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Comparison Between the Efficacy of Ginger and Sumatriptan in the Ablative

Treatment of the Common Migraine

Article in Phytotherapy Research · March 2014

DOI: 10.1002/ptr.4996 · Source: PubMed

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 PHYTOTHERAPY RESEARCH
Phytother. Res. 28: 412–415 (2014)
Published online 9 May 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/ptr.4996

Comparison Between the Efficacy of Ginger and

Sumatriptan in the Ablative Treatment of the
Common Migraine

Mehdi Maghbooli,* Farhad Golipour, Alireza Moghimi Esfandabadi and Mehran Yousefi
Zanjan University Of Medical Sciences, VALI-e-ASR Hospital, Neurology Department, Zanjan, Iran

Frequency and torment caused by migraines direct patients toward a variety of remedies. Few studies to date
have proposed ginger derivates for migraine relief. This study aims to evaluate the efficacy of ginger in the
ablation of common migraine attack in comparison to sumatriptan therapy. In this double-blinded randomized
clinical trial, 100 patients who had acute migraine without aura were randomly allocated to receive either ginger
powder or sumatriptan. Time of headache onset, its severity, time interval from headache beginning to taking
drug and patient self-estimation about response for five subsequent migraine attacks were recorded by patients.
Patients, satisfaction from treatment efficacy and their willingness to continue it was also evaluated after 1 month
following intervention. Two hours after using either drug, mean headaches severity decreased significantly.
Efficacy of ginger powder and sumatriptan was similar. Clinical adverse effects of ginger powder were less than
sumatriptan. Patients’ satisfaction and willingness to continue did not differ. The effectiveness of ginger powder
in the treatment of common migraine attacks is statistically comparable to sumatriptan. Ginger also poses a
better side effect profile than sumatriptan. Copyright © 2013 John Wiley & Sons, Ltd.

Keywords: common migraine; ginger; sumatriptan.

Supporting information may be found in the online version of this article.

1–4% essential oil, 5–8% resin and mucilage (Langner

INTRODUCTION
Migraine, a periodic chronic neurologic disorder, is one
of the most common causes of pain syndromes with a
prevalence rate of 12%. This disorder imposes exorbi-
tant expenditures and creates disadvantages on personal
function. These can vary from minimally disturbed
activities of daily living to complete, although temporary,
incapacitation requiring total rest. Unfortunately, the
wait-and-see approach often prolongs the symptoms
constituting the disease, while also decreasing the effec-
tiveness of the treatment.
Despite continuous improvements in the field of
migraine treatment, which has provided further opportuni-
ties to select more specific and effective remedies, many
patients prefer to relieve headaches by nonchemical
(herbal) means or readily available over-the-counter
(OTC) products. A part of this trend is a result of fears
associated with adverse drug reactions and apprehensions
of dependency. Patients often experience a loss of satisfac-
tion from their usual medications which contributes to
their unmet needs. Even the general chronic relapsing
nature of migraine disease poses frustrations for sufferers
that lead them to seek out alternative remedies.
Ginger is a native plant of southeastern Asia that has
been widely cultivated in Jamaica, China, India, Nigeria,
Sierra Leone, Haiti and Australia. These thick rhizomes,
in dehydrated form, contain 40–60% carbohydrate, 10%
protein, 10% fat, 5% fiber, 6% minerals, 10% water,
* Correspondence to: Maghbooli Mehdi, Zanjan University of Medical
Sciences, Vali-e-Asr University Hospital, Neurology ward, Zanjan, Iran.
E-mail: m.maghbooli@zums.ac.ir
Copyright © 2013 John Wiley & Sons, Ltd.
et al., 1998; Shri, 2003; Mascolo et al., 1989; Mustafa
et al., 1993, Awang, 1992).
Ginger products have long been used in the manage-
ment of motion sickness, dyspepsia, articular pain, local
pains and vertigo (Grant and Lutz, 2000; Yarnell, 2002;
Holtmann et al., 1989; Riebenfeld and Borzone, 1999;
Micklefield et al., 1999; Grøntved and Hentzer, 1986;
Altman and Marcussen, 2001).
One of the most favorable aspects of ginger is that there
are no serious or even frequent side effects reported with
its use. Anecdotal reports even indicate a therapeutic role
for ginger in vomiting, flatulence and memory problems
(Ernst and Pittler, 2000; Yamahara et al., 1989). Pharma-
cologic studies have revealed its effectiveness in the
reduction of blood sugar, normalizing of blood pressure,
strengthening of the overall cardiovascular system, inhib-
itory effects on prostaglandins and platelet aggregation,
as well as lipid lowering properties and hyposecretion of
gastric acid (Bordia et al., 1997; Tjendraputra et al.,
2001; Guh et al., 1995).
In a study performed by Cady et al., Gelstat (an OTC
drug which contains ginger extract) alleviated migraine
headache completely in 48%, and partially in 34% of
patients within 2 h of taking the drug (Cady et al., 2005).
Aurora et al., performed a double-blinded placebo-
controlled study demonstrating that the Gelstat-treated
group also had a significantly higher pain relief rate 2 h
following proper drug use, at 65% versus 36%, p = 0.038
(Aurora et al., 2006).
In a case report review, a 42 year old woman with classic
migraine achieved headache subsidence within a 30 min
period of taking a 500–600 mg water-soluble ginger
powder upon onset of visual aura. Patients, who continued
Received 09 September 2010
Revised 09 March 2013
Accepted 17 March 2013
 MIGRAINE ABLATION BY GINGER VERSUS SUMATRIPTAN
consumption of ginger powder, every 4 h for a total of
four days, reported both diminished headache severity
and frequency (Mustafa and Srivastava, 1990).
Given the high frequency, the variability in treatment
options, along with the diverse inclinations and satisfaction
of the sufferer population, the purpose of this study is to
determine the therapeutic effects of ginger powder on
the attacks of migraine without aura and compare it with
standard sumatriptan treatment.
METHODS AND MATERIALS
This is a double-blinded randomized controlled clinical
trial comparing the efficacy of ginger to sumatriptan in
the treatment of the common migraine. One hundred
study participants who are sufferers of common migraine
were enrolled after admission to the Neurology Clinic of
Zanjan Vali-e-Asr Hospital. Participants were assigned
to two coequal groups by way of simple, random
nonprobability sampling; one group was blindly given
ginger powder, while the other was given sumatriptan.
Inclusion criteria used (International Headache Soci-
ety Classification ICHD-II, Migraine, nd): (i) Confirmed
diagnosis of migraine without aura by a neurologist,
based on IHS criteria (ICHD-II), (ii) Aged ≥18 years,
(iii) Education level high school diploma or higher,
(iv) Headache frequency between 2 and 10 days/month.
Exclusion criteria were: (i) History of biliary calculus or
peptic ulcer disease, (ii) Allergic reaction, (iii) Hemorrhagic
diathesis or using anticoagulants, (iv) History of ischemic
heart disease or Prinzmetal’s angina, (v) Pregnancy or
lactation, (vi) Headache after head trauma.
After completion of an introductory questionnaire,
one sealed box containing five capsulets (sumatriptan
or ginger powder) was randomly delivered to each
subject. Subjects were instructed to take only one
capsulet upon headache onset. Each ginger capsulet
contained 250 mg powder of ginger rhizome, while each
Imegraz capsulet contained 50 mg of sumatriptan.
All patients were committed to keeping up with their
previous maintenance therapeutic regimens, and, with
each attack they were required to fill out a questionnaire
revealing: time of headache onset, headache severity
(rated on a visual analog scale), timing of drug taking,
response self-assessments following 30, 60, 90,120 min
and 24 h. Subjects also included any clinical adverse
drug reactions within the questionnaire. This study was
conducted for the duration of one month, at which point
Figure 1. Changes in mean headache severity after taking sumatriptan and Ginger during subsequent time intervals. This figure is available in
colour online at wileyonlinelibrary.com/journal/ptr.
Copyright © 2013 John Wiley & Sons, Ltd.
413
patients evaluated their overall satisfaction with regards
to treatment efficacy as well as their willingness to con-
tinue their respective treatments. All statistical analysis
was performed by using SPSS for windows (version 16)
software. Means of quantitative variables were com-
pared by using student T-test between the two groups.
In the case of categorical variables, Chi-square test was
applied. Headache severity in the study groups, before
and after intervention, was assessed with a paired sam-
ples T-test analysis. All P-values were two-tailed and a
P-value < 0.05 was considered significant.
RESULTS
One hundred patients with common migraine were
selected to take either sumatriptan or ginger (groups
equally proportioned).
The mean age of patients was 35.1  6.2 years old in
the sumatriptan group and 33.9  8.3 years old in the
ginger group. Females comprised 68% (34 patients)
sumatriptan subjects versus 74% (37patients) ginger.
Average duration of migraine diagnosis was 7.3  4.5
years in sumatriptan and 7.2  4.6 years in ginger group.
Average number of headache attacks in sumatriptan
and ginger-treated groups were 5.8  3.1 and 4.9  2.7
attack/month, respectively. This frequency was 4.6  0.9
attack/month during trial period in both groups.
Average time interval from headache onset to drug
intake was 24  15 min (median: 21 min) for sumatriptan
and 20  11 min (median: 20 min) for ginger patients.
Figure 1 represents changes of mean headache severity
in subsequent time intervals following consumption of
either drug.
Before taking the medication, 22% of the sumatriptan
group and 20% of the ginger group had severe headaches
(VAS ≥ 8); mean values were 56% versus 48% for moder-
ate severity (5 ≤ VAS ≤ 7) in the two groups, respectively
(P = 0.527).
Frequency distribution of mean headache severity at
2 h after drug use demonstrated similar effectiveness
for sumatriptan and ginger groups (P = 0.116) (Table 1).
Comparing mean headache severity before and 2 h after
treatment revealed a 4.7 unit reduction (according to
VAS) in the sumatriptan group (P < 0.0001) and a 4.6
unit reduction in the ginger group (P < 0.0001).
In this study, 70% of sumatriptan-treated and 64% of
ginger-treated patients showed favorable relief (≥90%
decrease in headache severity) at 2 h following drug
Phytother. Res. 28: 412–415 (2014)
414 M. MAGHBOOLI ET AL.

Table 1. Frequency of mean headache severity before each drug use and 2 h after its intake

Headache severity

Drug Free Mildb Moderatec Severed Sum

Sumatriptan Before 0 22 (11) 56 (28) 22 (11) 100 (50)

After 44 (22)a 48 (24) 8 (4) 0 100 (50)
Ginger powder Before 0 32 (16) 48 (24) 20 (10) 100 (50)
After 44 (22) 56 (28) 0 0 100 (50)
Sum Before 0 27 (27) 52 (52) 21 (21) 100 (100)
After 44 (44) 52 (52) 4 (4) 0 100 (100)
a
Digits outside and inside the brackets indicate percent and number of patients.
b
Headache severity as 1 ≤ VAS ≤ 4.
c
Headache severity as 5 ≤ VAS ≤ 7.
d
Headache severity as 8 ≤ VAS.
P = 0.116.

use. Frequency of favorable relief according to gender,
age group, duration of migraine history and maintenance
regimen was compared between the sumatriptan and
ginger groups and summarized in Table 2. These findings
indicated that both the sumatriptan and ginger signifi-
cantly impressed on pain relief and no significant differ-
ences were demonstrated in the headache subsidence
between the sumatriptan- and ginger-treated groups.
Subjective side effects arose from sumatriptan including
dizziness, a sedative effect, vertigo and heartburn.
The only reported clinical adverse effect of ginger was
dyspepsia. Prevalence rate of clinical complaints was
20% for sumatriptan in contrast with only 4% for ginger
(P = 0.028). 86% of subjects reported high or superior
satisfaction from the sumatriptan-treated group as com-
pared to 88% in ginger group (P = 0.736). Eighty-eight
percent of sumatriptan users and 72% of ginger recipients
were inclined to continue their randomly assigned drug
for the abortion of migraine attacks (P = 0.139).
DISCUSSION
The current study reveals that both sumatriptan and
ginger powder decrease mean severity of common
migraine attacks in within 2 h of use. A comparison of
efficacy in headache alleviation and patients’ content-
ment does not show any significant difference amongst
the two drugs. However, subjective side effects due to
ginger powder were significantly less than sumatriptan.
Despite availability of multiple drugs specifically for
the abortion of migraine attacks (such as ergots and
triptans), as well as advances in pharmacologic and
alternative therapies, problems including poor satisfac-
tion of drug efficacy as well as varied side effects persist.
Challenges also include the chronic and recurrent
nature of the disease; these can cause patients to
constantly reevaluate their treatment needs, a delay or
interruption in self management, and a tendency to take
OTC and herbal medications.
Anecdotally, oral ginger has been used for migraine
headache, nausea and vomiting (Kemper, 1999). The es-
sential oil of ginger has also been used topically as an an-
algesic (Srivastava and Mustafa, 1989). For migraine,
500 mg ginger taken at onset, repeated every 4 h up to
1.5–2 g per day, for 3–4 days has been recommended
(Mustafa and Srivastava, 1990).
Researchers at the city of London Migraine Clinic
found that feverfew also eliminated about two-thirds
of migraines in a selected group of headache patients,
which is similar to the effectiveness of most migraine
drugs. While some people experience a pronounced
effect, others may have none at all (Hylands et al.,
1985; Murphy et al., 1988).
The amount that has been shown to prevent migraine
attacks in research studies ranges from 50 to 114 mg per
day. Though most practitioners use capsules containing
250 mg of a standardized potency feverfew.
Mustafa et al. reported a 42-year-old woman, with a
16 years history of migraines, experienced enormous
relief after supplementing her diet with 1.5–2 g of dried
ginger daily.

Table 2. Frequency of ≥ 90% reduction in headache severity after 2 h following each drug use compared based on some features of subjects

Drug

Variable Sumatriptan Ginger powder PV

Sex Male 68.8 (11)a 69.2 (9) 0.978

Female 70.6 (24) 62.2 (23) 0.453
Age group <35 72 (18) 61.3 (19) 0.400
≥ 35 68 (17) 68.4 (13) 0.976
Duration of migraine history <5 73.3 (11) 62.5 (10) 0.519
≥5 68.6 (24) 64.7 (22) 0.733
Maintenance therapy With 78.1 (25) 78.6 (22) 0.967
Without 55.6 (10) 45.5 (10) 0.525
a
Digits outside and inside the brackets indicate percent and number of patients.

Copyright © 2013 John Wiley & Sons, Ltd. Phytother. Res. 28: 412–415 (2014)
 MIGRAINE ABLATION BY GINGER VERSUS SUMATRIPTAN
In double-blinded placebo-controlled study of Aurora
et al., Gelstat (ginger extract) relieved migraine headache
more significantly than placebo within 2 h of taking the
drug. There was no meaningful difference in relief rate
of headache by Gelstat and placebo (19% versus 7%
respectively).
In the present study, ginger powder reduced mean
headache severity up to 4.6 units in relation to before
taking drug.
Cady et al. performed an open-label study enrolling
30 patients that were treated in the mild pain phase with
Gelstat Migraine (a combination of ginger and fever-
few).Two hours after treatment, 48% were pain-free
with 34% reporting a headache of only mild severity.
Twenty-nine percent reported a recurrence within 24 h.
Side effects were minimal, and 59% of subjects were
satisfied. 41% preferred Gelstat Migraine or felt it was
equal to their pre-study medication. In our study, 2 h
after ginger intake, 44% of subjects became pain free
with 56% reporting a headache of only mild severity.
Clinical adverse reactions occurred in 4% of ginger
group, and 88% of patients rated headache relief as
great or excellent, and 72% preferred this drug for
long-term therapy.
The present investigation demonstrated an overall
44% palliation in all headache attacks 2 h following
treatment with sumatriptan or ginger powder. In
conjunction with evidence from other studies, it is antici-
pated that increasing the total amount of ginger intake
per attack can greatly enhance migraine relief rate.
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View publication stats
415
CONCLUSION
Consequently, ginger products are a favorable choice
for treatment of acute migraine without aura when com-
pared with sumatriptan. Therefore, it is recommended
for migrainous patients who are uneasy or poorly
responsive to other medications or in general simply
tend to use herbal remedies. It is suggested a more
extensive placebo-controlled study which can measure
the effectiveness of various doses of ginger-based
medications with differing types and severities of migraine
is examined.
Acknowledgements
We would like to thank all patients for participating in this study. We
are also very grateful to pharmacy companies Goldaru and Razak
for providing Zintoma and Imegraz. Thanks are also extended to
Mrs. Manizhe Asemani, Head nurse of Vali-e-Asr neuroclinic,
for her assistance in sample collection and patient follow-up.
This study was supported by a grant from Zanjan University of
Medical Sciences.
Conflict of Interest
The authors have declared that there is no conflict of interest.
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 Journal of Market Access & Health Policy

ISSN: (Print) 2001-6689 (Online) Journal homepage: https://www.tandfonline.com/loi/zjma20

From investigational product to active reference:

evolution of oral sumatriptan efficacy versus
placebo for the treatment of acute migraine
episodes and potential impact in comparative
analyses

Katia Thokagevistk, Clément François, Mélanie Brignone & Mondher Toumi

To cite this article: Katia Thokagevistk, Clément François, Mélanie Brignone & Mondher
Toumi (2019) From investigational product to active reference: evolution of oral sumatriptan
efficacy versus placebo for the treatment of acute migraine episodes and potential impact
in comparative analyses, Journal of Market Access & Health Policy, 7:1, 1603538, DOI:
10.1080/20016689.2019.1603538

To link to this article: https://doi.org/10.1080/20016689.2019.1603538

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JOURNAL OF MARKET ACCESS & HEALTH POLICY
2019, VOL. 7, 1603538
https://doi.org/10.1080/20016689.2019.1603538

ARTICLE

From investigational product to active reference: evolution of oral sumatriptan

efficacy versus placebo for the treatment of acute migraine episodes and
potential impact in comparative analyses
Katia Thokagevistka, Clément Françoisa,b, Mélanie Brignonec and Mondher Toumia,b
a
Health Economics and Outcomes Research, Creativ-Ceutical, Paris, France; bPublic Health Department- Research Unit, Aix-Marseille
University, Marseille, France; cHealth Economics and Outcomes Research, Lundbeck SAS, Paris

ABSTRACT ARTICLE HISTORY

Background: The relative efficacy and safety can vary among drugs over time. Sumatriptan, a first Received 3 August 2018
choice drug for acute migraine, can illustrate this phenomenon. Revised 28 March 2019
Objective: To assess the evolution of the relative efficacy and tolerability of oral sumatriptan Accepted 29 March 2019
against placebo between its approval in 1991 and 2006. KEYWORDS
Methods: A systematic literature review of randomized controlled trials (RCTs) of adults suffering Comparative evidence;
from acute migraine episodes was performed using Medline. Meta-analyses estimated odds ratios meta-analysis; acute
of the occurrence of pain-free at 2 hours and of any adverse event. migraine episodes;
Results: Out of the 67 RCTs identi.fied, pain-free at 2 hours and adverse events were reported in sumatriptan
25 and 28 studies, respectively. For pain-free, the relative effect of sumatriptan increases con-
siderably over time, despite an increase in the absolute placebo effect. The odds ratio (95% CI)
equaled 3.13 (1.67–5.86) around approval (1991–1994) and increased up to 4.14 (3.67–4.67) on
the following decade. No specific variation was observed in the relative tolerability effect of
sumatriptan over placebo over time.
Conclusions: The relative effect of sumatriptan evolved substantially over time. This phenom-
enon may impact the results of network meta-analysis and indirect comparisons performed to
evaluate the potential of a new drug, compared to widely prescribed older drugs.

Introduction observed depending on whether the drug was used as

investigational or comparative arm.
When introducing a new drug into the market, it is neces-
When randomized controlled trials (RCTs) include an
sary to submit evidence about its efficacy, safety and
active comparator arm, patients who previously received
tolerability profile. In the course of the registration pro-
the comparator drug and did not respond to it are
cess, several clinical studies are performed to evaluate the
usually not selected for participation in the trial or for-
benefit/risk ratio. The new drug will be typically tested
mally excluded. This exclusion is justified on ethical
over a placebo control, but may be also assessed versus
grounds but may create a selection bias. The issue is
an active reference drug to confirm assay sensitivity.
particularly problematic when network meta-analysis or
Few studies have shown that overall the estimated
indirect comparisons are subsequently performed, since
relative efficacy of widely used drugs varies substantially
this exclusion criterion may have a different impact in
over time whereas the absolute effect of the drug is not
the earlier trials using an active comparator than in the
supposed to vary substantially. Llorca et al. [1] demon-
later trials using the same comparator [3]. For example,
strated an improved relative efficacy and safety of the
when a drug became the Standard of Care after its
antidepressant escitalopram vs. other antidepressants
introduction, the proportion of patients who are exposed
over time, using change from baseline to 8 weeks on
to the comparator medication will increase over time,
Montgomery-Åsberg Depression Rating Scale total score,
and thus the selection bias may become significant.
and withdrawals due to adverse events. Variations in the
Therefore the relative effects of newer drugs will be
relative efficacy over time on two critical outcomes for
compared unfavorably versus the relative effect of
assessing drug relativeness effectiveness were also iden-
older drugs. The Regulatory Authorities have recognized
tified for tiotropium, a reference treatment in chronic
this selection bias. In their assessment of vortioxetine
obstructive pulmonary disease [2]. The difference was

CONTACT Clément François CFR@creativ-ceutical.com Public Health Department – Research Unit EA 3279, Aix Marseille Université, Jardin du Pharo, 58,
bd Charles Livon, Marseille 13284-Cedex 07
© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which
permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
2 K. THOKAGEVISTK ET AL.
(Brintellix), where exclusion of the non-responders to the
active reference duloxetine was an exclusion criteria, the
European Medicines Agency (EMA) acknowledged in
European public assessment report (EPAR) for Brintellix
that ‘The exclusion of non-responders and the inclusion
of previous responders in the active reference arm could
have introduced a bias in favor of the efficacy of the
active reference, so differences in the efficacy of vortiox-
etine versus the active reference cannot be inferred on
the basis of these studies’ [4].
This study aims to examine this phenomenon in
another disease area. Migraine was identified as a poten-
tial area of interest, as a highly prevalent disease, with a
considerable number of trials performed versus placebo
and the same active comparator, sumatriptan, steadily
been used as a reference treatment over time for acute
migraine episodes [5]. The objective of this study is then
to assess the evolution of the relative efficacy and toler-
ability in double-blind randomized clinical trials of oral
sumatriptan against placebo, since launch and the latest
assessment.
Methods
Data source and study selection
A systematic literature review of RCTs of adults suffering
from acute migraine episodes was performed using
Medline. The search was conducted via the Ovid interface
in July 2013, using the keywords related to migraine,
headache disorders or cephalgia, and sumatriptan. The
following limits/restrictions were used: enrolled patients
with acute migraine episodes; age group ≥18 years old;
randomized controlled trial; included a placebo control
group; reported in English; reported proportion of
patients with pain-free at 2 hours as a measure of efficacy
and/or reported proportion of any adverse events as a
measure of tolerability (see Appendix A). The search was
conducted for the period from and shortly after approval
(1991) to the following 15 years (up to 2006). This way of
analyzing the data was consistent with the health tech-
nology assessment (HTA) agency perspective as the entire
set of evidence is considered at time of evaluation.
Studies were excluded if they did examine the use of
sumatriptan as a prophylactic treatment, or if they included
<30 patients per treatment group.
Two analysts reviewed titles, abstracts and finally full
texts of the qualifying articles to determine whether they
met inclusion/exclusion criteria. Any discrepancy regarding
study eligibility for which a consensus was not achieved
was reviewed by a third independent researcher.
Only treatment arms including sumatriptan approved
100 mg oral dose, selected as the most effective standard
dose, and placebo were included in the analyses [6].
Outcomes of interest
Efficacy was evaluated as the proportion of patients with
pain-free at 2 hours, which is the primary efficacy end-
point recommended by the International Headache
Society (IHS) for clinical trials for acute treatments of
migraine, as it aligns with patient satisfaction and is less
subject to placebo effect [7]. Pain-free was defined as a
headache pain reduced from moderate or severe at base-
line to none at 2 hours after dosing. Headache pain was
recorded by the patient using a four-point Likert scale
(i.e., 0 = none, 1 = mild, 2 = moderate, 3 = severe), as
recommended by the clinical guidelines [8].
Any study without reported pain-free at 2 hours data
was not considered in this review, including the ones
that reported headache relief at 2 hours, or pain-free at
4 hours.
In addition to the efficacy endpoint, a tolerability end-
point was also considered: tolerability was defined as the
proportion of patients with any adverse events (AEs)
after initial dose of treatment, out of the total number
of patients randomly assigned to sumatriptan or placebo
and who received at least one dose of treatment.
Statistical analyses
For the first step, as a qualitative analysis, efficacy and
tolerability of sumatriptan 100 mg over time were pre-
sented using the mean differences to placebo (sumatrip-
tan-placebo difference scores). The publication date was
used as a proxy of the clinical trial assessment if not
reported. The trend in the relative efficacy and tolerability
of sumatriptan over placebo over time was illustrated
using the linear least squares fitting technique. Absolute
efficacy and tolerability outcome results in the sumatrip-
tan active treatment arm and the placebo arm were also
shown over time, to characterize the trend in the suma-
triptan-placebo differences over time.
As a second step, meta-analyses were performed
using the inverse-variance weighted average method
(fixed effect model) described by Sutton et al. [9] and
Thompson et al. [10] to estimate the odds ratios of the
occurrence of pain-free at 2 hours and of any adverse
event, based on available RCT data from launch in 1991
to 2006 on a yearly basis. The goal was to provide
quantitative summaries of clinical trials data performed
between the launch of oral sumatriptan to the following
15 years (up to 2006). Meta-analyses were implemented
to compare the group treated with sumatriptan and the
control group given placebo in terms of two outcomes:
pain-free at 2 hours for efficacy and any adverse events
for tolerability. The aim was to illustrate the year-to-year
re-evaluation of a drug according to all previous clinical
 JOURNAL OF MARKET ACCESS & HEALTH POLICY 3

trials performed. Outputs generated from these analyses Efficacy assessment

were presented as odds ratios of the occurrence of pain-
Of the 67 RCT studies, 25 studies included a placebo
free at 2 hours and of the occurrence of having any
and a sumatriptan 100 mg treatment arms, with avail-
adverse event by period.
able data on the proportion of patients with pain-free
As a last step, increases in odds ratio of the occur-
at 2 hours in the two arms.
rence of pain-free at 2 hours estimated by time period
Hence, 25 studies were selected for the efficacy
compared to 1991–1994 launch period were assessed,
evaluation to compile the results of acute migraine
and the analysis of variance (ANOVA) method was used
clinical trials published between 1991 and 2006, that
to test the linear relationship between estimated odds
included 9627 patients with migraine (with 5601
ratio increases and time periods.
patients assigned to sumatriptan 100 mg and 4026
All analyses were performed by one statistician, and
assigned to placebo). The list of references to these
quality control was conducted by another.
studies is available in Appendix B.
Results from analyses were then compared, and any
discrepancies were resolved by program examination
Qualitative description of the relative efficacy of
by the statisticians.
sumatriptan versus placebo over time
The magnitude of sumatriptan–placebo differences over
Results
15 years after launch was first evaluated, as shown in
Figure 1 describes the process for inclusion of articles in Figure 2.
the analysis, in agreement with the Preferred Reporting A considerable increase in absolute placebo effect
Items for Systematic Reviews and Meta-Analyses (PRISMA) was observed between the launch of sumatriptan and
guidelines [11]. Of the 63 publications selected by this later assessment. Assuming a linear placebo effect
process, four reported the results of two different trials over time, the proportion of patients with pain-free
[12–15]. Thus, a total of 67 trials were selected as potential evaluated in the RCTs increases from around 5% to
relevant RCTs for the analysis. 20% in 15 years.

Figure 1. PRISMA flowchart.

4 K. THOKAGEVISTK ET AL.

70%

Sumatriptan - Placebo difference in Pain free

60%

50% y = 0.006x - 11.805

40%
Difference vs. placebo

30% Placebo effect

Sumatriptan 100mg
20% effect

10%

0%
199019911992199319941995199619971998199920002001200220032004200520062007
Assessment date
Figure 2. Correlation of sumatriptan–placebo differences (difference between sumatriptan and placebo groups in the proportion of
patients with pain-free at 2 hours) with the year of assessment.

Despite this increase in the absolute placebo effect, a 32% increase compared to the first estimation based on
the relative effect of sumatriptan was found to increase RCT data from 1991 to 1994.
over time. With a linear effect assumption over time, Estimated increases in odds ratios for occurrences of
the sumatriptan-placebo differences observed in the pain-free at 2 hours, sumatriptan versus placebo, com-
RCTs increased by about 10 percentage points within pared to 1991–1994 launch period, are shown in Figure 4.
15 years after drug launch (1991). The ANOVA indicated the significant positive slope of the
This result confirms a positive correlation between regression line (p = 0.0232).
the relative effect of sumatriptan versus placebo and
the time of evaluation. Tolerability assessment

Meta-analysis – trend over time of the relative
efficacy of sumatriptan versus placebo
Figure 3 presents the odds ratios for occurrences of pain-
free at 2 hours of sumatriptan versus placebo, estimated
from meta-analyses of RCT data published within the
different time periods (from period 1991–1994 to period
1991–2006).
The relative efficacy of sumatriptan versus placebo
varied considerably over the different time periods. By
adding RCT data from 1995 to 1999 in the meta-analysis,
the estimated odds ratio [95% CI] was increasing from
3.13 [1.67–5.86] (1991–1994) to 4.45 [3.10–6.40]
(1991–1999). It decreases to 3.97 [3.04–5.18] by including
RCT data published until 2002 (1991–2002). The maxi-
mum odds ratio estimated was 4.64 [3.98–5.41], attained
using efficacy data of RCTs published until 2004 (1991–
2004). Finally, based on the 25 studies selected in our
review and published from 1991 to 2006, the odds ratio
for the occurrence of pain-free with sumatriptan com-
pared with placebo was estimated at 4.14 [3.67–4.67], or
Twenty-eight studies (10,162 patients) reported the prob-
abilities of numbers of patients with any adverse event
from the launch of sumatriptan from 1991 to 2006. The list
of references to these studies is available in Appendix C.
Qualitative description of the relative tolerability
of sumatriptan versus placebo over time
Figure 5 shows the sumatriptan–placebo differences
obtained in trials, by year of publication.
Both the absolute placebo effect and the absolute
sumatriptan effect declined over 15 years after launch.
The magnitude in a decrease of adverse events over time
was comparable in both treatment groups, as illustrated
by the parallel linear trend lines.
Therefore no significant variation was observed in the
relative difference in tolerability over the years, using the
occurrence of an adverse event as the tolerability out-
come. Assuming a relative linear effect over time, the
sumatriptan-placebo difference remains stable at around
12% from launch to the latest evaluated assessment.
 JOURNAL OF MARKET ACCESS & HEALTH POLICY 5

Sumatriptan versus Placebo (95% CI)

Odds ratio for Pain free at 2 hours -
6

5
4.45 4.45 4.64 4.52
4.21 4.21 4.13 4.14
4 3.97
3.69 3.69
3.13 3.23
3

Time period
Figure 3. Odds ratios for occurrences of pain-free at 2 hours, sumatriptan versus placebo.

60%
Increase in odds ratios for occurrences of pain-

y = 0.0235x + 0.1596
free at 2 hours, sumatriptan versus placebo,
compared to 1991-1994 launch period

50%
42.19% 42.19% 48.11% 44.37%
40%
34.32% 34.32%
30% 31.76%
32.19%
26.65%
20%
17.86% 17.86%
10%

3.05%
0%

Time period
Figure 4. Increase in odds ratios for occurrences of pain-free at 2 hours, sumatriptan versus placebo, compared to 1991–1994
launch period.

Meta-analysis – trend over time of the relative Discussion and conclusions

tolerability of sumatriptan versus placebo
This study aimed to assess the evolution of the relative
The odds ratios for occurrences of adverse events of efficacy and tolerability of the reference treatment in the
sumatriptan versus placebo, estimated from a meta-ana- prevalent migraine disorders disease – sumatriptan –
lysis of RCT data published within a period (from the between launch and later assessment. It was stated as a
launch of sumatriptan to year Y) are presented in Figure 6. hypothesis that the potential improvement in relative effec-
No apparent variation in the risk of adverse event tiveness and tolerability overtime for drugs widely used
compared with placebo over time was evaluated using could be linked to the exclusion of previous non-respon-
the successive meta-analyses of available RCT data from ders to the selected drugs, or non-inclusion of patients
launch to the latest assessment. expected not to respond according to clinician judgment.
6 K. THOKAGEVISTK ET AL.

50%

Sumatriptan - Placebo difference in

Proportion of any adverse events
40%

30%
y = 0.0011x - 2.0805

20% Difference vs.

placebo
10% Placebo effect

Sumatriptan
0%
100mg effect

-10%
199019911992199319941995199619971998199920002001200220032004200520062007
Assessment date
Figure 5. Correlation of sumatriptan–placebo differences (difference between sumatriptan and placebo groups in proportion of
patients with any adverse events) with the year of publication.

3.5
Odds ratio - Sumatriptan versus Placebo

3.0

2.5
2.42
(95% CI)

2.0
1.87 1.87 1.91 1.90 1.93
1.75 1.77 1.73 1.75
1.62 1.62 1.62
1.5

1.0

Time period
Figure 6. Odds ratios for occurrences of adverse events, sumatriptan versus placebo.

We found that the relative effect regarding efficacy
of sumatriptan vs placebo increased between launch
and later assessment. The average sumatriptan-placebo
difference was approximately evaluated at 20% using
the pain-free at 2 hours outcome in 1991 compared to
an average of about 30% in 2006, based on published
sumatriptan trials. These data confirmed the hypothesis
of a positive relationship between the relative effective-
ness of sumatriptan in comparison to placebo and the
time of evaluation.
Such variability in the relative effect of widely used
drugs after the market access can be explained by the
differences in study design of post-marketing trials, com-
pared to the design of the registration trials. It is expected
that among the post-marketing trials, some trials will be
profiling studies in patient subgroups in which the new
drug is expected to demonstrate a better effect. The
inclusion of post-marketing RCT data which demon-
strated a higher benefit in a specific selected patients’
subgroups for migraine treatment may then affect the
ranking in the following years after launch, with a trend
to improve.
Other factors that could have influenced the variability
in the relative effect include the change in the manage-
ment of migraine and potential bias in study selection.
However, while sumatriptan came to be one of the most
important therapeutic advances in migraine, after its dis-
covery, other triptans entered the market over time. These

new triptans presented minor changes in the original
molecule’s pharmacology and pharmacokinetics, but, on
balance, the triptans acted similarly and lead to similar
outcomes. In addition, the randomization would alleviate
most of the effect of a change in the management of
migraine. For the study selection, we conducted a
systematic literature review that did not identify specific
bias – the number of non-included studies did not follow
a specific pattern that could have influenced the results.
Changes in the treatment guidance and practice can
also influence the results obtained in different periods
of time of assessment. Therefore it is essential to take
precautions when assessing the evolution of the effect
of a drug over time.
We did not find any evident variation in the relative
tolerability of sumatriptan over time. Both absolute suma-
triptan and placebo effects regarding adverse events
decreased between launch and later assessment, with a
similar trend over time. A lower variability on the toler-
ability can be expected as it was previously reported by
Llorca et al. [1], who stated that ‘Typically, any variation in
the tolerability of drugs should not be as prominent as for
efficacy as it is expected that drugs will have similar toler-
ability profiles across slightly varying patients’ popula-
tions or disease’s characteristics.’ The decrease in the
tolerability odds ratio estimated from 1991–1994 time
periods to all other time periods may be linked to the
Weber effect. As sumatriptan was a completely new class
of drug, patients and physicians may have been more
alert to new side effects. As the drug started to be more
widely used and known, the reporting may have
decreased post-launch. Further research should be done
to explore this effect, as the Weber effect has become
more controversial in recent studies [16,17].
To our knowledge, no similar study assessing the
variation of relative efficacy and tolerability of a refer-
ence treatment in comparison to placebo over time was
previously published. However, the increase in placebo
responses over time has been already demonstrated by
a study conducted at McGill University in Montreal in
US clinical trials of neuropathic pain published between
1990 and 2013 [18]. Based on patient-reported pain
outcomes, the relative pain reliever effect of painkillers
versus placebo was evaluated at 27% in 1996, versus
only 9% in 2013. This significant increase in placebo
responses was driven by the US trials. Possible explana-
tions are direct-to-consumer advertising for drugs
allowed in the US, creating a stronger placebo effect,
but also the more extensive and more costly US trials
with a higher implication of nurses and the broader
influence of the effect of the drug to their dedicated
patients versus smaller trials.
JOURNAL OF MARKET ACCESS & HEALTH POLICY 7
It is important to note that this study is a preliminary
research for evaluating the hypothesis that the potential
improvement of relative effectiveness and tolerability
overtime for drugs widely used could be linked to the
exclusion of previous non-responders to the selected
drugs. However, the present study has several consider-
able limitations. Thus, for several reasons, our analyses
suggest directions for further research rather than firm
conclusions.
First, the literature review used to identify the RCTs was
a focused literature review in Medline. The methodology
was systematic but should be extended to a search in
other databases including at least Embase and Cochrane
Central Register of Controlled Trials. Including data from
unpublished sumatriptan trials would also increase the
quality of the systematic review.
Second, although the analysis of the relative efficacy
supported our primary assumption, it would be essential
to evaluate different factors that may be related to
changes in sumatriptan–placebo differences. With this
objective, we could suggest the use of meta-regressions
models to identify the various factors that have significant
associations with the sumatriptan-placebo pain-free dif-
ference. Covariates such as inclusion and exclusion cri-
teria, research design features and characteristics of the
population (e.g., mean age, gender ratio, baseline sever-
ity) could impact the relative effects, such as the exclusion
of non-responders to the reference drugs. This analysis
will, however, present some challenges, as the change in
patient populations participating in clinical trials across
the years, such as the exclusion of non-responders or non-
tolerable patients to the reference drug is not always
reported in the publication.
Lastly, assessing the evolution over time of the relative
effectiveness of sumatriptan should be evaluated using
other efficacy outcomes. Some of our preliminary analyses
suggest the increase in relative recurrence at 2 hours over
time. But the results need to be contrasted to the one in
headache relief, where the relative effect of sumatriptan
decreased over time, partly explained by a considerable
increase in the placebo effect. The subjective aspect of
pain relief might also affect the outcome assessment.
To conclude, these results demonstrate that the time
from market access may not be the most appropriate time
to evaluate the relative effectiveness and tolerability of new
drugs. Due to the limited value evidence collected for new
drugs compared to widely used older drugs, the compar-
ison may be biased. Also, sufficient time is needed to
capture all of the benefits of a new therapy, and this may
not be sufficiently revealed until post-registration addi-
tional data are collected [2]. Finally, publication and selec-
tion bias may have an impact on the current methods of
8 K. THOKAGEVISTK ET AL.
comparison. It is therefore of great importance to reevalu-
ate a drug over time.
However, as it is essential for HTA agencies and other
decision-makers to evaluate a new drug compared to
other therapies at the time of launch, one critical recom-
mendation would be to assess the comparison using RCT
data with very similar design features and patient char-
acteristics, such as using the data from pivotal studies
submitted as part of the registration package at the time
of launch.
In conclusion, the findings of this study highlighted
that it is needed to reassess the relative drug effect several
years after its introduction to the market. One way to
ensure this would be to perform an appropriate mixed
treatment comparison using all relevant RCT data when
clinical development of the drug is completed, and there
is likely to be less variation of drug relative efficacy and
tolerability over time, or within five years after the drug
launch, in most of the cases.
Disclosure statement
No potential conflict of interest was reported by the authors.
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 JOURNAL OF MARKET ACCESS & HEALTH POLICY 9

Appendices

Appendix A. Systematic literature review – Search strategy

ID PICOS Category Search terms Hits Medline

#1 P Indication exp *Migraine Disorders/ 17,256
#2 exp Headache/ 22,124
#3 exp Headache Disorders/ 26,346
#4 (migraine or headach$ or cephalgi$ or cephalalgi$).ti,ab. 70,465
#5 Hits of P 1 or 2 or 3 or 4 81,163
#6 I sumatriptan Sumatriptan/ 2,047
#7 sumatriptan.ti,ab. 2,373
#8 Hits of I 6 or 7 2,817
#9 S RCTs Randomized controlled trials as Topic/ 94,094
#10 Randomized controlled trial/ 3,79,058
#11 Random allocation/ 80,403
#12 Double blind method/ 1,28,467
#13 Single blind method/ 18,908
#14 Clinical trial/ 4,98,397
#15 exp Clinical Trials as Topic/ 2,84,843
#16 clinical trial/or clinical trial, phase i/or clinical trial, phase ii/or clinical trial, phase iii/or clinical trial, phase iv/or 6,38,636
multicenter study/
#17 or/9–16 10,27,511
#18 randomized controlled trial.pt. 3,79,058
#19 controlled clinical trial.pt. 88,604
#20 random allocation.sh. 80,403
#21 double blind method.sh. 1,28,467
#22 single blind method.sh. 18,908
#23 (clin$ adj25 trial$).tw. 2,67,767
#24 ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$ or dummy$)).tw. 1,35,302
#25 Placebos/ 33,207
#26 Placebo$.tw. 1,60,829
#27 placebos.sh. 33,207
#28 Random$.tw. 7,04,067
#29 or/18–28 11,35,515
#30 17 or 29 15,05,690
#31 Case report.tw. 1,98,265
#32 Letter/ 8,13,491
#33 Historical article/ 2,96,911
#34 31 or 32 or 33 12,97,438
#35 30 not 34 14,73,787
#36 Hits of P and I and 5 and 8 and 35 776
S
#37 Limits Humans limit 36 to humans 744
#38 Language limit 37 to english language 691

Appendix B. List of references corresponding to relevant RCTs used in the MTC analyses of
the efficacy outcome (22 publications – 25 RCTs)
Evaluation of a multiple-dose regimen of oral sumatriptan for the acute treatment of migraine. The Oral Sumatriptan International
Multiple-Dose Study Group. Eur Neurol 1991; 31 [5]:306–313.
Barbanti P, Carpay JA, Kwong WJ, Ahmad F, Boswell D. Effects of a fast disintegrating/rapid release oral formulation of
sumatriptan on functional ability in patients with migraine. Curr Med Res Opin 2004; 20 [12]:2021–2029.
Carpay J, Schoenen J, Ahmad F, Kinrade F, Boswell D. Efficacy and tolerability of sumatriptan tablets in a fast-disintegrating,
rapid-release formulation for the acute treatment of migraine: results of a multicenter, randomized, placebo-controlled study. Clin
Ther 2004; 26 [2]:214–223.
10 K. THOKAGEVISTK ET AL.

Cutler N, Mushet GR, Davis R, Clements B, Whitcher L. Oral sumatriptan for the acute treatment of migraine: evaluation of three
dosage strengths. Neurology 1995; 45(8 Suppl 7):S5-S9.
Dowson AJ, Massiou H, Lainez JM, Cabarrocas X. Almotriptan is an effective and well-tolerated treatment for migraine pain:
results of a randomized, double-blind, placebo-controlled clinical trial. Cephalalgia 2002; 22 [6]:453–461.
Geraud G, Olesen J, Pfaffenrath V, Tfelt-Hansen P, Zupping R, Diener HC et al. Comparison of the efficacy of zolmitriptan and
sumatriptan: issues in migraine trial design. Cephalalgia 2000; 20 [1]:30–38.
Goadsby PJ, Ferrari MD, Olesen J, Stovner LJ, Senard JM, Jackson NC et al. Eletriptan in acute migraine: a double-blind, placebo-
controlled comparison to sumatriptan. Eletriptan Steering Committee. Neurology 2000; 54 [1]:156–163.
Jelinski SE, Becker WJ, Christie SN, Ahmad FE, Pryse-Phillips W, Simpson SD. Pain-free efficacy of sumatriptan in the early
treatment of migraine. Can J Neurol Sci 2006; 33 [1]:73–79.
Kaniecki R, Ruoff G, Smith T, Barrett PS, Ames MH, Byrd S et al. Prevalence of migraine and response to sumatriptan in patients
self-reporting tension/stress headache. Curr Med Res Opin 2006; 22 [8]:1535–1544.
Landy S, Savani N, Shackelford S, Loftus J, Jones M. Efficacy and tolerability of sumatriptan tablets administered during the
mild-pain phase of menstrually associated migraine. Int J Clin Pract 2004; 58 [10]:913–919.
Mathew NT, Schoenen J, Winner P, Muirhead N, Sikes CR. Comparative efficacy of eletriptan 40 mg versus sumatriptan 100 mg.
Headache 2003; 43 [3]:214–222.
Myllyla VV, Havanka H, Herrala L, Kangasniemi P, Rautakorpi I, Turkka J et al. Tolfenamic acid rapid release versus sumatriptan
in the acute treatment of migraine: comparable effect in a double-blind, randomized, controlled, parallel-group study. Headache
1998; 38 [3]:201–207.
Nappi G, Sicuteri F, Byrne M, Roncolato M, Zerbini O. Oral sumatriptan compared with placebo in the acute treatment of
migraine. J Neurol 1994; 241 [3]:138–144.
Nett R, Landy S, Shackelford S, Richardson MS, Ames M, Lener M. Pain-free efficacy after treatment with sumatriptan in the mild
pain phase of menstrually associated migraine. Obstet Gynecol 2003; 102 [4]:835–842.
Pfaffenrath V, Cunin G, Sjonell G, Prendergast S. Efficacy and safety of sumatriptan tablets (25 mg, 50 mg, and 100 mg) in the
acute treatment of migraine: defining the optimum doses of oral sumatriptan. Headache 1998; 38 [3]:184–190.
Rederich G, Rapoport A, Cutler N, Hazelrigg R, Jamerson B. Oral sumatriptan for the long-term treatment of migraine: clinical
findings. Neurology 1995; 45(8 Suppl 7):S15-S20.
Sandrini G, Farkkila M, Burgess G, Forster E, Haughie S. Eletriptan vs. sumatriptan: a double-blind, placebo-controlled, multiple
migraine attack study. Neurology 2002; 59 [8]:1210–1217.
Sheftell FD, Dahlof CG, Brandes JL, Agosti R, Jones MW, Barrett PS. Two replicate randomized, double-blind, placebo-controlled
trials of the time to onset of pain relief in the acute treatment of migraine with a fast-disintegrating/rapid-release formulation of
sumatriptan tablets. Clin Ther 2005; 27 [4]:407–417.
Tepper SJ, Cady R, Dodick D, Freitag FG, Hutchinson SL, Twomey C et al. Oral sumatriptan for the acute treatment of probable
migraine: first randomized, controlled study. Headache 2006; 46 [1]:115–124.
Tfelt-Hansen P, Teall J, Rodriguez F, Giacovazzo M, Paz J, Malbecq W et al. Oral rizatriptan versus oral sumatriptan: a direct
comparative study in the acute treatment of migraine. Rizatriptan 030 Study Group. Headache 1998; 38 [10]:748–755.
Visser WH, Terwindt GM, Reines SA, Jiang K, Lines CR, Ferrari MD. Rizatriptan vs. sumatriptan in the acute treatment of
migraine. A placebo-controlled, dose-ranging study. Dutch/US Rizatriptan Study Group. Arch Neurol 1996; 53 [11]:1132–1137.
Winner P, Mannix LK, Putnam DG, McNeal S, Kwong J, O’Quinn S et al. Pain-free results with sumatriptan taken at the first sign
of migraine pain: 2 randomized, double-blind, placebo-controlled studies. Mayo Clin Proc 2003; 78 [10]:1214–1222.

Appendix C. List of references corresponding to relevant RCTs used in the MTC analyses of the
tolerability outcome (26 publications – 28 RCTs)
Acute treatment of migraine attacks: efficacy and safety of a nonsteroidal anti-inflammatory drug, diclofenac-potassium, in comparison
to oral sumatriptan and placebo. The Diclofenac-K/Sumatriptan Migraine Study Group. Cephalalgia 1999; 19 [4]:232–240.
Evaluation of a multiple-dose regimen of oral sumatriptan for the acute treatment of migraine. The Oral Sumatriptan
International Multiple-Dose Study Group. Eur Neurol 1991; 31 [5]:306–313.
Sumatriptan–an oral dose-defining study. The Oral Sumatriptan Dose-Defining Study Group. Eur Neurol 1991; 31 [5]:300–305.
Carpay J, Schoenen J, Ahmad F, Kinrade F, Boswell D. Efficacy and tolerability of sumatriptan tablets in a fast-disintegrating,
rapid-release formulation for the acute treatment of migraine: results of a multicenter, randomized, placebo-controlled study. Clin
Ther 2004; 26 [2]:214–223.
Cutler N, Mushet GR, Davis R, Clements B, Whitcher L. Oral sumatriptan for the acute treatment of migraine: evaluation of three
dosage strengths. Neurology 1995; 45(8 Suppl 7):S5-S9.
Dowson AJ, Massiou H, Lainez JM, Cabarrocas X. Almotriptan is an effective and well-tolerated treatment for migraine pain:
results of a randomized, double-blind, placebo-controlled clinical trial. Cephalalgia 2002; 22 [6]:453–461.
Dowson AJ, Massiou H, Aurora SK. Managing migraine headaches experienced by patients who self-report with menstrually
related migraine: a prospective, placebo-controlled study with oral sumatriptan. J Headache Pain 2005; 6 [2]:81–87.
Geraud G, Olesen J, Pfaffenrath V, Tfelt-Hansen P, Zupping R, Diener HC et al. Comparison of the efficacy of zolmitriptan and
sumatriptan: issues in migraine trial design. Cephalalgia 2000; 20 [1]:30–38.
 JOURNAL OF MARKET ACCESS & HEALTH POLICY 11

Goadsby PJ, Ferrari MD, Olesen J, Stovner LJ, Senard JM, Jackson NC et al. Eletriptan in acute migraine: a double-blind, placebo-
controlled comparison to sumatriptan. Eletriptan Steering Committee. Neurology 2000; 54 [1]:156–163.
Havanka H, Dahlof C, Pop PH, Diener HC, Winter P, Whitehouse H et al. Efficacy of naratriptan tablets in the acute treatment of
migraine: a dose-ranging study. Naratriptan S2WB2004 Study Group. Clin Ther 2000; 22 [8]:970–980.
Jelinski SE, Becker WJ, Christie SN, Ahmad FE, Pryse-Phillips W, Simpson SD. Pain-free efficacy of sumatriptan in the early
treatment of migraine. Can J Neurol Sci 2006; 33 [1]:73–79.
Kaniecki R, Ruoff G, Smith T, Barrett PS, Ames MH, Byrd S et al. Prevalence of migraine and response to sumatriptan in patients
self-reporting tension/stress headache. Curr Med Res Opin 2006; 22 [8]:1535–1544.
Mathew NT, Schoenen J, Winner P, Muirhead N, Sikes CR. Comparative efficacy of eletriptan 40 mg versus sumatriptan 100 mg.
Headache 2003; 43 [3]:214–222.
Myllyla VV, Havanka H, Herrala L, Kangasniemi P, Rautakorpi I, Turkka J et al. Tolfenamic acid rapid release versus sumatriptan
in the acute treatment of migraine: comparable effect in a double-blind, randomized, controlled, parallel-group study. Headache
1998; 38 [3]:201–207.
Nappi G, Sicuteri F, Byrne M, Roncolato M, Zerbini O. Oral sumatriptan compared with placebo in the acute treatment of
migraine. J Neurol 1994; 241 [3]:138–144.
Nett R, Landy S, Shackelford S, Richardson MS, Ames M, Lener M. Pain-free efficacy after treatment with sumatriptan in the mild
pain phase of menstrually associated migraine. Obstet Gynecol 2003; 102 [4]:835–842.
Pfaffenrath V, Cunin G, Sjonell G, Prendergast S. Efficacy and safety of sumatriptan tablets (25 mg, 50 mg, and 100 mg) in the
acute treatment of migraine: defining the optimum doses of oral sumatriptan. Headache 1998; 38 [3]:184–190.
Pini LA, Sternieri E, Fabbri L, Zerbini O, Bamfi F. High efficacy and low frequency of headache recurrence after oral sumatriptan.
The Oral Sumatriptan Italian Study Group. J Int Med Res 1995; 23 [2]:96–105.
Rederich G, Rapoport A, Cutler N, Hazelrigg R, Jamerson B. Oral sumatriptan for the long-term treatment of migraine: clinical
findings. Neurology 1995; 45(8 Suppl 7):S15-S20.
Sargent J, Kirchner JR, Davis R, Kirkhart B. Oral sumatriptan is effective and well tolerated for the acute treatment of migraine:
results of a multicenter study. Neurology 1995; 45(8 Suppl 7):S10-S14.
Sheftell FD, Dahlof CG, Brandes JL, Agosti R, Jones MW, Barrett PS. Two replicate randomized, double-blind, placebo-controlled
trials of the time to onset of pain relief in the acute treatment of migraine with a fast-disintegrating/rapid-release formulation of
sumatriptan tablets. Clin Ther 2005; 27 [4]:407–417.
Tepper SJ, Cady R, Dodick D, Freitag FG, Hutchinson SL, Twomey C et al. Oral sumatriptan for the acute treatment of probable
migraine: first randomized, controlled study. Headache 2006; 46 [1]:115–124.
Tfelt-Hansen P, Teall J, Rodriguez F, Giacovazzo M, Paz J, Malbecq W et al. Oral rizatriptan versus oral sumatriptan: a direct
comparative study in the acute treatment of migraine. Rizatriptan 030 Study Group. Headache 1998; 38 [10]:748–755.
Tfelt-Hansen P, Henry P, Mulder LJ, Scheldewaert RG, Schoenen J, Chazot G. The effectiveness of combined oral lysine
acetylsalicylate and metoclopramide compared with oral sumatriptan for migraine. Lancet 1995; 346(8980):923–926.
Visser WH, Terwindt GM, Reines SA, Jiang K, Lines CR, Ferrari MD. Rizatriptan vs. sumatriptan in the acute treatment of
migraine. A placebo-controlled, dose-ranging study. Dutch/US Rizatriptan Study Group. Arch Neurol 1996; 53 [11]:1132–1137.
Winner P, Mannix LK, Putnam DG, McNeal S, Kwong J, O’Quinn S et al. Pain-free results with sumatriptan taken at the first sign
of migraine pain: 2 randomized, double-blind, placebo-controlled studies. Mayo Clin Proc 2003; 78 [10]:1214–1222.
 Reduced efficacy of sumatriptan in
migraine with aura vs without aura

Jakob Møller Hansen, ABSTRACT

MD, PhD Objective: To determine whether acute migraine treatment outcome is different in migraine with
Peter J. Goadsby, MD, aura compared with migraine without aura.
PhD
Methods: We examined pooled outcome data for sumatriptan treatment of migraine with and without
Andrew Charles, MD
aura from the sumatriptan/naratriptan aggregate patient database. We also examined similar out-
come data for inhaled dihydroergotamine (DHE) from a single, large randomized controlled study.
Correspondence to Results: The pooled pain-free rates 2 hours postdose for sumatriptan 100 mg were significantly
Dr. Hansen: higher in patients treating attacks without aura (32%) compared with the group who treated at-
jmh@dadlnet.dk
tacks with aura (24%) (p , 0.001). The relative risk for pain freedom 2 hours postdose for attacks
without aura was 1.33 (95% confidence interval: 1.16–1.54). The number needed to treat for 2
hours of pain freedom was 4.4 for attacks without aura and 6.2 for attacks with aura. For the
clinical trial of DHE, the 2-hour pain-free rates did not differ between patients treating attacks
without aura (29.4%) compared with those who treated attacks with aura (27.2%; p 5 0.65). The
relative risk for pain freedom 2 hours postdose for attacks without aura vs with aura was 1.08
(95% confidence interval: 0.77–1.53). The number needed to treat for 2 hours pain free was 5.8
for attacks without aura and 5.0 for attacks with aura.
Conclusion: This post hoc analysis of pooled data from multiple randomized trials indicates that
sumatriptan is less effective as acute therapy for migraine attacks with aura compared with at-
tacks without aura. In the single study of inhaled DHE, the treatment had similar efficacy for
migraine attacks with and without aura. Different responses of migraine with vs without aura
to acute therapies may provide insight into underlying migraine mechanisms and influence the
choice of acute therapies for different types of migraine attacks. Neurology® 2015;84:1880–1885

GLOSSARY
DHE 5 dihydroergotamine; MA 5 migraine with aura; MO 5 migraine without aura; NNT 5 number needed to treat; RCT 5
randomized controlled trial; SNAP 5 sumatriptan/naratriptan aggregate patient.

Migraine is the most prevalent neurologic disorder, experienced by more than 80 million people
in Europe and the United States,1 and certainly the most disabling.2 Migraine is classified in 2
major subtypes: migraine with aura (MA) and migraine without aura (MO).3 About a third of
patients with migraine have attacks with aura,4 consisting of transient, recurrent, reversible focal
neurologic symptoms arising from the cortex or brainstem. Despite this marked difference in
clinical phenotype of attacks with and without aura, most randomized clinical trials (RCTs) for
acute migraine treatments have included mixed populations of MA and MO. The analysis of
pooled data from multiple clinical trials increases statistical power to detect specific outcomes,
and study effects among subsets of patients. Previous analyses of such databases have yielded
valuable clinical and mechanistic information on migraine that would be hard to gather from
single clinical trials enrolling smaller numbers of patients.5–7
The question of whether a history of migraine aura or the presence of aura in a given attack
influences the efficacy of acute migraine treatment has not been systematically examined. We
Editorial, page 1828
From the Headache Research and Treatment Program (J.M.H., A.C.), Department of Neurology, University of California Los Angeles; Headache
Group (P.J.G.), Department of Neurology, University of California San Francisco; NIHR–Wellcome Trust Clinical Research Facility (P.J.G.),
King’s College, London, UK; and Danish Headache Centre and Department of Neurology (J.M.H.), Glostrup Hospital, Faculty of Health and
Medical Sciences, University of Copenhagen, Denmark.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

1880 © 2015 American Academy of Neurology

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 based our analyses on data from the largest
available database of acute treatment
response—the sumatriptan/naratriptan aggre-
gate patient (SNAP) database.8 We also que-
ried other pharmaceutical companies
regarding data on acute treatment response
in migraine with vs without aura, and an addi-
tional dataset was made available to us: a large-
scale RCT of inhaled dihydroergotamine
(DHE).9 For each of these datasets, we per-
formed a post hoc comparison of the efficacy
of acute treatment in individual migraine
attacks with aura vs without aura, and for
sumatriptan we also compared patients with
a diagnosis of MA with MO. Some of the data
have been reported in preliminary form.10
METHODS Treatment data were retrieved from clinical data-
bases managed by the sponsors of the clinical trials.
Data extraction and eligibility. The present study examined
the efficacy of sumatriptan and DHE for individual migraine at-
tacks with aura vs without aura and for sumatriptan also for pa-
tients with a diagnosis of MA vs MO. Data from patients aged
18 years and older receiving either active treatment or placebo
for the first migraine attack in a double-blind study, reporting
moderate or severe pain at baseline, and reporting pain freedom
status 2 hours postdose were eligible for inclusion in the
analyses. Only studies providing information on the presence of
aura for the treated attack were included.
Endpoints and statistics. The primary effect variable was the 2-
hour pain freedom rates, defined as reduction of moderate or severe
predose pain to no pain at 2 hours, as recommended by the
International Headache Society clinical trials subcommittee.11 To
adjust for the placebo effect, we calculated the therapeutic gain,
defined as the response rate in the treatment group minus the
response rate in the placebo group and we present therapeutic
gains as a function of the presence of aura for the treated attack,
Figure 1 Flowchart of study participants in the sumatriptan studies
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
although the placebo rates for the pain-free outcomes were very
much in line with what is seen for pooled analyses.12 Because
both databases stratified data according to pretreatment severity
of pain, the presence of aura by pretreatment headache severity
was examined for its effect on the 2-hour postdose pain-free
response as a secondary endpoint. Difference between groups
was compared with Fisher exact test. Statistical analyses were
performed with SPSS 17.0 software (SPSS, Inc., Chicago, IL)
for Windows. Five percent (p 5 0.05) was chosen as the level of
significance.
Triptans. The SNAP database contained data from 128
open-label, placebo-controlled, or head-to-head comparator
studies conducted with sumatriptan or naratriptan from 1987
through 1998,8 and included data from 49,642 subjects, of
whom 28,407 patients meeting International Headache Society
criteria for migraine with or without aura13 treated 131,661 mi-
graines. Aura symptoms were self-reported by tick-box and the
exact timing regarding treatment was not available.
This analysis is based on studies of sumatriptan 100 mg, and is
based on a pooling of outcome data from 21 double-blind trials
with recordings of the presence of aura at the time treatment, in
3,714 patients: sumatriptan 100 mg, n 5 2,568; placebo, n 5
1,146; see figure 1. The majority of patients were female (83.5%),
predominantly white (98%), with a mean age of 39.7 years.
Given the nature of the trials included in the database, we were
also able to examine whether the inclusion diagnoses (MO/MA)
had an impact on the treatment response: total patients, n 5
3,427: MA 5 1,091 and MO 5 2,336. Preliminary analyses of
pooled data were conducted using recursive partitioning, paramet-
ric and nonparametric univariate statistical analysis, and regression
analysis techniques as previously described in more detail.8
Dihydroergotamine. We analyzed data from a large random-
ized, double-blind, placebo-controlled, 2-arm, phase 3, multi-
center study of MAP0004, an orally inhaled formulation of
dihydroergotamine (DHE) (emitted dose 0.63 mg; 1.0 mg
nominal dose).9 Attacks were recorded in real time by the patients
in an electronic diary. Before taking any medication, the diary
prompted the patients to answer “did you have an aura?” Based
on the answer, the patients were divided into the 2 groups: with
and without aura.
At time of treatment, all patients had moderate–severe head-
ache. Pain relief at 2 hours was the primary endpoint of the trial,
with the proportion of patients pain-free at 2 hours as a
Neurology 84 May 5, 2015 1881
 Figure 2 Flowchart of study participants in the dihydroergotamine study

predefined secondary endpoint.9 Patients (n 5 903) were ran- moderate/severe) (p # 0.05). In the placebo group,
domized from 102 centers in the United States, and 769 patients the 2-hour pain-free rates were 8.9% (71/794) for
could be included in the analysis for this report (see figure 2). The
attacks without aura and 8% (28/352) for attacks
majority of patients were female (91.3%), predominantly white
(86%), with a mean age of 40 years.
with aura (p 5 0.65).
The corresponding therapeutic gains for 2 hours
Standard protocol approvals, registrations, and patient pain-free for patients treating attacks without aura
consents. All study centers received approval from an ethical
were 23% compared with 16% in patients treating at-
standards committee on human experimentation (institutional
or regional) for any experiments using human subjects, and writ- tacks with aura (figure 4), and thus NNT for 2-hour
ten informed consent was obtained from all patients participating pain freedom was 4.4 for attacks without aura and 6.2
in the study. The DHE trial was registered with ClinicalTrials. for attacks with aura (table).
gov, number NCT00623636. Treatment outcome in patients according to inclusion
diagnoses: MA and MO. The
2-hour pain-free rates after
Among
RESULTS Sumatriptan. Migraine characteristics.
sumatriptan 100 mg were higher in patients included
patients who reported aura during their attack, 70%
had a diagnosis of MA recorded at study enrollment.
Of patients without aura during their attack, 77% Figure 3 Pain freedom 2 hours after treatment
had a diagnosis of MO. in attacks with and without aura
At the time of treatment, 32.3% of patients
(1,199/3,714) reported aura; 33% of patients
(847/2,568) were treated with sumatriptan and
30.7% (352/1,146) with placebo. For this mixed
group with and without aura (n 5 3,714), the pain
freedom rates at 2 hours were 29.4% for sumatriptan
and 8.6% for placebo (p , 0.001), yielding a thera-
peutic gain of 20.8% and number needed to treat
(NNT) of 4.8 for 2-hour pain freedom.
Treatment outcome in attacks with and without aura.
Among patients treating attacks without aura with su-
matriptan 100 mg, the 2-hour pain-free rates were
higher, 32%, compared with the group who treated For sumatriptan 100 mg, there is a significantly reduced
pain-free rate in patients who treated attacks with aura
attacks with aura, 24% (p , 0.001) (figure 3). Pain
compared with attacks without aura. For dihydroergota-
freedom rates at 2 hours in attacks with aura were mine, there was no difference between attacks with and
lower regardless of predose headache severity (mild/ without aura.

1882 Neurology 84 May 5, 2015

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


Figure 4 Therapeutic gain (pain freedom 2 hours
postdose) in attacks with and without
aura
Therapeutic gain calculated as the response rate in the
treatment group minus the response rate in the placebo
group.
with a diagnosis of MO, 31%, compared with the
MA group, 27% (p 5 0.039). In the placebo group,
the corresponding values were 9% for MO and
10.1% for MA (p 5 0.63). The therapeutic gains
for 2 hours pain free for patients included as MO
patients was 22% compared with 16.9% in patients
included with an MA diagnosis. The corresponding
NNT for 2-hour pain freedom in patients included as
MO was 4.5 and 6.0 for MA (table).
Dihydroergotamine. Migraine characteristics. At the time
of treatment, 302 patients reported aura: 162 patients
treated with MAP0004 and 140 patients treated with
placebo. For all patients (n 5 794), the pain freedom
rates at 2 hours were 28.4% for MAP0004 and
10.1% for placebo (p , 0.0001), yielding a therapeu-
tic gain of 17.9%, and NNT of 5.6 for 2 hours of
pain freedom.
Treatment outcome in attacks with and without aura.
The 2-hour pain-free rates after DHE did not differ
between patients treating attacks without aura
(29.4%) compared with those who treated attacks
with aura (27.2%, p 5 0.65; figure 3). The 2-hour
pain freedom rates did not differ between attacks
with aura and without aura for both moderate and
severe predose headache severity (p $ 0.05). In the
placebo group, the 2-hour pain freedom rates for
attacks with aura were 7.1%, and 12.2% for attacks
without aura (p 5 0.16).
The therapeutic gains for 2-hour pain freedom for
patients treating attacks without aura were 17.2%
compared with 20.0% in patients treating attacks
with aura (figure 4). The corresponding NNT for
2-hour pain freedom after DHE was 5.8 for attacks
without aura and 5.0 for attacks with aura (table).
DISCUSSION This post hoc analysis indicates that
migraine attacks with aura are less responsive to su-
matriptan than migraine without aura.
One possible explanation for this differential
response to sumatriptan is that migraine attacks that
include cortical symptoms may involve more diffuse
or severe derangements of brain physiology, and thus
may be more difficult to treat. Alternatively, attacks of
migraine with aura may involve distinct mechanisms
that result in different responses to therapy.
Consistent with this concept, tonabersat, which is
thought to block cortical spreading depression and
thereby migraine aura, was found in an RCT to pre-
vent attacks of migraine with aura but not those with-
out aura.14
Previous studies indicated that triptans, specifically
sumatriptan, eletriptan, and zolmitriptan,15–17 were not
effective in relieving migraine when taken during the
aura phase of an attack. These findings were challenged

Table Number of patients treated with sumatriptan, DHE, or placebo achieving pain freedom 2 hours postdose, relative risk to be pain-free at
2 hours in attacks without aura vs attacks with aura, and NNT to achieve 2-hour pain freedom in acute migraine attacks

Treatment Placebo

Attacks treated 2 h pain free Relative risk (95% CI) Attacks treated 2 h pain free Relative risk (95% CI) NNT

Sumatriptan 100 mg

Attacks with aura 847 203 1.33 (1.16–1.54) 352 28 1.12 (0.73–1.76) 6.2 (5.1–8.6)

Attacks without aura 1,721 551 794 71 4.4 (3.9–5.1)

MA (inclusion diagnosis) 795 214 1.15 (1.00–1.32) 296 30 0.89 (0.57–1.39) 6.0 (4.8–8.5)

MO (inclusion diagnosis) 1,691 524 645 58 4.5 (4.0–5.3)

DHE

Attacks with aura 162 44 1.08 (0.77–1.53) 140 10 1.70 (0.83–3.65) 5.0 (3.8–8.9)

Attacks without aura 221 65 246 30 5.8 (4.1–10.4)

Abbreviations: CI 5 confidence interval; DHE 5 dihydroergotamine; MA 5 migraine with aura; MO 5 migraine without aura; NNT 5 number needed to treat.
Data are absolute numbers and 95% CIs.

Neurology 84 May 5, 2015 1883

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 by a small open-label crossover study with sumatrip-
tan,18 and other studies also suggest that triptans may
work when taken during the aura phase.19,20
Two of the studies arguing against efficacy of trip-
tans administered during the aura16,17 were small.
One reported no significant difference in the propor-
tion of patients developing moderate to severe head-
ache within 6 hours postdose of eletriptan (61%, 22/
36 patients) vs placebo (46%, 19/41) (p 5 0.25).16
Despite the high placebo responder rate, these figures
translated to a therapeutic gain of 15% and an NNT
of 6.7 for eletriptan. This is not far from the thera-
peutic gain of 16% we report for MA patients after
sumatriptan. It is of interest that a large single-pulse
transcranial magnetic stimulation study (n 5 182)
investigated treatment during the aura and reported
a therapeutic gain of 17%, which was significantly
better than placebo,21 suggesting that treatment dur-
ing the aura may indeed be worthwhile. In the sem-
inal RCT of subcutaneous sumatriptan,22 the primary
endpoint was pain relief at 1 hour. Patients who had
aura with their migraine and those without aura re-
sponded similarly to sumatriptan with a therapeutic
gain of 43% for attacks with aura and 49% for attacks
without aura. Although the difference in response was
not statistically significant, it was consistent with our
report of numerically better treatment effect of suma-
triptan in attacks without aura. It can thus be specu-
lated that the pharmacokinetic properties of the
triptans are less important than the phenotype of
the attack being treated, but to our knowledge, this
has not been tested in RCTs.
In the current analysis, sumatriptan was adminis-
tered at the time of moderate pain severity, but the
timing of administration relative to the aura symp-
toms is not clear. Migraine headache may accompany
rather than follow aura in a significant percentage of
patients.23 The findings reported here raise the possi-
bility that a general reduced responsiveness to triptans
in attacks with aura, rather than simply the timing of
their administration during the attack, contributed to
the previously reported lower efficacy of triptans
when administered during the aura phase.
Analysis of the eletriptan database revealed that a
history of aura had no effect on the rate of headache
recurrence following treatment.24 In contrast, our
analyses show that in RCTs for sumatriptan
100 mg, both the attack phenotype (with or without
aura) as well as the inclusion diagnosis (MO/MA)
have substantial impact on treatment outcome. These
data were not available from the DHE trial, but
future studies should offer separate analyses of both
migraine diagnosis and the individual attacks.
In previous studies comparing sumatriptan and
DHE, both treatments were effective. Sumatriptan
provided greater headache relief, at the cost of more
1884 Neurology 84 May 5, 2015
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
adverse events25 and headache recurrence was more
likely with sumatriptan than after DHE.26 Our anal-
ysis of the results of a large-scale RCT indicated that
the response to inhaled DHE was not different for
attacks of migraine with aura vs without aura. Because
of significant differences in the nature and size of the
2 datasets, we are unable to directly compare the effi-
cacy of sumatriptan and DHE in attacks with vs with-
out aura. Systematic reviews have found insufficient
published data to perform any sensitivity analyses for
participants with and without aura.27–29
Even though few patients report only MA, the
group having both MO and MA is often substantial,
and is it therefore important to classify each individ-
ual attack being treated according to the International
Classification of Headache Disorders, as suggested by
the International Headache Society clinical trials sub-
committee.11 Our data indicate that this classification
of individual attacks may influence study results.
Although the absolute difference in treatment
between attacks with and without aura is small, an
8% overall difference in efficacy based on the type of
attack has the potential to have a significant impact
on the outcome of a clinical trial. Future studies
should evaluate whether potential gains in treatment
effects in certain migraine subgroups is offset by dif-
ferences in safety and tolerability in order to provide
an estimate of clinical efficacy. Similar analyses for the
gepants, calcitonin gene-related peptide receptor an-
tagonists, would be interesting, such as those from the
telcagepant clinical trial program.30–34 In the prepara-
tion of this study, we tried to gather results from other
large clinical trial programs, but were unsuccessful.
The present findings indicate that the attacks of
migraine with aura vs without aura may have different
responses to different acute therapies. This possibility
warrants further investigation to determine whether
patients should use different treatment strategies
based on a history of migraine with vs without aura,
or based on the presence or absence of aura during
an individual attack. Understanding these differential
responses to therapy may be an important step to per-
sonalized medicine in acute migraine treatment.
AUTHOR CONTRIBUTIONS
Dr. Jakob M. Hansen, Dr. Peter J. Goadsby, and Dr. Andrew Charles
have contributed in the analysis or interpretation of data as well as draft-
ing/revising the manuscript for content, including medical writing for
content.
ACKNOWLEDGMENT
The authors thank Allergan and the SNAP steering group for providing the
clinical trial data used for this study.
STUDY FUNDING
Supported by grants from the International Headache Society, the Skir-
ball Foundation, and the Danish Council for Independent Research–
Medical Sciences (DFF), grant 12-127798.
 DISCLOSURE
J. Hansen reports no disclosures relevant to the manuscript. P. Goadsby
reports having received research grants from Boston Scientific, Med-
tronic, GSK, MSD, MAP, Johnson & Johnson, and eNeura and having
received consulting fees or honoraria from Allergan, Almirall, ATI, BMS,
Boehringer, Boston Scientific, Coherex, CoLucid, Lilly, Medtronic, Min-
ster, MSD, MAP, eNeura, NeurAxon, NTP, and Pfizer. A. Charles has
received consulting fees from Amgen, St. Jude Medical, and eNeura. He
previously received research grant support from MAP Pharmaceuticals.
Go to Neurology.org for full disclosures.
Received April 14, 2014. Accepted in final form January 5, 2015.
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Neurology 84 May 5, 2015 1885
 Reduced efficacy of sumatriptan in migraine with aura vs without aura
Jakob Møller Hansen, Peter J. Goadsby and Andrew Charles
Neurology 2015;84;1880-1885 Published Online before print April 3, 2015
DOI 10.1212/WNL.0000000000001535

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