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PAIN 155 (2014) 2220–2228

www.elsevier.com/locate/pain

Comprehensive review

Evidence for efficacy 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 Nuffield 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

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

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Keywords:
Efficacy
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 identified randomised, double-blind trials of oral drugs treating episodic TTH with
moderate or severe pain at baseline, or that tested drugs at first pain onset. The aims were to review
methods, quality, and outcomes reported (in particular the IHS-recommended primary efficacy parameter pain-free after 2 hours), and to assess efficacy by meta-analysis. We identified 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previous reviews and searches, 2 unpublished reports, and 1 clinical trial report with results.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% confidence 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 efficacy is small in comparison
to the size of the clinical problem.
Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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

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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) classification [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, defined as at
least 10 episodes of headache on 1 to 14 days per month for at least
⇑ Corresponding author. Address: Pain Research and Nuffield Division of
Anaesthetics, Nuffield 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 deficiencies
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 find 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/Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

06/01/2015

78]). Outcomes in clinical trials The IHS has provided guidance on clinical trials in TTH [2]. double-blind comparisons of any active oral therapy with any oral placebo. 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.4. This study sought to carry out meta-analyses. briefly:  Patients who are pain-free after 2 hours (recommended as primary efficacy 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. Migraine patients want pain to be significantly reduced. we estimated the result from the graph. and with a minimum of 10 patients per treatment arm. but is not easily explained or understood by professionals or headache sufferers. This study sought to review outcomes reported in randomised. Where possible we preferred to use data from individual trials. we used a modified risk of bias approach as suggested by the Cochrane Collaboration. EMBASE. quickly. better functioning. or changes in emphasis over time. it may present data from different trials separately or combine them. dealing with incomplete outcome data. and whether an appropriate dichotomous outcome was either reported or calculable.      Use of rescue medication Global evaluation of the efficacy of the medication Adverse events Patient preference Consistency of effect (in crossover trials) These suggestions are similar to. 2. NNT was calculated [7] using the pooled number of observations only when there was a statistically significant difference of relative benefit or risk. Longerduration outcomes are not important for episodic TTH because the headache will resolve spontaneously. In addition. We obtained copies of all of the studies included in previous systematic reviews (principally [27. This document specifies what outcomes could be reported in drug trials dealing with the acute treatment of TTH. and treatment group size (Appendix 2). also uses early outcomes because these headaches usually resolve naturally in about an hour [41]. although not in any way comparable with TTH. blinding. and data extraction was done independently by 2 authors and checked by a third. allocation concealment. Efficacy calculations There was no prior intention to perform a meta-analysis of treatment efficacy because consistently reported outcomes for the same treatment were expected in no more than a few trials. double-blind trials of treatments for acute episodic TTH. 2. These additional outcomes are similar to the reporting of outcomes seen in Cochrane Reviews of acute treatments for migraine [40]. Searching Quality was assessed in 2 ways. and ideally without adverse effects [43]. Methods All searching. searched clinicaltrials. trial selection. using the criteria of appropriateness of method of randomisation. for example. Firstly. a 5-point scale based on reporting of randomisation. The exception was studies deliberately testing drugs at first onset of headache pain. 2014. and improved ability to work [50]. We examined each trial or report for a defined primary outcome matching one specified by the IHS guidance.gov for any ongoing trials with results. If it was available in graphic form. without recurrence. Relative benefit or risk was calculated using a fixed effect model [52] with no statistically significant difference between treatments assumed when the 95% confidence intervals included unity. as were those in which the occurrence of at least moderate pain could not be demonstrated. such as reduced depression. and Cochrane Central (Appendix 1). 06/01/2015 . using PubMed. 2. A systematic review of patients’ views indicated that the evidence we have is that a low pain state. 3. if possible. The pain intensity difference (PID) over 2 hours may demonstrate an analgesic effect. requested clinical trial reports of unpublished studies in TTH from Reckitt Benckiser. higher quality of life. iza 2.Ò 2221 R. improved sleep. and recommended as the primary efficacy parameter by the IHS. These are. we used the Oxford Quality Scale.5. If there were sufficient data (defined as at least 2 trials and 200 patients [48]). and to establish which report useful patient-centred outcomes. Inclusion criteria Co pi aa ut or Included trials had to be randomised. we calculated risk ratio and NNT with 95% confidence intervals. and/or another active therapy. is consistently rated highly by patients in clinical trials when validated against other outcomes. no worse than mild pain. studies enrolling patients with only mild pain were excluded. important. Secondly.3. and withdrawal and dropouts [32]. 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. A report may have data on one or more trials. The word trial is used to indicate a specific clinical trial. if a little different from. / PAIN 155 (2014) 2220–2228 2. Terminology We use the word report to indicate a published or unpublished document that contains information on one or more clinical trials. and examined bibliographies of trials and reviews for additional studies. to assess the evidence for efficacy of oral analgesic drugs in treating acute episodic TTH using patient-centred outcomes. Headache pain generally had to be moderate or severe. and easily explainable. the percentage of patients pain-free 2 hours after taking a medicine is understandable. The differences may reflect the different conditions. but in some cases this was not possible and aggregated data were then used if presented. each trial or report was examined to see whether each of the 11 outcomes was measured. blinding.6.2. cluster headache. but they may not have been reported. 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.1. performed electronic searches of the literature to January 31. 2. or our additional outcomes. Moore et al. DR 2. and outcomes were not used because the outcomes reported were the subject of specific study.A. Here a patient-centred outcome is defined as one important to patients. the guidance on outcomes for treatment of acute migraine [31]. Study duration was not included because it is inappropriate for acute treatments. in adults or children.

79. 34 had a placebo control.65]. [20] allowed headache frequency to be up to 20/month (median 6/month) and Langemark et al.gov (Appendix 3). These 55 trials involved 12. da 3. 1): they were in chronic TTH [3. All had a minimum duration for headache occurrence. The overall average trial size (of 55) was 225 patients. Others did not. 55 from searches and previous reviews.16. and those with IHS definitions usually used <15/month.56]. Von Graffenried et al.35–37. rectal administration [26]. There were 40 included reports [6. and 22 involved fewer than 100 (9% of the total). there was insufficient detail to report on them separately.66–69. and 1 clinical trial report with results from clinicaltrials. other reports provided some definition or diagnosis of tension or muscle contraction headache. and Sargent 1988 [66] reported mean headache frequency of 17/month (although the inclusion criteria stated recurrent severe headache 4 to 12/month). Gilbert et al. Göbel et al.13. [24] reported 2 trials in sufficient detail for each to be regarded as a separate trial.53. Co pi aa ut or iza Of the 40 reports. Göbel et al. 2 unpublished reports from Reckitt Benckiser [55. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart for the review.78] and updated searches (to January 2014). [37] up to 30/month (mean 15/month).71].64.70].17–25. were excluded for various reasons (Fig. We were able to analyse methods and results from 40 published reports that involved 55 randomised trials. Fig. Many studies had an upper limit on the number of headaches per month. Patients and trials by decade.82. 58 reports were identified.Ò 2222 R.11. Migliardi et al. Sixteen reports.22. Copies of 2 other publications (45 patients in total) could not be obtained [58.59–61. together with the median size of the trials in each decade.76]. 06/01/2015 . Fig.21.A. Moore et al. An additional 6 trials without results were identified on clinicaltrials. [25] reported a mean frequency of 14/month.74–77.1. some of whom would have participated in crossover studies and had several headaches treated.36. All but 2 involved patients with moderate or severe pain.54. Twenty-eight had a parallel design.28]. 84% of patients had migraine [14]. Searching po rC 31 trials involved fewer than 200 patients (18% of the total).30. not randomised and double-blind [5. An IHS definition was used in 17 of 38 reports. 2 involved treatment at onset of attack [64. 1. Four reports included more than 1 trial.30. duplicate publication [38. [79] reported on 8 studies with similar methods. but reported on combined results. or not full publications [1].33. including some included in previous reviews. which can reduce sensitivity [12. The 23 largest trials involved 82% of the patients. The trials used different criteria to classify TTH. and the Ad Hoc Committee definition in 6 of 38. Results 3. The number of headaches per month allowed in the trials was varied and not always reported.15. with a median of 144. Fig.39.80].55–57. 2 shows the numbers of patients involved in each decade since 1970. [46] reported on 6 studies with similar methods. without initial pain of at least moderate intensity.2.83]. whereas 6 used an active comparator only [6. 2. and Wood et al.143 patients.56]. actual headache frequency in 7 reports that provided this information was 5 to 17 per month. 44–47. with migraine excluded. Characteristics of included trials DR Using previous systematic reviews [27.gov [53]. For example. / PAIN 155 (2014) 2220–2228 3. [83] reported on 3 studies with similar methods.8.

Trials used both parallel and crossover designs. As many as 22 other individual drugs and combinations also were tested. and presented it [75]. po The details of the trials are in Appendix 4. 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. for the IHS-preferred outcome of pain-free at 2 hours. 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). Table 2 shows the number of trials or reports in which any of the 11 outcomes was measured or reported. By contrast. There was little difference among the drugs. and to estimate the efficacy of treatments if at all possible. Quality scoring performed using the Oxford Quality Scale [32] demonstrated that 2 studies scored 2 of 5 points. and inconsistent reporting of different outcomes. 12 scored 3 of 5. 4. It was possible to pool data from trials for some drugs (paracetamol 1000 mg. 3–5. ketoprofen 25 mg. and although 39 of 41 reports or trials scored 3 of 5 or more on the Oxford Quality Scale.3. consistency of effect in crossover trials was not mentioned in any trial. aspirin 650 to 1000 mg (12 arms). not individual trial. at about 9.143 patients. and intermediate (20% to 50% with placebo) for patient global assessment taking the top 2 categories of the scales used (mainly very good/excellent. The reasons were different categorical pain intensity scales (with 4 or 5 points on the scale. and global assessment. respectively. Adverse events were most frequently reported. 3.5.Ò 2223 R. and some reports of multiple trials with similar methods are scored by report. and reporting of PID over different time intervals (2. Although PID was the most reported outcome. double-blind trials of oral analgesics for the acute treatment of episodic TTH. and 6 hours). Appendix 5). Discussion The systematic review process sought to find randomised. plus fast-acting formulations in 2 arms). 3.A. pain-free after 2 hours. typically 2 to 6 hours (Appendix 6). although 1 other planned to use total or meaningful pain relief at 2 hours (Appendix 3). few small studies on a large variety of different drugs. mostly in terms of the absence of serious adverse events or adverse event discontinuations. Other measures used were muscle soreness. In terms of risk of bias. 16 scored 4 of 5. poor trial quality. 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 identified outcomes of importance to patients with tension-type headache. None of the trials used for these calculations used patients who may have had chronic TTH. and NNTs were high.gov clearly mentioned being pain-free at 2 hours as the primary outcome. / PAIN 155 (2014) 2220–2228 The drugs most frequently tested were paracetamol 500 to 1000 mg (19 arms). ibuprofen 400 mg. 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. 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 efficacy 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 . Risk of bias indication Co pi Table 1 Risk of bias on 5 criteria suggested by pain. and risk ratio and NNTs calculated by pooling. and some measure of usual activity or impairment. the mean event rates. only 17 were without at least 1 red flag for possible risk of bias. and 11 scored 5 of 5. We were unable to use PID for calculations of efficacy. Reporting of trials was such as to provide an unclear risk of bias for most assessments. Only 1 of 6 recent trials without results found in clinicaltrials. or good/very good). although a high risk of bias was generated in a significant number of trials for incomplete outcome assessment and because of small size (Table 1. rC 3. Only 1 trial declared the outcome of pain-free at 2 hours to be the primary outcome in the trial. Outcomes reported Dichotomous data were available in reasonable amounts for 3 outcomes. 41 reports or trials could be scored individually. and naproxen 275 to 550 mg (4 arms). Table 3 shows the amount of data available for pooling. We found 40 publications reporting results of 55 trials involving 12. The figures show very considerable inconsistencies among trials. 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). ibuprofen 200 to 400 mg (11 arms. Factors combining to detract from a consistent or meaningful estimation of efficacy included variable trial design. only for blinding were the majority of trials likely to have a low risk of bias. Efficacy calculations 3. In all cases. and supportive care review group of the Cochrane Collaboration.4. mild or no pain after 2 hours. but only sporadically. the variability in its reporting precluded any sensible analysis. The percentage of patients achieving the outcome is shown in each treatment arm for each therapy tested in Figs. ketoprofen 25 to 50 mg (5 arms). and aspirin 1000 mg) for some of these 3 outcomes. for example). Moore et al. to evaluate their methodological strengths and weaknesses. Quality of included trials aa ut or DR iza da All studies measured pain intensity or pain relief over various times. palliative.

Therefore. and global evaluations are less direct and often are more difficult to explain. An additional problem was whether all of the trials were conducted in what would today be regarded as frequent episodic TTH. especially given the somewhat inadequate and contradictory descriptions provided in the trials. The ideal outcome would combine sensitivity to discriminate between different degrees of efficacy with relevance both to clinical practice and to people with tension headache. rC Fig. and the cut off at 15 days/month is somewhat arbitrary.Ò R. Co pi aa ut or iza da po This is of importance in 2 ways. The clinical point is that treatments for acute headache will usually be an incorrect approach for chronic TTH. incomplete outcome data reporting. Size of trial arm is proportional to the size of the symbol (inset scale). of course. Most reported a minimum frequency for inclusion that would satisfy current IHS criteria. but a small number had upper limits above 15/month. although none of the trials with a potential for this provided any data in the pooled analyses. There is empirical evidence that what patients desire in most pain conditions is fast and effective relief [50]. however. We also looked for trials reporting the same outcome after 1 hour because it is faster. we concentrated on outcomes regarded as important by the most recent IHS guidance [2]. which did not allow us to perform any pooled analysis of like with like. 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. Drugs with dose in milligrams. Most efficacy outcomes were reported infrequently. random chance plays a large effect [48]. because although mild or no pain is a less complete response. this is a reflection of the fact that most of the studies predate the 2010 guidance. preference. 06/01/2015 . The IHSpreferred outcome of being pain-free 2 hours after dosing captures that. who often self-medicate. it is not clear how much these potential sources of bias might influence results in headache or acute pain trials.A. Moore et al. and for the outcome of mild or no pain at 1 and 2 hours. PID.51]. 4. 3. Inclusion of patients with more frequent headaches could lead to a lower estimation of efficacy. Size of trial arm is proportional to the size of the symbol (inset scale). Although these are problematic in chronic pain [49. Size of trial arm is proportional to the size of the symbol (inset scale). over half of the available data may be subject to bias that overestimates treatment effects. With small numbers of trials and patients. Potentially. together with 3 additional early outcomes of pain-free at 1 hour or mild or no pain at 1 or 2 hours to capture benefits that patients desire early after dosing. The most commonly reported efficacy outcome of pain Fig. PID outcomes also used different scales and reported over different time periods. Drugs with dose in milligrams. 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. it might well be valuable for other patients. 5. Percentage of patients with no or mild pain at 2 hours in individual treatment arms. In this analysis. but even then there was a lack of consistency in reporting. it is not the case that including some patients with headaches on more than 15 days/month will invalidate the results. / PAIN 155 (2014) 2220–2228 DR 2224 Fig. On the basis of information provided by the reports. Episodic and chronic TTH are not entities that can necessarily be clearly separated. More difficult is the issue of the disparate outcomes measured and reported. Drugs with dose in milligrams. Percentage of patients with pain-free outcome at 2 hours in individual treatment arms. Percentage of patients with top 2 categories on any global assessment in individual treatment arms. it seems that most patients fulfilled current criteria of frequent episodic TTH. but some might today be classified as chronic TTH. In part.

7 for 2-hour pain-free and mild or no pain outcomes. 3.2 to to to to 1. is difficult to translate into immediately interpretable results for patients or professionals. There is no solid evidence that any one outcome is better than the others.3 to 13) Migraine. and statistical significance and NNTs for drug compared with placebo.4 6.2 (1. aa ut Data for migraine taken from Derry et al.7) 1.2) TTH.5 (3. Co pi intensity difference over 2 hours (18 of 41).7 (6.9 to 18) 9. investigated different drugs and doses rather than lumping together all NSAIDs at any dose. Only for paracetamol 1000 mg. [10] (paracetamol) and Rabbie et al. 06/01/2015 .3 1.gov suffer from much the same problems.7 (6.6 1. Disappointingly. Percent with outcome with rC Number NNT(95% CI) Patients or attacks Active drug Placebo TTH. but not proven. naproxen.02 to 2. For self-medication of TTH.2 to 2. although the current review was much more stringent. Moore et al.2 to 15) 8.4 1.8. It is likely.3 (1. so more insight into the efficacy of drugs in TTH is unlikely in the near future unless new trials are designed and conducted.6) 1121 774 592 397 46 40 51 56 35 24 36 37 1. This was principally because of inadequate outcome reporting.gov (Appendix 3). and ketoprofen 25 mg can we be confident that the drug is more effective than placebo using the IHS-preferred efficacy parameter of pain-free rates after 2 hours. 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 1.3 (1.5) 2. pain-free at 2 h Paracetamol 1000 Ibuprofen 400 3 6 717 2575 19 26 10 12 12 (7.5 (1.4) 1.8.5 (5.A.8 (2.2) 7.9 to 18) Migraine. that aspirin.6 (1.2 (1. and included only 7 trials that included at least some TTH patients. ibuprofen 400 mg. It was not possible to judge whether different outcomes influenced estimates of efficacy. it recommended as first-line therapy the fixed-dose combination of acetaminophen.1 to 1.2 to 15) 8.0 (3.7 (4. mild or no pain at 2 h Paracetamol 1000 Ibuprofen 400 4 No data 1127 64 51 7. and 6. The German evidence-based recommendations for self-medication of migraine and TTH were based on systematic reviews [27]. by contrast. For ketoprofen 25 mg.3 (4. / PAIN 155 (2014) 2220–2228 Table 3 Data available for pooling for various outcomes. NNT = number needed to treat.5 to 8.7 to 6. These results are broadly in agreement with a previous review [78] that concluded that paracetamol and nonsteroidal antiinflammatory drugs (NSAIDs) were better than placebo.3 to 13) 3.6 (1. Few trials conformed to IHS guidance on the conduct of trials in episodic TTH [2]. There is no conclusive evidence that any one of these is likely to be better than any other. Trials included in this review were both randomised and double-blind. NNT values for all 3 drugs were high. Many other trials were not included because they failed to meet these minimum requirements.5 (5.5 8. One consequence of these deficiencies was that few trials provided useful information about the efficacy of drug therapies for the acute treatment of episodic TTH. and included over 1500 patients from newer trials.2 (2.7 to 7. although based on small numbers. analysis at the level of the individual patient would be the ideal way of testing different outcomes for both sensitivity and effect size.1 6.8 (5.6) 8.7) 1. which recommends ibuprofen as the drug of choice among NSAIDs or paracetamol or aspirin for acute treatment of TTH. the same 3 outcomes produced diverging values: 9.5 to 32) 7.Ò 2225 R. It was notable that the situation was not markedly better in the more recent trials registered in clinicaltrials.2 Global assessment by patient (top 2 categories) Paracetamol 1000 5 Ibuprofen 400 3 Ketoprofen 25 3 Aspirin 1000 2 (1.2 (5.2 to 1. Paracetamol 1000 mg produced similar NNT values of 7.8 to 3. but also because of lack of a placebo control. Both reviews included similar trials.3 to 2.0) 1.7) 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.9 (5. and new.5 to to to to 16) 10) 15) 10) CI = confidence interval. mild or no pain at 2 h Paracetamol 1000 Ibuprofen 400 3 7 717 1815 56 57 36 25 5.0) 1.9 (5.9 5. with generally acceptable risk of bias. but the magnitude of effect cannot be estimated on current data.1 to 146) Mild or no pain at 2 h Paracetamol 1000 Ketoprofen 25 4 2 1127 285 64 65 51 38 1.9) (5. ongoing trials found in clinicaltrials. and for the top 2 categories of global assessment (Table 3). However. pain-free at 2 h Paracetamol 1000 Ibuprofen 400 5 3 1387 826 34 29 22 18 8. [63] (ibuprofen).7 (1.9.7) 3. Some of these are not supported by any significant data. acetylsalicylic acid. this guideline was not based on a systematic review. Our results are also largely in agreement with the guideline from the European Federation of Neurological Societies [4]. and diclofenac in doses typically used are also more effective than placebo. and caffeine or the fixed combination of acetaminophen and caffeine as well as monotherapy with ibuprofen or acetylsalicylic acid or diclofenac. better research would be needed to determine this.9 to 9.

Sackett DL. Eur J Neurol 2005.72. Clin Ther 1986. Treatment of muscle contraction headache: micrainin vs. paracetamol and placebo in the treatment of episodic tension-type headache. [20] Gilbert MM. Effectiveness of Oleum menthae piperitae and paracetamol in therapy of headache of the tension type [German]. R. Proquazone for tension headache— a multicenter trial. NNT values for all 3 drugs were high.1. A double-blind study of zomepirac sodium and placebo in the treatment of muscle contraction headache. Wessely P. Tfelt-Hansen P.28:904–15. In this circumstance. there are no trials other than those in this review. Boyles WF. parallel group. Ibuprofen versus aspirin and placebo in the treatment of muscle contraction headache.25:127–33. Cochrane Database Syst Rev 2010. and R. single-dose.08.A. Moore et al. Fresenius J.32:314. sumatriptan. Voelker M.17:1318–25. Mitsikostas DD. Soyka JP. S.D. and has been a consultant to Reckitt Benckiser and has been on Reckitt Benckiser speaker panels.J.M.000 patients. Pollack M. [3] Bendtsen L. randomized. and Dr.A. Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults. Ford RG. Symptomatic treatment of chronically recurring tension headache: a placebo-controlled. Sheftell FD.34. Ashina S. Dworschak M. Headache 1981. [22] Glassman JM. Cerbo R. Cochrane Database Syst Rev 2014.4:74–8. BMJ 1995. and P.S. it would be reasonable to expect a greater degree of research interest in early-onset analgesics producing faster and better pain relief. Assessment of Fiorinal with codeine in the treatment of tension headache.16:117–23. performed data extraction. Zavaleta C. Pageler L.12:759–67. Friedman AP.62. DiSerio FJ. Buchgreitz L. is that for migraine there is a very large body of evidence on other drugs. Jensen R. [17] Friedman AP. Parno J.63]. Moore RA.73]. Moore RA. Centonze V.67:672–81. Heinze A.M. in the online version. May A. Linde M. all unrelated to this project. Rapoport A. Headache 1982. Z Allg Med 1998. and Reckitt Benckiser provided an unrestricted educational grant to Oxford Medical Knowledge to help fund it. Nervenarzt 1996. Z Allg Med 2001. Diener HC. Clin Ther 1987. Tavolato B. Meyer C. is the owner of Oxford Medical Knowledge. the Deutsche Gesellschaft für Neurologie (DGN). [11] Diamond S.25:776–87. Trenti T.34:138–48. however. and caffeine in the treatment of episodic tension-type headache: a double-blind. Smakman JG. Ritanserin is not effective in tension headache.310:452–4. European Headache Alliance & Migraine Association of Ireland. Acknowledgements Co pi aa ut or We thank Mrs. EFNS guideline on the treatment of tension-type headache—report of an EFNS task force. Stolze H. wrote the original draft. Cephalalgia 1996. Audrey Craven. Clin Ther 1988. [6] Cerbo R. Essential oils in the therapy of tension headache [German]. Ketoprofen. prochlorperazine. randomised. S. Medina JL.21:45–8.. nimesulide-controlled. or decisions on whether or where to publish.W. and P. and all authors contributed to the development of interim and final drafts. J Int Med Res 1976. Heinze A.5:CD009108. Sandrini G. President of the European Federation of Neurological Associations. [12] Diamond S. had previously participated in a grant from Reckitt Benckiser.12: 201–17.A. such as triptans. DMKG. Sumatriptan (all routes of administration) for acute migraine attacks in adults—overview of Cochrane Reviews. [24] Göbel H. Heinze-Kuhn. [14] Diener HC. Soyka D.Ò 2226 R. [27] Haag G.A. Ibuprofen plus caffeine in the treatment of tension-type headache. double-blind. The evidence available for treatment efficacy in episodic TTH is trivial in comparison to the size of the clinical problem. McQuay HJ. Combination of low-dose mirtazapine and ibuprofen for prophylaxis of chronic tension-type headache. International Headache Society Clinical Trials Subcommittee. Headache 1992. It is true that evidence about commonly available drugs such as paracetamol. Aicher B. Cephalalgia 2010.W. SKG. Garagiola U. Lampl C. / PAIN 155 (2014) 2220–2228 The lack of evidence on drug treatments of TTH is in contrast to that for migraine: for just one drug. and ibuprofen also is limited in migraine [10. Elkind AH. has been a consultant to Reckitt Benckiser and has been on Reckitt Benckiser speaker panels. Steiner TJ. and acted as a paid consultant to Oxford Medical Knowledge. DGN. S. 06/01/2015 . for providing a patient perspective. Schecter C. Cephalalgia 2005. Soyka JP. Morck H. [1] Ansink BJ.2014. [21] Glassman JM.A.11:CD008040. [26] Guidotti M. Curr Ther Res 1976. Clin Ther 2012. interference with work when present. Heinze A. The fixed combination of acetylsalicylic acid. Headache 1985. Derry S. Singer JM. Table 4 compares the available information and efficacy results for paracetamol 1000 mg and ibuprofen 400 mg for 2-hour outcomes.14:187–93. Guidelines for controlled trials of drugs in tension-type headache: second edition. Schoenen J. [13] Diamond S. J Headache Pain 2011.74:223–8. [18] Friedman AP. Headache 1983. Eur J Neurol 2010. [8] Dahlöf CG. [4] Bendtsen L. [23] Göbel H. Self-medication of migraine and tension-type headache: summary of the evidence-based recommendations of the Deutsche Migräne und Kopfschmerzgesellschaft (DMKG). References DR rC iza da po 4.M. [7] Cook D. aspirin. [9] Derry C. All authors read and approved the final manuscript. Assessment of the efficacy and safety profiles of aspirin and acetaminophen with codeine: results from 2 randomized.77:287–95. paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre. Hartman JW.22:101–9. Reviewers also made perceptive and welcome comments on the manuscript. Where available. [16] Friedman AP. Grazioli I. J Int Med Res 1989.M. Clin Pharmacol Ther 2000. Fiorinal with codeine in the treatment of tension headache—the contribution of components to the combination drug. acted as paid consultants to the project. Holroyd K. Efficacy of a fixed combination of indomethacin. ibuprofen 400 mg.23:206–10. Conclusions Paracetamol 1000 mg. design. Freitag FG. and developed data extraction criteria for outcomes. Evers S.68:312–9. [10] Derry S. controlled trials in individuals with tension-type headache and postoperative dental pain. conduct. Evers S. multicenter investigation of Fioricet and acetaminophen with codeine.M. at http://dx. Sternieri E.000 patients in trials examining 18 drug/dose/route of administration combinations [9]. OKSG. Richards BA. a Cochrane overview found information on over 50. Supplementary data Supplementary data associated with this article can be found. Uslenghi C. For TTH. Study of a new analgesic compound in the treatment of tension headache.8:703–21. The Oxford Pain Relief Trust provided institutional support for the work. and impact on activities of daily living have important economic consequences [42. The IHS guidance on clinical trials provides an intellectual underpinning for such research. The number needed to treat: a clinically useful measure of treatment effect. All authors were involved in defining the broad aims and objectives.B. [5] Borges J.D. Hobbs D.30:1–16. or writing of the work.17:48–54.pain. and ketoprofen 25 mg are more effective than placebo using the IHS-preferred outcome measure of pain-free rates after 2 hours. multicentre trial.10:69–81.org/10. Curr Ther Res 1980. Appendix A. Peil H. [2] Bendtsen L. Muscle contraction (tension) headache: a double-blind study comparing the efficacy and safety of meprobamate-aspirin with butalbital-aspirin-phenacetin-caffeine. Lurch A. L. [25] Göbel H. R. R. received a lecture fee from Oxford Medical Knowledge.1016/j. Mairead McIntyre of the West Hoe Surgery in Plymouth for providing a general practice perspective on outcomes. Analgesic efficacy and tolerability of locally applied Oleum menthae piperitae preparation LI 170 in patients with migraine or tension-type headache [German]. placebo-controlled parallel group study.20:53–8. Mitsikostas DD.. A major difference from the migraine literature. Headache is important because work loss.009. Balm TK. de Sola Pool N.10:303–15. Pfaffenrath V. developed the original concept for the study. Fisher M. Jacobs LD. the Österreichische Kopfschmerzgesellschaft (ÖKSG) and the Schweizerische Kopfwehgesellschaft (SKG). performed data analyses. R. [19] Gatoulis SG. analysis. Diener HC. Funding sources had no role in the concept.A. Eur J Neurol 2007. [15] DiSerio FJ.doi. Fillingim J. Analgesic/calmative effects of acetaminophen and phenyltoloxamine in treatment of simple nervous tension accompanied by headache. Straube A. Dworschak M. which runs to several hundred trials and involving perhaps 100. Pirprofen in the treatment of migraine and episodic headache attacks: a placebo-controlled crossover clinical trial. aspirin. Bigal ME. Zanasi S. Dworschak M. Gallagher RM. results are rather similar.

Brown A. [53] NCT01077973. Lost workdays and decreased work effectiveness associated with headache in the workplace. Work attendance despite headache and its economic impact: a comparison between two workplaces. Gabbe BJ. J Clin Pharmacol 1996. Edmond K. Comparison of 650 mg aspirin and 1. [54] Nebe J. cross-over study versus placebo and naproxen sodium. Headache as a model for assessing mild analgesic drugs. Di Loreto G. Delossantos A. Ear Nose Throat J 1979. May LG. Gavaghan DJ. Moore RA. De Leo D. Gardner MJ. [41] Law S. Ryan Jr RE. Driscoll T. Solbach P. Cephalalgia 1998. Brooks P. Statistics with confidence—confidence intervals and statistical guidelines. Moore et al. Dahodwala N. Prudenzano MP. Koronkiewicz K. Carabin H. Bin Abdulhak A. Aspirin in episodic tension-type headache: placebo-controlled dose-ranging comparison with paracetamol. Jayawardena S. A double-blind. Fèvre EM. ibuprofen and naproxen sodium in the treatment of tension-type headache. [30] Hirata K.Ò 2227 R. Derry S. Igarashi H. Headache 1987. Bowen DL. J Headache Pain 2013. Multi-center randomised control trial of etizolam plus NSAID combination for tension-type headache. Bernabé E. Dellavalle R. ibuprofen or placebo.5:709–13. Headache 2003. Cooper LT.25:216. Intern Med 2007. Erskine H. Gillings DB. Burney P. Ali MK. Derry S. Barrero LH. Moore RA. Ganatra Co pi aa ut or iza da [28] Hakkarainen H. [51] Moore RA. [35] Kubitzek F. Bartels DH.11:22–6. Diaz-Torne C. [50] Moore RA.7:155–62. Buchbinder R. [47] Miller DS. Headache 1977. Blencowe H. Lozano R. [77] van Gerven JM. Raulli P. Burch M. Ziegler G. Cochrane Database Syst Rev 2010. Hoedemaker HG. Ann Rheum Dis 2010.10:225S–31S. Colson KE. Randerson D. Ibuprofen with or without an antiemetic for acute migraine headaches in adults. Comparison ketoprofen. Canter CE. Abraham J. [70] Schattner P. double-blind. placebo. Bonaventure A. Chen H. Ackerman I. A controlled study of short-term treatment of tension headache. Ashraf E. Cascio IN. Dolk H. [63] Rabbie R.5:152–3. Aldington D. Denenberg J. Arrostuto A.27:392–6. Weaver M. Titus F. Derry S.20:131–44. Sumatriptan plus naproxen for acute migraine attacks in adults. Farzadfar F. Confin Cephalalgica 1994. [66] Sargent JD. van Toor BS. Steiner TJ. Anderson LM. Cephalalgia 2000. Erwin PJ. Nabumetone versus placebo in episodic tension headache. LaPegna G. Gavaghan D. Baxter A. Simpson W. Gold MS. Gustavsson A. Clin Pharmacol Ther 1991. home-monitored with an electronic patient diary. Cochrane Database Syst Rev 2013. Tiger Balm as a treatment of tension headache. Shibata K. Bhandari B. Carapetis J. Gakidou E. Furey SA. Stovner LJ. 3rd edition (beta version). Goldstein J. Burstein R. Cephalalgia 2003. A comparison of naproxen sodium. placebo-controlled trial. Barker-Collo S. Andrée C. Aldington D. Reints A. Gammaitoni AR.16:280–3. Jenkinson C. Accessed August 11. Zanchin G. [74] Steiner TJ. Takeshima T. Aggarwal R. Araki N. [38] Langemark M. acetaminophen and placebo in the treatment of muscle contraction headache.7:CD008042.55:1064–72. Ferri CP. double-blind. Dahiya M. Lainez JM. Headache pain model for assessing and comparing the efficacy of over-the-counter analgesic agents. Efficacy and safety of metamizol vs. Motrin—a new agent for the symptomatic treatment of muscle contraction headache. A clinical trial in general practice.43:1097–101. Talbot CA. Br J Clin Pharmacol 1980. Am J Med 1983. 218. Finucane MM. Leira R. Dayno JM. Riederer F. Campbell B. Andrews KG. placebo controlled cross-over study. McQuay H. Korey A. Szucs T. Packman E. Derrett S. Ortiz P P.46:467–72. Fladung B.15:531–5. Cella C. Flaxman AD. Calculating confidence intervals for relative risk. Bahalim AN. Cephalalgia 1985.40:561–7. Liaño H. Hamelsky SW.22:740–8. Cámara J.68:400–12. J Clin Pharmacol 1980. [79] von Graffenried B. Cornet ME. Thoden WR. Connor MD. Ouwersloot-van der Meij MJ. disability. [52] Morris JA. Bolliger I. Raffaelli Jr E. Cooperative Study Group. Schoemaker RC. Dabhadkar KC.19:703–11. Couser W. odds ratio and standardised ratios and rates. Franklin R. Pain measures and cut-offs—‘no worse than mild pain’ as a simple. Danaei G. J Occup Environ Med 1997. Self-medication of a single headache episode with ketoprofen. crossover. Collins SL. [62] Raak R. Liu JM. [46] Migliardi JR. Ahn SY. [78] Verhagen AP. [44] Martínez-Martín P. Shibuya K. Bridgett L. Triptans for acute cluster headache. Low-dose diclofenac potassium in the treatment of episodic tension-type headache. Davis A. Cross M. Cowie BC. Coffeng LE. Despuig J. [59] Peters BH. Lipton RB. Ketoprofen (25 mg) in the symptomatic treatment of episodic tension-type headache: double-blind placebo-controlled comparison with acetaminophen (1000 mg). Moore RA. Supplied by Reckitt Benckiser. Tramer MR.10:CD008541. Fransen M. Eur J Neurol 2012. [72] Schwartz BS.3:19–22.42:3–9. 220. Merlijn V. Berger MY. Ezzati M. Cooper KM. [60] Pini LA. Sarchielli P. Espindola P. McQuay HJ. Anderson HR. and placebo in the treatment of tension headache. [68] Schachtel BP. Felson DT. Cortinovis M. Diener HC. A double blind. and safety of a novel formulation in the treatment of episodic tension-type headache. placebo-controlled. Moore OA. relief.33:629–808. and with placebo in moderately severe headache. Ferrari A. [76] Thorpe P. acetaminophen. Lange R. [81] Vos T. Comparative efficacy of ibuprofen arginine and betacyclodextrin piroxicam as treatment for tensiontype headache. Headache 1988. Buckle G. Cochrane Database Syst Rev 2013. Tatsumoto M. double-dummy. [33] Kagan G. Di Trapani G. Duber H. Des Jarlais DC. [43] Lipton RB. Cochrane Database Syst Rev 2010. Nüesch E. Supplied by Reckitt Benckiser. Brayne C. Naproxen sodium for muscle contraction headache treatment. Criqui MH. Altman DG editors. [32] Jadad AR. Thoden WR. Peloso PM.39:320–7.4:CD008041. Cephalalgia 2002. Boufous S. Aust Fam Physician 1996. Eccleston C.14:29. Forouzanfar MH.10:CD008039. A randomised. Colquhoun S. Cephalalgia 1995. Del Bene E. [39] Laveneziana D. multicentre study.42:475–81. Guidelines for controlled trials of drugs in migraine: second edition. Benjamin EJ.74:36–42. Armellino JJ. [55] NL9701. Cooper S. Brooker S. Phillips C. Headache 1988. Controlled and uncontrolled studies on ‘‘Fiorinal-PA’’ for symptomatic relief in tension headache. Damsere-Derry J. Moore RA. Caffeine as an analgesic adjuvant in tension headache. BMJ 1995. Jacobs LD. [40] Law S. [56] NU2104. Self-reported headache among the employees of a Swiss university hospital: prevalence. A double-blind. multicentre trial comparing S + ibuprofen (S + Nurofen) with racemic ibuprofen (Nurofen) in the treatment of muscle contraction (tension) headache. PAINÒ 2012. Is anyone analgesic superior for episodic tension-type headache? J Fam Pract 2006. Peil H. Dherani M. Fluphenazine for tension headache. Straube S. A randomised. [75] Steiner TJ. Lentz R. Dorsey ER. 06/01/2015 . Drugs Exp Clin Res 1995. Nonprescription ibuprofen and acetaminophen in the treatment of tension-type headache. Lange R. [64] Ryan Sr RE. Anaesthesia 2013. Calabria B. Colan SD. The international classification of headache disorders. Moore RA. Med Proc 1971:359–68. Available at: http:// www. Fragoso YD. Nüesch E. Wang H. Br J Clin Pharmacol 1996. Hamunen K. Bhalla K. Tolerability and efficacy of a combination of paracetamol and caffeine in the treatment of tension-type headache: a randomised. double-blind. Clin Drug Invest 1996.9:367–73. Flaxman S.28:471–4. PAINÒ 1998. Derry S. Carmona L. Solubilized ibuprofen: evaluation of onset. Sándor PS. Konerman JP. Beaver WT. Bennett D. [73] Sokolovic E. Headache 1987. Black JA. Evaluation of the efficacy of a novel ibuprofen formulation in the treatment of episodic tension-type headache. Ebel B. Bourne R. Masheter HC. Blore JD. Cephalalgia 2001. Cohen AF. Derry S.50:322–9. Speranza R. Lampl C. Degenhardt L. Chugh SS. Headache 1977. Chou D.21:604–10.2:180–1. de Vaccaro KC. Rastenyte D. Madison DS. [48] Moore RA. Cheng AT. Corrao S. Heier M. universal outcome. Paredi G.58:423–6.21:89–96. Díez-Tejedor E. Granella F. J Headache Pain 2008. Naghavi M.27:90–5.17:216–8. Martino S. [61] Prior MJ.78:209–16. Reynolds DJ. Aboyans V. 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. The cost of headache disorders in Europe: the Eurolight project. Baddour LM.28:180–2. Hill RC. [31] International Headache Society Clinical Trials Subcommittee. double-dummy. Straube S. Barré J. Masel BE. Effervescent aspirin in the treatment of tension headache. Chaing DS. 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. Thoden WR. Syndol in the treatment of tension headache. Foreman K. Aspirin with or without an antiemetic for acute migraine headaches in adults. Tassorelli C. [42] Linde M. Bryan-Hancock C. In: Gardner MJ. Feigin V.18:38–43.A. [36] Lange R.38:579–89. double-blind. Headache 1998. Bucello C. Savi L. [65] Ryan Sr RE.36:1120–5. [67] Schachtel BP. Condon J. Onset of action of ibuprofen in the treatment of muscle-contraction headache. Voelker M.and active-controlled. [71] Scheepers F. Basáñez MG. Cephalalgia 2013. McQuay HJ. Elbaz A. Damen L. Lantéri-Minet M. Abdalla S. McQuay HJ. Sakai F. [58] Paterna S. Flood L. [34] Kirthi V. Fraim CJ. acetylsalicylic acid in patients with moderate episodic tension-type headache: a randomised. Bell ML. [29] Headache Classification Committee of the International Headache Society (IHS).20:765–86. Dharmaratne SD. Ali SE. Katsarava Z. Koes BW. [37] Langemark M. McQuay HJ. Boussinesq M. What do patients with migraine want from acute migraine treatment? Headache 2002. [69] Schachtel BP. Derry S. Passchier J. 2014. Fowkes FG. Clin Pharmacol Ther 1994. Med J Aust 1970.17:1–12. Peters K. Licata G. Bell RF. Alvarado M. Carroll D. Stewart WF. Estimate at your peril: imputation methods for patient withdrawal can bias efficacy outcomes in chronic pain trials using responder analyses. Corriere M. Headache 2000. placebo controlled study. Ketoprofen. Size is everything— large amounts of information are needed to overcome random effects in estimating direction and magnitude of treatment effects. Raak A. Birbeck G. Michaud C. Vix JM. Blyth F. [45] Mehlisch DR.gov/ct2/results?term=NCT01077973&Search=Search.clinicaltrials. Braithwaite T. Salomon JA. and economic impact. Dionisio P. / PAIN 155 (2014) 2220–2228 po rC DR [57] Packman B. [80] von Graffenried B. Non-migrainous headache for the evaluation of oral analgesics. Budke CM.23:59–66. Freeman MK.50–63. [49] Moore RA. Doyle G. Agosti R. Effervescent ASA versus solid ASA in the treatment of tension headache. Olesen J. Symptomatic treatment of tension headache. Low-dose ibuprofen in self-medication of mild to moderate headache: a comparison with acetylsalicylic acid and placebo. Atkinson C. current treatment. Charlson F. Wiffen P. Ruiz de la Torre E.000 mg acetaminophen with each other.69:374–9. Ewoigbokhan SE. Friedman M. double-blind study. Curr Med Res Opin 1978.56:576–86. Bikbov B. Efficacy and safety of acetaminophen and naproxen in the treatment of tension-type headache. Brugha TS.153:265–8. Ionescu E. Assessing the quality of reports of randomised clinical trials: is blinding necessary? Control Clin Trials 1996. Gabriel SE. Eur J Pain 2003.

Towbin JA. Zaidi AK. Sampson U. Jacobsen KH. Margolis DJ. Mallinger L. Gunnell D. Sliwa K. Shin H. Lipnick M. PerezRuiz F. Mayosi BM. Keren A.380:2163–96. Nair MN. James SL. Williams HC. Ibeanusi SE. Robinson C. Sleet DA. Mitchell PB. Ronfani L. Murdoch ME. Lim SS. Pourmalek F. Sacco RL. Remuzzi G. Hay RJ. Stapelberg NJ. Witt E. Lancet 2012. Loane M. Regan M. Rosenfeld LC. Prince Co pi aa ut or iza da po rC DR M. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Tamburlini G. Kobusingye O. Venketasubramanian N. Montico M. Taylor WJ. Miller M. Harrison JE. McDermott MM. Moradi-Lakeh M. Nelson PK. Arzneim-Forsch 1981. Wilkinson JD. Havmoeller R. O’Hanlon S. Gillum RF. Schwebel DC. Jasrasaria R. Moffitt TE. Groeger J. Ranganathan D. Limb E.31:914–7. Mwaniki MK. Singh GM. Rehm JT. Narayan KM. Polanczyk GV. Thurston GD. Hall W. 06/01/2015 . Singh D. Razavi H. Phillips MR. O’Donnell M. Miller TR. Omer SB. Pandian JD. Huang JJ. Tleyjeh IM. Gmel G. Segui-Gomez M. Naidoo K. Koranteng A. Rivero AP. Lipshultz SE.Ò 2228 R. Ma J. Laslett LL. Pullan RL. Kassebaum N. Taylor HR. Rivara FP. PAINÒ 1991. Leigh J. Steiner T. Tonelli M. [83] Wood A. McGrath J. Lalloo R. Knowlton LM. Newton CR. Malekzadeh R. Marks R. Nelson RG. Richardson K. Zheng ZJ. Krishnamurthi R. Pion S. De Leòn FR. Matzopoulos R. Meyer AC. Room R. Padilla RP. Sanchez-Riera L. [82] Ward N. Jayaraman S. Wang M. Scott JG. Sudfeld C. Mocumbi AO. Mokdad AA. Gupta R. Jonas JB. Osborne R. Manivannan S. Pope 3rd CA. Marcenes W. Ortblad K. Fluproquazone: analgesic activity in outpatients with non-migrainous headache. Lin JK. Dunner D. Pearce N. Hagan H. Roberts T. Weintraub R. Page A. Grainger R. Yeh PH. Jarvis D. Haring D. Shivakoti R. Murray CJ. van der Werf MJ. Matsumori A. van Os J.44:151–5. Meltzer M. White RA. Halasa YA. Norman R. Smith JL. Guillemin F. Haagsma J. Wulf S. Olives C. Wiersma ST. Perico N. Wolfe F. Pahari B. Nolte S. King CH. Singh JA. Lee YY. Popova S. Thomson WM. Mori R. Gaspari F. Weissman MM. Hotez PJ. McGill N. Porrini E. Ohno SL. Karthikeyan G. Haro JM. Medina-Mora ME. Ozgediz D. AlMazroa MA. Syed S. Watt K. Morawska L. Avery D. MacIntyre MF. Lyons R. Polinder S. Higashi H. Taylor JA. Thomas B. Phillips D. / PAIN 155 (2014) 2220–2228 HA. Undurraga EA. Ramaiah KD. Khoo JP. Patten SB. Williams SR. Tavakkoli M. Weatherall DJ. McAnulty JH. Whitney C. Smith E.A. The analgesic effects of caffeine in headache. Zonies D. Rein DB. Kawakami N. Norman P. Memish ZA. Moore et al. Gosselin R. Lathlean T. Monasta L. Mabweijano J. Merriman TR. Weisskopf MG. Weinstock MA. Lopez AD. Singleton J. Saha S. Steer A. Marks GB. Nevitt MC. Hoffman H. Vavilala MS. Naldi L. Johns N. Whiteford H. Pierce K. Ubeda C. March L. Rushton L. von Graffenried B. Stolk WA. Garcia B. Pesudovs K. Hoy D. Leasher JL. Wang W. Hill C. Shepard DS. Truelsen T. Tsilimbaris MK. Shahraz S. Miglioli V. Mensah GA. Stovner LJ. Liu W. Sanman E. Hoen B. Moran A. Woolf AD.