks of moderate severity who do not respond well to prednisone, prochlorperazine,
NSAIDs. The refractory migraine strategies may be useful for patients who do not and tramadol for the acute
treatment of migraine.
respond well to the NSAIDs or triptans alone and include using triptans and NSAIDs
* 2015, American Academy
simultaneously in combination, DHE, and rescue medications (eg, dopamine antago- of Neurology.
nists, combination analgesics, and corticosteroids) when the patient’s usual medica-
tions fail. Strategies for patients with contraindications to vasoconstricting drugs include
use of NSAIDs, combination analgesics, and dopamine antagonists.
Acetaminophen is the safest acute migraine drug during pregnancy, and acet-
aminophen with codeine is also an option. Sumatriptan may be an option during preg-
nancy for selected patients and is compatible with breast-feeding.

Continuum (Minneap Minn) 2015;21(4):953–972.

INTRODUCTION Use of acute medications among in-

Pharmacologic migraine treatment can dividuals with migraine is almost univer-
be divided into two categories: acute sal. More than 90% of migraine sufferers
migraine drug treatment for individual in the general population use one or more
attacks and prophylactic (preventive) drug acute migraine medications.1 Treating
treatment. It is critical that patients under- moderate or severe migraine attacks ef-
stand the differences between these two fectively is important. Migraine attacks
categories as the medications used are cause significant disability. Based on ictal
quite different. Also, while daily medica- disability during the migraine attack alone,
tion use is essential for successful preven- the World Health Organization (WHO)
tive treatment, the frequency of use of ranks migraine eighth among all disorders
acute medications must be limited to causing years of life lived with disability.2
avoid medication-overuse headache. Effective acute medication use should

Continuum (Minneap Minn) 2015;21(4):953–972 www.ContinuumJournal.com 953

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Acute Migraine Treatment

KEY POINTS
h Patients need to have the potential to markedly reduce on migraine attack severity and the re-
understand the the disability caused by migraine attacks by sulting disability. Thus, a triptan might be
difference between shortening attack duration and reducing prescribed as initial therapy for patients
acute and preventive attack severity. with severe disabling attacks that often
migraine medications. The cost of migraine to society, con- render them unable to function, while a
h The cost of migraine to sidering both direct and indirect costs nonsteroidal anti-inflammatory drug
society, considering
(eg, missed work) is enormous. A (NSAID) might be chosen as initial ther-
both direct and indirect
European study found that the cost of apy for a patient with less severe attacks.
costs, is enormous. A
headache to society greatly exceeded the This approach attempts to try the ‘‘best’’
European study found costs of many other neurologic disorders, medication for the patient first. Neurol-
that the cost of including stroke, multiple sclerosis, and
ogists should keep in mind that by the
headache to society Parkinson disease.3 Good acute pharma-
cologic migraine treatment might be ex- time patients with migraine consult, they
exceeded the costs of have invariably tried multiple over-the-
many other neurologic pected to reduce these costs.
For some individuals, migraine ap- counter simple and combination anal-
disorders, including
pears to be a progressive disorder. Ap- gesics, including NSAIDS. Therefore, a
stroke, multiple
proximately 1% of the general population stratified approach will be necessary for
sclerosis, and
Parkinson disease. has chronic migraine, a disabling migraine patients who present to a neurologist.
syndrome in which individuals suffer from
headache on 15 or more days per month Step-Care-Across-Attacks
for at least 3 months.4 Approximately 12% Approach
of the general population has migraine,5 In the step-care-across-attacks approach,
and essentially all individuals with chronic a less expensive medication or one with
migraine have a prior history of episodic greater perceived safety or fewer side ef-
migraine. Risk factors that predispose fects is chosen first for a patient. If this is
patients to the development of chronic ineffective, other medications are tried in
migraine include obesity, snoring, caf- turn for subsequent attacks as previously
feine use, allodynia, depression, stressful
used medications fail. This approach
situations, acute medication overuse,
head injury, and suboptimal acute treat- may result in several failed therapeutic
ment of individual attacks. Peripheral trials with simple analgesics and NSAIDs
and central sensitization of pain path- before an effective medication is found
ways due to repeated migraine attacks for the patient with relatively severe
may play a role in the pathophysiology migraine attacks. It may also result in a
of chronic migraine, and, indeed, a high patient becoming a ‘‘lapsed consulter’’
migraine attack frequency is a major as patients may feel little can be done
risk factor for its development.6 for them. They may then rely on over-
the-counter nonprescription medica-
APPROACH TO ACUTE MIGRAINE tions, often with poor therapeutic results.
TREATMENT In practice, given the availability of many
Many medications are used for acute medications without prescription, many
migraine treatment, and both the prac- patients have already tried a number of
titioner and the patient need to have an medications before consulting a physi-
organized approach to medication choice. cian for their headaches. Thus, they may
Three basic approaches or strategies have be well advanced along a step-care-across-
been identified based upon attack severity attacks approach at the time of consulting.
and migraine-related disability.7
Step-Care-Within-Attack
Stratified Approach Approach
In the stratified approach, the medica- With the step-care-within-attack approach,
tion chosen for a given patient is based a patient takes a simple analgesic (eg,
954 www.ContinuumJournal.com August 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 KEY POINTS
acetaminophen or an NSAID) at migraine 4. An appropriate medication h For patients with
attack onset and then ‘‘steps up’’ later in formulation should be chosen relatively severe and
the course of the attack to another med- based on the characteristics of the disabling migraine
ication class (eg, a triptan) if the initial patient’s migraine attacks. Some attacks, a stratified
medication fails to provide adequate re- patients may require more than approach to acute
lief. This approach may be effective for one formulation. Attack features medication choice,
patients with attacks that build up slowly to consider include: which tries the best
or for patients with attacks of variable drug first, is often the
& For patients without significant best approach.
severity, but all acute medications for mi- nausea, regular oral tablets may
graine generally work better when taken be a good choice, but orally h When migraine attacks
early in the attack. The second more- disintegrating tablets (wafers), usually build up to a
effective medication may also not work nasal sprays, and injections may moderate or severe
well for the patient if it is taken later in intensity, acute
all be appropriate options. Among
the attack. Patients using the step-care- medications are generally
the triptans, subcutaneous
more effective when
within-attack approach need to monitor sumatriptan has the highest taken early in the attack
their success rate with their initial medi- response rate,9 but also produces while the pain is still
cation, preferably with a headache diary, the most discomfort and is mild, but care must be
and if the success rate is low, they would associated with the highest rate taken to avoid medication
be well advised to go directly to the more of side effects. The triptan nasal overuse in patients with
effective medication early in their attacks. sprays, because of partial frequent attacks.
absorption through the nasal
GENERAL PRINCIPLES OF ACUTE mucosa, particularly with
MIGRAINE TREATMENT zolmitriptan nasal spray, may
Practitioners need to consider several have a faster onset of action than
principles of acute migraine treatment the tablets.
when recommending an acute medica- & The triptan orally disintegrating
tion for a specific patient, which include tablets (wafers) can be helpful
the following: for patients with mild nausea, or
1. Early treatment in the attack when nausea is exacerbated by
should be a goal for most patients. taking fluids, and allow for early
All acute medications, including treatment even if water is not
triptans,8 tend to be more effective available. They are not absorbed
if taken early in the attack compared through the buccal mucosa and,
to when the attack has progressed therefore, do not have a faster
or is fully established. onset of action than regular tablets.
2. The response of a patient to an acute & For patients with greater degrees
medication cannot be predicted of nausea and for those who may
with certainty. The physician’s first vomit later in the attack, the triptan
recommendation may not be effective, nasal sprays can be very useful.
and patients need to understand However, the dysgeusia associated
that other options are available. with nasal sprays may exacerbate
Patient follow-up is often critical in nausea and should be monitored.
achieving a successful outcome. & For migraine attacks that build
3. An appropriate treatment approach up very rapidly and for those
needs to be chosen, as discussed that are fully developed upon
above. Some patients have attacks awakening, an injectable
of differing severity and may need formulation (eg, injectable
more than one acute treatment sumatriptan) often has the
option for best results. greatest chance of providing

Continuum (Minneap Minn) 2015;21(4):953–972 www.ContinuumJournal.com 955

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Acute Migraine Treatment

KEY POINTS
h Although most patients relief. This is particularly true if treatment of migraine. These
prefer an oral medication, the patient tends to vomit early medications, although helpful for
a nonoral formulation, in the attack. some patients, are less effective
particularly subcutaneous & For less severe attacks that build than many of the other medications
sumatriptan, may be much up rapidly or if patients desire a available and tend to lead to
more effective for attacks faster onset of action, several oral escalation in frequency of use and
with early vomiting. formulations that are designed to medication-overuse headache.
h Opiate-containing deliver a fast onset of action can
combination analgesics be recommended. These include MEDICATION CHOICE
should not be used diclofenac powder for oral Randomized, double-blind controlled-trial
routinely for migraine solution,10 solubilized evidence exists that a number of med-
treatment, as better (liquid-containing) NSAID ications are effective for acute migraine
options are available formulations (eg, ibuprofen), treatment. When choosing an appropri-
for most patients. effervescent acetylsalicylic acid ate acute medication for a specific pa-
(ASA), and the sumatriptan tient, an organized approach is important.
fast-dissolving tablet. Organizing the available medications into
5. Two or more acute medications can a small number of strategies that can be
be combined if necessary. The most applied to a specific clinical situation may
studied combination has been be helpful (Table 1-1).13 This approach
sumatriptan and naproxen, and the is discussed further below.
combination is more effective than
either drug alone.11 Metoclopramide Antiemetics
can also be added to a triptan or Metoclopramide (usual dose 10 mg, may
NSAID or a combination of both to be used up to 4 times a day) has the
treat nausea and may also enhance strongest evidence for efficacy in mi-
absorption of the acute migraine graine, and some evidence exists for
drug. Caffeine enhances the the use of domperidone (not available
effectiveness of analgesics, but in the United States; usual dose 10 mg,
needs to be balanced against negative may be used up to 4 times a day). Al-
effects such as interference with though metoclopramide poses some
sleep and caffeine-withdrawal risk of extrapyramidal side effects and
headache caused by excessive use. domperidone has been reported to cause
6. Acute medication overuse needs to QT prolongation, these are uncommon
be avoided. Individuals with with the intermittent oral dosing used to
migraine appear to be particularly treat migraine attacks. Many patients use
susceptible to exacerbation of their dimenhydrinate because of its availability
headache syndrome by the frequent without prescription, but dimenhydrinate
use of analgesics. Frequent ergotamine is a complex formulation and contains
and triptan use can also lead to both an antihistamine (H1 antagonist)
increased headache frequency. Use and a stimulant (theophylline derivative)
of acetaminophen or NSAIDs on 15 or The medication has abuse potential, and
more days per month, or combination its efficacy in treating migraine-related
analgesics, opioids, ergotamines, or nausea lacks evidence. Metoclopramide
triptans on 10 or more days per month and domperidone are better choices.
are considered to place patients at risk For refractory patients, prochlorperazine
for medication-overuse headache.12 can also be used, both orally (usual dose
7. Opiates and opiate-containing 10 mg, may be given up to 4 times a day)
combination analgesics should or by suppository (dosage range 10 mg to
not be used for the routine 25 mg, maximum daily dose 50 mg), but

956 www.ContinuumJournal.com August 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 KEY POINTS

TABLE 1-1 Acute Migraine Treatment Strategies h When an antiemetic is

necessary, a dopamine
Strategy Medications antagonist, in particular
metoclopramide, is
Acetaminophen and nonsteroidal Acetaminophen (primarily for
often the best choice.
anti-inflammatory drug strategy for milder attacks)
attacks of mild to moderate severity h The nonsteroidal
Acetylsalicylic acid
anti-inflammatory drugs
Ibuprofen with the best evidence
Naproxen sodium for efficacy for acute
migraine treatment
Diclofenac potassium are acetylsalicylic acid,
Triptan strategy for moderate and Sumatriptan ibuprofen, naproxen
severe attacks sodium, and
Rizatriptan
diclofenac potassium.
Eletriptan
Zolmitriptan
Almotriptan
Frovatriptan
Naratriptan
Refractory migraine strategies Triptan and nonsteroidal
anti-inflammatory drug combinations
Dihydroergotamine
Various rescue medications
(eg, dopamine antagonists)
Combination analgesics without opioids
Combination analgesics with opioids
(not for routine use)
Strategies for patients with Nonsteroidal anti-inflammatory drugs
contraindications to
Dopamine antagonists
vasoconstricting drugs
Combination analgesics without opioids
Combination analgesics with opioids
(not for routine use)

has more extrapyramidal side effects. potassium) have good evidence support-
Metoclopramide, domperidone, and ing their use for migraine. Oral ketorolac
prochlorperazine can each be added does not have randomized controlled trial
to all the acute treatment strategies evidence, although parenteral ketorolac
discussed below.13 has been studied in the emergency de-
partment setting. The preferential use of
Acetaminophen–Nonsteroidal oral medications with a sound evidence
Anti-Inflammatory Drug base is prudent.
Strategy for Attacks of Mild to Acetaminophen has the advantage
Moderate Intensity of less gastric irritation, and because it
Acetaminophen and four NSAIDs (ASA, does not block prostaglandin synthesis
ibuprofen, naproxen sodium, and diclofenac in platelets, it does not affect platelet

Continuum (Minneap Minn) 2015;21(4):953–972 www.ContinuumJournal.com 957

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Acute Migraine Treatment

KEY POINT
h Specialized nonsteroidal function. Acetaminophen is considered unique among the NSAIDs commonly
anti-inflammatory drug less effective than the NSAIDs and suit- used for acute migraine treatment. How-
formulations with a able for relatively mild migraine attacks. ever, naproxen sodium has a slower
more rapid onset of The recommended dose of acetamino- onset of action, and the number need-
action than regular phen for migraine is 1000 mg per dose, ed to treat for the 2-hour pain-free end
tablets are available. and, because of its short half-life (2 to point is 15, which is higher than for the
3 hours), patients may need to repeat this other NSAIDs. It has a favorable car-
dose. It is important that the daily dose diovascular risk profile compared to
be kept below 4000 mg in a 24-hour ibuprofen and diclofenac potassium,
period to avoid hepatotoxicity. although the relevance of this to the in-
Ibuprofen is likely the most com- termittent dosing used by patients with
monly used NSAID by individuals with migraine is unclear. The usual dose is
migraine. Good evidence for efficacy 500 mg or 550 mg, although one study
exists, with a number needed to treat of suggested the 825-mg dose was more
3.2 for headache relief at 2 hours (pain effective.15 Total daily dose should not
reduced to mild or no pain) and 7.2 for exceed 1375 mg. The naproxen sodium
pain free at 2 hours.14 A solubilized form salt should be used for faster absorption.
(liquid-containing capsules) has a some- ASA is usually used in doses of
what faster onset of action as compared 975 mg to 1000 mg (maximum daily
to regular tablets. Ibuprofen also suf- dose 4000 mg). Effervescent ASA has a
fers from a short half-life (2 hours), so faster onset of action than regular tab-
repeated dosing may be necessary. In lets and has shown efficacy similar to
controlled trials, higher doses were no that of sumatriptan 50 mg.16 Including
more effective than the 400-mg dose, its active salicylate metabolite, ASA has
which is the most appropriate dose a relatively long half-life of 6 hours. Like
(maximum daily dose 2400 mg). Ibupro- all the NSAIDs and acetaminophen, the
fen may cause less gastric irritation than medication can be combined with meto-
ASA and is at least as effective. Although clopramide 10 mg.
the response of an individual patient to Other NSAIDs may also be effective,
any particular drug cannot be predicted, but cannot be recommended because
ibuprofen appears to be preferable to of a lack of good randomized controlled
ASA for most patients. trials. This includes ketorolac, although
Diclofenac potassium is another NSAID ketorolac is of some interest because it
with a rapid onset of action. Maximal combines rapid absorption (maximum
plasma concentrations are achieved in plasma levels occur in less than 1 hour)
under an hour with the tablet and in with a relatively long half-life (5 hours).
less than 15 minutes with the powdered The usual dose is 10 mg, and the max-
formulation for oral solution.10 Num- imum daily dose 40 mg; it is recom-
bers needed to treat for the 2-hour pain- mended that patients not use ketorolac
free end point (at least for the powder for more than 5 to 7 consecutive days be-
formulation) are similar to ibuprofen. Like cause of potential renal and gastroin-
ibuprofen, the half-life is short (2 hours). testinal toxicity.
The usual dose of diclofenac potassium Clinical trials suggest that the NSAIDs
is 50 mg; the maximum daily dose for can be effective even in severe migraine
diclofenac potassium tablets is 150 mg. attacks, which has been recognized by
For diclofenac powder, one dose per several guidelines.17,18 However, clinical
day is recommended. experience indicates that for many pa-
Naproxen sodium, with its long dura- tients with severe migraine attacks, the
tion of action (half-life of 14 hours) is triptans are often a better choice. For a
958 www.ContinuumJournal.com August 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

summary of the acetaminophen-NSAID should be considered first line. When pa-
strategy, see Table 1-2. tients are usually NSAID responsive but
have occasional treatment failures, a triptan
Triptan Strategy for Moderate can be prescribed as a rescue medication.
and Severe Attacks In fact, when an NSAID is prescribed for
The triptans are considered second line a patient with relatively severe migraine
by some, after the NSAIDs, but perhaps attacks, a triptan could be preemptively
the only reason for this approach is that prescribed as a rescue medication in case
they are considerably more expensive the NSAID is not satisfactory. If necessary,
than the NSAIDs. The triptans have been the triptan could become the patient’s
proven to be very safe in patients free of primary acute medication.
vascular disease and are generally well The triptans have become the most
tolerated.19 For many patients with se- used migraine-specific medications be-
vere migraine attacks, these medications cause of their pharmacologic specificity,

TABLE 1-2 Acetaminophen and Nonsteroidal Anti-inflammatory a,b

Drug Strategy for Attacks of Mild to Moderate Severity

Usual Dose and Maximum

Medication Dose per Dayc
Acetaminophen (primarily for 1000 mg
milder attacks)d
Maximum 4000 mg/d
Ibuprofen tablets 400 mg
Maximum 2400 mg/d
Ibuprofen solubilized (liquid) tablets 400 mg
Maximum 2400 mg/d
Diclofenac potassium tablets 50 mg
Maximum 150 mg/d
Diclofenac powder for oral solution 50 mg
Maximum single dose/d
recommended
Naproxen sodium 500Y550 mg (up to 825 mg)
Maximum 1375 mg/d
Acetylsalicylic acid 975Y1000 mg
Maximum 4000 mg/d
Effervescent acetylsalicylic acid 975Y1000 mg
Maximum up to 2000 mg/d
recommended
a
For acetaminophen and all nonsteroidal anti-inflammatory drugs, limit use to 14 days a month or
fewer to avoid medication-overuse headache.
b
Patients may experience gastrointestinal irritation, increased blood pressure, and renal toxicity with
excessive use of all nonsteroidal anti-inflammatory drugs. Avoid the use of these drugs if gastrointestinal
ulcers are present or if the patient has asthma with acetylsalicylic acid.
c
Dosages are for adults. For acute migraine treatment, only one or two doses are usually recommended.
d
Liver toxicity with excessive dose or concomitant use of alcohol.

Continuum (Minneap Minn) 2015;21(4):953–972 www.ContinuumJournal.com 959

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Acute Migraine Treatment

KEY POINTS
h Because they are highly which usually allows them to be used Some attempt can be made to tailor
specific medications, in adequate doses without major side triptan choice to the characteristics of
the triptans offer an effects. They are 5-hydroxytryptamine the patient’s migraine attacks. If pa-
excellent clinical (5-HT1B, 5-HT1D) receptor agonists, and tients awaken with full-blown attacks or
benefit-to-side-effect their antimigraine actions are mediated if they tend to vomit early in the attack,
ratio for many patients. mainly through these receptors. Triptans subcutaneous sumatriptan 6 mg may be
h Despite the pharmacologic have a great advantage over ergotamine the best choice; it is also a good choice
similarities among the and dihydroergotamine (DHE) in that for patients who do not respond well to
various triptans, individual these older drugs affect a number of other triptan formulations (Case 1-1).
patients may respond other receptor types that often pro- For patients with lesser degrees of nau-
much better to one triptan duce side effects, in particular nausea, sea, sumatriptan nasal spray 20 mg or
than another. at therapeutic doses. zolmitriptan nasal spray 5 mg may be
All seven triptans currently available good choices. The nasal sprays may also
have strong evidence for efficacy. Al- be helpful for any patients who do not
though they largely share a common respond well to the oral triptans. If taking
mechanism of action, some patients will oral fluids exacerbates nausea, the orally
greatly prefer one triptan over another dissolving tablets (wafers) (rizatriptan
because of greater effectiveness, fewer 10 mg and zolmitriptan 2.5 mg) may
side effects, or both. This phenomenon be a good choice. The wafers also allow
remains unexplained, although it may for early treatment when water is not
relate to the different genetic factors that readily available. The wafers are not ab-
may underlie the migraine disorder in sorbed through the oral mucosa, how-
different patients. In general, there is no ever, and do not have a faster onset of
‘‘best’’ triptan overall, and for any given action than the standard oral tablets. For
patient, the best triptan in the one that most patients, the standard oral tablets
is most effective and best tolerated by work well. For patients with attacks that
that patient. If a patient’s response to a build up rapidly to a high intensity, speed
specific triptan is not optimal, then sev- of action and a high response rate are
eral other triptans should be tried for important. For these, rizatriptan 10 mg
subsequent attacks as they may work and eletriptan 40 mg might be the most
much better. However, not all patients useful oral triptans. Zolmitriptan nasal
with migraine respond to the triptans, spray 5 mg should also be considered,
and some will need other options. particularly if significant nausea is pres-
Triptan choice. Despite their sim- ent. Of the zolmitriptan administered
ilarities, pharmacokinetic and other intranasally, 30% is absorbed through the
differences exist between the various trip- nasal mucosa and, therefore, enters the
tans and their formulations, which have blood stream very rapidly. Zolmitriptan
significant clinical implications. Suma- nasal spray 5 mg provides pain relief in
triptan 6 mg administered by subcuta- some patients (superiority over placebo)
neous injection has the lowest number within 15 minutes, and pain-free re-
needed to treat for any triptan formula- sponses exceed placebo at 30 minutes.21
tion (2.3 for 2 hours pain free). Among If frequent headache recurrence after initial
the oral triptans, a recent meta-analysis successful treatment is an issue, eletriptan
found that eletriptan 40 mg and rizatriptan 40 mg and frovatriptan 2.5 mg are good
10 mg provided the highest pain-free choices as both have a longer half-life
rates at 2 hours, and eletriptan also pro- than most triptans and a lower headache
vided the highest 24-hour sustained pain- recurrence rate.22 If side effects are an
free rate (no recurrence of headache issue, almotriptan 12.5 mg may be better
for 24 hours).20 tolerated but still offers a good response
960 www.ContinuumJournal.com August 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Case 1-1
A 34-year old-woman who had experienced episodic migraine attacks since her teenage years
presented for a neurologic evaluation, where she reported having about four attacks per month,
most of which occurred during the day and responded well to oral rizatriptan 10 mg if treated shortly
after attack onset. She reported waking once a month with a fully developed migraine attack and
vomiting within an hour of awakening. These attacks did not respond to oral rizatriptan, and she
was unable to go to work on those days. She had no significant past medical history. Neurologic
examination was normal.
She was advised to use sumatriptan 6 mg by subcutaneous self-injection for the severe attacks that
were present on awakening and to continue with oral rizatriptan for other attacks. She was prescribed
oral metoclopramide 10 mg tablets and advised to take one tablet with the sumatriptan to assist in
managing her nausea. She was also advised that if nausea and vomiting remained a problem, another
option for treatment of her nausea would be prochlorperazine suppositories (10 mg to 25 mg).
Comment. Subcutaneous sumatriptan remains the triptan with the highest response rate in
treating migraine attacks and is particularly useful for patients with early vomiting during the attack.
Most patients prefer an oral medication if possible; thus, it can be useful both in terms of patient
convenience and cost to make more than one formulation available. Patients can then tailor their
treatment to the nature of the migraine attack being treated. Although an antiemetic may not be
necessary if the triptan works well, antiemetics can be a useful addition to the triptan in patients
with significant nausea or vomiting. Prochlorperazine has more extrapyramidal side effects than
metoclopramide, but the suppository formulation can be very helpful, particularly if patients vomit
with some of their attacks.

rate and a low headache recurrence rate. that such attacks are likely to progress
Four triptans contain a sulfonyl group to moderate or severe intensity and
or a sulfonamide moiety (sumatriptan, respond less well when a triptan is taken
almotriptan, eletriptan, and naratriptan). later in the attack. Caution must be exer-
Although patients with a sulfonamide al- cised in patients with relatively frequent
lergy usually tolerate these triptans well, migraine attacks, as medication overuse
if previous allergic reactions to sulfon- needs to be avoided. If patients are at
amides have been severe, a sulfur-free risk for medication-overuse headache,
triptan can be chosen (eg, rizatriptan, preventive medications and behavioral
frovatriptan, or zolmitriptan). For a sum- interventions should be considered.
mary of the triptan strategy, see Table 1-3. Headache recurrence within 24 hours
Much of the data on which triptan of initial successful treatment is usually
comparisons are based derive from meta- best treated with a second dose of the
analyses of studies in which patients were same triptan that was taken initially. Sev-
treated when the pain was moderate or eral options are available to reduce the
severe in intensity, but fewer data exist recurrence rate in patients prone to head-
on how the various triptans compare ache recurrence after triptan treatment
when they are taken early in the migraine (Case 1-2). Naproxen sodium 500 mg to
attack. When triptans are taken earlier 550 mg can be added to the triptan, as
while pain is still mild, headache relief and headache recurrence after sumatriptan
pain-free response rates are higher23 and has been shown to be reduced when
headache recurrence rates may also be naproxen is added to the sumatriptan.11
lower. Taking a triptan early while pain Alternatively, another triptan with a rela-
is still mild is advantageous for most tively low recurrence rate (eg, eletriptan,
patients if past experience has shown frovatriptan, or naratriptan) can be tried,

Continuum (Minneap Minn) 2015;21(4):953–972 www.ContinuumJournal.com 961

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Acute Migraine Treatment

a,b,c
TABLE 1-3 Triptan Strategy for Moderate and Severe Attacks

Usual and Maximum

Medication Daily Dosed
Almotriptan tabletse 12.5 mg
Maximum 25 mg/d
Eletriptan tablets 40 mg
Maximum 80 mg/d
Frovatriptan tablet 2.5 mg
Maximum 5 mg/d
Naratriptan tablets 2.5 mg
Maximum 5 mg/d
Rizatriptan tabletse,f 10 mg
Maximum 20 mg/d
e,f
Rizatriptan wafers (orally dispersible tablets) 10 mg
Maximum 20 mg/d
e
Sumatriptan tablets 100 mg (50 mg also used)
Maximum 200 mg/d
e
Sumatriptan intranasal 20 mg
Maximum 40 mg/d
e
Sumatriptan injection 4Y6 mg
Maximum 12 mg/d
e
Zolmitriptan tablets 2.5Y5 mg
Maximum 10 mg/d
e
Zolmitriptan wafers (orally dispersible tablets) 2.5 mg
Maximum 10 mg/d
e
Zolmitriptan intranasal 5 mg
Maximum 10 mg/d

a
Selected side effects of triptans include flushing, hot or warm sensation, paresthesia, and chest or
jaw discomfort or tightness.
b
Limit the use of triptans to fewer than 10 days per month to avoid medication-overuse headache.
c
Triptans are contraindicated in cerebrovascular, cardiovascular, and peripheral vascular disorders;
in uncontrolled hypertension and ischemic bowel disease; and in concomitant use within 24 hours
of ergot-containing medications.
d
Dosages are for adults. For acute migraine treatment, only one dose is usually recommended, followed
by a second dose (2 hours or more after the first dose) if the headache reoccurs after initial relief.
e
Avoid the use of almotriptan, rizatriptan, sumatriptan, and zolmitriptan with monamine oxidase
inhibitors and within 2 weeks after discontinuation of monamine oxidase inhibitors.
f
For rizatriptan, reduce the dose to 5 mg (maximum 10 mg per day) if the patient is also on propranolol.

962 www.ContinuumJournal.com August 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 KEY POINTS

Case 1-2 h Headache recurrence

can be minimized by
A 28-year-old man with a long history of severe migraine attacks, which
treatment early in the
increased rapidly in intensity after onset, was concerned because, although
migraine attack,
his headaches responded well to oral sumatriptan 100 mg taken early in
choosing a triptan with a
the attack, his headaches usually recurred after 8 to 12 hours. He took
relatively longer half-life
acetaminophen with codeine for these recurrent headaches, but obtained
(eg, eletriptan, frovatriptan),
only partial relief from this approach.
combining a long
Several therapeutic options were discussed with him, and it was decided
half-life nonsteroidal
to switch his triptan to eletriptan 40 mg as this triptan has a longer half-life
anti-inflammatory
than sumatriptan, and evidence exists that it has a lower headache recurrence
drug with the triptan
rate than sumatriptan. He tried this strategy, but he continued to experience
(eg, naproxen sodium), or
frequent headache recurrence with the eletriptan and often needed to take
using dihydroergotamine.
a second dose later in the day for the recurrent headache. At this point, he was
advised to take naproxen sodium 550 mg simultaneously with the eletriptan h For headache recurrence
when treating his initial migraine attack. after initial relief, a
Comment. Headache recurrence after triptan treatment is not second triptan dose is
uncommon. A second dose of the triptan is very useful in treating headache often the best treatment
recurrence, in contrast to headache persistence (no or little relief after option. In contrast, for
initial triptan treatment) where a second triptan dose is of questionable headache persistence
benefit. The triptans appear to differ in their recurrence rates, but this is (no response to the initial
hard to assess as a headache can only recur if it responds to the initial triptan triptan dose), another
treatment. Frovatriptan, which has the longest half-life of all the triptans, has rescue medication is
a low recurrence rate and can be useful in patients with headache recurrence. usually the best option.
However, frovatriptan has lower response rates at early time points after
dosing as compared to eletriptan and therefore was not considered for this
patient. Adding a nonsteroidal anti-inflammatory drug can also improve
responsiveness to triptans, and naproxen sodium, with its long half-life,
appears especially well suited for reducing headache recurrence. Treatment
with the triptan early in the attack also has the potential
to reduce headache recurrence.

but frovatriptan and naratriptan have a because the initial triptan dose is still
slower onset of action and higher num- active. It may be prudent to use another
bers needed to treat for pain free at rescue medication if the initial triptan
2 hours (8.5 for frovatriptan and 8.2 for dose fails.
naratriptan). DHE also has a long half- Although early treatment is recom-
life and a low headache recurrence rate. mended for patients with migraine with-
Headache persistence is said to oc- out aura, data from several small clinical
cur when the initial triptan dose fails to trials do not support triptan treatment
provide a clinically meaningful response. during the migraine aura, at least for
In contrast to headache recurrence, clin- subcutaneous sumatriptan and oral
ical trials suggest that a second triptan eletriptan. As a result, it has been recom-
dose is no more helpful than placebo mended that patients experiencing mi-
under these circumstances.24 Some pa- graine with aura take their triptan at the
tients do indicate that a second triptan onset of the pain phase of the migraine
dose is helpful to them, but this is difficult attack. Nevertheless, some patients do
to interpret given the high placebo re- report success with triptan treatment dur-
sponse to medication taken for head- ing the aura.25 Triptan treatment during
ache persistence in clinical trials, perhaps typical aura appears to be safe,26 and if
Continuum (Minneap Minn) 2015;21(4):953–972 www.ContinuumJournal.com 963

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Acute Migraine Treatment

KEY POINT
h Triptan effectiveness patients report success with treatment NSAID combinations appears reason-
can be enhanced by during the aura, there is no need to able. Most triptans have a relatively short
taking the triptan early discourage this strategy. half-life, and, because of its long half-life,
in the attack and, if Triptans taken alone will often relieve naproxen sodium may be particularly
necessary, by taking migraine-related nausea satisfactorily, well suited for triptan/NSAID combi-
a nonsteroidal but metoclopramide or domperidone nation therapy as compared to other
anti-inflammatory drug can be added to any triptan if necessary. NSAIDs, particularly in reducing the rate
(eg, naproxen sodium) The prokinetic effect of metoclopramide of migraine recurrence. If the intent is to
with the triptan. may also promote triptan absorption. improve headache relief at 2 hours, a
In one study it was found that patients faster-acting NSAID, such as ibuprofen
who did not receive adequate relief or diclofenac, might be more effective.
from sumatriptan 50 mg alone had bet- A recent clinical trial that compared a
ter headache relief with the addition combination of frovatriptan 2.5 mg (a
of metoclopramide.27 long half-life triptan) to a combination
of frovatriptan and a fast-acting, short
Refractory Migraine Strategies half-life NSAID (dexketoprofen) sup-
Several options are available for patients ported this concept in that the com-
who do not respond adequately to either bination resulted in higher pain-free
NSAIDs or triptans (Case 1-3). Clinical rates at 2 hours than frovatriptan alone
trials have clearly shown that when na- (51% versus 29%).28
proxen sodium is combined with suma- For patients who usually, but not
triptan, migraine attack response rates always, respond to a triptan/NSAID combi-
are better than with either drug alone.11 nation, it may be helpful to provide a re-
Despite a lack of evidence, extending scue medication to use when their usual
these observations to other triptan/ medication fails. However, the options

Case 1-3
A 44-year-old woman reported that her sumatriptan 100 mg tablets provided
only incomplete relief from her migraine attacks. Early treatment of her
attacks reduced their severity, but she was still left with a mild headache, which
remained troublesome for another 12 hours. She had also tried rizatriptan,
eletriptan, almotriptan, and frovatriptan in the past and felt that, of all of the
triptans she had tried, sumatriptan provided her with the best overall relief.
She was advised to take naproxen sodium 550 mg simultaneously with
her sumatriptan to enhance the efficacy of her acute treatment.
Comment. Adding naproxen to sumatriptan has been shown to
improve efficacy. Many clinicians will use naproxen sodium with other
triptans based on these findings or use triptans with other nonsteroidal
anti-inflammatory drugs (NSAIDS), which seems reasonable, although the
sumatriptan/naproxen combination is the only one that has been well
studied. Although there have not been randomized controlled trials to
address all these issues, if an NSAID is being added in a patient with
migraine attacks that build up rapidly and more rapid complete relief is
desired, use of a rapidly acting NSAID such as ibuprofen or diclofenac may
be most useful. If headache recurrence or long-lasting lower level pain is
being addressed, then naproxen with its long half-life may be a more
reasonable choice. Naproxen sodium is preferred over other forms of
naproxen because of faster absorption.

964 www.ContinuumJournal.com August 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

are limited if vomiting reduces the use- sics, isometheptene is combined with
fulness of oral medications. If a triptan dichloralphenazone. Dichloralphenazone
has already been used, further vasocon- is a mixture of antipyrine (an NSAID) and
strictors need to be avoided. Dopamine chloral hydrate (a hypnotic) and may not
antagonists are options, including pro- be an ideal medication for the modern
chlorperazine orally (10 mg, with up to treatment of migraine. A recent review
four doses in 24 hours) or by supposi- of combination analgesics and migraine
tory (10 mg to 25 mg, maximum daily treatment summarized the evidence for
dose 50 mg), and chlorpromazine orally the use of isometheptene combination
(10 mg to 50 mg, with up to four doses analgesics for migraine, but did not pro-
in 24 hours) or intramuscularly (25 mg vide conclusions with regard to the place
to 50 mg, with up to four doses in of these treatments in migraine therapy.31
24 hours). Both are powerful antiemetics, Combination analgesics with codeine
and the sedation they provide may also or tramadol are additional options for
be helpful. rescue mediations when triptans occa-
NSAIDs for rescue may be problematic sionally fail or for patients who do not
if the patient has already taken naproxen respond to triptans. Opiates should not
sodium. Ketorolac 60 mg by IM self- be used routinely in migraine therapy,
injection can be used safely at home if but occasional use when necessary in
patients are adequately trained.29 Indo- selected patients is a potential option.
methacin orally (50 mg to 75 mg) or by There is concern that opioid use can
suppository (50 mg to 100 mg) can be lead to receptor changes, which may
used, but evidence for efficacy is limited. make patients with migraine less re-
A short course of prednisone (60 mg sponsive to other drugs, and opioid use
on the first day with a rapid taper over may escalate over time and lead to
3 or 4 days) or dexamethasone (8 mg on medication-overuse headache. Intrana-
the first day with a rapid taper over 3 or sal butorphanol is best avoided because
4 days) can be considered for occasional of risk of addiction and dependence, al-
use. Dexamethasone 4 mg plus rizatriptan though it may be useful in selected cases
10 mg in a single-dose study resulted in as it can be used even if patients are
a higher proportion of patients achieving vomiting. Frequency of use of all opioids
a 24-hour sustained pain-free end point should be carefully monitored. Combi-
(50.7%) than rizatriptan alone (32.2%) in nation analgesics with barbiturates (eg,
a menstrually related migraine study.30 butalbital) should be avoided and used
Therefore, steroids may be of some use only under very exceptional circum-
in patients in whom triptan therapy stances, if at all, as barbiturate-containing
occasionally fails, but the evidence is combination analgesics are a potent
very limited. cause of medication-overuse headache.
Combination analgesics containing A large, randomized, double-blind cross-
isometheptene have been widely used over trial demonstrated that a sumatriptan/
in the past for migraine, although little naproxen combination was superior to a
evidence exists for the effectiveness of butalbital, acetaminophen, caffeine com-
isometheptene alone. Isometheptene is bination tablet on most end points.32
a sympathomimetic amine that is thought Some patients who do not respond
to exert its effects through vasoconstric- well to triptans will respond to ergotamine
tion and is often combined with acetamin- or DHE. DHE is the preferred drug, and
ophen and caffeine. Physicians should be can be given by nasal spray (one 0.5-mg
aware that in some combination analge- spray in each nostril, repeated after 15

Continuum (Minneap Minn) 2015;21(4):953–972 www.ContinuumJournal.com 965

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Acute Migraine Treatment

KEY POINTS
h For patients who do not to 30 minutes [maximum dose 4 mg per and ASA without caffeine, to ASA alone,
respond to nonsteroidal day]) or by subcutaneous or IM self- and to acetaminophen alone.36 Combi-
anti-inflammatory injection (usual dose 1 mg, preceded by nation analgesics without opiates may be
drugs or the triptans, metoclopramide 10 mg orally [maximum helpful when triptans are contraindicated
dihydroergotamine, daily dose for parenteral DHE 3 mg or ineffective. A combination of acet-
metoclopramide, per day]). Nausea is a common side ef- aminophen 400 mg per day, ASA 500 mg
prochlorperazine, and a fect. If leg cramps or coldness and tin- per day, and caffeine 100 mg given as a
number of combination gling of the hands and feet occur, DHE single dose was found to be effective
analgesics (with and should be reduced or discontinued. A even in patients with severe headache
without tramadol or new orally inhaled formulation of DHE attacks compared to placebo.37 Combi-
codeine) are potential has shown promise of good efficacy nation analgesics containing isomethep-
therapeutic options. (28.4% pain free at 2 hours) but is not tene are considered contraindicated in
h Medication use should be yet available.33 DHE is not available in patients with vascular disease because
minimized as much as oral formulations. of its vasoconstrictor properties.
possible during pregnancy, Ergotamine tartrate is not recom- Pharmacologic prophylactic therapy
but acetaminophen, mended for routine use, and triptans and behavioral treatment approaches
acetaminophen with are a better option for most patients.
codeine, and
should be maximized for all patients
Ergotamine tartrate may be helpful in where acute pharmacologic therapy is
metoclopramide are patients with prolonged attacks who do
considered safe acute problematic or ineffective.
not respond well to the triptans. Patients
treatments for migraine.
need to find a subnauseating dose that MIGRAINE DURING PREGNANCY
Available data indicate
sumatriptan is also
is effective for their migraine attacks No drug has been proven to be safe during
relatively safe and could (usual dosage range is 0.5 mg to 2 mg).34 pregnancy, so drug use should be avoided
be considered for use Refractory migraine strategies are sum- as much as possible and behavioral ap-
during pregnancy marized in Table 1-4 and Table 1-5. proaches maximized. Acetaminophen
where warranted. and metoclopramide are considered safe,
Strategies for Patients With while acetaminophen with codeine is
Contraindications to also considered relatively safe, although
Vasoconstricting Drugs caution should be observed toward the
Acute treatment options for patients end of pregnancy because of potential
with contraindications to vasoconstrict- withdrawal symptoms in the neonate and
ing drugs (Table 1-6) include the NSAIDs because of a slight association with acute
and most of the rescue medications cesarean delivery and postpartum hem-
previously discussed (eg, dopamine an- orrhage.38 Other opioids may also cause
tagonists, ketorolac injections, indo- harmful effects on the fetus or neonate
methacin, steroids, and combination without causing malformations.
analgesics with codeine or tramadol). If ASA should be avoided in pregnancy.
acute medications are used frequently, Other NSAIDs are preferable because of
however, it should be kept in mind that less prolonged effects on platelet func-
many NSAIDs have been associated with tion. All NSAIDs should be avoided after
an increased risk of cardiovascular events. the 32nd week of gestation because of
Naproxen sodium may be an exception effects on the ductus arteriosus, and it
and may be the preferred NSAID in pa- may be best to avoid NSAIDs in the first
tients with cardiovascular disease.35 trimester because of a possible increased
Nonopioid combination analgesics risk of spontaneous abortion, although in
may also be helpful. Combination anal- a recent historical cohort study, exposure
gesics containing acetaminophen, ASA, to NSAIDs during pregnancy was not
and caffeine have been found superior an independent risk factor for sponta-
to the combination of acetaminophen neous abortion.39
966 www.ContinuumJournal.com August 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 1-4 Refractory Migraine Strategies

Usual and Maximum

Medication Daily Dosea Selected Side Effects Comments
Sumatriptan and Sumatriptan 100 mg, See Table 1-2 and Table 1-3 The combination is more
naproxen sodium naproxen sodium effective than either
taken simultaneously 500Y550 mg (other drug alone
doses are also used in
See Table 1-2 and Table 1-3
combination tablets)
Maximum two doses
Other triptans and See Table 1-2 and See Table 1-2 for Randomized clinical trials
other nonsteroidal Table 1-3 for individual drugs not available for most
anti-inflammatory individual drugs combinations
drug combinations
Dihydroergotamine 0.5 mg in each nostril, Nausea, vomiting, muscle Contraindicated in
intranasal repeat dose in 15 minutes; cramps, paresthesia, and vascular disease
may repeat four-spray other side effects related
Limit use to under 10 days a
sequence in 6 hours to vasoconstriction; rhinitis
month for most patients,
if necessary and taste disturbance
but relationship to
Maximum 4 mg/d medication-overuse
headache uncertain.
Avoid dihydroergotamine
with CYP3A inhibitors
(eg, clarithromycin,
ketoconazole, ritonavir)
Dihydroergotamine 0.5Y1 mg, dose may Nausea, vomiting, muscle Contraindicated in
subcutaneous or be repeated in 3 hours cramps, paresthesia, and vascular disease
IM injection if necessary other side effects related
Limit use to under 10 days a
to vasoconstriction
Maximum 3 mg/d month for most patients,
but relationship to
medication-overuse
headache uncertain.
Avoid dihydroergotamine
with CYP3A inhibitors
(eg, clarithromycin,
ketoconazole, ritonavir)
Ergotamine tartrate 0.5Y2 mg Nausea, vomiting, muscle Contraindicated in
sublingual tablets cramps, paresthesia, and vascular disease
Maximum 6 mg/d
other side effects related
Limit use to fewer than
to vasoconstriction
10 days a month to avoid
medication-overuse headache
IM = intramuscular.
a
Dosages are for adults.

Although ergotamines must be avoided sociation between sumatriptan use in

owing to uterotonic effects, triptans ap- the first trimester and fetal malforma-
pear much safer during pregnancy. A tions or adverse pregnancy outcomes.
large observational study found no as- Sumatriptan use in the second and

Continuum (Minneap Minn) 2015;21(4):953–972 www.ContinuumJournal.com 967

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Acute Migraine Treatment

a
TABLE 1-5 Refractory Migraine Strategies: Rescue Medications

Medication Usual Doseb Selected Side Effects Comments

Prochlorperazine 10 mg Extrapyramidal symptoms, Dopamine antagonist
tablets drowsiness
Maximum 40 mg/d
Prochlorperazine 10Y25 mg Extrapyramidal symptoms, Dopamine antagonist, helpful
suppositories Maximum 50 mg/d drowsiness if severe nausea or vomiting

Chlorpromazine 10Y50 mg Extrapyramidal symptoms, Limited evidence for efficacy

tablets drowsiness
Maximum 200 mg/d
Ketorolac by IM 60 mg Gastrointestinal disturbance, Patients must be
self-injection Maximum 120 mg/d renal toxicity, injection site pain adequately trained

Indomethacin 50Y75 mg See nonsteroidal anti-inflammatory Limited evidence

tablets Maximum 200 mg/d drugs in Table 1-2 for efficacy

Indomethacin 50Y100 mg See nonsteroidal anti-inflammatory Limited evidence for efficacy

suppositories Maximum 200 mg/d drugs in Table 1-2

Prednisone tablets 60 mg on the first day, Insomnia, behavioral change, Only for occasional use for
with rapid taper over other steroid side effects prolonged attacks
several days
Dexamethasone 8 mg on the first day, Insomnia, behavioral change, Only for occasional use for
tablets with rapid taper over other steroid side effects prolonged attacks
several days
Combination analgesics Individualized dosing Depends on tablet ingredients Isometheptene is a
with isometheptene vasoconstrictor; avoid in
vascular disease
Combination Individualized dosing Drowsiness, constipation Monitor frequency of use
analgesics with as a risk of medication
tramadol or codeine overuse-headache exists
Butorphanol 1 mg (1 spray) in one CNS depression, sedation, Use only in exceptional
intranasal nostril, repeat once in 60 respiratory depression, circumstances and limit
to 90 minutes if necessary; dependence, abuse, possible use to fewer than 8 days
repeat two-dose sequence addiction per month to avoid
in 6 hours if necessary medication-overuse headache
Butalbital-containing Avoid if possible
combination analgesics
Strong opiates (eg, Avoid if possible
morphine, oxycodone)
IM = intramuscular; CNS = central nervous system.
a
Rescue medications to be used when primary medication fails; consider whether related drugs have been used in past 24 hours.
With migraine, most rescue medications are meant for occasional use, and some are potential options for primary medications
in patients who are unresponsive to nonsteroidal anti-inflammatory drugs and vasoconstrictors.
b
Dosages are for adults.

third trimester was associated with sial, sumatriptan may be an option for
atonic uterus and blood loss of greater pregnant women with difficult migraine
than 500 mL during labor and delivery.40 that often renders them incapable of
Much fewer data exist with regard to the carrying out tasks of daily living or results
other triptans. Although still controver- in dehydration.
968 www.ContinuumJournal.com August 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 a
TABLE 1-6 Strategies for Patients With Contraindications to Vasoconstricting Drugs

Medication Usual Dose Selected Side Effects Comments

Acetylsalicylic acid, Individualized Gastric irritation (acetylsalicylic Combinations may be more
acetaminophen, and dosing acid), liver toxicity at high effective than individual
caffeine combination doses (acetaminophen), drugs alone
analgesics insomnia (caffeine)
Combination analgesics Individualized Drowsiness, constipation, Limit use to fewer than
with tramadol or dosing others according to ingredients 10 days per month to avoid
codeine medication-overuse headache

a
Nonsteroidal anti-inflammatory drugs including indomethacin, dopamine antagonists, and many of the rescue medications discussed in
the refractory migraine strategies are also options for patients with contraindications to vasoconstricting drugs. Please see previous tables in
this article for dosing and side effects.

Lidocaine is safe in pregnancy, so oc- codeine) may be much higher than ex-
cipital nerve blocks can be considered. pected if the mother is a fast metabolizer
Prochlorperazine and other phenothia- of codeine (5% to 40% of individuals,
zines are not considered to be terato- depending on ethnic background).44
genic, but their use near term may be
associated with extrapyramidal effects in CONCLUSION
the newborn. Short courses of steroids Many drugs have shown efficacy for
given after 10 weeks gestation appear acute migraine treatment in double-
not to pose a risk to the fetus.41 blind, randomized controlled trials. How-
ever, choosing the best medication for
MIGRAINE DURING LACTATION a specific patient remains a complex
Acetaminophen is considered safe dur- task and requires careful consideration
ing breast-feeding. Among the NSAIDs, of the patient’s clinical features and pref-
ibuprofen is preferred. Occasional use of erences. Adequate patient education
diclofenac and ketorolac is considered and an organized approach to medica-
compatible with breast-feeding, but ASA tion choice is important.
in analgesic doses should be avoided. Patients may have more options for
The amount of infant exposure from acute migraine treatment in the future,
maternal use of sumatriptan appears to including single-pulse transcranial mag-
be small, and sumatriptan use is consid- netic stimulation, which has shown prom-
ered compatible with breast-feeding.42 ise for acute treatment of migraine with
Metoclopramide, domperidone, prochlor- aura,45 and noninvasive vagal nerve stim-
perazine, and dimenhydrinate are all ulation, which is under investigation.46
considered safe.43 New delivery systems for sumatriptan,
If an opioid must be used, morphine is which may eventually be applied to other
the opioid of choice, but the milk should drugs as well, are either becoming avail-
be discarded if the mother experiences able or are under active investigation
significant sedation. Caution should be and include a needle-free injection sys-
exercised, particularly with premature tem,47 transdermal drug delivery systems,48
infants and infants under 1 month of age. and breath-powered devices for better
Because of variable maternal metabolism, drug delivery through the nasal mucosa.49
codeine should be avoided as exposure Research in these areas and others bodes
of the infant to morphine (a metabolite of well for the treatment of acute migraine

Continuum (Minneap Minn) 2015;21(4):953–972 www.ContinuumJournal.com 969

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Acute Migraine Treatment

attacks in the near future. An updated Neurology 2007;68(5):343Y349. doi:10.1212/

01.wnl.0000252808.97649.21.
assessment of the evidence for the avail-
able pharmacologic therapies for acute 6. Katsarava Z, Schneeweiss S, Kurth T, et al.
Incidence and predictors for chronicity of
migraine treatment has also recently headache in patients with episodic migraine.
been published.50 Neurology 2004;62(5):788Y790. doi:10.1212/
01.WNL.0000113747.18760.D2.

USEFUL WEBSITES 7. Lipton RB, Stewart WF, Stone AM, et al. Disability
in Strategies of Care Study group. Stratified
Scottish Intercollegiate Guidelines care vs step care strategies for migraine: the
Network (SIGN). SIGN provides a Disability in Strategies of Care (DISC) Study:
a randomized trial. JAMA 2000;284(20):
clinical guideline for the diagnosis and 2599Y2605. doi:10.1001/jama.284.20.2599.
management of headache in adults,
8. Brandes JL, Kudrow D, Cady R, et al.
including assessment tools and treat- Eletriptan in the early treatment of acute
ment recommendations. migraine: influence of pain intensity and
www.sign.ac.uk/pdf/sign107.pdf time of dosing. Cephalalgia 2005;25(9):
735Y742. doi:10.1111/j.1468-2982.2005.00981.x.
Toward Optimized Practice (TOP). 9. Treatment of migraine attacks with sumatriptan.
TOP provides a variety of resources The Subcutaneous Sumatriptan International
Study Group. N Engl J Med 1991;325(5):316Y321.
for headache management, including
10. Lipton RB, Grosberg B, Singer RP, et al. Efficacy
guidelines and assessment tools.
and tolerability of a new powdered formulation
www.topalbertadoctors.org/cpgs/10065 of diclofenac potassium for oral solution for the
acute treatment of migraine: results from
Motherisk, published by The Hospital the International Migraine Pain Assessment
for Sick Children, University of Toronto. Clinical Trial (IMPACT). Cephalalgia 2010;30(11):
1336Y1345. doi:10.1177/0333102410367523.
Motherisk provides links to published
11. Brandes JL, Kudrow D, Stark SR, et al.
studies on the safety or risk of specific Sumatriptan-naproxen for acute treatment
drugs during pregnancy. of migraine: a randomized trial. JAMA
2007;297(13):1443Y1454. doi:10.1001/
www.motherisk.org/women/drugs.jsp jama.297.13.1443.
12. Headache Classification Committee of the
REFERENCES International Headache Society (IHS). The
1. Cooke LJ, Becker WJ. Migraine prevalence, International Classification of Headache Disorders,
treatment and impact: the canadian women 3rd edition (beta version). Cephalalgia 2013;
and migraine study. Can J Neurol Sci 33(9):629Y808. doi:10.1177/0333102413485658.
2010;37(5):580Y587. 13. Worthington I, Pringsheim T, Gawel MJ,
2. Vos T, Flaxman AD, Naghavi M, et al. Years lived et al. Canadian Headache Society Guideline:
with disability (YLDs) for 1160 sequelae of acute drug therapy for migraine headache.
289 diseases and injuries 1990Y2010: a systematic Can J Neurol Sci 2013;40(5 suppl 3):S1YS80.
analysis for the Global Burden of Disease 14. Rabbie R, Derry S, Moore RA. Ibuprofen
Study 2010. Lancet 2012;380(9859):2163Y2196. with or without an antiemetic for acute
doi:10.1016/S0140-6736(12)61729-2. migraine headaches in adults. Cochrane
3. Andlin-Sobocki P, Jonsson B, Wittchen HU, Database Syst Rev 2013;4:CD008039.
Olesen J. Cost of disorders of the brain in doi:10.1002/14651858.CD008039.pub3.
Europe. Eur J Neurol 2005;12(suppl 1):1Y27. 15. Suthisisang CC, Poolsup N, Suksomboon N,
doi:10.1111/j.1468-1331.2005.01202.x. et al. Meta-analysis of the efficacy and safety
4. Buse DC, Manack AN, Fanning KM, et al. Chronic of naproxen sodium in the acute treatment
migraine prevalence, disability, and of migraine. Headache 2010;50(5):808Y818.
sociodemographic factors: results from the doi:10.1111/j.1526-4610.2010.01635.x.
American Migraine Prevalence and Prevention
16. Lampl C, Voelker M, Diener HC. Efficacy and
Study. Headache 2012;52(10):1456Y1470.
safety of 1,000 mg effervescent aspirin:
doi:10.1111/j.1526-4610.2012.02223.x.
individual patient data meta-analysis of three
5. Lipton RB, Bigal ME, Diamond M, et al. trials in migraine headache and migraine
Migraine prevalence, disease burden, accompanying symptoms. J Neurol 2007;254(6):
and the need for preventive therapy. 705Y712. doi:10.1007/s00415-007-0547-2.

970 www.ContinuumJournal.com August 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

17. Diagnosis and management of headache frovatriptan alone in the treatment of
in adults: a national clinical guideline. migraine attacks with or without aura: a
Scottish Intercollegiate Guidelines Network. randomized study. Cephalalgia 2014;34(6):
www.sign.ac.uk/pdf/sign107.pdf. Published 434Y445. doi:10.1177/0333102413515342.
November 2008. Accessed June 16, 2015.
29. Turkewitz LJ, Casaly JS, Dawson GA, et al.
18. Primary care management of headache in Self-administration of parenteral ketorolac
adults. Toward Optimized Practice website. tromethamine for head pain. Headache
www.topalbertadoctors.org/cpgs/10065. 1992;32(9):452Y454. doi:10.1111/j.
Published July 2012. Accessed June 16, 2015. 1526-4610.1992.hed3209452.x.
19. Dodick D, Lipton RB, Martin V, et al.
30. Bigal M, Sheftell F, Tepper S, et al. A
Consensus statement: cardiovascular
randomized double-blind study comparing
safety profile of triptans (5-HT agonists)
rizatriptan, dexamethasone, and the
in the acute treatment of migraine.
combination of both in the acute
Headache 2004;44(5):414Y425.
treatment of menstrually related migraine.
doi:10.1111/j.1526-4610.2004.04078.x.
Headache 2008;48(9):1286Y1293.
20. Thorlund K, Mills EJ, Wu P, et al. Comparative doi:10.1111/j.1526-4610.2008.01092.x.
efficacy of triptans for the abortive treatment
of migraine: a multiple treatment comparison 31. Loder E. Fixed drug combinations for the
meta-analysis. Cephalalgia 2014;34(4):258Y267. acute treatment of migraine: place in
doi:10.1177/0333102413508661. therapy. CNS Drugs 2005;19(9):769Y784.
doi:10.2165/00023210-200519090-00004.
21. Tepper SJ, Chen S, Reidenbach F, Rapoport AM.
Intranasal zolmitriptan for the treatment of 32. Derosier F, Sheftell F, Silberstein S, et al.
acute migraine. Headache 2013;53(suppl 2): Sumatriptan-naproxen and butalbital: a
62Y71. doi:10.1111/head.12181. double-blind, placebo-controlled crossover
study. Headache 2012;52(4):530Y543.
22. Geraud G, Keywood C, Senard JM.
doi:10.1111/j.1526-4610.2011.02039.x.
Migraine headache recurrence:
relationship to clinical, pharmacological, 33. Aurora SK, Silberstein SD, Kori SH, et al.
and pharmacokinetic properties of MAP0004, orally inhaled DHE: a randomized,
triptans. Headache 2003;43(4):376Y388. controlled study in the acute treatment of
doi:10.1046/j.1526-4610.2003.03073.x. migraine. Headache 2011;51(4):507Y517.
23. Goadsby PJ, Zanchin G, Geraud G, doi:10.1111/j.1526-4610.2011.01869.x.
et al. Early vs. non-early intervention in 34. Baron EP, Tepper SJ. Revisiting the role of
acute migraine-‘Act when Mild (AwM)’. ergots in the treatment of migraine and
A double-blind, placebo-controlled trial headache. Headache 2010;50(8):1353Y1361.
of almotriptan. Cephalalgia 2008; doi:10.1111/j.1526-4610.2010.01662.x.
28(4):383Y391. doi:10.1111/j.
1468-2982.2008.01546.x. 35. Fosbol EL, Folke F, Jacobsen S, et al.
Cause-specific cardiovascular risk associated
24. Tepper SJ, Donnan GA, Dowson AJ, et al. with nonsteroidal antiinflammatory drugs
A long-term study to maximise migraine among healthy individuals. Circ Cardiovasc
relief with zolmitriptan. Curr Med Res Opin Qual Outcomes 2010;3(4):395Y405.
1999;15(4):254Y271. doi:10.1161/CIRCOUTCOMES.109.861104.
25. Aurora SK, Barrodale PM, McDonald SA, 36. Diener HC, Pfaffenrath V, Pageler L, et al.
et al. Revisiting the efficacy of sumatriptan The fixed combination of acetylsalicylic acid,
therapy during the aura phase of migraine. paracetamol and caffeine is more effective
Headache 2009;49(7):1001Y1004. than single substances and dual combination
doi:10.1111/j.1526-4610.2009.01429.x. for the treatment of headache: a multicentre,
26. Bates D, Ashford E, Dawson R, et al. randomized, double-blind, single-dose,
Subcutaneous sumatriptan during the placebo-controlled parallel group study.
migraine aura. Sumatriptan Aura Study Cephalalgia 2005;25(10):776Y787.
Group. Neurology 1994;44(9):1587Y1592. doi:10.1111/j.1468-2982.2005.00948.x.
doi:10.1212/WNL.44.9.1587. 37. Diener HC, Peil H, Aicher B. The efficacy
and tolerability of a fixed combination of
27. Schulman EA, Dermott KF. Sumatriptan plus
acetylsalicylic acid, paracetamol, and
metoclopramide in triptan-nonresponsive
caffeine in patients with severe headache:
migraineurs. Headache 2003;43(7):729Y733.
doi:10.1046/j.1526-4610.2003.03130.x. a post-hoc subgroup analysis from a
multicentre, randomized, double-blind,
28. Tullo V, Valguarnera F, Barbanti P, et al. single-dose, placebo-controlled parallel
Comparison of frovatriptan plus group study. Cephalalgia 2011;31(14):
dexketoprofen (25 mg or 37.5 mg) with 1466Y1476. doi:10.1177/0333102411419682.

Continuum (Minneap Minn) 2015;21(4):953–972 www.ContinuumJournal.com 971

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Acute Migraine Treatment

38. Nezvalova-Henriksen K, Spigset O, Nordeng H. for acute treatment of migraine with

Effects of codeine on pregnancy outcome: aura: a randomised, double-blind,
results from a large population-based cohort parallel-group, sham-controlled trial. Lancet
study. Eur J Clin Pharmacol 2011;67(12):1253Y1261. Neurol 2010;9(4): 373Y380. doi:10.1016/
doi:10.1007/s00228-011-1069-5. S1474-4422(10)70054-5.

39. Daniel S, Koren G, Lunenfeld E, et al. Fetal 46. Goadsby P, Grosberg B, Mauskop A, et al.
exposure to nonsteroidal anti-inflammatory Effect of noninvasive vagus nerve stimulation
drugs and spontaneous abortions. CMAJ 2014; on acute migraine: an open-label pilot study.
186(5):E177YE182. doi:10.1503/cmaj.130605. Cephalalgia 2014;34(12):986Y993.
doi:10.1177/0333102414524494.
40. Nezvalova-Henriksen K, Spigset O, Nordeng H.
Triptan exposure during pregnancy and the 47. Cady RK, Aurora SK, Brandes JL, et al.
risk of major congenital malformations and Satisfaction with and confidence in
adverse pregnancy outcomes: results from the needle-free subcutaneous sumatriptan in
Norwegian Mother and Child patients currently treated with triptans.
Cohort Study. Headache 2010;50(4):563Y575. Headache 2011;51(8):1202Y1211. doi:10.1111/
doi:10.1111/j.1526-4610.2010.01619.x. j.1526-4610.2011.01972.x.

41. Drugs in pregnancy. Motherisk website. 48. Meadows KP, Pierce M, O’Neill C, et al.
Sumatriptan transdermal system can be
www.motherisk.org/women/drugs.jsp.
correctly assembled and applied during
Accessed June 16, 2015.
migraine attacks. Headache 2014;54(5):
42. American Academy of Pediatrics Committee on 850Y860. doi:10.1111/head.12352.
Drugs. Transfer of drugs and other chemicals
into human milk. Pediatrics 2001;108(3):776Y789. 49. Obaidi M, Offman E, Messina J,
et al. Improved pharmacokinetics of
43. Worthington I, Pringsheim T, Gawel MJ, sumatriptan with Breath PoweredTM nasal
et al. Canadian Headache Society Guideline: delivery of sumatriptan powder. Headache
acute drug therapy for migraine headache. 2013;53(8):1323Y1333. doi:10.1111/
Can J Neurol Sci 2013;40(5 suppl 3):S1YS80. head.12167.
44. Hendrickson RG, McKeown NJ. Is maternal
50. Marmura MJ, Silberstein SD, Schwedt TJ.
opioid use hazardous to breast-fed infants?
The acute treatment of migraine in adults:
Clin Toxicol (Phila) 2012;50(1):1Y14.
the American Headache Society evidence
doi:10.3109/15563650.2011.635147.
assessment of migraine pharmacotherapies.
45. Lipton RB, Dodick DW, Silberstein SD, et al. Headache 2015;55(1):3Y20. doi:10.1111/
Single-pulse transcranial magnetic stimulation head.12499.

972 www.ContinuumJournal.com August 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.