PAIN 155 (2014) 22202228

www.elsevier.com/locate/pain

Comprehensive review

Evidence for efcacy of acute treatment of episodic tension-type

headache: Methodological critique of randomised trials for oral
treatments
R. Andrew Moore a,, Sheena Derry a, Philip J. Wiffen a, Sebastian Straube b, Lars Bendtsen c
c

Pain Research and Nufeld Division of Anaesthetics, University of Oxford, The Churchill, Oxford, UK
Division of Preventive Medicine, University of Alberta, Edmonton, Alberta, Canada
Danish Headache Centre, Department of Neurology, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark

DR

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

i n f o

or

ut

Co
pi

aa

Keywords:
Efcacy
IHS outcomes
Systematic review
Tension-type headache

The International Headache Society (IHS) provides guidance on the conduct of trials for acute treatment
of episodic tension-type headache (TTH), a common disorder with considerable disability. Electronic and
other searches identied randomised, double-blind trials of oral drugs treating episodic TTH with
moderate or severe pain at baseline, or that tested drugs at rst pain onset. The aims were to review
methods, quality, and outcomes reported (in particular the IHS-recommended primary efcacy parameter pain-free after 2 hours), and to assess efcacy by meta-analysis. We identied 58 reports: 55 from
previous reviews and searches, 2 unpublished reports, and 1 clinical trial report with results. We included
40 reports of 55 randomised trials involving 12,143 patients. Reporting quality was generally good, with
potential risk of bias from incomplete outcome reporting and small size; the 23 largest trials involved
82% of patients. Few trials reported IHS outcomes. The number needed to treat values for being pain-free
at 2 hours compared with placebo were 8.7 (95% condence interval [CI] 6.2 to 15) for paracetamol
1000 mg, 8.9 (95% CI 5.9 to 18) for ibuprofen 400 mg, and 9.8 (95% CI 5.1 to 146) for ketoprofen
25 mg. Lower (better) number needed to treat values were calculated for outcomes of mild or no pain
at 2 hours, and patient global assessment. These were similar to values for these drugs in migraine. No
other drugs had evaluable results for these patient-centred outcomes. There was no evidence that any
one outcome was better than others. The evidence available for treatment efcacy is small in comparison
to the size of the clinical problem.
2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

iza

Article history:
Received 24 April 2014
Received in revised form 11 August 2014
Accepted 12 August 2014

po

a b s t r a c t

da

a r t i c l e

rC

1. Introduction
Tension-type headache (TTH) was the second most prevalent
condition in the 2010 analysis of the global burden of disease
[81]. Its prevalence of 21% was higher than that of migraine
(15%), the third most prevalent condition. The 2013 International
Headache Society (IHS) classication [29] divides TTH into episodic
or chronic on the basis of the number of headache days per month.
This review is concerned with frequent episodic TTH, dened as at
least 10 episodes of headache on 1 to 14 days per month for at least
Corresponding author. Address: Pain Research and Nufeld Division of
Anaesthetics, Nufeld Department of Clinical Neurology, University of Oxford,
The Churchill, Oxford OX3 7LE, UK. Tel.: +44 1865 225674.
E-mail address: andrew.moore@ndcn.ox.ac.uk (R.A. Moore).

3 months (P12 and <180 days per year). Infrequent TTH has
<1 day of headache per month, and chronic TTH P15 days per
month.
Trials for the treatment of acute episodes of TTH are relatively
few in number [27,78]. The trials have methodological deciencies
that may lead to bias, and the outcomes used are often complicated
and rarely consistent between trials; many test drugs that are not
in common use. We therefore undertook a systematic review of
clinical trials of oral agents for treating acute attacks of episodic
TTH. It had a number of objectives.
1. This study sought to nd all the randomised, double-blind trials
of oral drug therapy for episodic TTH, and to review the
methods used and quality issues that might arise using IHS
guidelines for controlled trials of drugs in TTH [2].

http://dx.doi.org/10.1016/j.pain.2014.08.009
0304-3959/ 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

06/01/2015

2221

R.A. Moore et al. / PAIN 155 (2014) 22202228

2. This study sought to review outcomes reported in randomised,

double-blind trials of treatments for acute episodic TTH, and to
establish which report useful patient-centred outcomes. Here
a patient-centred outcome is dened as one important to
patients, and easily explainable; for example, the percentage
of patients pain-free 2 hours after taking a medicine is understandable, important, and recommended as the primary efcacy
parameter by the IHS. The pain intensity difference (PID) over
2 hours may demonstrate an analgesic effect, but is not easily
explained or understood by professionals or headache sufferers.
3. This study sought to carry out meta-analyses, if possible, to
assess the evidence for efcacy of oral analgesic drugs in treating acute episodic TTH using patient-centred outcomes.
2. Methods
All searching, trial selection, and data extraction was done independently by 2 authors and checked by a third.







Use of rescue medication

Global evaluation of the efcacy of the medication
Adverse events
Patient preference
Consistency of effect (in crossover trials)

These suggestions are similar to, if a little different from, the

guidance on outcomes for treatment of acute migraine [31]. The
differences may reect the different conditions, or changes in
emphasis over time.
A systematic review of patients views indicated that the
evidence we have is that a low pain state, no worse than mild pain,
is consistently rated highly by patients in clinical trials when
validated against other outcomes, such as reduced depression,
improved sleep, better functioning, higher quality of life, and
improved ability to work [50]. Migraine patients want pain to be
signicantly reduced, quickly, without recurrence, and ideally
without adverse effects [43]. This suggests that additional patientcentred outcomes of interest in TTH might usefully be:

rC

po

Clearly any trial using periodic measures of headache pain will

have these results recorded, but they may not have been reported.
These additional outcomes are similar to the reporting of outcomes
seen in Cochrane Reviews of acute treatments for migraine [40];
cluster headache, although not in any way comparable with TTH,
also uses early outcomes because these headaches usually resolve
naturally in about an hour [41]. One-hour outcomes might be
particularly important in studies of formulation or route of administration of drugs in which speed of onset was an issue. Longerduration outcomes are not important for episodic TTH because
the headache will resolve spontaneously.
We examined each trial or report for a dened primary outcome
matching one specied by the IHS guidance, or our additional
outcomes. In addition, each trial or report was examined to see
whether each of the 11 outcomes was measured, and whether an
appropriate dichotomous outcome was either reported or calculable. If it was available in graphic form, we estimated the result
from the graph.

iza

2.2. Inclusion criteria

Co
pi

aa

ut

or

Included trials had to be randomised, double-blind comparisons

of any active oral therapy with any oral placebo, and/or another
active therapy, in adults or children, and with a minimum of 10
patients per treatment arm. Headache pain generally had to be
moderate or severe; studies enrolling patients with only mild pain
were excluded, as were those in which the occurrence of at least
moderate pain could not be demonstrated. The exception was
studies deliberately testing drugs at rst onset of headache pain.
2.3. Quality assessment

 Patients who are pain-free after 1 hour

 Patients with mild or no pain after 2 hours
 Patients with mild or no pain after 1 hour

da

We searched for trials in 5 ways. We obtained copies of all of

the studies included in previous systematic reviews (principally
[27,78]); performed electronic searches of the literature to January
31, 2014, using PubMed, EMBASE, and Cochrane Central (Appendix
1); searched clinicaltrials.gov for any ongoing trials with results;
requested clinical trial reports of unpublished studies in TTH from
Reckitt Benckiser; and examined bibliographies of trials and
reviews for additional studies.

DR

2.1. Searching

Quality was assessed in 2 ways. Firstly, we used the Oxford

Quality Scale, a 5-point scale based on reporting of randomisation,
blinding, and withdrawal and dropouts [32]. Secondly, we used a
modied risk of bias approach as suggested by the Cochrane
Collaboration, using the criteria of appropriateness of method of
randomisation, allocation concealment, blinding, dealing with
incomplete outcome data, and treatment group size (Appendix
2). Study duration was not included because it is inappropriate
for acute treatments, and outcomes were not used because the
outcomes reported were the subject of specic study.
2.4. Outcomes in clinical trials
The IHS has provided guidance on clinical trials in TTH [2]. This
document species what outcomes could be reported in drug trials
dealing with the acute treatment of TTH. These are, briey:
 Patients who are pain-free after 2 hours (recommended as
primary efcacy parameter and with presentation of a number
needed to treat [NNT])
 Results based on a categorical pain scale, with PID over 2 hours
as a possible outcome
 Some measure of disability

2.5. Efcacy calculations

There was no prior intention to perform a meta-analysis of
treatment efcacy because consistently reported outcomes for
the same treatment were expected in no more than a few trials.
If there were sufcient data (dened as at least 2 trials and 200
patients [48]), we calculated risk ratio and NNT with 95% condence intervals. Relative benet or risk was calculated using a xed
effect model [52] with no statistically signicant difference
between treatments assumed when the 95% condence intervals
included unity. NNT was calculated [7] using the pooled number
of observations only when there was a statistically signicant
difference of relative benet or risk.
2.6. Terminology
We use the word report to indicate a published or unpublished
document that contains information on one or more clinical trials.
The word trial is used to indicate a specic clinical trial. A report
may have data on one or more trials; it may present data from
different trials separately or combine them. Where possible we
preferred to use data from individual trials, but in some cases this
was not possible and aggregated data were then used if presented.

06/01/2015

2222

R.A. Moore et al. / PAIN 155 (2014) 22202228

3. Results
3.1. Searching

po

rC

31 trials involved fewer than 200 patients (18% of the total), and
22 involved fewer than 100 (9% of the total). The 23 largest trials
involved 82% of the patients.
The trials used different criteria to classify TTH. An IHS denition
was used in 17 of 38 reports, and the Ad Hoc Committee denition
in 6 of 38; other reports provided some denition or diagnosis of
tension or muscle contraction headache, with migraine excluded.
All had a minimum duration for headache occurrence.
The number of headaches per month allowed in the trials was
varied and not always reported; actual headache frequency in 7
reports that provided this information was 5 to 17 per month.
Many studies had an upper limit on the number of headaches
per month, and those with IHS denitions usually used <15/month.
Others did not. For example, Gilbert et al. [20] allowed headache
frequency to be up to 20/month (median 6/month) and Langemark
et al. [37] up to 30/month (mean 15/month). Gbel et al. [25]
reported a mean frequency of 14/month, and Sargent 1988 [66]
reported mean headache frequency of 17/month (although the
inclusion criteria stated recurrent severe headache 4 to 12/month).

Co
pi

aa

ut

or

iza

Of the 40 reports, 34 had a placebo control, whereas 6 used an

active comparator only [6,21,22,30,36,56]. Twenty-eight had a parallel design. All but 2 involved patients with moderate or severe
pain; 2 involved treatment at onset of attack [64,76].
We were able to analyse methods and results from 40 published
reports that involved 55 randomised trials. These 55 trials involved
12,143 patients, some of whom would have participated in crossover studies and had several headaches treated. Fig. 2 shows the
numbers of patients involved in each decade since 1970, together
with the median size of the trials in each decade. The overall
average trial size (of 55) was 225 patients, with a median of 144;

Fig. 2. Patients and trials by decade.

da

3.2. Characteristics of included trials

DR

Using previous systematic reviews [27,78] and updated

searches (to January 2014), 58 reports were identied, 55 from
searches and previous reviews, 2 unpublished reports from Reckitt
Benckiser [55,56], and 1 clinical trial report with results from
clinicaltrials.gov [53]. An additional 6 trials without results were
identied on clinicaltrials.gov (Appendix 3).
Sixteen reports, including some included in previous reviews,
were excluded for various reasons (Fig. 1): they were in chronic
TTH [3,28]; 84% of patients had migraine [14]; rectal administration [26]; duplicate publication [38,80]; not randomised and
double-blind [5,54,70]; without initial pain of at least moderate
intensity, which can reduce sensitivity [12,13,15,16,33,65]; or not
full publications [1]. Copies of 2 other publications (45 patients
in total) could not be obtained [58,71].
There were 40 included reports [6,8,11,1725,30,3537,39,
4447,53,5557,5961,64,6669,7477,79,82,83]. Four reports
included more than 1 trial. Gbel et al. [24] reported 2 trials in sufcient detail for each to be regarded as a separate trial. Migliardi
et al. [46] reported on 6 studies with similar methods, but reported
on combined results. Von Graffenried et al. [79] reported on 8
studies with similar methods, and Wood et al. [83] reported on 3
studies with similar methods; there was insufcient detail to
report on them separately.

Fig. 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) owchart for the review.

06/01/2015

2223

R.A. Moore et al. / PAIN 155 (2014) 22202228

The drugs most frequently tested were paracetamol 500 to

1000 mg (19 arms), aspirin 650 to 1000 mg (12 arms), ibuprofen
200 to 400 mg (11 arms, plus fast-acting formulations in 2 arms),
ketoprofen 25 to 50 mg (5 arms), and naproxen 275 to 550 mg (4
arms). As many as 22 other individual drugs and combinations also
were tested, but only sporadically.

Table 2 shows the number of trials or reports in which any of

the 11 outcomes was measured or reported. Adverse events were
most frequently reported, mostly in terms of the absence of serious
adverse events or adverse event discontinuations. By contrast, consistency of effect in crossover trials was not mentioned in any trial.
3.5. Efcacy calculations

3.3. Quality of included trials

aa

ut

or

DR

iza

da

All studies measured pain intensity or pain relief over various

times, typically 2 to 6 hours (Appendix 6). Other measures used were
muscle soreness, and some measure of usual activity or impairment.
There was little consistency among published trials for outcomes
measured and reported and for time at which or over which they
were measured and reported (Appendix 6). Only 1 trial declared
the outcome of pain-free at 2 hours to be the primary outcome in
the trial, and presented it [75]. Only 1 of 6 recent trials without
results found in clinicaltrials.gov clearly mentioned being pain-free
at 2 hours as the primary outcome, although 1 other planned to
use total or meaningful pain relief at 2 hours (Appendix 3).

rC

3.4. Outcomes reported

Dichotomous data were available in reasonable amounts for 3

outcomes, pain-free after 2 hours, mild or no pain after 2 hours,
and global assessment. The percentage of patients achieving the
outcome is shown in each treatment arm for each therapy tested
in Figs. 35, respectively. Response rates were lowest for pain-free
after 2 hours (10% to 25% with placebo) and highest for mild or no
pain after 2 hours (40% to 55% with placebo), and intermediate
(20% to 50% with placebo) for patient global assessment taking
the top 2 categories of the scales used (mainly very good/excellent,
or good/very good). The gures show very considerable inconsistencies among trials. None of the trials used for these calculations
used patients who may have had chronic TTH.
It was possible to pool data from trials for some drugs (paracetamol 1000 mg, ibuprofen 400 mg, ketoprofen 25 mg, and aspirin
1000 mg) for some of these 3 outcomes. Table 3 shows the amount
of data available for pooling, the mean event rates, and risk ratio
and NNTs calculated by pooling. There was little difference among
the drugs, and NNTs were high, at about 9, for the IHS-preferred
outcome of pain-free at 2 hours.
We were unable to use PID for calculations of efcacy. The reasons were different categorical pain intensity scales (with 4 or 5
points on the scale, for example), and reporting of PID over different time intervals (2, 3, 4, and 6 hours). Although PID was the most
reported outcome, the variability in its reporting precluded any
sensible analysis.

po

The details of the trials are in Appendix 4; 41 reports or trials

could be scored individually, and some reports of multiple trials
with similar methods are scored by report, not individual trial.
Quality scoring performed using the Oxford Quality Scale [32]
demonstrated that 2 studies scored 2 of 5 points, 12 scored 3 of
5, 16 scored 4 of 5, and 11 scored 5 of 5. In terms of risk of bias,
only for blinding were the majority of trials likely to have a low risk
of bias. Reporting of trials was such as to provide an unclear risk of
bias for most assessments, although a high risk of bias was generated in a signicant number of trials for incomplete outcome
assessment and because of small size (Table 1; Appendix 5). Only
17 of 41 trials or reports were without at least 1 design or reporting characteristic that was at high risk of bias because of small size
or incomplete outcome data reporting.

Risk of bias indication

Co
pi

Table 1
Risk of bias on 5 criteria suggested by pain, palliative, and supportive care review
group of the Cochrane Collaboration.

Randomisation method
Allocation concealment
Blinding
Incomplete outcome assessment
Size

Risk of bias
Low

Unclear

High

12
5
29
8
2

29
36
12
20
22

0
0
0
13
17

4. Discussion
The systematic review process sought to nd randomised,
double-blind trials of oral analgesics for the acute treatment of
episodic TTH, to evaluate their methodological strengths and
weaknesses, and to estimate the efcacy of treatments if at all
possible. We found 40 publications reporting results of 55 trials
involving 12,143 patients. Factors combining to detract from a consistent or meaningful estimation of efcacy included variable trial
design, poor trial quality, few small studies on a large variety of
different drugs, and inconsistent reporting of different outcomes.
Trials used both parallel and crossover designs, and although 39
of 41 reports or trials scored 3 of 5 or more on the Oxford Quality
Scale, only 17 were without at least 1 red ag for possible risk of
bias. In all cases, high risk of bias derived from small size or from

Table 2
Numbers of reports or trials presenting data for International Headache Society and other identied outcomes of importance to patients
with tension-type headache.
Outcome

Number of reports or
individual trials

Number with outcome

recorded

Number with dichotomous

information available

Patients pain-free at 2 h
Patients pain-free at 1 h
Patients with mild or no pain at 2 h
Patients with mild or no pain at 1 h
Pain intensity difference over 2 h
Measure of disability
Use of rescue medication
Global evaluation of efcacy
Adverse events
Patient preference
Consistency of effect in crossover trials

41
41
41
41
41
41
41
41
41
41
29

10
5
4
0
18
7
9
12
37
3
0

10
5
4
0
1
2
8
12
32
2
0

06/01/2015

R.A. Moore et al. / PAIN 155 (2014) 22202228

DR

2224

Fig. 5. Percentage of patients with top 2 categories on any global assessment in

individual treatment arms. Drugs with dose in milligrams. Size of trial arm is
proportional to the size of the symbol (inset scale).

rC

Fig. 3. Percentage of patients with pain-free outcome at 2 hours in individual

treatment arms. Drugs with dose in milligrams. Size of trial arm is proportional to
the size of the symbol (inset scale).

Co
pi

aa

ut

or

iza

da

po

This is of importance in 2 ways. Episodic and chronic TTH are

not entities that can necessarily be clearly separated, and the cut
off at 15 days/month is somewhat arbitrary. Therefore, it is not
the case that including some patients with headaches on more
than 15 days/month will invalidate the results, especially given
the somewhat inadequate and contradictory descriptions provided
in the trials. Inclusion of patients with more frequent headaches
could lead to a lower estimation of efcacy, although none of the
trials with a potential for this provided any data in the pooled
analyses. The clinical point is that treatments for acute headache
will usually be an incorrect approach for chronic TTH.
More difcult is the issue of the disparate outcomes measured
and reported. The modest number of trials and the large number
of treatments tested combine with inconsistency in outcome
reporting to make sensible judgements impossible regarding what
might be the most appropriate outcome in TTH trials and reviews.
With small numbers of trials and patients, random chance plays a
large effect [48]. The ideal outcome would combine sensitivity to
discriminate between different degrees of efcacy with relevance
both to clinical practice and to people with tension headache,
who often self-medicate.
In this analysis, we concentrated on outcomes regarded as
important by the most recent IHS guidance [2], together with 3
additional early outcomes of pain-free at 1 hour or mild or no pain
at 1 or 2 hours to capture benets that patients desire early after
dosing. There is empirical evidence that what patients desire in
most pain conditions is fast and effective relief [50]. The IHSpreferred outcome of being pain-free 2 hours after dosing captures
that. We also looked for trials reporting the same outcome after
1 hour because it is faster, and for the outcome of mild or no pain
at 1 and 2 hours, because although mild or no pain is a less complete response, it might well be valuable for other patients. PID,
preference, and global evaluations are less direct and often are
more difcult to explain. PID outcomes also used different scales
and reported over different time periods, which did not allow us
to perform any pooled analysis of like with like.
Most efcacy outcomes were reported infrequently, and the outcome regarded as most important by the IHS of being pain-free at
2 hours was available in only 10 of 41 trials or reports. In part, of
course, this is a reection of the fact that most of the studies predate
the 2010 guidance, but even then there was a lack of consistency in
reporting. The most commonly reported efcacy outcome of pain

Fig. 4. Percentage of patients with no or mild pain at 2 hours in individual

treatment arms. Drugs with dose in milligrams. Size of trial arm is proportional to
the size of the symbol (inset scale).

incomplete outcome data reporting. Although these are problematic in chronic pain [49,51], it is not clear how much these potential sources of bias might inuence results in headache or acute
pain trials. Potentially, however, over half of the available data
may be subject to bias that overestimates treatment effects.
An additional problem was whether all of the trials were conducted in what would today be regarded as frequent episodic
TTH. Most reported a minimum frequency for inclusion that would
satisfy current IHS criteria, but a small number had upper limits
above 15/month. On the basis of information provided by the
reports, it seems that most patients fullled current criteria of frequent episodic TTH, but some might today be classied as chronic
TTH.

06/01/2015

2225

R.A. Moore et al. / PAIN 155 (2014) 22202228

Table 3
Data available for pooling for various outcomes, and statistical signicance and NNTs for drug compared with placebo.
Drug and dose (mg)

Number

Percent with outcome with

Risk ratio (95% CI)

NNT (95% CI)

Trials

Patients

Active drug

Placebo

Pain-free at 2 h
Paracetamol 1000
Ibuprofen 400
Ketoprofen 25

5
3
2

1387
826
285

34
29
27

22
18
18

1.5 (1.2 to 1.7)

1.6 (1.2 to 2.0)
1.6 (1.02 to 2.6)

8.7 (6.2 to 15)

8.9 (5.9 to 18)
9.8 (5.1 to 146)

Mild or no pain at 2 h
Paracetamol 1000
Ketoprofen 25

4
2

1127
285

64
65

51
38

1.3 (1.1 to 1.4)

1.7 (1.3 to 2.2)

7.5 (5.3 to 13)

3.8 (2.7 to 6.6)

1121
774
592
397

46
40
51
56

35
24
36
37

1.3
1.6
1.4
1.5

8.4
6.1
6.9
5.2

Global assessment by patient (top 2 categories)

Paracetamol 1000
5
Ibuprofen 400
3
Ketoprofen 25
3
Aspirin 1000
2

(1.2
(1.3
(1.2
(1.2

to
to
to
to

1.5)
2.0)
1.7)
1.9)

(5.7
(4.3
(4.5
(3.5

to
to
to
to

16)
10)
15)
10)

CI = condence interval; NNT = number needed to treat.

Percent with outcome with

rC

Number

NNT(95% CI)

Patients or attacks

Active drug

Placebo

TTH, pain-free at 2 h
Paracetamol 1000
Ibuprofen 400

5
3

1387
826

34
29

22
18

8.7 (6.2 to 15)

8.9 (5.9 to 18)

Migraine, pain-free at 2 h
Paracetamol 1000
Ibuprofen 400

3
6

717
2575

19
26

10
12

12 (7.5 to 32)
7.2 (5.9 to 9.2)

TTH, mild or no pain at 2 h

Paracetamol 1000
Ibuprofen 400

4
No data

1127

64

51

7.5 (5.3 to 13)

Migraine, mild or no pain at 2 h

Paracetamol 1000
Ibuprofen 400

3
7

717
1815

56
57

36
25

5.0 (3.7 to 7.7)

3.2 (2.8 to 3.7)

or

iza

po

Trials

da

Drug and dose (mg)

DR

Table 4
Comparison of data available for pooling for various outcomes for TTH and migraine.

aa

ut

Data for migraine taken from Derry et al. [10] (paracetamol) and Rabbie et al. [63] (ibuprofen).

Co
pi

intensity difference over 2 hours (18 of 41), is difcult to translate

into immediately interpretable results for patients or professionals.
It was notable that the situation was not markedly better in the
more recent trials registered in clinicaltrials.gov (Appendix 3).
It was not possible to judge whether different outcomes inuenced estimates of efcacy. Paracetamol 1000 mg produced similar
NNT values of 7.5 to 8.7 for 2-hour pain-free and mild or no pain outcomes, and for the top 2 categories of global assessment (Table 3).
For ketoprofen 25 mg, by contrast, the same 3 outcomes produced
diverging values: 9.8, 3.8, and 6.9, although based on small numbers. There is no solid evidence that any one outcome is better than
the others; analysis at the level of the individual patient would be
the ideal way of testing different outcomes for both sensitivity
and effect size.
Few trials conformed to IHS guidance on the conduct of trials in
episodic TTH [2]. This was principally because of inadequate outcome reporting, but also because of lack of a placebo control. Trials
included in this review were both randomised and double-blind,
with generally acceptable risk of bias. Many other trials were not
included because they failed to meet these minimum requirements. Disappointingly, ongoing trials found in clinicaltrials.gov
suffer from much the same problems, so more insight into the efcacy of drugs in TTH is unlikely in the near future unless new trials
are designed and conducted.
One consequence of these deciencies was that few trials
provided useful information about the efcacy of drug therapies
for the acute treatment of episodic TTH. Only for paracetamol
1000 mg, ibuprofen 400 mg, and ketoprofen 25 mg can we be

condent that the drug is more effective than placebo using the
IHS-preferred efcacy parameter of pain-free rates after 2 hours.
NNT values for all 3 drugs were high. It is likely, but not proven,
that aspirin, naproxen, and diclofenac in doses typically used are
also more effective than placebo, but the magnitude of effect cannot be estimated on current data. There is no conclusive evidence
that any one of these is likely to be better than any other, and new,
better research would be needed to determine this.
These results are broadly in agreement with a previous review
[78] that concluded that paracetamol and nonsteroidal antiinammatory drugs (NSAIDs) were better than placebo. Both
reviews included similar trials, although the current review was
much more stringent, investigated different drugs and doses rather
than lumping together all NSAIDs at any dose, and included over
1500 patients from newer trials. Our results are also largely in
agreement with the guideline from the European Federation of
Neurological Societies [4], which recommends ibuprofen as the
drug of choice among NSAIDs or paracetamol or aspirin for acute
treatment of TTH. However, this guideline was not based on a systematic review. The German evidence-based recommendations for
self-medication of migraine and TTH were based on systematic
reviews [27], and included only 7 trials that included at least some
TTH patients. For self-medication of TTH, it recommended as
rst-line therapy the xed-dose combination of acetaminophen,
acetylsalicylic acid, and caffeine or the xed combination of acetaminophen and caffeine as well as monotherapy with ibuprofen
or acetylsalicylic acid or diclofenac. Some of these are not
supported by any signicant data.

06/01/2015

2226

R.A. Moore et al. / PAIN 155 (2014) 22202228

The lack of evidence on drug treatments of TTH is in contrast to

that for migraine: for just one drug, sumatriptan, a Cochrane overview found information on over 50,000 patients in trials examining
18 drug/dose/route of administration combinations [9]. It is true
that evidence about commonly available drugs such as paracetamol, aspirin, and ibuprofen also is limited in migraine [10,34,63].
Table 4 compares the available information and efcacy results
for paracetamol 1000 mg and ibuprofen 400 mg for 2-hour outcomes. Where available, results are rather similar. A major difference from the migraine literature, however, is that for migraine
there is a very large body of evidence on other drugs, such as triptans, which runs to several hundred trials and involving perhaps
100,000 patients. For TTH, there are no trials other than those in
this review.
Headache is important because work loss, interference with
work when present, and impact on activities of daily living have
important economic consequences [42,62,72,73]. In this circumstance, it would be reasonable to expect a greater degree of
research interest in early-onset analgesics producing faster and
better pain relief. The IHS guidance on clinical trials provides an
intellectual underpinning for such research.

References

DR

rC

iza

da

po

4.1. Conclusions
Paracetamol 1000 mg, ibuprofen 400 mg, and ketoprofen 25 mg
are more effective than placebo using the IHS-preferred outcome
measure of pain-free rates after 2 hours. NNT values for all 3 drugs
were high. The evidence available for treatment efcacy in episodic
TTH is trivial in comparison to the size of the clinical problem.

[1] Ansink BJ, Hartman JW, Smakman JG. Ritanserin is not effective in tension
headache. Headache 1992;32:314.
[2] Bendtsen L, Bigal ME, Cerbo R, Diener HC, Holroyd K, Lampl C, Mitsikostas DD,
Steiner TJ, Tfelt-Hansen P, International Headache Society Clinical Trials
Subcommittee. Guidelines for controlled trials of drugs in tension-type
headache: second edition. Cephalalgia 2010;30:116.
[3] Bendtsen L, Buchgreitz L, Ashina S, Jensen R. Combination of low-dose
mirtazapine and ibuprofen for prophylaxis of chronic tension-type headache.
Eur J Neurol 2007;14:18793.
[4] Bendtsen L, Evers S, Linde M, Mitsikostas DD, Sandrini G, Schoenen J. EFNS
guideline on the treatment of tension-type headachereport of an EFNS task
force. Eur J Neurol 2010;17:131825.
[5] Borges J, Zavaleta C. Study of a new analgesic compound in the treatment of
tension headache. J Int Med Res 1976;4:748.
[6] Cerbo R, Centonze V, Grazioli I, Tavolato B, Trenti T, Uslenghi C, Sternieri E.
Efcacy of a xed combination of indomethacin, prochlorperazine, and
caffeine in the treatment of episodic tension-type headache: a double-blind,
randomized, nimesulide-controlled, parallel group, multicentre trial. Eur J
Neurol 2005;12:75967.
[7] Cook D, Sackett DL. The number needed to treat: a clinically useful measure of
treatment effect. BMJ 1995;310:4524.
[8] Dahlf CG, Jacobs LD. Ketoprofen, paracetamol and placebo in the treatment of
episodic tension-type headache. Cephalalgia 1996;16:11723.
[9] Derry C, Derry S, Moore RA. Sumatriptan (all routes of administration) for
acute migraine attacks in adultsoverview of Cochrane Reviews. Cochrane
Database Syst Rev 2014;5:CD009108.
[10] Derry S, Moore RA, McQuay HJ. Paracetamol (acetaminophen) with or without
an antiemetic for acute migraine headaches in adults. Cochrane Database Syst
Rev 2010;11:CD008040.
[11] Diamond S, Balm TK, Freitag FG. Ibuprofen plus caffeine in the treatment of
tension-type headache. Clin Pharmacol Ther 2000;68:3129.
[12] Diamond S, Medina JL. A double-blind study of zomepirac sodium and placebo
in the treatment of muscle contraction headache. Headache 1981;21:458.
[13] Diamond S. Ibuprofen versus aspirin and placebo in the treatment of muscle
contraction headache. Headache 1983;23:20610.
[14] Diener HC, Pfaffenrath V, Pageler L, Peil H, Aicher B. The xed combination of
acetylsalicylic acid, paracetamol and caffeine is more effective than single
substances and dual combination for the treatment of headache: a
multicentre, randomised, double-blind, single-dose, placebo-controlled
parallel group study. Cephalalgia 2005;25:77687.
[15] DiSerio FJ, Friedman AP, Parno J, Singer JM. Proquazone for tension headache
a multicenter trial. Headache 1985;25:12733.
[16] Friedman AP, Boyles WF, Elkind AH, Fillingim J, Ford RG, Gallagher RM, Hobbs
D, Rapoport A, Richards BA, Sheftell FD. Fiorinal with codeine in the treatment
of tension headachethe contribution of components to the combination
drug. Clin Ther 1988;10:30315.
[17] Friedman AP, DiSerio FJ. Symptomatic treatment of chronically recurring
tension headache: a placebo-controlled, multicenter investigation of Fioricet
and acetaminophen with codeine. Clin Ther 1987;10:6981.
[18] Friedman AP. Assessment of Fiorinal with codeine in the treatment of tension
headache. Clin Ther 1986;8:70321.
[19] Gatoulis SG, Voelker M, Fisher M. Assessment of the efcacy and safety proles
of aspirin and acetaminophen with codeine: results from 2 randomized,
controlled trials in individuals with tension-type headache and postoperative
dental pain. Clin Ther 2012;34:13848.
[20] Gilbert MM, de Sola Pool N, Schecter C. Analgesic/calmative effects of
acetaminophen and phenyltoloxamine in treatment of simple nervous
tension accompanied by headache. Curr Ther Res 1976;20:538.
[21] Glassman JM, Soyka JP. Muscle contraction (tension) headache: a double-blind
study comparing the efcacy and safety of meprobamate-aspirin with
butalbital-aspirin-phenacetin-caffeine. Curr Ther Res 1980;28:90415.
[22] Glassman JM, Soyka JP, Pollack M. Treatment of muscle contraction headache:
micrainin vs. aspirin. Headache 1982;22:1019.
[23] Gbel H, Fresenius J, Heinze A, Dworschak M, Soyka D. Effectiveness of Oleum
menthae piperitae and paracetamol in therapy of headache of the tension type
[German]. Nervenarzt 1996;67:67281.
[24] Gbel H, Heinze A, Dworschak M, Heinze-Kuhn, Stolze H. Analgesic efcacy
and tolerability of locally applied Oleum menthae piperitae preparation LI 170
in patients with migraine or tension-type headache [German]. Z Allg Med
2001;77:28795.
[25] Gbel H, Heinze A, Lurch A, Dworschak M. Essential oils in the therapy of
tension headache [German]. Z Allg Med 1998;74:2238.
[26] Guidotti M, Zanasi S, Garagiola U. Pirprofen in the treatment of migraine and
episodic headache attacks: a placebo-controlled crossover clinical trial. J Int
Med Res 1989;17:4854.
[27] Haag G, Diener HC, May A, Meyer C, Morck H, Straube A, Wessely P, Evers S,
DMKG, DGN, OKSG, SKG. Self-medication of migraine and tension-type
headache: summary of the evidence-based recommendations of the Deutsche
Migrne und Kopfschmerzgesellschaft (DMKG), the Deutsche Gesellschaft fr
Neurologie (DGN), the sterreichische Kopfschmerzgesellschaft (KSG) and
the Schweizerische Kopfwehgesellschaft (SKG). J Headache Pain 2011;12:
20117.

Acknowledgements

Co
pi

aa

ut

or

We thank Mrs. Audrey Craven, President of the European Federation of Neurological Associations, European Headache Alliance &
Migraine Association of Ireland, for providing a patient perspective,
and Dr. Mairead McIntyre of the West Hoe Surgery in Plymouth for
providing a general practice perspective on outcomes. Reviewers
also made perceptive and welcome comments on the manuscript.
The Oxford Pain Relief Trust provided institutional support for the
work, and Reckitt Benckiser provided an unrestricted educational
grant to Oxford Medical Knowledge to help fund it. Funding
sources had no role in the concept, design, conduct, analysis, or
writing of the work, or decisions on whether or where to publish.
R.A.M. is the owner of Oxford Medical Knowledge, and has been
a consultant to Reckitt Benckiser and has been on Reckitt Benckiser
speaker panels. S.D. and P.J.W. acted as paid consultants to the
project. S.S. had previously participated in a grant from Reckitt
Benckiser, received a lecture fee from Oxford Medical Knowledge,
and acted as a paid consultant to Oxford Medical Knowledge, all
unrelated to this project. L.B. has been a consultant to Reckitt
Benckiser and has been on Reckitt Benckiser speaker panels.
R.A.M. developed the original concept for the study. All authors
were involved in dening the broad aims and objectives, and
developed data extraction criteria for outcomes. R.A.M., S.D., and
P.W. performed data extraction, and R.A.M. performed data analyses. R.A.M. wrote the original draft, and all authors contributed to
the development of interim and nal drafts. All authors read and
approved the nal manuscript.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.pain.2014.08.009.

06/01/2015

2227

R.A. Moore et al. / PAIN 155 (2014) 22202228

po

rC

DR

[57] Packman B, Packman E, Doyle G, Cooper S, Ashraf E, Koronkiewicz K,

Jayawardena S. Solubilized ibuprofen: evaluation of onset, relief, and safety
of a novel formulation in the treatment of episodic tension-type headache.
Headache 2000;40:5617.
[58] Paterna S, Martino S, Arrostuto A, Cascio IN, Corrao S, Licata G. Nabumetone
versus placebo in episodic tension headache. Conn Cephalalgica
1994;3:1922.
[59] Peters BH, Fraim CJ, Masel BE. Comparison of 650 mg aspirin and 1,000 mg
acetaminophen with each other, and with placebo in moderately severe
headache. Am J Med 1983;74:3642.
[60] Pini LA, Del Bene E, Zanchin G, Sarchielli P, Di Trapani G, Prudenzano MP,
LaPegna G, Savi L, Di Loreto G, Dionisio P, Granella F. Tolerability and efcacy
of a combination of paracetamol and caffeine in the treatment of tension-type
headache: a randomised, double-blind, double-dummy, cross-over study
versus placebo and naproxen sodium. J Headache Pain 2008;9:36773.
[61] Prior MJ, Cooper KM, May LG, Bowen DL. Efcacy and safety of acetaminophen
and naproxen in the treatment of tension-type headache. A randomised,
double-blind, placebo-controlled trial. Cephalalgia 2002;22:7408.
[62] Raak R, Raak A. Work attendance despite headache and its economic impact: a
comparison between two workplaces. Headache 2003;43:1097101.
[63] Rabbie R, Derry S, Moore RA, McQuay HJ. Ibuprofen with or without an
antiemetic for acute migraine headaches in adults. Cochrane Database Syst
Rev 2010;10:CD008039.
[64] Ryan Sr RE, Ryan Jr RE. Symptomatic treatment of tension headache. Ear Nose
Throat J 1979;58:4236.
[65] Ryan Sr RE. Motrina new agent for the symptomatic treatment of muscle
contraction headache. Headache 1977;16:2803.
[66] Sargent JD, Peters K, Goldstein J, Madison DS, Solbach P. Naproxen sodium for
muscle contraction headache treatment. Headache 1988;28:1802.
[67] Schachtel BP, Furey SA, Thoden WR. Nonprescription ibuprofen and
acetaminophen in the treatment of tension-type headache. J Clin Pharmacol
1996;36:11205.
[68] Schachtel BP, Thoden WR, Konerman JP, Brown A, Chaing DS. Headache pain
model for assessing and comparing the efcacy of over-the-counter analgesic
agents. Clin Pharmacol Ther 1991;50:3229.
[69] Schachtel BP, Thoden WR. Onset of action of ibuprofen in the treatment of
muscle-contraction headache. Headache 1988;28:4714.
[70] Schattner P, Randerson D. Tiger Balm as a treatment of tension headache. A
clinical trial in general practice. Aust Fam Physician 1996;25:216. 218, 220.
[71] Scheepers F. Syndol in the treatment of tension headache. Med Proc
1971:35968.
[72] Schwartz BS, Stewart WF, Lipton RB. Lost workdays and decreased work
effectiveness associated with headache in the workplace. J Occup Environ Med
1997;39:3207.
[73] Sokolovic E, Riederer F, Szucs T, Agosti R, Sndor PS. Self-reported headache
among the employees of a Swiss university hospital: prevalence, disability,
current treatment, and economic impact. J Headache Pain 2013;14:29.
[74] Steiner TJ, Lange R, Voelker M. Aspirin in episodic tension-type headache:
placebo-controlled dose-ranging comparison with paracetamol. Cephalalgia
2003;23:5966.
[75] Steiner TJ, Lange R. Ketoprofen (25 mg) in the symptomatic treatment of
episodic tension-type headache: double-blind placebo-controlled comparison
with acetaminophen (1000 mg). Cephalalgia 1998;18:3843.
[76] Thorpe P. Controlled and uncontrolled studies on Fiorinal-PA for
symptomatic relief in tension headache. Med J Aust 1970;2:1801.
[77] van Gerven JM, Schoemaker RC, Jacobs LD, Reints A, Ouwersloot-van der Meij
MJ, Hoedemaker HG, Cohen AF. Self-medication of a single headache episode
with ketoprofen, ibuprofen or placebo, home-monitored with an electronic
patient diary. Br J Clin Pharmacol 1996;42:47581.
[78] Verhagen AP, Damen L, Berger MY, Passchier J, Merlijn V, Koes BW. Is anyone
analgesic superior for episodic tension-type headache? J Fam Pract
2006;55:106472.
[79] von Graffenried B, Hill RC, Nesch E. Headache as a model for assessing mild
analgesic drugs. J Clin Pharmacol 1980;20:13144.
[80] von Graffenried B, Nesch E. Non-migrainous headache for the evaluation of
oral analgesics. Br J Clin Pharmacol 1980;10:225S31S.
[81] Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K,
Salomon JA, Abdalla S, Aboyans V, Abraham J, Ackerman I, Aggarwal R, Ahn SY,
Ali MK, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C,
Baddour LM, Bahalim AN, Barker-Collo S, Barrero LH, Bartels DH, Basez MG,
Baxter A, Bell ML, Benjamin EJ, Bennett D, Bernab E, Bhalla K, Bhandari B,
Bikbov B, Bin Abdulhak A, Birbeck G, Black JA, Blencowe H, Blore JD, Blyth F,
Bolliger I, Bonaventure A, Boufous S, Bourne R, Boussinesq M, Braithwaite T,
Brayne C, Bridgett L, Brooker S, Brooks P, Brugha TS, Bryan-Hancock C, Bucello
C, Buchbinder R, Buckle G, Budke CM, Burch M, Burney P, Burstein R, Calabria
B, Campbell B, Canter CE, Carabin H, Carapetis J, Carmona L, Cella C, Charlson F,
Chen H, Cheng AT, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S,
Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de
Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahiya
M, Dahodwala N, Damsere-Derry J, Danaei G, Davis A, De Leo D, Degenhardt L,
Dellavalle R, Delossantos A, Denenberg J, Derrett S, Des Jarlais DC,
Dharmaratne SD, Dherani M, Diaz-Torne C, Dolk H, Dorsey ER, Driscoll T,
Duber H, Ebel B, Edmond K, Elbaz A, Ali SE, Erskine H, Erwin PJ, Espindola P,
Ewoigbokhan SE, Farzadfar F, Feigin V, Felson DT, Ferrari A, Ferri CP, Fvre EM,
Finucane MM, Flaxman S, Flood L, Foreman K, Forouzanfar MH, Fowkes FG,
Franklin R, Fransen M, Freeman MK, Gabbe BJ, Gabriel SE, Gakidou E, Ganatra

Co
pi

aa

ut

or

iza

da

[28] Hakkarainen H. Fluphenazine for tension headache; double-blind study.

Headache 1977;17:2168.
[29] Headache Classication Committee of the International Headache Society
(IHS). The international classication of headache disorders, 3rd edition (beta
version). Cephalalgia 2013;33:629808.
[30] Hirata K, Tatsumoto M, Araki N, Takeshima T, Igarashi H, Shibata K, Sakai F.
Multi-center randomised control trial of etizolam plus NSAID combination for
tension-type headache. Intern Med 2007;46:46772.
[31] International Headache Society Clinical Trials Subcommittee. Guidelines for
controlled trials of drugs in migraine: second edition. Cephalalgia
2000;20:76586.
[32] Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay
HJ. Assessing the quality of reports of randomised clinical trials: is blinding
necessary? Control Clin Trials 1996;17:112.
[33] Kagan G, Masheter HC. A controlled study of short-term treatment of tension
headache. Curr Med Res Opin 1978;5:70913.
[34] Kirthi V, Derry S, Moore RA, McQuay HJ. Aspirin with or without an antiemetic
for acute migraine headaches in adults. Cochrane Database Syst Rev
2010;4:CD008041.
[35] Kubitzek F, Ziegler G, Gold MS, Liu JM, Ionescu E. Low-dose diclofenac
potassium in the treatment of episodic tension-type headache. Eur J Pain
2003;7:15562.
[36] Lange R, Lentz R. Comparison ketoprofen, ibuprofen and naproxen sodium in
the treatment of tension-type headache. Drugs Exp Clin Res 1995;21:8996.
[37] Langemark M, Olesen J. Effervescent ASA versus solid ASA in the treatment of
tension headache. A double-blind, placebo controlled study. Headache
1987;27:905.
[38] Langemark M. Effervescent aspirin in the treatment of tension headache. A
double blind, placebo controlled cross-over study. Cephalalgia 1985;5:1523.
[39] Laveneziana D, Speranza R, Raulli P, Paredi G. Comparative efcacy of
ibuprofen arginine and betacyclodextrin piroxicam as treatment for tensiontype headache. Clin Drug Invest 1996;11:226.
[40] Law S, Derry S, Moore RA. Sumatriptan plus naproxen for acute migraine
attacks in adults. Cochrane Database Syst Rev 2013;10:CD008541.
[41] Law S, Derry S, Moore RA. Triptans for acute cluster headache. Cochrane
Database Syst Rev 2013;7:CD008042.
[42] Linde M, Gustavsson A, Stovner LJ, Steiner TJ, Barr J, Katsarava Z, Lainez JM,
Lampl C, Lantri-Minet M, Rastenyte D, Ruiz de la Torre E, Tassorelli C, Andre
C. The cost of headache disorders in Europe: the Eurolight project. Eur J Neurol
2012;19:70311.
[43] Lipton RB, Hamelsky SW, Dayno JM. What do patients with migraine want
from acute migraine treatment? Headache 2002;42:39.
[44] Martnez-Martn P, Raffaelli Jr E, Titus F, Despuig J, Fragoso YD, Dez-Tejedor E,
Liao H, Leira R, Cornet ME, van Toor BS, Cmara J, Peil H, Vix JM, Ortiz P P, Cooperative Study Group. Efcacy and safety of metamizol vs. acetylsalicylic acid
in patients with moderate episodic tension-type headache: a randomised,
double-blind, placebo- and active-controlled, multicentre study. Cephalalgia
2001;21:60410.
[45] Mehlisch DR, Weaver M, Fladung B. Ketoprofen, acetaminophen, and placebo
in the treatment of tension headache. Headache 1998;38:57989.
[46] Migliardi JR, Armellino JJ, Friedman M, Gillings DB, Beaver WT. Caffeine as an
analgesic adjuvant in tension headache. Clin Pharmacol Ther 1994;56:57686.
[47] Miller DS, Talbot CA, Simpson W, Korey A. A comparison of naproxen sodium,
acetaminophen and placebo in the treatment of muscle contraction headache.
Headache 1987;27:3926.
[48] Moore RA, Gavaghan D, Tramer MR, Collins SL, McQuay HJ. Size is everything
large amounts of information are needed to overcome random effects in
estimating direction and magnitude of treatment effects. PAIN 1998;78:20916.
[49] Moore RA, Moore OA, Derry S, Peloso PM, Gammaitoni AR, Wang H. Responder
analysis for pain relief and numbers needed to treat in a meta-analysis of
etoricoxib osteoarthritis trials: bridging a gap between clinical trials and
clinical practice. Ann Rheum Dis 2010;69:3749.
[50] Moore RA, Straube S, Aldington D. Pain measures and cut-offsno worse than
mild pain as a simple, universal outcome. Anaesthesia 2013;68:40012.
[51] Moore RA, Straube S, Eccleston C, Derry S, Aldington D, Wiffen P, Bell RF,
Hamunen K, Phillips C, McQuay H. Estimate at your peril: imputation methods
for patient withdrawal can bias efcacy outcomes in chronic pain trials using
responder analyses. PAIN 2012;153:2658.
[52] Morris JA, Gardner MJ. Calculating condence intervals for relative risk, odds
ratio and standardised ratios and rates. In: Gardner MJ, Altman DG editors.
Statistics with condencecondence intervals and statistical guidelines. BMJ
1995;5063.
[53] NCT01077973. Evaluation of the efcacy of a novel ibuprofen formulation in
the treatment of episodic tension-type headache. Available at: http://
www.clinicaltrials.gov/ct2/results?term=NCT01077973&Search=Search. Accessed
August 11, 2014.
[54] Nebe J, Heier M, Diener HC. Low-dose ibuprofen in self-medication of mild to
moderate headache: a comparison with acetylsalicylic acid and placebo.
Cephalalgia 1995;15:5315.
[55] NL9701. A randomised, double-blind, placebo-controlled, double-dummy,
parallel group comparison of commercial ibuprofen (single dose of 400 mg)
versus commercial paracetamol (single dose of 1000 mg) in patients with
tension type headache. Supplied by Reckitt Benckiser.
[56] NU2104. A double-blind, crossover, multicentre trial comparing S + ibuprofen
(S + Nurofen) with racemic ibuprofen (Nurofen) in the treatment of muscle
contraction (tension) headache. Supplied by Reckitt Benckiser.

06/01/2015

2228

R.A. Moore et al. / PAIN 155 (2014) 22202228

HA, Garcia B, Gaspari F, Gillum RF, Gmel G, Gosselin R, Grainger R, Groeger J,
Guillemin F, Gunnell D, Gupta R, Haagsma J, Hagan H, Halasa YA, Hall W,
Haring D, Haro JM, Harrison JE, Havmoeller R, Hay RJ, Higashi H, Hill C, Hoen B,
Hoffman H, Hotez PJ, Hoy D, Huang JJ, Ibeanusi SE, Jacobsen KH, James SL,
Jarvis D, Jasrasaria R, Jayaraman S, Johns N, Jonas JB, Karthikeyan G, Kassebaum
N, Kawakami N, Keren A, Khoo JP, King CH, Knowlton LM, Kobusingye O,
Koranteng A, Krishnamurthi R, Lalloo R, Laslett LL, Lathlean T, Leasher JL, Lee
YY, Leigh J, Lim SS, Limb E, Lin JK, Lipnick M, Lipshultz SE, Liu W, Loane M,
Ohno SL, Lyons R, Ma J, Mabweijano J, MacIntyre MF, Malekzadeh R, Mallinger
L, Manivannan S, Marcenes W, March L, Margolis DJ, Marks GB, Marks R,
Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM,
McGill N, McGrath J, Medina-Mora ME, Meltzer M, Mensah GA, Merriman TR,
Meyer AC, Miglioli V, Miller M, Miller TR, Mitchell PB, Mocumbi AO, Moftt TE,
Mokdad AA, Monasta L, Montico M, Moradi-Lakeh M, Moran A, Morawska L,
Mori R, Murdoch ME, Mwaniki MK, Naidoo K, Nair MN, Naldi L, Narayan KM,
Nelson PK, Nelson RG, Nevitt MC, Newton CR, Nolte S, Norman P, Norman R,
ODonnell M, OHanlon S, Olives C, Omer SB, Ortblad K, Osborne R, Ozgediz D,
Page A, Pahari B, Pandian JD, Rivero AP, Patten SB, Pearce N, Padilla RP,
PerezRuiz F, Perico N, Pesudovs K, Phillips D, Phillips MR, Pierce K, Pion S,
Polanczyk GV, Polinder S, Pope 3rd CA, Popova S, Porrini E, Pourmalek F, Prince

Co
pi

aa

ut

or

iza

da

po

rC

DR

M, Pullan RL, Ramaiah KD, Ranganathan D, Razavi H, Regan M, Rehm JT, Rein
DB, Remuzzi G, Richardson K, Rivara FP, Roberts T, Robinson C, De Len FR,
Ronfani L, Room R, Rosenfeld LC, Rushton L, Sacco RL, Saha S, Sampson U,
Sanchez-Riera L, Sanman E, Schwebel DC, Scott JG, Segui-Gomez M, Shahraz S,
Shepard DS, Shin H, Shivakoti R, Singh D, Singh GM, Singh JA, Singleton J, Sleet
DA, Sliwa K, Smith E, Smith JL, Stapelberg NJ, Steer A, Steiner T, Stolk WA,
Stovner LJ, Sudfeld C, Syed S, Tamburlini G, Tavakkoli M, Taylor HR, Taylor JA,
Taylor WJ, Thomas B, Thomson WM, Thurston GD, Tleyjeh IM, Tonelli M,
Towbin JA, Truelsen T, Tsilimbaris MK, Ubeda C, Undurraga EA, van der Werf
MJ, van Os J, Vavilala MS, Venketasubramanian N, Wang M, Wang W, Watt K,
Weatherall DJ, Weinstock MA, Weintraub R, Weisskopf MG, Weissman MM,
White RA, Whiteford H, Wiersma ST, Wilkinson JD, Williams HC, Williams SR,
Witt E, Wolfe F, Woolf AD, Wulf S, Yeh PH, Zaidi AK, Zheng ZJ, Zonies D, Lopez
AD, Murray CJ, AlMazroa MA, Memish ZA. Years lived with disability (YLDs) for
1160 sequelae of 289 diseases and injuries 19902010: a systematic analysis
for the Global Burden of Disease Study 2010. Lancet 2012;380:216396.
[82] Ward N, Whitney C, Avery D, Dunner D. The analgesic effects of caffeine in
headache. PAIN 1991;44:1515.
[83] Wood A, von Graffenried B. Fluproquazone: analgesic activity in outpatients
with non-migrainous headache. Arzneim-Forsch 1981;31:9147.

06/01/2015