ISSN 0017-8748

Headache doi: 10.1111/j.1526-4610.2011.02062.x

2011 American Headache Society Published by Wiley Periodicals, Inc.

Review Article
Rescue Therapy for Acute Migraine, Part 1: Triptans,
Dihydroergotamine, and Magnesium head_2062 114..128

Nancy E. Kelley, MD, PhD; Deborah E. Tepper, MD

Objective.To review and analyze published reports on the acute treatment of migraine headache with triptans, dihydro-
ergotamine (DHE), and magnesium in emergency department, urgent care, and headache clinic settings.
Methods.MEDLINE was searched using the terms migraine and emergency, and therapy or treatment.
Reports from emergency department and urgent care settings that involved all routes of medication delivery were included.
Reports from headache clinic settings were included only if medications were delivered by a parenteral route.
Results.Acute rescue treatment studies involving the triptans were available for injectable and nasal sumatriptan, as well
as rizatriptan. Effectiveness varied widely, even when the pain-free and pain-relief statistics were evaluated separately. As these
medications are known to work best early in the migraine, part of this variability may be attributed to the timing of triptan
administration.
Multiple studies compared triptans with anti-emetics, dopamine antagonists, and non-steroidal anti-inflammatory drugs.
The overall percentage of patients with pain relief after taking sumatriptan was roughly equivalent to that recorded with
droperidol and prochlorperazine. Sumatriptan was equivalent to DHE when only paired comparisons were performed.
While the data extracted suggest that magnesium may be effective in treating all symptoms in patients experiencing
migraine with aura across all migraine patients, its effectiveness seems to be limited to treating only photophobia and
phonophobia.
Conclusions.Although there are relatively few studies involving health-care provider-administered triptans or DHE for
acute rescue, they appear to be equivalent to the dopamine antagonists for migraine pain relief. The relatively rare inclusion of
a placebo arm and the frequent use of combination medications in active treatment arms complicate the comparison of single
agents with each other.
Key words: migraine, emergency, treatment, dihydroergotamine, triptan, magnesium

(Headache 2012;52:114-113)

This review is the first installment of a 3-part
series evaluating health-care provideradministered
rescue therapy for acute migraine in the setting of an
emergency department (ED), urgent care center, or
headache clinic infusion center. Part 1 summarizes
the results from published clinical studies involving
From the Center for Headache and Pain, Neurological Insti-
tute, Cleveland Clinic, Cleveland, Ohio, USA.
Address all correspondence to D. Tepper, Center for Headache
and Pain C-21, Cleveland Clinic Foundation, 9500 Euclid
Avenue, Cleveland, OH 44195, USA, email: debtepper@
gmail.com
Accepted for publication September 26, 2011.
triptans, dihydroergotamine (DHE), or magnesium.
Pertinent information concerning migraine patho-
physiology and the methodology commonly used for
the assessment of migraine rescue therapy is also
included. Part 2 will address the dopamine antago-
nists, antihistamines, serotonin (5HT)3 antagonists,
valproate and others (octreotide, lidocaine, nitrous
oxide, propofol, and bupivacaine). Part 3 will
address studies involving opioids, non-steroidal anti-
inflammatory drugs (NSAIDs), steroids, and postdis-
charge medications, as well as a general discussion of
all therapies presented in the 3 articles.
By the time he or she reaches 18 years of age,
nearly every human has some personal experience

114
Headache
with headache. About half of the global adult popu-
lation has an active headache disorder.1 Appro-
ximately 10% of the global adult and pediatric popu-
lation has migraine, with the highest prevalences in
Europe and North America (15% and 13%, respec-
tively) and the lowest in Africa (5%).1 Based on one
recent survey, migraine prevalence in the USA is 12%
overall (women 18%, men 6%).2
Headache is the fourth most common reason for
adults in the USA to seek emergency care. Various
studies have indicated that headache accounts for 1.4-
3.3 million ED visits annually in the US (1-3% of
visits); at least two thirds of these visits involve a
primary headache disorder.3-5
Patients who come to the ED for treatment of
migraine generally have the following characteristics:
symptoms unusually severe and/or prolonged; symp-
toms not typical of their usual headache; and/or usual
acute migraine treatment has been ineffective. Over
half of migraineurs use over-the-counter simple
analgesics to treat their headaches, and these
are often ineffective.6 Few ED patients have used
migraine-specific medications, such as triptans or
ergotamine.7 Fiesseler et al8 reported that 14% of
patients did not use any medications at all before
presenting to the ED. This was significantly more
likely to be the case in men than women (31% vs 9%,
P = .003) and in those patients not previously seen by
a neurologist (22% vs 5%, P = .004).
By the definition provided by the International
Classification of Headache Disorders (ICHD-2),9
migraine is a headache lasting 4-72 hours, with at least
two characteristics of unilateral location, pulsating
quality, moderate-to-severe intensity, aggravated by
routine activity, and accompanied by photophobia
and phonophobia or nausea and/or vomiting. The
individual must have had at least 5 attacks, and the
attacks must not be secondary. If headache has not
occurred previously or is atypical, prolonged, and
intractable, the individual may present for emergency
evaluation and treatment.
General management of migraines in the ED
includes sufficient investigation for secondary causes
of the acute headache and provision of effective treat-
ment. Once the diagnosis of migraine has been estab-
lished, the patient should be assessed for volume
115
depletion, especially if there is a recent history of
vomiting or reduced oral intake.
Blood pressure should be managed and intrave-
nous (IV) rehydration provided, in addition to a
quiet, darkened, restful environment.
Published reports suggest that medical treat-
ment of migraine in the ED can be highly vari-
able.10,11 For a variety of reasons, parenteral
medications are used more often than oral medica-
tions to treat acute migraine in ED and headache
clinics. Many patients already have tried oral medi-
cations at home, sometimes for several days, and
these obviously have been ineffective. By the time
patients arrive at the ED, they may have severe gas-
troparesis, nausea, and vomiting, and therefore be
less able to retain and absorb oral medications. In
addition, ED physicians are motivated to use fast-
acting therapies or cost-effective medications that
give rapid relief of migraine with consequent
discharge from the ED.
Patients want rapid, complete relief of migraine
pain and associated symptoms, with complete relief
rated more important than rapid relief; also impor-
tant to patients is that they are able to resume normal
activities, that their migraine does not recur, and that
any treatment-related side effects are mild and tran-
sient.12,13 Migraine persists or recurs, however, in over
50% of patients after leaving the ED. Discharge plans
seldom include measures to prevent recurrence or to
re-treat if pain persists.14
Parenteral opiates/opioids (narcotics) and
anti-emetics are commonly used as first-line migraine
agents in US and Canadian EDs.15 There is, however,
considerable variability in the frequency of narcotic
use for migraine across treatment centers, ranging
from 16% to 71%.11 Gupta et al7 reported that
patients in their ED most often (67.5%) received
dopamine antagonists, such as metoclopramide,
prochlorperazine, and chlorpromazine, followed
closely by opioids (64.1%), usually meperidine.
About a third of their patients were treated with
NSAIDs, and less than 10% received migraine spe-
cific parenteral medications, such as sumatriptan
or DHE. Patients in EDs outside of North America
were most likely to be treated with parenteral
NSAIDs.16,17
116
PATHOPHYSIOLOGY OF MIGRAINE AND
POTENTIAL TARGETS FOR TREATMENT
Whatever the anatomical site of migraine biogen-
esis, migraine process clearly involves meningeal
mechanisms that activate nociceptive afferents that
carry signals back to the brainstem.18 Migraine with
aura is thought to involve cortical spreading depres-
sion which progresses anteriorly from the visual
cortex at a rate of 3-4 mm/minute and produces a
consequent reduction in regional cerebral blood flow
(oligemia).19
The perception of head pain involves trans-
duction and transmission of pain signals from pain
receptors and the interpretation of these pain signals
by centrally located structures. Pain signals may
arise from receptors located in the dura mater, the
meningeal vessels, the intracranial segments of CN V,
CN IX, and CN X, and the intracranial segments of
the basilar, vertebral, and carotid arteries; all can
transmit pain signals to the trigeminal nucleus cauda-
lis (TNC) in the medulla and to the dorsal horn of the
upper cervical spine.18 The activity of second order
neurons in those two areas can be modified by inputs
from the nucleus raphe magnus (serotonergic), peri-
aqueductal gray area, locus ceruleus (noradrenergic),
and rostral trigeminal nuclei, and by descending
inhibitory transmissions from the cerebral cortex.
These correspondingly modified signals are then
relayed to the contralateral dorsomedial and ventro-
posteromedial nuclei of the thalamus, a common des-
tination for pain transmissions, and then on to the
insular cortex, the anterior cingulate cortex, and the
somatosensory cortex.
Treatments for acute migraine, therefore, poten-
tially may target the pain circuitry peripherally, cen-
trally, or both. During the natural course of a migraine
attack, both initial peripheral sensitization and, in
most cases, subsequent central pain sensitization
occurs.
During peripheral sensitization, primary afferent
neurons may become irritable and increase their
spontaneous firing because of neurogenic inflamma-
tion and dilation of meningeal blood vessels. With the
onset of migraine, there is increased release of sub-
stance P, inflammatory cytokines, and the vasodilator
calcitonin gene-related peptide (CGRP), a potential
January 2012
vasodilator. There is also increased mast cell degra-
nulation and release of histamine, sensitizing the
individual to small changes in intracranial pressure,
and causing the characteristic throbbing quality of
migraine pain.20
Central sensitization is often marked by the
development of cutaneous allodynia (the perception
of pain in response to a normally non-painful sti-
mulus), and this may involve the scalp, face, and
even the arms. Cutaneous allodynia occurs in 79% of
migraineurs.21 During central sensitization, the exci-
tatory thresholds of second order neurons in the TNC
and the dorsal horn of the cervical spine is reduced.22
THE STUDIES: METHODS
Key words ([{migraine} AND emergency]
AND [therapy OR treatment]) were searched in
MEDLINE; hand searching of journals of emergency
medicine and headache journals was performed,
and reference lists from relevant studies also were
searched. Studies included trials performed in EDs,
urgent care clinics, and headache clinics. Most studies
included were randomized and double-blind; if not,
specific justification is provided for including the
study in this review. If a study included patients with
headaches other than migraine, that also has been
noted.
COMMON INCLUSION AND
EXCLUSION CRITERIA
Most studies included patients with moderate
to severe head pain at baseline. A few studies also
included patients with mild head pain; when this was
the case, these patients were a small proportion of the
total number randomized. Many studies, but not all,
limited participation to patients who met ICHD cri-
teria for migraine with aura or migraine without aura.
Some studies based inclusion on the participants self-
report of a prior diagnosis, while others utilized ED
physicians or neurologists to diagnose the patients in
the ED after informed consent was obtained but prior
to randomization.
Typical exclusion criteria included: (1) age <18 or
>60/65 (although some studies included patients up to
age 70); (2) no well-established history of migraine;
(3) recent trauma; (4) suspected secondary headache
Headache
(thunderclap headache, fever, meningismus, altered
mental status, focal neurological symptoms); (5) preg-
nancy; (6) contra-indication to study drug(s); or (7)
use of study drug(s) (or drug from same class) within
the previous 24-48 hours.
MEASURES TAKEN
The International Headache Societys Clinical
Trial Subcommittee recommends that the primary
endpoint in acute migraine treatment research should
be the proportion of patients who are pain-free at
2-hour post-medication administration; but, this crite-
rion is rarely used in studies conducted in the ED
setting.23 Especially if they are headache-free or sat-
isfied with treatment and the ED physician believes
them ready for discharge, it is impractical to retain
study patients in a busy ED for the full 2 hours
required.
Even so, the outcome measures of pain-free at 30
minutes to 2 hours was used in some studies, as was
sustained pain-free (ie, the proportion of those who
were pain-free at 1-2 hours and were still pain-free
24-48 hours after discharge).
More typically reported were headache relief,
which utilizes: (1) a 4-point pain scale (4-PPS)
0 = none, 1 = mild, 2 = moderate, and 3 = severe; (2)
an 11-PPS, where in 0 signifies no pain up to 10 extracerebral arteries. 5HT1B constricts blood vessels
that most often is used to signify the worst pain imag-
inable or the worst pain ever experienced; or (3) a
visual analog scale (VAS). A 10-cm horizontal non-
hatched line marked from 0 on the left to 100 on the
right and upon which patients rate the subjective
intensity of these symptoms.
Headache relief is defined as either a >50%
decrease in VAS scores following administration of
medication and/or a 4-PPS score of 0 or 1 compared
with a score of 2 or 3 at baseline. Sustained headache
relief is defined as having headache relief while still
in the ED and persisting for 24-48 hours.
Many studies also evaluated functional disability,
with pain assessments in the ED and then at postdis-
charge follow-up. A 4-point disability scale is typically
used: 0 = none (capable of normal daily activities),
1 = mild (some difficulty performing normal activi-
ties), 2 = moderate (a great deal of difficulty perform-
ing normal activities), 3 = severe (unable to get out of
117
bed). When disability was reported for postdischarge
follow-up, it was usually reported as the proportion of
patients who achieved sustained disability-free (0 or
none) status.
Newer outcome measures attempt to incorporate
the patients overall assessment of a medications
efficacy in treating headache pain and accompany-
ing symptoms, as well as treatment side effects and
mode of administration. This assessment is typically
reported as the proportion of patients that respond in
the affirmative to would take again or satisfied
with current treatment.
TRIPTAN, DHE, AND MAGNESIUM
When treatments from 2 different classes of
medications were compared, a summary of results
appears under both classes (for example, a study com-
paring DHE to sumatriptan would appear under both
DHE and triptans), but details of the results will only
appear under one class. Where combinations of medi-
cations were used, all members of the combination
are represented within their own medication class.
Triptans.Two triptans (sumatriptan and rizatrip-
tan) have been studied for treatment of acute
migraine in the ED setting. These triptans act prima-
rily as selective serotonin 1B/D (5HT1B/1D) agonists on
dilated by CGRP, and 5-HT1D further inhibits CGRP
release from the activated peripheral nociceptive
C-fibers.24 The triptans also inhibit the release of
inflammatory peptides in the meninges and interfere
with the transduction of pain signals to the TNC.
The serum concentration of sumatriptan admin-
istered subcutaneously (SQ) peaks between 10-12
minutes and is 97% bio-available.25 Rizatriptan
reaches maximum concentration faster than other
oral triptans.26 Triptans generally have been found to
be safe and efficacious in the outpatient treatment of
acute migraines. Their most common side effects are
chest pressure, neck tightness, limb heaviness, tin-
gling, dizziness, and flushing. Triptans are contraindi-
cated for patients who have vascular disease, basilar/
hemiplegic migraine, or uncontrolled hypertension,
are pregnant or at risk for pregnancy (Pregnancy
Class C), or have used a different triptan or
ergotamine/DHE within the previous 24 hours.27
118
Because triptans do not affect the 5HT2A serotonin
receptors, there is likely to be no risk of serotonin
syndrome when used in monotherapy and no
increased risk from combination with serotonin
reuptake inhibitors.28
Seven randomized, double-blind studies com-
pared sumatriptan 6 mg SQ with placebo or various
other agents. One compared sumatriptan 20 mg nasal
with ketorolac 30 mg IV. There was one study involv-
ing rizatriptan 10 mg orally dissolvable tablets and
one with sumatriptan 6 mg SQ, neither of which used
a placebo or comparison group; these were included
because they were carried out in an ED setting with
a relatively large number of patients (98 and 147,
respectively).
Hay et al29 used rizatriptan orally dissolvable
10 mg tablets to treat 98 migraine patients in the ED
and found that 73.5% were pain-free at 2 hours and
93% had headache relief. Miner et al30 determined
the efficacy of sumatriptan 6 mg SC for patients with
three headache diagnoses: migraine (M; n = 84), prob-
able migraine (pM; n = 45), and tension-type head-
aches (TTH; n = 18). Headache relief at 1 hour was
similar across the groups (M 60% vs pM 56% vs TTH
67%, P = .61). Headache persisted at 48 hours in 66%.
Common side effects included chest/neck tightness
(8%), followed by drowsiness, increased head pain,
and nausea (all 4%).
Akpunonu31 found pain relief was greater with
sumatriptan SQ 6 mg compared with placebo (70% vs
35%, P < .01). Side effects, most commonly dizziness
or vertigo and tingling, were reported in 52% for
sumatriptan SQ vs 27% for placebo. Five of 88 patients
in the sumatriptan group reported benign chest tight-
ness that resolved within 1 hour without treatment.
Winner et al32 compared sumatriptan SQ 6 mg with
DHE SQ. Each medication could be repeated once at
2 hours. More patients taking sumatriptan had pain
relief at 2 hours (85.3% vs 73.1%, P = .002), but this
advantage had dissipated at 3 hours (sumatriptan 86%
vs DHE 90%).Common side effects included injection
site discomfort (DHE 38.4% vs sumatriptan 17.7%),
nausea (15.9% vs 5.9%), vomiting (6.5% vs 3.8%), and
chest pain (0.9% vs 5.9%).
Four studies compared sumatriptan with an anti-
emetic. Kelly et al33 compared sumatriptan SQ 6 mg
January 2012
with chlorpromazine 12.5 mg IV (repeated up to
37.5 mg). All patients received IV metoclopramide
10 mg. At 2 hours, there was no difference in
pain reduction as measured via VAS (sumatriptan
-63.3 mm vs chlorpromazine -54.3 mm). No dystonia
was reported. Friedman et al34 compared sumatriptan
SQ 6 mg with IV metoclopramide 20 mg (repeated
up to 80 mg) combined with IV diphenhydra-
mine 25 mg. Pain reduction (11-PPS) at 2 hours
was similar (sumatriptan -6.3 vs metoclopramide/
diphenhydramine -7.2), but the percentage pain-free
was greater with metoclopramide/diphenhydramine
(59% vs 35%, P = .04). Common side effects included
weakness, drowsiness, and a feeling of heaviness, the
last greater for sumatriptan (11% vs 0%, P = .05).
Friedman et al35 compared sumatriptan SQ 6 mg
to trimethobenzamide 200 mg intramuscular (IM)
plus diphenhydramine 25 mg IM. Pain reduction (11-
PPS) at 2 hours was similar (trimethobenzamide/
diphenhydramine -4.4 vs sumatriptan -6.1). Kostic
et al36 compared sumatriptan SQ 6 mg to prochlor-
perazine 10 mg IV plus diphenhydramine 12.5 mg
SQ. Pain reduction (VAS) at 80 minutes favored
prochlorperazine/diphenhydramine (-73 vs -50,
P < .05). Nine of 31 patients in the prochlorperazine/
diphenhydramine group reported restlessness, but
none needed treatment.
Meredith37 compared sumatriptan 20 mg nasal
spray to ketorolac 30 mg IV. Mean pain reduction
(VAS) at 1 hour favored ketorolac over sumatriptan
(-71.5 vs -22.9, P < .05). Jakubowski et al38 com-
pared sumatriptan SQ 6 mg to ketorolac 15 mg IV
bolused twice successively (30 mg total) for the
delayed treatment (4 hours) of migraine with cuta-
neous allodynia. No patient in the sumatriptan
group was pain-free after 2 hours compared with
64% in the ketorolac group at 1 hour (P < .05).
Table 1 summarizes details of the studies involving
sumatriptan and rizatriptan.
DHE.DHE is an ergot extract that activates
5HT1B and 5HT1D receptors, as do the triptans, but
DHE can also activate 5HT1A, 5HT2A, 5HT1F, 5HT2C,
5HT3, and dopamine1- and dopamine2-receptor sub-
types. DHE can block activation of the TNC by block-
ing the release of prostaglandins from the glia39 and
is associated with a low headache recurrence rate.
 Table 1.Studies Comparing Rizatriptan (RTP) and Sumatriptan (STP) Individually With Other Agents for Migraine Therapy
Headache

Group 1 (G1) mg or Group 2 (G2) mg or Venue # If Research Mean Group 1 Group 2

Study Authors (year) Treatment mg/kg Route Treatment mg/kg Route Multiple Sites Design % Women Age # pts # pts

Hay et al (2003)29 RTP 10 PO ED3 -/-/- 88 40 98

Akpunonu et al (1995)31 STP 6 SQ PCB SQ ED12 R/DB/P 88 40 88 48
Miner et al (2007)30 STP 6 SQ ED -/-/- 74 28 84
Winner et al (1996)32 STP 6 SQ DHE 1 SQ CL26 R/DB/- 88 41 150 145
Kelly et al (1997)33 STP 6 SQ CPZ 12.5 IV ERD R/-/- 67 34 20 23
Friedman et al (2005)34 STP 6 SQ MTC 20 IV ERD R/DB/- 86 34 38 40
plus DPH 25 IV
Friedman et al (2006)35 STP 6 SQ TMB 200 IM ED R/DB/- 92 33 20 20
plus DPH 25 IM
Kostic et al (2010)36 STP 6 SQ PCZ 10 IV ED R/DB/- 64 29 35 31
plus DPH 12.5 IV
Meredith et al (2003)37 STP 20 NL KET 30 IV ED R/DB/- 86 34 16 13

% Pain % Sustained % Requiring % Patient

% Pain-Free Relief Pain Relief % Disability-Free Rescue Satisfaction

Study Authors (year) G1 G2 G1 G2 G1 G2 G1 G2 G1 G2 G1 G2

Hay et al (2003)29 74 93 74 85 74
Akpunonu et al (1995)31 31 13 70 35 33 8 75 44
Miner et al (2007)30 60 64 35
Winner et al (1996)32 85 73 77 90 85 68
Kelly et al (1997)33 42 41 85 72 95 95
Friedman et al (2005)34 35 59 70 83 27 40 26 5 73 87
plus
Friedman et al (2006)35 45 30 80 70 75 85 53 84 30 20 60 70
plus
Kostic et al (2010)36 70 96 37 57
plus
Meredith et al (2003)37 27 77

Superior performance is indicated by bolding; if treatment 1 superior, then also underlined; if treatment 2 superior, then also italicized.
CL = clinic; CPZ = chlorpromazine; DB = double blind; DHE dihydroergotamine; DPH = diphenhydramine; ED = emergency department; IM = intramuscular;
IV = intravenous; KET = ketorolac; MTC = metoclopramide; P = placebo-controlled; PCB = placebo; PO = oral; R = randomized, SB = single blind, SQ = subcutaneous;
TMB = trimethobenzamide; = not study data point.
119
120
While DHE has fewer side effects than ergota-
mine tartrate, its predecessor, it can still cause nausea,
vomiting, diarrhea, abdominal cramping, vasocon-
striction, and leg pain. The appearance of nausea sug-
gests that the patient has been given too high a dose
of DHE, mediated by activation of the 5HT2 and
5HT3 receptors. DHE is generally non-sedating. It can
be easily mixed with lidocaine to prevent injection
site burning. As with the triptans, DHE is contraindi-
cated for patients who have vascular disease, basilar/
hemiplegic migraine, or uncontrolled hypertension,
are pregnant or at risk (Pregnancy Class X), or have
used a triptan or ergotamine within the previous 24
hours.28 Because DHE, unlike the triptans, does affect
the 5HT2A serotonin receptor, there may be a risk of
serotonin syndrome when used in combination with
serotonin reuptake inhibitors.
Three studies compared DHE 1 mg IV or SQ as a
single agent with other single agents or with combi-
nations of DHE and an anti-emetic, and an additional
seven studies compared a combination of DHE 0.5-
1.0 mg IV plus an anti-emetic (usually metoclopra-
mide 5-10 mg IV) with another active agent. Bell
et al40 compared DHE 1 mg IV (could be repeated
once) with chlorpromazine 12.5 mg IV (repeated up
to 37.5 mg) and to lidocaine 50 mg IV (repeated up to
150 mg). Although there was no difference in the
pain-free rate, pain reduction (11-PPS) was greater
for chlorpromazine than for lidocaine or DHE
(-79.5% vs -50% vs -36.7%, P < .05). As stated pre-
viously, Winner et al33 showed that DHE 1 mg SQ
afforded less headache relief at 2 hours than
sumatriptan 6 mg SQ (73.1% vs 8.3%, P = .002), but
there was no difference at 4 hours. Saadah41 compared
DHE 1 mg IV with DHE 0.5 mg plus prochlorpera-
zine 5 mg, DHE 1 mg plus prochlorperazine 10 mg,
and DHE 1 mg plus prochlorperazine 3.5 mg. The
percentage pain-free at 4 hours for DHE 1 mg alone
was 83%, DHE 0.5 mg + prochlorperazine 5 mg 80%,
DHE 1 mg + prochlorperazine 3.5 mg 89%, and DHE
1 mg + prochlorperazine 10 mg 95%. Side effects
were reported in 100% of the patients receiving DHE
alone, with the most common being sedation (30%),
nausea (67%), and chest discomfort (75%).
Haugh et al42 showed that DHE 1 mg IV plus
metoclopramide 10 mg IV was not more effective
January 2012
than DHE 1 mg IV alone in the percentage of
patients with headache relief at 1 hour (38%).
Klapper and Stanton43 compared DHE 0.75-1 mg IV
plus metoclopramide 5-10 mg IV with dexametha-
sone 6 mg IV plus metoclopramide 5-10 mg IV and
with placebo/normal saline IV. Headache relief at
30 minutes was equal for DHE/metoclopramide
(82%) and dexamethasone/metoclopramide (78%)
vs placebo (20%, P < .002). Edwards et al44 showed
that DHE 1 mg IV plus metoclopramide 10 mg IV
was similar in headache relief at 4 hours to valproate
500 mg IV (60%). Klapper and Stanton45 found that
DHE 1 mg IV plus metoclopramide 5 mg IV pro-
duced more headache relief at 1 hour than ketorolac
60 mg IM (78% vs 33%, P = .031). Belgrade et al46
compared DHE 1 mg plus metoclopramide 10 mg IV
with meperidine 75 mg IM plus hydroxyzine 50 mg
IM and with butorphanol 2 mg IM. Pain reduction
(VAS) was greater with DHE/metoclopramide (-59)
and butorphanol (-54) vs meperidine/hydroxyzine
(-37, P < .01). There were more patients with >90%
pain reduction with DHE/metoclopramide (38%)
than butorphanol (16%) or meperidine/hydroxyzine
(0%, P < .01). The most common side effect with
meperidine/hydroxyzine was sedation (18%). With
DHE/metoclopramide nausea (33%), dysphoria
(43%), restlessness (19%), and flushing (29%) were
the most common side effects; with butorphanol, it
was dizziness (21%) and nausea (26%). Klapper and
Stanton47 compared DHE 1 mg plus metoclopramide
10 mg IV with meperidine 75 mg plus hydroxyzine
75 mg IM. Pain reduction (4-PPS) was greater in the
DHE plus metoclopramide group (-2.14 vs -0.86,
P = .006). Scherl and Wilson48 showed that DHE
0.5 mg plus metoclopramide 10 mg IV was equally
effective in providing 1 hour headache relief as
meperidine 75 mg plus promethazine 25 mg IM
(86.2% vs 77.2%); there were more lethargy and
dizziness reported with promethazine/meperidine
(7.2% vs 3.9%, P = .006).
Carleton et al49 compared DHE 1 mg IV plus
hydroxyzine 0.7 mg/kg (could repeat once) with mep-
eridine 1.5 mg/kg plus hydroxyzine 0.7 mg/kg. Pain
reduction (VAS) was similar in the two groups (DHE
-41 vs meperidine -45, P = .81). Dizziness (DHE 2%
vs meperidine 15%, P < .05) and drowsiness (DHE
Headache
21.5% vs meperidine 22.6%) were the most common
side effects. Callaham and Raskin50 pretreated all
their study participants with prochlorperazine 5 mg
IV, and after 30 minutes, average pain (11-PPS)
dropped from 10.0 to 6.3 (NS). Three patients
dropped out of the study at this point because of
sufficient pain relief, and the remaining patients were
randomized to receive either DHE 0.75 mg IV or NS
placebo IV. Additional pain relief at 30 minutes was
similar (5.2 vs 4.7). At this point, another seven
patients left the study because of sufficient pain relief,
four in DHE group and three in the placebo group.
Then, the patients who had received DHE were given
placebo and vice versa. A half hour later, those
patients receiving DHE in the first round had more
pain relief (2.5 vs 4.7, P = .05). Table 2 summarizes the
DHE studies.
Magnesium.Magnesium can affect a number
of neurochemical processes that are known to be
involved in migraine pathophysiology. Magne-
sium maintains calcium homeostasis by binding to
N-methyl-D-aspartate glutamate receptors, modu-
lates the release of substance P, and regulates the
production of nitric oxide.51 Ionized magnesium can
affect vascular tone52 and inhibits cortical spreading
depression in rats.53
Mauskop et al54 found that 80% of patients
treated with magnesium 1 g IV were pain-free 15
minutes postinfusion (P < .001). Of the 20% requir-
ing rescue medications, the majority had chronic
migraine (88%), and only 37.5% had low ionized
magnesium (0.54 mmol/L or lower) compared with
89% who had sustained pain-freedom at 24 hours.
Almost all patients experienced brief flushing with
magnesium. Demirkaya et al55 compared magnesium
1 g IV with placebo/normal saline IV. Seventy percent
of the patients had migraine with aura. A greater
percentage receiving magnesium group was pain-free
at 30 minutes (86.6% vs 6.6%; P < .0001). Mild side
effects of flushing and face/neck burning were expe-
rienced by 86.6% of the patients in both groups.
Cete et al56 compared magnesium 2 g IV with
metoclopramide 10 mg IV and with placebo/NS IV.
Pain reduction (VAS) was similar for metoclopra-
mide vs magnesium vs placebo (-38 vs -33 vs -24),
but a smaller percentage in the metoclopramide and
121
magnesium groups required rescue medications vs
the placebo group (38% and 44% vs 65%; P = .04).
Three percent of those taking metoclopramide com-
plained of dystonia, and 8% taking magnesium
complained of flushing. Corbo et al57 compared
magnesium 2 g IV with placebo/NS IV. All patients
received metoclopramide 20 mg IV (repeated up to
60 mg). Pain reduction (VAS) was not different
between the groups (magnesium -55 vs placebo -71),
but return to normal functioning on a 4-point disabil-
ity scale was greater for the placebo group (magne-
sium 8% vs placebo 17%; P < .05). The most common
side effect noted was flushing (magnesium 48% vs
placebo 22%, not significant). Bigal et al58 compared
magnesium 1 g IV with placebo/NS IV. Although they
did have significantly less photophobia and phono-
phobia, for patients without aura, headache relief at 1
hour was not greater with magnesium compared with
placebo (33.3% vs 16.6%). Patients with aura had
greater headache relief at 1 hour with magnesium
(50% vs 13.3%; P < .05). Ginder et al59 compared
magnesium 2 g IV with prochlorperazine 10 mg IV
for undifferentiated acute headache. At 30 minutes
postinfusion, prochlorperazine provided greater
headache relief (90% vs 56%; P = .04). One patient
(5%) reported dysphoria with prochlorperazine, and
four patients (25%) reported IV burning pain with
magnesium. Frank et al60 compared magnesium 2 g
IV with placebo/normal saline IV. There was no dif-
ference in pain reduction (VAS) at 30 minutes (mag-
nesium -16 vs placebo -15; P = .85). There were more
side effects for magnesium (62% vs 29%, P = .03),
most commonly flushing. Table 3 summarizes studies
involving magnesium.
CONCLUSIONS: TRIPTANS, DHE,
AND MAGNESIUM
Triptans.In the only study to use an oral triptan
in the ED, 73.5% of migraineurs were pain-free
at 2 hours using rizatriptan 10 mg orally dissol-
vable tablets. This was, however, not a randomized,
controlled trial.
In terms of percent pain-free at two hours,
sumatriptan was similar to prochlorperazine (both
~40%) but inferior to metoclopramide plus diphen-
hydramine (59% vs 35%); this percent pain-free in
 122

Table 2.Studies Comparing Dihydroergotamine (DHE) With Other Agents for Migraine Therapy

Group 1 (G1) mg or Group 2 (G2) mg or Venue # If Research Mean Group 1 Group 2

Study Authors (year) Treatment mg/kg Route Treatment mg/kg Route Multiple Sites Design % Women Age # pts # pts

Klapper and Stanton (1991)43 DHE 1 IV PCB IV CL R/DB/P 9 10

plus MTC 10 IV
Saadah (1992)41 DHE 1 IV DHE 1 IV CL -/-/- 80 41 10 28
plus PCZ 10 IV
Haugh et al (1992)42 DHE 1 IM DHE 1 IM CL R/DB/- 94 36 8 8
plus MTC 10 IM
Klapper and Stanton (1991)45 DHE 1 IV KET 60 IM CL R/DB/- 9 9
plus MTC 10 IV
Scherl and Wilson (1995)48 DHE 0.5 IV MEP 75 IM ED R/-/- 70 31 14 13
plus MTC 10 IV PMZ 25 IM
Edwards et al (2001)44 DHE 1 IV VPT 500 IV ED R/-/- 88 42 20 20
plus MTC 10 IV
Belgrade et al (1989)46 DHE 1 IV MEP 75 IM ED R/-/- 63 30 21 22
plus MTC 10 IV HDX 50 IM
Klapper and Stanton (1993)47 DHE 1 IV MEP 75 IM ED R/DB/- 14 14
plus MTC 10 IV HDX 75 IM
Bell et al (1990)40 DHE 1 IV CPZ 12.5 IV ED2 R/SB/- 79 26 24
Winner et al (1996)32 DHE 1 SQ STP 6 SQ CL26 R/DB/- 88 41 145 150
Carleton et al (1998)49 DHE 1 IV MEP 1.5 IV ED11 R/DB/- 82 32 78 78
plus HDX 0.7 IV HDX 0.7 IV
January 2012
 Headache

Table 2.Continued

% Pain % Sustained % Requiring % Patient

% Pain-Free Relief Pain Relief % Disability-Free Rescue Satisfaction

Study Authors (year) G1 G2 G1 G2 G1 G2 G1 G2 G1 G2 G1 G2

Klapper and Stanton (1991)43 78 20 44 0

plus
Saadah (1992)41 83 95
plus
Haugh et al (1992)42 13 25 38 38 86 87 57 87
plus
Klapper and Stanton (1991)45 78 33 100 89 11 67
plus
Scherl and Wilson (1995)48 86 77 54 33
plus
Edwards et al (2001)44 45 50 90 60
plus
Belgrade et al (1989)46 38 0 >90 pain reduction
plus
Klapper and Stanton (1993)47 93 21
plus
Bell et al (1990)40 23 33 37 80 53 89 50 21 26 67
Winner et al (1996)32 73 85 90 77 68 85
Carleton et al (1998)49 54 56 36 29 32 14 21 18
plus

Superior performance is indicated by bolding; if treatment 1 superior, then also underlined; if treatment 2 superior, then also italicized.
CL = clinic; CPZ = chlorpromazine; DB = double blind; DPH = diphenhydramine; ED = emergency department; HDX = hydroxyzine; IM = intramuscular; IV = intravenous;
KET = ketorolac; MEP = meperidine; MTC = metoclopramide; P = placebo-controlled; PCB = placebo; PCZ = prochlorperazine; PMZ = promethazine; R = randomized,
SB = single blind, SQ = subcutaneous; STP = sumatriptan; VPT = valproate; = not study data point.
123
 124

Table 3.Studies Comparing Magnesium (MAG) With Other Agents for Migraine Therapy

Group 1 (G1) mg or Group 2 (G2) mg or Venue # If Research Mean Group 1 Group 2

Study Authors (year) Treatment mg/kg Route Treatment mg/kg Route Multiple Sites Design % Women Age # pts # pts

Demirkaya et al (2001)55 MAG 1000 IV PLB IV CL R/SB/P 80 35 15 15

Corbo et al (2001)57 MAG 2000 IV PLB IV ED2 R/DB/P 95 38 21 23
Frank et al (2004)60 MAG 2000 IV PLB IV ED2 R/DB/P 76 33 21 21
Bigal et al (2002)58 MAG 1000 IV PLB IV CL2 R/DB/P 65 29 30 30
with aura 78 28 30 30
Cete et al (2004)56 MAG 1000 IV PLB IV ED2 R/DB/P 84 40 36 40
Also versus MTC 10 IV 37
Ginder et al (2000)59 MAG 2000 IV CPZ 10 IV ED R/DB/P 69 16 20
Mauskop et al (1996)54 MAG 1000 IV CL -/-/- 73 38 40

% Pain % Sustained % Requiring % Patient

% Pain-Free Relief Pain Relief % Disability-Free Rescue Satisfaction

Study Authors (year) G1 G2 G1 G2 G1 G2 G1 G2 G1 G2 G1 G2

Demirkaya et al (2001)55 87 0 100 7

Corbo et al (2001)57 15 22 8 17
Frank et al (2004)60 19 24 81 86
Bigal et al (2002)58 23 10 33 17 67 47
37 7 50 13 83 73
Cete et al (2004)56 47 35 48 48 44 65
Also versus 52 57 38
Ginder et al (2000)59 12 40 56 90 50 50
Mauskop et al (1996)54 80 56 20

Superior performance is indicated by bolding; if treatment 1 superior, then also underlined; if treatment 2 superior, then also italicized.
CL = clinic; CPZ = chlorpromazine; DB = double blind; ED = emergency department; IV = intravenous; MTC = metoclopramide; P = placebo-controlled; PCB = placebo;
R = randomized; SB = single blind; = not study data point.
January 2012
Headache
the metoclopramide group (59%) was, however, sub-
stantially higher than that recorded in a separate
study that compared percent pain-free at 2 hours for
three doses of metoclopramide (10, 20, and 40 mg).61
In terms of pain relief, diphenhydramine plus
prochlorperazine surpassed sumatriptan; this was
not the case, however, for trimethobenzamide plus
diphenhydramine. Sumatriptan was faster than DHE
in providing pain relief, but the advantage was not
sustained over time, with headache recurrence at
24 hours being less in the DHE group. In addition,
sumatriptan nasal spray was not as effective as
ketorolac IV in relieving pain.
Of special note, sumatriptan was not at all effec-
tive (zero patients pain-free at 2 hours) when admin-
istration was delayed until after the development of
central sensitization, as determined by the presence
of cutaneous allodynia in the scalp and/or face of the
patient.
Sumatriptan SQ 6 mg as a single agent was supe-
rior to placebo, with 70% having pain relief and about
one third being pain-free before discharge from the
ED and remaining pain-free for 24 hours. These per-
centages appear modest compared with phenothia-
zines (to be reviewed in a subsequent paper in this
series), but with the minimal side effects resolving
on their own before patients even leave the ED,
sumatriptan certainly can be recommended as first-
line therapy for migraine patients who have not
developed cutaneous allodynia.
These emergent and urgent care results are
similar to those of studies using triptans for outpa-
tient treatment of their migraines in which up to 40%
of individual headaches were not relieved by triptans
and up to 25% of patients did not respond to triptans
for any of their headaches.62 Of some interest, in
studies that looked at ED physician medication
choices rather than efficacy of medications, patients
treated with triptans tended to spend less time in the
ED than those treated with other medications (112
minutes vs 265 minutes).63
DHE.As a single agent, DHE 1 mg IV or SQ
has not been as effective as prochlorperazine IV,
but DHE did appear to enhance the pain relief
of prochlorperazine when administered 30 minutes
after, as opposed to 60 minutes after, the initial dose
125
of prochlorperazine. Relief with DHE was slower
than with sumatriptan SQ; but ultimately, DHE pro-
vided similar pain relief prior to ED discharge and
greater sustained pain relief at 24 hours.
Five additional studies compared the commonly
used combination of DHE and metoclopramide with
other active agents. This combination was superior
in pain relief to ketorolac and to meperidine plus
hydroxyzine (2 studies) but similar to butorpha-
nol, valproate, and meperidine plus a neuroleptic
(promethazine or metoclopramide). The question
arises as to the relative contributions of DHE and
metoclopramide to pain relief. One study suggested
that any additional pain relief afforded by the meto-
clopramide may be minimal, given that the combina-
tion of DHE plus metoclopramide was no more
effective for pain relief than DHE alone.
When IV DHE is used as a single agent, nausea is
a common adverse event (33-67%). Pretreatment
with an anti-emetic is recommended to anticipate
IV DHE-induced nausea. Other side effects include
sedation (22-30%), dysphoria (43%), flushing (29%),
and chest discomfort (as high as 75% in one study),
which usually resolve without intervention.
Magnesium.Magnesium can be effective in treat-
ing all symptoms of patients who have migraine with
aura, although it appears effective in treating only
associated symptoms of photophobia and phonopho-
bia across all migraine patients. Using magnesium
in conjunction with metoclopramide, however, may
worsen the therapeutic outcome perhaps through
magnesium causing cerebral vasodilation. Mag-
nesium has minimal side effects, chief among them
being loose stools. Magnesium also can lower blood
pressure temporarily. When used in combination
with DHE, magnesium can help mitigate the blood
pressure increase at times associated with DHE.
Magnesium is safe to use in pregnancy.
As noted in the introduction, Part 2 of this
series will address the neuroleptics, antihistamines,
serotonin (5HT)3 antagonists, valproate, and others
(octreotide, lidocaine, nitrous oxide, propofol, and
bupivacaine). Part 3 will address the opiates/opioids,
NSAIDs, steroids, and postdischarge medications,
including as well, a general discussion of all therapies
presented in the 3 articles.
126
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