Download Acute Migraine Treatment in Adults

ISSN 0017-8748
doi: 10.1111/head.12550
Published by Wiley Periodicals, Inc.
Headache
© 2015 American Headache Society
Review Article
Acute Migraine Treatment in Adults
Werner J. Becker, MD, FRCPC
There are many options for acute migraine attack treatment, but none is ideal for all patients. This study aims to review
current medical office-based acute migraine therapy in adults and provides readers with an organized approach to this
important facet of migraine treatment. A general literature review includes a review of several recent published guidelines.
Acetaminophen, 4 nonsteroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, acetylsalicylic acid [ASA], naproxen sodium,
and diclofenac potassium), and 7 triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and
zolmitriptan) have good evidence for efficacy and form the core of acute migraine treatment. NSAID–triptan combinations,
dihydroergotamine, non-opioid combination analgesics (acetaminophen, ASA, and caffeine), and several anti-emetics
(metoclopramide, domperidone, and prochlorperazine) are additional evidence-based options. Opioid containing combination
analgesics may be helpful in specific patients, but should not be used routinely. Clinical features to be considered when choosing
an acute migraine medication include usual headache intensity, usual rapidity of pain intensity increase, nausea, vomiting,
degree of disability, patient response to previously used medications, history of headache recurrence with previous attacks, and
the presence of contraindications to specific acute medications. Available acute medications can be organized into 4 treatment
strategies, including a strategy for attacks of mild to moderate severity (strategy one: acetaminophen and/or NSAIDs), a triptan
strategy for patients with severe attacks and for attacks not responding to strategy one, a refractory attack strategy, and a
strategy for patients with contraindications to vasoconstricting drugs. Acute treatment of migraine attacks during pregnancy,
lactation, and for patients with chronic migraine is also discussed. In chronic migraine, it is particularly important that
medication overuse is eliminated or avoided. Migraine treatment is complex, and treatment must be individualized and tailored
to the patient’s clinical features. Clinicians should make full use of available medications and formulations in an organized
approach.
Key words: migraine, acute, treatment, adult, triptan, nonsteroidal anti-inflammatory drug
Abbreviations: AAC acetaminophen, ASA and caffeine, ASA acetylsalicylic acid, NNT number needed to treat, NSAIDs
nonsteroidal anti-inflammatory drugs
(Headache 2015;55:778-793)
The acute therapy of migraine has a long history,
as patients and their physicians have tried to relieve
the pain of migraine attacks. Caffeine was recommended for acute migraine treatment for hundreds of
years, and it was recognized over a century ago that
patient response to medications for migraine attacks
is idiosyncratic and that treatment must be tailored to
the individual. This was based on the observation that
measures that worked well in one case would fail in
another apparently similar case.1,2
From the Department of Clinical Neurosciences, University of
Calgary, Calgary, Alberta, Canada; The Hotchkiss Brain Institute, Calgary, Alberta, Canada.
Address all correspondence to W.J. Becker, Division of Neurology, Foothills Hospital, 1403 29th Street NW, Calgary, AB
T2N 2T9, Canada.
Conflict of Interest: Dr. Becker has served on medical advisory
boards for Allergan, Pfizer, Tribute, Amgen, ElectroCore, and
St. Jude. He has received speaker’s honoraria from Serono,
Allergan, Tribute, and Pfizer, and research support from St.
Jude Medical, Pfizer, Allergan, and Amgen.
Accepted for publication February 20, 2015.
Financial Support: None.
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In the modern era in Western nations, acute
medications for migraine attacks are used almost universally by migraine sufferers, with over 90% using
some type of acute medication.3 Medication choice
for the acute treatment of migraine attacks is not a
simple matter, given the multiple medications available, and as has been recognized for over a century,
one cannot predict which medication will work best
for any given patient.2 Also, migraine attacks are generally treated in settings where the patient must
usually act without outside assistance. The patient
must therefore become an informed and knowledgeable member of the treatment team and partner with
the health-care provider. The ability to take acute
medications appropriately is an important skill which
the patient must master, along with many other selfmanagement skills, if migraine is to be managed as
successfully as possible.
Pharmacological management is only one part of
migraine management. It was pointed out over half a
century ago that it was more important for a patient
to live within his or her limitations, then to try an
endless round of medications.4 Acute migraine medications have improved a great deal since that time,
but this statement is still largely true. While patients
differ in how severe their migraine tendency is, lifestyle and other environmental factors are very significant for many patients. Dealing with these may be
difficult, and not all patients are willing to make the
personal adjustments necessary for optimal migraine
management.2 However, pharmacological management should be only one facet of a much broader
approach to migraine management.5
Medication Choices.—Many different medications
have been used, but the mainstays of modern acute
migraine treatment are the nonsteroidal antiinflammatory drugs (NSAIDs) and the triptans. The
evidence base for many acute migraine medications
has recently been reviewed.6
Acetaminophen and NSAIDs.—Acetaminophen is
widely used, and has randomized controlled trial evidence for efficacy in migraine,7,8 but is generally considered effective primarily for attacks of mild or
moderate severity. As with the NSAIDs, it can be
combined with an anti-emetic if the patient has significant nausea. A recent systematic review con-
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cluded that acetaminophen 1000 mg plus metoclopramide 10 mg had 2-hour headache relief rates
similar to those of sumatriptan 100 mg (39% vs 42%,
respectively).9
NSAIDs.—The NSAIDs are generally a good
starting point for acute migraine treatment, although
acetaminophen can be tried if there are contraindications to NSAID use, and triptans are another
option. Ibuprofen,10 naproxen sodium,11 acetylsalicylic acid (ASA),12 and diclofenac potassium13 all
have double-blind randomized controlled trial
evidence for efficacy that has been analyzed in systematic reviews. These NSAIDs have different pharmacokinetics, and this has implications for their
usefulness in a specific patient. Ibuprofen and
diclofenac potassium have very rapid absorption
from the gastrointestinal tract, and therefore the
potential for a rapid onset of action (Table 1).
Although they may completely abort a migraine
attack, their short half-life may make repeated dosing
necessary for a single attack in some patients.
Naproxen sodium, on the other hand, has slower
absorption but a much longer half-life.
Both ibuprofen and diclofenac potassium have
special formulations with more rapid absorption and
therefore a more rapid onset of action that have been
shown to have advantages over their oral tablet counterparts. Solubilized ibuprofen 400 mg has generally
shown a higher response rate for headache relief
(headache reduced from moderate or severe intensity
to mild or no headache) at 1 hour as compared to
the corresponding standard ibuprofen tablet.14
Diclofenac potassium powder for oral solution
(50 mg) has been compared directly to the corresponding oral tablet. For the pain free at 2 hours end
point, the powdered formulation (sachets) was superior to the tablet, with 24.7% of patients pain free
with the sachet, and 18.5% with the tablet (P = .0035).
With the sachet, analgesic effects were noted within
15 minutes.15
ASA also has a relatively rapid absorption
(Table 1), and an intermediate half-life of 5-6 hours if
active metabolites are included. Effervescent ASA
has a faster absorption than regular tablets.16
Ibuprofen is one of the most frequently used
NSAIDs for migraine.3 This may reflect its low cost,
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Table 1.—Acetaminophen and Nonsteroidal Anti-Inflammatory Drugs: Pharmacokinetic, NNTs, and Dosage
Drug
Acetaminophen
Acetylsalicylic acid
(ASA) (tablet)
ASA (effervescent)
Tmax
(Hours)
0.5-1
1-2
∼20 minutes
Elimination
Half-Life
(Hours)
2
ASA: 0.25
Salicylate (active):
5-6 (after 1 g dose)
NNT: 2
Hour
NNT: 2
Headache
Hour
Relief
Pain Free
5.0
12
4.9
8.1
3.2
7.2
as above
Ibuprofen (tablet)
1-2
2
Ibuprofen (solubilized)
<1
2
2
14
6.0
<1
2
6.2
8.9
15 min
2
5.1
7.4
Naproxen sodium‡
Diclofenac potassium
(tablet)
Diclofenac potassium
(powder for oral
solution)
11
Dose (mg)†
Dosage Interval
(If Repeated) and
Maximum Daily Dose†
1000
Every 4 hours,
max. 4000 mg
975-1000
Every 4-6 hours;
max: 5.4 g/day (varies
depending on
indication)
975-1000
Every 4 hours;
max: 8 (325 mg) tablets
400
Every 4 h;
max: 2400 mg
400
Every 4 hours;
max: 2400 mg
500-550
Twice a day;
(up to 825 mg) max: 1375 mg
50
3-4 times a day;
max: 150 mg
50
Single dose
recommended for
migraine attack
†For acute migraine treatment, only 1 or 2 doses are usually recommended; doses are for adults.
‡Absorbed more quickly than naproxen.
Tmax = time to maximum plasma concentration; NNT = number needed to treat: the number of patients that must be treated to
obtain a response on a given end point over and above the response rate obtained from placebo.
availability, and relatively good efficacy. In a large
double-blind cross-over study, response rates for the
headache relief end point at 2 hours were 60.2% for
ibuprofen 400 mg, 55.8% for sumatriptan 50 mg,
52.5% for effervescent ASA, and 30.6% for placebo,17
although ibuprofen has not been compared directly
with sumatriptan 100 mg, a more optimal sumatriptan
dose. It may produce less gastric irritation than ASA,
and the proportion of patients with headache relief at
2 hours is at least as high with the ibuprofen 400 mg
tablet18 as with a dose of 900-1000 mg ASA.12
Naproxen sodium has the advantage of a long halflife, but headache relief rates at 2 hours are lower
than for ibuprofen.11,19 Pharmacokinetics, dosages,
and headache response rates (given as NNTs
[number needed to treat]) for acetaminophen and the
NSAIDs are shown in Table 1.5,9,12,13,18,19
Combination analgesics with both acetaminophen and ASA have also been investigated for efficacy in acute migraine treatment. A combination of
acetaminophen, ASA, and caffeine has been shown to
have greater efficacy than any one of its components
in comparable doses alone.20 Caffeine does appear to
make a significant contribution to analgesia when
included in combination tablets,21 but this needs to be
balanced with possible interference with sleep if rest
is to be part of the treatment paradigm. Another
study that compared an acetaminophen/ASA/
caffeine (AAC) combination tablet to ibuprofen
400 mg found the AAC tablet to be superior on
several end points.22 Adding metoclopramide 10 mg
to ASA improves relief of nausea and vomiting.12
Triptans and Triptan-NSAID Combinations.—
Triptans.—The triptans, unlike the NSAIDs, are serotonergic agonists that target primarily the 5HT1b and
5HT1d receptors. Although the ergotamines are agonists at the same receptors, these older drugs are
much less specific and affect other receptor types as
well. These older drugs therefore tend to have more
side effects at therapeutically effective doses. All
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Table 2.—Triptans: Pharmacokinetics, NNTs, and Dosage
Drug
Almotriptan
Oral 12.5 mg
Eletriptan
Oral 40 mg
Frovatriptan
Oral 2.5 mg
Naratriptan
Oral 2.5
Rizatriptan
Oral 10 mg
ODT 10 mg
Sumatriptan
Subcut. 6 mg
Sumatriptan
Nasal 20 mg
Sumatriptan
Oral 50 mg
Sumatriptan
Oral 100 mg
Zolmitriptan
Nasal 5 mg
Zolmitriptan
Oral 2.5 mg
ODT 2.5 mg
Tmax (Hours)
1-3
Elimination
Half-Life
(Hours)
3-4
NNT: 2 – Hour
PainFree†
Usual Dose
(mg)‡
5.2
12.5
Dosage Interval (If
Repeated for Headache
Recurrence) and
Maximum Daily Dose‡
2 hours; Max daily dose 25 mg
1-2
3.8
4.5
40
2 hours; Max daily dose 40 to 80 mg§
2-4
26
12
2.5
4 hours; Max daily dose 5 mg
5-8
8.2
2.5
4 hours; Max daily dose 5 mg
2-3
3.1
10
2 hours; Max daily dose 20 mg
2
2.3
6
2 hours; Max daily dose 12 mg
2
4.7
20
2 hours; Max daily dose 40 mg
2.5
2
6.1
50
2 hours; Max daily dose 200 mg
2.5
2
4.7
100
2 hours; Max daily dose 200 mg
2
2.5-3
4.6
5
2 hours; Max daily dose 10 mg
2
2.5-3
5.9
2.5
2 hours; Max daily dose 10 mg
2-3
1.5
0.25
1-1.5
†NNTs may be lower when attacks are treated early at mild intensity.
‡Dosages are for adults.
§Depends on jurisdiction.
Tmax = time to maximum plasma concentration; NNT = number needed to treat: the number of patients that must be treated to
obtain a response on a given end point over and above the response rate obtained from placebo; ODT = orally dissolving tablet.
available triptans are vasoconstrictors and are therefore contraindicated in patients with cardiovascular
disease. Although several head-to-head clinical trials
have suggested that NSAIDs are as effective as the
triptans,23 and for some patients they no doubt are,
clinical experience suggests that overall the triptans
are the most effective acute migraine drugs available.
Seven triptans are currently available in oral
form, and all have good evidence for efficacy in acute
migraine therapy. Although all share a relatively
similar molecular structure, individual patients
respond to different triptans in profoundly different
ways, both in terms of effectiveness for pain relief and
side effects. The response of an individual patient’s
response to one triptan compared to another cannot
be predicted with certainty, although in terms of
patient groups some generalizations can be made
based at least in part on pharmacokinetic differences.
Not all the factors which govern a specific patient’s
response to the different triptans are understood,
however, and the clinical implications of this are that
if the patient’s response to one triptan is not excellent, another triptan should be tried to see if a better
response can be obtained.
The 7 triptans currently available in North
America along with their various formulations are
shown in Table 2. In general, 2 triptans, frovatriptan
and naratriptan, both with relatively long plasma halflives, tend to have a slow onset of action and a low
headache recurrence rate in the following 24 hours if
relief occurs. Oral rizatriptan and eletriptan have a
fast onset of action, although differences in this
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respect between them and the remaining 3 triptans,
sumatriptan, almotriptan, and zolmitriptan, are not
marked. Tablet formulation can play a significant role,
and a systematic review found that the onset of action
of the fast-dissolving sumatriptan tablet was comparable to rizatriptan, an oral triptan with a recognized
very fast onset of action.24 The differences between
patients are in general considered to be greater than
the efficacy differences between the oral triptans, and
side effect profiles and headache recurrence rates are
additional factors to be considered when deciding
which triptan to use. A recent meta-analysis found
that eletriptan 40 mg and rizatriptan 10 mg provided
the highest pain-free rates at 2 hours, and eletriptan
provided in addition the highest 24-hour sustainedfree rate with no recurrence of headache for 24 hours
after treatment.25 Pharmacokinetics, 2-hour pain-free
rates (given as NNTs), and dosages are given in
Table 2 for commonly used formulations for the 7
available triptans.5,26
Triptan–NSAID Combinations.—There is good
evidence that combining sumatriptan with naproxen
provides greater efficacy than using either drug alone.
The combination provides a higher 2-hour headache
relief rate than either drug alone, with a 65% rate for
a combination of sumatriptan 85 mg /naproxen
sodium 500 mg as compared to 55% for sumatriptan
monotherapy (P = .009) in one study, and 57% vs
50% in another (P = .02).27 The combination also has
been shown to provide a higher 24-hour sustained
pain response (no more than mild pain and no rescue
medication at 2 hours and for 24 hours post-dose)
than either drug alone. Twenty-four hour sustainedpain responses were seen in 46% of subjects with a
combination of sumatriptan 50 mg and naproxen
500 mg, in 29% of those who took sumatriptan 50 mg
alone, in 25% with naproxen 500 mg alone, and in
17% of those who took placebo.28 Headache attacks
meeting criteria for probable migraine also respond
to a sumatriptan 85 mg/naproxen sodium 500 mg
combination tablets as compared to placebo (29%
pain free at 2 hours with the combination vs 11% with
placebo).29
It might be expected that similar results should
be obtained with other triptan/NSAID combinations,
although few trials have been done. A combination of
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frovatriptan 2.5 mg and dexketoprofen (an NSAID
with a short half-life) has been compared to use of
frovatriptan alone. The combination therapy resulted
in higher pain-free rates at 2 hours than with
frovatriptan alone (51% vs 29%).30
Combining an NSAID with a triptan would
therefore appear to be a good strategy for patients
who do not respond well to a triptan alone. Most of
the available evidence for this strategy has come
from studies using a sumatriptan–naproxen sodium
combination.
Ergot Alkaloids.—The ergotamines, although
effective for some patients, have been largely
replaced by the triptans, which have the advantage
of greater pharmacological specificity and fewer
side effects.31 Dihydroergotamine is still a very
useful drug and can be used intranasally and subcutaneously,32,33 but is not available in an oral form for
acute treatment because of poor absorption.
Other Medication Combinations.—Combination
analgesics with isometheptene, a vasoconstrictor, are
also used for migraine,34 but there is little evidence
for the effectiveness of isometheptene alone.
Combination analgesics with opioids including
codeine should not be used routinely in migraine
because of poor evidence for efficacy beyond that
provided by NSAIDs and risk of overuse with resultant medication overuse headache. When their use is
necessary because of unresponsiveness or contraindications to other medications, combination
analgesics with tramadol may be the preferred
option.35 Use of barbiturate-containing analgesics
and stronger opioids like morphine and butorphanol should be limited to exceptional cases
because of risk of addiction and medication overuse
headache.36
Medications containing barbiturates in particular
appear to place patients at risk for overuse and medication overuse headache, and the evidence suggests
that they are no more effective than less detrimental
medication combinations.A randomized double-blind
controlled cross-over trial compared a butalbital–
acetaminophen–caffeine combination analgesic to a
sumatriptan–naproxen sodium combination. There
was no significant difference in the primary study end
point, but the sumatriptan–naproxen combination was
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superior on most secondary end points.37 There is also
concern that using opioids may make patients more
refractory to other acute medications including the
triptans. A post hoc analysis of a rizatriptan clinical
treatment trial found that recent opioid use was associated with a lower response rate to rizatriptan,
but current data cannot differentiate whether this was
an effect of the prior opioid use or whether opioid use
was a marker for patients with more refractory
migraine.38
Clinical Use of Acute Medications.—There are a
large number of pharmacological options available
for acute migraine treatment, and none of them are
ideal for all patients. The art and science of headache
neurology involves recommending the best option for
a specific patient.36,39 The clinical features of both of
the patient’s general medical condition and of the
attacks themselves need to be woven into the
decision-making process.
Headache Intensity.—Headache intensity is
an important factor in medication choice. If headaches are usually of mild to moderate intensity, acetaminophen, or an NSAID may give good relief. If
headaches are more severe, this is less likely although
an NSAID may still be effective. A post hoc analysis
that examined the response of patients who treated
migraine when the headache intensity was severe
with acetaminophen/ASA/caffeine (AAC), ibuprofen, or placebo found that 2-hour headache response
rates (headache reduced to mild or none) were 62%
for AAC vs 54% for ibuprofen (P = .036). This study
suggests that many patients with severe migraine
attacks do respond to NSAIDs, and that the AAC
combination is an effective acute migraine medication.40 The ACC combination studied, which contained 500 mg ASA, 500 mg acetaminophen, and
130 mg of caffeine, was significantly superior to ibuprofen 400 mg on a number of study end points
(P < .04).
With a stratified approach to care, the acute
medication is chosen according to the degree of disability caused by migraine. There is evidence that this
is the most effective approach.41 In this approach,
patients with greater disability are started on a triptan
initially, while those with attacks of lesser intensity
may be given an NSAID first, and escalated to a
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triptan in later attacks if the NSAID does not
produce satisfactory results. The stratified approach is
based on the principle that the triptans are more
effective for severe migraine attacks than the
NSAIDs, an assumption that is based more on clinical
experience than on good randomized controlled
head-to-head trial data.
The alternative to the stratified approach is the
step care across attacks approach, where all patients
are tried on an NSAID or other nonspecific analgesic
first, and then escalated to a triptan for later attacks if
the first medication is not satisfactory. One of the
main reasons for this approach is to avoid the costs
involved with using triptans. A disadvantage of this
approach is that it may delay finding an effective
medication for the patient, and thereby lead to
increased patient disability, disillusionment with the
health-care system, and the patient may stop consulting for migraine. In a clinical trial that compared
stratified care to the step care across attacks
approach, disability time (from 0-4 hours after treatment) averaged across all 6 attacks was significantly
lower for stratified care than for the step care across
attacks strategy.41
The question of whether to use stratified vs step
care across attacks care is somewhat academic, in that
most patients who see physicians for migraine have
already usually tried a number of analgesics prior to
consultation, so the step care across attacks approach
has already been started. The step care across attacks
approach would seem the most appropriate one for
most patients with migraine, assuming that the patient
is also educated with regard to other treatment
options. For those with severe attacks that often
require bed rest, however, a stratified approach would
seem more appropriate. This has been termed the
combined acute medication treatment approach5 and
is discussed in the Canadian Headache Society
Guideline: Acute Drug Treatment for Migraine
Headache.
Among the triptans, subcutaneous sumatriptan
(6 mg) has shown the highest headache response
rates in patient groups,42 and is an option that should
be considered in patients with severe migraine
attacks, particularly if they have not had a satisfactory
response to oral triptans. Intranasal zolmitriptan
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5 mg can also be a helpful option for these patients.43
Intranasal zolmitriptan 5 mg has shown a significantly
higher 2-hour headache relief rate (70.3%) as compared to the 2.5 mg zolmitriptan tablet (61.3%)
(P < .05).43
Nausea.—Nausea is one of the most common
associated symptoms of the migraine attack. Not only
can it be significantly disabling in its own right, it can
affect the effectiveness of oral medications. Depending on the severity of the nausea, and whether vomiting is present, one of several treatment options can
be pursued.
1. If nausea is mild, but exacerbated by taking fluids,
patients may find the orally dissolving tablets
(wafers) helpful.44 These include rizatriptan and
zolmitriptan, and melt in the mouth. They are not
absorbed trans-buccally, but rather drug is swallowed with saliva. Because liquids are not
required, they may exacerbate nausea less, and can
also be taken early in the attack even when fluids
are not available.
2. If nausea is moderate in degree, an anti-emetic
given with the NSAID or oral triptan can be
helpful. The anti-emetic with the greatest evidence
for efficacy in migraine is oral metoclopramide
(10 mg).12,45-47 Although it may produce extrapyramidal side effects, these are rare with intermittent
oral use for migraine attacks. Prochlorperazine
10 mg orally is another option, although it
may have more extrapyramidal side effects.
Domperidone 10 mg can also be used.48,49 It has
less evidence for efficacy than metoclopramide but
has the advantage that it does not cross the blood–
brain barrier and therefore does not cause extrapyramidal side effects. There are concerns about
the cardiac safety of domperidone,50 although the
risks with intermittent use in otherwise healthy
individuals with migraine are likely very low.
Promethazine 25 mg, a phenothiazine, has been
shown to improve efficacy when combined with
sumatriptan 50 mg as compared to sumatriptan alone
(39% pain free at 2 hours as compared to 26%,
P = .038).51 Somnolence was a common side effect,
however, and 4.3% of patients reported extrapyrami-
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dal symptoms as compared to no extrapyramidal
symptoms in the sumatriptan plus placebo group. Parenteral use of promethazine should be avoided where
possible because of its association with severe local
adverse events.52 Ondansetron has not been investigated for efficacy in migraine related nausea, and has
been reported to cause migraine-like headache in
children.53
3. If patients have severe nausea or vomiting, subcutaneous sumatriptan 6 mg should be considered, especially if vomiting occurs early in the
migraine attack. Intranasal zolmitriptan 5 mg,
which has good evidence for significant absorption through the nasal mucosa,54 can also be considered, particularly if vomiting occurs later in
the attack. Intranasal sumatriptan and intranasal
dihydroergotamine are also available, but have
less evidence for significant amounts of transnasal absorption. Anti-emetics can be used with
these medications, and for patients with vomiting,
prochlorperazine suppositories 10-25 mg may be
helpful.55
Rapidity of Pain Increase After Onset.—For
migraine attacks where the pain intensity builds up
rapidly, several medication formulations designed for
a rapid onset of action may be helpful. These include
diclofenac powder for oral solution 50 mg,15 solubilized ibuprofen 400 mg,14 and effervescent ASA
1000 mg.56 Several oral triptans also have a fast onset
of action, including rizatriptan, eletriptan, and the
fast-dissolving sumatriptan tablet.24,25 Sumatriptan 6
mg subcutaneously, nasal sumatriptan 20 mg, and
nasal zolmitriptan 5 mg are also good choices, with
subcutaneous sumatriptan having a particularly fast
onset of action.42 Of note, the orally dissolving
rizatriptan and zolmitriptan tablets (wafers) have no
advantage over the regular oral tablets in terms of
rapidity of onset of action.
For migraine attacks that build up more slowly
but that have a relatively long duration, some of the
slower but longer acting treatment options may be
more helpful when treatment is taken early in
the attack, including naproxen and frovatriptan. If
patients have migraine attacks of different intensities,
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and these tend to build up slowly, an NSAID can be
tried first by the patient early in the attack, and then
a fast-acting triptan later if the NSAID fails.
However, if patients find that they have to go on to
the triptan for most attacks, then it is usually best if
they use a triptan as their first-line medication, as
essentially all acute migraine medications do work
best if taken early in the attack.
Headache Recurrence.—For patients who experience initial headache relief with treatment but who
experience the return of moderate to severe headache within 24 hours, several options are available.
These include:
1. Most patients with headache recurrence after
triptan therapy will respond well to a second dose
of the same triptan.57 Although there is less
research, clinical experience indicates that the
same is also true for NSAIDs.
2. Early treatment of the attack may reduce the tendency for headache recurrence.
3. For recurrence after triptan therapy, the patient
may find that they have less frequent headache
recurrence if they switch to another triptan for
future attacks. Eletriptan and frovatriptan appear
to have relatively low recurrence rates.25,58
4. Naproxen sodium 500-550 mg can be taken simultaneously with the patient’s triptan for initial
attack therapy.27
5. For patients with major headache recurrence
problems on triptan therapy, dihydroergotamine,
either by nasal spray or by subcutaneous selfinjection, can be used. Dihydroergotamine has a
low headache recurrence rate.33 A new inhaled
form of dihydroergotamine has shown therapeutic
promise and may soon be available.59
Headache Persistence.—If patients do not
respond to their triptan for some attacks, with persistence of the head pain as opposed to initial relief
followed by recurrence, a second dose of a triptan is
unlikely to be of additional benefit.60 A rescue medication from another drug class is usually recommended in this situation.
Migraine With Aura.—The available evidence
from clinical trials suggests that both subcutaneous
785
sumatriptan and oral eletriptan are not as effective as
might be expected when taken during the migraine
aura.61,62 The recommendation is therefore that
patients take their triptan at pain onset. More data
are needed on this question, however. Many patients
do have their pain onset during the aura.63 Anecdotally, patients in the clinic do report success with
triptan use during the aura, and triptan use during a
typical migraine aura is considered safe. Finally, a
recent open-label trial reported good success with
sumatriptan taken during the aura.64
Refractory Migraine.—If patients are having difficulty finding an acute medication that works well for
them, several factors should be considered.
1. Is the diagnosis correct, or is a secondary headache
a possibility? Further investigation may be needed.
2. Are there lifestyle factors such as excessive stress
which might be contributing to the patient’s intractability? These may need to be addressed.
3. Is the patient treating too late in the migraine
attack? For most drugs, including the triptans, early
treatment when pain is still mild is usually more
effective than treatment later in the attack.65-67
4. Medication combinations may be more effective
for the patient. Triptan–NSAID combinations, and
triptan–NSAID–metoclopramide combinations
can be tried.
5. Medication overuse may contribute to intractability. Use of NSAIDs or acetaminophen on 15 days a
month or more, or use of triptans or combination
analgesics including those with codeine on 10 days a
month or more, is considered to place patients at
risk for medication overuse headache.68 The above
limits are based largely on expert opinion,and there
is some evidence that even lower frequencies of use
of opioid and/or barbiturate containing analgesics
may predispose to medication overuse headache in
individuals with migraine.69 If present, medication
overuse needs to be stopped, and the patient educated with regard to acceptable frequency of use
limits for any acute medications used in the future.
6. Dihydroergotamine may be a useful acute treatment option in patients who do not respond well to
more commonly used medications including the
triptans.
786
7. Some patients do not respond well to any of the
available acute migraine medications. For these
patients, pharmacological migraine prophylaxis
and behavioral approaches need to be maximized.
Patients Must Be Evaluated for Contraindications.—NSAIDs are contraindicated in patients
with peptic ulcer disease, renal disease, and in patients
on anticoagulants. Triptans are vasoconstrictors and
are contraindicated in patients with coronary artery
disease, peripheral vascular disease, and stroke. It is
important to note that use of selective serotonin
reuptake inhibitor antidepressants is not considered a
contraindication to triptans by most clinicians, and
although clinicians should be vigilant for the possibility of serotonin syndrome with this combination,
current evidence does not support limiting the use of
triptans with selective serotonin reuptake inhibitors or
serotonin and norepinephrine reuptake inhibitors.70
There are no data showing serious side effects, but
triptans are listed as contraindicated in hemiplegic
migraine by their manufacturers based on theoretical
considerations. They have not been proven safe in
hemiplegic migraine, and their use is controversial. A
study of 76 patients with hemiplegic migraine treated
with triptans concluded that they were safe and effective,71 but this study was too small to exclude potentially serious side effects. Others have indicated that
triptans may be safe in hemiplegic migraine,72 are
often used in hemiplegic migraine,73 or have listed
them as treatment options if NSAIDs and other analgesics have failed.74
Organizing Acute Migraine Medication Treatment
Options.—Given the many options for acute
migraine treatment, it is helpful to organize them into
a logical framework of strategies.Then an appropriate
strategy can be chosen for a specific patient, depending on the clinical circumstances. For most patients
with migraine, one of the 4 strategies shown in Table 3
would be appropriate, depending on patient history
and clinical features. The first 2 strategies are based
primarily on attack severity and on whether or
not the patient responds satisfactorily to acetaminophen and/or NSAIDs. If strategy 1 (acetaminophen/
NSAIDs) fails, then strategy 2 (triptan strategy)
should be tried. For some patients with severe attacks,
June 2015
Table 3.—Acute Migraine Treatment Strategies†
Strategy 1: For Initial Treatment of Migraine Attacks of Mild
to Moderate Severity‡ (Acetaminophen–NSAID Strategy)
Acetaminophen (primarily for milder attacks)
Ibuprofen
Diclofenac potassium
Naproxen sodium
Acetylsalicylic acid
Combination analgesics without opioids or barbiturates
Strategy 2: For Severe Attacks, and for Attacks of Moderate
Severity Not Responding to Strategy 1 (Triptan Strategy)
Sumatriptan
Rizatriptan
Eletriptan
Zolmitriptan
Almotriptan
Frovatriptan
Naratriptan
Strategy 3: For Migraine Attacks Refractory to Strategies
1 and 2
Triptan–NSAID combinations
Dihydroergotamine
Various rescue medications (dopamine antagonists,
steroids, etc)
Combination analgesics without opioids or
barbiturates
Combination analgesics with opioids (not for routine
use)
Strategy 4: For Patients With Contraindications to
Vasoconstricting Drugs
NSAIDs
Dopamine antagonists
Combinations analgesics without opioids or
barbiturates
Combination analgesics with opioids (not for routine
use)
†Anti-emetics (metoclopramide, domperidone) may be added
to all medications above as necessary except for dopamine
antagonists.
‡Some severe attacks may also respond to NSAIDs.
Headache
the choice may be made to go to the triptan strategy
directly as a first line option.
Some patients with migraine have attacks of differing severity75 and may benefit from having medications from more than one strategy available to
them. This can be helpful particularly if they are able
to predict the severity of the attack soon after it starts.
For example, they may find it best to take an NSAID
for their milder attacks, and a triptan for their more
severe attacks.
For patients that are refractory to the first 2 strategies, a number of options exist, as shown in Table 3
(strategy 3 for refractory migraine attacks). This strategy may involve various rescue medications to be
used by the patient for occasional failures of their
usual medications (for example, they may be taking a
triptan–NSAID combination as their usual medication, and may occasionally use a prochlorperazine suppository for rescue when their usual
acute medication fails). A complete discussion of possible rescue medications is beyond the scope of this
review, and it is suggested the reader consult the
Canadian Headache Society Guideline: Acute Drug
Therapy for Migraine Headache.5
Strategy 4 lists options available for acute
migraine attack treatment for patients with
contraindications to vasoconstricting drugs. Many
NSAIDs have been associated with an increased risk
of cardiovascular disease, but it is unclear how significant this is with intermittent use as in acute
migraine treatment. Naproxen sodium appears to
have a relatively good cardiovascular safety profile
as compared to many other NSAIDs.76,77 Patients
with contraindications to vasoconstricting drugs who
do not respond to NSAIDs may be one group in
whom the use of opioid-containing analgesic combination tablets becomes necessary.78 It is important to
educate the patient regarding medication overuse
headache and to monitor frequency of use in this
circumstance.
Using the Acute Migraine Treatment Strategies.
—In summary, the strategies summarized in Table 3
can be applied quite easily to the individual patient.
For most patients, presenting with migraine for the
first time, the acetaminophen–NSAID strategy will be
appropriate, unless the patient has already sufficiently
787
tried this strategy with over-the-counter medications.
If patients have severe attacks that usually render
them bedridden for a time, it may be best to omit the
acetaminophen–NSAID strategy and go directly to
the triptan strategy.
For most patients, if the acetaminophen–NSAID
strategy has failed, the triptan strategy is the next
logical choice if there are no contraindications. If
patients do not do well on the triptan strategy, strategy 3 for refractory patients should be initiated. If
there are contraindications for vasoconstrictor drugs,
then strategy 4 should be initiated instead of strategies 2 and 3.
Each strategy has a number of options, and decisions need to be made in conjunction with the patient
as to how many options to try in each strategy. For
strategy 2, example, it would usually be appropriate to
try several triptans before moving on to strategy 3
(refractory patient strategy).
Finally, if patients have attacks of differing severity, they may need medications from 2 different strategies. They may use, for example, an NSAID for
milder attacks and a triptan for more severe attacks.
Some patients may need to have available more
than one agent from a single strategy. For example,
patients may need injectable sumatriptan for severe
headache attacks that are present on awakening, but
they may prefer to use an oral triptan for attacks that
occur during the day when they can treat early in the
attack.
Special Situations.—Pregnancy.—Acetaminophen
and metoclopramide are considered safe, although no
drug has been proven to be safe in pregnancy, and
drug exposure should be minimized as much as possible. Acetaminophen with codeine is relatively safe,79
although caution should be observed toward the end
of pregnancy because of potential withdrawal symptoms in the neonate, and because of a slight association with acute cesarean section and postpartum
hemorrhage.80 Although not known to cause malformations, other opioids may also produce harmful
effects on the fetus or neonate.
ASA should be avoided in pregnancy as other
NSAIDs are preferable because of less prolonged
effects on platelet function. All NSAIDs should be
avoided after the 32nd week of gestation because of
788
effects on the ductus arteriosus. There is concern that
in the first trimester, they may cause an increased risk
of spontaneous abortion, although in a recent historical cohort study, exposure to NSAIDs during pregnancy was not an independent risk factor for
spontaneous abortion.81
Ergotamines must be avoided due to uterotonic
effects, but triptans appear much safer during pregnancy. No association between sumatriptan use in the
first trimester and fetal malformations or adverse
pregnancy outcomes was found in a large observational study, although sumatriptan use in the second
and third trimester was associated with atonic uterus
and blood loss >500 mL during labor and delivery.82
A pregnancy registry that included 528 pregnant
women with first trimester sumatriptan exposure concluded that no signal of teratogenicity associated with
major birth defects was detected.83 There are much
less data with regard to other triptans. It might be
concluded, therefore, that for pregnant women with
difficult migraine that greatly interferes with tasks of
daily living or results in dehydration, sumatriptan
may be an option during pregnancy.
Migraine During Lactation.—During breast
feeding, acetaminophen is considered safe, and
among the NSAIDs, ibuprofen is preferred. ASA in
analgesic doses should be avoided, but occasional
use of diclofenac and ketorolac is compatible with
breast feeding.79 Infant exposure after maternal use
of sumatriptan would appear to be small, and
sumatriptan use is considered compatible with
breast feeding.84 Metoclopramide, domperidone,
prochlorperazine, and dimenhydrinate are all considered safe.5
Morphine is the opioid of choice if an opioid must
be used, but if the mother experiences significant
sedation the milk should be discarded, and it is important to be cautious with infants under 1 month of age
and premature infants. Codeine should be avoided
during lactation because of variable maternal
metabolism.85
Chronic Migraine.—Patients with chronic migraine
represent the more severe end of the migraine spectrum.To meet diagnostic criteria for chronic migraine,
patients must have a history of migraine, and have
had headache on more than 14 days a month for at
June 2015
least 3 months. Importantly, at least 8 of these headache days must meet diagnostic criteria for migraine
or have responded well to migraine specific medication.68 The acute medications used for migraine
attacks in chronic migraine are the same as the ones
used in episodic migraine (migraine with headache on
14 days a month or less). Acute migraine treatment in
chronic migraine, however, presents a difficult challenge for both the patient and the physician because
of the high headache frequency, as it is important to
avoid acute medication overuse and resultant medication overuse headache. Patient education is vital to
meet this challenge, and migraine prophylactic
therapy and behavioral treatment modalities should
be maximized.5,86 Use of combination analgesics containing opioids and barbiturates should be avoided if
possible or minimized because of their propensity to
cause medication overuse headache.
Comprehensive Migraine Management and New
Directions.—For many patients, acute medications
are only part of the overall treatment plan, which
must also include a number of other modalities. These
include lifestyle modification and management of
migraine triggers specific for that patient, behavioral
treatment modalities like relaxation techniques,
pacing,87 and stress management,88 and pharmacological prophylaxis.89
Fortunately, new acute therapies are under active
investigation or becoming available. These include
new treatment modalities like non-invasive vagal
nerve stimulation90 for migraine attacks and singlepulse transcranial magnetic stimulation for migraine
with aura.91 New drug delivery systems including
transdermal drug delivery systems92,93 and breathpowered devices for better drug delivery through the
nasal mucosa94 also hold promise for the future.
CONCLUSION
Acute migraine treatment is complex and often
requires careful attention both from the patient and
the health-care provider if the patient’s migraine is to
be managed as successfully as possible. Even with
appropriate use of current acute therapies, not all
patients can be treated satisfactorily. New research
will no doubt add to our understanding of migraine
Headache
pathophysiology and lead to new therapies. As a
result, our patients can expect acute migraine treatment to be more effective in the future than it is
today.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Werner J. Becker
(b) Acquisition of Data
Werner J. Becker
(c) Analysis and Interpretation of Data
Werner J. Becker
Category 2
(a) Drafting the Manuscript
Werner J. Becker
(b) Revising It for Intellectual Content
Werner J. Becker
Category 3
(a) Final Approval of the Completed Manuscript
Werner J. Becker
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