Headache Medicine 2021, 12(3):182-230 p-ISSN 2178-7468, e-ISSN 2763-6178
182
ASAA
DOI: 10.48208/HeadacheMed.2021.32
Headache Medicine
© Copyright 2021
Review
Comparison between metamizole and triptans for migraine
treatment: a systematic review and network meta-analysis
Mario Fernando Prieto Peres
1
, Wanessa Alessandra Ruiz Scala
2
, Ricardo Salazar
3
1
Instituto de Psiquiatria, Hospital das Clínicas da FMUSP, Brazil
2
Sano Pharmaceuticals, CHC Brazil Medical Aairs, Brazil
3
Regional Medical Head LATAM, Government and Public Aairs & Advocacy for Latin America, Consumer Healthcare, Sano, Brazil
Abstract
Objective
The aim of this systematic review was to evaluate the efcacy of metamizole and triptans for
the treatment of migraine.
Methods
Randomized controlled trials including people who received metamizole or triptan by multiple
routes of administration and at all doses as treatment compared to subjects who received ano-
ther treatment or placebo were included in the systematic review. The primary outcomes were
freedom from pain at 2 hours; pain relief at 2 hours; sustained headache response at 24 hours;
sustained freedom from pain at 24 hours. The statistical analysis of all interventions of interest
were based on random effect models compared through a network meta-analysis.
Results
209 studies meeting the inclusion and exclusion criteria were analyzed. Of these, 130 had
data that could be analyzed statistically. Only 3.0% provided enough information and were
judged to have a low overall risk of bias for all categories evaluated; approximately 50% of
the studies presented a low risk of selection bias. More than 75% of the studies presented a
low risk of performance bias, and around 75% showed a low risk of detection and attrition
bias.
Conclusion
There is no evidence of a difference between dipyrone and any triptan for pain freedom
after 2 hours of medication. Our study suggests that metamizole may be equally effective as
triptans in acute migraine treatment.
Mario Fernando Prieto Peres
marioperes@yahoo.com
Edited by:
Marcelo Moraes Valença
Keywords:
Metamizole
Triptans
Migraine disorders
Headache
Tension-type headache
Dipyrone
Received: December, 15 2021
Accepted: December, 22 2021
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Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Introduction
M
igraine is a highly prevalent condition manifesting as
moderate or severe intermittent headache attacks with
associated symptoms, lasting 4 to 72 hours if not properly
treated.
1-3
Migraine is not only a headache but also a syndrome of
various phases, each with its own distinct mechanisms and
treatment approaches. Briey, the migraine prodrome, or
premonitory phase, can occur several hours to days before
a headache and may be hypothalamically modulated,
although other brainstem and limbic structures may play a
causal role as well.
4
The relationship between migraine and cognition is
complex. Cognitive symp-toms are part of the subjective
experience of migraine attacks and contribute to attack-
related disability, interfering with work performance, family
and social life, besides self-management of the attacks.
This transient impairment may occur along all phases of
a migraine attack. While pain is the main determinant
of disability, cognitive dysfunction also contributes to
attack-related impairment, and should be considered as a
migraine therapeutic target, together with pain, to evaluate
the efcacy of an acute attack treatment.
5
While it is clear that migraine attacks include some degree
of cognitive impair-ment, in the long run, migraine is
not associated with any signicant impact on cognitive
performance or age-associated cognitive decline in the
general popu-lation. So, acute cognitive dysfunction during
a migraine attack is reversible. However, individuals with
more severe and frequent migraine attacks and sub-jects
with chronic migraine tend to maintain cognitive difculties
between at-tacks.
5
The acute management of migraines includes the use
of non-steroidal anti-inammatory drugs (NSAIDs),
acetaminophen, metamizole, ergots, and triptans. Gepants
and ditans have been recently added to the list.
6
Metamizole is a well-established and highly used drug
to treat acute attacks in emergency settings in Brazil, as
well as the most common analgesic medication used for
migraine treatment in the population.
7,8
Triptans represent a large therapeutic group with a good
therapeutic prole, but their vasoconstriction adverse events
warrant caution in patients with cardio-vascular risk. Other
side effects, such as nausea, dizziness and chest symp-
toms, preclude some patients from using triptans, while a
few patients do not respond well to triptans. Compliance
and tolerability of triptans are certainly different for
each medicine. Triptans are considered to be safe, with
a very low potential risk of clinically signicant serious
adverse events. Contraindications to triptan use include
uncontrolled hypertension, ischemic heart disease, coro-
nary vasospasm, cerebrovascular disease, peripheral
vascular disease, and basilar or hemiplegic migraine.
9, 10
Metamizole and triptans are both major medications in
the acute therapy arse-nal, however, they have never been
directly compared.
To evaluate the efcacy of metamizole and triptans for
the treatment of migraine, we conducted this systematic
review and network meta-analysis to address the following
focused questions: (1) “what is the evidence for the efcacy
and safety of metamizole for the treatment of migraines
compared with triptans?” and (2) “how effective are those
treatments in improving cognitive dysfunction in patients
with migraine?”
Methods
TThe systematic review has been developed in accordance
with the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses Protocols (PRISMA) statement
11-13
,
using methodology described in the Cochrane
Handbook for Systematic Review of Interventions.
14
This
protocol was registered within the PROSPERO database
(CRD42020216360).
Study eligibility criteria
Only randomized controlled trials reporting study-specic
data for migraine outcomes in people who received
metamizole or triptan as treatment were included in
the systematic review. The population of interest was
participants with migraine, of any age, gender and
severity of migraine. We have used investigator-reported
denitions (according to accepted diagnostic criteria,
such as the International Classication of Diseases, or
according to the criteria established by the International
Headache Society).
15
We examined papers from all
countries, subjects who have used metamizole or triptan
treatment (test group), by multiple routes of administration
(tablets, oral disintegrating tablets, injection, transdermal,
nasal spray, rectal suppositories) and at all doses (any
frequency or strength), compared to subjects who have
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Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
received another treatment or placebo. Metamizole and
Triptans were not allowed to be used in combination
with other drugs. The primary outcomes were freedom
from pain at 2 hours; pain relief at 2 hours; sustained
headache response at 24 hours; sustained freedom
from pain at 24 hours. Secondary outcomes were relief
of other symptoms associated with migraine, specically
nausea, vomiting, photophobia and phonophobia, fatigue,
dizziness, cognitive impairment, any adverse effects
(AEs), withdrawals due to adverse events, use of rescue
medication, patient satisfaction, absenteeism, functional
disability and quality of life.
We excluded studies in which metamizole or triptan was
not the intervention of interest, studies comparing combined
metamizole preparations with another treatment, studies
comparing combined triptan preparations with another
treatment, studies where metamizole or triptan have not
been studied in only one separate intervention group,
studies in which migraine is not reported as the outcome
of interest, studies that do not have adequate information
regarding whether metamizole or triptan and its derivatives
are not related to migraine improvement, studies involving
secondary headache disorders (post-puncture headache,
post-traumatic headache, cancer-related headache etc.),
studies that do not have adequate information on the
classication of primary headache or animal studies. There
was no restriction of study setting.
Information sources
We searched the literature in the following databases:
MEDLINE via PubMed, EMBASE, LILACS, EbscoHost and
all references of the included studies, with no language
restrictions from inception to November 2020. MesH terms
and keywords were combined with Boolean operators and
used as search strategies: #1 - migraine OR headache OR
“tension-type headache”; #2 - dipyrone OR metamizole;
#3 – triptan OR sumatriptan OR zolmitriptan OR rizatriptan
OR naratriptan OR frovatriptan OR almotriptan OR
eletriptan; #4 - #1 AND #2; #5 - #1 AND #3; #6 - #4
OR #5. Two reviewers screened all articles identied from
the search independently. Any disagreements between
reviewers were solved by discussion with a third reviewer
to meet a consensus. Studies meeting the inclusion criteria
underwent a validity assessment and data extraction.
Reasons for rejecting studies were recorded for each study.
Data extraction (study characteristics and results) /
Data management
Two reviewers extracted data independently. Disagreements
were solved with discussion with a third reviewer. Data
were transferred to Excel sheets for analysis. Measures
of central tendency (mean or median) and dispersion
(standard deviations and percentiles) for different biometric
parameters were extracted. For continuous outcomes, the
following was extracted: means, SD and sample sizes
at baseline and follow-up. If these were unavailable,
change scores or mean differences were extracted. For
dichotomous outcomes, the number of cases and total
sample size were extracted. Safety outcomes included the
number of participants reporting any or serious AEs or
withdrawn from the study because of AEs.
All interventions of interest were compared through a
network meta-analysis. A graph summarized the results of
interest, allowing us to easily assess the structure of existing
evidence.
Risk of bias within individual studies
The risk of bias of the included studies was evaluated
according to the Cochrane Collaboration’s Tool for
Assessing Risk of Bias.
14
Briey, randomization and
allocation methods (selection bias), completeness of
follow-up period/incomplete outcome data (attrition bias),
masking of patients (performance bias) and examiners
(detection bias), selective reporting (reporting bias),
and other forms of bias were classied as adequate (+),
inadequate (-), or unclear (?). Based on these domains,
the overall risk of bias was categorized as follows: 1) low
risk of bias; 2) unclear risk of bias; or 3) high risk of bias.
Summary measures
To inform on comparative efcacy, effectiveness, and
safety between all interventions, we conducted a network
meta-analysis. We modeled log odds ratios using the
conventional logistic regression network meta-analysis
setup.
16
The network meta-analysis was based on logistic
model with random study effects.
17
Assessment of inconsistency
Consistency was assessed by comparison of the
conventional network meta-analysis model for which
consistency was assumed with a model that does not
assume consistency (a series of pairwise meta-analyses
analyzed jointly). If the trade-off between model t and
complexity favors the model with assumed consistency,
this model was preferred. Moreover, we calculated the
difference between direct and indirect evidence in all
closed loops in the network; inconsistent loops were
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Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
identied with a signicant (95% CI that excludes 0)
disagreement between direct and indirect evidence.
Risk of bias across studies
Publication bias or small study effects were assessed by
inspection of the funnel plots for asymmetry and with
Egger’s test
18
and Begg’s test
19
, with the results considered
to indicate potential small study effects when p<0.10.
Results
The search identied 4,003 articles. After excluding
duplicate references, a total of 1,601 titles and abstracts
retrieved from electronic databases and hand searching
were analyzed. Based on the eligibility criteria, the texts of
450 publications were reviewed in full. Of these, 198 were
eligible according to the inclusion and exclusion criteria
(see Figure 1). Ten articles published results from more than
one study, thus 209 studies were analyzed.
20-29
Figure 1. Diagram.
All of the included studies were published between 1991
and 2019. Most of them were large, multicenter, double-
blind, placebo-controlled trials conducted in a variety of
countries in the ve continents.
The number of randomized patients who received some
treatment totaled 94,570 subjects, diagnosed with migraine
headaches according to the International Headache
Society criteria for migraine. Excluding four studies that did
not mention participants’ sexes30-33, female participants
were the majority, with approximately 84.2%.
The types of treatments varied widely both in dosage
and route of administration. The seven types of triptans
(almotriptan, eletriptan, frovatriptan, naratriptan,
rizatriptan, sumatriptan, and zolmitriptan) appeared
among the selected studies. However, sumatriptan was the
most common and was found in 18 different variations:
it appeared with oral, subcutaneous, nasal spray,
iontophoretic transdermal patch (TDS) and suppository
administration, combining dosages from 1 mg to 200 mg.
Some treatment arms used triptan in combination therapies
with other drugs: frovatriptan 2.5 mg + dexketoprofen
25 mg or 37.5 mg
34
; naratriptan 2.5 mg orally + rectal
suppository of prochlorperazine 25 mg
35
; rizatriptan 10
mg + acetaminophen 1,000 mg orally
36
, and rizatriptan
10 mg + dexamethasone 4 mg orally
37
. All studies with
combination therapy included in this review had an
exclusive triptan arm and a placebo comparative arm.
Only 6 studies with metamizole to treat migraine (dosage
of 500 mg and 1,000 mg orally and IV) met all the
inclusion criteria to be considered in this systematic review.
Four studies utilizing the intravenous metamizole route
were performed in Brazil
8,38-40
, one in Spain
41
and the last
one in Turkey
42,43
, with the last two studies including oral
metamizole.
Most studies included in this review were conducted in
the adult population and only 13 were carried out with
adolescents.
43-55
Most of the selected studies evaluated improvement or
complete relief of headache after 1 hour, 2 hours and in
the rst 24 hours, although some studies have evaluated
different times of symptomatic relief after 30 minutes, in
addition to the use of rescue medication in the period.
Some studies have evaluated relief of migraine-associated
symptoms, such as photophobia, phonophobia, nausea
and vomiting. The characteristics of the included studies is
in supplementary table (Table 1).
The results of the risk of bias assessment are shown in
gure 2. Of all 209 studies, only six (3.0%) provided
enough information and were judged to have a low overall
risk of bias for all categories evaluated; 146 studies had
insufcient information, mainly in the selective reporting
domain, so the overall risk of bias was unclear, and 46
presented a high overall risk of bias.
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Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Figure 2. Risk of bias graph: review authors' judgements about each domain
presented as percentages across all included studies.
Approximately 50% of the studies presented a low risk of
selection bias. More than 75% of the studies presented a
low risk of performance bias, and around 75% have shown
a low risk of detection and attrition bias.
The statistical analysis below was based on random effect
models from network meta-analyses. The calculations were
made with the netmeta package of the R library, developed
by Rücker et al.
56
and based on the methodology described
in Schwarzer et al.
57
Since there are no direct comparisons of dipyrone versus
any of the triptans, consistency tests were not performed.
Pain freedom after 2 hours of medication
Figure 3 illustrates the connections between the active
substances. The thickness of the edges indicates the
weights of the direct comparisons. Studies with more than
two treatments were excluded in this analysis.
20,36
There is no evidence of a difference between dipyrone and
any triptan.
Figure 3. Network graph for pain-free data after 2 hours of medication.
Figure 4. Estimates of the effect of triptans and dipyrone in relation to
placebo.
Pain relief after 2 hours of medication
Figure 5 illustrates the connections between the active
substances.
The condence intervals for differences in pain relief ratios
after 2 hours of medication between triptan and placebo
versus dipyrone are shown in the forest plot. There is no
evidence of a difference between dipyrone and any triptan.
Figure 5. Network graph for pain relief data after 2 hours of medication.
Figure 6. Estimates of the effect of triptans and dipyrone in relation to
placebo.
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Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Table 1. Characteristics of Included Studies
Author, publica-
tion year
Population Comparisons Outcomes
Ahonen et al.
44
Children/Adolescents - 12.4
(SD 2.4, range 8.1 to 17.5)
years
n=94 (51 boys and 43 girls)
Sumatriptan 10 mg (20 to 39
kg)
Sumatriptan 20 mg (≥40 kg)
Placebo
A single dose of sumatriptan
nasal spray and a matching
placebo were administered at
home during two attacks.
The primary efcacy endpoint was headache relief by two grades
on a 5-grade face scale at 2 hours.
Sumatriptan (n 53/83; 64%); placebo (n 32/83; 39%)
Ahonem et al.
43
Adolescents - 12.0 years (SD
2.4; range 6.1 to 16.1 years)
n=116 (63 girls and 53 boys)
Oral rizatriptan 5 mg (20 to
39 kg);
Oral rizatriptan 10 mg (40 kg
or more);
Placebo
Two doses of rizatriptan and
a matching placebo were
administered at home during
three attacks.
Ninety-six patients used all three treatments, 10 used two, and
10 only the rst. At 2 hours, the primary endpoint (headache
relief by two grades on a ve-grade face scale at 2 hours) was
reached twice as often after both treatments of rizatriptan [rst
n=71/96 (74%); second n=70/96 (73%)] as after placebo [n
= 35/96 (36%)] (p<0.001). Already at 1 hour, rizatriptan was
clearly more effective as headache relief was reported by 50%
(n = 48/96) and 55% (n = 53/96) of children after the rst and
the second dose of rizatriptan, compared to 29% (n= 28/96)
after placebo (p=0.004). Rizatriptan was superior at 3 and 4
hours, and the other endpoints also favored rizatriptan. Efcacy
of rizatriptan was constant over the two treated attacks, and the
ndings were similar in children using the dose of 5 and 10 mg.
The use of the higher 10 mg adult dose in adolescents caused
adverse effects with a frequency comparable to what has been
observed in adults. But no serious adverse effects were observed.
Ahrens et al.
58
Adults –
Placebo - 41.6 (18 to 72)
years; Rizatriptan 5 mg - 42.7
(19 to 67) years; Rizatriptan 10
mg 43.1 (19 to 67) years.
n=555 (64 male and 491
female)
Rizatriptan 10 mg
Rizatriptan 5 mg
Placebo
Single attack
The primary efcacy endpoint was pain relief at 2 h. From 30 min
onwards, signicantly more patients experienced pain relief and
became pain-free after rizatriptan 10 mg compared to placebo.
At 2 h, the percentage of patients with pain relief was signicantly
higher after rizatriptan 10 mg (74%), 5 mg (59%) compared with
placebo (28%). Rizatriptan 10 mg was superior to rizatriptan 5
mg on pain relief at 1.5 and 2 h (p < 0.05). Signicantly more
patients were pain-free at 2 h after rizatriptan 10 mg (42%), 5
mg wafer (35%) compared with placebo (10%). Both doses of
rizatriptan wafer were well tolerated.
Akpunon et al.
59
Adults –
Plac - 39.8 (SD 9.4) - 22 to 59
SUM - 39.8 (SD 10) - 22 to 71
years;
n=136 (17 Male; 119 Female)
Sum - Male 10 (11%); Female
78 (89%)
Sumatriptan 6 mg SC
Placebo
Nº of patients with meaningful relief - Plac 17 (35%); Sum 66
(75%) Time to meaningful relief (min) median- Plac 66; Sum 43
Nº of patiens with nopain or mild pain at discharge - Plac 17
(35%); Sum 62 (70%)
Nº of patients with no pain at discharge - Plac 6 (13%); Sum
27 (31%)
Allais et al.
60
Adults – 34.92 ± 7.99 years
n=122 (all female)
Almotriptan 12.5 mg oral
Placebo
One single menstrual migraine
attack per menstrual cycle
was treated in four different
menstrual cycles.
Data suggest that almotriptan shows excellent efficacy on
menstrual migraine in comparison to the placebo, with a
signicant reduction in the percentages of suffering patients
over a 2-h period of time.
Allais et al.
61
Adults – 34.9±8.0 (18 to 50)
years
n=147 (all females)
Almotriptan 12.5 mg oral
Placebo
One tablet after pain onset
during two menstrual cycle
Signicantly more patients were pain-free at two hours (risk ratio
[RR] = 1.81; p=0.0008), pain-free from 2-24 hours with no
rescue medication (RR = 1.99; p=0.0022), and pain-free from
2-24 hours with no rescue medication or adverse events (RR =
1.94; p=0.0061) with almotriptan versus placebo. Nausea
(p = .0007) and photophobia (p=0.0083) at two hours were
signicantly less frequent with almotriptan. Almotriptan efcacy
was consistent between three attacks, with 56.2% of patients
pain-free at two hours at least twice. Adverse events were similar
with almotriptan and placebo.
Almas et al.
62
Adults – eletriptan-40 mg:
41.7±10.7 years; eletriptan-80
mg: 41.7±10.3 years.
n=971 (803 females and 168
males)
[eletriptan-40 mg: 453 females
and 86 males; eletriptan-80
mg: 350 females and 82
males;]
Eletriptan 40 mg or 80 mg
Placebo
four-attack consistency of
response study in which three
attacks were treated with ELE-40
or ELE-80, and one randomly
chosen attack was treated with
placebo
On a repeated measure logistic regression analysis across all
treated attacks, the probability of achieving a headache response
at 2 hours ranged from 71% to 74% on ELE-40 vs. 17% to 28% on
placebo ( p<0.0001), and from 66% to 74% on ELE-80 vs. 21%
to 27% on placebo ( p<0.0001). The incidence, per attack, of
adverse events, was low for both ELE-40 and ELE-80. Few adverse
events occurred with incidence ≥10% on ELE-40 (asthenia, 5.0%)
or ELE-80 (asthenia, 10%; nausea, 5.8%). Discontinuations
because of adverse events were 0.2% on ELE-40, and 1.6% on
ELE-80. (ELE: eletriptan)
Banerjee,
Findley
63
Adults - 18 to 65 years (mean
35 years)
n=94 (80 female; 14 male)
Sumatriptan 200 mg oral
Placebo
Up to three attacks
Each patient was treated for a maximum of three separate attacks
of migraine with aura within a three months' period. Three attacks
were treated so that we could examine consistency of response
across more than one attack. For attack 1, 200 mg sumatriptan
was signicantly more effective, safe and well tolerated than
placebo at relieving headache 2 h after treatment was given
(p=0.023). In subsequent attacks, i.e. in attacks 2 and 3, there
was no such signicant effect of sumatriptan compared with
placebo in relieving headache
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Barbanti et al.
64
Adults: 41 years [(41.5±11.9
years sumatriptan 50 mg,
39.7±10.3 years sumatriptan
100 mg, 40.6±10.3 years
placebo)]
n=432 (358 females and 74
males)
Sumatriptan 50 mg or 100
mg oral
Placebo
Single migraine attack
Normal functional ability was restored in a signicantly (p<0.05)
greater percentage of patients treated with sumatriptan than
placebo beginning 45 min postdose for sumatriptan 100 mg
and 1 h postdose for sumatriptan 50 mg. During the 24 h after
initial dosing, the median (range) lost time equivalents for the
combination of paid work activities and activities outside of
paid work were signicantly lower in the groups treated with
sumatriptan (1.1 [0-10] sumatriptan 100 mg; 0.8 [0-36]
sumatriptan 50 mg) compared with placebo (2.9 [0-24]) (p≤0.01
each sumatriptan group versus placebo). The corresponding
mean +/- SD values for lost time equivalents were 1.9 ± 2.3
and 2.5 ± 4.7 for sumatriptan 100 mg and 50 mg, respectively,
compared with 3.5 ± 4.3 for placebo.
Barbanti et al.
65
Adults –
Rizatriptan = 43.95 ± 12.24
Placebo = 41.41 ± 11.7
n=80 (13 male; 67 female)
Rizatriptan 10 mg
Placebo
Single migraine attack
The primary endpoints were pain freedom at 2 h and total
migraine freedom (pain freedom and absence of associated
symptoms) at 2 h.
Pain freedom 2h - Rizatriptan 54% vs Placebo 8% (p<0.001).
Migraine freedom 2h - Rizatriptan - 51% vs Placebo 8% (p<0.001)
Binomial regression analysis showed that a signicantly larger
percentage of patients assigned to rizatriptan than to placebo
reported pain freedom at 2 h post dosing (54 % [95 % CI 38,
70 %] vs. 8 % [95 % CI -1, 17 %]) (p<0.001) and total migraine
freedom at 2 h post dosing (51 % [95 % CI 36, 67 %] vs. 8 %
[95 % CI -1, 17 %]) (p<0.001)
Bartolini et al.
66
Adults – 40 ± 10 years
n=114 (96 female; 18 male)
Frovatriptan 2.5 mg
Almotriptan 12.5 mg
Treating 1–3 attacks
The primary study endpoint was the between-treatment
comparison of the direction and average strength of preference
at the end of the study. Preference score averaged to frovatriptan
3.1 ± 1.3 for vs to almotriptan 3.4 ± 1.3 for (P = NS); 63%
of patients expressed a clear preference for a triptan (29% for
frovatriptan and 34% for almotriptan, p=NS).
Pain free at 2 hours post dose - frovatriptan 30% and almotriptan
32%
Pain relief at 2 h post dose - frovatriptan - 54% and almotriptan
- 56%
Bigal et al.
8
Adults – Placebo
MO = 29.3 years
D i p y r o n e M O = 3 2 . 4 y e a r s
P l a c e b o M A = 2 8 . 2 y e a r s
Dipyrone MA = 35.5 years
n=134 (38 male; 96 female)
Dypirone - intravenous injection
of 1 g dipyrone, diluted to 10
mL of 0.9% physiological saline
Placebo - intravenous injection of
10 mL 0.9% physiological saline
Positive headache response was dened as a patient’s pain
changing from 2 or 3 to 1 or 0 after study drug at particular
end points.
Headache response 1h - Placebo MO - 5/30 (16.7%) vs
Dipyrone MO 20/44 (65.9%) p<0.05. Placebo MA 4/30
(13.3%) vs Dipyrone MA 19/30 (63.3%) p<0.05.
Pain-free 1h - Placebo MO 3/30 (10%) vs Dipyrone MO 19/44
(43.2%) p<0.05. Placebo MA 2/30 (6.7%) vs Dipyrone MA
15/30 (50%) p<0.05. Recurrence - Placebo MO 50% vs
Dipyrone MO 17% p<0.05. Placebo MA 42% vs Dipyrone MA
16% p<0.05.
PS: MO (migraine without aura); MA (migraine with aura)
Bigal, Bordini,
Speciali
38
Adults – Placebo 37.6 years;
dipyrone: 44.2 years;
n=60 (31 women and 29 men)
Dipyrone 1 g in 10 ml saline.
Placebo (intravenous injection of
10 ml saline)
Patients receiving dipyrone showed a statistically signicant
improvement (p<0.05) of pain compared to placebo up to 30
min after drug administration. The therapeutic gain was 30% in
30 min and 40% in 60 min. The number of patients needed to
be treated for at least one to have benet was 3.3 in 30 min
and 2.2 in 60 min. There were statistically signicant reductions
in the recurrence (dipyrone = 25%, placebo = 50%) and use of
rescue medication (dipyrone = 20%, placebo = 47.6%) for the
dipyrone group.
Bigal et al.
37
Adults – 18 to 55 years
n= 35 (all female)
Rizatriptan 10 mg +
dexamethasone 4 mg
Rizatriptan 10 mg
Dexamethasone 4 mg
Tablets for 6-attack crossover
study.
Rizatriptan (RI) and
Dexamethasone (DE)
The primary endpoint of this study was 24-hour sustained relief
and the secondary was 24-hour sustained pain-free.
2-24h sustained pain relief - RI+DE 81.5%, RI 62.7%,
DE 33.3%. RI was superior to DE (p=0.001), and
R I + D E w a s s u p e r i o r t o R I ( p < 0 . 0 5 ) a n d D E . ( p < 0 . 0 0 1 ) .
2-24h sustained pain-free - RI+DE 50.7%, RI 32.2% and DE
12.1%. RI+DE was superior to RI (p<0.05), and DE (p<0.001).
RI was superior to DE (p<0.05). The proportion of attacks that
were considered to have been satisfactorily treated with RI+DE
was not signicantly different to RI only (75.3% vs 69.4%). Both
were superior to DE only (37.8%, p<0.01). More attacks treated
with DE+RI (33.8%) were associated with side effects compared
to the RI (18.6%) and DE (15.2%).
Bigal et al.
67
Adults – Nausea at Baseline:
40.6±11.7 years; No Nausea
at Baseline: 41.1±10.3 years.
n=454 (386 female and 68
male)
Sumatriptan TDS 6.5 mg
(iontophoretic transdermal
system)
Placebo TDS
over a 4-hour period treating
one migraine attack.
A total of 130 participants free of nausea at baseline were
treated with sumatriptan iontophoretic transdermal system (TDS),
while 109 participants free of nausea at baseline were treated
with placebo TDS. The occurrence of TEN (treatment-emergent
nausea) (over 24 hours post-treatment was signicantly lower
with the sumatriptan TDS than with placebo (p=0.0011). These
differences were statistically signicant at 1 hour (13.8% vs 9.2%,
p<0.01), 2 hours (13.8% vs 4.6% p<0.001) and 3 hours (13.8%
vs 8.5%, p<0.01). The efcacy of sumatriptan TDS was similar
regardless of the presence or absence of nausea at baseline for
all clinical parameters.
189
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Bomhof et al.
68
Adults – mean age 39.2 years
n=522 [438 female (84%) and
84 male (16%)]
Rizatriptan 10 mg
Naratriptan 2.5 mg
Placebo
Tablets for the treatment of a
single attack.
Rizatriptan was more effective than naratriptan. Rizatriptan
provided earlier headache relief than naratriptan (hazard ratio
1.62, p=0.001), acting as early as 30 min. More patients
were pain free at 2 h on rizatriptan than on naratriptan (44.8
vs. 20.7%, p=0.001). Rizatriptan also provided earlier relief
of associated migraine symptoms within 2 h than naratriptan
and more patients had normal function at 2 h (39.3 vs. 22.6%,
p<0.001). Both active treatments were effective compared to
placebo.
Bousser, D’Allens,
Richard
69
Adults – Sumatriptan = 43 ±
1.4
Placebo = 39 ± 1.3
n=96 (17 male and 79 female)
Sumatriptan 6 mg SC
Placebo
Two consecutive early-morning
migraine attacks
The primary outcome measure was headache relief.
Headache relief at 2h - First attack Sumatriptan 78% vs.
Placebo 28%; Second Attack - Sumatriptan 73% vs. Placebo
20% (p<0.0001). Sumatriptan was also superior to placebo for
all secondary endpoints: headache relief at 1 h, pain-free rates
(grade 0) at 1 and 2 h, use of a second injection of the study
treatment, use of rescue medication, duration of inability to work.
Brandes et al.
70
Adults – mean age 39 years
n=613 (484 female and 129
male)
Eletriptan 20 mg
Eletriptan 40 mg
Placebo
to treat one attack
For the total patient sample (mild-to-severe headaches), 2-h
pain-free rates were signicantly higher than placebo (22%) on
both eletriptan 20 mg (35%; P < 0.01) and eletriptan 40 mg
(47%; P < 0.0001). For the cohort of patients who treated their
headache when the pain intensity was mild, the 2-h pain-free
rate on eletriptan 40 mg was 68% compared with 25% on
placebo (P < 0.0001).
Brandes et al.
20
Adults – Sum+Naproxen= 40.3
(SD 11) / Sum= 40.1 (SD
10.9) / Naproxen=39.4 (SD
11.3) / Plac =40 (SD 11.1)
n=1,441 (187 male and 1,254
female)
Sumatriptan 85 mg + Naproxen
Sodium 500 mg
Sumatriptan 85 mg
Naproxen sodium 500 mg
Placebo
Single tablet for treatment of a
single migraine attack
Incidence of headache relief after 2 hours after dosing -
Sum+Naprox - 65%, Sum - 55%, Naprox - 44%, Plac - 28%.
Brandes et al.
20
Adults – Sum+Naproxen= 39.4
(SD 11.2) / Sum= 40.3 (SD
11.4) / Naproxen= 40.4 (SD
11.6) / Plac= 40.6 (SD 10.7)
n=1,468 (151 male and 1,317
female)
Sumatriptan 85 mg + Naproxen
Sodium 500 mg
Sumatriptan 85 mg
Naproxen sodium 500 mg
Placebo
Single tablet for treatment of a
single migraine attack
Incidence of headache relief after 2 hours after dosing
- Sum+Naprox - 57%, Sum - 50%, Naprox - 43%, Plac -
29%. Similar pattern of results was observed for absence of
photophobia and absence of phonophobia. After imbalances
in incidences of nausea, the incidence of absence of nausea
2 hours after dosing was signicantly higher wih sum+naprox
than with placebo. But not differ between sum+naprox and
placebo in study 2.
Brandes et al.
71
Adults – Frovatriptan 2.5
mg Q.D.=37.8 (±7.9)
Frovatriptan 2.5 mg B.I.D.=38.9
(±7,6)
Placebo=37.9 (±7.2)
n=427 (all female)
Frovatriptan 2.5 mg QD
Frovatriptan 2.5 mg BID
Placebo
Day 1 - q.d. group received 5
mg of active drug in the morning
and placebo in the evening;
the b.i.d. group received 5 mg
frovatriptan in both the morning
and evening;
placebo group received two
placebo tablets in the morning
and evening. Thereafter, patients
received placebo, frovatriptan
2.5 mg q.d., or frovatriptan 2.5
mg b.i.d. on days 2–6.
The mean number of headache-free PMPs (perimenstrual periods)
per patient (primary endpoint) was signicantly higher in the two
frovatriptan groups [0.69 PMPs (q.d.) and 0.92 PMPs (b.i.d.)
compared with placebo (0.42 PMPs) representing 64% (q.d.)
and 119% (b.i.d.) increases in the mean number of headachefree
PMPs per patient. Patients in the b.i.d. group experienced an
increase in the mean number of headachefree days with each
progressive PMP, increasing to 4.1 (1.7) in PMP 1, 4.5 (1.6) in
PMP 2, and 4.7 days (1.4) in PMP 3. Over all PMPs, the mean
(SD) number of headache-free days was 3.6 (1.4) for placebo
vs. 4.0 (1.4) for the q.d. frovatriptan regimen and 4.2 (1.5) for
the b.i.d. frovatriptan regimens (p<0.0001 frovatriptan q.d. or
b.i.d. vs. placebo).
Bussone et al.
72
Adults – 37±10.6 (18-65) years
n=233 (male 49; female 184)
oral sumatriptan (50 mg)
placebo (PLO)
multiple attacks of migraine (a
total of 12 migraine attacks,
within each block of 4 attacks,
three were treated with active
medication and one with
placebo)
In all attacks, the efcacy rate was statistically signicant for
sumatriptan versus placebo (PLO) in 2 or 4 hours (2 hours:
sumatriptan 60%, PLO 38%, p<0.001; 4 hours sumatriptan
79%, PLO 47%, p <0.001). Oral sumatriptan was also effective
in relieving associated symptoms and reducing clinical disability
in most attacks. The reported adverse events were few, all of
them of mild to moderate intensity and resolved spontaneously.
The most frequently reported symptoms were gastrointestinal.
Although the incidence of adverse events did not differ between
treatment groups.
Cady et al.
21
Adults – Sumatriptan 39.8 ±
9.6; Placebo -39.6 ± 9.7
n=574 (501 female and 73
male)
Sumatriptan 6 mg SC
Placebo
(0.5-mL subcutaneous injection
over the deltoid muscle)
Pain relief and pain-free at 1h after treatment.
Pain relief 1h - Sumatriptan 79% (515/734) vs Placebo 22%
(81/370) (p<0.001).
Pain-free 1h - Sumatriptan 49% (356/734) vs Placebo 9%
(35/370) (p<0.001).
Cady et al.
21
Adults – Sumatriptan 40 ± 9.8;
Placebo 37.7 ± 10
n=530 (478 female and 52
male)
Sumatriptan 6 mg SC
Placebo
Pain relief and pain-free at 1h after treament.
Pain relief 2h - Sumatriptan 81% vs Placebo 34% (p<0.001).
Related migraine sysptoms 1h - Photophobia - Sumatriptan -
43% vs Placebo 76% (p<0.001). Nausea - Sumatriptan 27% vs
Placebo 51% (p<0.001).
190
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Cady et al.
73
Adults - mean age 41.2 and
(range 18-76 years)
n=100 (male 9 and female 91)
Sumatriptan 6 mg sc,
Placebo
Four headaches of moderate or
severe intensity (grade 2 or 3)
were treated in the clinic with
a single dose of either 6 mg
SC sumatriptan (three attacks)
or placebo (one attack) in the
upper arm or thigh
Sumatriptan statistically outperformed placebo on all efcacy
measures, including pain severity; presence/absence of nausea,
vomiting, phonophobia, and photophobia; rescue medication
use; and clinical disability. Efcacy was consistently maintained
with repeated administration. For all attacks, pain relief 90
minutes postdose occurred in 86% to 90% of sumatriptan-treated
patients, compared with 9% to 38% of placebo-treated patients
Cady et al.
74
Adults – mean: 41.5 years
[frovatriptan-placebo: 40.4
years; placebo-frovatriptan:
42.5 years;]
n=275 (36 males and 239
females)
Oral frovatriptan 2.5 mg
Placebo
The patients could take up to
two doses of study medication
per migraine attack.
When patients received frovatriptan as the rst dose, it was more
effective than placebo in terms of the proportion of patients who
were pain free at 2 h (28% vs 20%, p=0.04). This benet was
sustained up to 4 h post-dose (p=0.003). Early use of frovatriptan
signicantly reduced re-medication (p<0.001). Twenty-four-hour
headache recurrence was low in both early (4%) and later use
(6%) groups. Sustained pain-free response occurred in 40% of
frovatriptan early use patients compared with 31% of later use
patients (p<0.05). Early use prevented headache progression:
69%-78% had mild/no headache 2-4 h after dose 1 frovatriptan
compared with 54%-63% taking dose 1 placebo (p<0.001). Early
use reduced pain burden and functional disability (p≤0.001).
More patients rated early use of frovatriptan as excellent or good
(57% vs 46%).
Cady et al.
75
Adults – Rizatriptan - 40y;
Placebo - 42
n=207 (187 female and 20
male)
Rizatriptan 10 mg ODT (orally
disintegrating tablet)
placebo
The percentage of participants reporting pain freedom at 2
hours after taking study drug was significantly greater for
rizatriptan ODT (66%) compared with placebo. The percentage of
participants reporting sustained pain freedom between 2 and 24
hours post-dose also was signicantly greater for rizatriptan ODT
(52%) compared with placebo. The proportion of participants
reporting 2-hour pain freedom in the placebo groups was similar
regardless of education.
Cady et al.
74
Adults – 42.0(10.5) years
n=212 (Male 35 and Female
177)
22 mg AVP-825 nasal spray (a
drug–device combination of low-
dose sumatriptan powder - 22
mg loaded dose)
Placebo device
A signicantly greater proportion of AVP-825 patients reported
headache relief at 2 hours post-dose compared with those
using the placebo device (68% vs 45%, p=0.002, odds ratio
2.53, 95% condence interval [1.45, 4.42]). Between-group
differences in headache relief were evident as early as 15
minutes, reached statistical signicance at 30 minutes post-
dose (42% vs 27%, p=0.03), and were sustained at 24 hours
(44% vs 24%, p=0.002) and 48 hours (34% vs 20%, p=0.01.
Patients treated with AVP-825 were pain-free (34%) at 2 hours
compared with placebo device (17%; p=0.008). More AVP-825
patients reported meaningful pain relief (patient interpretation)
of migraine within 2 hours of treatment vs placebo device (70%
vs 45%, p<0.001), and fewer required rescue medication (37%
vs 52%, p=0.02). Total migraine freedom (patients with no
headache, nausea, phonophobia, photophobia, or vomiting)
reached signicance following treatment with AVP-825 at 1 hour
(19% vs 9%; p=0.04). There were no serious adverse events
(AEs), and no systemic AEs occurred in more than one patient.
Cady et al.
74
Adults – 39,8 (SD 10,4) (Range
from 19 to 61 years)
n=20 (80% female and 20%
male)
3 mg SC sumatriptan
6 mg SC sumatriptan
to treat 1 attack
The primary efficacy endpoint was the proportion of
s u b j e c t s r e p o r t i n g f r e e d o m f r o m p a i n a t 6 0 m i n p o s t d o s e .
Pain-free 60 min postdose – 3 mg SC Sumatriptan - 50% vs 52.6%
6mg SC Sumatriptan (p=0.087). There was no difference in pain-
f r e e b e t w e e n t r e a t m e n t s i n 3 0 , 6 0 , 9 0 a n d 1 2 0 m i n p o s t d o s e .
Pain relief 60 minutes postdose – 3 mg SC Sumatriptan 83.3% vs
6 mg SC Sumatriptan 73.7% (p=0.48). As pain-free there were
no difference between treatments at 30, 90 and 120 minutes
post dose. No difference also, in patients experienced relief
from nausea (p=0.91), photophobia (p=0.89), or phonophobia
(p=0.88).
Carpay et al.
76
Adults – 18-65 years
n=124 (male 23 and female
101)
Group A: sumatriptan 0.5 ml of
the 15 mg/ml subcutaneous rst
and oral sumatriptan 100 mg
during the second period
Group B: the order was reversed
Efficacy was evaluated 2 h after the administration of
subcutaneous and 4 h after the administration of oral sumatriptan.
Subcutaneous sumatriptan was signicantly more effective than
oral sumatriptan in relieving headache (over all 3 attacks 78%
vs 61% improvement), improving clinical disability (55% vs 41%
improvement) and relieving nausea (69% vs 53%), vomiting (72%
vs 32%) and phono or photophobia (67% vs 49%). Median time
to recurrence was shorter after subcutaneous (12.5 h) than after
oral sumatriptan (18 h); the number of patients experiencing a
recurrence was similar. Patients reported more adverse events
after subcutaneous sumatriptan (1.32 per attack) than after the
oral form (0.85 per attack), but all adverse events were mild to
moderate in intensity and of short duration.
Carpay et al.
77
Adults – Sumatriptan 50
m g t a b l e t = 4 1 . 5 ( S D 1 1 . 9 )
Sumatriptan 100mg
t a b l e t = 3 9. 7 ( S D 1 0 . 9 )
Placebo = 40.6 (SD 10.3)
n=432 (358 female and 74
male)
Sumatriptan 100 mg and 50
mg tablets
Placebo
single migraine attack
Sumatriptan tablets 50 mg and 100 mg were signicantly more
effective than placebo in conferring freedom from pain 2 hours
after dosing (primary end point). In the intent-to-treat population,
66.2% of patients who received sumatriptan 100 mg and 51.1%
of patients who received sumatriptan 50 mg were pain free 2
hours after dosing, compared with 19.6% of those who received
placebo.
191
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Charlesworth
et al.
78
Adults - Men and women
18–65 years.
n=1458 (female 1343 and
male 115)
Zolmitriptan nasal spray (5.0,
2.5, 1.0, 0.5 mg),
Zolmitriptan oral tablets 2.5 mg
Placebo
treatment of three separate
moderate or severe migraine
headaches
Each dose of zolmitriptan nasal spray produced a greater 2-hour
headache response rate than placebo (70.3%, 58.6%, 54.8%
and 41.5% for zolmitriptan nasal spray 5.0, 2.5, 1.0 and 0.5 mg,
compared with 30.6% for placebo [all p<0.001 vs placebo]).
The 2-hour headache response rate for zolmitriptan nasal spray
5.0mg was signicantly higher than that of the zolmitriptan
2.5mg oral tablet (61.3%; p<0.05), while comparisons of nasal
spray 0.5, 1.0 and 2.5 mg with zolmitriptan 2.5 mg oral tablet
were not statistically signicant. The nasal spray 5.0 and 2.5
mg showed a rapid onset of action, with a signicant difference
in headache response compared with placebo from 15 minutes
through 4 hours after administration and a signicant difference
between the nasal spray 5.0mg and 2.5 mg oral tablet from 15
minutes through to 2 hours (the other nasal spray doses were
not statistically signicant compared with 2.5 mg oral tablet).
Zolmitriptan nasal spray resulted in pain-free rates that were
dose dependent. While all doses from 1.0mg upwards produced
signicant pain-free outcomes from 30 minutes versus placebo,
only the 5.0 mg dose produced pain-free rates signicantly
superior to both placebo and the 2.5 mg oral tablet
Christie et al.
79
Adults - mean age 37.3 years
(18-70)
n=439 (16,6% male and
83.4% female)
Rizatriptan 10 mg tablet
Ergotamine 2 mg + caffeine
200 mg tablet
a single migraine attack
There are 2 co-primary efficacy analysis: 1. preference
for one medication over the other and 2. pain free at 2 h.
Pain free 2 h - 49% rizatriptan vs 24.3% ergotamine/caffeine.
Medication preference – 69.9% (223) rizatriptan vs 30.1% (96)
ergotamine/caffeine, 39 patients (10.9%) did not express a
preference for one of the two treatments. The hazard ratio respect
to time to headache relief was 2.05 (95% CI 1.72, 2.44). This
means that at any time in the 2-hour period, headache in a patient
on rizatriptan was more than twice as likely to be relieved within
the next few minutes than in a patient taking ergotamine/caffeine.
Colman et al.
80
Adults – Almotriptan:
41.25±10.09 (18 to 71) years;
Sumatriptan: 40.26 ± 10.08
(18-65) years.
n=1,173 (1044 female and
129 male)
Almotriptan 12.5 mg capsule
Sumatriptan 50 mg capsule
The rst dose of study
medication was taken at the
onset of a moderate or severe
migraine. The second dose was
taking if patient experienced
a relapse (an increase in pain
severity to moderate or severe
within 24 hours after the initial
dose, for those responding to
the initial dose)
A total of 1,173 patients were treated with almotriptan or
sumatriptan. There were no signicant differences between the 2
treatment groups in terms of satisfaction with pain relief; however,
patients in the almotriptan group were signicantly more satised
(less bothered) with side effects than those receiving sumatriptan
(p=0.016).
Connor et al.
81
Adults – Telcagepant 280
mg/300 mg - 42.5±10.9
years; Rizatriptan 10 mg -
41.9±11.1 years.
n=954 (739 female and 215
male)
Telcagepant 280/300 mg
Rizatriptan 10 mg
Both telcagepant and rizatriptan were generally well tolerated.
The overall incidence of clinical adverse events was similar
between the treatment groups. Rizatriptan appeared numerically
more effective than telcagepant for treating mild, moderate, or
severe migraine attacks at 2 hours post dose. At 24 hours post
dose, telcagepant showed higher responder rates for absence
of phonophobia and nausea, and comparable rates for 2 to 24-
hour sustained pain freedom and photophobia. Both telcagepant
and rizatriptan demonstrated a consistent treatment effect over
time, without evidence to suggest the development of tolerance.
Cull, Price,
Dunbar
82
Adults – Group A - 41±10.8;
Group B - 40.5±10.3 years.
n=881 (155 male 726 female)
Dose 1 - Sumatriptan 6 mg sc
– both group at the onset of a
migraine headache of moderate
or severe intensity
Dose 2 (headache recurrence
only):
Group A Sumatriptan 6 mg SC
Goup B Placebo
At each attack, 6 mg sumatriptan given subcutaneously was
signicantly (p<0.0005) more effective than placebo at relieving
recurrent headache after one hour; 83% of patients reported
headache relief one hour after the initial dose of sumatriptan.
Sumatriptan was generally well tolerated.
Dahlöf, Edwards,
Tolth
83
Adults – 45 ± 11 years
n=27 (22 female 5 male)
Sumatriptan SC 8 mg
Placebo (saline)
0.5 ml
One migraine attack
Primary outcome measure was the number of patients who
obtained complete or almost complete headache relief
w i t h i n 3 0 , 6 0 , 9 0 , 1 2 0 m i n o f t a k i n g s t u d y m e d i c a t i o n .
Headache relief at 60 min - Sumatriptan 84% vs Placebo 11%
(p<0.001); 90 min - Sumatriptan 73% vs Placebo 7% (p <
0.001); 120 min
Sumatriptan 63% vs Placebo 0.
Sumatriptan was signicantly more effective than placebo in
relieving nausea and photophobia. Before treatment 95% of
patients had this symptom. After 120 minutes – Sumatriptan –
16% vs Placebo 79%.
Rescue medication at 120 min – taken by 89% from placebo vs
11% from sumatriptan group (p<0.001).
Dasbach et al.
84
Adults – mean age 40,6 years
n=407 (84% female and 66
16% male)
Rizatriptan 10 mg
Placebo
3 migraine attacks with
rizatriptan and 1 with placebo
Hours of work loss due to absenteeism - Placebo – 2.2h/
Rizatriptan – 0.7h.
Period working with symptoms - Placebo - 4,7h/ Rizatriptan - 4,2h
Effectiveness on the job - Patients taking rizatriptan was 4,5%
greater in comparison with placebo. Rizatriptan decreased the
total number of hours of work loss by 1.1h per migraine attack
treated compared with placebo.
192
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Diamond et al.
85
Adults - mean of 40 years of
age.
n=1086 (956 females and 130
males)
Sumatriptan nasal spray (5, 10,
or 20 mg)
Placebo
up to 3 migraine attacks.
Administered via a 1-shot nasal
applicator into either nostril
Across attacks, headache relief in the 20, 10, and 5 mg drug
and placebo groups was experienced 120 minutes postdose by
60%, 54%, 44%, and 32% of patients, respectively (p<0.05 for
each sumatriptan nasal spray group vs placebo, for the 10-mg
vs 5-mg drug group, and for the 20-mg vs 5-mg drug group).
Two thirds of the 20 mg patients treating 3 attacks experienced
relief at 2 hours postdose for at least 2 of 3 attacks. Clinical
disability scores at 120 minutes in the 20, 10, and 5mg drug and
placebo groups reected no or mild impairment in 70%, 67%,
57%, and 50% of patients, respectively (p<0.05 for the 10 or
20 mg drug group vs placebo group, and for the 20-mg vs 5-mg
drug group). Similar efcacy rates were observed for nausea,
photophobia, and phonophobia. The incidence of adverse events
was not dose related. The most frequently reported adverse event
in the active treatment groups was taste disturbance (bad, bitter,
or unpleasant).
Dib et al.
86
Adults – 38.1±11.4 years
n=235 (female 83.4% female
and 16.6% male)
Ketoprofen 75 mg; Ketoprofen
150 mg; Zolmitriptan 2.5 mg
Placebo; (comparisons between
all treatments)
four consecutive attacks with
severe or moderate headache
Each treatment was enclosed in
opaque soft gelatin capsules
Results are based on 838 attacks with a severe or moderate
headache that were evaluable at 2 hours. Relief was reported for
62.6% of headaches treated with ketoprofen 75 mg, 61.6% with
ketoprofen 150 mg, and 66.8% with zolmitriptan. The difference
between the three active treatments and placebo (27.8% relief)
was highly signicant. Headaches at 2 hours disappeared more
frequently for the active treatments than for placebo.
Diener
87
Adults – L-ASA = 41.5y (SD:
11.8); Sumatriptan = 40.9y
(SD 11); Placebo = 39,8y (SD
11.7)
276 (55 male and 221 female)
Lysine acetylsacicylate iv 1.8 g
Sumatriptan sc 6 mg
Placebo
One administration
The main result of this study was the significant difference
(p=0.001) in efcacy, expressed as headache relief from grade 3
or 2 to grade 1 or 0, within 2 hours after administration of L-ASA
and sumatriptan compared to placebo. Placebo was signicantly
inferior to both verum drugs (p<0.0001). Sumatriptan achieves
a higher rate of headache-free patients after 2h, however was
associated with a signicantly higher incidence of adverse events.
Diener et al.
88
Adults - ranged from 18 to 64
years (median age 41 years)
n=924 (781 females and 143
males)
Alniditan (1.4 mg and 1.8
mg) sc
Sumatriptan (6 mg) sc
Placebo
one single treatment.
The number of subjects who were pain free at 2 h (primary
endpoint) was: 22 (14.1%) with placebo, 174 (56.3%) with
alniditan 1.4 mg, 87 (61.7%) with alnditan 1.8 mg and
209 (65.9%) with sumatriptan 6 mg. Alniditan 1.4 mg was
signicantly better (P < 0.001) than placebo and sumatriptan
was signicantly better (P = 0.015) than alniditan 1.4 mg. The
number of responders (reduction of headache severity from
moderate or severe headache before treatment to mild or absent
at 2 h), was 59 (37.8%) on placebo, 250 (80.9%) on alniditan
1.4 mg, 120 (85.1%) on alniditan 1.8 mg, and 276 (87.1%) on
sumatriptan. Recurrence rates were: 22 (37.3%) with placebo,
87 (34.8%) with alniditan 1.4 mg, 35 (29.2%) with alniditan 1.8
mg and 108 (39.1%) with sumatriptan. Adverse events occurred
in 577/924 (62.4%) subjects, 39.5% with placebo, 69.3% with
alniditan 1.4 mg, 64.5% with alniditan 1.8 mg and 66.2% with
sumatriptan 6 mg.
Diener et al.
89
Adults – Eletriptan 80 mg - 40
± 11; Eletriptan 40 mg - 40 ±
11; Cafergot 40 ± 10; Placebo
42 ± 11
n=733 (640 female and 93
male)
E l et r i p t an 80 an d 40 mg
Cafergot (ergotamine tartrate 2
mg, caffeine 200 mg)
Placebo tablets
The primary efficacy endpoint was headache response
(improvement from severe or moderate to mild or no pain) at
2 h - Eletriptan 80 mg 68%, Eletriptan 40 mg 54%, Cafergot
3 3 % a n d P l a c e b o 2 1 % ( p < 0 . 0 1 f o r a l l c o m p a r i s o n s ) .
Secondary efcacy measures: pain-free rates at 2 h - Eletriptan
80mg 38%, eletriptan 40mg 28%, Cafergot - 10%, Placebo - 5%.
Diener et al.
30
Adults – Acetylsalicylic
acid 38.8, Ibuprofen 38.4,
Sumatriptan 38.2 and Placebo
38.3 years.
n=313
effervescent acetylsalicylic acid
(ASA) 500 mg
capsule Ibuprofen 400 mg
gelatin capsules containing
sumatriptan tablets 50 mg
Placebo
Single dose
The percentage of patients with reduction in headache severity
from moderate or severe to mild or no pain (primary endpoint)
was 52.5% for ASA, 60.2% for ibuprofen, 55.8% for sumatriptan
and 30.6% for placebo. All active treatments were superior
to placebo (P<0.0001), whereas active treatments were not
statistically different. The number of patients pain-free at 2 h was
27.1%, 33.2%, 37.1% and 12.6% for those treated with ASA,
ibuprofen, sumatriptan or placebo, respectively. The difference
between ASA and sumatriptan was statistically significant
(p=0.025).
Diener
90
Adults – Almotriptan 12.5mg
– 41.1 (SD 11.4); Placebo –
41.4 (SD 12) years
n=221 (192 female and 29
male)
Almotriptan 12,5mg
Placebo
tablets
Efcacy measure was pain relief at 2 h after administration
of study medication. An additional endpoint assessed here is
complete relief.
Pain relief 2h for patients with a severe baseline pain intensity -
Almotriptan 46,4% vs Placebo - 25% (p<0.05).
Pain relief 2h for patients with a moderate baseline pain intensity
- Almotriptan 50% vs Placebo 15% (p<0.05).
Complete pain relief 2h - Almotriptan 17,1% vs Placebo 4,4%;
(p<0.05).
193
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Diener et al.
91
Adults – sumatriptan: 41.1
(14.2), Almotriptan 41.1
(11.4), placebo 41.4 (12.0)
n=221 (male 29 and female
192)
Almotriptan 12.5 mg
Placebo
Tablets
In the rst attack, 221 of 302 participants (73%) did not achieve
2-hour pain relief with sumatriptan and were randomized to
treatment of their second attack with almotriptan 12.5 mg or
placebo. Of the 198 sumatriptan nonresponders who treated
their second attack (99 almotriptan; 99 placebo), 70% had
severe headache pain at baseline. Two-hour pain-relief rates
were signicantly higher with almotriptan compared to placebo
(47.5% vs 23.2%; p<0.001). A signicant treatment effect for
almotriptan was also seen in pain-free rates at 2 hours (33.3%
vs 14.1%; P < .005) and sustained freedom from pain (20.9%
vs 9.0%; p<0.05). In the second attack, 7.1% of patients in the
almotriptan group experienced adverse events compared to 5.1%
in the placebo group (P = .77).
Díez, Straube,
Zanchin
92
Adults – 36.3 (10.4) years
n=372 (Female: 319 and Male:
53)
Rizatriptan 10 mg followed by
almotriptan 12.5 mg,
and
reverse sequence
tablets for the acute treatment of
two migraine attacks
Almotriptan was preferred by 55% of patients but the difference
was not statistically significant. Efficacy was the principal
determinant of patient preference for one or the other triptan, but a
signicantly greater proportion of patients preferring almotriptan
did so because they experienced fewer AEs associated with
treatment. The two treatments were of comparable efcacy in
measures of pain relief (74% versus 76%, almotriptan versus
rizatriptan) and both treatments were safe and well tolerated
Djupesland,
Docekal
93
Adults – 42 years [sumatriptan
10 mg - 40.6 (21.0–59.0)
years; sumatriptan 20 mg
- 42.7 (18.0–58.0) years;
placebo - 42.8 (21.0–64.0)
years;]
n=117 (100 females and 17
males)
Sumatriptan 10 mg or 20 mg
Placebo
single treatment day
Nose powdered drug device
with nosepiece
A greater proportion of subjects who received sumatriptan were
pain-free at 120 minutes compared with those who received
placebo (10 mg/20 mg sumatriptan vs. placebo 54% / 57% vs.
25%, p<0.05). Signicant benets were also observed for pain
relief at 120 minutes (84% / 80% vs. 44%, P<0.001/.01) and
as early as 60 minutes (73% / 74% vs. 38%, P<0.01) and for
48 hours sustained pain-free (P<0.05). Treatment-related adverse
events were rare, with a metallic taste being the most commonly
reported (10% / 13%).
Dodick et al.
94
Adults – Zolmitriptan 5mg nasal
spray - 40.7 ± 10.4 years;
Placebo - 40.7 ± 10.3 years
n=1868 (1,620 female and
248 male)
Zolmitriptan 5mg nasal spray
Placebo
Treat up to two migraine attacks,
each with a single dose of study
medication
The headache response rate at 2 hours post-dose was 66.2% for
the zolmitriptan group, compared with 35.0% for the placebo
group (p<0.001). Zolmitriptan nasal spray also produced
signicantly higher headache response rates than placebo at all
earlier timepoints assessed, starting as early as 15 minutes post-
dose (p<0.001). Similar results were obtained for the analysis of
the rst attack. Signicantly higher pain-free rates were obtained
with zolmitriptan nasal spray, compared with placebo, from
15 minutes post-dose onward (p<0.005). Zolmitriptan nasal
spray was also signicantly superior to placebo for headache
response at 4 hours, sustained headache response at 24 hours
and sustained pain-free rate at 24 hours. Zolmitriptan nasal
spray was well tolerated, with most adverse events being of short
duration and mild or moderate intensity.
Dowson et al.
95
Adults range: 17 and 66
years; Almotriptan 12.5 mg
- 42.8±10.7; Almotriptan 25
mg - 41.4±11.0; Sumatriptan
100 mg - 42.0±10.5; placebo -
40.2±10.1.
n=668 (101 male and 567
female)
Oral almotriptan (12.5 mg and
25 mg)
Sumatriptan (100 mg)
Placebo
single oral dose (capsules)
The primary efficacy assessment was migraine pain relief,
improvement from severe or moderate pain to mild or no pain,
at 2 h after treatment. Response rates, stratied for variation in
baseline pain levels, for both almotriptan doses were equivalent to
sumatriptan and signicantly better than placebo. Other efcacy
assessments conrmed the equivalence of the almotriptan groups
with the sumatriptan group. Almotriptan 12.5 mg was as well
tolerated as placebo (P=0.493) and signicantly better tolerated
than sumatriptan (P<0.001), in terms of the overall incidence
of adverse
events. There was no statistically signicant difference in the
incidence of adverse events between almotriptan 25 mg and
sumatriptan 100 mg (P=0.376).
Dowson et al.
96
Adults – Placebo: 206 female
and 33 male; 204 female and
27 male;
n=470 (410 female and 60
male)
Zolmitriptan 2.5 mg (orally
disintegrating tablets)
Placebo
Acute treatment of a single
moderate or severe migraine
headache
Headache relief following zolmitriptan 2.5mg (63%) was
significantly greater than with placebo (22%) at 2h post-
dose (primary endpoint; p<0.0001). The zolmitriptan orally
disintegrating tablet was also significantly more effective
than placebo for 1, 2 and 4h pain-free response (8% vs.
3%, P=0.0207, 27% vs. 7%, p<0.0001, and 37% vs. 11%,
p<0.0001, respectively). Of those patients stating a preference,
70% of patients preferred the orally disintegrating tablet to a
conventional tablet.
Dowson,
Massiou,
Aurora
97
Adults – Group 1 - 37 (19-49);
Group 2 - 40 (19-50)
n=115 (female only)
Sumatriptan 100 mg oral
Placebo
Four menstrual periods.
The primary study efcacy endpoints were the proportions of
patients who reported headache relief at 4h post treatment. A
small number of patients had mentrually related migraine, but
e f c a c y a n a l y s e s w e r e c o n d u c t e d f o r t h e w h o l e s t u d y s a m p l e .
Headache relief at 4h - Patients inside menstrual window -
Sumatriptan 67% vs Placebo 33% (p=0.0072) Outside menstrual
w i n d o w - S u m a t r i p t a n 7 9 % v s P l a c e b o 3 1 % ( p = 0 . 0 0 0 1 ) .
Complete headache relief at 4h - Inside menstrual window -
Sumatriptan 49% vs Placebo - 10% (p=0.0001). Outside
menstrual window - Sumatriptan 60% vs Placebo 9% (p=0.0001)
194
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Evers et al.
48
Adolescents – 13.9 ± 2.8 years
n=32 (18 female and 14 male)
Oral zolmitriptan 2.5mg
Ibuprofen 200 or 400 mg
(according to child age)
Placebo
Three migraine attacks
The number of patients with pain relief after 2 hours was chosen
as the primary outcome measure.
Pain relief 2h - Zolmitriptan 62% vs Placebo - 28% (p<0.05) and
Ibuprofen 69% (in comparison with placebo p<0.05).
Pain free 2h - Zolmitriptan 45% vs Placebo - 7% (p<0,01)
a n d I b u p r o f e n 4 8 % ( i n c o m p a r i s o n w i t h p l a c e b o p < 0 . 0 1 ) .
Sustained pain-free - Zolmitriptan 34% vs Placebo - 7% (p<0.05)
and Ibuprofen 38% (in comparison with placebo p<0.05)
Facchinetti et al.
98
Adults - mean age 37.5
n=226 (female only)
Sumatriptan 6 mg
Placebo
Pre-lled syringe in
subcutaneous injection
The efcacy results were consistent for attacks one and two:
2 h after treatment in attacks one and two, 53 (73%) and 51
(81%;) of the sumatriptan-treated subjects, respectively, reported
headache relief (reduction of a severe or moderately severe
headache to a mild or no headache), compared with 27 (31%)
and 18 (29%) of the placebo-treated subjects (p<0.001). Within
24 hours of treatment in attack one, 28 (53%) and 14 (52%) of
the initial responders to sumatriptan and placebo, respectively,
experienced headache recurrence.
Färkkilä et al.
99
Adults – Eletriptan 80mg – 40.9
± 10.2; Eletriptan 40mg – 41.4
± 10.6; Placebo – 40.9 ±12
n=446 (385 female and 61
male)
Eletriptan 40 (E40) and 80 mg
(E80)
Placebo
Oral tablets
The primary efcacy endpoint was 2h headache response after
rst attack.
2h headache response - E80 70% (106/152), E40 59%
(91/154), Placebo 30% (22/74); E80 and E40 were signicantly
superior to placebo (p<0.0001) and E80 was significantly
supererior to E40 (p<0.05).
2h pain free-response - E80 42% (64/152), E40 35% (54/154),
Placebo 7% (5/74). Both doses are superior to placebo
(p<0.0001). Sustained response - E80 45%
(56/124), E40 39% (55/140), placebo 14% (10;74), both
doses are superior to placebo (p<0,0005).
Consistently response - The percentage of subjects who reported
a response in 2 out of 3 headaches was signicantly higher on
E40 (66% - 74/112) and E80 (72% - 72/100) compared with
placebo (15% - 5/34) (p<0.001).
Fernandes et al.
39
Adults - Dipyrone – male 32.2
(DP 12.6) female 34.3 (DP
9.6); Metoclopramide – male
29 (DP 8.6) female 35.8 (DP
6.4) years.
n=27 (14 male and 13 female)
Dipyrone IV
Metoclopramide IV
One migraine attack
Among male patients, it was observed that the percentage
variation in pain scores before and after treatment was, in
general, greater in patients treated with metoclopramide than
in patients treated with dipyrone (p=0.052). No difference was
seen between female patients (p=0.748).
Ferrari et al.
100
Adults – Sum100 mg+Sum100
mg – 40.5 ±10.5
Sum100 mg+Placebo – 40.5
± 10.5
n=1246 (1021 female and
225 male)
Sumatriptan 100 mg
Placebo
Tablets to treat up to three
migraine attacks
The primary objective of the study was to compare headache
improvement from moderate or severe at time 0 to none or mild at
4 h on sumatriptan 100 mg + sumatriptan 100mg and 100 mg +
placebo. Headache
improvement - 2 h after the rst dose of 100 mg sumatriptan - 56%
Sum+Sum vs 55% Sum+Plac.
H e a d a c h e i m p r o v e m e n t a t 4 h - 7 7 % S u m + S u m v s 8 0 % S u m + P l a c .
Headache recurrence - 25% Sum+Plac vs 22% Sum+Sum
Freitag et al.
101
Adults – Isometheptene
Combination- 40.9 ± 9.6
Sumatriptan succinate – 43.3
± 9.6 n=126 (112 female and
14 male)
Isometheptene Combination
(65 mg isometheptene, 100 mg
dichloralphenazone, and 325
mg acetaminophen) - 5 capsules
taken over several hours
Sumatriptan Succinate 25 mg (2
doses) capsules
Placebo
Single migraine attack
Primary outcome: % of patients with mild or no headache at 2
hours and/or 4 hours after the rst dose of study medication,
and % of patients who did not suffer a recurrence of headache
within 24 hours of the initial dose.
No or mild headache at 4 hours - Isometheptene combination
76% vs Sumatriptan 80% (X2 = 0.22).
Patients without headache or had only a mild migraine at 24
hours - 82% in both groups.
Freitag et al.
102
Adults – Rizatriptan 10 mg - 40
years; Placebo - 41 years
n=277 (249 female and 28
male)
Rizatriptan 10 mg ODT
Placebo
Single migraine attack
There was a greater percentage of patients with elimination of
nausea at 2 hours (primary efcacy endpoint) in the rizatriptan
ODT group compared with the placebo group (70.3% vs 62.0%),
P = 0.165, odds ratio (95% CI) = 1.45 (0.86, 2.46) - not
statistically signicant.
There was a signicantly greater percentage of patients who
achieved 2-hour pain relief (secondary efcacy endpoint) with
rizatriptan ODT compared with placebo (69.7% vs 54.3%), P =
.012, odds ratio (95% CI) = 1.94 (1.16, 3.25).
195
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Freitag et al.
103
Adults – 40.4(10.8)
n=315 (274 female and 41
male)
Almotriptan 12.5mg
Placebo
3 consecutive migraine attacks
Pharmaceutical form not
informed
Attack 1: 2 h posttreatment 54.4%, 32.5%, 13.1%, and 0% of
almotriptan-treated patients reported normal function, disturbed
function, bed rest required, and ER/hospitalization respectively,
compared with 38.1%, 45.2%, 16.1%, and 0.6% of placebo-
treated patients.
The differences in level of functional disability between the
2 treatment groups were statistically signicant at 2 hours (P
=0.007; Cochran-Mantel-Haenszel, stratied by center) and
at 4 hours (P <0.001). Resolution of pain was associated with
a normal level of function; at 2 hours posttreatment, 91.7% of
patients in the total population who achieved pain-free reported
normal function compared with 44.8%, 8.0%, and 0% of patients
with mild, moderate, and severe pain, respectively. The absence
compared with the presence of photophobia, phonophobia,
and nausea at 2 hours also was associated with less disability
(P < 0.0001 for each symptom). Treatment with almotriptan
compared with placebo resulted in consistently better 24-hour
MQoL scores with signicant results for all 3 migraine headache
attacks in the social function and feelings/concern domains. A
logistic regression model determined that pretreatment functional
level (P = 0.0117), pretreatment pain intensity (P = 0.0089),
and pretreatment MIDAS score (P = 0.0152) were signicant
covariates of the proportion of patients who achieved normal
function at 2 hours posttreatment.
Freitag et al.
36
Adults – RA – 41.5 years (SD
10.3); R – 44.3 years (SD
10.6); A - 42 years (SD 11.7);
P – 45.3 years (SD 10.9)
n=172 (151 female and 21
male)
Rizatriptan 10 mg +
Acetaminophen 1000 mg
(RA); Rizatriptan 10 mg (R);
Acetaminophen 1000 mg (A);
Placebo (P)
Oral tablet formulations to treat
a single attack of migraine
The primary efcacy endpoint was pain relief (Grade 0 or 1) at
2 h. Pain relief 2h - RA 90%, R 77%, A 70%, P 46%. RA
was statistically superior to A and P.
Pain-freedom 2h - RA 54%, R 40%, A 26%, and p 15%. RA was
statistically superior to A and P.
Pain relief sustained 24h - RA 62%, R 53%, A 42% and P 15%.
RA was statistically superior to P only.
RA was statistically superior to A for absence of phonophobia
(85% vs 60%, P = .009) and statistically superior to P for absence
of phonophobia (85% vs 67%, P = .039), absence of nausea
(92% vs 72%, P = .021), and absence of functional disability
(65% vs 41%, P = .024).
Friedman et al.
104
Adults – 31 to 37 years
Metoclopramide = 34 years
(31-37); Sumatriptan = 34
years (31/37)
n=78 (67 female and 11 male)
Metoclopramide 20 mg +
diphenhydramine 25 mg
administered IV
Sumatriptan 6 mg sc
Single attack of migraine
The primary outcome, a comparison of the change in NRS
(numeral rating scale) scores between time 0 and 2 hours in
each arm, demonstrated a clinically and statistically insignicant
advantage for the metoclopramide arm: 1.0. The secondary
outcome, a comparison of the change in NRS (numeral rating
scale) score between time 0 and 24 hours, revealed a clinically
and statistically insignicant advantage for the metoclopramide
arm: 1.1. At 2
hours - 59% of metoclopramide subjects and 35% of sumatriptan
subjects were pain-free.
Friedman et al.
105
Adults – TMB/DPH 34 (9.7)
and Sumatriptan 32 (8.9) years
n=40 (37 female and 3 male)
Trimethobenzamide 200 g +
diphenhydramine 25 mg (TMB/
DPH) as a single intramuscular
injection
Sumatriptan 6mg SC
By 2 hours sumatriptan subjects had improved by a mean of 6.1
and the TMB/DPH subjects had improved by a mean of 4.4 (95%
CI for difference of 1.7: −0.1 to 3.4).
By 24 hours after medication administration, sumatriptan subjects
had a mean improvement from baseline of 4.9 as compared to
5.3 for TMB (95% CI for difference of −0.4: −2.4 to 1.6).
The need for rescue medication was comparable between the
groups. No serious or frequent adverse effects were noted in
either group
Friedman et al.
106
Adults - 18 to 64 years
n=166 (144 female and 22
male)
Oral Naproxen 500mg
Oral Sumatriptan 100 mg
Single attack migraine
Naproxen group improved by a mean of 4.3 NRS (numeral rating
scale) points, whereas the sumatriptan group improved by 4.1
points (95% CI for difference of 0.2 points: 0.7 to 1.1 points).
Findings were virtually identical among the migraine subset (4.3
versus 4.2 NRS points; 95% CI for difference of 0.1 points: 1.3
to 1.5 points).
Would patients want to take the same medication the next time:
71% Naproxen (95% CI 62% to 80%) and 75% (95% CI 66%
to 84%) of sumatriptan patients answered yes.
Adverse effect proles were also comparable
Friedman et al.
107
Adults - 18 to 63 years
n=35 (28 females and 7 males)
Maxillary intraoral chilling (MIC)
40 minutes of bilateral
Sumatriptan 50 mg oral
Sham (tongue) chilling
Signicant mean headache relief was obtained by maxillary
chilling and sumatriptan at all time intervals (1, 2, 4 and 24
hours), with poor relief obtained by placebo. Maxillary chilling
was more effective than sumatriptan at all time intervals.
Signicant nausea relief was obtained by maxillary chilling
and sumatriptan at posttreatment and 2 and 4 hours later. At
24 hours, some headache and nausea recurrence were noted
with sumatriptan. The repeated-measures analysis of variance
indicated that both treatments, drug (P = 0.024) and maxillary
chilling (P = 0.001), reduced the headache compared to the
control group.
196
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Fujita et al.
49
Children and adolescents:
Sumatriptan 25 mg: 14.5
(2.18); Sumatriptan 50 mg:
14.1 (1.96) and Placebo: 13.9
(2.04)
n=144 (female 84 and male
60)
Sumatriptan 25 and 50 mg oral
Placebo
Single migraine attack
Patients who report pain relief at 2h post-treatment for the primary
endpoint was higher in the placebo group than in the pooled
sumatriptan group (38.6% vs 31.1%, 95% CI: 23.02 to 8.04,
p=0.345).
Patients who reported pain relief at 4h post-dose was higher in
the pooled sumatriptan group (63.5%) than in the placebo group
(51.4%) but failed to achieve statistical signicance (p=0.142).
At 4h post-dose, percentages of patients who were pain free
or had complete relief of photophobia or phonophobia were
numerically higher in the sumatriptan pooled group compared
to placebo.
Gallagher et
al.
108
Adults – zolmitriptan 2.5 mg
39.9 (10.0); 5 mg 40.2 (10.5);
Sumatriptan 25 mg 39.6
(10.2); 50 mg 40.6 (10.2)
years
n=1212 (1062 female and
150 male)
Zolmitriptan 2.5 mg, 5mg tablet
Sumatriptan 25 and 50 mg
tablet
Treat a rst and second
(recurrence a single migraine
attack) migraine attack
A headache response at 2 hours was noted in 67.1% of
patients taking zolmitriptan 2.5 mg, and 64.8% of those taking
zolmitriptan 5 mg, versus 59.6% of patients taking sumatriptan
25 mg, and 63.8% of those taking sumatriptan 50 mg. At 2
and 4 hours, the differences between zolmitriptan 2.5 mg, and
sumatriptan 25 mg, were statistically signicant (odds ratio=1.49
and 1.67, respectively; both P<.001). Statistically signicant
differences between zolmitriptan 2.5 mg, and sumatriptan 50
mg, were seen at 2 and 4 hours post dose (odds ratio=1.21
and 1.23, respectively; both P<.05). At 1 hour post dose, the
headache response rate for zolmitriptan 2.5 mg, was numerically
higher than response rates for sumatriptan 25 mg and 50mg
(odds ratio=1.16, odds ratio=1.06, though they failed to
reach statistical signicance; P=.061, P=.461 respectively).
Differences between zolmitriptan 5 mg, and sumatriptan 25
mg, were statistically signicant at 1, 2, and 4 hours (odds
ratio=1.43, 1.46, and 1.78, respectively; all P<.001) and at 1
and 4 hours versus sumatriptan 50 mg (odds ratio=1.28, P=.002;
odds ratio=1.29, P=.012, respectively). Although not statistically
signicant at 2 hours, more patients responded to zolmitriptan
5 mg, than to sumatriptan 50 mg (odds ratio=1.16, P=.064).
Patients receiving zolmitriptan 2.5 mg or 5 mg, achieved more
pain relief over 24 hours than patients receiving sumatriptan 25
mg (odds ratio=1.47, and 1.54 respectively, both P<.001) or
sumatriptan, 50 mg (odds ratio=1.17, P=.021; odds ratio=1.22,
P=0.005, respectively
Garcia-Ramos et
al.
109
Adults – Eletriptan – 36.3 ±
11.1; Naratriptan 37.5 ± 11;
Placebo 36.4 ± 11.1 years
n=483 (390 female and 93
male)
Eletriptan 40mg tablet
Naratriptan 2.5mg capsule
Placebo
Single migraine attack
The primary efficacy endpoint for the study was headache
response at 2 h after the rst dose of study medication for the
index attack.
Headache response 2 h - eletriptan (56%) compared to
naratriptan 42%, P < 0.01).
Headache response at 1 h - Eletriptan - 34%, Natriptan - 25%
and Placebo - 21% and 4 h Eletriptan - 80%, Naratriptan - 67%,
Placebo - 44%. Eletriptan showed higher pain-free rates at both 2
and 4 h (35% and 56%) compared with both naratriptan (18%; P
<0.001 and 41%, P <0.01) and placebo (19%, P <0.001; 24%,
P <0.0001). Among
patients who achieved a 2 h headache response, headache
recurrence rates were consistently low for eletriptan (29%),
naratriptan (26%), and placebo (28%).
Geraud et al.
110
Adults – Zolmitriptan-38.3±10.4
years; Sumatriptan-38.0±10.6
years; Placebo-37.9±9.7 years.
n=1058 (174 male; 884
female)
zolmitriptan 5 mg or
sumatriptan 100 mg
placebo
a single oral dose
A reduction in headache pain from moderate/severe at baseline
to mild or no pain 2 h after taking study medication with no
moderate or severe recurrence within 24 h (Primary Endpoint)
was reported by 39%, 38% and 32% of patients treated with
zolmitriptan, sumatriptan and placebo, respectively, with no
significant difference between treatment groups. In patients
with moderate headache at baseline, complete response
was significantly greater following zolmitriptan than after
placebo (48% vs. 27%; P50.01); there was no significant
difference between sumatriptan and placebo groups (40%
vs. 27%). In patients with severe baseline headache (where
a greater reduction in headache intensity is required for a
headache response), there was no significant difference
b e t w e e n a n y g r o u p s i n c o m p l e t e h e a d a c h e r e s p o n s e r a t e s .
Secondary objectives were to compare headache and pain-free
response rates at 1, 2 and 4 h post-dose. In addition, other
secondary objectives were to compare the proportion of patients
whose migraine-associated symptoms were effectively treated,
use of escape medication after 2 h, incidence of recurrence,
meaningful migraine relief, time to meaningful migraine relief,
and degree of activity impairment at 1, 2, 4 and 24 h. For these
secondary endpoints, active treatment groups were signicantly
superior to placebo for: 1-, 2- and 4-h headache response (e.g.
2-h headache response rates: zolmitriptan 59%; sumatriptan
61%; placebo 44%; P=0.01 vs. placebo); pain-free response
rates at 2 and 4 h; alleviation of nausea and vomiting; use
of escape medication and restoration of normal activity. The
incidence of adverse events was similar between zolmitriptan and
sumatriptan groups but was slightly lower in the placebo group.
197
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Geraud,
Compagnon,
Rossi
111
Adults – 41.6±10.0 and
40.9±10.7 years n=666 (100
male and 566 female)
Zolmitriptan 2.5 mg oral
Acetylsalicylic acid 900 mg +
metoclopramide 10 mg oral
First and second (recurrence a
single migraine attack) migraine
attack
The percentage of patients with a 2-hour headache response after
the rst dose (primary endpoint) was 33.4% with zolmitriptan and
32.9% with acetylsalicylic acid plus metoclopramide [odds ratio
1.06, 95% condence interval (CI) 0.77–1.47; p = 0.7228].
For most secondary endpoints, the two treatments demonstrated
comparable efcacy.
Ghaderibarmi,
Tavakkoli,
Rossi
112
Adults – Sumatriptan -
36.17±7.57;
Valproate - 38.61 ± 11.41
years
n=37 (7 male and 30 female)
Sumatriptan 6mg SC
Valproate 15 mg/Kg IV
Single migraine attack
The outcomes including pain severity at 0.5, 1, 2, 4, 24, and 48
hours after injection (VAS score was used to migraine severity).
Sumatriptan VAS Score (before treatment: 0.84): 0.5h - 0.01,
1h - 0.023, 2h - 0.3, 4h -0.99, 24h - 0.68, 48h - 0.46.
Valproate VAS Score (before treatment: 8.31): 0.5h - 3.31, 1h -
2.26, 2h - 2.15, 4h - 2.10, 24h - 1.68, 48h - 1.31.
Gijsmant et al.
113
Adults - mean age 39.2 years
n=418 (Female: 361 and
Male: 57)
Rizatriptan 2.5mg, 5 mg, 10 mg
Placebo
Sigle migraine attack
At the primary timepoint of 2 h after the initial dose, the proportion
of patients reporting pain relief was 47.6% for rizatriptan 10 mg;
45.4% for rizatriptan 5 mg; 21.3% for rizatriptan 2.5 mg; and
17.9% for pacebo. Seventy percent of patients on rizatriptan 10
mg reported pain relief at 4 h.
Goadsby et al.
114
Adults – 39 (SD 10) years
n=61 (10 male and 51 female)
Oral Sumatriptan 100mg
Placebo
Single migraine attack
Positive result was dened as a reduction in headache grade
from 3 or 2 to 0 or 1.
Reduction headache grade - Sumatriptan 45/89 [51 %] vs
Placebo 9/93 [10%]; p < 0.01, x2 test).
Use of rescue medication at 2 h - Sumatriptan 88% vs Placebo
41% (p < 0.05).
Of the 28 patients who were headache-free at 2 h after
sumatriptan, 11 (39%) had a recurrence of headache within
the next 24 h.
Goadsby et al.
115
Adults – 40 years (18 to 64)
[placebo: 41±10 (21–66)
years; sumatriptan-100mg:
40±10 (18–68) years;
eletriptan-20mg: 40±11
(18–68) years; eletriptan-
40mg: 41±11 (19–71) years;
eletriptan-80 mg: 40±11 years
(18–67);] years.
n=692 (568 females and 124
males)
Eletriptan (20 mg, 40 mg, or 80
mg) tablet
Sumatriptan (100 mg) capsules
Placebo
Single migraine attack, a
second double-blind dose of
study medication could be
administered
At the primary endpoint (2 hours after dosing), headache
response rates were 24% (30/126) for placebo; 55% (63/115)
for sumatriptan 100 mg; 54% (70/129) for eletriptan 20 mg;
65% (76/117) for eletriptan 40 mg; and 77% (91/118) for
eletriptan 80 mg. There was a difference compared with placebo
(p<0.001) for all doses of eletriptan, and at 2 hours there was
a difference between sumatriptan 100 mg, and eletriptan 80
mg (p<0.001).
Headache-free rates at 2 hours were superior to placebo (6%;
p<0.001) for both the 80-mg dose of eletriptan (37%) and the
40-mg dose (29%), with the 80-mg dose also being superior to
100 mg of sumatriptan (23%; p<0.05).
Eletriptan and sumatriptan were well tolerated, and the majority
of adverse events were mild or moderate in intensity and transient.
Goadsby et al.
116
Adults - Almotriptan 39 ±11
and Zolmitriptan 40 ± 11 years
n=1062 (902 female and 160
male)
Almotriptan 12.5 mg oral
Zolmitriptan 2.5 mg oral
single migraine attack
The primary endpoint was sustained pain free plus no adverse
events, other endpoints included pain relief and pain free at
several time points, sustained pain free, headache recurrence,
use of rescue medication, functional impairment, time lost because
of migraine, treatment acceptability, and overall treatment
satisfaction.
2-h pain relief: Almotriptan 65.4%; Zolmitriptan: 70.2 % (p =
0.094)
Pain relief at 24 h: Almotriptan 82.9%; Zolmitriptan: 83.8 %
(p = 0.699)
2 h pain free: Almotriptan 43.5%; Zolmitriptan: 48.3 % (p =
0.117).
Göbel et al.
117
Adults – mean age 45 years
n=253 (230 female and 23
male)
Naratriptan 2.5 mg tablet
Sumatriptan 100 mg tablet
single migraine attack
Of the 164 naratriptan-treated and 181 sumatriptan-treated
patients experiencing headache relief after ≥1 attack, headache
recurrence 4 to 24 hours after treatment was reported by 74
naratriptan-treated patients (45%) and 101 sumatriptan-treated
patients (57%; not statistically signicant).
In a subset of patients experiencing headache relief after 2
attacks, headache recurrence 4 to 24 hours after initial dosing
was reported by 55 naratriptan and 77 sumatriptan-treated
patients (41% and 57%, respectively; P = 0.005).
The overall incidence of adverse events was 22% after treatment
with naratriptan and 33% after treatment with sumatriptan. This
incidence did not increase after the use of the second dose of
naratriptan (20%) or sumatriptan (31%).
Goldstein et al.
118
Adults - mean age 40.2 years
n=1,329 (1,167 female and
male 162)
Rizatriptan 5 and 10mg oral
Sumatriptan 25 and 50mg oral
two migraine attacks
The outcomes were time to pain relief (comparison between
drugs) and pain relief at 2 hours.
Pain relief - HR rizatriptan 5mg vs sumatriptan25 mg = 1.16,
suggesting that patients on rizatriptan 5mg are 16% more likely
to achieve pain relief in comparison to patients on sumatriptan 25
mg. HR rizatriptan10mg vs sumatriptan 50mg = 1.14 suggesting
that patients on rizatriptan10 mg are 14% more likely to achieve
p a i n r e l i e f i n c o m p a r i t o n t o p a t i e n t s o n s u m a t r i p t a n 5 0 m g .
Pain relief at 2h – Rizatriptan 5mg - 33%, Sumatriptan 25mg -
28%, Rizatriptan 10mg - 72%, Sumatriptan 50mg - 68%, Placebo
-38%
198
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Goldstein et al.
119
Adults – mean age 38.1 years
n=171 (136 female and 35
male)
AAC (acetaminophen 500 mg,
aspirin 500 mg, caffeine 130
mg)
Sumatriptan succinate 50mg (25
mg per tablet)
Placebo
All study medications were
individually encapsulated in
hard gelatin capsules
AAC group experienced significantly greater pain intensity
reduction or pain relief than those taking S50 or placebo. Pain
intensity reduction and pain relief score for Sumatriptan 50mg
group were higher than placebo group, but not to a statistically
signicant degree.
Reduction of headache pain intensity from moderate/severe to
mild/none - Sumatriptan 50mg group was signicantly superior to
AAC (30 minutes postdose); AAC group was signicantly greater
than in the Sumatriptan 50mg group (2, 3 and 4 hours postdose).
The response rate of AAC versus placebo was signicant from
90 minutes. The rate of response in the Sumatriptan 50mg group
was greater than that in the placebo group at all time points, but
not to a statistically signicant degree.
Utilization of the rescue medication showed statistically signicant
difference between Sumatriptan 50mg group (11.9% subjects)
versus the AAC group (1.5% of subjects), at 4 hours postdose.
Goldstein et al.
120
Adults – Sumatriptan ITS - 40,7
(SD 11,2) Placebo - 41 (SD
11) years
n=454 (386 female and 68
male)
Sumatriptan transdermal system
6.5 mg
Placebo patch
Dose timing began at patch
activation. Patients remained
on study until one migraine
headache was treated with
the study patch or 2 months
following randomization,
whichever occurred rst
Signicantly greater proportion of patients who received the
sumatriptan transdermal system were headache pain-free 2
hours after patch activation compared with placebo (18% vs
9%, respectively; p=0.0092). The sumatriptan transdermal system
was associated with a signicantly higher percentage of patients
reporting headache pain relief 2 hours postdose (52.9% vs
28.6%, respectively; P <0.0001).
Gross et al.
121
Adults – Sumatriptan - 44 ±
10.2; Placebo - 43 ± 11.3
years
n=86 (69 female and 17 male)
Sumatriptan 6 mg sc
Placebo
Single migraine attack
Primary efcacy was headache relief at 60 minutes after the
rst injection.
Headache relief 1 hour post treatment - Sumatriptan 42/48 (88%)
vs Placebo 2/18 (11%) (P <0.001).
Rate treatment as good or excellent - Sumatriptan (47/60, 78%)
vs Placebo (4/26, 15%).
Second dose - Sumatriptan (17/ 20, 85%) to treat recurrence and
Placebo (21/24, 88%) to treat an ongoing headache following
an ineffective response to the rst dose.
Adverse events - Sumatriptan 55% (33/60) vs Placebo 15%
(4/26).
Gruffydd-Jones
et al.
121
Adults – had been less than 50
years old.
n=401 (329 female and 72
male)
Sumatriptan 100mg oral and
Sumatriptan 6 mg subcutaneous
Three migraine attacks
Over 70% of patients who treated attack 1 in both treatment
periods of the crossover phase reported headache relief with
each formulation at 4 h. Only 3% of patients failed to respond
to at least one of the formulations at this time point.
At the end of the crossover phase patient preference for the
injection more than doubled from the pretreatment level in those
patients who were previously naive to sumatriptan. During the
optional phase of the study, 38% of patients chose to treat some
attacks with oral and some with subcutaneous sumatriptan
Gruffyd-Jones et
al.
122
Adults – Zolmitriptan 5mg =
41.7 ± 10.6; Zolmitriptan
2,5mg = 42.1 ± 10.7;
Sumatriptn 41.9 ± 10.7 years.
n=1522 (1299 female and 223
male)
Zolmitriptan 5 and 2.5mg
tablets
Sumatriptan 50mg tablets
Single migraine attack
There were 2 primary efcacy endpoints: headache response at
2 h after treatment and proportion of patients with a headache
response at 2 h after the rst dose of study medication across all
attacks treated. Headache
response at 2h: Zolmitriptan 5mg – 65.7% vs Zomitriptan 2,5mg
– 62.9% vs Sumatriptan 50mg - 66,6% (there were no difference
between response rates in all treated attacks with 3 study
medications, there were no statistically difference post 1 or 4h).
Proportion of patients with 2h response: Zolmitriptan 5mg –
44.4% patients had a response in >80% of attacks, Zolmitriptan
2.5mg - 38,6% patients had a response in >80% of attacks,
Sumatriptan 50mg – 43.1% patients had a response in >80% of
attacks (p=0.14 versus zolmitriptan 2.5 mg and p=0.55 versus
zolmitriptan 5 mg).
Hämäläinen,
Hoppu,
Santavuori
50
Adolescents - 12,3 (8,3 - 16,4)
years
n=23 [12 female (52%) and 11
male (48%)]
Sumatriptan 50 mg oral for a
body surface area of 0.75 to
1.5 m2
Oral Sumatriptan 100 mg for a
body surface area of > 1.5 m2
Placebo
One migraine attack with
sumatriptan and for one with a
matching placebo in random
order
The primary endpoint of clinical efcacy was reduction of pain
intensity by at least 50% after 2 hours.
At 2 hours, reduction of pain intensity by 50% -
Sumatriptan 7/23 (30%) vs placebo 5/23 (22%)
( d i f f e r e n c e 9 % , 9 5 % C I f o r d i f f e r e n c e - 2 1 t o 3 8 % , p = n s ) .
Headache-free - Sumatriptan 5/23 (22%) vs placebo 2/23
(9%) (difference 13%, 95% CI for difference -9 to 35%, p = ns).
Havanka et al.
123
Adults – 18 to 65 years
n=643 (566 female and 77
male)
Naratriptan tablets (1, 2.5, 5,
7.5, and 10 mg)
Sumatriptan tablets (100 mg)
Placebo
Single oral dose for a single
migraine attack
1 hour headache relief: Narat 1 mg (25/85); Narat 2.5 mg
(30/87); Narat 5 mg (34/93); Narat 7.5 mg (43/93); Narat 10
mg (40/96); Sumat 100 mg (35/98); Plac (20/91).
2 hours headache relief: Narat 1 mg (58/85); Narat 2.5 mg
(52/87); Narat 5 mg (54/93); Narat 7.5 mg (68/93); Narat 10
mg (69/96); Sumat 100 mg (60/98); Plac (31/91).
4 hours headache relief: Narat 1 mg (64/85); Narat 2.5 mg
(63/87); Narat 5 mg (65/93); Narat 7.5 mg (80/93); Narat 10
mg (80/96); Sumat 100 mg (80/98); Plac (39/91).
199
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Henry, d’Allens
124
Adults – Mean age was
Sumatriptan 44±1.7 and
Placebo 42±1,6 years.
n=76 (10 males and 66
females)
Sumatriptan 6mg SC
Placebo
Patients having inadequate relief
were allowed to use a second
injection of test medication 1
hour later and rescue treatment
between 2 hours and 24 hours
after the rst dose.
Headache relief was achieved within 2 hours after Sumatriptan in
26 patients (70%) compared to 8 patients (21%) in the placebo
group (p<0.0001). Of these patients, 19 (51%) and 3 (8%) were,
respectively, pain free at this time.
A second injection of Sumatriptan was used respectively by 13
(35%) and 22 (58%) patients (p<0,024).
Ho et al.
51
Adolescents 6-17 years old and
mean 13.0 (2.9) years.
n=977 (female 550 and male
427)
Rizatriptan (5 mg for <40 kg,
10 mg for ≥ 40 kg)
Placebo
Patients with moderate/
severe pain (non-responders)
proceeded to take study
medication in Stage 2
A higher proportion of 12–17 year old on rizatriptan had pain
freedom at 2 hours compared with those on placebo, 87/284
(30.6%) versus 63/286 (22.0%), odds ratio = 1.55 [95% CI:
1.06 to 2.26], p = 0.025. Adverse events within 14 days of dose
in 12–17 year old were similar for rizatriptan and placebo. The
pattern of ndings was similar in 6–17 year old.
Ishkanian et al.
125
Adults – sumatriptan 39.6±12.3
(18 -70) years; placebo
41.0±11.3 (18-60) years.
n=215 (151 females and 64
males)
Sumatriptan 50 mg tablet
Placebo
Single migraine attack
Significantly more patients treated with sumatriptan 50 mg
achieved a positive headache response at 2 and 4 hours after
administration compared with those treated with placebo (69%
vs 43% at 2 hours and 76% vs 49% at 4 hours, respectively;
both, P < 0.001).
Signicantly more sumatriptan-treated patients were free from
sinus pain compared with placebo recipients at 2 hours (63% vs
49% placebo, P = 0.049) and 4 hours (77% vs 55%, P = 0.001).
All treatments were generally well tolerated. The most common
drug-related AEs reported in the sumatriptan and placebo groups,
respectively, were dizziness (5% vs < 1%), nausea (3% vs 2%).
No patients experienced any serious adverse effects.
Jelinski et al.
126
Adults – mean age of 40 years
[(39.8±9.7 years sumatriptan
50 mg, 39.8±11.4 years
sumatriptan 100 mg, 40.7±9.8
years placebo)] years
n=361 (309 females and 52
males)
Sumatriptan 50 mg
Sumatriptan 100 mg
Placebo
Single migraine attack
Two-hour pain free rates were 16%, 40%, and 50% in the
placebo group, sumatriptan 50 mg group, and the sumatriptan
100 mg group respectively (p < 0.001, active treatment groups
vs placebo).
The percentage of subjects who sustained a pain-free response
for both 50 mg and 100 mg sumatriptan groups (24% and 27%)
was signicantly higher than in the placebo group (6%).
After 4 hours, 25% of the 50 mg sumatriptan group and 13% of
the 100 mg sumatriptan group experienced worsening of their
migraine pain, compared to 46% of placebo patients (both
p<0.001).
Jensen et al.
127
Adults – 43 years (range 20-65)
n=138 (125 female and 13
male)
Sumatriptan 6 mg subcutaneous
Placebo
Sumatriptan 6 mg sc was signicantly better than placebo at
30, 60, 90 and 120 min after injection in relieving moderate
or severe headache to mild or none as well as relieving any
headache to none. At 60 min after injection, the treatment
response rate was 61% for sumatriptan and 6% for placebo.
During the following open-phase trial of four attacks treated with
sumatriptan, treatment response rates were 68-74%.
During the total of 538 attacks treated, 12 attempts at using the
self-injector failed. In the double-blind and open phases, 81%
and 90% of patients respectively found the device easy or very
easy to use. Adverse effects were benign and short lasting, but
led 7 patients to discontinue the study.
Kelly et al.
128
Adults – mean age sumatriptan
32 and chlorpromazine 35
years
n=43 (29 Female and 14 male)
Sumatriptan 6 mg IM
Chlorpromazine IV 12.5 mg
increments to a maximum of
37.5 mg
No difference in efcacy between the sumatriptan regimen and
the chlorpromazine regimen was found. Adverse effects were
mild and equally distributed between the groups.
Klapper,
O’Connor
31
Subjects age not mentioned.
n=30
Rizatriptan 10 mg wafer
sublingual
Placebo
Single migraine attack
The primary efcacy measure was pain relief in 1 hour.
Pain relief in 1 hour – Rizatriptan 50% (8/16) vs Placebo 50%
(7/14). The average time to onset of signicant relief - Rizatriptan
was 25 min vs. Placebo 27 min (t=1.25, NS).
Klapper et al.
129
Adults – Zolmitriptan 2.5mg
– 41.1 ± 11.3 years; Placebo -
42 ± 10.3 years
n=280 (39 male and 241
female)
Zolmitriptan 2.5 mg oral
Placebo
Single migraine headache
Primary endopoint was pain-free rate (i.e. ‘no pain’) at 2 h after
the rst dose of zolmitriptan 2.5 mg or placebo.
Pain-free at 2 h - Zolmitriptan 43.4% vs. Placebo 18.4%; odds
ratio (OR) 3.28, 95% CI 1.90–5.66, P < 0.0001.
Progressed to more severe intensity within 2 h after treatment
-Zolmitriptan 53.7% vs. Placebo 70.4%, P < 0.01.
At 2 h after dosing patients able to perform normal activities
-Zolmitriptan 68.4% vs. Placebo 50.7%, P < 0.01.
200
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Klassen et al.
130
Adults – 40.2 years
n=613 (533 female and 80
male)
Naratriptan tablets 2.5mg, 1
mg, 0.25 mg or 0.1 mg
Placebo
One moderate or severe
migraine attack
Headache relief (moderate or severe pain at dosing reduced
to mild or no pain) 4 hours postdose was reported in 60% of
patients receiving naratriptan 2.5 mg compared with 50%, 35%,
32%, and 34% of patients receiving naratriptan 1 mg, 0.25 mg,
0.1 mg, and placebo, respectively (P<0.05 naratriptan 2.5 mg
and 1 mg versus placebo, 1 mg versus 0.1 mg, and 2.5 mg
versus 0.1 mg and 0.25 mg).
Clinical disability 4 hours postdose was reported as mild or none
for 70% of patients receiving naratriptan 2.5 mg compared with
63%, 47%, 48%, and 48% of patients receiving naratriptan 1 mg,
0.25 mg, 0.1 mg, or placebo, respectively (P<0.05 naratriptan
2.5 mg and 1 mg versus placebo, 1 mg versus 0.1 mg, and
2.5 mg versus 0.1 mg and 0.25 mg). Four-hour efcacy for
absence of nausea, photophobia, and phonophobia was similar
to efcacy for headache relief at each dose. The adverse event
prole of each dose of naratriptan was similar to that of placebo.
No clinically relevant change in any safety measure was reported.
Kolodny et al.
131
Adults – mean age 40 years
n=1,447 (1,244 female and
203 male)
Rizatriptan 5mg tablets
Rizatriptan 10mg tablets
Sumatriptan 25mg tablets
Sumatriptan 50mg tablets
Placebo
Acute treatment of migraine,
two-attack crossover study
The primary objective of the study was to compare
rizatriptan 10 mg and sumatriptan 50 mg in terms of
t i m e - t o - p a i n r e l i e f d u r i n g t h e 2 h a f t e r t a k i n g s t u d y d r u g .
Hazard ratio [rizatriptan 10 mg vs sumatriptan 50 mg] = 1.10
[95% condence interval (CI) 0.96, 1.26; P = 0.161]. Hazard
ratio [Rizatriptan 5 mg vs sumatriptan 25 mg] = 1.22 (95% CI
1.06, 1.41, P = 0.007).
Pain-free rates at 2h - Rizatriptan 5mg 33,4% vs Sumatriptan
25mg 27,4% [OD=1,34 - 95%CI 1.05, 1.72 p=0,002] /
Rizatriptan 10mg - 38% vs Sumatriptan 50mg 33,6% [OD=1.23
- 95%CI 0.99, 1.52, p=0,059].
Kostic et al.
132
Adults – IV Prochlorperazine
with diphenhydramine - 31
(SD - 10); SC Sumatriptan - 28
(SD - 6) years
n=66 (42 female and 24 male)
Prochlorperazine 10 mg IV with
diphenhydramine 12.5 mg
Sumatriptan 6 mg SC
Single migraine attack
The primary outcome measure was the mean change in pain
intensity from baseline to 80 minutes. The mean decrease in
pain intensity in the IV prochlorperazine with diphenhydramine
group was 73 mm compared with 50 mm in the subcutaneous
sumatriptan group.
Krymchantowski,
Filho, Bigal
133
Adults - mean age of 39.7 years
n=32 (75% female and 25%
male)
Rizatriptan 10 mg tablet plus
trimebutine 200 mg capsule
Rizatriptan 10 mg
Placebo,
Two consecutive moderate or
severe attacks
At 1 h postdose, 30 (46.8%) of 64 attacks treated with the
combination resolved completely, vs. eight (12.5%) of the
rizatriptan-treated attacks, a difference of 34% (P < 0.01). At
2 h postdose, 47 (73.4%) attacks treated with the combination
vs. 20 (31.2%) of those treated with rizatriptan alone resolved
completely, a difference of 42% (95% condence interval 26, 58,
P < 0.001). Regarding nausea and photophobia, the combination
was also associated with signicantly better response
Krymchantowski
et al.
40
Adults – mean age 31 (aged
18 to 48) years
n=30 (2 male and 28 female)
Lysine clonixinate (LC) 200
mg IV
Dipyrone (metamizol) 1000
mg IV
Single migraine attack
At 30 minutes, 0% of the dipyrone group 13% of the lysine
clonixinate (LC) group were pain free (p=0.46). At 60 and 90
minutes, 2 (13%) and 5 (33%) patients from the dipyrone group
and 11 (73%) and 13 (86.7%) patients from the LC group were
pain free (p<0.001).
At 60 minutes, signicantly more patients from the LC group were
nausea-free (p<0.001). Regarding photophobia, there were no
differences between groups at 60 minutes (p=0.11).
The use of rescue medication at 2 hours did not differ among
groups (p=0.50). Pain in the site of the injection was reported
by more patients of the LC group compared to the dipyrone
group (p<0.0001).
Lainez et al.
134
Adults – almotriptan:
33.15 years (±8.8 years);
ergotamine+caffeine: 33.84
years (±10.1 years)
n=229 (199 females and 30
males)
Almotriptan 12.5 mg
Ergotamine 2 mg plus caffeine
200 mg
Treatment of two migraine
attacks
Treatment with almotriptan was associated with a signicantly
greater proportion of patients achieving 2h pain-free (20.9% vs.
13.7%; P<0.05) and 2h pain relief (57.7% vs. 44.5%; P<0.01)
compared with ergotamine plus caffeine therapy; signicant
differences were not seen at 1h. Rates for sustained pain-free
and sustained pain-free plus no adverse events (AEs) also were
signicantly greater after almotriptan treatment than after the use
of ergotamine plus caffeine (P<0.05). Almotriptan was associated
with a signicantly lower rate of photophobia at 90 min (P<0.05),
phonophobia at 60, 90, and 120 min (P<0.05 to <0.01), and
nausea and vomiting at 90 and 120 min (P<0.01) compared
with ergotamine plus caffeine.
A signicantly greater proportion of patients were more satised
with almotriptan (55.7% and 64%, 1st and 2nd attacks,
respectively) than with ergotamine plus caffeine (36% and
44.3%,1st and 2nd attacks, respectively) - (P<0.05).
Sixteen patients reported adverse events during almotriptan
treatment and 27 patients during the ergotamine plus caffeine
therapy. Most adverse events were mild-to-moderate and did not
result in treatment-related discontinuations.
201
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Landy et al.
22
Adults – 37 years (37.8±8.5
years sumatriptan 50 mg;
37.9±8.4 years sumatriptan
100 mg; 37.6 ±7.6 placebo)
n=447 (403 females and 44
male)
Sumatriptan 50 mg tablets
Sumatriptan 100 mg tablets
Placebo
Single migraine attack
Sumatriptan 50 mg and 100 mg tablets were signicantly more
effective than placebo at conferring pain-free response 2 h post-
dose (p<0.001 each sumatriptan group vs. placebo). The onset
of efcacy vs. placebo for pain-free response was observed by
1 h post-dose for sumatriptan 100 mg (p<0.05).
Sustained freedom from pain from 2 through 24 h post-dose was
reported by 30 and 35% of patients in the sumatriptan tablets
50mg and 100mg groups, respectively, compared with 8% of
placebo-treated patients (p<0.001 each sumatriptan group vs.
placebo).
Both doses of sumatriptan were well tolerated. The adverse events
were generally slightly higher in the sumatriptan groups than in
the placebo groups.
Landy et al.
22
Adults – mean age - 37 years -
35.5±7.8 years sumatriptan 50
mg; 37.3±8.7 years sumatriptan
100 mg; 36.9±7.6 placebo;)
n=369 (349 female and 20
male)
Sumatriptan 50 mg tablets
Sumatriptan 100 mg tablets
Placebo
Single migraine attack
Sumatriptan 50 mg and 100 mg tablets were signicantly more
effective than placebo at conferring pain-free response 2 h post-
dose (p<0.001 each sumatriptan group vs. placebo). The onset
of efcacy vs. placebo for pain-free response was observed by
1 h post-dose for sumatriptan 100 mg (p<0.05). Sumatriptan
50 mg and 100 mg tablets were 30 and 31% compared with
14% of placebo-treated patients (p<0.05 each sumatriptan
group vs. placebo).
Both doses of sumatriptan were well tolerated. The adverse events
were generally slightly higher in the sumatriptan groups than in
the placebo group.
Lewis et al.
135
Adults – mean age: 14.2 years
n=171 (98 female and 73
male)
Zolmitriptan 5 mg nasal spray
Placebo
Crossover study 2-attacks
The onset of signicant pain relief was apparent 15 minutes after
treatment with zolmitriptan nasal spray. At 1 hour after the dose,
zolmitriptan nasal spray produced a higher headache response
rate than did placebo (58.1% vs 43.3%). Zolmitriptan nasal spray
was also signicantly superior to placebo in improvement in pain
intensity, pain-free rates, sustained resolution of headache, and
resolution of associated migraine symptoms. Return to normal
activities was also consistently faster with zolmitriptan nasal
spray than with placebo, with less use of any escape medication.
Treatment with zolmitriptan nasal spray was well tolerated.
Linder et al.
52
Adolescents – Placebo - 14.4
(12-17) years;
Almotriptan 6.25 mg - 14.4
(12-17) years;
Almotriptan 12.5 mg - 14.2
(12-17) years;
Almotriptan 25 mg - 14.4 (12-
17) years.
n=548 (227 male and 321
female)
Almotriptan 6.25 mg oral
Almotriptan 12.5 mg oral
Almotriptan 25 mg oral
Placebo
1 dose of study medication
The 2-hour pain-relief rate was signicantly higher with almotriptan
25 mg compared with placebo (66.7% vs 55.3%; P = .022).
The incidence of nausea, photophobia, and phonophobia at 2
hours (adjusted for baseline pain intensity) for the almotriptan
25 mg and placebo groups was not signicantly different. The
2-hour pain-relief rates (unadjusted) were signicantly higher with
almotriptan 6.25 mg (71.8%), 12.5 mg (72.9%), and 25 mg
(66.7%) than with placebo (55.3%; P = .001, P <.001, and P
= 0.028, respectively).
Rates for sustained pain relief also were signicantly greater
with almotriptan 6.25 mg (67.2%), 12.5 mg (66.9%), and 25
mg (64.5%) than with placebo group (52.4%), P < 0.01 for
the 6.25- and 12.5-mg doses and P < .05 for the 25-mg dose.
Age group subanalysis demonstrated signicantly greater 2-hour
pain relief rates with all 3 doses of almotriptan compared with
placebo for patients aged 15 to 17 years, a signicantly lower
incidence of photophobia and phonophobia at 2 hours with
almotriptan 12.5 mg compared with placebo for patients
aged 15 to 17 years, and a signicantly lower incidence of
photophobia with almotriptan 12.5 mg compared with placebo
for those aged 12 to 14 years.
Almotriptan treatment was well tolerated, with the most common
adverse events nausea, dizziness, and somnolence.
Lines,
Vandormael,
Malbecq
136
Adults - mean age 40 years
n=872 (715 female and 157
male)
Oral rizatriptan 5 mg,
Oral sumatriptan 50 mg
Placebo
Single migraine attack
Active drugs were superior to placebo at reducing headache
pain and were similarly effective.
Lipton et al.
137
Adults - (mean age, 38.1 years)
n=249 (female 86% and male
14%)
Sumatriptan 50 mg tablets
Placebo
Series of 5 headaches
Sumatriptan was superior to placebo for headache response 4
hours postdose (primary endpoint) across all headache types
(migraine 66% versus 48%; P<.001; migrainous 71% versus
39%; P<.01; tension-type 78% versus 50%, P<.001).
Sumatriptan was also superior to placebo for pain-free response
4 hours postdose for migraine (41% versus 24%, P<.001) and
tension-type headaches (56% versus 36%, P=.001). Sumatriptan
provided superior pain-free response 2 hours postdose for
migraine (18% versus 7%, P<.0001) and tension-type headache
(28% versus 14%, P=.0005) compared with placebo.
Loder et al.
138
Adults – mean age 37.3 years
n=524 (429 female and 95
male)
Rizatriptan ODT 10 mg
Sumatriptan 50 mg tablet
Two migraine attacks
Percentage of patients who preferred rizatriptan ODT 10-mg
(57%, n=213) was signicantly greater than those who preferred
sumatriptan 50-mg tablet (43%, n=161) (P.01).
A signicantly greater percentage of patients reported pain relief
after taking rizatriptan ODT than sumatriptan at the 45- and
60-minute time points (38% versus 29% and 58% versus 49%,
respectively) (P.01). In addition, a signicantly greater percentage
of patients taking rizatriptan ODT reported a pain-free status at
the 60- and 120-minute time points (23% versus 17% [P.05] and
60% versus 52% [P.01], respectively).
202
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Loder et al.
139
Adults – mean: 37 years range:
18 to 55 years [zolmitriptan:
37.2±7.4 (18-55) years and
placebo: 37.9±7.2 (19-51)
years]
n=510 (all female)
Zolmitriptan 2.5 mg oral
Placebo
in a series of 5 headaches
A 2-hour headache response was achieved in 48% of zolmitriptan-
treated attacks as compared with 27% of placebo-assigned
attacks (P <.0001). Zolmitriptan was superior to placebo in
achieving a headache response as early as 30 minutes (18%
versus 14%, P=.03) and at 1 hour (33% versus 23%, P <.001).
Drug-related adverse events were reported in 16% of subjects
receiving zolmitriptan and 9% of subjects receiving placebo.
Loder et al.
140
Adults – 40.0 ± 10.6
(Zolmitriptan 2.5 mg); 42.7 ±
10.5 (Placebo).
n=565 (482 female and 83
male)
Zolmitriptan 2.5 mg orally
disintegrating tablets (ODT)
Placebo
Patients treated up to 2 migraine
attacks
Zolmitriptan 2.5mg ODT demonstrated a signicant pain-free rate
vs. placebo at 2h (40% vs. 20%, p < 0.001), 1.5h (25% vs.
15%, p < 0.001), and 1h (13% vs. 8%, p = 0.004). Sustained
pain-free rate was signicantly higher than placebo (31% vs.
15%; p < 0.001).
Signicantly more patients treated with zolmitriptan 2.5 mg ODT
were able to return to routine activities (work, school, or other
daily activities) when compared with placebo at 1h (p = 0.004),
1.5h (p < 0.001), and 2h (p < 0.001).
Zolmitriptan 2.5 mg ODT was well tolerated. Overall, 33%
(92/282) of patients treated with zolmitriptan 2.5 mg ODT
experienced adverse events versus 14% (41/284) of placebo-
treated patients. The adverse events most commonly reported
in patients treated with zolmitriptan 2.5 mg ODT were those
commonly associated with the use of triptans, including dizziness,
somnolence, paresthesia, tightness, and asthenia.
Maghbooli et
al.
141
Adults
Ginger group – 33.9 ± 8.3
Sumatriptan Group – 35.1 ±
6.2
n=100 (71 female and 29
male)
Ginger 250 mg powder capsule
Sumatriptan 50 mg capsule
One capsulet upon headache
onset
Frequency distribution of mean headache severity at 2 h after
drug use demonstrated similar effectiveness for sumatriptan and
ginger groups (P = 0.116).
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).
Mannix et al.
23
Adults – mean age Rizatriptan -
38 years Placebo - 37 years
n=403 (Female only)
Rizatriptan 10mg tablet
Placebo
Single migraine attack
The primary endpoint for efcacy analysis was pain relief at 2h.
2h pain relief - Rizatriptan 70% vs 53% placebo (OR 2.11, 95%
CI 1.34, 3.32, P = 0.001).
24h Sustained pain relief - Rizatriptan 46% vs Placebo 33% (OR
1.75, 95% CI 1.11, 2.77, P = 0.016).
Mannix et al.
23
Adults - Rizatriptan - 37 years;
Placebo – 37.5
n=399 (Female only)
Rizatriptan 10mg tablet
Placebo
Single migraine attack
The primary endpoint for efcacy analysis was pain relief at 2h.
2h pain relief - Rizatriptan 73% vs Placebo - 50% (OR 2.69, 95%
CI 1.66, 4.36, P< 0.001).
24h Sustained pain relief - Rizatriptan 46% vs Placebo 33% (OR
1.74, 95% CI 1.08, 2.82, P = 0.024).
Marín et al.
142
Addults – mean age 35.9 years
n=42 (Male 3 and Female 39)
Eletriptan Relpax 80 mg oral
Placebo oral and intranasal
spray
Tetracaina 0,80 mg intranasal
spray
single migraine attack
After 30 minutes of therapeutic intervention both groups were
compared by an unpaired Student t to obtain an average pain
in the tetracaine group and an average of 1,952 for the pain
group eletriptan of 4.0, with p = 0.0115. The improvement in
pain and quality of life were correlated by Pearson’s method with
the following results r = 0.7833 and p < 0.0001y for eletriptan
group r = 0.5143, p = 0.0171.
Martínez et al.
41
Adults - 18 to 65 years of age
n=360 (271 women and 89
men)
Metamizole (0.5 and 1 g) oral
Acetylsalicylic acid (1 g) oral
Placebo
The pain intensity reduced steadily for all three active treatments
in comparison with placebo up to 4h after administration. The
analgesic efcacy of 0.5 and 1 g metamizol vs placebo was
highly statistically signicant for sum of pain intensity differences,
maximum pain intensity difference, number of patients with at
least 50% pain reduction, time to 50% pain reduction, maximum
pain relief and total pain relief.
A trend towards an earlier onset of a more profound pain relief of
0.5 and 1 g metamizol over 1 g Acetylsalicylic acid was noticed.
Adverse events were experienced during the treatment phase of
the study in all groups, but differences statistics were not observed.
Global assessment of tolerability by the patients was good or
satisfactory in more than 90% of all patients.
Massiou et al.
143
Adults - aged 18 to 65 years
n=257 (Female only)
Naratriptan 2.5 mg
Placebo
single migraine attack
A higher percentage of subjects in the naratriptan group (58%)
reported complete pain relief 4 h after medication than in
the placebo group (30%) (P < 0.001). Signicant differences
between the naratriptan and placebo groups and in favor of
naratriptan were also found for: total pain relief at 2 h (P =
0.004), sustained pain-free response within 4–24 h (P < 0.001),
absence of all associated symptoms at 2 and 4 h (P =0.004),
ability to work and carry out daily activities at 2 h (P = 0.036),
and patient overall satisfaction (P <0.001).
Mathew et al.
144
Adults – mean age 41.2 years
(SD = 9.6)
n=682 (614 female and 68
male)
Naratriptan tablet 2.5, 1 and
0.25 mg
Placebo
Treat 4 migraine attacks
Headache relief 4 hours postdose occurred in 68%
naratriptan 2.5 mg vs 57% naratriptan 1.0 mg vs 3%
naratriptan 0.25 mg vs 33% placebo (p < 0.001
n a r a t r i p t a n 2 . 5 m g a n d 1 m g v e r s u s p l a c e b o o r 0 . 2 5 m g ) .
Headache was eliminated 4 hours postdose - 45% naratriptan
2.5 mg vs 33% naratriptan 1 mg, 20% naratriptan 0,25 mg and
15% placebo (p < 0.001 naratriptan 2.5 mg and 1 mg versus
placebo or 0.25 mg).
203
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Mathew et al.
145
Adults - aged to 18 to 65
Eletriptan 40 mg – 41.1 (10.8)
Sumatriptan – 41.8 (10.4)
Placebo – 41.6 (10.6)
n=2,072 (Female 1795 and
277 male)
Eletriptan 40 mg tablet
Sumatriptan 100 mg capsules
Placebo
Single migraine attack
Headache response rates at 2 hours postdose were signicantly
higher for eletriptan 40 mg (67%) than for sumatriptan 100 mg
(59%; P .001) and placebo (26%; P .0001).
Eletriptan 40 mg consistently showed signicant (P .01) efcacy
over sumatriptan 100 mg across secondary clinical outcomes,
including 1-hour headache response; 2-hour pain-free response;
absence of nausea, photophobia, and phonophobia; functional
improvement; use of rescue medication; treatment acceptability;
and sustained headache response (P<0.05). Overall, treatment-
related adverse events were low.
Mathew,
Kailasam,
Meadors
146
Rizatripitan 10 mg - 39.0 ± 9.5
years;
Placebo - 42.0 ± 7.2 years.
n=112 (103 female and 9
male)
Rizatriptan 10 mg tablets
Placebo
Three migraine attacks
Pain-free response at 2 hours after early treatment was noted in
70% of attacks in the rizatriptan group and in 22% in the placebo
group (P < .01). Pain-free response at 1 hour occurred in 45%
and 8% attacks, respectively (P < .01). When the attacks were
categorized by headache severity at the time of treatment, the
pain-free response at 2 hours was higher for mild attacks than
for moderate or severe attacks (P < .01).
Sustained pain-free response after treatment was signicantly
higher for attacks treated with rizatriptan (60%) than for those
treated with placebo (17%) (P < .001). Adverse events were
reported in 62 attacks (29%) in the rizatriptan group and 15
attacks (14%) in the placebo group.
Mathew et al.
147
Adults – mean age 40.4 years
n=378 (328 female and 50
male)
Almotriptan 12.5 mg tablet
Placebo
Consecutive 3 migraine attacks
Pain free at 2 hours portdose for the 1st headache - (Almotriptan
37% vs Placebo 23.9% p=0,010).
2-hour pain relief (Almotriptan 59.9% vs Placebo 42.6% p<0.001)
and modied 2-hour pain relief (Almotriptan 59.9% vs Placebo
42.6% p<0.001).
Signicant differences in pain free, pain relief and modied
pain relief between almotriptan and placebo was also observed
at 1 hour.
McGinley et al.
148
Adults – mean age 40.0 (12.3)
years.
n=259 (84.6% female and
15.4% male)
Sumatriptan 22 mg nasal
powder
Sumatriptan 100mg tablets
Treat up to 5 attacks
The primary outcomes for these analyses were migraine pain
intensity and migraine related disability. Average pain intensity
for Sumatriptan 22 mg nasal treated attacks was signicantly
lower than sumatriptan treated ones at all time points from 10
to 90 minutes (P < .05 for all). The mean
portion of the models showed that Sumatriptan 22 mg nasal had
signicantly lower disability from 10 to 90 minutes.
Meredith, Wait,
Brewer
149
Adults - mean age of 33 years
(18 -54 years)
n=29 (4 male and 25 female)
Sumatriptan 20 mg nasal
Ketorolac 30 mg intravenous
Sigle migraine attack
Patients scored the severity of their headache on a 100-mm
visual analog scale (VAS) of pain prior to medication and again
1 hour after medication. Differences between initial and 1-hour
scores were analyzed. Before treatment, no difference existed
between the groups in the intensity of headache. One hour after
medication, the sumatriptan group had a decrease in pain score
of 22.937 mm and the ketorolac group a decrease of 71.462
mm on the VAS. The decrease in pain score with ketorolac was
signicantly greater than that with sumatriptan (P < 0.001).
Miljkovic et al.
150
Adults - 18 to 64 years
n=201 (168 female and 33
male)
Sumatriptan tablet
Ergotamine combination tablet
(propyphenazone, caffeine,
camylon chloride, mecloxamine
citrate)
Placebo
Higher percentage of patients was completely free of the
headache 2 hours after dose administration in the ergotamine-
based medication group compared to the sumatriptan group,
regardless whether all (51.12 % vs 33.70 %) or only repeated
attacks were taken into account (50.91 % vs 23.73 %). The
salvage therapy (diclofenac) utilization rate was also lower in
the ergotamine-based medication group (relative risk 0.61).
Misra et al.
151
Adults - mean age of 32.6 ±
2.57 years.
n=40 (Female 27 and Male 13)
Naproxen 500mg
Sumatriptan 50 mg
Rizatriptam 10 mg
Ergotamine tartrate (2 mg) +
caffeine (100 mg) + cyclizine
HCL (50mg)
Single dose during migraine
attack
Naproxen, rizatriptan and sumatriptan were better than
ergotamine in causing freedom from the associated symptoms
of nausea, vomiting, photophobia and phonophobia at 2-hour
postdose. Naproxen, rizatriptan and sumatriptan were also
efficacious in causing functional normalization at 2 hours
postdose as compared to ergotamine.
Misra, Kalita,
Yadav
152
Adults - Rizatriptan 29.15± 8.7,
Ibuprofen 30.5 ± 10.6 and
control 31.78 ± 9.9 years
n=155 (female 114 and 41
male)
Rizatriptan 10 mg,
Ibuprofen 400 mg
Placebo
Single migraine attack
Efcacy was assessed by headache relief and headache freedom
at 2h and 24h. Two-hour headache relief was noted in 73%
in rizatriptan, 53.8% in ibuprofen and 8% in placebo groups.
Headache freedom was achieved in 37.7% in rizatriptan, 30.8%
in ibuprofen and 2% in placebo groups.
Monda et al.
153
Adults - 34,6 years (SD 9,6)
n=101 (73 female and 28
male)
Indomethacin 25 mg +
prochlorperazine 4mg and
caffeine 75 mg suppository
Sumatriptan 25 mg suppository
Treatment of 4 consecutive
migraine attacks
Pain-free at 2 hours postdose - Indomethacin 25 mg +
prochlorperazine 4mg and caffeine 75 mg suppository
was superior to sumatriptan in the second attack (52% versus
33%; P < .05) and in the total attacks (49% versus 34%; P < .01
). The
time to a pain-free response was signicantly (P < .05) higher
with Indomethacin 25 mg + prochlorperazine 4mg and caffeine
75 mg suppository than with sumatriptan in the rst, second, and
total attacks. Headache relief rates in the total attacks at 2 hours
postdose were 71% with Indomethacin 25 mg + prochlorperazine
4mg and caffeine 75 mg suppository and 65% with sumatriptan,
without any statistically signicant difference between the drugs.
204
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Moon et al.
154
Adults - aged 18 to 65 years
- frovatriptan: 36.75±10.23
years; placebo: 38.07±9.22
years.
n=229 (207 females and 22
males)
Frovatriptan 2.5 mg
Placebo
Frovatriptan signicantly increased the 2-hour headache response
rate compared with placebo (52.9% vs. 34.0%, p=0.004). The
headache response rates at 4, 6, and 12 hours were signicantly
higher in the frovatriptan group than in the placebo group, as
was the pain-free rate at 2 hours (19.0% vs. 5.7%, p=0.004),
4 hours (40.7% vs. 23.0%, p=0.006), and 6 hours (56.1% vs.
34.0%, p=0.002).
The median time to a headache response was signicantly shorter
in the frovatriptan group than in the placebo group (2.00 hours
vs. 3.50 hours, p<0.001).
The use of rescue medications was more common in the placebo
group (p=0.005).
Moshtaghion et
al.
155
Adults - sumatriptan group
33.36 + 7.91 and Propofol
group 33.08 + 8.12 years
n=90 (68 female and 22 male)
Sumatriptan 6 mg SC
Propofol IV in 30 to 40 mg
bolus
Single migraine attack
Pain intensity was signicantly lower in the propofol group 30
minutes after treatment (P = 0.001); however, after 1 and 2
hours, there were no signicant differences between the groups.
The need for antiemetic therapy and the recurrence of symptoms
were signicantly lower in the propofol group (P = 0.045 and P
= 0.001, respectively).
Muller, Lohse
156
Adults - Men = 45.31 ± 13.89
years; Women = 41.98 ±
12.54 years
n=57 (13 male and 44 female)
Parecoxib 40 mg infusion
Sumatriptan (6 mg/0.5 mL)
Rizatriptan ODT 10 mg
Single migraine attack
Rizatriptan decreased pain intensity 20 minutes after intake,
(44.33; P<0.0001; post hoc analysis) more than parecoxib
and sumatriptan, but parecoxib was more efficacious than
sumatriptan. At 30 minutes after drug application, rizatriptan
was superior (26.51; P<0.0001; post hoc analysis) to parecoxib
and sumatriptan, but parecoxib showed a better effect on pain
symptoms than sumatriptan.
Mushet et al.
24
Adults - 40 (18 to 65) years
(sumatriptan - 40.4 years and
placebo - 37.9 years)
n=80 (69 female and 11
males)
Sumatriptan 6 mg SC
Placebo
Single migraine attack
By 120 minutes after SC dosing, 73% of sumatriptan-treated
patients compared with 28% of placebo-treated experienced
headache relief (P≤0.05). Clinical disability scores 120 minutes
after dosing showed that 75% of sumatriptan-treated patients,
compared with 30% of placebo-treated patients, were normal
or only mildly impaired (P≤0.05). Similar efcacy rates were
observed for nausea, phonophobia, and photophobia. No
serious or unusual adverse events occurred, and no clinically
relevant abnormalities in laboratory test values were reported.
Mushet et al.
24
Adults - 40 (18 to 65) years:
sumatiptan: 40.2 years;
placebo: 40.2 years.
n=78 (10 males and 68
females)
Sumatriptan 6 mg SC
Placebo
Single migraine attack
By 120 minutes after SC dosing, 79% of sumatriptan-treated
patients, compared with 37% of placebo-treated patients
experienced headache relief (P≤0.05). Clinical disability scores
120 minutes after dosing showed that 85% of sumatriptan-treated
patients, compared with 42% of placebo-treated patients, were
normal or only mildly impaired (P≤0.05).
Similar efcacy rates were observed for nausea, phonophobia,
and photophobia. No serious or unusual adverse events occurred,
and no clinically relevant abnormalities in laboratory test values
were reported.
Myllylä et al.
157
Adults - Tolfenamic Acid Rapid
Release - 39±8.3 years;
Placebo - 39±9.5 years;
Sumatriptan - 40±10.0 years.
n=140 (126 female and 14
male)
Tolfenamic acid rapid release
tablets 200 mg
Sumatriptan 100 mg oral
Placebo
Two successive migraine attacks.
For first attack, 77% of patients receiving tolfenamic acid
experienced a reduction of the initial severe or moderate
headache to mild or no headache after 2 hours, as compared
to 79% in the sumatriptan group and 29% in the placebo group.
No signicant difference was found between active treatments (P
= 0.85, 95% CI [-22%, 18%]), however, both active treatments
were signicantly better than placebo; P = 0.001, 95% CI (26%,
69%) for tolfenamic acid and P = 0.001, 95% CI (28%, 71%)
for sumatriptan.
For second attack, results were similar with 70% of patients
receiving tolfenamic acid experiencing relief, as compared to
64% in the sumatriptan group and 39% in the placebo group.
No significant differences were observed in accompanying
symptoms. Both drugs were well tolerated with the frequency of
adverse events; 30% for tolfenamic acid and 41% for sumatriptan
(nonsignicant difference).
Nappi et al.
158
Adults - 18 and 65 year; mean
age 38 (11) placebo and
Sumatriptan 38 (9).
n=244 (188 female and 56
male)
Sumatriptan 100 mg tablet
Placebo
First dose at the earliest sign of
migraine
Sumatriptan was signicantly more effective than placebo at
relieving headache (dened as reduction in severity from severe
or moderate pain to mild or no pain) at 2 h (51% versus 31%, P
= 0.003) and 4 h (71% versus 35%, P < 0.001).
Fewer sumatriptan-treated patients required a second dose
compared with placebo-treated patients (49% versus 74%, P <
0.001). More sumatriptan treated patients were completely pain
free compared with placebo-treated patients at both 2 h (24%
versus 12%) and 4 h (48% versus 18%).
Nett et al.
159
Adults - Placebo = 36.8 ± 7.7;
Sumatriptan 50mg = 35.3 ±
7.8; Sumatriptan 100mg = 37.1
± 8.8.
n=349 (Female only)
Sumatriptan 50 and 100
mg tablet
Placebo
Single menstrually
associated migraine
Sumatriptan was superior to placebo in providing patients with
pain-free relief at 2 hours.
Pain-free relief at 2 hours - sumatriptan 100mg (61%) and
sumatriptan 50mg (51%) compared with the placebo (29%) (both
P <0.001). Sustained
pain-free - Sumatriptan 100mg (31%) and 50mg (30%) compared
with Placebo (14%) (100 mg versus placebo P =0.004; 50 mg
versus placebo P= .007).
205
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Newman et al.
160
Adults - Naratriptan 2.5mg –
36.3
Naratriptan 1mg - 38
Placebo – 36.4
n=206 (all female)
Naratriptan 1 and 2.5mg oral
Placebo
Menstrual associated
migraine
Headache-free Naratriptan 1mg 50% versus Placebo 25%,
(P=.003). More patients treated with naratriptan 1 mg were
headache free compared with placebo (23% versus 8%),
although statistical tests were not performed.
Signicantly more patients treated with naratriptan 1 mg reported
menstrual associated migraine 50% or less compared with
placebo-treated patients. Patients treated with naratriptan 1 mg,
also had signicantly fewer menstrual associated migraine days
compared with placebo-treated patients.
The Finnish
Sumatriptan
Group and the
Cardiovascular
Clinical Research
Group
161
Adults - 18-60 years
[sumatriptan: 38±10; placebo:
40±9;]
n=74 (11 male and 63 female)
Sumatriptan (insufation 20 mg
plus 20mg) Intranasal
Placebo
Sumatriptan (20 mg plus 20 mg) was more effective than placebo
at relieving headache, dened as reduction in severity from
moderate or severe to mild or none, at 60 and 120 min. At
120 min, 75% of patients in the sumatriptan group reported
headache relief, compared with 32% of patients in the placebo
group (p<0.001); 53% of patients in the sumatriptan group were
completely pain-free compared with 11% in the placebo group.
Nausea incidence was significantly lower in sumatriptan
group compared with placebo at both 60 min (17 vs. 43%;
p=0.014) and 120 min (14 vs. 38%; p=0.021). Photophobia
was signicantly lower in sumatriptan group, compared with
placebo at 60 min (28 vs. 57%; p=0.013) and 120 min (19vs.
51%; p=0.005).
Sumatriptan was signicantly more effective at reducing functional
disability of patients at 30 min (p=0.024) and at 60 and 120
min (p<0.001). However, similar number of patients reported
migraine recurrence, within 24 h in both treatment groups.
The Subcutaneous
Sumatriptan
International
Study Group
162
Adults - (41±11 years
sumatriptan 6 mg; 40±11 years
sumatriptan 8 mg; 39±11 years
placebo)
n=639 (521 females and 118
males)
Sumatriptan 6 or 8 mg SC
Placebo
After 60 minutes, the severity of headache was decreased in 72%
of the 422 patients given 6 mg of sumatriptan, 79% of the 109
patients given 8 mg of sumatriptan, and 25% of the 105 patients
given placebo. As compared with the placebo group, 47% more
patients who had received 6 mg of sumatriptan and 54% more
patients who had received 8 mg of sumatriptan had a decrease
in the severity of headache (P<0.001 for both comparisons).
After 120 minutes, 86 to 92% of the 511 patients treated with
sumatriptan had improvement in the severity of headache, as
compared with only 37% of the 104 patients who received
placebo once or twice (P<0.001 for all comparisons).
The Multinational
Oral Sumatriptan
and Cafergot
Comparative
Study Group
163
Adults - mean age: 39.5 years
[sumatriptan: 39±10 years;
cafergot: 40±10 years;]
n=577 (98 males and 479
females)
Sumatriptan 100 mg oral
Cafergot (ergotamine tartrate 2
mg + caffeine 200 mg) capsules
Three migraine attacks
Sumatriptan was signicantly more effective than Cafergot at
reducing the intensity of headache from severe or moderate to
mild or none; 66% (145/220) of those treated with sumatriptan
improved by 2 h, compared with 48% (118/246) of those treated
with Cafergot (p < 0.001). The onset of headache resolution was
more rapid with sumatriptan, whereas recurrence of migraine
headache within 48 h was lower with Cafergot.
Sumatriptan was also signicantly more effective at reducing
the incidence of nausea (p < 0.001), vomiting (p < 0.01) and
photophobia/phonophobia (p < 0.001) 2h after treatment, and
fewer patients on sumatriptan (24%) than on Cafergot (44%, p <
0.001) required other medication after 2h. The overall incidence
of patients reporting adverse events was 45% after sumatriptan
and 39% after Cafergot; the difference was not signicant.
Pascual et al.
164
Adults - Rizatriptan 10mg 38.5
years; Zolmitriptan 2.5mg 39.4
years; Placebo 38.2 years.
n=766 (639 female and 127
male)
Rizatriptan 10mg tablet
Zolmitriptan 2.5mg tablet
Single migraine attack
The primary efcacy endpoint was pain free within 2h.
Rizatriptan was superior to zolmitriptan, a HR = 1.26, rizatriptan
was 26% more likely to be eliminated in the next few minutes
than in a patient taking zolmitriptan.
Headache relief at 2h - Rizatriptan 70.5% vs Zolmitriptan 66.8%
vs Placebo 29.5%. Headache recurrence at 24h - Rizatriptan -
28%, Zolmitriptan 29% and placebo 26%.
Pascual et al.
165
Adults - placebo 41.2 years
(19±63); Almotriptan 6.25
mg 40.8 years (19±66);
Almotriptan 12.5 mg 41.9
years (18±65).
n=909 (788 female and 121
male)
Almotriptan 6.25 and 12.5 mg
tablet
Placebo
Three consecutive migraine
attacks
The total number of attacks relieved (severe or moderate pain
reduced to mild or no pain) at 2 h post-dose was signicantly
higher (P<0.001) after treatment with almotriptan 6.25 or
12.5 mg compared with placebo (60% and 70% vs. 38%,
respectively). Moreover, a consistent response was achieved
across and within patients for almotriptan 6.25 or 12.5 mg
compared with placebo (pain relief in at least 2 out of 3 attacks
within 2h for 64% and 75% vs. 36%, respectively) and less than
one-third of the patients relapsed within 24h.
Almotriptan was well tolerated with no signicant differences
between the almotriptan and placebo treatment groups in the
percentage of patients reporting adverse events.
206
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Pascual et al.
166
Adults - 33.7 years (16–66)
n=481 (399 female and 82
male)
Rizatriptan 10mg (rapidly
disintegrating tablets)
Sumatriptan 50mg (tablets)
Single migraine attack
The patients preferred rizatriptan 10mg rapidly disintegrating
tablet to sumatriptan 50mg tablet (64.3 vs. 35.7%, p < or =
0.001). Faster relief of headache pain was the most important
reason for the preference, cited by 46.9% of patients preferring
rizatriptan and 43.4% of patients who preferred sumatriptan.
Headache relief at 2h was 75.9% with rizatriptan and 66.6% with
sumatriptan (p < or = 0.001), with rizatriptan being superior to
sumatriptan within 30 min of dosing. Fifty-ve percent of patients
were pain free 2 h after rizatriptan, compared with 42.1% treated
with sumatriptan (p < or = 0.001), rizatriptan being superior
within 1 h of treatment. Forty-one percent of patients taking
rizatriptan were pain free at 2 h and had no recurrence or need
for additional medication, compared to 32.3% of patients on
sumatriptan. Rizatriptan was also superior to sumatriptan in terms
of the proportions of patients with no nausea, phonophobia or
photophobia, and patients with normal function 2h after treatment
intake (p < 0.05).
More patients were satised 2 h after treatment with rizatriptan
(73.3%) than 2 h after treatment with sumatriptan (59.0%) (p <
or = 0.001). Both active treatments were well tolerated.
The most common side effects with rizatriptan and sumatriptan
were nausea (6.6 and 6.9% of patients, respectively), dizziness
(6.1 and 5.8%) and somnolence (7.4 and 6.7%).
Pini et al.
167
Adults - mean age 37.0 years,
range 18 – 65 years).
n=238 (52 males and 186
females)
Sumatriptan 100 mg oral
Placebo
Single migraine attack
Reduction in headache intensity - sumatriptan 65% versus
placebo 40%. Reductions in accompanying symptoms of
migraine - nausea/vomiting (33 versus 53%) and photophobia/
phonophobia (37 versus 62%), respectively.
Sumatriptan was very effective in reducing headache severity in
patients with a history of prolonged migraine attacks (sumatriptan
67% versus 26% placebo).
Pini et al.
168
Adults - male 33.6± 10.5 and
female 35.6 ±9.6 years.
n=92 (Male 31 and Female 61)
Paracetamol 1000mg + caffeine
130 mg sachet
Sumatriptan 50 mg soft gel
capsule
Two migraine attacks
There was no difference between the two treatments regarding
total pain relief pain during the 4-hour observation period.
Rahimdel et al.
169
Adults - sodium valproate
31.3±3.5 years, Sumatriptan 6
mg 30.1±3.1 years.
n=90 (67 female and 23 male)
Sodium valproate 400 mg IV
Sumatriptan 6 mg SC
Single migraine attack
In both groups, pain decrement at the mentioned time points was
signicant (P<0.001) but had no signicant difference (P>0.05),
indicating the similar effect of both drugs on pain improvement.
In the Sodium valproate group, photophobia, phonophobia,
nausea, and vomiting were improved significantly, while in
the Sumatriptan group, only photophobia and vomiting were
decreased signicantly. Nausea, vomiting, facial paresthesia, and
hypotension were more signicantly frequent in the Sumatriptan
group than in the Sodium valproate group (P<0.05).
Rao et al.
170
Adults - 36.3±9.8 years
n=54 (Female 98.1 % and
Male 1.9 %)
Ketorolac nasal spray 31.5 mg
Sumatriptan nasal spray 20 mg
Placebo
At least one attack
Both ketorolac (72.5%, P< .001) and sumatriptan (69.4%, P=
.001) were more effective than placebo (38.3%) for 2-hour pain
relief and 2-hour pain freedom (ketorolac: 43.1%, P= .004;
sumatriptan: 36.7%, P= .046; placebo: 18.4%).
Ketorolac but not sumatriptan was more effective than placebo
in 2-hour absence of nausea. Both ketorolac and sumatriptan
were more effective than placebo for 24-hour sustained pain
relief (ketorolac: 49%, P< .001; sumatriptan: 31%, P= .01,
placebo: 20%). Only ketorolac was superior to placebo for 24-
hour (ketorolac: 35.3%, P=.003; sumatriptan: 22.4%, P= .18,
placebo: 12.2%) sustained pain freedom.
Nasal burning and dysgeusia were the most common adverse
effects for active treatments.
Rapoport et al.
171
Adults - 18 to 65 years
(sumatriptan 6mg+placebo:
42.3 years; sumatriptan-
6mg+100mg:42.5 years)
n=667 (118 male and 549
female)
Sumatriptan 6 mg SC +
Sumatriptan 100 mg (oral - 4hs
later)
Sumatriptan 6 mg SC + Placebo
(oral - 4hs later)
Three migraine attacks
The primary efcacy endpoint was the number of successfully
treated patients without headache recurrence (HR) within 24
hours after the initial SC injection for the first study attack.
237/317 patients who received oral sumatriptan at 4 hours
(75%) and 249/312 patients who received placebo at 4 hours
(80%) reported no or mild headache pain at 2 hours after the
initial open dose of 6 mg SC sumatriptan. By 4 hours, relief was
reported by 78% of the patients who received oral sumatriptan
and 82% of the patients who received placebo.
Of 442 assessable patients, 82/212 in the sumatriptan-treated
group (39%) and 89/230 in the placebo-treated group (39%)
reported HR in attack 1. Median times to recurrence were
15.6 hours after sumatriptan and 10.3 hours after placebo
(p = 0.006). After placebo, 58% of the recurrences occurred
within 12 hours, compared with only 32% within 12 hours after
sumatriptan.
Similar results were observed for attacks 2 and 3.
207
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Rapoport et al.
172
Adults 41.3 ± 9.5 (12-66)
years.
n=999 (123 Male and 876
Female)
Zolmitriptan 1, 2.5, 5, or 10 mg
Placebo
Oral
Single migraine attack
The headache response rates with zolmitriptan doses ≥ 2.5 mg
were 44 to 51% at 1 hour, 65 to 67% at 2 hours, and 75 to 78%
at 4 hours (all signicantly superior to placebo). Also, zolmitriptan
effectively relieved migraine-associated symptoms such as nausea,
photophobia and phonophobia, and reduced activity impairment.
Rates of headache recurrence, headache persistence, and use
of escape medication were lower with zolmitriptan doses ≥ 2.5
mg than with placebo. In patients with persistent or recurrent
headache, a second zolmitriptan dose effectively treated both
headache and nonheadache symptoms.
Rothner et al.
173
Adolescents - aged 12 to
17 years (14.2±1.7 years
zolmitriptan 10 mg; 14.3±1.7
years zolmitriptan 5 mg;
14.3±1.7 years zolmitriptan
2.5 mg; 14.2±1.7 years
placebo)
n=696 (408 females and 288
males)
Zolmitriptan 2.5, 5, or 10 mg
oral tablet
Placebo
Single migraine attack
There was no statistically significant improvement between
zolmitriptan 10 mg (2 x 5 mg tablet) and placebo for the primary
efcacy variable headache response at 2 hours, nor any of the
secondary variables tested. Two-hour headache response rates
were 54%, 53%, and 57% for zolmitriptan 10, 5, and 2.5 mg,
respectively, and 58% for placebo. Two-hour pain-free rates
were 25%, 19%, and 23% for zolmitriptan 10, 5, and 2.5 mg,
respectively, and 20% for placebo.
Zolmitriptan was well tolerated, with a tolerability prole similar
to the pattern seen in adults.
Russell et al.
174
Adults – mean age 44 years
(±9.7 years)
n=209 (females 189 and males
20)
Sumatriptan 6 mg SC
Placebo
Two migraine attacks
When sumatriptan was compared to placebo, signicantly more
of the 209 evaluable patients reported headache relief at 1 h
(56% vs 8%, p < 0.001) and 2 h (62% vs 15%, p < 0.001)
after the first injection. Resolution of nausea, photophobia,
and phonophobia was signicantly more common in patients
on sumatriptan than in those on placebo (p < 0.001 for all
comparisons).
Ryan et al.
25
Adults - Suma 20mg -39.8/
Suma10mg – 40.4/ Placebo –
40.2 years.
n=409 (58 male and 351
female)
Sumatriptan 20 and 10mg
nasal spray
Placebo
One migraine attack
The primary efcacy endpoint was headache relief 120 minutes
after the rst administration of study drug.
Headache relief - 62 to 63% patients in the sumatriptan 20-mg,
43 to 54% sumatriptan 10-mg, 29 to 35% of placebo (p <0.05).
Pain-free 2h - 31 to 32% sumatriptan 20-mg groups, 20 to 23%
sumatriptan 10-mg, 4 to 20% placebo (p < 0.05).
Incidence of nausea, photophobia, and phonophobia reduced
after sumatriptan 20mg (p < 0.05), sumatriptan nasal spray 10
mg compared with placebo reduced the incidence of nausea
(p < 0.05).
Ryan et al.
25
Adults - Suma20mg – 41.1/
Suma10mg – 41.2/ Placebo
- 41.6.
n=436 (63 male and 373
female)
Sumatriptan 20 and 10mg
nasal spray
Placebo
One migraine attack
The primary efcacy endpoint was headache relief 120 minutes
after the rst administration of study drug.
Headache relief - 62 to 63% patients in the sumatriptan 20-mg,
43 to 54% sumatriptan 10-mg, 29 to 35% of placebo (p <0.05
sumatriptan 20 mg vs placebo).
Pain-free 2h - 31 to 32% sumatriptan 20-mg groups, 20 to 23%
sumatriptan 10-mg, 4 to 20% placebo (p < 0.05 sumatriptan
20 mg and 10 mg vs placebo).
Incidence of nausea, photophobia, and phonophobia reduced
after sumatriptan 20mg (p < 0.05), sumatriptan nasal spray 10
mg compared with placebo reduced the incidence of nausea
(p < 0.05).
Ryan et al.
26
Adults - Frovatriptan 42.3 (SD
9.9 - Range 18 - 63)/Placebo
40.2 (SD 10.3 - Range 18 -
65) n=322
(42 male and 280 female)
Frovatriptan 2.5mg tablet
Placebo
Single dose
Response at 2 hours range from 27% to 46% for frovatriptan
compared with 21% to 27% for placebo. Likewise, at 4 hours,
frovatriptan was consistently signicantly more effective than
placebo to provide headache relief.
Response forfrovatriptan ranged from 56% to 65% compared
with 31% to 38% for placebo (p<0,001). Frovatriptan was also
signicantly superior to placebo at rendering patients pain-free.
At 2 hours, the proportion of patients pain-free was 9% to 14%
for frovatriptan compared with 2% to 3% for placebo (p<0,001).
At 4 hours post dose, 27% to 32% of patients takins frovatriptan
were pain-free compared with 9% to 14% in the placebo group
(p<0,001).
Ryan et al.
26
Adults - Frovatriptan 41.1 (SD
10 - Range 18 -69)/Placebo
41.1 (SD 10.4 - Range 18 -
69). n=1148 (131 male and
1017 female)
Frovatriptan 2.5mg tablet
Placebo
Patients could take up to 2
doses per attack for headache
recurrence within 24 hours of
the rst dose
Response at 2 hours ranged from 27% to 46% for frovatriptan
compared with 21% to 27% for placebo. Likewise, at 4 hours,
frovatriptan was consistently signicantly more effective than
placebo to provide headache relief.
Response for frovatriptan ranged from 56% to 65% compared
with 31% to 38% for placebo (p<0,001). Frovatriptan was also
signicantly superior to placebo at rendering patients pain-free.
At 2 hours, the proportion of patients pain-free was 9% to 14%
for frovatriptan compared with 2% to 3% for placebo (p<0,001).
At 4 hours post dose, 27% to 32% of patients taking frovatriptan
were pain-free compared with 9% to 14% in the placebo group
(p<0,001).
208
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Ryan et al.
26
Adults - Frovatriptan 41.1
(SD 10.4 - Range 18 - 69)/
Placebo 40.3 (SD 10.8 - Range
19 - 69).
n=724 (106 male and 618
female)
Frovatriptan 2.5mg tablet
Placebo
Patients could take up to two
doses per attack for headache
recurrence within 24 hours of
the rst dose
Response at 2 hours ranged from 27% to 46% for frovatriptan
compared with 21% to 27% for placebo. Likewise, at 4 hours,
frovatriptan was consistently signicantly more effective than
placebo ar providing headache relief. Response for frovatriptan
ranged from 56% to 65% compared with 31% to 38% for
placebo (p<0.001). Frovatriptan was also signicantly superior to
placebo at rendering patients pain-free. At 2 hours, the proportion
of patients pain-free was 9% to 14% for frovatriptan compared
with 2% to 3% for placebo (p<0.001). At 4 hours post dose, 27%
to 32% of patients taking frovatriptan were pain-free compared
with 9% to 14% in the placebo group (p<0.001).
Sandrini et al.
174
Adults - 18 to 65 years
[placebo: 37.5±10.9;
suma50mg: 37.4±10.2;
suma100mg: 38.2±10.2;
ele40mg: 38.0±10.1;
ele80mg:39.9±10.7]
n=774 (681 female and 93
male)
Eletriptan 40mg
Eletriptan 80mg tablets
Sumatriptan 50mg
Sumatriptan 100mg
Placebo
gelatin capsules
Multiple migraine attack
Headache response rates were 12% at 1 hour and 31% at
2 hours for placebo; 24% at 1 hour and 50% at 2 hours for
sumatriptan 50 mg; 27% at 1 hour and 53% at 2 hours for
sumatriptan 100 mg; 30% at 1 hour and 64% at 2 hours for
eletriptan 40 mg; and 37% at 1 hour and 67% at 2 hours for
eletriptan 80 mg.
More patients receiving eletriptan 80 mg achieved a 1-hour
headache response than did patients receiving sumatriptan 50
mg (p < 0.05). All doses of eletriptan were superior to sumatriptan
at 2 hours for headache response and complete pain relief (p <
0.05). Signicantly more patients on eletriptan 80 mg achieved
headache response in all attacks than did patients receiving
sumatriptan.
Eletriptan 40 mg was superior to both sumatriptan doses in
functional improvement (p < 0.005). The 40- and 80-mg doses
of eletriptan were signicantly more effective than placebo or
sumatriptan in reducing the associated migraine symptoms of
nausea, photophobia, and phonophobia after 2 hours.
The 40- and 80-mg doses of eletriptan were signicantly superior
to oral sumatriptan or placebo in achieving and sustaining both
headache response and pain-free response at 24 hours. The
superior efcacy of both eletriptan doses was associated with
higher rates of patient acceptability than sumatriptan 50 mg
(p < 0.05).
Eletriptan and sumatriptan were well tolerated.
Sandrini et al.
175
Adults – mean age 35 ± 9.8
years
n=281 (78% female and 22%
male)
Sumatriptan 50mg tablets
Indoprocaf-coated tablets
Indoprocaf-effervescent tablets
Two consecutive migraine
attacks
Indoprocaf - indomethacin,
prochlorperazine and caffeine
Pain-free rates at 2 h (all attacks) - 34% Indoprocaf and 37%
sumatriptan (p=NS). Headache relief at 2 h (all attacks) postdose
- 62% Indoprocaf and 56% with sumatriptan (p=NS).
Pain free 2h post first attack (indoprocaf coated-tablets vs
effervescent tablets) - Indoprocaf-effervescent tablets 41% vs.
Coated-tablets 22%(P<0.05). Headache relief rate at 2 h
postdose in the rst attack - Effervescent tablets 66% vs. Coated-
tablets 49% (p < 0.05). Pain-free rate total attacks - Effervescent
tablet 84% vs. Coated-tablets 73%. The total pain-free rate of
Indoprocaf-coated tablets was lower than that of effervescent
tablets, but higher than sumatriptan.
Sang et al.
176
Adults - mean age 40 ± 9
years.
n=44 (20 male and 24 female)
Ly293558 (nonselective AMPA/
KA (GluR5) receptor antagonist
with 1.2 mg/kg IV
Sumatriptan 6 mg SC
Placebo
Simgle migraine attack
The primary efcacy variable was the headache response rate,
i.e. headache score improvement from moderate/severe at
baseline to mild/none at 2 h. Response rates were 69% for
LY293558 (P = 0.017 vs. placebo), 86% for sumatriptan (P <
0.01 vs. placebo) and 25% for placebo.
LY293558 and sumatriptan were superior to placebo (P < 0.01
for all comparisons) on all other measures of improvement in pain
and migraine associated symptoms.
Fifteen percent of patients who took LY293558 reported adverse
events, 53% patients who took sumatriptan and 31% of those
who received placebo reported adverse events.
Santanello et
al.
177
Adults - Rizatriptan 10mg –
36.8 (SD 9); Rizatriptan 5mg
– 37.6 (SD 8.2); Rizatriptan
2.5mg – 38.7 (SD 9.1);
Placebo – 39.7 (SD 9.7) years
n=247 (222 female and 25
male)
Rizatriptan 2.5, 5 and 10mg
Placebo
Oral
One migraine attack
Statiscally signicant mean improvements were observed for those
treated with rizatriptan 10mg compared with those treated with
placebo on three of ve domains: social functioning (p=0,007),
migraine symptoms (p=0.005), and feeling/concerns (p=0.015).
Patients who took the 5-mg and 10mg rizatriptan doses were
signicantly less disabled as 2h than those who took placebo
(p=0.003); however, the patients who took 2,5mg rizatriptan
remained about as functionally disabled as patients on placebo.
Savi et al.
178
Adults – 37±9 years
n=125 (99 female 26 male)
Frovatriptan 2.5 mg
Rizatriptan 10 mg
Capsules
Treat 1–3 attacks
Patient’s preference for one drug or the other did not differ
between the study treatments. Frovatriptan was chosen mainly
because of the rapid speed of action (71% of patients), good
tolerability (42% of patients), and reduction in pain severity
(33%).
A relevant result of study was that recurrence rate within 48 h were
signicantly lower under frovatriptan than under rizatriptan. These
differences may be explained by the different pharmacokinetics of
the two drugs. Frovatriptan has a time to maximum concentration
typically of 2 to 3 h, but the longest half-life among triptans,
greater 5-HT1B binding receptor potency, and multiple pathways
metabolism. The headache recurrence was signicantly less
frequent with frovatriptan than under rizatriptan.
209
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Savi, Mogavero,
Egan.
179
Adults – 39.4 ± 7.8 years
n=18 (55.5% female and
44.4% male)
Frovatriptan 2.5 mg
Rizatriptan 10 mg
Two-treatmen migraine attack
The primary endpoint of interest was the correlation between
plasma concentration of each triptan (and more specically the
concentration: maximum concentration (Cmax) ratio and the
pain-free (PF) and pain-relief (PR) rates at each time point. PF
4h – Frovatriptan 38.4% vs Rizatriptan 5.6% (p=0.045). PR at
4h - Frovatriptan 61.1% vs Rizatriptan 72.2% (p=NS).
There was a positive correlation between frovatriptan
concentration: Cmax ratio (%) and the proportion of patients
that were either pain free or experienced pain relief over the
entire study period. No such correlation was seen for rizatriptan.
Schulman
180
Adults – aged 18-66 years
- mean (SD) 40.7 (11.2
(Transdermal Sumatriptan and
41.0 (11.0) Placebo.
n=454 (male 68 and female
386)
Sumatriptan transdermal patch
Placebo
Single migraine attack
In the overall study population, transdermal sumatriptan was
signicantly superior to placebo at 1 hour post-activation for pain
relief (29% vs 19%, respectively; P < .0135) and freedom from
nausea (71% vs 58%, respectively; P < .05) and at 2 hours post-
activation for freedom from pain (18% vs 9%, respectively; P <
.009), pain relief (53% vs 29%, respectively; P < .0001), freedom
from nausea (84% vs 63% respectively; P < .001), freedom from
photophobia (51% vs 36%, respectively; P < .0028), freedom
from phonophobia (55% vs 39%, respectively;P < .0002); and
freedom from migraine (16% vs 8%, respectively;P < .0135).
In the post-hoc analysis, transdermal sumatriptan was markedly
superior to placebo for pain relief and freedom from pain,
nausea, photo and phonophobia at 1 and 2 hours post-activation.
Scott et al.
181
Adults – Group SS(S): 41.0 +
11.1 years; Group SS(P): 40.4
±10.7 years; Group SP(S):
40.6
±10.5 years; Group: SP(P):
42.1
±10.6 years.
n=1440 (214 male and 1226
female)
Sumatriptan 100 mg tablet oral
Placebo
Three migraine attack
Headache was relieved by the rst sumatriptan dose in about
70% of patients, but the second dose did not produce signicantly
more relief than placebo, either in non-responders or in the group
as a whole, nor did it reduce other symptoms (photophobia,
nausea, vomiting, etc.) at 8 h, or inuence the incidence of
headache recurrence.
The drug was well-tolerated, and a further single dose was
effective in treating recurrence after initial relief. Of those
patients who treated at least one attack and expressed a view
of the treatment, 80% (n = 1056) said that they would take the
medication again.
Seeburger et
al.
182
Adults – 43.8 years (20–68)
[Riza/riza/placebo 43.3 years
(20–68); Riza/placebo/riza
44.8 years (28–61); Placebo/
riza/riza 43.5 years (23–64);]
n=102 (female 88 and 14
male)
Rizatriptan 10 mg ODT tablet/
oral lyophilisate
Placebo
Three migraine attack crossover
Pain relief at two hours was signicantly greater with rizatriptan
compared with placebo (51% vs. 20%, p<.001). Response rates
also favored rizatriptan on two-hour pain freedom (22% vs. 12%,
p=.013) as well as 24-hour sustained pain relief (38% vs. 14%,
p<.001) and sustained pain freedom (20% vs. 11%, p=.036).
Treatment was generally well-tolerated.
Seeburger et
al.
183
Adults – mean age 43.8 years
(SD 11.6) (Range from 18 to
66).
n=100 (92 female and 8 male)
Rizatriptan ODT 10 mg
Placebo
Multiple-attack study
The primary efcacy endpoint was the proportion of treated
attacks resulting in pain relief at 2 hours postdose.
Pain relief at 2h – Rizatriptan 55% of attacks vs Placebo 17%;
o d d s r a t i o [ O R ] 5 . 8 0 , 9 5 % C I : [ 3 . 1 3 , 1 0 . 7 6 ] , P < . 0 0 1 ] .
Secundary endpoints: sustained pain relief 2-24h and 2h pain
freedom were also better in favor of rizatriptan.
Sheftell, Ryan,
Pitman
184
Eletrip 20mg - 41 (19-73);
40mg – 42 (18-78); 80mg – 41
(19-75); Placebo – 42 (18 – 69)
years
n=1190 (1037 female and
153)
Eletriptan 20, 40 and 80mg
oral
Placebo
Three migraine attacks
A signicantly higher proportion of patients treated with eletriptan
reported a headache response at 2 hours compared to the
placebo group (47%, 62%, and 59% for the 20-mg, 40-mg, and
80-mg doses, respectively, compared with 22% in the placebo
group, P <0.0001 for all eletriptan doses).
Sheftell et al.
27
Adults – Sumatriptan 100mg
– 41.5 (SD 11.2); Sumatriptan
50mg – 41.6 (SD 10.8);
Placebo – 41.2 (SD 10.8)
years.
n=1366 (1170 female and
196 male)
Sumatriptan 100mg tablets
rapid release
Sumatriptan 50mg tablets rapid
release
Placebo
Single migraine attack
Using pooled data, the cumulative percentages patients with pain
relief by 2 hours after dosing were 67% for sumatriptan tablets
50 mg and 72% for sumatriptan tablets 100 mg, compared with
42% for placebo (P < 0.001, both sumatriptan doses vs placebo).
The cumulative percentages of patients with a pain-free response
by 2 hours after dosing were 40% for sumatriptan tablets 50
mg and 47% for sumatriptan tablets 100 mg, compared with
15% for placebo.
Sheftell et al.
27
Adults – Sumatriptan 100mg
– 40.1 (SD 10.8); Sumatriptan
50mg 39.9 (SD 10.8); Placebo
– 39.2 (SD 10.5)
n=1330 (1126 female and
204 male)
Sumatriptan 100mg tablets
rapid release
Sumatriptan 50mg tablets rapid
release
Placebo
Single migraine attack
Using pooled data, the cumulative percentages patients with pain
relief by 2 hours after dosing were 67% for sumatriptan tablets
50 mg and 72% for sumatriptan tablets 100 mg, compared with
42% for placebo (P < 0.001, both sumatriptan doses vs placebo).
The cumulative percentages of patients with a pain-free response
by 2 hours after dosing were 40% for sumatriptan tablets 50
mg and 47% for sumatriptan tablets 100 mg, compared with
15% for placebo.
210
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Silberstein et
al.
185
Adults – mean age 40 years
n=1419 (female only)
Rizatriptan 5mg and 10 mg oral
Placebo
In the subgroup of 335 women with menstrually associated
migraine, rizatriptan was effective compared with placebo. At
2 hours after dosing, 68% of 139 women taking rizatriptan
10 mg and 70% of 115 women taking rizatriptan 5 mg with a
menstrually associated migraine had pain relief compared with
44% of 81 patients taking placebo (P < .05). In all women,
rizatriptan was as effective in treating menstrual as well as
nonmenstrual migraine: 68% of 139 patients taking rizatriptan
10 mg with a menstrually associated migraine had pain relief at
2 hours after dosing compared with 69% of 393 patients with
nonmenstrually associated attacks (test of menstrual association 5
nonsignicant; the analysis had 80% power to detect a difference
of six percentage points between groups). Similar results were
found for rizatriptan 5 mg (menstrual 70%, nonmenstrual 66%;
not statistically signicant).
Silberstein et
al.
186
Adults – 37.6 years (18 – 56)
n=546 (female only)
Frovatriptan 2.5 mg tablet QD
Frovatriptan 2.5 mg tablet BID
Placebo
Three-way crossover design
Use of frovatriptan reduced the occurrence of menstrually
associated migraine. The incidence of menstrually associated
migraine during 6-day was 67% for placebo, 52% for frovatriptan
2.5 mg QD, and 41% for frovatriptan 2.5 mg BID.
Both frovatriptan regimens were superior to placebo (p < 0.0001),
and the BID regimen was superior to the QD regimen (p < 0.001).
Both frovatriptan regimens also reduced menstrually associated
migraine severity (p < 0.0001), duration (p < 0.0001), and the
use of rescue medication (p < 0.01 QD; p < 0.0001 BID) in a
dose-dependent manner.
The incidence and type of adverse events for both regimens were
similar to placebo and consistent with those reported for short
term migraine management.
Silberstein et al.
32
Adults –18-65 years.
n=275
Sumatriptan 22mg nasal
powder
Sumatriptam 100mg oral
Two treatment sequences
Treatment with sumatriptan 22mg nasal powder provided greater
reduction in migraine pain intensity, which was statistically
signicant vs oral sumatriptan in the rst 30 minutes postdose,
regardless of whether attacks were treated when pain was mild
(least squares mean SPID-30 = 3.90 vs 0.24, P = 0.0013) or
moderate/severe (least squares mean SPID-30 = 13.83 vs 10.07,
P = 0.0002).
At every time point from 15 to 90 minutes postdose, the proportion
of attacks achieving total migraine freedom was greater and
statistically signicant after treatment with sumatriptan 22mg
nasal powder vs 100 mg oral sumatriptan. Sumatriptan 22mg
nasal powder treatment resulted in greater odds of achieving
pain freedom (odds ratio, OR = 1.29, P< 0.01) and meaningful
pain relief (OR = 1.32, P< .0001), which were also statistically
signicant compared with oral sumatriptan.
In addition, a greater proportion of attacks treated with
sumatriptan 22mg nasal powder vs oral sumatriptan was
associated with sustained pain freedom, achieving statistical
signicance when assessed from 1 h postdose through 24 hours
postdose (33.3% vs 27.9%; P < .05) and through 48 hours
postdose (32.7% vs 27.4%; P< .05)
Smith et al.
187
Adults - Sumatriptan 50 mg E
+ Naproxen sodium 500 mg
- 42.5±11.0; Sumatriptan 50
mg E - 41.2±11.3; Naproxen
sodium 500 mg - 42.1±10.7;
Placebo - 41.2±10.2 years.
n=972 (880 female and 92
male)
Sumatriptan 50 mg tablet
Naproxen 500 mg tablet
Sumatriptan 50 mg + Naproxen
sodium 500 mg
Placebo
Single migraine attack
In the sumatriptan plus naproxen sodium group, 46% of subjects
achieved 24-hour pain relief response (primary endpoint), which
was signicantly more effective than sumatriptan alone (29%),
naproxen sodium alone (25%), or placebo (17%) (P < .001).
Two-hour headache response also significantly favored the
sumatriptan 50 mg plus naproxen sodium 500 mg therapy (65%)
versus sumatriptan (49%), naproxen sodium (46%), or placebo
(27%) (P < .001). A similar pattern of between-group differences
was observed for 2-hour pain-free response and sustained pain-
free response (P < .001).
The incidence of headache recurrence up to 24 hours after
treatment was lowest in the sumatriptan plus naproxen sodium
group (29%) versus sumatriptan alone (41%; P = .048), versus
naproxen sodium alone (47%; P = .0035), and versus placebo
(38%; P = .08).
The incidences of the associated symptoms of migraine were
signicantly lower at 2 hours following sumatriptan 50 mg plus
naproxen sodium 500 mg treatment versus placebo (P < .001).
The frequencies and types of adverse events reported did not
differ between treatment groups, with dizziness and somnolence
being the most common.
Solomon et al.
188
Adults - Zolmitriptan 2.5 mg
40.7 ± 11.26 -Placebo 40.2 ±
11.84 years
n=301 (45 male and 256
female)
Zolmitriptan 2.5 mg oral
Placebo
Single migraine attack
Patients treated a single moderate or severe migraine headache
with 2.5 mg zolmitriptan or placebo and recorded clinical
efcacy and adverse events on a diary form. Headache response
at 2 hours was 62% for zolmitriptan compared with 36% for
placebo (p < 0.001). At 4 hours, headache response was 70%
with zolmitriptan and 37% with placebo (p < 0.001). Headache
recurrence in patients treated with 2.5 mg zolmitriptan was 22%
(versus placebo 30%).
The headache response at 4 hours, pain-free rate, and response
rate of nonheadache symptoms favored zolmitriptan over placebo.
211
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Spierings et al.
189
Adults - mean age 41.2 ±10.1
years (almotriptan) and 40.3 ±
10.1 (Sumatriptan)
n=1173 (129 male and 1044
female)
Almotriptan 12.5 mg capsule
oral
Sumatriptan 50 mg capsule oral
Single migraine attack
At 2 hours, almotriptan treatment provided headache relief in
58.0% of the subjects and sumatriptan treatment in 57.3%;
headache freedom was provided by the medications in 17.9%
and 24.6%, respectively (P =.005).
Rescue medications were taken by 36.7% of the subjects in the
almotriptan-treated group and by 33.2% in the sumatriptan-
treated group; headaches returned to moderate or severe intensity
in 27.4% and 24.0%, respectively.
Treatment-emergent adverse events occurred in 15.2% of the
subjects in the almotriptan-treated group and in 19.4% in the
sumatriptan-treated group (P =.06); treatment-related adverse
events occurred in 9.1% and 15.5% of the subjects, respectively
(P =.001), including chest pain, which occurred in 0.3% and
2.2%, respectively (P =.004).
Spierings et al.
190
Adults - mean age 42 years
n=670 (female 580 and male
90)
Zolmitriptan 5 mg ODT
Placebo
Two migraine headaches
Zolmitriptan 5mg ODT was signicantly more effective than
placebo in achieving a headache response (reduction in migraine
headache intensity from moderate or severe to mild or no pain)
at 30 minutes (16.5% vs 12.5%; p = 0.048; primary endpoint),
1 hour (p < 0.0001), and 2 hours (p < 0.0001).
Significantly more patients achieved a sustained headache
response for 24 hours with zolmitriptan 5mg ODT than with
placebo (42.5% vs 16.4%; p < 0.0001). Zolmitriptan 5mg
ODT also produced a higher pain-free rate than placebo at all
timepoints (0.5, 1 and 2 hours post-dose), with the differences
becoming signicant at 1 hour.
Spierings,
Keywood
191
Adults - 18 to 65 years
n=496 (58 male and 438
female)
Frovatriptan 2.5mg oral
Placebo
24-hour period
With regard to the rst attack treated, 173 (36%) of the 486
subjects in the study did not take a second dose at 2 hours for
nonresponse. At 2 hours and 4 hours, these “rapid responders”
experienced a decrease in headache intensity from moderate
or severe to mild or no pain in 84% and 98%, respectively
(“headache response”). Six percent of them experienced a
recurrence of moderate or severe headache within 24 hours
following a response at 4 hours and 12% took rescue medication.
Stark et al.
192
Adults – mean age 41.7 ± 8.7
years
n=347 (female: 312 and male:
35)
Sumatriptan 50 mg oral during
attack 1
Naratriptan 2.5 mg oral during
attack 2
Placebo
Two migraine attacks
Attack 1: About two thirds of this selected migraine population did
not respond to sumatriptan. Attack 2: Naratriptan was statistically
superior to placebo for headache relief at 2 hours and 4 hours,
as well as for most other features of migraine attacks. These data
suggest an intrinsic efcacy of naratriptan in this patient subset
and not a coincidental response. No unexpected tolerability
issues arose.
Stark et al.
193
Adults - placebo: 42 (20 to 62)
years; eletriptan 40 mg: 42 (18
to 68) years; eletriptan 80 mg:
42 (19 to 66) years.
n=1153 (191 males and 962
females)
Eletriptan (40 mg and 80 mg)
Placebo
Oral
Up to 2 doses of study
medication
In the initial attack, signicantly more eletriptan patients reported
headache relief and complete pain relief at 2 h vs placebo (40
mg 62% and 32%, 80 mg 65% and 34%, placebo 19% and 3%;
P < 0.0001). Headache relief occurred faster after eletriptan, with
more patients at both doses reporting relief 30 min (40mg 8% ,
80 mg 11% vs. placebo 2%, P<0.01 and P<0.001, respectively)
and 1 h (33% of patients in both eletriptan groups vs. 9% in
placebo group, P < 0.0001) after treatment than after placebo.
There was a signicantly lower recurrence rate with eletriptan
80 mg compared with placebo (80mg 21% vs. placebo 40%,
P < 0.01). Treatment acceptability for patients taking one or two
doses was high and signicantly better after either eletriptan 40
mg or 80 mg than placebo (78% and 83% vs. 38%, P<0.001
for each analysis).
Steiner et al.
194
Adults - Eletriptan 40 mg -
40.3±10.4 (19-64) years;
Eletriptan 80 mg - 40.4±10.5
(18–64) years; Zolmitriptan 2.5
mg - 40.1±10.5 (18–64) years;
Placebo - 39.9±10.6 (19–61)
years.
n=1337 (203 male and 1134
female)
Eletriptan 80 mg
Eletriptan 40 mg
Zolmitriptan 2.5 mg
Placebo
Single migraine attack
The primary analysis was between eletriptan 80 mg and
zolmitriptan. For the primary efcacy endpoint of 2-h headache
response, rates were 74% on eletriptan 80 mg, 64% on eletriptan
40 mg, 60% on zolmitriptan (P < 0.0001 vs. eletriptan 80 mg)
and 22% on placebo (P < 0.0001 vs. all active treatments).
Eletriptan 80 mg was superior to zolmitriptan on all secondary
endpoints at 1, 2 and 24 h, in most cases with statistical
signicance. Eletriptan 40 mg had similar efcacy to zolmitriptan
2.5 mg in earlier endpoints, and signicantly (P < 0.05) lower
recurrence rate and need for rescue medication over 24 h.
All treatments were well tolerated: 30-42% of patients on active
treatments and 40% on placebo reported all-causality adverse
events that were mostly mild and transient.
Stronks et al.
33
Adults - 42.2 years (SD 9.8;
range, 20 to 59).
n=12 patients
Naratriptan 2.5 mg tablet
Naproxen 500 mg capsule
To treat 2 migraine attacks
During the rst hours after intake of the study medication, the
objective behavioral parameeters showed no signicant effect
time and no significant differences between naproxen and
naratriptan, but naratriptan showed improve of symptoms and
the interval between treatment and relief was signicantly shorter
after intake of naratriptan.
212
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Talabi et al.
195
Sumatriptan – 26.8 (SD 4)
Metoclopramide – 34.9 (SD 9)
n=124 (77 male and 47
female)
Sumatriptan 6mg SC
Metoclopramide 20mg IV
Single migraine attack
At time 0 and 60 min, pain score with metoclopramide group
were 6.74 ± 0.84 and 0.66 ± 0.59, respectively, according to
the result of paired t-test. The other group showed similar results:
baseline painscore in sumatriptan group was 6.12 ± 0.73 that
decreased to 1.1 ± 0.70 after 60 min of treatment.
Analysis with ANCOVA showed that the mean difference in
T60 pain score between the two groups was 0.55 ± 0.13 (95%
CI: 0.25-0.79 cm). This difference was statistically signicant
(P< 0.001).
Teall et al.
196
Adults - Rizatriptan 10mg 40.7
± 9.6; Rizatriptan 5mg 40.5 ±
9.6; Placebo 40.6 ± 10.5 years
n=1218 (1055 female and
163 male)
Rizatriptan 10 and 5mg oral
Placebo
One migraine attack
The primary efcacy endpoint was the percentage of responders
at 2 hours after the initial dose.
Response rates at 2 hours - Rizatriptan 62% 5mg vs 71% 10mg
vs 35% placebo (P<0.001).
Pain-free at 1h - Rizatriptan 5mg 33% vs 10mg 42% vs Placebo
10%.Recurrence - Rizatriptan 44% 5mg vs 47% 10mg vs 40%
placebo.
Tepper et al.
197
Adults – mean age 41.3 (12-70
years)
n=2,800 (2,399 female and
401 male)
Zolmitriptan 2.5 and 5mg
tablets
Placebo
The two-hour pain-free response rate was higher in patients who
treated persistent headache of any intensity with any dose of
zolmitriptan compared with placebo. However, there were no
statistical differences between the two-hour headache response
rate for 5mg, 2,5 mg of zolmitriptan or placebo.
Tepper et al.
198
Adults - Placebo: 37.8 ± 12.0;
Sumatriptan 25 mg: 37.9 ±
11.6; Sumatriptan 50 mg: 39.1
± 12.2 and Sumatriptan 100
mg: 39.3 ± 11.4 years.
n=400 (female 295 and male
105)
Sumatriptan 25mg, 50mg,
100mg tablets
Placebo
Single headache
At 2 hours, more patients treated with sumatriptan achieved
headache relief, the primary efcacy measure, compared with
placebo, but differences only approached statistical signicance
for 100 mg (P = .053). The 2-hour headache relief rate in the
sumatriptan 25 or 50 mg groups was not signicantly different
than placebo.
The time to use of rescue was signicantly shorter in the placebo
group compared with the sumatriptan 100 mg group (P = .002).
The time to use of rescue in the sumatriptan 25 or 50 mg groups
was not signicantly different than placebo.
More patients treated with placebo (22%) lost headache relief
within 4 hours compared with patients treated with sumatriptan
25 mg (17%), 50 mg (14%), or 100 mg (7%).
Tfelt-Hansen et
al.
199
Adults - mean age (range):
Placebo 39 (18-63); LAS+MTC
40 (18-62); Sumatriptan 39
(18-58)
n=421 (female 327 and male
94)
Lysine acetylsalicylate oral
(equivalent to 900 mg aspirin)
and 10 mg metoclopramide
(LAS+MTC)
Sumatriptan 100 mg oral
Placebo
Two consecutive attacks with
moderate or severe headache
LAS+MTC was as effective as sumatriptan with a decrease of
headache from severe or moderate to mild or none of 57% and
53%, respectively, for the rst migraine attack treated.
Both treatments were better than placebo (success rate 24%,
p<0,0001). LAS+MTC was signicantly more effective in the
treatment of nausea than sumatriptan (p<0,0001) and was
better tolerated (adverse events in 18% and 28%, respectively,
p<0;05)..
Tfelt-Hansen et
al.
200
Adults - 18 to 65 years, mean
age:
Placebo – 38.3 ± 10.3;
Rizatliptan 5 mg - 38.3 ± 10.3;
Rizatriptan 10 mg 37.0 ± 10.0;
Sumatriptan 100 mg 39.2 ±
10.1.
n=1099 (898 female and 201
male)
Rizatriptan 10 mg
Rizatriptan 5 mg
Sumatriptan 100 mg
Placebo
Oral
Headache relief rates after rizatriptan 10 mg were consistently
higher than sumatriptan at all time points up to 2 hours, with
signicance at 1 hour (37% versus 28%, P = 0.010). All active
agents were signicantly superior to placebo with regard to
headache relief and pain freedom at 2 hours (P < or = 0.001).
The primary efcacy endpoint of time to pain relief through 2
hours demonstrated that, after adjustment for age imbalance,
rizatriptan 10 mg had earlier onset than sumatriptan 100 mg (P
= 0.032; hazard ratio 1.21). Rizatriptan 10 mg was also superior
to sumatriptan on pain-free response (P = 0.032), reduction in
functional disability (P = 0.015), and relief of nausea at 2 hours
(P = 0.010).
Signicantly fewer drug-related clinical adverse events were
reported after rizatriptan 10 mg (33%, P = 0.014) compared
with sumatriptan 100 mg (41%).
Tfelt-Hansen et
al.
201
Adults - Male - Plac 48 (SD
10)/Sum 40 (SD 12); Female
- Plac 36 (SD 11)/ Sum 36
(SD 9)
n=101 (22 male and 79
female)
Sumatripan 50mg
Placebo
Single migraine attack
Pain-free at 2h - Sumatriptan 20/51 (39%) vs Placebo 8/45
(18%) [difference 21%; 95% condence interval (CI): +4%–
+39%; p=0.03, Fisher’s exact test]
The oral
Sumatriptan
and Aspirin plus
Metoclopramide
Comparative
Study Group
202
Adults - Sumatriptan
100mg: 42 ± 12; Aspirin +
metoclopramide: 39 ± 11 years
n=355 (283 female and 72
male)
Sumatriptan ODT 100mg
Aspirin 900 mg +
metoclopramide 10 mg oral
Up to three migraine attacks
The primary efcacy analisys was based on headache relief
for attack1 from grande 3 or 2 to grade 0 or 1 after 2h
. Pain relief 2h after attack
1 - Sumatriptan - 74/113 (56%) vs Aspirin+metoclopramide -
62/138 (45%) (p=0,078 NS). Pain-free - Sumatriptan 26% vs
Aspirin+metoclopramide 14% (p=0.016)
Pain relief 2h after attack 2 - Sumatriptan - 58% vs
Aspirin+metoclopramide - 36% (p=0.001). Pain-free - Sumatriptan
23% vs Aspirin+metoclopramide 15% (p=NS).
Pain relief 2h after attack 3 - Sumatriptan - 65% vs
Aspirin+metoclopramide - 34% (p<0,001). Pain-free -
S u m a t r i p t a n 3 4 % v s A s p i r i n + m e t o c l o p r a m i d e 1 2 % ( p < 0 . 0 0 1 ) .
Both treatments are equally effective at reducing nausea. There
was no difference between treatments in the number of patients
vomiting. Photophobia and phonophobia were relieved equally
well within 2h by both treatments.
213
ASAA
Peres MFP, Scala WAR, Salazar R
Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
The Oral
Sumatriptan
International
Multiple-Dose
Study Group
203
Adults – Placebo: 40 ± 10;
Sumatriptan: 42 ± 10 years
n=232 (34 male and 198
female)
Sumatriptan ODT 100mg
Placebo
Patients who received sumatriptan showed a significantly
(p<0.001) greater improvement in headache relief compared
with the placebo group 2h after treatment (50 vs 19%,
respectively) and more patients were pain-free (headache grade
0) in sumatriptan group at 2h (25 vs 5%) and at 4h (48 vs 13%).
AT 2h fewer patients in the sumatriptan group experienced
nausea, vomiting, photophobia/phonophobia. Headache
recurred in 48% of patients receiving placebo and in 42% of
sumatriptan-treated patients within 24h of the initial resolution
headache.
Adverse events were reported by 38% of patients in the
sumatriptan-treated group compared with 23% in the placebo
group (p=0.019).
The Sumatriptan
Auto-Injector
Study Group
204
Adults - mean age 41 years
n=235 (192 female and 43
male)
Sumatriptan 6 mg SC
Placebo
Single migraine attack
The primary measure of treatment efcacy was based on a
comparison of the number of patients in the two treatment
groups who had a reduction in headache severity from severe
or moderate to mild or none at 1 and 2 h. At 1 h, 77% of
patients treating with 6 mg sumatriptan compared to 26% treating
with placebo (p<0.001) had mild headache or none. At 2 h,
the response rates for all patients had risen to 83 and 30%,
respectively.
Of those patients requiring a second dose at 1 h, improvement
to mild or no headache at 2 h was achieved in 61% of patients
receiving sumatriptan compared to 15% of those receiving
placebo.
Tietjen et al.
35
Adults - 36.7 years (range 24 to
52 years)
n=15 (female only)
Naratriptan 2.5 mg oral +
Prochlorperazine 25 mg rectal
suppository
Naratriptan 2.5 mg oral +
placebo
Multiple migraine attack
Reduction in headache severity was observed at 2 hours (P <
.001) and at 4 hours (P <.001) from headache onset, with no
difference between the two treatment regimens (P = .34). A
signicant decrease in clinical disability at 2 hours (P < .001) and
at 4 hours (P < .001) was observed, with no difference between
the two treatment regimens (P = .28). The pain-free state at 4
hours was reported in a higher proportion with the naratriptan/
placebo regimen (50% vs 25%), but the trial size would need to
be doubled to signicantly prove the endpoints.
Resolution of adverse effects was similar with both regimens at 2
hours and at 4 hours, although nausea resolved more often for
those using the naratriptan/prochlorperazine regimen.
Touchon et al.
205
Adults – mean age 42 ± 10
years
n=266 (36 male and 230
female)
Sumatriptan 6 mg SC
Dihydroergotamine (DHE) nasal
spray (1 mg plus optional 1 mg)
Placebo
Two migraine attack
Patients took SC sumatriptan for one attack and DHE nasal spray
for the other in random order. Data from both treatment periods
show that at all time points from 15 minutes, SC sumatriptan
was signicantly better than DHE nasal spray at providing both
headache relief (moderate / severe headache improving to mild
/ none) and resolution of headache. Similarly, SC sumatriptan
was superior to DHE nasal spray for the other efcacy end points
assessed in the study.
Patients reported that both treatments were well tolerated. Adverse
events were reported by 43% of patients taking SC sumatriptan
and 22% of patients taking DHE nasal spray, and these were
usually mild and transient.
Tuchman et al.
206
Adults – Zolmitriptan: 38.3
(20-51); Placebo: 38.7 (20-53)
years
n=334 (Female only)
Zolmitriptan 2.5mg tablet oral
Placebo
Menstrual migraine attacks
Primary efficacy endopoint was headache response at 2
hours after initial treatment, using a 4-point severity scale.
2-hour response: Zolmitriptan – 65.7% vs Placebo – 31.8%
(p<0.0001).
4-hour response: Zolmitriptan – 81.7% vs Placebo – 57.9%
(p<0.0001).
Adverse events: Zolmitriptan – 62.9% vs placebo 26.7% - majority
were mild or moderare intensity.
Tullo et al.
207
Adults – mean age 38.3 ± 9.9
years.
n=107 (85 female and 22
male)
Frovatripan 2.5mg
Zolmitriptan 2.5mg
Three migraine attacks
Patients (77%) expressed a preference for a triptan.
Average preference - Frovatriptan – 2.9±1.3 vs Zolmitriptan – 3.0
±1.3. Most
common reasons - Rapid activity (83% F vs 72% Z), reduction
of headache severity (53 F vs 42% Z) and no side efffects (40
F vs 40% Z).
Tullo et al.
34
Adults - 38.6 ± 10
n=314 (272 female and 42
male)
Frovatriptan 2.5 mg
Frovatriptan 2.5 mg +
dexketoprofen 25 mg
(FroDex25)
Frovatriptan 2.5 mg +
dexketoprofen 37.5 mg
(FroDex37.5)
oral
At least one migraine attack
The proportions of subjects without pain at two hours (primary
endpoint) were 29% (27/93) with Frovatriptam alone compared
with 51% (48/95 FroDex25 and 46/91 FroDex37.5) with each
combination therapies (p < 0.05).
FroDex25 and FroDex37.5 showed a similar efcacy both for
primary and secondary endpoints. It seems there is no dose
response curve for the addition of dexketoprofen.
Tulunay et al.
34
Adults – mean age 32.7 ± 8.7
years.
n=56 (47 female and 9 male)
Dipyrone 1g mg (2 tablets of
500 mg) oral
Placebo
Total pain relief and pain relief were primary outcomes.
Pain relief at 2h - Dipyrone 59/112 (52.7%) vs Placebo 13/56
(23.2%) (p<0,01). At 4h - Dypirone 64/112 (57.1%) vs Placebo
16/56 (28.6%) (p<0.001).
Total pain relief at 2h - Dypirone 42/112 (37.5%) vs Placebo
6/56 (10.7%) (p<0.001). At 4h - Dipyrone 45/112 (40.2%)
vs Placebo 7/56 (12.5%) (p<0.001).
Pain recurrence after total pain relief - Dipyrone 16.7% (7/42
attacks) and Placebo 33.3% (2/6 attacks).
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Visser et al.
208
Adults – Placebo: 39 (SD 10);
Sumatriptan 1mg: 41 (SD 11);
Sumatriptan 2mg: 40 (SD 11);
Sumatriptan 3mg: 39 (SD 10).
n=685 (165 male and 520
female)
Sumatripan 1, 2 and 3 mg SC
Placebo
One migraine attack
By 30 minutes post dose 17% (95% CI 8% to 27%) more patients
had improved with 1 mg sumatriptan, 22% (95% CI 13% to
32%) with 2 mg sumatriptan and 34% (95% CI 24% to 44%)
with 3 mg sumatriptan than with placebo (p < 0.001 for all
three comparisons versus placebo). The number of patients who
were improved increased signicantly with increasing dose (p
< 0.002; chi-square test for trend). Complete resolution of pain
was obtained at 30 min by 5% of placebo-treated patients, 9%
of patients treated with 1 mg sumatriptan and by 14% treated
with 2 mg or 3 mg sumatriptan, respectively.
Visser et al.
209
Adults - range: 18 to 55 years
[Placebo: 39±9 years; Riza-
10mg: 40±9 years; Riza-20mg:
40±8 years; Riza-40 mg - 41±9
years; Suma-100 mg: 41±10
years;]
n=449 (402 female and 47
male)
Rizatriptan 10, 20, 40 mg
Sumatriptan succinate 100 mg
Placebo
oral
One migraine attack
The proportion of patients with headache relief was 18% for
placebo; 46% for sumatriptan; and 52% for 10-mg, 56% for 20-
mg, and 67% for 40-mg rizatriptan. All differences with placebo
were statistically signicant (P<.001), and 40-mg rizatriptan was
superior to sumatriptan (P=.01).
The proportion of patients who became free of pain at 2 hours
was 3% for the placebo-treated group; 22% for the sumatriptan-
treated group; and 26%, 35%, and 47% for the group of
patients who took the 10-, 20-, and 40-mg doses of rizatriptan,
respectively (all differences with placebo, P<.005; 40-mg
rizatripan vs sumatriptan, P=.001).
The recurrence of headache within 24 hours was found to be
equal across all treatment groups—approximately 40%. Adverse
events (most commonly short-lasting mild or moderate dizziness
and drowsiness) occurred more frequently after a 40-mg dose of
rizatriptan was given than after other treatments.
Visser et al.
53
Adolescents - Rizatiptan 14.3
(SD 1.7) / Placebo – 14.1 (SD
1.8) years
n=476 (264 female and 212
male)
Rizatriptan 5mg oral
Placebo
Single attack
Primary efcacy measure was 2h pain relief: Rizatriptan 68.2%
vs Placebo 68.8% (P=NS). Considering just patients who treated
migraine on weekend - Rizatriptan 74% vs Placebo 58.3%
(p=0.022). There was no difference in adverse events - Rizatriptan
34.3% vs Pla cebo 30.2%.
Wang, Fuh,
Wu
210
.
Adults - Sumatriptan 20mg:
37.0 ± 10.8 years; Placebo:
37.4 ± 9.8 years.
n=56 (48 female and 8 male)
Sumatriptan 20mg spray
Placebo spray
A signicant difference in headache relief rates between the 2
groups was observed at 30 minutes postdose (46% vs. 21%,
p < 0.05). One-hour postdose, 61% of sumatriptan recipients
experienced headache relief compared with 43% of placebo
recipients (p = 0.181). The difference in relief rates between
groups diminished over time, mainly due to a high placebo
response (54% at 2 hours postdose).
Nausea, photophobia and phonophobia were alleviated in
the majority of patients in the sumatriptan nasal spray group,
although the benet in comparison to placebo did not reach
statistical signicance.
Most of the adverse events reported in the sumatriptan group were
mild and transient, and none were considered serious.
Wells, Steiner
211
Adults - mean age 18 – 29
(13.9%); 30 – 45 (48.7%); >45
(37.4%) years
n=674 (565 female and 109
male)
Eletriptan 40mg
Eletriptan 80mg
Placebo
Patients receiving either dose of the active compound were unable
to perform their usual activities for a median period of 4 hours
compared with 9 hours experienced by those taking placebo. This
difference was highly statistically signicant (p < 0.001). The time
saving associated with eletriptan usage reected the differences
in efcacy ndings in the clinical component of the study.
Wendt et al.
212
Adults - Sumatriptan 4mg: 38.3
(SD 9.5 - Range 18-59) Placebo
– 38.1 (SD 9.7 - Range 18-59).
n=577 (501 female and 76
male)
Sumatriptan 4mg SC
Placebo SC
Single migraine attack
The primary efcacy measurement was pain relief at 2 hours.
Pain relief at 2h: Sumatriptan 4mg - 70% (n = 268) and Placebo
- 22% (n = 42) (P < 0.001). Pain free at 2h: Sumatriptan - 50%
(n = 192) and placebo - 11% (n = 21) (P < 0.001).
Use of rescue medication: Placebo - 45% (n = 86) Sumatriptan
- 22% (n = 84).
Adverse events: Sumatriptan - 66% (n = 265) and Placebo - 39%
(n = 75) (P < 0.001).
Winner et al.
213
Adults - DHE-45: 40.5±8.6
years and range of 20 to 63
years; sumatriptan: 41.5 years
and range of 22 to 59 years.
n=310 (272 females and 38
males)
Dihydroergotamine mesylate
(DHE-45) 1 mg SC
Sumatriptan succinate 6 mg SC
Single migraine attack
At 2 hours, 73.1% of the patients treated with dihydroergotamine
and 85.3% of those treated with sumatriptan had relief (P=.002).
There was no statistical difference in headache relief between the
groups at 3 or 4 hours. Headache relief was achieved by 85.5%
of those treated with dihydroergotamine and by 83.3% of those
treated with sumatriptan by 4 hours.
By 24 hours 89.7% of dihydroergotamine-treated patients and
76.7% of sumatriptan-treated patients had relief (P=.004).
Headache recurred within 24 hours after treatment in 45%
of the sumatriptan-treated patients and in 17.7% of the
dihydroergotamine-treated patients (P≤.001).
215
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Winner et al.
54
Adolescents - 14.1±1.6 (12 to
17) years; [Placebo -14.2±1.6,
Suma-5mg 14.1±1.7, Suma-
10mg 14.0±1.6, Suma-20mg
14.0±1.6 ]
n=510 (250 male and 260
female)
Sumatriptan 5mg, 10mg, or
20mg nasal spray
Placebo
Headache relief 1-hour postdose was signicantly greater for
patients using 10 mg (56%) and 20 mg (56%) of sumatriptan
nasal spray compared with placebo (41%). Headache relief 2
hours postdose was signicantly greater for patients using 5
mg of sumatriptan nasal spray (66%) compared with placebo
(53%) and approached statistical signicance for 20 mg (63%)
compared with placebo (53%). Complete relief 2 hours postdose
was signicantly greater for patients using 20 mg of sumatriptan
nasal spray compared with placebo (36% vs 25%, respectively).
Photophobia and phonophobia were signicantly reduced 2
hours postdose for sumatriptan nasal spray (20 mg), compared
with placebo (36% vs 48% and 25% vs 44%, respectively). Taste
disturbance was the most commonly reported adverse event (2%,
19%, 30%, and 26% for placebo, 5 mg, 10 mg, and 20 mg,
respectively). No drug-related serious adverse events or clinically
relevant changes were reported.
Winner et al.
55
Adolescents – mean age 14
years
n=296 (161 female and 135
male)
Rizatriptan 5mg oral
Placebo
The percentage of patients pain-free at 2 hours was 32% for
rizatriptan 5 mg versus 28% for placebo (P.474). The percentage
of patients with pain relief (reduction of predose pain intensity to
mild or none) at 2 hours was 66% for rizatriptan versus 56% for
placebo (P.079). Compared with placebo, rizatriptan signicantly
improved functional disability at 1.5 and 2 hours, and nausea
at 1 and 1.5 hours.
Rizatriptan 5 mg was well tolerated. The most commonly reported
adverse events among patients receiving rizatriptan were dry
mouth, dizziness, asthenia/fatigue, nausea, and somnolence.
Winner et al.
28
Adults – mean age 40.3
years (aged 18-65 years) -
Placebo: 40.7±10.5 years;
Sumatriptan-50 mg: 39.8±10.5
years; sumatriptan-100 mg
40.5±10.0 years.
n=354 (311 females and 43
male)
Sumatriptan 50 mg and 100
mg tablets
Placebo
Single migraine attack
Signicantly more patients treated with sumatriptan, 100 mg and
50 mg were pain-free relief at 2 and 4 hours after treatment vs
patients treated with placebo (at 2 hours, 53% and 48% vs 29%;
at 4 hours, 71% and 66% vs 32%; for both, P<.001).
Also, signicantly more patients treated with sumatriptan 50 mg
and 100 mg were migraine-free (no pain or associated symptoms)
vs those treated with placebo at 2 and 4 hours after treatment (at
2 hours, 41% and 48% vs 25%; at 4 hours, 58% and 66% vs
30%; for both, P<.001). The incidence of overall adverse events
was low with the 50- and 100-mg dose of sumatriptan (placebo,
8%; sumatriptan at 50 mg, 18%; sumatriptan at 100 mg, 19%).
Winner et al.
28
Adults - mean 42.6 years
(aged 18-65 years) -
Placebo: 42.7 ±9.8 years;
Sumatriptan-50 mg: 43.5±10.4
years; sumatriptan-100 mg
41.7±11.0 years.
n=337 (298 females and 39
males)
Sumatriptan 50 mg and 100
mg tablets
Placebo
Single migraine attack
Signicantly more patients treated with sumatriptan 100 mg
and 50 mg, with pain-free relief at 2 and 4 hours after treatment
vs patients treated with placebo (at 2 hours, 62% and 53% vs
29%; at 4 hours, 65% and 55% vs 30%; for both, P<.001). The
incidence of overall adverse events was low with the 50- and
100-mg dose of sumatriptan (placebo, 6%; sumatriptan at 50
mg, 9%; sumatriptan at 100 mg, 12%).
Winner et al.
47
Adults – Sumatriptan: 40.2 (SD
9.7)/Placebo: 41.1 (SD 10.4)
years
n=297 (247 female and 50
male)
Sumatriptan 6mg SC
Placebo
P a i n - f r e e 2 h : S u m a t r i p t a n - 4 8 % v s P l a c e b o 1 8 % ( P < 0 . 0 0 1 ) .
Headache relief 2h: Sumatriptan 72% vs Placebo 32% (P <
0.001).
Winner et al.
47
Adults – Sumatriptan: 38.8 (SD
10.1)/ Placebo: 39.3 (SD 9.7)
n=287 (38 male and 249
female)
Sumatriptan 6mg SC
Placebo
P a i n - f r e e 2 h : S u m a t r i p t a n - 5 7 % v s P l a c e b o 1 9 % ( P < 0 . 0 0 1 ) .
Headache relief 2h: Sumatriptan 77% vs Placebo 41% (P <
0.001).
Winner et al.
45
Adolescents - Sumatriptan
20mg: 14.3 ± 1.8 (12 - 18);
Sumatriptan 5mg: 14.3 ± 1.6
(12-18); Placebo: 14.2 ± 1.7
(11-17).
n=731 (400 female and 331
male)
Sumatriptan 20 and 5mg Nasal
Spray
Placebo
Single migraine attack
The primary efcacy endpoints were headache relief rates at
1 hour and sustained relief rates from 1 to 24 hours postdose.
Headache relief at 1 h: Sum nasal spray 20mg - 61% vs Sum
nasal spray 5mg - 53% vs Placebo - 52% (p=0.087).
Pain-free headache 2h: Sum nasal spray 20mg - 44% vs Placebo
30% (p<0.001). Sustained relief 1-24h - Sum nasal spray 20mg
- 4 1 % v s S u m n a s a l s p r a y 5 m g - 3 7 % v s P l a c e b o 3 2 % ( P = N S ) .
Overall incidence of adverse events in each treatment group (8%
placebo; 26% sumatriptan nasal spray 5 mg; 33% sumatriptan
nasal spray 20 mg).
Winner et al.
46
Adolescents – Eletriptan: 14
± 1.65 years; Placebo: 14 ±
1.65 years
n=274 (157 female and 117
male)
Eletriptan 40mg oral
Placebo
Single migraine attack
The primary outcome measure was 2-hour headache response.
Headache response rates were almost identical on eletriptan 40
mg and placebo by 2 hours (57% vs 57%). Pain-free rates were
also similar at 2 hours (22% vs 15%). Absence of associated
symptoms at 2 hours eletriptan 40 mg and placebo, respectively,
for nausea (75% vs 78%), photophobia (62% vs 64%), and
phonophobia (70% vs 67%). Use of rescue medication for
nonresponse was somewhat lower on eletriptan 40 mg than on
placebo (32% vs 39%).
Signicant differences in efcacy - 24-hour outcomes measures:
sustained headache response (52% vs 39%; P < .005) and
sustained pain-free response (22% vs 10%; P < .005).
216
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Winner et al.
29
Adolescents - Zolmitriptan 5mg:
14.5 (SD1.67); Zolmitriptan
2.5mg: 14.6 (SD1.77);
Zolmitriptan 0.5mg: 14.5 (SD
1.72); Placebo - 14.3 (SD
1.67).
n=798 (305 male and 493
female)
Zolmitriptan 5, 2.5 and 0.5mg
nasal spray
Placebo
Single migraine attack
The primary outcome variable is pain-freestatus 2 hours post-
treatment.
Pain-free 2 hours post treatment: Zolmitriptan nasal spray 5mg -
68/229 (29,7%) vs Placebo 42/253 (OR 2.18; 95% CI 1.40,
3.39 (16,6%) (P< .001).
Headache response at 2h: Zolmitriptan nasal spray 5 mg 51%
[116/229] vs Placebo 39% [99/253]; P =0.010.
Sustained headache response 2h: Zolmitriptan (any dose) - 30%
(120/396) vs Placebo 24% (59/251) - not statistically signicant.
Zhang et al.
214
Adults - Rizatriptan Group:
36.6±12.8 years; Propacetamol
group: 35.6±10.8 years.
n=148 (76 female and 72
male)
Propacetamol (1 g) IV
Rizatriptan 5 mg oral
Propacetamol showed superior efcacy at 1 h and there was
no signicant difference at 30 min or at 2 h. This indicates that
propacetamol is at least as effective as rizatriptan in the treatment
of acute migraine attacks.
217
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Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
Discussion
Our study suggests that overall response to triptans is as
effective as that observed with dipyrone in acute migraine
treatment.
Several studies involving triptans have evaluated the
efcacy of different doses compared to placebo or
included an evaluation of comparative efcacy between
different triptans or doses. In general, all types of triptan
were more effective than placebo in relieving migraine,
with a good safety standard, although some drugs have
achieved similar results as those for placebo. Attention
to exceptional positive results for placebo in migraine
treatment in some double-blind studies should be given,
especially in the adolescent population. Symptoms related
to migraine (nausea and vomiting, phonophobia and
photophobia) also had a good response with triptans.
In general, triptans were effective in relieving associated
symptoms and reducing clinical disability compared to
placebo. A poor response to one triptan does not predict a
poor response to other agents belonging to the class.
Regarding dipyrone (metamizole) results, Bigal showed that
the number of patients required to be treated with dipyrone
1 g by intravenous injection compared to placebo for at
least one to benet was 3.3 in 30 min and 2.2 in 60 min.
There were statistically signicant reductions in recurrence
(dipyrone = 25%, placebo = 50%) and use of rescue
medication (dipyrone = 20%, placebo = 47.6%) for the
dipyrone group.
38
A few studies have evaluated the restoration of functional
ability after a migraine crisis and, to a lesser extent, lost
time from work. A good number of studies evaluated the
possibility of returning to normal functions or the number of
patients who were able to return to normal activities after
an average of 2 hours from initial treatment for a migraine
episode. All studies involved triptans and no study was
performed with dipyrone.
24, 35, 36, 55, 68, 69, 73, 85, 129, 130, 135, 140,
143, 145, 152, 161, 166, 177, 211
Barbanti et al evaluated equivalent work time loss after
a migraine attack, and the results showed 1.9 ± 2.3 and
2.5 ± 4.7 hours lost from work for sumatriptan 100 mg
and 50 mg, respectively, compared with 3.5 ± 4.3 for
placebo. Sumatriptan 100 mg was also able to better
restore functional ability.
64
Freitag et al. (REF) evaluated normal function disability,
bed rest required, and ER/hospitalization resulting from
a migraine attack in order to compare almotriptan and
placebo responses at 2h- and 4h-posttreatment. The
study showed that pain resolution was associated with a
normal level of function, and the absence of photophobia,
phonophobia, and nausea at 2 hours was also associated
with less disability. In the study, treatment with almotriptan
compared with placebo resulted in consistently better 24-
hour quality of life scores, with restored social function.
A logistic regression model determined that pretreatment
functional level and pretreatment pain intensity were
signicant covariates of the proportion of patients who
achieved normal function at 2 hours posttreatment.
103
Dasbacj et al.
84
demonstrated that rizatriptan decreased
the total number of lost work hours by 1.1h per treated
migraine attack compared with placebo.
Most studies that evaluated migraine in the menstrual
period involved triptans.
97, 159, 160, 185, 206
Silverstein et al.
demonstrated that treatment results with rizatriptan in
menstrual period migraine were similar compared to those
for migraine unrelated to the menstrual period.
185
Some studies have associated hormonal drugs and mainly
NSAIDs with the use of triptan in one of the tested arms,
with good therapeutic results in general, especially when
there was an association of a triptan with a NSAID,
with superior results when compared to the drug alone.
Naproxen, ketoprofen and ibuprofen were the most
common NSAIDs evaluated in the studies.
20, 30, 33, 34, 48, 86,
106, 187
Tullo et al. evaluated the factors that inuenced the selection
of a treatment for migraine, comparing frovatriptan and
zolmitriptan in the selected study, and found the following
order of priority: 1) speed of action; 2) reduction in pain
intensity and 3) absence of side effects.
207
On the other
hand, Savi et al.
178
demonstrated the following order of
choice by patients: rapid speed of action, good tolerability
and reduction in pain severity, being decisive for the
selection of frovatriptan over rizatriptan. Although these
studies have evaluated triptans, rapid pain relief appears
to be the main attribute of drug selection for migraine
relief.
92, 171, 207
Regarding the question presented in this study: “what is the
evidence for the efcacy and safety of metamizole for the
treatment of migraines compared with triptans?” The result
is that overall response to metamizole is as effective as that
observed with triptans in acute migraine treatment. The
second point of evaluation in this systematic review was:
“how effective are those treatments in improving cognitive
218
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dysfunction in patients with migraine?” Unfortunately,
cognitive improvement is not a goal evaluated in most
studies included in the review. A few triptan studies showed
that pain resolution was associated with a normal level of
function, and also a logistic regression model determined
that pretreatment functional level and pretreatment pain
intensity were signicant covariates of the proportion
of patients who achieved normal function at 2 hours
posttreatment. There are no data regarding cognitive
dysfunction improvement related to metamizole utilization,
so it may just be an inference related to metamizole.
This systematic review involved different forms of
administration and doses of metamizole and triptans, which
allowed us to have a complete and comprehensive view
of studies involving both studied medications in migraine
treatment, but limits some more direct comparisons between
doses and routes of administration. Most studies performed
with triptans utilized oral administration and most studies
with metamizole in this review utilized the intravenous route
of administration.
No direct comparisons between metamizole and triptans
have been performed in a controlled and randomized
clinical study and most studies involving triptans have been
conducted in European countries and the US.
The main weakness of this systematic review and meta-
analysis is the small number of studies involving metamizole
included. The literature on metamizole is scarce. In
the setting of the present analyses, only 5 articles with
metamizole had a placebo arm and the estimates obtained
were all indirect. This fact is directly related to the absence
of drug availability in expressive markets, such as the US
and some European countries. Studies with metamizole
included in this review were limited to Brazil, Spain and
Turkey.
8, 37, 39-42
Despite the adverse event of agranulocytosis being the
main reason for metamizole withdrawal from the market
in some countries, this health risk was not proven true
in the pharmacovigilance data and other scientic
evidence generated in countries that maintained product
commercialization.
215-217
The data did not show a signicant difference between
metamizole and triptans in neither pain relief nor pain
absence 2 hours after medication. In support of relief
within 24 hours after medication, eletriptan, rizatriptan and
zolmitriptan showed statistically different proportions from
metamizole. There is no evidence of a difference between
metamizole and triptans in absence of pain 24 hours after
medication.
Considering the equivalence of therapeutic benet and
adverse events with triptans, especially cardiovascular
ones, in addition to pharmacoeconomic aspects, as
metamizole is far cheaper than triptans, metamizole could
be a good medicine option for migraine treatment.
Conclusion
Metamizole may be equally effective as triptans in acute
migraine treatment, with a good tolerability prole and
a potentially better cost-benet ratio with signicant
implications to healthcare policies. More studies are
necessary to conrm our results.
Conflict of interest statement: MP has received consultant
fees from Sano, Lundbeck, Ache, Eurofarma, Libbs,
Novartis, Eli Lilly, Allergan Abbvie, Teva, Hefesto Medtech.
WS and RS are employees of Sano, Sano nanced the
study.
Abbreviations
AEs, adverse effects
Bid, twice daily
CI, Condence Interval
IV, intravenous
NS, nasal spray
NSAIDs, non-steroidal anti-inammatory drugs
ODT, orally disintegrating tablet
PRISMA, Preferred Reporting Items for Systematic Reviews
and Meta-Analyses Protocols
qd, once daily
SC, subcutaneous
TDS: iontophoretic transdermal patch
US, United States
Authors’ contributions: All Authors contributed equally to
the conception, design, drafting and critical revisions of
the manuscript. All authors read and approved the nal
manuscript.
Funding: This work was supported by Sano. Editorial
support in the preparation of this publication was paid for
by Sano. The authors, individually and collectively are
responsible for all content and editorial .decisions related
to the development/presentation of this publication.
Mario Fernando Prieto Peres
https://orcid.org/0000-0002-0068-1905
Wanessa Alessandra Ruiz Scala
219
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Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis
https://orcid.org/0000-0003-3423-5222
Ricardo Salazar
https://orcid.org/0000-0002-3529-5254
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