TE C H N I Q U E S I N R E G I O N A L AN E S T H E S I A A N D PA I N M A N A G E M E N T 16 (2012) 2529

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Intravenous treatment of migraine

Sait Ashinaa,b,, Russell K. Portenoya,b

a
Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, New York
b
Albert Einstein College of Medicine, Bronx, New York

artic le info abstract

Migraine is a common primary headache disorder. A subset of patients may become

Keywords: disabled by frequent, severe, or treatment-refractory headache. Most patients respond
Headache adequately to drugs administered by the oral, intramuscular, or subcutaneous route.
Infusion Intravenous therapy is an option for the treatment of severe headache in a monitored
Intravenous setting. The most common scenario is the treatment of acute refractory headache in the
Migraine emergency department. Intravenous treatment may be undertaken with common analge-
Treatment sics, such as acetaminophen, ibuprofen, and ketorolac, or an opioid, or with a drug used
specifically for migraine. Among the latter drugs are antiemetic dopamine antagonists,
dihydroergotamine, magnesium, valproate sodium, and glucocorticoids. Some of the latter
agents have been studied in controlled trials but data are too limited to inform clinical
guidelines. Larger placebo-controlled trials of these and other agents will be needed to
better position the intravenous drugs in the treatment strategies for acute refractory
headache, refractory chronic migraine, and withdrawal headache during the management
of medication overuse headache.
& 2013 Elsevier Inc. All rights reserved.

Introduction
Migraine is a common primary headache disorder associated
with substantial disability and burden.1 The standard acute
treatment for patients at home relies on triptans delivered by
the oral, intranasal, or subcutaneous (SC) routes, and on
acetaminophen or nonsteroidal antiinflammatory drugs
(NSAIDs) administered orally.2 Few patients benefit from
access to a short-acting opioid. When headache is refractory
to treatment, care may be sought in the emergency depart-
ment (ED) or related settings. Although this is a rare occur-
rence from the perspective of a very large population with
migraine, it is observed commonly by the health profes-
sionals. Indeed, headache accounts for 2% of all ED visits.3
In the ED setting, and other settings with adequate mon-
itoring, acute treatment may be more effectively undertaken
using drugs administered via the intravenous (IV) route. The
IV route eliminates the need for absorption and yields drug
effects that have an onset more quickly than other routes of
drug delivery. The IV access established for drug delivery can
be used concurrently for hydration, which can be particularly
important if vomiting has occurred. If multiple treatments
are needed, repeated skin punctures are avoided, often
lessening distress in patient. The major pharmacodynamic
risk associated with the IV drug deliverypeak concentration
toxicitycan be mitigated by using brief infusions, typically
20-30 minutes.
Understanding the options for IV therapy of migraine
provides a potential option for a variety of challenging
scenarios (Table 1).4-7 Safe and effective IV treatment requires
specific policies and procedures, trained nursing staff, and a
setting that includes a comfortable room with a reclining
chair or bed.5 The most common setting for IV therapy is the
ED,6 but other settings, including office-based practices, that
meet the requirement for policies, trained staff, and environ-
ment of care would be able to offer these treatments.5,7

Corresponding author at: Headache Program, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, 10 Union
Square East, Suite 2Q-R, New York, NY 10003.
E-mail address: sashina@chpnet.org (S. Ashina).

1084-208X/$ - see front matter & 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1053/j.trap.2012.11.004
26 T E C H N I Q U E S I N R E G I O N A L
Table 1 Possible indications for the treatment of
migraine with intravenous medications.
1. Status migrainous
2. Intractable headache with nausea/vomiting
3. Refractory migraine/intractable chronic daily headache
4. Medication overuse headache/withdrawal headache
5. Migraine flare-ups
The empirical data related to the IV treatment of migraine
derives mostly from small observational surveys and a few
randomized trials. The indications for this approach, there-
fore, are not evidence-based . Rather, they reflect clinical
judgments about severity and refractoriness of headache,
combined with the capability to provide IV treatments safely.
The most common scenario for a trial of IV therapy is
treatment in the ED of patients with prolonged severe head-
ache that have not responded to usual therapy, including
patients who meet criteria for a diagnosis of status migrai-
nosus, and patients who develop severe headache associated
with repeated vomiting. Less commonly, the IV therapy is
offered by some headache and pain management outpatient
practices for intractable chronic daily headache and migraine
flare-ups .5 The latter settings also may be the places that can
offer supplemental treatment with the IV therapy during
management of medication overuse headache with detoxifi-
cation or withdrawal of short-acting abortive therapies.4,7
Intravenous drugs used in the treatment of
migraine
Migraine is a pain syndrome and it may be addressed with
medications used specifically for migraine, common analge-
sic drugs, or a combination of these therapies. Medications
that are used specifically for migraine and have been eval-
uated as the IV therapy include dopamine antagonists:
dihydroergotamine (DHE), magnesium, valproate sodium,
and corticosteroids. The common analgesics available in
the IV formulations include acetaminophen, ibuprofen, and
a large number of opioid drugs such as morphine, hydro-
morphone, and fentanyl. Although some of these drugs have
been studied in controlled trials, the data are inadequate to
judge comparative efficacy and safety. The clinical approach
to the management of migraine using IV drugs is therefore
empirical, based on knowledge of the options and an assess-
ment of risk and benefit in the individual patient.
Anti-emetic dopamine antagonists
Intravenous anti-emetic dopamine antagonists have long
been used in the treatment of migraine. These medications
have been suggested to be a first-line treatment of acute
migraine in the ED.6 They also can be used in inpatient
settings and in outpatient infusion clinics. The drugs include
metoclopramide, droperidol, and phenothiazines such as
chlorpromazine and prochlorperazine.
The mechanism of action of the anti-emetic dopamine
antagonist in migraine is unknown. Central dopaminergic
pathways may be involved in the migraine attack,8,9 and this
A N E S T H E S I A A N D PA I N MA N A G E M E N T 16 (2012) 2529
suggests that the effects of these drugs on central dopamine
receptors mediate benefits for headache. For the patient with
severe nausea and vomiting, a prompt antinauseant effect
also may speed recovery from the attack.
Several dopamine antagonists have been studied in con-
trolled trials for the treatment of acute migraine. The major
limitation of these studies is the small sample size. IV
metoclopramide 10 mg was demonstrated to be efficacious
in placebo-controlled trials,10,11 and a randomized, double-
blind, comparative trial showed that IV metoclopramide
20 mg was superior to 6 mg of SC sumatriptan in overall
efficacy.12 A controlled trial of IV prochlorperazine found that
this drug was efficacious compared with both metoclopra-
mide and placebo.13 In contrast to the studies noted pre-
viously, metoclopramide and placebo did not differ from each
other in the latter trial.
Chlorpromazine at a dose of 0.1 mg/kg IV was studied in
the ED setting in 128 migraineurs and was shown to signifi-
cantly reduce pain scores compared with placebo.14 In a
randomized, single-blinded comparative study, IV chlorproma-
zine 12.5-37.5 mg was significantly superior to IV DHE 1-2 mg in
reducing mean headache intensity.15 Compared with placebo,
intramuscular (IM) droperidol at doses of 2.75, 5.5, and 8.25 mg
was efficacious,16 and a pilot study of IV droperidol 2.5 mg
administered every 30 minutes for up to 3 doses showed
efficacy (480% relief at 2 hours) in status migrainosus.17
These trials support the potential for prompt benefit in
acute migraine following the IV administration of antiemetic
dopamine antagonists. The data are too limited to confirm
efficacy and do not illuminate key clinical questions, includ-
ing comparative safety and efficacy across drugs and com-
parative therapeutic index of this group compared with other
IV treatments. The positioning of these drugs relative to
other treatments, when patients present for acute therapy
in a setting capable of providing IV therapy safely, must be
based on a careful individualized assessment of risk and
potential benefit. This assessment, in turn, should be
informed by an understanding of the side effects and toxi-
cities that characterize these medications (Table 2).
The most common side effect of the antiemetic dopamine
antagonists is drowsiness.18 Anticholinergic effects, such as
dry mouth, also occur often but are rarely a problem in the
acute treatment setting. A more serious concern is the
potential for extrapyramidal side effects, including acute
dystonic reactions and akathisia. The risk of these extrapyr-
amidal effects can be minimized by the administration of IV
or IM benztropine 1 mg, or IV or IM diphenhydramine 25 mg,
prior to infusion of the dopamine antagonist.19,20 Chlorpro-
mazine has been reported to cause postural hypotension,
which can possibly be prevented by a bolus of 250-500 mL of
normal saline before treatment.6,14,18
The antiemetic dopamine antagonists, droperidol in particu-
lar, can prolong the QTc interval, a potentially serious effect.18
An electrocardiogram (ECG) prior to administration of prochlor-
perazine, chlorpromazine, and droperidol is recommended.6,18
Dihydroergotamine
DHE, a semisynthetic formulation of an ergot alkaloid, has
been a well-established treatment for migraine for the past
 TE C H N I Q U E S I N R E G I O N A L
Table 2 Anti-emetic dopamine antagonists for migraine treatment.
Medication Dose
Metoclopramide 510 mg to be infused over 1530 min
q68 h; maximum dose 3060 mg/24 h
Prochlorperazine 510 mg to be infused over 1530 min
q68 h; maximum dose 40 mg/24 h
Chlorpromazine 12.550 mg to be infused over 1530 min
q68 h; maximum dose 150 mg/24 h
Droperidol 0.6252.5 mg to be infused over 1530 min
q68 h; maximum dose: 10 mg/24 h
50 years.21 It is commercially available in the United States as
a parenteral preparation (DHE-45s), which can be adminis-
tered via the IV, IM, or SC routes. DHE is a vasocontrictive
agent acting on both veins and arteries.21 Its therapeutic
mechanism in migraine is not understood. It acts on multiple
norepinephrine, epinephrine, dopamine, and serotonin
receptors with varying degrees of affinity, and affects adre-
nergic, dopaminergic, and serotonergic systems in humans.21
The therapeutic activity of DHE in migraine is generally
attributed to its agonist effect on serotonin receptors, speci-
fically the HT1D receptor subtype, which is proposed to
vasoconstrict selected intracranial blood vessels or inhibit
pro-inflammatory neuropeptide release from sensory nerve
endings of the trigeminovascular system, or both.
The efficacy of DHE in migraine is supported by controlled
trials. A combination of IV prochlorperazine 5 mg (which was
given to prevent the nausea caused by DHE) and 0.75 mg of IV
DHE was significantly better than prochlorperazine at the
same dose plus placebo.22 DHE at the IV dose of 0.75-1 mg
combined with 5-10 mg of metoclopramide was shown to be
superior to placebo in a study conducted in an outpatient
clinic23; this study indicated that the efficacy of DHE at this
dose was comparable with the IV dexamethasone 6 mg
combined with metoclopramide. Nausea and vomiting were
the most common side effects associated with the IV DHE.
Another controlled trial found that IV chlorpromazine
resulted in a significantly greater mean reduction in pain
intensity than IV DHE.14,15
IV DHE has been widely used to treat refractory daily
migraine. The original protocol for this indication was
described by Raskin in 1986.24 This protocol, which has been
used in both inpatient and outpatient settings, involves the
IV administration of DHE every 8 hours in combination with
IV metoclopramide 10 mg for 25 days. An alternative proto-
col25 recommends the administration of oral metoclopra-
mide 10 mg and 4 doses of IV DHE, to achieve a total dose of
4 mg; an observational study of this protocol in 62 patients
with chronic daily headache suggested that the approach is
safe and efficacious. Interestingly, recent data suggest that IV
DHE given over 5 days results in relatively greater pain-free
rate and a larger improvement in disability than shorter
courses of the medication.26
In inpatient settings, DHE is usually administered at a dose
of 0.5-1 mg infused over 30-60 minutes and repeated every 8
hours until the maximum dose is reached.6,15,21-24,27 The
maximum dose in a 24 hour period is 2 mg; the maximal
weekly dosage should not exceed 6 mg. In the ED or
AN E S T H E S I A A N D PA I N M A N AG E M E N T 16 (2012) 2529 27
Side effects
Dizziness, akathisia , dystonia, parkinsonism, somnolence, hypertension,
fluid retention, low seizure threshold
Dizziness, akathisia , dystonia, parkinsonism, somnolence, hypotension;
Droperidol may cause QT prolongation - clinically significant
arrhythmia. Chlorpromazine can cause hypotension
outpatient environment, IV DHE can be given at a dose of
0.5-1 mg, again infused over 30-60 minutes, followed by a
dose of 0.5-1 mg 1-4 hours later.6,28
To prevent nausea in all settings, DHE usually is coadmi-
nistered with IV metoclopramide 10 mg, which should be
given prior to the DHE infusion. Contraindications to IV DHE
include severe hypertension, coronary artery disease, preg-
nancy, hemiplegic or basilar migraine, recent use of suma-
triptan (within the past 24 hours), current use of macrolide
antibiotics, or current use of retroviral therapy. Other than
nausea and vomiting, side effects may include diarrhea,
abdominal cramps, or leg pain. It is recommended that an
electrocardiogram be obtained prior to administration of IV
DHE; findings consistent with coronary disease or arrhyth-
mia contraindicate the treatment.
Magnesium sulfate
Magnesium ions reduce flux through N-type calcium chan-
nels, preventing extracellular calcium ions from entering the
cell.29 In the central neurons involved in the processing of
information about noxious events, increasing the concentra-
tion of magnesium opposes actions (such as activation of the
N-methyl D-aspartate receptor) that increase ionic flux
through the channel and underlie the development of central
sensitization. The latter phenomenon may be important in
the development of chronic migraine pain.30,31 Magnesium
may be useful in migraine both by reducing activity in central
nociceptive neurons and by suppressing the occurrence of
central sensitization.32
In a randomized, double-blind, placebo-controlled study, IV
magnesium 1 g was efficacious for pain and all associated
symptoms in patients with migraine with aura, and was
efficacious for some symptoms but not pain in patients with
migraine without aura.33 In a small randomized, single-blind,
placebo-controlled trial of 30 patients with moderate or
severe migraine attacks,34 IV magnesium 1 g was superior
to placebo in response rate and the pain-free rate. A study
that evaluated IV magnesium 2 g for acute migraine in the ED
did not show benefit35; however, a placebo-controlled study
that determined the effect of IV magnesium 2 g added to IV
metoclopramide 20 mg observed decreased effectiveness of
the metoclopramide.36
These data are inconclusive. Nonetheless, IV magnesium
has been used in the management of migraine due to its
tolerability.5,28,32 The usual dosage recommended for the
treatment of migraine is 500, 1000, or 2000 mg depending
28 T E C H N I Q U E S I N R E G I O N A L
on renal function. Although the likelihood of serious side
effects is low, particularly if an infusion over 30-60 minutes is
used, these possibly include muscular weakness progressing
to flaccid paralysis, ataxia, drowsiness, confusion, flushing,
sweating, hypotension, hypothermia, and bradycardia.5,28
History of heart block and myocardial damage are contra-
indications to the treatment with IV magnesium.
Valproate sodium
IV valproate sodium has been used in the management of
migraine in the ED, outpatient and inpatient settings.46 ,28 In
open-label studies, IV valproate sodium 300 and 500 mg have
demonstrated favorable results.37,38 In an open-label study IV
valproate sodium 500 mg was reported to be similar in
efficacy to the combination of metoclopramide 10 mg IM
and DHE 1 mg as an acute treatment for prolonged
moderate-to-severe acute migraine.37 In a controlled trial,
IV prochlorperazine 10 mg was superior to IV valproate
500 mg for the treatment of acute migraine.39
Given these limited data, the efficacy of IV valproate for
migraine remains unknown and typically the drug is con-
sidered only if other therapies, including DHE and dopamine
antagonists, are contraindicated or have been ineffective.6 If
treatment is undertaken, the usual dose is 500-1000 mg IV
infused over 30 minutes.6 Valproate sodium must be avoided
in pregnancy due to risk for neural tube defects. Other
possible adverse effects include hepatotoxicity, pancreatitis,
and thrombocytopenia. Assessment of complete blood count
and comprehensive metabolic profile is recommended prior
to the start of treatment.4
Corticosteroids
In a randomized, placebo-controlled, double-blind study, IV
dexamethasone reduced headache recurrence at 48-72-hour
following administration in the ED.40 Although another
placebo-controlled study41 did not demonstrate this effect,
2 meta-analyses 42,43 support a recommendation to admin-
ister IV dexamethasone 10-24 mg as a single dose to standard
acute therapy in order to reduce the risk of headache
recurrence.
Common analgesics
Intravenous NSAIDs have been used in EDs, inpatient and
outpatient settings.6,44 Ketorolac at doses of 30-60 mg has
been shown to be effective in the treatment of acute
migraine in randomized trials.45-47 IV acetaminophen and
IV ibuprofen are now commercially available, but have not
been studied in the treatment of migraine. IV ibuprofen 600-
800 mg is likely to be efficacious and safer than ketorolac but
this would have to be confirmed.
There is an extensive experience in the use of opioids to
treat acute pain and headache in the ED setting. However, IV
opioid therapy has not been specifically studied for migraine.
Risks are very limited if a short-acting drug is selected, doses
are appropriate, and regular monitoring during the period
immediately after a dose is administered. Given the potential
for respiratory depression, treatment should be undertaken
A N E S T H E S I A A N D PA I N MA N A G E M E N T 16 (2012) 2529
only by professional staff with skills in opioid treatment and
only in settings that afford adequate opportunity for
monitoring.
Conclusion
Despite very limited data, IV medications are commonly used
to manage severe and refractory migraine headache in EDs,
inpatient and outpatient settings. Treatment selection largely
reflects local custom and clinician experience, as would be
expected given the lack of evidence. An aggressive approach
for the ED management of a patient with status migrainosus
and vomiting might include administration of a NSAID (IV
ketorolac 30 mg or IV ibuprofen 600 mg) or an opioid (eg, IV
hydromorphone 1.0 mg), or both, in combination with a
dopamine antagonist such as metoclopramide 10 mg IV and
dexamethasone 10 mg. Alternative, migraine-specific thera-
pies would include IV DHE 1 mg plus IV metoclopramide
10 mg, IV magnesium 1000 mg, or IV valproate sodium
500 mg. Additional doses of one of the common analgesics,
or the latter drugs might be considered if the initial therapy is
not helpful.
Larger placebo-controlled trials are needed to confirm the
efficacy of both common analgesics and drugs used specifi-
cally for migraine. Studies are required to clarify the role of
these drugs in the treatment of status migrainosus, refrac-
tory chronic migraine, withdrawal headache from medica-
tion overuse headache, and exacerbation of chronic
migraine.
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