Original Article

Cephalalgia
2014, Vol. 34(4) 258267
Comparative efficacy of triptans ! International Headache Society 2013
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DOI: 10.1177/0333102413508661
cep.sagepub.com
A multiple treatment comparison
meta-analysis

Kristian Thorlund1,2, Edward J Mills2,3, Ping Wu3,

Elodie Ramos4, Anjan Chatterjee4, Eric Druyts3 and
Peter J Goadsby5

Abstract
Background: Migraine is the most common neurological condition in developed countries. The abortive treatment of
migraine attacks is important both for quality of life and costs associated with illness. Triptans, serotonin 5-HT1B/1D
receptor agonists, effectively relieve the pain, disability, and associated symptoms of migraine while improving health-
related quality of life. Although a number of direct head-to-head triptan comparisons have been made, data for all
possible permutations are not available, and unlikely to ever be so, although in clinical practice such information would be
useful.
Objective: We aimed to determine the relative efficacy of all available triptans to abort migraine headache among patients
with previous adequate response to migraine treatments.
Methods: We included only double-blinded randomized clinical trials comparing triptans to either placebo or another
triptan. Our primary outcomes were pain-free response at two hours and 24-hour sustained pain-free response, and our
secondary outcomes were headache response at two hours and 24-hour sustained headache response. We used
Bayesian multiple treatment comparison meta-analyses of seven triptans used in adult patients to abort migraine attacks.
We applied a random-effects analysis with meta-regression adjusting for dose. Results are reported as odds ratios with
95% credible intervals.
Results: We included data from 74 randomized clinical trials. All triptans were significantly superior to placebo for all
outcomes, with the exception of naratriptan for 24-hour sustained pain-free response. Eletriptan consistently yielded the
highest treatment effect estimates. For the two-hour endpoints, eletriptan was statistically significantly superior to
sumatriptan, almotriptan, naratriptan, and frovatriptan for at least one of the two outcomes. Rizatriptan yielded the sec-
ond highest treatment effects followed by zolmitriptan. For the 24-hour endpoints, eletriptan was statistically significantly
superior to sumatriptan, rizatriptan, almotriptan, and naratriptan for at least one of the two outcomes. Frovatriptan data
were not available at that endpoint.
Further, the probability that eletriptan is the most likely of all triptans to produce a favorable outcome was 68% for
pain-free response at two hours, and 54% for 24-hour sustained pain-free response.
Conclusion: Triptans appear to offer differing treatment effects. In the populations studied eletriptan was most likely to
produce pain-free responses that were sustained.

Keywords
Migraine, triptans, headache, meta-analysis, multiple treatment comparison, pain-free response, sustained response
Date received: 25 March 2013; revised: 19 June 2013; 27 June 2013; accepted: 2 July 2013

5
Headache Center, Department of Neurology, University of
California, USA
1 A.C. was formerly at Pfizer Ltd, USA.
Department of Clinical Epidemiology & Biostatistics, McMaster
University, Canada Corresponding author:
2
Stanford Prevention Research Center, Stanford University, USA Kristian Thorlund, Stanford Prevention Research Center, Stanford
3
Faculty of Health Sciences, University of Ottawa, Canada University, 1265 Welch Road, Stanford, CA 94305-5411, USA.
4
Pfizer Ltd, USA Email: thorluk@mcmaster.ca
Thorlund et al.
Introduction
Migraine is a chronic neurological disorder aecting
about 18% of women and 5% of men in developed
countries (1). It is probably the most common neuro-
logical condition reported in developed countries, and
is very costly to society (24). Typical migraine head-
aches last from four to 72 hours and occur on average
about 34 times per year for men and 37 times for
women (5,6). Because migraine headaches can often
be severe and because migraine is often associated
with nausea, vomiting, photophobia, and phonopho-
bia, its impact on quality of life and health-related
resource utilization can be large (7,8).
Treatments for migraine aim to prevent attacks or
abort migraine once started. Treatments range from
complementary therapies to pharmacological interven-
tions, including analgesics, anticonvulsants, calcitonin
gene-related peptide receptor blockers, ergotamines,
corticosteroids, antiemetics, and triptans (911). In
the United States (US), triptans, serotonin 5-HT1B/1D
receptor agonists, are the most commonly prescribed
migraine-specic treatments. The potential mechan-
ism(s) of action of triptans include cranial vasoconstric-
tion and inhibition of peripheral and central trigeminal
nerve transmission and altered modulation of nocicep-
tive processing (12,13).
Although seven triptans are available and have been
evaluated in randomized clinical trials, the relative e-
cacy of each triptan is uncertain since relatively few
have been evaluated in direct (head-to-head) compara-
tive randomized clinical trials (14). We aimed to deter-
mine the relative ecacy of all triptans using a
relatively new statistical approach known as a multiple
treatment comparison (MTC) meta-analysis, a meta-
analysis technique that allows for the integration of
direct and indirect comparisons (15,16). MTC meta-
analysis is now widely accepted by health technology
appraisal agencies worldwide, and are frequently used
to inform comparative eectiveness and safety between
multiple interventions in the context of decision-
making (15,16). MTCs are particularly valuable as
they permit inferences into the relative ecacy of treat-
ments that may not have been compared to each other
in direct randomized clinical trials, and they allow
strengthening of the evidence-base by combining
head-to-head with indirect evidence (15,16).
Methods
Trial eligibility
We considered all marketed triptans for our analysis
(eletriptan, sumatriptan, rizatriptan, almotriptan,
259
zolmitriptan, naratriptan, and frovatriptan). We
included double-blind (patient and provider) rando-
mized clinical trials (both parallel and cross-over
designs) investigating the treatment eects of one or
more triptans for adults (1865 years) with episodic
migraine with or without aura according to the
International Headache Society (IHS) criteria. We
included trials in which patients had at least one
migraine attack every six weeks. We included both
single and multiple migraine attack trials. We included
randomized clinical trials in which 1) treatment was
given orally in standard encapsulated format; 2) treat-
ment was taken within four to six hours of migraine
onset; 3) the patients had a history of moderate to
severe migraine attacks; 4) no analgesic or antiemetic
medication was given within four to six hours prior to
dosing, and no triptan or ergot medication was given
within 48 hours.
We excluded trials in which 1) treatment was not
given orally or in a nonconventional oral formulation
(e.g. wafer); and in which patients 2) suered from
other frequent nonmigrainous headaches; 3) had a his-
tory of treatment-resistant migraines (i.e. previous poor
response to a triptan); 4) had other clinical signicant
illnesses; 5) or had standard contraindications to
triptans.
Search strategy
We systematically searched the medical literature for
relevant randomized clinical trials (from inception to
March 2012) using MEDLINE, EMBASE, LILACS
and the Cochrane Controlled Trials Register. The
online appendix displays our search strategy. We did
not exercise any language restrictions. We also searched
the websites of the pharmaceutical companies manufac-
turing the considered triptans to identify any unpub-
lished clinical trials. All identied articles were
assessed independently by two reviewers (KT and
PW) using predesigned eligibility forms, according to
our prospectively dened eligibility criteria.
Outcomes and data extraction
We considered the following outcomes 1) the propor-
tion of patients who had a pain-free response at two
hours; 2) the proportion of patients with 24-hour sus-
tained pain-free response; 3) the proportion of
patients who had a headache response at two hours;
and 4) the proportion of patients with 24-hour sus-
tained headache response. All endpoints were con-
sidered with respect to the rst migraine attack.
Our primary endpoints were comparative eectiveness
estimates (odds ratios) between all triptans for pain-
free response at two hours, and 24-hour sustained
260
pain-free response (17). Secondary endpoints were
comparative eectiveness estimates (odds ratios)
between all triptans for headache response at two
hours, and 24-hour sustained headache response.
The time point of two hours reects short-term
response and 24 hours reects prevention of recur-
rence (17). We did not consider endpoints of adverse
eects. Although such are important for informing
clinical practice, the complexity of MTCs increases
exponentially with the addition of endpoints. To
retain simplicity of this manuscript, we therefore
focused on ecacy endpoints only.
Two reviewers (KT and PW) independently
extracted and recorded data in a Microsoft Excel
spreadsheet. All data extraction was then checked by
a third reviewer (EM). Additionally, for each trial, the
following trial characteristics were extracted: countries
of origin; number of centers; study design (parallel or
cross-over); number of participants; type of migraine;
migraine with aura; mean age (and standard devi-
ation); proportion of females; criteria used to diagnose
migraine; number with moderate to severe attacks;
medication schedule; maximum dosage/day; study
duration; and proportion of patients excluded from
the analysis (e.g. in modied intention-to-treat
analysis). Study quality items included reporting of
randomization sequence generation, allocation con-
cealment, reporting of who was blinded, use of inten-
tion to treat versus per protocol with justication for
approach used, and proportion with >20% loss to
follow-up.
Statistical analysis
In order to assess inter-rater reliability on inclusion of
articles, we calculated the Phi () statistic, rst devel-
oped to provide a measure of inter-observer agreement
independent of chance (18).
We rst conducted DerSimonian-Laird random-
eects pairwise meta-analysis of the direct trials
(19,20). We visually inspected the forest plots for
possible heterogeneity and calculated I2 values, which
provide an estimate of the percentage of variability of
eects that is unlikely to be chance (12). The direct
meta-analysis outcomes were used to check potential
inconsistency with indirect evidence.
MTC meta-analysis. We rst plotted the geometric dis-
tribution of the network of randomized clinical trial
treatment comparisons (21). We used the conventional
Bayesian MTC models for binary outcomes to esti-
mate comparative odds ratios and associated 95%
credible intervals between all triptans for the consid-
ered outcomes (22). All Bayesian MTC meta-analyses
were carried out in WinBUGS version 1.4.3
Cephalalgia 34(4)
(Cambridge, UK). A more detailed description of
the employed statistical model, including key distribu-
tional and deterministic relationships as well as the
statistical WinBUGS code, is presented in the
appendix.
Primary analysis. In keeping with the guidelines for con-
trolled trials of drugs in migraine, third edition (17), for
our primary analyses we examined data from patients
who had at least one migraine attack, were not lost to
follow-up and did not violate the trial protocol. When
studies that did not report this number, we used the
modied intention-to-treat (ITT) data (i.e. all patients
who suered at least one migraine attack, rather than
all patients who were randomized). We analyzed data
from the rst migraine attack only for crossover or
multiple attack studies.
We incorporated the eect of dose in our analysis.
As our primary analysis we employed meta-regression
to control for the eect of doubling or halving the
common dosage (23). Our model assumed the same
relative change in odds ratios associated with doubling
and halving the dose. Accordingly, the dose covariate
was constructed to contain the categories half,
common, and double, and the common was
used as the reference category in the regression
model. The considered doses for each triptan are pre-
sented in Table 1 of the online appendix. For all trip-
tans except for sumatriptan, each common dose was
the single dose indicated by the Food and Drug
Administration (FDA). We chose the common dose
as the reference dose to facilitate meta-regression on the
eect of doubling and halving the dose. As a secondary
model we employed MTC meta-analysis without meta-
regression on the doses but considered each dose as a
dierent treatment.
We obtained odds ratios and 95% credible intervals
for all comparisons. We also produced treatment rank-
ings in the form of probabilities that each treatment is
likely to work best, second best, third best, etc.
Technically these probabilities, for each triptan, are
the probability that the triptan in question is at highest
odds of producing a favorable response, e.g. pain-free
response at two hours. As such, treatment probabilities
for each treatment were calculated as the proportion of
Markov Chain Monte Carlo samples (20,000 in total)
where odds ratio was larger than the odds ratio for all
other treatments.
Analysis of common indicated doses in the US. We addition-
ally estimated the comparative eectiveness between
triptans with respect to the common indicated single
dose in the US, which varies slightly from other coun-
tries: 100 mg for sumatriptan, and common dose for
all other doses.
Thorlund et al. 261

Table 1. Odds ratios estimates and 95% credible intervals for all treatment comparisons based on the multiple treatment
comparison model regressing on dose.
Two-hour outcomes 24-hour sustained outcomes

Comparison Pain-free response Headache response Pain-free response Headache response

a
Placebo vs
Eletriptan (40 mg) 4.95 (3.756.59) 4.69 (3.915.59) 3.66 (2.635.15) 3.65 (2.765.10)
Sumatriptan (50 mg) 3.24 (2.663.97) 2.88 (2.453.39) 1.94 (1.432.63) 2.16 (1.682.79)
Rizatriptan (10 mg) 4.44 (3.515.69) 3.87 (3.264.60) 2.85 (2.004.10) 1.92 (1.402.67)
Almotriptan (2.5 mg) 2.45 (1.773.39) 2.87 (2.203.73) 2.98 (1.974.51) 2.44 (1.593.91)
Zolmitriptan (12.5 mg) 3.40 (2.544.53) 3.80 (3.054.77) 3.36 (2.284.96) 2.61 (1.893.74)
Naratriptan (2.5 mg) 1.68 (1.042.72) 2.24 (1.613.13) 1.37 (0.642.83) 2.01 (1.173.52)
Frovatriptan (2.5 mg) 3.52 (2.255.66) 2.21 (1.632.99)
Eletriptan (40 mg) vs
Sumatriptan (50 mg) 1.53 (1.162.01) 1.64 (1.292.03) 1.89 (1.372.62) 1.69 (1.382.17)
Rizatriptan (10 mg) 1.12(0.801.55) 1.21 (0.951.54) 1.28 (0.782.10) 1.88 (1.233.01)
Almotriptan (2.5 mg) 2.03(1.382.96) 1.63 (1.192.23) 1.22 (0.742.06) 1.50 (0.832.58)
Zolmitriptan (12.5 mg) 1.46(1.022.09) 1.23 (0.931.61) 1.09 (0.701.70) 1.39 (0.962.06)
Naratriptan (2.5 mg) 2.95 (1.784.90) 2.09 (1.462.99) 2.68 (1.365.59) 1.82 (1.122.99)
Frovatriptan (2.5 mg) 1.41 (0.822.37) 2.12 (1.483.01)
Sumatriptan (50 mg) vs
Rizatriptan (10 mg) 0.73 (0.560.94) 0.75 (0.600.93) 0.67 (0.421.09) 1.13 (0.741.69)
Almotriptan (2.5 mg) 1.32 (0.951.84) 1.00 (0.761.34) 0.65 (0.391.09) 0.89 (0.521.47)
Zolmitriptan (12.5 mg) 0.95 (0.691.32) 0.58 (0.760.98) 0.58 (0.360.93) 0.82 (0.571.16)
Naratriptan (2.5 mg) 1.93 (1.173.17) 1.29 (0.891.86) 1.46 (0.683.08) 1.08 (0.631.81)
Frovatriptan (2.5 mg) 0.92 (0.551.49) 1.30 (0.921.84)
Rizatriptan (10 mg) vs
Almotriptan (2.5 mg) 1.85 (1.242.67) 1.34 (0.991.84) 0.95 (0.561.68) 0.79 (0.441.33)
Zolmitriptan (12.5 mg) 1.31 (0.921.87) 1.02 (0.771.33) 0.84 (0.501.46) 0.73 (0.451.17)
Naratriptan (2.5 mg) 2.65 (1.614.38) 1.73 (1.202.47) 2.09 (0.944.88) 0.97 (0.491.77)
Frovatriptan(2.5 mg) 1.26 (0.742.10) 1.75 (1.232.49)
Almotriptan (2.5 mg) vs
Zolmitriptan (12.5 mg) 1.04 (0.611.79) 0.58 (0.390.84) 0.89 (0.581.36) 0.93 (0.531.64)
Naratriptan (2.5 mg) 2.10 (1.104.12) 0.98 (0.631.55) 2.19 (0.972.19) 1.21 (0.612.64)
Frovatriptan (2.5 mg) 1.44 (0.832.53) 0.77 (0.521.16)
Zolmitriptan(12.5 mg) vs
Naratriptan (2.5 mg) 0.72 (0.491.06) 0.75 (0.551.02) 2.46 (2.465.53) 1.32 (0.712.35)
Frovatriptan (2.5 mg) 0.69 (0.391.20) 1.29 (0.861.93)
Naratriptan (2.5 mg) vs
Frovatriptan (2.5 mg) 0.96 (0.561.64) 1.71 (1.182.51)

Comparative odds ratios with 95% credible intervals (CrI) from the multiple treatment comparison (MTC) analyses of pain-free response and headache
response at two hours, and 24-hour sustained pain-free response and headache response. Odds ratio larger than 1.00 indicate superiority of the first of
two triptans in a comparison (and the triptan in the placebo comparisons). The first column indicates the comparison; the second and third column
present the pain-free response and headache response outcomes at two hours; and the fourth and fifth column present the 24-hour sustained pain-free
and headache response outcomes.
a
Comparisons with placebo are reported as triptan vs placebo and odds ratios larger than 1.00 therefore indicate superiority of the triptan over placebo.

Data consistency check. We examined inconsistency

between direct and indirect estimates both visually
and using z-tests.
Statistical software. Variable recoding was handled in
Microsoft Excel. All statistical analyses were conducted
in WinBUGS (MRC Biostatistics Unit, Cambridge,
UK) and StatsDirect (StatsDirect Ltd, UK).
Results
We included 67 publications with 74 randomized clin-
ical trials examining triptans for the treatment and pre-
vention of migraine attacks (Figure 1, online appendix
Table 9 for included studies and study characteristics).
Five publications each included two trials and one pub-
lication included three trials. Placebo was compared to
262 Cephalalgia 34(4)

two-hour pain-free response. The remaining consist-

430 Abstracts initially
screened for inclusion
ency tables are available from the authors
upon request. Eletriptan, sumatriptan, and rizatriptan
279 Abstracts excludes
as clearly outside the
were informed by many placebo-controlled trials.
inclusion criteria. Almotriptan and zolmitriptan were generally informed
by a moderate number of placebo-controlled trials,
151 full-text articles
screened for inclusion whereas naratriptan and frovatriptan were typically
23 papers were excluded:
9: endpoints did not match. informed only by a few placebo-controlled trials. For
6: not acute migraine treatment
related.
the two-hour outcomes, head-to-head comparisons
1: treated with avitriptan existed for many of the triptans; however, only suma-
4: no placebo used as control/used
standard care as control. triptan was compared with other triptans (eletriptan,
3: history of poor response to triptans
128 full-text papers rizatriptan, and almotriptan) in more than one trial.
were further reviewed For the 24-hour outcomes, ve head-to-head compari-
sons were available between triptans for both
61: papers were further excluded:
12: sub-group analysis of included outcomes, and except for eletriptan versus sumatriptan,
papers.
31: used non-oral formulation (ex.
each head-to-head comparison comprised only
injection, nasal spray or suppository) one trial.
4: used non-conventional oral
formulation (e.g., wafer)
14: did not report 1st attack results
67 studies (74 RCTs) met
inclusion criteria and were Primary analysis
included in the systematic
review Table 1 displays the comparative odds ratios and 95%
credible intervals for all outcomes from the primary
MTC model adjusting for dose. Table 2 presents the
Figure 1. Flowchart of included and excluded studies.
treatment rankings for all unadjusted and adjusted ana-
RCT: randomized clinical trials.
lysis for each outcome. Figure 4 (a) and (b) display
forest plots of the primary endpoints for individual
eletriptan, sumatriptan, rizatriptan, zolmitriptan, almo- triptans versus placebo based on the MTC ndings.
triptan, naratriptan, and frovatriptan in 15, 30, 16, 5, At the two-hour time point, all triptans were signi-
9, 5, and 4 trials, respectively. Fifteen trials included cantly superior to placebo (dened as the 95% credible
head-to-head comparisons between the seven triptans. interval precluding 1.00). At the 24-hour time point all
Four trials were cross-over designs, of which two trials triptans except for naratriptan were signicantly super-
reported results after the rst stage, and two reported ior to placebo. Eletriptan consistently yielded higher
results after the second stage. Sixty-three trials reported odds ratios than the other triptans. For both two-
the outcome of pain-free response at two hours; 25 hour outcomes, eletriptan was signicantly superior to
reported 24-hour sustained pain-free response; 61 sumatriptan, almotriptan, and naratriptan. Eletriptan
reported headache response at two hours; and 16 was also signicantly superior to zolmitriptan for
reported 24-hour sustained headache response. Figure achieving pain-free response at two hours, and signi-
2 shows the network of available comparisons for the cantly superior to frovatriptan for achieving headache
endpoint of pain-free response at two hours, and Figure response at two hours. For both 24-hour outcomes,
3 displays the network for the endpoint of 24-hour sus- eletriptan was signicantly superior to sumatriptan
tained pain-free response. Online appendices Figures 1 and naratriptan. Eletriptan was also signicantly super-
and 2 display the networks for headache response at ior to rizatriptan for achieving 24-hour sustained head-
two hours, and 24-hour sustained headache response, ache response. The probability that eletriptan is the
respectively. most likely of all triptans to produce a pain-free
response at two hours and a headache response at
two hours was 67.7% and 71.6%, respectively. The
Strength and diversity of treatment networks probability that eletriptan is the most likely of all trip-
Inspection and analysis of direct and indirect estimates tans to produce a 24-hour sustained pain-free response
did not reveal inconsistency beyond the play of chance and a 24-hour sustained headache response was 54.1%
for any of the outcomes. Generally, direct and indirect and 87.8%, respectively. The highest probability of
estimates were of similar magnitude and direction. being the second best was found with rizatriptan for
In the few cases in which comparative estimates of dif- the two-hour outcomes, and with zolmitriptan for the
ferent directions occurred, 95% condence intervals 24-hour outcomes (online appendix Table 8). The high-
were very wide. Online appendix Table 7 shows the est probability of being the third best was found with
inconsistency checks for triptan standard doses for zolmitriptan for the two-hour outcomes, and shared
Thorlund et al.
Figure 2. Network of eligible treatment comparisons for the multiple treatment comparison meta-analysis of the pain-free response
at two hours.
between almotriptan and zolmitriptan for the 24-hour
outcomes (online appendix Table 8).The above results
apply to the common doses of triptans (see online
appendix Table 1). Meta-regression incorporating
the dose covariate demonstrated a signicant eect of
doubling (or halving) the dose for both the two-hour
outcomes and the 24-hour outcomes. The eect modi-
cation by dose was larger for the pain-free response
outcomes (log odds ratio coecient estimates of 0.24
and 0.41) than for the headache response outcomes
(log odds ratio coecient estimates of 0.19 and 0.22).
Inspection of the model t statistics, deviance infor-
mation criterion (DIC), revealed that the primary
model, the regression model on dose, yielded a notably
better t than the secondary model for the pain-free
response at two hours. For the other outcomes, the
models yielded similar ts (online appendix Table 2).
This suggests that the dose-regression model is well-
justied as the primary model.
Secondary analysis
Online appendix Table 3 displays the comparative odds
ratios and 95% credible intervals for all outcomes from
the primary multiple treatment comparison model
adjusting for dose. Generally, the results were highly
263
similar to the primary analysis. However, for 24-hour
sustained pain-free response, eletriptan also
became signicantly superior to rizatriptan and
almotriptan (in addition to sumatriptan and naratrip-
tan). For sustained 24-hour headache response, the
statistical signicance was lost for the comparison
with rizatriptan.
Sensitivity analysis
Online appendices Tables 4 and 5 display the results
from the primary and secondary MTC models, respect-
ively, where 100 mg was considered the common
dose for sumatriptan. Online appendix Table 6 displays
the treatment ranking from the primary MTC model
considering 100 mg sumatriptan as the common dose.
Overall, sumatriptan had more favorable comparative
eectiveness estimates than in the primary analysis.
Eletriptan still yielded larger treatment eect estimates
than sumatriptan, albeit not statistically signicant.
The probabilities of eletriptan being the most likely to
produce a favorable outcome did not change with
100 mg being the common sumatriptan dose.
Sensitivity analysis including six additional eligible
but unpublished trials comparing 50 mg and 100 mg
sumatriptan with placebo did not cause noticeable
264 Cephalalgia 34(4)

Figure 3. Network of eligible treatment comparisons for the multiple treatment comparison meta-analysis of sustained 24-hour
pain-free response.

Table 2. Treatment rankings.

Two-hour outcomes 24-hour sustained outcomes

Pain-free Headache Pain-free Headache

Triptan response response response response

Eletriptan 68.7% 71.6% 54.1% 87.8%

Sumatriptan 0.0% 0.0% 0.0% 0.0%
Rizatriptan 22.6% 15.7% 9.2% 0.1%
Almotriptan 0.0% 0.0% 10.4% 3.5%
Zolmitriptan 0.7% 12.6% 26.1% 7.7%
Naratriptan 0.0% 0.1% 0.2% 0.9%
Frovatriptan 8.0% 0.0%
Probabilities of each of the triptans being the best for each of the four outcomes.

changes in the eect estimates or width of the credible
intervals (results not shown).
Discussion
Our study examined whether triptans oer diering
eects for the abortive treatment of migraine and
found statistically signicant dierences between avail-
able triptans. We found that all triptans oered
favorable response compared with placebo both for
short-term and sustained pain-free response and head-
ache response. Eletriptan appeared to oer the most
favorable outcomes in terms of pain-free response and
headache response in relation to other triptans both for
short-term and sustained outcomes. Rizatriptan, zolmi-
triptan and high-dose (100 mg) sumatriptan also appear
eective at two hours, whereas only Zolmitriptan and
high-dose sumatriptan appear to maintain their ecacy
Thorlund et al. 265

Figure 4. Forest plot of the primary multiple treatment comparison meta-analysis results, triptans versus placebo.
(a) Pain-free response at two hours; (b) 24-hour sustained pain-free response.

at 24 hours. These ndings should be of interest both to
clinicians and patients as they provide guidance in the
choice of the most favorable drugs available.
MTC meta-analysis permits inferences into the rela-
tive eects of treatments even if they have not been dir-
ectly compared in head-to-head trials. The methods for
the conduct and interpretation of MTCs have been
extensively reviewed elsewhere (16,2125) Several
important considerations are necessary to allow for
valid MTCs. These include that the trials of each triptan
are suciently similar to combine, that the trials of dif-
fering triptans are suciently similar in terms of patient
populations and outcomes to compare, and that the
direct evidence is suciently similar in direction and
magnitude to the indirect evidence. We believe that
these considerations have been met in this analysis.
Our study has several strengths. Our searches were
sensitive and we believe that all completed and pub-
lished trials have been included (26). When we applied
a variety of sensitivity analyses, we found that our pri-
mary analysis ndings were robust. Limitations of this
analysis include the quality of reporting at the level of
individual trials. Although most trials reported their
ndings according to established guidelines (17), there
is some debate about the use of intention to treat versus
per protocol in the analysis of migraine trials as it is
266 Cephalalgia 34(4)

necessary that a randomized patient experience at least
one migraine attack for them to have an endpoint of
pain-free response or headache response at any time
point (27). We examined this in a sensitivity analysis
and did not nd important dierences. Our treatment
networks display that some treatment comparisons are
informed by considerably more randomized clinical
trials than others (21). Most treatments had a large
number of placebo comparison trials at the two-hour
endpoint, yet naratriptan and frovatriptan had much
fewer trials informing their comparisons. It is possible
that the ndings of our analysis would dier if a large
number of new head-to-head randomized clinical trials
became available. It is also possible that publication
bias explains the lower number of trials of specic
drugs (26,28). Finally, our study did not examine
adverse events and it is possible that dierent triptans
exhibit diering adverse events (29).
Dierent dosages of drug treatments are frequently
employed in migraine treatment. We accounted for the
eect of dosage both in our primary and secondary
model. Our study displays that treatment dosage does
have an important role in the choice of drug and treat-
ment outcomes. Our sensitivity analysis in which the
common dose of sumatriptan was considered to be
100 mg further inform comparative eectiveness par-
ticularly pertinent to the US.
It should be noted that the results should not readily
be generalized to patient populations that were
not included in our MTC. Particularly, the comparative
ecacy between triptans may be dierent in
patients with a history of a previous poor response
to migraine treatments (e.g. to triptans) and patients
suering from frequent nonmigranious headaches or
other clinically signicant illnesses. Of course, if a
patient has previously responded poorly to a triptan,
following the results of our analysis, a natural choice in
clinical practice could well be to (or if a patient did not
respond well to eletriptan, try one of the triptants that
appear second or third best).
In conclusion, our study displays a hierarchy of
treatment eects oered by the currently available
triptans. Eletriptan appears to oer consistently the
largest treatment ecacy at two and 24 hours.
Rizatriptan appears to oer the second most favorable
treatment outcome at two hours, but does not main-
tain the same degree of ecacy at 24 hours ecacy.
Zolmitriptan and high-dose sumatriptan oer the
third highest chance of pain-free response and head-
ache response, and appear to maintain their ecacy at
24 hours. Clinicians will want to target a triptan that
balances ecacy, tolerability, and costs for their
patients.

Clinical implications
. The relative ecacy of all triptans for the abortive treatment of migraine has remained uncertain as most
randomized trials have compared the available triptans to placebo.
. A multiple treatment comparison meta-analysis combining placebo and head-to-head trials was used to
establish which triptan has the highest odds of producing favorable relief outcomes.
. Eletriptan consistently has the highest odds of producing two-hour pain relief, two-hour headache response,
24-hour sustained pain relief, and 24-hour sustained headache response.
. Rizatriptan, zolmitriptan, and high-dose (100 mg) sumatriptan also appear eective at two hours, whereas
only zolmitriptan and high-dose sumatriptan appear to maintain their ecacy at 24 hours.

Funding MacReviews Inc. MacReviews Inc was nancially supported

This study was sponsored by Pzer Inc. With the exception of
physician expert Anjan Chatterjee, as well as pre-analysis-
stage discussion about overall trial eligibility criteria, the
company had no role in the conduct, analysis or interpret-
ation of the results and had no say in where this would be
published.
Conflicts of interest
Kristian Thorlund and Edward Mills have consulted with
Merck, Pzer, Novartis, Nycomed, Johnson & Johnson,
and GlaxoSmithKline on multiple treatment comparison
and systematic review issues. Edward Mills is the owner of
MacReviews Inc. Kristian Thorlund is an employee of
by Pzer Inc to develop and conduct this study and manu-
script. In addition, they have received grants from the
Canadian Institutes of Health Research (CIHR) and con-
sulted with the Canadian Agency for Drugs and
Technology in Health and US Agency for Healthcare
research and Quality (AHRQ). Kristian Thorlunds salary is
supported by CIHR. Edward Mills salary is supported by a
CIHR Canada Research Chair. Edward Mills is the president
of MacReviews Inc, and was a paid consultant to Pzer Inc in
connection with the development of this manuscript. Kristian
Thorlund is a director at MacReviews Inc, and was a paid
consultant to Pzer Inc in connection with the development
of this manuscript. Peter Goadsby has received research
grants from Boston Scientic, Medtronic, GSK, MSD,
Thorlund et al.
MAP, Johnson & Johnson, and Neuralieve and has received
consulting fees or honoraria from Allergan, Almirall, ATI,
BMS, Boehringer, Boston Scientic, Coherex, Colucid,
Lilly, Medtronic, Minster, MSD, MAP, Neuralieve,
NeurAxon, NTP, and Pzer. Elodie Ramos is currently
a full-time employee of Pzer Inc. Anjan Chatterjee was a
full-time employee of Pzer Inc at the time this study was
conducted. Ping Wu and Eric Druyts have no conicts of
interest to report.
Acknowledgments
We would like to thank Mary Almas, Younos Abdulsattar,
and Rahul Bhambri from Pzer for their valuable suggestions
during the pre-analysis stage about the design and analysis of
this study.
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