The Place of Corticosteroids in Migraine Attack Management - A 65-Year Systematic Review With Pooled Analysis and Critical Appraisal (2015)

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The place of corticosteroids in migraine ! International Headache Society 2015
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DOI: 10.1177/0333102414566200
cep.sagepub.com
systematic review with pooled analysis
and critical appraisal
YW Woldeamanuel1, AM Rapoport2 and RP Cowan1
Abstract
Background and objectives: Headaches recur in up to 87% of migraine patients visiting the emergency department (ED),
making ED recidivism a management challenge. We aimed herein to determine the role of corticosteroids in the acute
management of migraine in the ED and outpatient care.
Methods: Advanced search strategies employing PubMed/MEDLINE, Web of Science, and Cochrane Library databases
inclusive of a relevant gray literature search was employed for Clinical Studies and Systematic Reviews by combining the
terms migraine and corticosteroids spanning all previous years since the production of synthetic corticosteroids ca.
1950 until August 30, 2014. Methods were in accordance with MOOSE guidelines.
Results: Twenty-five studies (n 3989, median age 37.5 years, interquartile range or IQR 3541 years; median male:female
ratio 1:4.23, IQR 1:2.16.14; 52% ED-based, 56% randomized-controlled) and four systematic reviews were included.
International Classification of Headache Disorders criteria were applied in 64%. Nineteen studies (76%) indicated
observed outcome differences favoring benefits of corticosteroids, while six (24%) studies indicated non-inferior out-
comes for corticosteroids. Median absolute risk reduction was 30% (range 6%48.2%), and 11% (6%48.6%) for 24-, and
72-hour headache recurrence, respectively. Parenteral dexamethasone was the most commonly (56%) administered
steroid, at a median single dose of 10 mg (range 424 mg). All meta-analyses revealed efficacy of adjuvant corticosteroids
to various abortive medicationsindicating generalizability. Adverse effects were tolerable. Higher disability, status
migrainosus, incomplete pain relief, and previous history of headache recurrence predicted outcome favorability.
Conclusions: Our literature review suggests that with corticosteroid treatment, recurrent headaches become milder than
pretreated headaches and later respond to nonsteroidal therapy. Single-dose intravenous dexamethasone is a reasonable
option for managing resistant, severe, or prolonged migraine attacks.
Keywords
Corticosteroids, migraine, migraine attack management, emergency room management of migraine, neurogenic inflam-
mation, prolonged migraine, recurrent migraine, systematic review, pooled analysis, critical appraisal
Date received: 15 May 2014; accepted: 15 October 2014
Background
Burden of recurrent migraine 1
Stanford Headache and Facial Pain Program, Department of Neurology
and Neurological Sciences, Stanford University School of Medicine, USA
Primary headache disorders are increasingly important 2
Department of Neurology, The David Geffen School of Medicine at
causes of disabling public health and socioeconomic UCLA in Los Angeles, USA
burden worldwide (1). In the United States (US)
alone, more than 30 million people suer from migraine Corresponding author:
(24), and an estimated 3 million headache patients Yohannes W. Woldeamanuel, Stanford Headache and Facial Pain Program,
Stanford University School of Medicine, Department of Neurology and
visit emergency departments (EDs) annually (4,5). Neurological Sciences, Room H3160, 300 Pasteur Drive, Stanford, CA
Migraines are often underestimated and misdiagnose- 94305-5235, USA.
dand thus are under- or mistreated (2,6). Email: ywoldeam@stanford.edu; yohannes.woldeamanuel@gmail.com
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Migraine costs the US economy nearly $17 billion theory has not been shown to be signicant in the
annually; direct costs are increased by incomplete human condition of migraine; dierences and transla-
pain relief, and repeated ED visits. Lost productivity tional challenges in neuroethological approaches need
due to headache accounts for the bulk of the economic to be considered. In addition, multiple SNI inhibitors
burden (7,8). (e.g. neurokinin receptor antagonists (35), neuroster-
Studies indicate that post-ED recurrent headaches oids (36,37)) have failed to be ecacious for both
occur within 24 hours in up to 87% of migraine acute and preventive treatment of migraine. Among
patients visiting the ED (5,915), and more than half neuropeptides, a recent systematic review (38) has
of these recurrent headaches are functionally disabling shown four clinical studies reporting increased calci-
(14,16). Previous history of headache recurrence, longer tonin gene-related peptide (CGRP) during migraine
headache duration, severe baseline pain, and persistent attacks (3942), while another three clinical studies
pain at discharge all contribute to post-ED headache found no dierence (4345).
recurrence (5,15). Repeated ED visits are a continuing Corticosteroids are the main humoral mediators of
problem in the ED setting (17), making ED recidivism a stress, and their increased secretion in response to
signicant management challenge (17,18). adverse stimuli normally results in a cascade of physio-
Undertreated or poorly treated headaches (18), medi- logical and behavioral homeostatic mechanisms (46).
cation-seeking behavior (18,19), and medication over- The term corticosteroids embraces two prototypic
use (17) are features associated with the ED-repeater steroids, i.e. glucocorticoids and mineralocorticoids.
phenotype. Lower headache recurrence rates are By virtue of their physical features of lipophilicity
found to be signicant measures according to patients (4749) and small mass size (ca. 300 Da) (50,51), cor-
self-reported satisfaction for optimum outcome (20). ticosteroids can readily pass the blood-brain barrier
(4749,52) and participate in a variety of behavioral
Algogenic properties of neurovascular and physiological processes, as well as taking part in
their own secretion (46). In this respect, they serve as
inflammation in migraine messengers between the periphery and brain, and also
Current evidence indicates that migraine is a neurovas- between the external and internal environments and the
cular inammatory disorder (2123). It is a dysfunction brain. Since corticosteroids act against the background
of sensory processing of painful stimuli (24). Pain is of increased monoamine secretion, it is thought that
generated either peripherally from trigeminocervical they act to ne-tune the individuals response to stress
neurons through abnormal activation at primary aer- (53). Unlike the transient monoamine response, cor-
ents (25) or centrally due to anomalous modulation at ticosteroids exert sustained actions on cellular activity
second-order neurons (2628). Once nociceptive pri- and behavior, and therefore are essential for ensuring
mary aerent trigeminocervical systems are peripher- the orchestration of a coordinated adaptive response as
ally activated, signals travel orthodromically and well as preparedness of the individual to cope with
neuropeptides are released onto receptors on second- future challenges (53).
order neurons of the trigeminal nucleus caudalis Corticosteroids have been used as pain relief adju-
(23,29,30). The same peptidergic nociceptive primary vants in dierent neurological conditions; an adjuvant
aerents subserve sensory-eerent functions whereby pain medication should be considered at all stages of
peptides are likewise released at their peripheral peri- the World Health Organizations (WHO) pain ladder
vascular terminals (30). Neuropeptides modulate neu- for mild to severe painful conditions (54).
roregulation of arteriolar vasodilation, inammation, Corticosteroids reduce pain by inhibiting prostaglandin
and smooth muscle changes (23,31). Neurally induced synthesis, which leads to inammation, and by reducing
inammatory discharge of algogenic pro-inammatory vascular permeability that results in tissue edema (55).
mediators, plasma protein extravasation, meningeal Exogenous administration of corticosteroids suppresses
irritation, perivascular edema, and dural platelet aggre- excessive stress and inammatory response from the
gation are inherent in animal models of trigeminal gan- hypothalamic-pituitary axis (46). Steroid receptors are
glion stimulation or pouring pro-inammatory found in the central and peripheral nervous systems
mediators over animal dura mater (23,32). Vascular and are responsible for growth, dierentiation, devel-
and inammatory changes follow neuronal changes opment, and plasticity of neurons (55). In particular,
(23,32,33). This complex inammation-pain interplay corticosteroids reduce spontaneous discharge in an
is broadly termed sterile neurogenic inammation injured nerve, which reduces neuropathic pain (56).
(SNI) (23,32). SNI contributes to development of Corticosteroids oer extended suppression of SNI
hyperalgesia, pain prolongation, and peripheral sensi- (57) and modulate neuroplasticity, thereby reducing
tization of polymodal receptors in animal models pain (56). Corticosteroids have long been used to
(23,26,34). Here, it is important to note that the SNI manage migraine (5862).
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Woldeamanuel et al. 3
Aim 4. Advanced PubMed/MEDLINE search was used by
In this systematic review, we make a pooled analysis implementing auto-suggested MeSH Terms and
and critical appraisal of the published literature on clin- Boolean logic operator AND as (migraine
ical studies of corticosteroid treatment for migraine. [MeSH Terms]) AND corticosteroids[MeSH
Our objectives are to assess the ecacy of corticoster- Terms].
oid administration in the ED and outpatient clinical 5. The Cochrane Library Advanced Search strategy
settings on the primary outcome of reducing headache was used by adding the search line Search All
frequency. We also compared corticosteroid adminis- Text and employing the search terms migraine
tration to other standard drug regimens. AND corticosteroids.
Identication, screening, selection, and inclusion of 6. A Web of Science Advanced Search was employed
clinical studies followed Preferred Reporting Items for by using the eld tag TS for topic, the Boolean
Systematic Reviews and Meta-Analyses (PRISMA) operator AND, and parentheses to create our
procedures as described within the Methods and mater- query as TS (migraine AND corticosteroids)
ials part of our study. on Indexes CPCI (Conference Proceedings
Citation Index), Science Citation Index Expanded
(SCI-EXPANDED), Timespan All years. Results
Methods and materials included all languages and all document types.
A combination of the following search strategies using 7. Unpublished studies and a relevant reference search
dierent search databases was employed to capture our were exhaustively conducted. This enabled us to
topic of interest, i.e. studies on corticosteroids for locate and capture unpublished studies from the
migraine management. gray literature (e.g. conference abstracts or research
letters) on our topic of interest, with the goal of
1. A PubMed/MEDLINE search was employed for elucidating the impact of unpublished studies and
Clinical Studies Categories and Systematic Reviews ultimately avoiding publication bias of negative or
on the PubMed Clinical Queries tool combining the positive studies.
terms migraine AND corticosteroids; the Boolean
logic operator AND was applied to connect the A PRISMA (64) ow diagram describing the selec-
two search terms. The Clinical Studies Category was tion method is displayed in Figure 1. An additional
selected for Therapy, Etiology, Diagnosis, relevant reference search was made to extract complete
Prognosis, Clinical Prediction Guides, and the previous data on corticosteroids and migraine.
scope of the search was made specic to Broad to Scientic abstracts and several prepublication trial
enable sensitivity and specicity search values of registries for investigations related to the research ques-
99% and 70% (63), respectively. The PubMed tion were searched. All published studies up to August
equivalent for this search method was 30, 2014, were covered; this meant that all clinical stu-
((clinical[Title/Abstract] AND trial[Title/ dies since the production of synthetic corticosteroids
Abstract]) OR clinical trials as topic[medical subject were reviewed. Two authors (YWW and RPC)
headings (MeSH) Terms] OR clinical reviewed each abstract, and where disagreement
trial[Publication Type] OR random*[Title/Abstract] occurred, discussion and consensus was achieved with
OR random allocation[MeSH Terms] OR thera- input from the third author (AMR). Clinically relevant
peutic use[MeSH Subheading]). data, useful evidence-based recommendations,
2. A second PubMed/MEDLINE search was employed strengths, limitations, and unaddressed areas of
for Clinical Studies Categories and Systematic selected studies were carefully examined in this review.
Reviews on the PubMed Clinical Queries Tool com- Where applicable, study quality was evaluated using
bining the terms migraine AND corticosteroids. the Jadad scale (65) and the Consolidated Standards of
The Clinical Studies Category was selected for Reporting Trials (CONSORT) checklist (66) (Table 1);
Therapy, and the scope of the search was made the former measures adequacy of reported randomiza-
specic to Narrow to enable sensitivity and speci- tion, blinding, and management of withdrawals and
city search values of 93% and 97% (63), respect- dropouts, while the latter similarly assesses enrollment,
ively. The PubMed equivalent for this search method allocation, loss to follow-up, and analysis. Each study
was (randomized controlled trial [Publication Type] was awarded a score out of a maximum of 5 points
OR (randomized [Title/Abstract] AND controlled for the Jadad scale. Methods were in accordance
[Title/Abstract] AND trial [Title/Abstract])). with Meta-analysis of Observational Studies in
3. A third PubMed/MEDLINE search was employed Epidemiology (MOOSE) guidelines (67).
without using the Clinical Queries Tool. Search To help interpret the results of the dierent studies
terms used were migraine AND corticosteroids. included, the following methods were applied. For the
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Studies identified through the first 6 search strategies described

Identification
on Methods and Materials. Additional published studies identified through

Total n = 1149 relevant reference grey literature and
unpublished studies search
Search method #1 = 515 studies (n = 9)
Search method #2 = 22 studies
Screening
Identified Studies Screened Studies and duplicate ineligible excluded

(n = 1158) (n = 1080)
Duplicate eligible studies excluded from

Eligibility
Full-text articles assessed for eligibility simultaneous identification by the different

(n = 78) search strategies and databases
(n = 53)
Included
Studies included in final systematic review,

pooled analysis synthesis, and critical appraisal
(n = 25)
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram displaying the method of
how selection of studies was made.
primary outcome, i.e. frequency of headache, relative found under the Systematic Reviews search (Table 2).
risk (RR) ratios were calculated from the numbers of Two clinical studies were found from a gray literature
headache events in the control and intervention groups search on conference abstracts. Fourteen (56%) studies
of each study. Where headache recurrence was reported were designed as randomized, double-blinded, con-
as a dichotomous variable (present/absent), the pres- trolled trials. Thirteen (52%) studies were from ED-
ence of headache was included as an event for the pri- based settings, while the remaining 12 (48%) were
mary outcome. For adverse events, the number of from non-ED-based outpatient settings. Sixteen
events in each study group was scored. Absolute risk (64%) studies applied International Headache Society
reductions (ARRs) were calculated by subtracting event (IHS) headache diagnostic criteria.
rate (headache frequency) in the intervention arm from Fourteen studies (56%) had a Jadad score (65) of 5,
event rate in the control (or study arm not of primary and fullled the complete CONSORT (66) check-
interest). Numbers needed to treat (NNT) were calcu- listindicating rigorous methodological quality; two
lated by dividing 100% by the ARR values. All pub- studies (8%) had a Jadad score 3, and missed blinding
lished studies relevant to our question stem were from the CONSORT checklistindicating adequate
included and their outcomes were completely assessed methodological quality; four studies (16%) had a
so as to avoid publication bias and selective reporting. Jadad score of 0 and did not fulll any of the
CONSORT checklist (Figure 2).
Nineteen studies (76%) indicated observed outcome
Results dierences favoring benets of corticosteroids, while six
A total of 25 studies with an aggregate number of 3989 (24%) studies indicated non-inferior outcomes for cor-
(median age of 37.5 years, interquartile range or IQR ticosteroids. Stratifying the studies to those that
3541 years; median male:female ratio of 1:4.23, IQR addressed headache recurrence (56%) and acute reduc-
1:2.16.14) (Figure 7(a) and (b)) patients were found tion of migraine attacks (68%), respectively, revealed
under the combined search methodologies described that 78.6% and 61.2% of the studies observed favor-
within the Method and Materials section (Table 1). able outcome dierences indicating benets of cortico-
Four systematic reviews and meta-analyses were steroids; 21.4% and 38.8% indicated non-inferior
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Table 1. Comprehensive summary of included clinical studies reviewed.

Appraisals and clinical bottom
First author, title of article, lines (CONSORT) and
name of journal, year of Jadad scale compiled,
publication, and study setting Study design Outcomes among intervention arms where possible)
1. Gallagher (60). Emergency Three-arm retrospective chart M, P D, M M, P, D Favorable outcomes for dexa-
treatment of intractable review of six-month period; all (Meperidine (75-100 mg) and (Dihydroergotamine (Meperidine (75100 mg), methasone
Woldeamanuel et al.
migraine. Headache, 1986. parenteral administrations promethazine (50 mg); (1 cc) and meperidine promethazine (50 mg) ED convenience sampling may
ED setting, suburban hos- Overall average headache (n 73); male-to-female (75100 mg); (n 32); and dexamethasone create unrecognized source
pital. NJ, USA. duration 54 hours. (M:F) ratio 1:2.47) M:F ratio 1:2.20) (8 mg); (n 57); M:F population bias
n 162 ratio 1:2.56) ARR of 35% between M,P,D and
Mean age 41 years. D,M; 33% between M,P,D and
[7.1.201510:03am]
No/mild headache (no inter- 29% 37% 72%

M:F ratio 1:2.45. ference with usual activity) M.P.
Minimum headache duration 24 hours post-treatment Retrospective chart review may
36 hours. introduce recall bias of written
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record on charts; difficulty to

control confounders due to
retrospective nature of study
(CEP)
2. Foroughipour et al. (68) Randomized, two-arm, double- Dexamethasone Valproate Non-inferior outcomes for dexa-
Randomized clinical trial blind. (16 mg IV) (900 mg IV) methasone
of intravenous valproate All status migranosus patients. n 12 n 19 ED and Headache Clinic, conve-
(orifil) and dexametha- n 31 Headache recurrence within 66.67% 68.42% nience sampling used
[PREPRINTER stage]
[129]
sone in patients with M:F 1:9.3 72 hours Six lost to follow-up from dexa-
migraine disorder. Iran J Mean age 33.4 years methasone reduced final
Severe recurrent migraine 33.33% 26.32%
Med Sci 2013. ED and 900 mg IV valproate vs 16 mg IV number analyzed this may
attacks provoking another
Headache Clinic, Iran. Dexamethasone affect result
physician visit
IV dexamethasone diluted in CONSORT: enrollment, rando-
150 cc normal saline and Mean age (years) 32.50 11.19 33.89 13.34 mization, blinding, allocation,
infused for 10 minutes Mean migraine history 6.00 8.07 6.26 8.99 loss to follow-up, and analysis
IHS criteria applied (per month) methods clearly explained
Clinical trial registration: Presence of aura 8.34% 38.84% Jadad scale: 5 rigorous (2 for
IRCT13891146234N2 Recovery from nausea 91.67% 68.42% randomization, 2 for blinding,
1 for description of withdra-
Recovery from photophobia 91.67% 78.95%
wals and dropouts)
Pain-free response after 33.33% 26.32%
treatment
3. Soleimanpour et al. (69) Double-blind, randomized, two- Dexamethasone Propofol Non-inferior outcomes for dexa-
Effectiveness of intrave- arm (0.15 mg/kg IV to a maximum (10 mg IV every methasone
nous dexamethasone n 90 of 16 mg, slowly) (n 45) 510 minutes to a Study could have benefited from
versus propofol for pain Mean age 35.9 years maximum of 80 mg, follow-up post-discharge
relief in the migraine M:F ratio 1:2.1 slowly) (n 45) Propofol administered in titration
headache: A prospective IV propofol (n 45) (10 mg every as compared to dexametha-
double blind randomized 510 minutes to a maximum of sone bolus formthis may
clinical trial. BMC Neurol 80 mg, slowly) versus IV dexa- create pharmacokinetic differ-
2012. ED, Hospital. Iran. methasone (n 45) (0.15 mg/ ence
kg to a maximum of 16 mg, ED setting: convenience sample
slowly) used
IHS criteria applied CONSORT: enrollment, rando-
Clinical trial registration: mization, blinding, allocation,
IRCT201008122496N4 loss to follow-up, and analysis
(continued)
5
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6
Table 1. Continued.
methods clearly explained

Jadad scale: 5 rigorous (2 for
randomization, 2 for blinding,
wals and dropouts)
1. Mean age (years) 36.27 35.65
1. M:F ratio 1:1.65 1:2
[7.1.201510:03am]
1. Mean VAS score VAS 8.11 1.31 8 1.52

baseline
1. VAS 10 minutes 5.13 1.47 3.08 1.7
1. VAS 20 minutes 3.73 1.81 1.87 1.28
1. VAS 30 minutes 3.06 2 1.44 1.63

(CEP)
4. Saadah (61). Abortive Inclusion: headache severity, pro- Dexamethasone 10 mg IV Dexamethasone 20 mg IV Prochlorperazine 3.5 mg Favorable outcomes for dexa-
migraine therapy in office tracted duration, or resistance over five minutes (n 22) over 10 minutes IV over five minutes methasone
with dexamethasone and to abortive home therapy (n 39) followed by 20 mg of Increasing dexamethasone dose
prochlorperazine. n 108 dexamethasone over from 10 to 20 slightly
[PREPRINTER stage]
[129]
Headache 1994. Health mean age 39 years 10 minutes (n 47) improved outcome, while side
Center, OK, USA M:F 1:7.6 Mean age (years) 35.5 43 38.5 effects were reduced.
IHS criteria applied for diagnosis Definitions of outcome terms of
M:F ratio 1:8.3 1:4.6 1:5.7
Premedication with 40 mg of oral relapse, resolution, remission
famotidine for those receiving not clearly stated.
dexamethasone Complete resolution of 80%, 29%, 57% 89%, 35%, 71% 89%, 28%, 83% Non-randomized design lacking
headache, relapses, remis- blinding, and being based on
sions (over one week) patient preference may intro-
Side effects (GI discomfort, 19% 15% 22% duce bias.
flushing, insomnia, seda- All included patients had failed
tion, akathasia) abortive therapy with NMEC
(naproxen sodium 550 mg
metoclopramide 10 mg
ergotamine tartrate 1 mg
caffeine 100 mg), analgesics,
intramuscular DHE or subcu-
taneous sumatriptan.
Comparison of post-dexametha-
sone abortive treatment indi-
cated oral or parenteral
abortive therapies that were
ineffective prior to dexa-
methasone became effective
afterward.
Study conducted before
CONSORT and Jadad scale
became applicable.
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Table 1. Continued.
Woldeamanuel et al.
5. Monzillo et al. (70) Acute Dexamethasone (4 mg) IV versus Outcome: post-treatment percentage of Dexamethasone Haloperidol Non-inferior outcomes for dexa-
treatment of migraine in haloperidol (5 mg) IV in ED. patients with average VAS score 4 mg IV 5 mg IV methasone
emergency room: n 29 (n 15) (n 14) ED setting convenience sampling
Comparative study Mean age 31.5 years Baseline VAS 10 for all (100%) VAS 10 for 100% used
[7.1.201510:03am]
between dexametasone M:F ratio 1:6.25 Non-randomized design lacking

30 minutes 86.7% 64.3% (3.8)
and haloperidol. Patients were asked about pain blinding may introduce bias
(VAS 8.4)
Preliminary results [article intensity at 30, 60, 90 and 120 CONSORT checklist not men-
in Portuguese]. Arq minutes after use of either 60 minutes 80% (6.6) 7% (4) tioned; Jadad scale indicates
Neuropsiquiatr 2004. ED, drug. 90 minutes 65% (6.2) 0 (0) poor score.
Hospital, Sao Paolo, Brazil. Recurrence defined as returning Two hours 53.4% (6.6) 0 (0)
(CEP)
of headache after two hours

and before 24 hours, once
headache intensity has
decreased from severe/mod-
erate to mild/none.
IHS criteria applied for diagnosis
[PREPRINTER stage]
[129]
6. Krymchantowski et al. (71) n 400 Recurrence rate Favorable outcomes for dexa-
Dexamethasone mean age 38 years 23.4% (mean) in 18 patients methasone
decreases migraine recur- M:F 1:3.87 50% in two patients Study setting: private headache
rence observed after Sumatriptan/zolmitriptan/rizatrip- center: convenience sampling
treatment with a triptan tan plus 4 mg dexamethasone Side effects: heartburn in 30%,
combined with a nonster- oral (maximum of twice a asthenia in 25%, somnolence in
oidal anti-inflammatory week) to their usual triptans 15%
drug. Arq Neuropsiquiatr for six consecutive moderate/ For generalizability purpose, it
2001. Private Headache severe migraine attacks was useful that study
Clinic. Rio de Janeiro, Recurrence defined as returning described including different
Brazil. of headache after two hours abortive combinations of trip-
and before 24 hours, once tans and NSAIDs used by
headache intensity has patients: rizatriptan 10 mg plus
decreased from severe/mod- rofecoxib (n 11); rizatriptan
erate to mild/none. 10 mg plus tolfenamic acid
IHS criteria applied for diagnosis (n 4); zolmitriptan 2.5 mg
plus rofecoxib (n 3); zolmi-
triptan plus tolfenamic acid
(n 1); sumatriptan 100 mg
plus tolfenamic acid (n 1)
Non-randomized design lacking
blinding may introduce bias.
CONSORT checklist not men-
tioned; Jadad scale indicates
poor score.
(continued)
7
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Table 1. Continued.
7. Kelly et al. (72). Impact of Double-blind, randomized, pla- Dexamethasone Control Favorable outcomes for dexa-
oral dexamethasone cebo-controlled, multi-cen- n 31 n 32 methasone
versus placebo after ED tered (8 mg po) Convenience ED sampling fol-
treatment of migraine Adult patients (n 63), physician- Median age (years) 39 40.5 lowed by outpatient follow-up.
with phenothiazines on diagnosed migraine; treated ARR of 12% and 30% among those
Rate of recurrent headache at 27% (8/31) 39% (12/32)
the rate of recurrent with IV phenothiazine with headache lasting <24
4872 hours
headache: A randomized M:F ratio 1:1.29 hours is clinically significant.
[7.1.201510:03am]
controlled trial. BMJ 2007. Median age 39.75 Rate of recurrent headache 15% (3/20) 45% (9/20) RR use provides valid measure
ED, Hospital, Australia. At discharge, patients were ran- for 40 patients with head- as this was a prospective trial.
domized to receive either ache lasting <24 hours at Study could have included NNT
4872 hours
8 mg oral dexamethasone computations, as this makes

(n 31) or placebo (n 32) as Adverse effects In dexamethasone group No adverse effects were results of randomized trials
a single dose. there was one report of reported in placebo more meaningful.
(CEP)
Telephone follow-up at 4872 facial flushing, one of group. NNT was (100/128.3) among all,
hours and proportion of nausea, two of new-onset and (100/303.33) among 40
patients with recurrent head- transient tingling in hands patients with headache lasting
ache overall was recorded or feet, one of blurred <24 hours.
vision, one of a hot sen- Phenothiazines pre-treatment
sation in legs and one of
[PREPRINTER stage]
[129]
impact was not analyzed.

diarrhea. Sample size not adequate.
CONSORT: enrollment, rando-
mization, blinding, allocation,
loss to follow-up, and analysis
wals and dropouts)
8. Baden E et al. (73) Randomized, double-blind, pla- Dexamethasone Placebo (n 24) Favorable outcomes for dexa-
Intravenous dexametha- cebo-controlled, two-arm (10 mg IV) methasone
sone to prevent the n 55 (n 31) ARR of 48.6% on headache
recurrence of benign Mean age 33.5 years Mean age (years) 34.5 32.6 recurrence 4872 hours post-
headache after discharge M:F ratio 1:1.75 administration and 20.4% on
M:F ratio 1:1.38 1:2.43
from the emergency Headache evaluation and therapy severe headache.
department: A rando- were determined by the Headache recurrence 4872 9.7% (3/31) 58.3% (14/24) Convenience ED sampling used.
mized, double blind, pla- treating physician, and, before hours post-administration CONSORT: enrollment, rando-
cebo-controlled clinical discharge, patients were Severe headaches seeking 12.9% (4/31) 33.3% (8/24) mization, blinding, allocation,
trial. CJEM 2006. ED, administered either 10 mg of repeated ED visits loss to follow-up, and analysis
Hospital, TX, USA. IV dexamethasone or placebo methods clearly explained
Participating patients were con- Jadad scale: 5 rigorous (2 for
tacted 48-72 hours following randomization, 2 for blinding,
discharge and asked whether 1 for description of withdra-
headache was wals and dropouts)
- better,
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(continued)
Table 1. Continued.
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- worse or
- remained unchanged
when compared with symptoms
at discharge.
Woldeamanuel et al.
Headache recurrence defined as

those with treatment failures
whose headaches were
worse or unchanged, and
[7.1.201510:03am]
those who reported return of

headache after being pain free
at discharge.
Recurrent headaches were
further subclassified as
- severe (i.e. provoking another
physician visit or interfering
(CEP)
with daily activity)

- mild (i.e. requiring self-medica-
tion or no treatment).
[PREPRINTER stage]
[129]
9. Rowe et al. (74). All received standard IV abortive Dexamethasone Placebo Favorable outcomes for dexa-
Randomized controlled therapy at discretion of treat- (IV, 15 mg) n 62 methasone
trial of intravenous dexa- ing physician. n 64 Controlling for treatment assign-
methasone to prevent n 126 Age, mean (SD), years 35 (11) 34.6 (10) ment, relapse was more
relapse in acute migraine Mean age (years) 35 common when headache pain
M:F ratio 1:4 1:4.55
headache. Headache 2007. M:F ratio 1:4.26 was incompletely relieved
ED, Hospital, Canada. Concealed allocation of patients Relapses at 4872 hours 14/64 (22%) 20/62 (32%) (VAS >2) at ED discharge
was employed and patients Relapses by day 7 18/64 (28%) 25/62 (40%) (OR 2.2; 95% CI: 1.15.4).
were randomized to receive IV (OR 0.6; 95% CI: 0.31.3). ARR of 10 and 12 (in 72 hours and
Dexamethasone (15 mg) or seven days) is clinically signifi-
placebo in a double-blind cant. OR is less valid to analyze
design. effects in this study, as this was
Relapse was defined as return to not a case-control study.
ED, urgent clinic visit, or Relapse was closely associated
headache that precluded with incomplete pain relief at
normal activity reported discharge.
during follow-up telephone Convenience ED sampling; IHS
interviews 4872 hours and criteria applied.
seven days after ED discharge. CONSORT: enrollment, rando-
Intention-to-treat analysis was mization, blinding, allocation,
conducted loss to follow-up, and analysis
wals and dropouts)
(continued)
9
XML Template (2015)
10
Table 1. Continued.
10. Jivad et al. (75) Is dexa- DHE 1 mg IV or dexamethasone Mean headache score DHE Dexamethasone (n 36) Non-inferior outcomes for dexa-
methasone a suitable 8 mg IV (n 36) 8 mg IV methasone
alternative for dihydroer- n 72 1 mg IV Convenience sampling ED setting
gotamine on migraine M:F ratio 1:2.6 Baseline 12.9 1.6 12.7 1.9 20 patients on DHE had side
attacks? International Mean age N/A effects, i.e. chest tightness,
At 10 minutes 7.6 2.6 8.6 2.2
Journal of Pharmacology Age range 15-55 hypertension, claudication, and
At 30 minutes 3.3 1.9 4.3 2.6
[7.1.201510:03am]
2005. ED, Hospital, Iran. No differences in duration and vomiting.

frequency of headaches No patients on dexamethasone
between two arms at baseline showed side effect.
IHS criteria applied Lowering of headaches as early as
Outcome: Headache severity 10 minutes among dexa-

using McGill method on 115 methasone arm suggests
scale method at baseline, 10 another mechanism apart from
(CEP)
minutes, 30 minutes. anti-inflammation.

Non-randomized design lacking
blinding may introduce bias;
CONSORT checklist not
mentioned; Jadad scale indi-
[PREPRINTER stage]
[129]
cates poor score.

11. Taheraghdam et al. (76) Double-blinded, randomized, Dexamethasone Morphine Favorable outcomes for dexa-
Intravenous dexametha- two-arm (8 mg IV) (n 93) (0.1 mg/kg IV) (n 97) methasone
sone versus morphine in n 190 Convenience sampling ED setting
relieving of acute migraine mean age 44.2 In both groups headaches started
headache. Pak J Biol Sci M:F ratio 1:1.6 to lower within 10 minutes.
2011. ED, Hospital, Iran. IHS criteria applied Difference between means of
1. Dexamethasone 8 mg IV versus Mean age 45.93 42.34 VAS baseline and VAS 10 min-
morphine 0.1 mg/kg IV utes between two arms was
1. M:F ratio 1:1.27 1:2.013
Outcome: Headache severity not statistically significant
1. using VAS at baseline, 10 min- VAS baseline 8.49 1.5 8.75 1.43 (p 0.236, 0.481). Means of
1. utes, 60 minutes, and 24 hours VAS 10 minutes 5.6 1.55 5.39 2.1 VAS 60 minutes and VAS 24
1. VAS 60 minutes 2.33 1.73 2.89 1.45 hours were significantly lower
in dexamethasone group than
1. VAS 24 hours 0.64 0.71 1.03 1.27 in morphine (p 0.017,
0.010).
CONSORT: enrollment, rando-
mization, blinding, allocation,
loss to follow-up, and analysis
wals and dropouts)
(continued)
Cephalalgia 0(0)
XML Template (2015)
Table 1. Continued.
Woldeamanuel et al.
12. Fiesseler et al. (77) Randomized double-blind, two- Steroids (n 94) Placebo (n 87) Favorable outcomes for dexa-
Steroids for migraine armed, placebo-controlled Dexamethasone methasone and prednisolone
headaches: A randomized n 181 (n 46), prednisolone for recurrent headache
[7.1.201510:03am]
double-blind, two-armed, mean age 37 (n 48) Non-inferior results for acute

placebo-controlled trial. J M:F ratio 1:6.14 Age (years) 37 (SD 10) 38 (SD 10) attack management
Emerg Med 2011. ED, IHS criteria applied in 86% ED setting convenience sample
Hospital, NJ, USA. Dexamethasone (10 mg IV) if IV used.
Male 12 (7%) 13 (7%)

access was used or prednisone Discharge VAS 0100 while arrival
(40 mg by mouth 2 days) if 010.
Female 82 (45%) 74 (41%)
(CEP)
no IV access was obtained. Study could have benefited from

Each medication was matched M:F ratio 1:6.83 1:5.7 separately analyzing predniso-
with identical-appearing pla- Arrival VAS (mean 010) 8.9 8.9 lone and dexamethasone out-
cebo. Discharge VAS (mean 0109) 2.5 2.7 comes
Patients were contacted 2472 ARR of 10% on headache recur-
Discharge VAS 0 13 10
hours after ED visit to assess rence at 2472 hours.
[PREPRINTER stage]
[129]
headache recurrence. Returned to ED 15 11 CONSORT: enrollment, rando-

Thought needed added 33 36 mization, blinding, allocation,
treatment loss to follow-up, and analysis
Mean patient satisfaction 4.9 4.7 methods clearly explained
Patient felt needed further 43 48
work-up
Recurrent headache at 2472 20/91 (22%) 26/82 (32%) wals and dropouts)
hours (95% CI 13.530.5) (95% CI 21.942.1)
13. Donaldson et al. (78) IV Multicenter, double-blinded, pla- Recurrence of migraine Dexamethasone Placebo (n 55) Favorable outcomes for dexa-
dexamethasone vs placebo-controlled randomized, headache (n 40) 24 mg IV methasone
cebo as adjunctive therapy two-arm Mean age 37.48 35.17 ED setting convenience sample
to reduce the recurrence n 95 used.
M:F ratio 1:6.69 1: 2.7
rate of acute migraine M:F ratio 1:4.23 ARR of 10% at three-day and 5%
headaches: A multicenter, Mean age (years) 36.33 At three-day follow-up 35% 45% at 30-day follow-up. Small
double-blinded, placebo- IHS criteria applied (95% CI 24%-48%) (95% CI 31%-60%) sample size.
controlled randomized placebo or 24 mg dexamethasone At 30-day follow-up 19 (47.5%) 24 (42.9%) CONSORT: enrollment, rando-
clinical trial. Am J Emerg IV mization, blinding, allocation,
Med 2008. ED, Hospital, To ensure generalizability, all loss to follow-up, and analysis
MI, USA. other aspects of patient care methods clearly explained
left to discretion of emergency Jadad scale: 5 rigorous (2 for
physician. randomization, 2 for blinding,
Baseline characteristics and 1 for description of withdra-
adverse event profiles equiva- wals and dropouts)
lent in both study groups.
(continued)
11
Table 1. Continued.
XML Template (2015)
12
14. Bigal et al. (16) A rando- Randomized, double-blind, RI vs DE po RI DE vs RI po RI DE vs DE po Favorable outcomes for dexamethasone
mized double-blind study six-attack crossover study Primary endpoint: 24-hour 62.7% vs 33.3% 81.5% vs 62.7% 81.5% vs 33.3% ARR 19%
comparing rizatriptan, n 35 sustained relief for RI DE vs RI
dexamethasone, and the M:F ratio ARR 48.2%
Secondary endpoint: 24-hour 32.2% 50.7% vs 32.2% 50.7% vs 32.2%
combination of both in the Mean age for RI DE vs DE
sustained pain free vs
acute treatment of men- rizatriptan (RI, 10 mg po) vs Tolerability: More attacks treated with DERI
12.1%
strually related migraine. dexamethasone (DE, 4 mg (33.8%) were associated with side effects,
Headache 2008. Hospital, po); RI DE vs RI; RI compared to RI (18.6%) and DE (15.2%).
[7.1.201510:03am]
NJ, USA DE vs DE AEs were mild, nonspecific, and typical of

35 patients and 190 attacks triptan sensations experienced in previous
IHS criteria applied clinical trials of triptans (drowsiness, aches,
tenderness in the neck, shoulders, and
chest) and of steroids with DE (dyspepsia,

etc.). No serious AEs reported. No special
treatment required for AEs.
(CEP)
CONSORT: enrollment, randomization, blind-

ing, allocation, loss to follow-up, and ana-
lysis methods clearly explained
Jadad scale: 5 rigorous (2 for randomization,
2 for blinding, 1 for description of with-
[PREPRINTER stage]
[129]
drawals and dropouts)
15. Rabe et al. (79) Randomized, double-blind, Prednisolone/5 days Placebo/5 days (n 48) Favorable outcomes for prednisolone.
Prednisone for the treat- placebo-controlled, paral- 100 mg po (n 48)
ment of withdrawal head- lel designed multicenter Mean age 43.2 40 All patients reported decline in narcotic use.
ache in patients with trial Benefit from each infusion lasted more than
M:F ratio 1:11.3 1:3.56
medication overuse head- n 96 two weeks.
ache: A randomized, M:F ratio 1:5.5 Primary endpoint: 20.9 18.2 All patients reported improved quality of life.
double-blind, placebo- Mean age 41 years Hours with severe or mod- Three patients did not respond.
controlled study. IHS criteria applied erate headache within first CONSORT: enrollment, randomization, blind-
Cephalalgia 2012. Prednisolone 100 mg or pla- three days ing, allocation, loss to follow-up, and ana-
Headache Centers and cebo for five days Secondary endpoint: 29.6 27.7 lysis methods clearly explained
Neurology Department, Data on 18 patients not Hours with severe or mod- Jadad scale: 5 rigorous (2 for randomization,
Germany. complete because of erate headache within five 2 for blinding, 1 for description of with-
patients not returning or days drawals and dropouts)
not completing their Hours with severe or mod- 74.9 69.8
headache diaries erate headache within 14
days
Rescue medication (intake 3.6 6.4
frequency) within 14 days
Rescue medication (intake 1.1 2.3

frequency) within first five
days
Further withdrawal symp- 39.2% 27.8%
toms (nausea, vomiting,
photo-, phono-, osmo-
Cephalalgia 0(0)
phobia) within five days
(continued)
XML Template (2015)
Table 1. Continued.
16. Askari et al. (80) Pulse IV Patients who failed migraine Primary efficacy endpoints: Favorable outcomes for IV methylpredni-
steroid and IV valproate therapy with or without nar- 13 patients were treated. solone
combination therapy for cotic use for >12 months 10 patients showed >50% decline in severity and frequency Patients with chronic headaches having
Woldeamanuel et al.
sustained relief of chronic, were selected for treatment (pain scale declined from 89/10 to 34/10). depression and/or bipolar disorder can
treatment refractory with IV methylprednisolone More than 60% decline was reported in the frequency of related ER visit. show significant benefit from pulse
headaches in patients with 500 mg and IV valproate 1 g. All patients reported decline in narcotic use. therapy by IV methylprednisolone and
psychiatric disorders. All patients also had bipolar dis- Benefit from each infusion lasted more than two weeks. IV valproic acid administered every
Neurology 2010. Hospital, order or depression. All patients reported improved quality of life. three weeks.
[7.1.201510:03am]
MO, USA Medications were kept constant Three patients did not respond. Improves patients quality of life, decreases
up to three months after infu- ER visits and saves cost.
sions. Non-randomized design lacking blinding
Stat bolus of IV valproic acid, may introduce bias. CONSORT
immediately followed by IV checklist not mentioned; Jadad scale

infusion of methylprednisolone indicates poor score.
(CEP)
500 mg was administered over

60 minutes and repeated every
three weeks.
17. Tfelt-Hansen et al. (81) Randomized, double-blind, and Frequency of post-GTN Prednisolone (n 15) Placebo (n 15) Favorable outcomes for prednisolone.
Prednisolone reduces placebo-controlled, two-arm, migraine in first 90 min- 150 mg All participants had been headache free for
[PREPRINTER stage]
[129]
nitric oxide-induced crossover study utes IHS criteria three days, and had to refrain from
migraine. Eur J Neurol N 15 Intensity (peak) of post-GTN 4/15 9/15 caffeine containing and alcoholic bev-
2009. Hospital, Denmark Mean age 39.1 years headache in first 90 erages, smoking as well as OTCs for 12
M:F ratio 1:14 minutes hours prior to study start. The patients
15 migraineurs with migraine were examined with a minimum of
Intensity (summed) of post- 2 (05) 3 (07)
without aura were pre-treated three-week intervals and at a fixed time
GTN headache in first 90
with 150 mg of prednisolone of examination, 08.00 hours.
minutes
or placebo followed by a 20- One patient felt a slight, passing headache
minute infusion of glyceryl tri- Intensity (peak) of post-GTN 6 (017) 15 (055) when bending forward after each
nitrate (GTN) (0.5 ug/kg/min). headache in 12 hours intake of prednisolone, one patient felt
One hour after GTN infusion, Time to first migraine attack 2 (08) 4 (08) slightly nauseated after intake of pla-
participants were sent home, Intensity (summed) of post- 6 hours 3.2 hours cebo.
but continued to rate head- GTN headache in 12 (70 minutes13 hours) mean (10 miutesn12 hours) GTN infusion caused moderate hypoten-
ache and possible associated hours sion in one and severe hypotension in
symptoms by filling out a Triptans as rescue medication 0 to 40 0 to 53 (18) another patient, reversed by raising the
headache diary every hour for (mean of 7) foot end of the beds. One patient had
12 hours. polypnoea during GTN infusion, and
OTC as rescue medication 3 7
IHS criteria applied another felt tiredness after GTN infu-
sion, both on placebo day.
Prednisolone could exert its effect via
inhibition of COX-2,
CONSORT: enrollment, randomization,
blinding, allocation, loss to follow-up,
and analysis methods clearly explained.
Jadad scale: 5 rigorous (2 for randomi-
zation, 2 for blinding, 1 for description
of withdrawals and dropouts).
(continued)
13
XML Template (2015)
Table 1. Continued.
14

18. Innes et al. (82). Randomized, double-blind, two- Dexamethasone (24 mg IV) Placebo Favorable outcomes for dexamethasone:
Dexamethasone prevents centered; IHS criteria applied n 49 n 49 ARR of 27% for severe headache.
relapse after emergency n 98 Mean age (years) 34 36 Lack of standardized abortive therapy
department treatment of Mean age 35 years could conceivably introduce a bias if
M:F ratio 1:2.77 1:6
acute migraine: a rando- M:F ratio 1:4.44 one group received different treatment
mized clinical trial. CJEM Dexamethasone (24 mg IV) or Severe (classes A and B) 9 of 49 (18%) 22 of 49 (45%) from the other. But randomization
1999. ED, Canada. placebo. recurrent headache 48 to (OR 0.28; 95% CI: 0.11 to 0.69) seemed to balance this. Abortive ther-
[7.1.201510:03am]
Patients recorded headache 72 hours later apy included: antiemetics, IV nonster-

severity on VAS at time T 0, class A 0 11 oidal agents, DHE or opioids. Placebo
T 30 minutes and T 60 class B 9 11 recipients more likely to be female;
minutes and at discharge. class C 11 7 other baseline characteristics similar

They were contacted 4872 hours between groups.
class D 12 4
later and asked whether they OR use validity may not be appreciable as
(CEP)
had suffered a recurrence of this was not a case-control study.

their headache, categorized as Convenience sampling from ED setting
class A (severe, provoking may create unrecognized bias.
another physician visit), class B CONSORT: enrollment, randomization,
(severe, interfering with daily blinding, allocation, loss to follow-up,
[PREPRINTER stage]
[129]
activity but not provoking a and analysis methods clearly explained.

physician visit), class C (mild, Jadad scale: 5 rigorous (2 for randomi-
requiring self-medication but zation, 2 for blinding, 1 for description
not limiting activity) or class D of withdrawals and dropouts).
(mild, requiring no treatment).
19. Be et al. (83) Randomized, double-blind, pla- Prednisolone (n 49) Placebo (n 48) Non-inferior favorable outcomes for pre-
Prednisolone does not cebo controlled. study Age, years 43.2 (39.846.8) 41.3 (38.145.5) dnisolone.
reduce withdrawal head- n 97 Mixture of tension headaches to migraine
ache. A randomized, M:F ratio 1:2.85 assessment
Total days of headache during 25.0 (23.426.7) 25.7 (24.227.1)
double-blind study. Mean age (years) 42.25 Follow-up for six days.
last 30 days before
Neurology 2007. Hospital, IHS criteria applied CONSORT: enrollment, randomization,
withdrawal
Norway. Placebo vs prednisolone 60 mg blinding, allocation, loss to follow-up,
oral on days 1 and 2, 40 mg on Headaches during first six Mean headache score 1.6 (1.41.8) 1.5 (1.31.7) and analysis methods clearly explained.
days 3 and 4, and 20 mg on days after withdrawal Jadad scale: 5 rigorous (2 for randomi-
days 5 and 6 Days with zero or mild 3.1 (2.53.6) 2.7 (2.13.2) zation, 2 for blinding, 1 for description
Sixty-five had migraine, 13 had headache of withdrawals and dropouts).
tension-type headache, and 22 Days with moderate or 2.9 (2.43.5) 3.4 (2.83.9)
had both migraine and tension- severe headache
type headache. Days without headache 1.1 (0.71.6) 1.1 (0.61.6)
(continued)
Cephalalgia 0(0)
XML Template (2015)
Table 1. Continued.
20. Friedman et al. (84) Randomized, double-blind, placebo- Dexamethasone 10 mg IV Placebo (n 99) Favorable outcomes for dexamethasone
Woldeamanuel et al.
Randomized trial of IV controlled multicenter, two-arm, (n 106) Side effect profiles were similar, with
dexamethasone for acute dexamethasone 10 mg IV or pla- exception of acute medication reac-
migraine in the emergency cebo tions, which occurred more commonly
department. Neurology n 205 in dexamethasone group.
2007. ED, Hospital, NY, Mean age 36.5 years ARR 6% in headache recurrence reduction
[7.1.201510:03am]
USA. M:F ratio 1:5.61 24 hours

1. IHS criteria applied Mean age (years) 36 37 ARR 25% in headache recurrence reduc-
All patients (n 205) received 20 mg tion 72 hours
1. M:F ratio 1:4.58 1:7.25
IV metoclopramide and 2.5 mg Study results generalizability is limited

1. diphenhydramine (both mixed in Persistent pain-free outcome 25% 19% because all received metoclopramide
50 ml normal saline, run-in 20 of 24 hours (primary and diphenhydramine.
(CEP)
minutes) following dexametha- outcome) Convenience ED sampling

1. sone/placebo. No functional impairment 67% 59% CONSORT: enrollment, randomization,
Patients were asked to characterize after ED discharge (24 blinding, allocation, loss to follow-up,
migraine pain as none, mild, hours) and analysis methods clearly explained.
1. moderate or severe. Scale was Persistent pain free among 38% 13% Jadad scale: 5 rigorous (2 for randomi-
[PREPRINTER stage]
[129]
administered at baseline and every migraine >72 hours zation, 2 for blinding, 1 for description
30 minutes until two hours had of withdrawals and dropouts).
elapsed. This scale was then admi-
nistered by telephone 24 hours
after medication administration.
Functional impairment scale: patients
described their disability as 1)
none; 2) mildly impaired (having a
little bit of difficulty doing what I
usually do); 3) moderately
impaired (having a great deal of
difficulty doing what I usually do
and can only do very minor activ-
ities); or 4) severely impaired
(requiring bed rest).
Two patients from dexamethasone
group did not complete study.
Persistent pain free required partici-
pants to attain a pain level of none
on this categorical scale before
two hours had elapsed in the ED
and to maintain level of none
throughout post-ED discharge
period.
(continued)
15
Table 1. Continued.
XML Template (2015)
16
21. Krymchantowski et al. Prospective randomized open- Prednisone PO (60 mg/ No regular medications Naratriptan (2.5 mg Non-inferior outcome for pre-
(85) Out-patient detoxifi- label trial; IHS criteria applied day two days, 40 mg/ to take for first six twice a day) for first dnisolone
cation in chronic migraine: 150 chronic migraine patients day two days and days (n 50) six days (n 50) Comparable results of headache
Comparison of strategies. (125 women, 25 men; ages 18 20 mg/day two days) frequency reduction among
Cephalalgia 2003. 80 years, mean 40.3 13.8) for first six days three arms during five weeks
Outpatient, Hospital, Rio with overuse of symptomatic (n 50) post-intervention
de Janeiro, Brazil medication divided into three Open-label nature of study may
1. study arms n 50 each Baseline percentage of seven- 27 (54%) 23 (46%) 25 (50%) introduce bias
Mean age 40.3 years day headache Showed efficacy of steroids in a
[7.1.201510:03am]
M:F 1:5 non-ED setting i.e. outpatient

1. Adherence to treatment after 44 (88%) 41 (82%) 35 (70%)
In each group, 50 patients setting; this helps save costs
five weeks
received education and orien- and time associated with ED-
1. tation and were then abruptly Baseline headache frequency 27 (54%) 23 (46%) 25 (50%) setting therapy or inpatient
withdrawn from all sympto- seven days per week for hospitalization.
matic medication. last four weeks No major side effects
(CEP)
1. All patients had similar profiles of Baseline headache intensity: 13 (26%) 12 (24%) 21 (42%) CONSORT: enrollment, rando-
headache characteristics and severe headache mization, allocation, loss to
1. consumption (quality and Total number of headache 264 246 210 follow-up, and analysis meth-
quantity) of symptomatic days during the first 6 days ods clearly explained; blinding
1. medication before initiation of Absence of headaches during 69 (26.2%) 62 (25.2%) 62 (29.5%) not performed.
treatment, but most were not Jadad scale: 3 (2 for randomiza-
[PREPRINTER stage]
[129]
the first 6 days

severe headache sufferers, (refers to the total number of tion, 0 for blinding, 1 for
heavy medication overusers or days considering the total description of withdrawals and
were overusing opioids. number of six-day periods dropouts).
Day 7 onward: For all patients: Six among all patients who
initial days: (atenolol 10 mg returned in all three
nortriptyline 4 mg flunari- groups.
zine 1 mg) capsules. Six fol-
1. Number of patients with 36 (81.8%) 40 (97.5%) 24 (68.6%)
lowing days: (atenolol 20 mg
withdrawal symptoms
nortriptyline 8 mg flunarizine
during first six days
2 mg) capsules. Four following
1. weeks: (atenolol 30 mg Headache frequency reduc- From week 3 onward From week 2 onward From week 3 onward
nortriptyline 16 mg flunari- tion of >50%
1. zine 2.5 mg) capsules. Headache frequency reduc- 66% 57.1%
After five weeks headache fre- tion of >50% after five 63.4%
quency and intensity, preva- weeks
lence and frequency of
withdrawal symptoms and
consumption of rescue medi-
cations during first six days
were compared between
groups.
Adherence to treatment (who
returned or not and for which
reasons, between groups) and
headache frequency, week by
week, among the groups of
patients were also compared.
Cephalalgia 0(0)
(continued)
XML Template (2015)
Table 1. Continued.
Woldeamanuel et al.
22.Krymchantowski et al. Prospective, single-arm study Baseline (two months previous to study) 30 days after treatment Favorable outcome for predniso-
(86). Prednisolone as using six-day course of oral 24 headache days/30 days 176 (44%) lone
initial treatment of prednisone taper, comparing Showed efficacy of steroids in a
25 headache days/30 days 121 (30.2%)
analgesic-induced daily mean headache frequency at non-ED setting i.e. outpatient
headache. Cephalalgia baseline with mean frequency 26 headache days/30 days 56 (14%) setting, helps save costs and
[7.1.201510:03am]
2000. Tertiary headache after 30-day period 27 headache days/30 days 26 (6.5%) time associated to ED-setting
center, Rio de Janeiro, n 400; 318 women and 82 men; 28 headache days/30 days 169 (42.2%) 21 (5.2%) therapy or inpatient hospitali-
Brazil M:F ratio 1:3.88; mean age 29 headache days/30 days 132 (33%) zation.
38 years (1964); sequential Not randomized, not blinded
30 headache days / 30 days 99 (24.8%)

selection No major side effects
all presented with headache for Inadequate description to assess
(CEP)
>28 days per month for using CONSORT checklist and

longer than six months Jadad scale.
mean baseline headache
frequency 0.96 (calculated
considering number of head-
ache days divided per 30-day
[PREPRINTER stage]
[129]
period of each patient and

taking into account mean
number for all patients) during
previous two months
mean headache intensity 1.9
(using analog scale of 0none,
1mild, 2moderate,
3severe)
average daily headache duration
was four to eight hours during
previous two months
Exclusion criteria: barbiturate,
benzodiazepine, opioid habi-
tuation; cardiovascular, cere-
brovascular, hematopoietic
diseases, active peptic disease,
basilar migraine, medical and
psychiatric comorbidities
According to patients own judg-
ment: 319 (79.7%) patients had
frequent presence of anxiety
and/or depression; 281
(70.2%) reported sleep distur-
bances
Method of intervention:
Instructed to suddenly stop over-
used medications.
(continued)
17
XML Template (2015)
18
Table 1. Continued.
Stop gradually over period of

seven days preventive medica-
tions that were being taken.
Take only prednisone and raniti-
dine for first six days and pre-
ventive medications afterward.
[7.1.201510:03am]
Dosage of prednisone, oral:

60 mg/day for two days, 40 mg/
day for two days, 20 mg/day
for two days plus ranitidine
300 mg /day
23. Kaniecki (87). Sample size: total n 1654, 2758 Response on intent-to-treat analysis Patients with AEs necessitat- Favorable outcome for dexa-
(CEP)
Management of status instances of status migrainosus ing withdrawal from study methasone
migrainosus with IHS criteria employed for all Three days of oral dexa- 90.3% (n 851) 37 Superior results showing efficacy
dexamethasoneA pro- patients with migraine attacks methasone (n 942, of three-day dexamethasone
spective comparison extending beyond 72 hours. instances) course to be superior than
versus methylergonovine Only patients using triptans as ergots or symptomatic non-
Three days of oral methyler- 81.6% (n 734) 58
[PREPRINTER stage]
[129]
and symptomatic care. abortive were included. steroidal care (ARR 9.3,
gonovine (n 900)
Headache 2006. University Patients with headaches lasting 19.3).
Hospital, Headache more than seven days were No additional care (n 916) 70.6% (n 696) 14 Adequate randomization; blinding
Center, Pittsburgh, PA, excluded. information not available;
USA All patients instructed to use attrition rate not fully
symptomatic agents etodolac explained.
for pain (400 mg tid prn) and CONSORT: enrollment, rando-
metoclopramide for nausea mization, allocation, and ana-
(10 mg tid prn). lysis methods clearly
Random and prospective assign- explained.
ment of patients to one of Jadad scale: 2 (2 for randomiza-
three treatment arms: tion, 0 for blinding, 1 for
- three days of dexamethasone description of withdrawals and
(4 mg tid, bid, qd each for one dropouts).
day)
- three days of methylergonovine
(2 mg tid, bid, qd each for one
day)
- no additional care.
Response defined as complete
resolution of migraine pain
within three-day treatment
phase (primary endpoint).
(continued)
Cephalalgia 0(0)
XML Template (2015)
Table 1. Continued.
24. Kopjas et al. (88). 112 selected patients (81 females In around 90% of patients, severity of migraine headache subsided in an Favorable outcome for IV dexamethasone.
Woldeamanuel et al.
Migraine treatment with and 31 males, M:F ratio of average of two hours after slow IV dexamethasone injection. Study showed efficacy of IV dexamethasone administered
dexamethasone. Headache 1:2.61, average age of 37 Average headache-free periods after first injection lasted 60 hours. with decreasing frequency of twice a week for
1967. Outpatient, IL, USA years). Second injection increased pain-free period to an average first two weeks, then once a week for two weeks and
Contraindication to steroid of three and one-half days. then once a month for two months.
administration ruled out. Second series of IV injections once a week showed very satisfactory Selection method unclear.
[7.1.201510:03am]
Each patient received IV 4 mg of results in more than 60% of patients. Jadad and CONSORT not applicable.
dexamethasone twice a week Usual daily attacks not noticed for several days, and the experienced
for first two weeks, then once headaches were mild and much shorter in duration.
a week for two weeks and Monthly injections for the two-month period were mostly beneficial
then once a month for two in female patients who were still noticing some headaches
months. around their menstrual periods.
(CEP)
All patients had acute headaches Around 35% of patients returned approximately once every three
with history of an average of months for an intravenous injection, stating that after
five years migraine. the therapy headaches are relieved from six to
Study conducted prior to devel- eight weeks and the intensity is lessened.
opment of IHS criteria.
[PREPRINTER stage]
[129]
25. Frohner (58). Cortisone 20 patients with migraine included Number of patients (%) Outcome Favorable outcome for oral cortisone.
in migraine and histamine in study over period of two 9 (45%) Complete dramatic relief two hours Selection criteria not clear.
headaches. Rocky Mt Med J years. post-administration Jadad and CONSORT checklist not applicable.
1953. MT, USA 50 mg of oral cortisone given All patients in this cohort had migraine
when headache was clearly by most rigid study criteria
established
3 (15%) Partial relief with headache recurrence
Study design not clear.
Objective outcome measurands 8 (40%) No benefit
not clearly described. This cohort was suspected to have probable
Study conducted prior to devel- tension headache on closer,
opment of IHS criteria. more rigid re-examination
First author, title of article, name of journal, year of publication, and study setting are described in the first column. The second column provides important methods employed for study design. Outcomes
are fully elaborated in the third column. Critical appraisals, clinical bottom lines, Consolidated Standards of Reporting Trials (CONSORT) and Jadad scale are presented in the last (fourth) column. M: male; F:
female; IHS: International Headache Society; tid: three times per day; prn: as needed; IV: intravenously; ED: emergency department; VAS: visual analog scale; CI: confidence interval; OTC: over-the-counter;
po: orally; ER: emergency room; GI: gastrointestinal; ARR: absolute risk reductions; NSAIDs: nonsteroidal anti-inflammatory drugs; RR: relative risk; OR: odds ratio; DHE: dihydroergotamine; AEs: adverse
events.
19
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20 Cephalalgia 0(0)
In the systematic reviews and meta-analysis

Methodological Quality of Included Studies appraised in this study, the objectives and inclusion
assessed using Jadad score
criteria were clear among all. Relevant sources were
60%
searched without restriction by language or publication
50% status. Steps were taken to minimize bias and error by
40% Percentage of Studies having more than one reviewer independently conduct
study selection, validity assessment and data extraction.
30%
Appropriate statistical methods were used to combine
20% studies and to assess for heterogeneity and publication
10% bias. Potential biases and sources of confounding were
well addressed in the text. Although the trials were
0%
5 3 0 small, they were of acceptable quality and their results
re re re
s co s co s co were consistent. All systematic reviews were well con-
d ad d ad d ad
Ja Ja Ja ducted and the authors conclusions appear reliable. All
systematic reviews and meta-analyses revealed the
Figure 2. Methodological quality of included studies as assessed
importance of adjuvant corticosteroids to various
using the Jadad score. The Jadad score measures adequacy of abortive medicationsindicating generalizability of
reported randomization, blinding, and management of withdrawals results. Three meta-analyses showed that a single dose
and dropouts. Fourteen studies (56%) had a Jadad score (63) of 5, of adjuvant parenteral dexamethasone was associated
and fulfilled the complete CONSORT (64) checklistindicating with 11.1% ARR (absolute risk reduction), NNT of 9,
rigorous methodological quality; two studies (8%) had a Jadad score and 26% RRR for 72-hour headache recurrence. The
3, and missed blinding from the CONSORT checklistindicating fourth meta-analysis indicated that parenteral dexa-
adequate methodological quality; four studies (16%) had a Jadad methasone delivered the highest ecacy. Adverse
score of 0 and did not fulfill any of the CONSORT checklist. eects were tolerable.
Cumulative evidence from our systematic review
outcomes for corticosteroids (Figure 4). Median absolute shows that higher disability, prolonged migraine dur-
risk reduction was 30% (range 6%48.2%), and 11% ation, status migrainosus, incomplete pain relief, and
(6%48.6%) for 24-, and 72-hour headache recurrence headache recurrence were the settings in which cortico-
(Figure 3(a)), making the NNT 3.3, and 9.1 for 24-, and steroids were benecial. One study indicated that abort-
72-hour headache recurrence (Figure 3(b)), respectively. ive medications that were ineective prior to
Parenteral dexamethasone was the most commonly used dexamethasone became eective subsequently (61).
(14 studies, 56%) corticosteroid. Dexamethasone was Among the ED-based studies, there was an increased
administered with an average single dose of 12.8 mg chance of headache recurrence among patients with
(range 424 mg; interquartile range 816 mg; median 10; higher levels of pain at ED discharge than among
mode 8, 10 mg) (Figure 5). All the ED-based studies used patients with lower levels of pain at ED discharge;
parenteral dexamethasone, and showed favorable this may indicate that migraine attacks treated when
observed outcome ecacy of dexamethasone. One the pain is mild are less likely to recur. One randomized
study used 500 mg intravenous methylprednisolone. double-blind study showed that adjunctive dexametha-
Ten of the 13 non-ED-based studies administered oral sone resulted in higher sustained relief periods as com-
corticosteroids, nine of which showed favorable observed pared to triptan monotherapy (16).
outcome ecacy. Two studies administered 4 mg oral
dexamethasone; one study used 8 mg oral dexametha-
sone; another study used a ve-day course of 100 mg
Discussion
oral prednisolone; three studies used a six-day Migraine recurrence is commonly observed following
tapering course of oral prednisolone 60 mg on days 1 successful ED management. Various clinical features
and 2, 40 mg on days 3 and 4, 20 mg on days 5 and 6; have been associated with poor pain outcomes after
one study administered pre-treatment with 150 mg oral treatment for headache. In the outpatient setting, a
prednisolone; one study administered a three-day patients history of headache-related functional disabil-
course of oral dexamethasone (4 mg three times per day ity can be used to predict long-term medication needs
(tid), twice per day (bid), once per day (qd) each for prospectively and to decrease the economic burden of
1 day); and one study administered a single oral dose of illness. Some ED patients cannot access neurology or
50 mg cortisone (Figure 6). Parenteral dexamethasone headache specialty care. Timely primary care appoint-
(56%), oral prednisolone (12%), and oral dexamethasone ments can also be dicult to obtain, and ED patients
(8%) were the top three common steroid forms adminis- frequently fail to appear for scheduled appointments.
tered, in descending order (Figure 6). Therefore, it is important for the emergency physician
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Table 2. Comprehensive summary of included systematic reviews and meta-analysis.
First author, title of article, name of Systematic review,

journal, year of publication meta-analysis results Clinical bottom lines
Neill A et al. (89) Towards evidence-based Two systematic reviews with meta-analysis of seven randomized Patients who have received successful abortive
emergency medicine: Best BETs from the controlled trials each; total of 738 and 742 patients each; out- treatment for migraine in the ED should be
Woldeamanuel et al.
Manchester Royal Infirmary. BET 2: come: recurrence of headache at 24 hours; key results: recur- considered for a single dose of IV dexametha-
Dexamethasone for reduction of migraine rent headache reduction RR of 0.74 (95% CI 0.600.90) and sone before discharge to reduce risk of recur-
recurrence. Emerg Med J 2013. 0.87 (95% CI 0.800.95). rence, in absence of any of usual relative
contraindications to steroid therapy.
[7.1.201510:03am]
Colman et al. (5). Parenteral dexamethasone Seven randomized controlled double-blinded studies. When added to standard abortive therapy for
for acute severe migraine headache: Meta- All trials used standard abortive therapy and subsequently migraine headache, single-dose parenteral
analysis of randomized controlled trials for compared single-dose parenteral dexamethasone with placebo, dexamethasone is associated with 26% relative
preventing recurrence. BMJ 2008. examining pain relief and recurrence of headache within 72 reduction in headache recurrence (number
hours. Dexamethasone and placebo provided similar acute pain needed to treat9) within 72 hours.
(CEP)
reduction (weighted mean difference 0.37, 95% CI 0.200.94).

Dexamethasone was, however, more effective than placebo in
reducing recurrence rates (fixed-effects weighted RR of 0.74,
95% confidence interval 0.60 to 0.90). Similar side effect profiles
[PREPRINTER stage]
[129]
between dexamethasone and placebo groups.

Huang et al. (90). Steroids for preventing Eight studies with 905 patients were included. Pooled analysis When steroids are added to standard abortive
recurrence of acute severe migraine head- showed that when steroids were added to standard abortive therapy for migraine headaches, they are
aches: A meta-analysis. Eur J Neurol 2013 therapy they reduced rate of moderate or severe headache effective and safe for preventing moderate or
recurrence after 2472 hours of follow-up evaluation (RR severe headache recurrence.
0.71; 95% CI 0.590.86). No significant benefit of steroids
compared with placebo in proportion of totally resolved
migraines (RR 1.11; 95% CI 0.941.32). Side effects of
steroids are mild and not significant except for dizziness.
Subgroup meta-analysis showed parenteral dexamethasone
tends to be more effective in reducing moderate or severe
recurrent headaches (RR 0.68; 95% CI 0.550.84).
However, no significant differences found between oral admin-
istration and parenteral administration of steroids (p 0.37).
Singh et al. (91). Does the addition of dexa- Seven ED-based randomized, controlled trials involving 742 Dexamethasone is efficacious in preventing
methasone to standard therapy for acute patients. Pooled results suggest a modest but significant benefit headache recurrence and safe when added to
migraine headache decrease the incidence when dexamethasone is added to standard antimigraine therapy standard treatment for management of acute
of recurrent headache for patients treated to reduce rate of patients with moderate or severe headache migraine headache in the ED.
in the emergency department? A meta- on 24- to 72-hour follow-up evaluation (RR 0.87, 95% CI
analysis and systematic review of the lit- 0.800.95; absolute risk reduction 9.7%). The treatment of
erature. Acad Emerg Med 2008. 1000 patients with acute migraine headache using dexametha-
sone in addition to standard antimigraine therapy would be
(continued)
21
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22 Cephalalgia 0(0)
former further included a meta-analysis of adverse events, while the latter provided symmetric inverted funnel plots to describe the lack of systematic difference and publication bias between the larger and
Table 2 displays included systematic reviews and meta-analysis (first author, title of article, name of journal, and year of publication in the first column), important results of clinical relevance combined from
dexamethasone compared to placebo with standard abortive therapy. The review by Neill and Brannigan further discussed the weaknesses of three selected RCTs. RR: relative risk; CI: confidence interval;
the statistical analysis (second column), and clinical bottom lines (third column). The systematic reviews by Colman et al. and Singh et al. included the same seven randomized-controlled trials (RCTs); the
to understand the magnitude of post-discharge head-
ache and to identify which patients are most at risk.
the smaller study effect sizes. The systematic review by Huang et al. included one more RCT than the seven; this study added a meta-analysis elucidating the superiority of adjunctive parenteral
Having this information can be used to guide choice
of medication, discharge instructions, and urgency of
specialty referral.
During this study, we did not perform a sub-analysis
of outcomes depending on the type of abortive treat-
ment used because, in the real world, dierent drug
combinations are often required and because all
Clinical bottom lines
patients do not respond to a standard regimen. Lack

of standardized abortive therapy could conceivably
introduce a bias if one group received dierent treat-
ment from another. Moreover, patients often know
what agents work best for them, and physicians often
have treatment preferences. We felt that mandating
specic abortive therapies would make the study more
complex, and would not emulate clinical heterogeneity
in practice. Given the inter-study dierences in design,
expected to prevent 97 patients from experiencing outcome of
luation. Sensitivity analysis yielded similar results with sequential
for overall result. Adverse effects related to administration of a

trial elimination, indicating that no single trial was responsible
in methodology, and in outcome and ecacy measur-

moderate or severe headache at 2472 hours after ED eva-
ands, we were not able to perform statistical heterogen-

single dose of dexamethasone were infrequent, mild and
eity and weighted meta-analysis tests.

The fact that dexamethasone recipients suered
fewer severe recurrences and had fewer repeat physician
visits (73,74,80,82) suggests that there are quality-of-life
and productivity benets to this therapy; performing
formal economic analysis and demonstrating these
benets will further support this notion. While being
ecacious in both situations of reducing headache
recurrence and acute headache attacks, corticosteroid
administration showed higher potency in the former,
i.e. controlling headache recurrence (Figure 4).
Parenteral administration within the ED setting
meta-analysis results
Systematic review,
using single-dose intravenous dexamethasone at 10 mg

shows adequate ecacy in controlling attacks, and
transient.
transferring care to the outpatient. Parenteral adminis-

tration can be useful to avoid poor drug absorption
secondary to gastric stasis commonly experienced by
chronic migraineurs. In the outpatient setting, six to
eight short, oral, tapering courses of steroids per year
with close follow-up of adverse eects shows ecacy; it
is essential to note that corticosteroid administration is
intended to control acute, severe attacks in an eort to
smoothe transfer of care to better acute care and/or
ED: emergency department; IV: intravenously.
preventive management targets (92).

First author, title of article, name of
Being a long-acting corticosteroid with a biologic

half-life of 3672 hours (93,94), dexamethasone should
eectively suppress inammation during the period
journal, year of publication
when patients are most likely to experience a headache

recurrencepotentially making it an ideal agent for a
Table 2. Continued.
one-time administration before ED discharge. At

equipotent anti-inammatory doses, dexamethasone
almost completely lacks the sodium-retaining property
of hydrocortisone, minimizing unwanted side eects. In
our review the incidence of minor eects was rare and
was similar to placebo, with no reported severe adverse
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(a) Absolute Risk Reduction (ARR) (b)

in Headache Recurrence NNT (Number Needed to Treat) measurand
60 for effectiveness of corticosteroids in reducing
24-hour and 72-hour headache recurrence
40
ARR %
72-hour
20
0 NNT
24-hour
u r ur
-ho -ho
24 72
Migraine Headache Recurrence 0 2 4 6 8 10 12
Figure 3. (a) Median headache reduction (shown by horizontal dotted lines) was found to range from 30% in 24-hour to 11% in
72-hour respectively following administration of corticosteroids. Error bars indicate interquartile range (IQR) values; two studies each
from both 24-hour and 72-hour comparison were found to be outliers to the IQR. (b) Similar to the results displayed on Figure 3a,
the Numbers Needed to Treat (NNT) was found to be 3 for 24-hour and 10 for 72-hour headache recurrence.
120%
Stratification of the included
clinical studies as per their
100% primary outcome measures of
either reduction of headache
21.40%
recurrence or acute headache-
80% 38.80% to compare between proportion
of superior and non-inferior
outcomes in each strata.
60%
Non-inferior outcomes for

40% 78.60%
corticosteroids
61.20%
Observed outcome differences
20% favoring superior benefits of
corticosteroids
0%
Headache Recurrence Reduction Acute Headache Reduction
Figure 4. Nineteen studies (76%) indicated observed outcome differences favoring benefits of corticosteroids, while six (24%)
studies indicated non-inferior outcomes for corticosteroids. Stratifying the studies to those that addressed headache recurrence (56%)
and acute reduction of migraine attacks (68%), respectively, revealed that 78.6% and 61.2% of the studies observed favorable outcome
differences indicating benefits of corticosteroids; 21.4% and 38.8% indicated non-inferior outcomes for corticosteroids.
reactions. That outcomes compare favorably both in the those presenting with the rst or worst headache syn-
ED- and non-ED settings indicates that convenience drome alarming the patient and causing the visit to the
sampling is not a likely source of confounding bias; ED. The former comprise the ED-frequenter migraine
this, in fact, further promotes the generalizability of suerers who have been described as sharing certain
benets of steroids for relief of recurrent headache in salient features of emotional decompensation, compul-
both outpatient and ED settings. sive preoccupation with symptoms, and occasional
It is worthwhile to dierentiate migraine suerers manipulative behavior, besides their head pain (19).
presenting to the ED with the last straw headache These refractory patients might be victims of mis-
syndrome of consecutive bouts of headaches from diagnosis, mistreatment, undertreatment, or
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24 Cephalalgia 0(0)
overmedication, while the latter present as a more chal- at the cost of more side eect burden. Always observe
lenging subset of new headache or genuine refractori- for inadequate trial duration, inappropriate dosage and
ness that is dicult to manage with readily available consideration of medication overuse when patients are
medications. Addressing limitations of current therapy not doing well. Using a headache calendar or diary to
is important while monitoring refractory headaches. log headache types and frequency, treatment eective-
Reviewing treatment plans at regular visits and balan- ness, menstrual cycle, ED visits, and other health care
cing short-term pain relief with longer-term goals of visits are essential to the care of migraineurs, especially
disease management needs to be emphasized. dicult-to-manage migraineurs.
Management of expectations is an increasingly import- Dexamethasone causes less uid retention than other
ant tool in handling patients with chronic pain in both steroids due to the fact that it has less mineralocorticoid
the ED and outpatient settings. eect. Because these headaches often recur over the
In patients presenting with frequent migraine days and months following ED discharge, the respon-
attacks, careful selection needs to be made as to sibility of the emergency physician includes identifying
which attack to treat aggressively; this may involve as yet unmet treatment needs and ensuring successful
less convenient but more eective non-oral medications transition of care of these patients to an appropriate
outpatient health care provider. Prior to administering
dexamethasone, it is important to remember the vari-
ous contraindications, i.e. pregnancy, known peptic
Parenteral Dexamethasone
Dosage ulcer disease, diabetes, or systemic fungal infections.
30 Clinicians deciding which medication to prescribe for
Parenteral Dosage of
Dexamethasone, mg
Dosage of parenteral recurrence can therefore be guided by considerations

dexamethasone used among
20 the included studies such as cost, contraindications, adverse eects, and a
patients previous overall experience with the medica-
10 tion. Careful evaluation and management for opioid
administration, barbiturate use, and stressful life
0
events are salient features characteristic of multidiscip-
linary approaches toward a long-term control of pro-
longed and refractory migraine. Where resources are
Figure 5. Dexamethasone was administered with an average available, it is important to use existing opportunities
single dose of 12.8 mg (range 424 mg; interquartile range 816 mg, to optimize emergency care of migraine attacks by real-
shown by error bars; median 10, shown by the dotted horizontal time consultations between the emergency and head-
line; mode 8, 10 mg). ache specialty departments.
Proportion of different forms of corticosteroids adminstered among the included clinical studies
4%
4%
4%
Parenteral Dexamethasone (median 10mg)

12% Pareneral Methylprednisolone (500mg)
Oral Dexamethsone (4mg)
Oral Dexamethasone (8mg)
4% Oral Prednisolone (100mg) 5-day-taper
56% Oral Prednisolone (60-40-20mg) 6-day-taper

4% Oral Prednisolone (150mg)
Oral Dexamethasone (12-8-4mg) 3-day taper
8% Oral Cortisone (50mg)
4%
Figure 6. Parenteral dexamethasone was the most commonly used (14 studies, 56%) corticosteroid. Oral prednisolone (3 studies,
12%) and oral dexamethasone (2 studies, 8%) were the other two common corticosteroid forms administered.
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important component while preparing this systematic

(a) Mean Age (years) review. One of the limitations we faced was the incon-
50
sistent availability of variables, and outcome and e-
45
Mean age (years)
cacy measurands across the dierent included studies.

40 Future studies can benet by providing consistently
35
available data so that weighted meta-analysis, hetero-
Mean age of participants geneity statistics, and meta-regressions can accurately
30 within included studies
be computed, and trends and interactions can easily be
25 detected. Forthcoming studies can elucidate further on
the ecacy dierences between dierent dosages of oral
and parenteral corticosteroid administration, and mix-
(b) M:F ratio ture parenteral infusions. Our recommendations
ratio of female-to-male participants
15
include conducting full clinical studies expanding to
ratio of female-to-male other migraine patient populations apart from pro-
10 participants longed migraine attack cohorts and emergency settings.
5
Broader global utility
0 In lower-resource emergency settings or on an out-
patient basis, where the burden of migraine is increas-
ing and where triptans and parenteral infusion forms of
emergency abortive headache medications (e.g. intra-
Figure 7. (a) Median (37.5 years) and interquartile range venous magnesium, dihydroergotamine, levetiracetam,
(3541 years) of the mean age of all participants (both sexes) and valproic acid) (1,96,97) are unavailable, cortico-
within the included studies. (b) Median (1:4.23) and interquartile
steroids provide ecacious and low-cost therapeutic
range (1:2.16.14) of Male:Female ratio among all participants
options to control prolonged and highly disabling
within the studies included.
migraine attacks. Corticosteroids are readily and inex-
pensively accessible both in oral and parenteral forms
Steroids have been ecacious for detoxication of in lower-resource clinical settings; hence, our study can
overused substances in patients with medication- be help optimize their application in a clinically rele-
overuse headache (MOH) (79,95). Concurrent admin- vant manner.
istration of nonsteroidal anti-inammatory drugs
(NSAIDs) and steroids must be avoided to reduce
potential risk of gastrointestinal bleeding.
Conclusions
Comparison between titration versus bolus dosage of Our literature review suggests that with corticosteroid
dexamethasone administration can aect headache treatment for acute migraine attacks, recurrent head-
recurrence and other outcome measures. Some of the aches decrease, become milder than pretreated head-
studies reviewed herein dened headache recurrence as aches and then may respond to nonsteroidal therapy.
24 hours after headache relief from the study drug, Intravenous dexamethasone provides a reasonable
while others used a 48-hour or longer timepoint. option for managing resistant, severe, recurrent or
Panel A (available online) provides commonly applied prolonged migraine attacks in the ED. Our recom-
denitions of recurrence and ecacy measures; these mendations are consistent with the literature review
terms are inter-related and their consistent use can and include up to six to eight administrations of cor-
help enhance daily practice and research methods. ticosteroids per year with follow-up of adverse eects.
Conducting mega-trials and mega-studies has its Although documented by fewer studies, we consider it
own challenges of operational limitations in organizing is reasonable to use oral dexamethasone on an out-
resources for longer durations, recruiting larger number patient basis in similar settings. It can be benecial to
of study patients, and securing funding. For these rea- provide a one-time dexamethasone administration
sons, performing systematic reviews and pooled ana- before ED discharge to a headache specialist for
lysis provide perceivable options to assess long-term management. Reasonable and achievable
accumulating evidence and aggregate data from dier- goals of pain reduction should be made clear to the
ent studies addressing similar question. Locating stu- presenting patient in the ED setting or in the oce
dies from literature database searches was the most during the initial visit.
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26 Cephalalgia 0(0)
Clinical implications
. Studies indicate that post-emergency department (ED) recurrent headaches occur within 24 hours in up to
87% of migraine patients visiting the ED.
. With corticosteroid treatment, recurrent headaches become milder than pretreated headaches and later
respond to nonsteroidal therapy.
. Corticosteroids provide a reasonable option for managing resistant, severe, prolonged or recurring migraine
attacks.
Funding department treatment of migraines. Neurology 2005; 64:

This research received no speciEc grant from any funding 463468.
agency in the public, commercial, or not-for-proEt sectors. 12. Carleton SC, Shesser RF, Pietrzak MP, et al. Double-
blind, multicenter trial to compare the efficacy of intra-
muscular dihydroergotamine plus hydroxyzine versus
Conflict of interest
intramuscular meperidine plus hydroxyzine for the emer-
None declared. gency department treatment of acute migraine headache.
Ann Emerg Med 1998; 32: 129138.
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YW Woldeamanuel1, AM Rapoport2 and RP Cowan1

Studies identified through the first 6 search strategies described

on Methods and Materials. Additional published studies identified through

Identified Studies Screened Studies and duplicate ineligible excluded

Duplicate eligible studies excluded from

Full-text articles assessed for eligibility simultaneous identification by the different

Studies included in final systematic review,

Table 1. Comprehensive summary of included clinical studies reviewed.

No/mild headache (no inter- 29% 37% 72%

record on charts; difficulty to

methods clearly explained

1. Mean VAS score VAS 8.11 1.31 8 1.52

1. VAS 20 minutes 3.73 1.81 1.87 1.28

1. VAS 30 minutes 3.06 2 1.44 1.63

between dexametasone M:F ratio 1:6.25 Non-randomized design lacking

of headache after two hours

8 mg oral dexamethasone computations, as this makes

impact was not analyzed.

Appraisals and clinical bottom

Headache recurrence defined as

those who reported return of

with daily activity)

2005. ED, Hospital, Iran. No differences in duration and vomiting.

Outcome: Headache severity 10 minutes among dexa-

minutes, 30 minutes. anti-inflammation.

cates poor score.

double-blind, two-armed, mean age 37 (n 48) Non-inferior results for acute

Male 12 (7%) 13 (7%)

no IV access was obtained. Study could have benefited from

headache recurrence. Returned to ED 15 11 CONSORT: enrollment, rando-

NJ, USA DE vs DE AEs were mild, nonspecific, and typical of

chest) and of steroids with DE (dyspepsia,

CONSORT: enrollment, randomization, blind-

drawals and dropouts)

Rescue medication (intake 1.1 2.3

phobia) within five days

immediately followed by IV checklist not mentioned; Jadad scale

500 mg was administered over

Appraisals and clinical bottom

Patients recorded headache 72 hours later apy included: antiemetics, IV nonster-

minutes and at discharge. class C 11 7 other baseline characteristics similar

had suffered a recurrence of this was not a case-control study.

activity but not provoking a and analysis methods clearly explained.

USA. M:F ratio 1:5.61 24 hours

IV metoclopramide and 2.5 mg Study results generalizability is limited

minutes) following dexametha- outcome) Convenience ED sampling

M:F 1:5 non-ED setting i.e. outpatient

the first 6 days

30 headache days / 30 days 99 (24.8%)

>28 days per month for using CONSORT checklist and

period of each patient and

Stop gradually over period of

Dosage of prednisone, oral:

In the systematic reviews and meta-analysis

Table 2. Comprehensive summary of included systematic reviews and meta-analysis.

First author, title of article, name of Systematic review,

reduction (weighted mean difference 0.37, 95% CI 0.200.94).

between dexamethasone and placebo groups.

patients do not respond to a standard regimen. Lack

luation. Sensitivity analysis yielded similar results with sequential

for overall result. Adverse effects related to administration of a