Review Article

Emergency Department
Address correspondence to
Dr Todd D. Rozen, Geisinger
Specialty Clinic, MC 37-31,
1000 East Mountain Blvd,
Wilkes-Barre, PA 18711,
tdrozmigraine@yahoo.com.
Relationship Disclosure:
and Inpatient
Dr Rozen reports no disclosure.
Unlabeled Use of
Products/Investigational
Management of Status
Use Disclosure:
Dr Rozen discusses the
unlabeled/investigational
Migrainosus and
Intractable Headache
use of magnesium sulfate,
dopamine receptor
antagonists (metoclopramide,
promethazine, prochlorperazine,
droperidol, chlorpromazine), Todd D. Rozen, MD, FAAN
ketorolac, levetiracetam,
methylprednisolone, and
dexamethasone for the treatment
of migraine headache. ABSTRACT
* 2015, American Academy Purpose of Review: This article discusses the treatment of status migrainosus in the
of Neurology.
emergency department and the treatment of intractable migraine in an inpatient setting.
Recent Findings: Multiple agents of various drug classes have been tried for the treat-
ment of acute migraine in the emergency department, but few have adequate medical
evidence to support their use. Opioids, which are less effective than other medications
used for the acute treatment of migraine and also carry the risk of adverse CNS side
effects, habituation, and addiction, have been prescribed for migraine in the emergency
department at an increasing rate over the last decade, which is a worrisome trend. Very
few patients with migraine derive sustained relief from pain after emergency department
treatment, and most have a high frequency of headache recurrence.
Summary: Treatment of status migrainosus and intractable migraine should focus on
adequate fluid hydration and combination IV therapy with multiple nonopioid medications
from multiple drug classes. Dopamine receptor antagonists appear to have some of the
highest medical evidence for efficacy.

Continuum (Minneap Minn) 2015;21(4):1004–1017.

INTRODUCTION patient with intractable migraine in an

Migraine can be a very debilitating pain
syndrome and sometimes requires treat-
ment in an emergency department or
inpatient hospital setting. The treatment
of long-duration migraine in these envi-
ronments can be challenging. Medicinal
agents from various drug classes can be
used, but medical evidence for their use
is lacking in many instances. The use of
opioids in these settings should be dis-
couraged, while IV fluids and a combi-
nation of parenteral medications should
be encouraged. This article discusses spe-
cific strategies and goals of treatment for
the patient with status migrainosus in
the emergency department and for the
1004 www.ContinuumJournal.com
inpatient hospital setting.
EMERGENCY DEPARTMENT
MANAGEMENT OF STATUS
MIGRAINOSUS
One of the last things patients with mi-
graine want to do when they have a se-
vere headache is end up in a busy, noisy
emergency department (ED) with fluo-
rescent lights beaming in their eyes. It
should be the goal of all neurologists and
headache specialists alike to keep their
patients out of the ED as it is the least
hospitable environment for a patient
with migraine, but sometimes it is the only
place to break an unrelenting severe
August 2015

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

headache. By the time patients have
reached this destination, they typically
have tried all their usual acute treatments,
rescue therapies, and sometimes even
added treatments such as corticosteroids.
In many instances, patients may have
also vomited several times, so they are
dehydrated, which definitely exacerbates
their pain and disability. So how does a
neurologist approach the patient with
status migrainosus (migraine lasting longer
than 72 hours) who presents to the ED?
For the sake of this discussion, it is as-
sumed the patient does not have a sec-
ondary headache syndrome.
The general principles of treating mi-
graine in the ED include: (1) adequately
hydrate all patients with IV fluids if no
contraindication exists; (2) treat head pain
with nonopioid medications if options
to do so are available; (3) provide rapid
relief with IV medications; and (4)
establish the correct expectations for
the patient. This means if a patient with
a 20-year history of chronic headache
presents with an exacerbation, the goal
of ED treatment is to provide adequate
relief of the single exacerbation (which
could mean taking a 10/10 headache to
the patient’s baseline daily headache
intensity of 3/10), not trying to make
pain free someone who has not seen a
pain-free moment in 2 decades. How-
ever, if the patient has episodic mi-
graine, the goal of ED treatment is
sustained pain freedom for that par-
ticular headache.
Before specific treatment is admin-
istered in the ED, the treating physician
should consider the following:
& Ask about and check the patient’s
medical record for comorbid
medical illnesses that could influence
drug selection:
) If the patient has a history of
uncontrolled hypertension or
cardiovascular, cerebrovascular,
or peripheral vascular disease,
drugs that have the potential for
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vasoconstriction (triptans,
ergotamine, dihydroergotamine
[DHE]) should be avoided.
) If the patient has a history of
recent gastrointestinal bleeding,
nonsteroidal anti-inflammatory
drugs (NSAIDs) should be avoided.
) If hypotension is present, IV fluid
boluses should be considered
prior to and after the administration
of medications such as dopamine
receptor antagonists
(prochlorperazine, droperidol,
haloperidol, chlorpromazine)
and magnesium sulfate, which can
cause precipitous drops in blood
pressure after IV administration.
& Ask about past response to treatment
in the ED, headache infusion units,
or inpatient headache units,
which can then guide treatment.
& Look at the patient’s current
medication list and what the
patient has already taken prior to
the ED visit so as not to add a
contraindicated medication or
create a potentially hazardous
combination of medications. This
could include adding opioids to
benzodiazepines, which can lead
to respiratory suppression; adding
IV sodium valproate to oral
topiramate, which can potentially
cause hyperammonemia and
encephalopathy; or administering
DHE to a patient who has taken a
triptan within the preceding
24 hours, which can lead to
cerebral or coronary vessel spasm.
& Always try to contact the patient’s
current treating physician to get
background information about
past treatment response and
determine if the patient has a
history of opioid use or abuse. The
more information gathered about
the patient, the greater the success
in safely and effectively treating
that individual in the ED.
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 Emergency and Inpatient Management
KEY POINTS
h All patients treated in
the emergency
department for acute
migraine should receive
IV fluid hydration unless
contraindications exist.
h IV magnesium sulfate
has shown mixed
efficacy for acute
migraine and migraine
with prolonged aura.
It can lead to hypotension
as a dose-dependent
side effect.
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Medication Choices for Acute
Treatment of Status Migrainosus
in the Emergency Department
Terminating a severe headache normally
requires a combination of medications
that have synergistic effects and different
mechanisms of action. To alleviate a se-
vere migraine headache, the concept is
that glutamate effect must be blocked,
GABA levels enhanced, dopamine and
histamine effect blocked, serotonin
levels raised, and CNS inflammation
blocked, and the patient must be hydrated,
and that cannot be accomplished by a
single agent. Thus, combination therapy
seems to work best for severe intractable
headaches (Table 4-1).
Intravenous fluids. It seems clear
that the patient with migraine who has
vomited before coming to the ED would
need fluid rehydration, but in reality all
patients in status migrainosus should
receive IV hydration. In the author’s
experience, IV fluids alone can be as
successful in reducing pain intensity as
medication. To date, no studies have
looked at the efficacy of IV fluids alone
for treating acute migraine; however, a
study by Harden and colleagues1 com-
pared the efficacy of ketorolac 60 mg,
meperidine 50 mg plus promethazine
25 mg, and normal saline all given by IM
injection and noted that all treatments
produced a significant reduction in
head pain (PG.0001), but that pain
reduction did not differ among the
treatments. This could indicate that sa-
line was as effective as ketorolac and
meperidine for migraine or that there
was an equally robust placebo effect for
all. IV fluids are also essential in that they
protect against some of the hypotensive
effects caused by the dopamine receptor
antagonists and IV magnesium sulfate
that are used to treat status migrainosus
in the ED.
Magnesium sulfate. Magnesium sul-
fate may exert a therapeutic effect through
its antagonism of N-methyl-D-aspartate
(NMDA) receptors, its blockade of cortical
spreading depression, or both. It can
be used for both status migrainosus and
prolonged aura or aura status. Studies
have shown mixed evidence of effective-
ness for acute migraine in the ED. Two
placebo-controlled trials evaluated the
efficacy of IV magnesium sulfate, and
while one showed no improvement ver-
sus placebo, the other demonstrated a
significant difference favoring magne-
sium sulfate in a migraine with aura sub-
group.2,3 In the original open-label trial of
IV magnesium sulfate in acute migraine,
35 of 40 patients treated achieved 50%
or greater reduction in pain intensity. Low
serum ionized magnesium levels appeared
to predict sustained treatment response
to IV magnesium, as 86% of patients (18
of 21 subjects) with serum ionized mag-
nesium levels below 0.54 mmol/L had
pain relief lasting over 24 hours com-
pared with only 16% (3 of 19 subjects)
with ionized magnesium levels at or
above 0.54 mmol/L (PG.001).4
Dopamine receptor antagonists.
Dopamine receptor antagonists are readily
used in the ED for status migrainosus
and actually have multiple positive effects
that make them valuable agents. Their
antiemetic effects are useful for the
nausea and vomiting that accompany a
severe migraine headache. Dopamine
antagonism may also provide relief of
both pain and aura symptoms. Finally,
their antihistaminic and anticholinergic
properties provide a sedative effect, and
for most patients with migraine, sleep
has therapeutic value. The three sub-
classes of dopamine receptor antagonists
include metoclopramide, phenothia-
zines (prochlorperazine, promethazine,
and chlorpromazine), and the butyro-
phenones (droperidol and haloperidol).
In this author’s opinion, the higher the
degree of CNS dopamine receptor block-
ade, the greater the efficacy in providing
migraine relief but the higher potential
for adverse events (in descending order
August 2015
TABLE 4-1 Acute Migraine-Abortive Medications for Emergency Department and
Inpatient Treatment

Class and Medication Dosing and Route Issues

Magnesium sulfate 500Y1000 mg IV Hypotension
Dopamine receptor antagonists
Metoclopramide 10 mg IV Akathisia, dystonia
Promethazine 12.5Y25 mg IM or IV Akathisia, dystonia
(possible tissue injury)
Prochlorperazine 10 mg IV Akathisia, dystonia
Droperidol 0.625Y2.5 mg IV Delayed akathisia, severe confusion at higher
dose, prolonged QT interval
Chlorpromazine 2.5Y25 mg IV Significant hypotension, prolonged QT interval
Nonsteroidal anti-inflammatory drug
Ketorolac 30Y60 mg IV or IM Gastritis
Antiepileptic drugs
Sodium valproate 400Y1200 mg IV Caution regarding acute hyperammonemia
and encephalopathy in those treated with
topiramate, also contraindicated in patients
with hepatic disease
Levetiracetam 250Y1000 mg IV
Vasoconstrictors
Dihydroergotamine 0.5Y1 mg IV Pretreat with antiemetic, bradycardiaVsuggest
against use in emergency department unless
patient is known to physician; unless the
cardiovascular, cerebrovascular, and aura history
of patient is known, a risk of potential
cardiac or brain ischemic event with agent
exists if given to a patient with contraindicated
medical/headache conditions
Sumatriptan 6 mg subcutaneous, Suggest against use in emergency department
20 mg intranasal unless patient is known to physician; unless
the cardiovascular, cerebrovascular, and aura
history of patient is known, a risk of potential
cardiac or brain ischemic event with
agent exists if given to a patient with
contraindicated medical/headache conditions
Corticosteroids
Methylprednisolone 100Y200 mg IV Data do not suggest benefit; must warn
about avascular necrosis
Dexamethasone 4Y16 mg IV May prevent headache recurrence after
emergency department visit; must warn
about avascular necrosis
IV = intravenous; IM = intramuscular.

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 Emergency and Inpatient Management
KEY POINTS
h Three subclasses of of degree of dopamine receptor block-
dopamine receptor ade and efficacy in providing migraine
antagonists have shown relief: haloperidol, chlorpromazine,
efficacy for acute droperidol, prochlorperazine, prometh-
migraine in the azine, metoclopramide). Based on a recent
emergency department: systematic review of the entire literature
metoclopramide, on the use of drugs for the treatment
phenothiazines, and of migraine in the ED, prochlorperazine
butyrophenones. Side and metoclopramide have received a
effects can include strong recommendation supporting their
akathisia, dystonia, and
use based on high and moderate levels
prolonged QT interval.
of evidence, respectively.5 Chlorproma-
h Lower doses of dopamine zine received a weak recommendation,
receptor antagonists may despite a moderate level of evidence, on
be more efficacious for
the basis of a more significant adverse
acute migraine treatment
event profile.
than higher doses.
Regardless of which dopamine re-
h Data do not support the ceptor antagonist is chosen, IV fluid boluses
use of corticosteroids in
should be administered as a pretreat-
the acute treatment of
ment because of the potential for hypo-
migraine in the
emergency department,
tension. In addition, an ECG with QT
but some data suggest interval measurement should be obtained
the potential benefit of prior to administering butyrophenones
using dexamethasone and chlorpromazine, as these agents can
to prevent headache prolong QT intervals and are contra-
recurrence up to 72 hours indicated if a patient has a baseline pro-
after discharge from the longed QT interval. Low dosages should
emergency department. be used initially, as superior efficacy for
some dopamine receptor antagonists,
including metoclopramide, droperidol,
and prochlorperazine, has been dem-
onstrated at lower doses compared to
higher doses.6Y8 Lower doses of dopa-
mine receptor antagonists also have a
better side effect profile. Prior to admin-
istering antidopaminergic drugs, patients
should be cautioned about their poten-
tial side effects. Pretreatment with IV
benztropine or diphenhydramine is rec-
ommended to minimize or avoid extra-
pyramidal side effects, especially with
dopamine receptor antagonists that have
a high incidence of posttreatment akathisia
and dystonia. Akathisia, a common adverse
event secondary to dopamine receptor
antagonists, can eliminate any positive
headache response from these medica-
tions, because it can be as disabling to
the patient as the pain itself. Akathisia
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can occur almost immediately after
dosing with some antidopaminergic
medications but can also be a delayed
reaction, especially with droperidol,
starting many hours after medication
administration and thus after the
patient has left the ED. IV diphenhy-
dramine should eliminate this side
effect and may itself have migraine-
alleviating properties.9
Nonsteroidal anti-inflammatory
drugs. In the United States, the only
available IV NSAID is ketorolac, which is
frequently given as a first-line agent for
migraine in the ED. A recent systematic
review looked at 34 studies, including
eight trials, assessing the efficacy of
ketorolac for the acute treatment of
migraine.10 The overall assessment was
that this NSAID is effective, with similar
pain relief to meperidine (with less ad-
dictive potential), and more efficacious
than sumatriptan, but not as effective as
phenothiazines and metoclopramide.
The Canadian Headache Society strongly
recommends IM or IV ketorolac for mi-
graine treatment in the ED based on a
systematic review of the literature, clini-
cal experience, and a favorable side ef-
fect profile.5 Typical dosing is 30 mg IV,
but 60 mg IV can have efficacy rates up
to 80%.11 The author almost always
suggests ketorolac as a treatment in the
ED if no gastrointestinal contraindica-
tions exist.
Corticosteroids. It is very common
to see the addition of IV corticosteroids
to a migraine treatment regimen in the
ED. In a recent meta-analysis, 25 studies
involving 3989 patients indicate the
potential benefit of using IV dexameth-
asone to prevent headache recurrence
up to 72 hours after discharge from the
ED.12 However, evidence suggests that
IV dexamethasone is not effective for the
acute treatment of migraine in the ED.5,12
All patients who receive corticosteroids
must recognize the potential risk of
avascular necrosis of the hip, which is
August 2015

exceedingly rare with single dosing but
has been known to arise with short
courses of treatment.13 In the author’s
experience, patients may respond to IV
methylprednisolone 100 mg to 200 mg
or dexamethasone 4 mg to 16 mg in the
ED; if no contraindications are present
(concomitant infection, diabetes mellitus,
history of tuberculosis) and first-line
treatments are unsuccessful, the author
will prescribe this therapy.
IV antiepileptic drugs. IV sodium
valproate (typical dosing 500 mg to
1000 mg) has some support for its use
in open-label studies and some recent
support in comparator trials, but no
placebo-controlled studies have evalu-
ated its efficacy in patients with status
migrainosus or intractable migraine.14Y16
Based on the author’s clinical experience,
however, this medication can be helpful
for status migrainosus and could be
tried if more conventional treatments (eg,
IV NSAIDs, dopamine receptor antago-
nists) have failed and the patient has no
medical contraindications, including liver
dysfunction, failure, or transplant, or preg-
nancy. Surprisingly, the author has seen
hyperammonemia with encephalopathy
develop acutely after a single dose of IV
sodium valproate when given to patients
with migraine who are on oral topiramate
for migraine prevention. It is known that
oral combination therapy with valproic
acid and topiramate can cause this meta-
bolic response, but it is somewhat alarm-
ing that it can occur after a single IV dose
of medication.17 IV levetiracetam has not
been thoroughly studied for the treat-
ment of status migrainosus, although
one single case has been reported in
the literature stating its efficacy.18 The
author has seen a positive effect with
this medication in both the ED and
inpatient setting on multiple occasions
with minimal or no adverse events, so
in cases where typical first-line drugs are
not helpful, IV levetiracetam is another
alternative medication to consider.
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KEY POINTS
Opioids. A crisis exists in the United h Hyperammonemia with
States and other countries around the encephalopathy may
world with the inordinate amount of develop acutely after
opioids being used for noncancer pain single dosing of IV
syndromes. One of the largest culprits sodium valproate when
is the use of opioids for migraine in the given to a patient with
ED. Although consensus guidelines have migraine who is on oral
advised against the use of opioids for topiramate as a
migraine, a recent publication noted a preventive agent.
70% increase in the use of hydromor- h Opioids are less effective
phone, morphine, and oxycodone in US in the acute treatment
emergency departments from 2001 to of migraine compared
2010.19 The question is why? Looking at with multiple
the data, opioids are typically less ef- nonopioid agents,
including ketorolac,
fective or, at most, equally effective as
dihydroergotamine,
multiple nonopioid acute migraine treat-
and dopamine
ments, including ketorolac,20 DHE,21,22 receptor antagonists.
corticosteroids,23 and multiple dopamine
receptor antagonist compounds.22 In
addition, opioids have the added dis-
tinction of being associated with habitu-
ation and abuse. Opioids drain medical
resources, as they have been shown to
lead to an increase in headache relapse
and need for a return to the ED for further
treatment.24 A recent study has also shown
that if patients in the ED are administered
opioids, it results in longer ED stays than
if nonopioid treatment is used.25 In this
author’s opinion, opioids should only be
used on infrequent occasions, including
pregnancy (if treatment with IV fluids,
antiemetics, and IV magnesium sulfate
has failed) and in the rare patient who
presents to the ED with no history of
abuse (opioid or other drugs or alcohol)
and has multiple documented medical
contraindications to almost every other
class of acute migraine medication that
can be delivered in the ED for status mi-
grainosus, thus on very rare occasions.
Vasoconstrictors. In the author’s
opinion, the use of migraine-specific
vasoconstrictive compounds (triptans and
DHE) in an ED setting is a problematic
one. This does not relate at all to the effec-
tiveness of these medications. Injectable
sumatriptan has shown efficacy rates
higher than 70% in an ED setting,26
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 Emergency and Inpatient Management
KEY POINTS
h Both sumatriptan and
dihydroergotamine have
shown efficacy for use
in an emergency
department setting for
acute migraine. Prior to
use, however, the
patient should be
cleared from a cardiac
standpoint with a normal
ECG and should have no
history of thunderclap
headache, hemiplegic
migraine, or prolonged
aura. Dihydroergotamine
should not be administered
within 24 hours of
triptan administration.
h Greater occipital nerve
blockade can be a useful
adjunctive treatment in
the emergency
department for breaking
status migrainosus.
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while DHE has shown a 60% reduc-
tion in head pain at 1 hour with IV
administration in the ED.27 The issue is
in giving medications that can constrict
cardiac and cerebral arteries to patients
on whom neurologists may be consult-
ing in the ED (and therefore not pre-
viously known to the neurologist). The
consulting neurologist is likely not
completely familiar with the cardiac
and stroke history of the patient as well
as the migraine aura history (eg, if the
patient ever had prolonged auras or a
history of hemiplegic auras). As so
many nonvasoconstrictive medication
choices are available, why even take the
chance of administering DHE or suma-
triptan in the ED with the risk of causing
a myocardial infarction or a stroke, or
even exacerbating vasospasm in a missed
case of reversible cerebral vasoconstric-
tion syndrome (which is more likely to
occur in a patient with a history of mi-
graine), if, by chance, a thunderclap onset
of headache was missed in the history?
Triptans or DHE should typically
only be administered in the ED set-
ting if the neurologist is very familiar
with the patient’s medical and migraine
history or has personally spoken with
the patient’s treating neurologist, who
requests for these medications to be
given. If these medications are felt to be
necessary and the patient has not had a
recent ECG, an ECG should be obtained
to look for ischemic changes. Contraindi-
cations to the use of triptans and DHE
include uncontrolled hypertension, past
stroke or myocardial infarction, periph-
eral vascular disease, and certain types
of aura, including hemiplegic aura and
prolonged (more than 1 hour) aura.
Nerve blockade. If IV therapy in the
ED has failed and the patient continues to
have unabated head pain, then a greater
occipital nerve block can be helpful.
Other procedures, including supraorbital,
auriculotemporal, and supratrochlear
nerve blocks, may also be beneficial. In
addition, the patient may appreciate the
extra effort the neurologist is making.
This type of intervention has not been
studied in the ED setting, but is com-
monly used by headache specialists in the
office to alleviate status migrainosus.28
Guidelines for Headache
Treatment in the Emergency
Department
In a recent publication, the Canadian
Headache Society presented the results
of a systematic review of 44 studies of
acute treatment of migraine in the ED
to try to provide physicians with a bet-
ter guide to choosing treatment based
on medical evidence.5 Unfortunately, it
determined that the studies reviewed
were generally of low quality and lack-
ing in comparator trials. Four treatments
were deemed to be strongly recom-
mended for use in the ED: sumatrip-
tan, prochlorperazine, metoclopramide,
and ketorolac. Both IV dexamethasone
and IV haloperidol were strongly not
recommended for use in the ED as
acute therapies based on the lack of
rigorous data and the potential for
significant adverse events.5
Can Status Migrainosus Be
Successfully Treated in the
Emergency Department?
Do patients with migraine actually im-
prove in the ED? The data suggest they
typically do not, and that puts respon-
sibility on the treating neurologist to
prescribe adequate rescue therapies for
patients with migraine to have at home
so they can avoid the ED altogether. A
suggested goal for ED treatment of
patients with episodic migraine should
be headache free upon discharge and
continuing pain freedom for at least
48 hours postdischarge (known as sus-
tained headache freedom).6 Most ED
trials suggest this only occurs in about
20% to 25% of patients.6,26,29 In a study
by Friedman and colleagues,30 about
August 2015
30% of patients with migraine report a
moderate to severe headache within
1 day after ED discharge, and 50% are
functionally disabled by that headache.
Predictors of poor post-ED outcomes
included severe pain at baseline, pres-
ence of nausea, and longer duration of
headache. Thus, ED treatment overall is
not adequate. The reason can only be
surmised. The author suggests that not
enough IV fluid hydration is provided,
there is a lack of combination therapies
being used, and too many opioids are
being given, all of which have been
shown to lead to recurrence. A combi-
nation treatment approach has yet to be
studied in the ED and should be inves-
tigated to determine if this approach
can achieve higher efficacy than single-
or two-drug regimens. It should also be
said that failure to adequately relieve pain
may not relate to the approach of drugs
used, but to the fact that many of the
treatments used in the ED are not
migraine specific, and thus we lack the
therapeutic ability at times to effectively
relieve the established pain of a
prolonged migraine attack since these
medications do not treat the mechanisms
underlying the generation and mainte-
nance of the pain.
Emergency Department Acute
Migraine Treatment Protocol
As long as no contraindications to any
stated class of medication exist, a sug-
gested starting protocol for ED treat-
ment of patients with migraine is to use
a combination of medications and IV
fluids, which are given in succession
(Table 4-2). If this fails to provide
sufficient relief, the ED physician may
be instructed to call the neurologist
for further suggestions.
Special Treatment Situation:
Migraine With Prolonged Aura
Although the typical migraine aura (5- to
60-minute duration) is somewhat un-
pleasant for the patient, it does not
require treatment because of its short
duration and very small, if any, risk of
causing permanent neurologic dysfunc-
tion. During an aura, regional cerebral
blood flow is reduced by about 30%. A
prolonged aura is an aura with a dura-
tion longer than 60 minutes and may
reflect a continuous state of cortical

a
TABLE 4-2 Typical Emergency Department Treatment Strategy

1. IV fluids, normal saline 2Y3 L bolus or 80Y100 cc/h for as long as patient is
in emergency department
2. IV diphenhydramine 12.5Y25 mg
3. IV dopamine receptor antagonist medication (typically use
metoclopramide 10 mg or prochlorperazine 10 mg)
4. IV magnesium sulfate 500 mgY1 g
5. IV ketorolac 30 mg
6. If patient does not improve, other options include IV sodium valproate
(500 mg), IV levetiracetam (500 mg), or IV methylprednisolone (200 mg)
7. IV dihydroergotamine 0.5Y1.0 mg may be used if patient has not used a
triptan within 24 hours and no contraindications exist
IV = intravenous.
a
Medications are given in succession separated by 15 to 20 minutes.

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 Emergency and Inpatient Management

KEY POINT
h Various treatments may
be effective in terminating
or shortening migraine
with prolonged aura,
including oral divalproex,
oral acetazolamide,
intranasal ketamine,
IV furosemide, and
IV magnesium sulfate
combined with
an IV dopamine
receptor antagonist.
spreading depression, but along with
this, a persistent reduction in cerebral
blood flow with a remote risk of mi-
grainous infarction. Patients with a pro-
longed aura (either visual, sensory, or
language) may present to the ED for
these symptoms. They should be eval-
uated for a migrainous infarction, but, if
imaging is negative for ischemia, a
strong effort should be made to termi-
nate the aura. Various treatments have
shown efficacy to terminate or shorten a
prolonged migraine aura, including oral
divalproex,31 oral acetazolamide,32 and
intranasal ketamine33; however, several
other IV therapies (furosemide,34 mag-
nesium sulfate combined with a dopa-
mine receptor antagonist35) may be more
suited for ED use. A suggested treatment
protocol for migraine with prolonged
aura in the ED is presented in Table 4-3.
INPATIENT MANAGEMENT
OF INTRACTABLE
MIGRAINE/HEADACHE
It should be rare that patients with mi-
graine need admission to the hospital for
headache, especially if they have episodic
migraine. Some headache centers in the
United States and abroad have dedicated
multidisciplinary inpatient programs that
cater to patients with the most intractable
headaches that have basically failed all
outpatient management strategies.
The following are suggested criteria
for hospital admission for headache:
& Severe chronic or near-daily headache
with chronic medication overuse:
) Daily use of opioids or
butalbital-containing compounds
with a risk of withdrawal
seizure/syndrome if abruptly
discontinued
) Daily use of triptans, simple analgesics,
or ergotamines with a failed trial
of outpatient discontinuation
) Impaired daily function despite
3 days of outpatient infusion therapy
& Coexistent psychiatric disease that
makes outpatient treatment
impractical or unlikely to succeed
& Coexistent medical conditions
necessitating monitoring as an
inpatient when establishing a
headache treatment program
& Patient continues with intractable
daily head pain after a single or
multiple visits to the ED
& Patient continues with intractable
daily head pain after home rescue
therapies failed with no access to
outpatient infusion therapy

TABLE 4-3 Acute IV Protocol for Migraine With Prolonged Aura

1. Initiate IV fluids
2. IV prochlorperazine 10 mg and IV magnesium sulfate 1 g35
3. If steps 1 and 2 fail, IV furosemide34 20 mg (furosemide will inhibit the
generation and duration of cortical spreading depression in a cat model
of potassium chlorideYtriggered cortical spreading depression36 and
has been shown to suppress prolonged auras in humans)
4. If steps 2 and 3 fail, IV divalproex sodium 500 mgY1 g or IV
methylprednisolone 200 mg
5. If steps 2 through 4 fail, admit for inpatient treatment with repetitive
treatments of IV prochlorperazine with magnesium sulfate
6. Other choices: intranasal ketamine or oral acetazolamide
IV = intravenous.

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Inpatient Treatment Program
Medications. An example of an inpatient
intractable migraine treatment protocol
is as follows:
IV one-half normal saline at 80 cc/h
(continuous) + IV diphenhydramine
25 mg every 8 hours + IV metoclopramide
10 mg every 8 hours + IV magnesium
sulfate 500 mg every 8 hours + IV DHE
(0.5 mg every 8 hours for two doses,
then, if need be, increase to 0.75 mg or
1 mg every 8 hours depending on head-
ache response). This protocol may be
tried for 1 to 2 days; if the headache
does not respond or only partially re-
sponds, either the entire protocol or
individual medications may be changed
to alternatives such as IV sodium valproate,
IV levetiracetam, IV methylprednisolone,
IV ketorolac, or other dopamine recep-
tor antagonists such as prochlorperazine
or droperidol.
Regional anesthesia. Some inpa-
tient headache programs employ pain
anesthesiologists, while most hospital
programs have access to pain anes-
thesia. If patients do not improve with
medications, nerve blocks can be sug-
gested to try to break intractable headache
cycles. Various nerve block procedures
can be used, including greater occipital
nerve blocks, cervical facet blocks, cer-
vical epidural steroid injections, auri-
culotemporal blocks, and supraorbital
and supratrochlear nerve blocks. Phys-
ical examination, including evaluat-
ing for cervical facet tenderness by neck
extension and rotation maneuvers, su-
pratrochlear and supraorbital notch ten-
derness, occipitonuchal tenderness, and
temporal tenderness, can help to deter-
mine which blocks to use.
Medication detoxification. Full de-
toxification strategies are beyond the
scope of this article, and medication-
overuse headache is discussed in the
article ‘‘Risk Factors for and Management
of Medication-Overuse Headache’’ by
Richard B. Lipton, MD, FAAN, in this issue
of ; however, part of
Continuum (Minneap Minn) 2015;21(4):1004–1017
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
inpatient treatment of intractable mi- h Both clonazepam and
graine is removal of ‘‘rebounding com- phenobarbital are helpful
pounds’’ that may be driving the pain for the detoxification
syndrome itself. Various agents can of patients taking
lead to medication-overuse headache, butalbital-containing
including over-the-counter analgesics, compounds.
triptans, butalbital-containing com-
pounds, and opioids; it is typically the
latter two that need detoxification in an
inpatient setting. Sometimes triptan and
over-the-counter analgesic overuse and
withdrawal can be very difficult to man-
age as an outpatient and will also need
inpatient treatment.
Detoxification Strategies
Over-the-counter analgesics. Discon-
tinuation of over-the-counter analgesics
is normally an outpatient procedure. Tran-
sition to a longer-acting NSAID, such as
naproxen sodium or indomethacin, for
7 days while acutely stopping the offend-
ing overused compound and the use
of an acute medication in a limited fash-
ion not prone to causing medication-
overuse headache (eg, DHE) may be
an effective strategy.
Triptans. Discontinuation of triptans
is normally an outpatient procedure.
Triptan withdrawal is typically brief and
can sometimes be overcome with a short
course of oral corticosteroids or 3 days
of DHE (IM or nasal formulation). If
inpatient detoxification is needed, switch-
ing over to an IV DHE protocol norm-
ally works very well (Case 4-1).37,38 A
24-hour time period should elapse be-
tween the last dose of triptan and the first
dose of DHE.
Butalbital. For detoxification of pa-
tients on butalbital-containing medica-
tions, a serum butalbital level is necessary
as patients often underestimate or mini-
mize their actual usage. If serum levels are
in the toxic range or very elevated, the
patient will need inpatient hospitalization
because of the risk of withdrawal seizures
when the drug is abruptly discontinued.
Two approaches can be used for quick
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 Emergency and Inpatient Management

detoxification of butalbital. The first is clonazepam is initiated, butalbital is

administering oral clonazepam 0.25 mg to completely stopped. The duration of
0.5 mg 2 or 3 times a day. The moment clonazepam treatment will depend on

Case 4-1
A 36-year-old woman with a history of episodic migraine since her teens had a slow progression of her
headache frequency to daily by the age of 25 years. She had tried multiple preventives over time without
benefit, including topiramate, amitriptyline, verapamil, and propranolol. She used to take daily
over-the-counter agents, and it was during this time her headaches became daily. For the past 3 years,
she needed to take a triptan 2 times per day to get pain relief. The triptan allowed her to function and
decreased her migraine attacks from 6 to 3 times per week. If she missed a dose, a migraine ensued almost
immediately. She had been told about ‘‘rebound headache’’ and had tried to stop her triptan, but she
would develop status migrainosus, repeatedly vomit, and need emergency department treatment. She
presented to a dedicated headache center where a diagnosis of chronic migraine and medication-overuse
headache from daily triptans was made. Because she was so disabled by her headaches and unable to get
off her daily triptans, she was admitted to an inpatient treatment unit. During hospitalization, her
triptans were acutely stopped, and IV dihydroergotamine (DHE) 1 mg 3 times a day was started 24 hours
after her last dose of triptan. Other IV medications were used to break her daily headache cycle, including
diphenhydramine, metoclopramide, ketorolac, and magnesium sulfate, along with continuous IV fluids.
Metoprolol XL 25 mg was started and increased to 50 mg on day 3, and nortriptyline 25 mg was started
and increased to 50 mg on day 3. The patient had severe headaches within the first 24 hours, but by day
2 the intensity decreased and by day 3 she was almost pain free. By day 5, she had been pain free for
48 hours. Parenteral medications were discontinued, and the patient was discharged with outpatient
appointments for biofeedback, cognitive-behavioral therapy, and a follow-up appointment in headache
clinic in 2 weeks.
The case patient, in addition to establishing a preventive regimen with metoprolol and nortriptyline,
was also provided with a nonrebounding abortive program for home use. This included indomethacin for
mild to moderate pain, maximum use 3 to 4 days per week; baclofen 10 mg for moderate to severe pain,
maximum use 3 to 4 days per week; and IM DHE 1 mg for severe pain, maximum use 2 days per week.
She was also provided with metoclopramide 10 mg for nausea and headache, maximum use 2 days per
week, and hydroxyzine 25 mg as a rescue therapy (which can provide sedation as well as migraine pain
relief), maximum use 2 to 3 days per week. She left the hospital pain free and off her daily triptans.
Comment. Many things can be accomplished when treating intractable headache in an inpatient setting,
including quickly discontinuing overused acute medications in a setting where severe withdrawal
headaches can be managed. Many patients will not succeed at this step as an outpatient. It is too easy to
go back to their overused medication if the pain spikes when they are going through the detoxification
process and have little else available to help manage the pain.
Treatment in an inpatient setting can also provide the opportunity to learn what medications will successfully
treat the patient’s headaches; from this information, an effective abortive/preventive treatment program can
be developed. In this case, IV DHE was helpful, which typically translates to using an ergotamine
derivative such as DHE as an effective acute treatment. In addition, while the patient previously ‘‘failed’’
to respond to a beta-blocker and tricyclic, the use of combination (dual) therapy at an adequate dose and
in the absence of acute medication overuse may now provide an effective prevention regimen. Also,
indomethacin and baclofen were successful and thus can be used for more mild to moderate headaches
on a limited basis with IM DHE for more severe migraine attacks.
An inpatient setting also provides the opportunity to educate the patient about medication overuse.
This patient’s previous migraine preventives probably did not work as she was overusing acute medications
at the same time she was taking her preventives. It is important to establish reasonable expectations with the
patient, especially with regard to the time taken for the effect of medication-overuse headache to resolve,
which is often months.

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the length of time the patient has been
on butalbital and on whether the patient
shows withdrawal symptoms when try-
ing to wean clonazepam. The second
approach is phenobarbital orally or IV
60 mg to 120 mg per dose. This dose
may need to be repeated depending on
whether withdrawal symptoms persist.
Loder and Biondi39 studied 18 patients,
acutely stopping butalbital and giving
phenobarbital 120 mg orally on an hourly
basis until patients reached a predeter-
mined score on a scale measuring various
neurologic symptoms, including nystag-
mus, dysarthria, ataxia, drowsiness, and
emotional lability. Average dosing to
counteract withdrawal was nine doses or
1080 mg of phenobarbital. All patients
were effectively treated with no serious
adverse events. Phenobarbital dosing
could not be predicted by the patient’s
prior intake of butalbital.
In this author’s opinion, phenobarbital
does not need to be dosed to this dose
during typical cases of butalbital detoxi-
fication. It can be given at the suggested
starting dose of 120 mg, but subsequent
doses can be spaced more infrequently
with phenobarbital’s long half-life and
dosed as needed depending on whether
the patient is having withdrawal symp-
toms. Phenobarbital is definitely effective
for the treatment of butalbital withdrawal.
Opioids. If the patient has been on
chronic daily opioids for more than
1 year or on large dosages, he or she
should be hospitalized for detoxifica-
tion if possible. For long-acting opioids
(eg, methadone), the suggested detox-
ification strategy is to taper fairly quickly
(decreasing the dose every 2 to 3 days)
and monitor for withdrawal. For short-
acting opioids, a quick tapering sched-
ule of the same short-acting opioid can
be provided over several days or another
short-acting opioid such as oxyco-
done or even a dose of buprenorphine
sublingual can be used, which may need
to be repeated on a daily basis for 2
Continuum (Minneap Minn) 2015;21(4):1004–1017
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
to 3 days. As-needed medications for
withdrawal should be available, includ-
ing clonazepam and clonidine trans-
dermal or oral. Auricular acupuncture
is very effective for withdrawal nausea,
and, of course, the patient will need
encouragement.40 Most hospitals em-
ploy a pain management/addiction spe-
cialist who can help formulate an opioid
withdrawal schedule.
Goals of Inpatient Headache
Treatment
Overall, the goals of inpatient treatment
will be different if trying to treat status
migrainosus versus treating chronic mi-
graine in someone with daily pain for
many years. For status migrainosus, the
goal should be pain free at discharge and
sustained pain freedom without head-
ache recurrence for at least the next
72 hours. For chronic migraine, the goals
for inpatient treatment are: (1) reduce
daily pain intensity and possibly intro-
duce pain-free time; (2) detoxify acute
medication overuse if present; (3) iden-
tify response to IV medications so an
outpatient treatment program (acute and
preventive medications) can be estab-
lished; (4) rule out secondary causes of
intractable headache (eg, intracranial
hypotension or elevated CSF pressure);
(5) educate about chronic pain and
medication-overuse headache; (6) pro-
vide psychiatric/psychological evalua-
tion to establish if any underlying
psychiatric conditions exist and to
implement biobehavioral therapies
(eg, biofeedback, relaxation therapy,
cognitive-behavioral therapy); and (7)
establish the need for outpatient ser-
vices, including physical therapy, psycho-
logical services, and pain anesthesiology.
CONCLUSION
The treatment of status migrainosus
and intractable migraine can be very
challenging for the neurologist. Treat-
ment should focus on the use of IV fluids,
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 Emergency and Inpatient Management
a combination of medications rather
than a single agent, and the avoidance
of opioids. Treatment goals will depend
upon migraine subtype (episodic versus
chronic), the duration of symptoms,
and the presence or absence of medi-
cation overuse.
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