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Original Investigation |

Differential Effectiveness of Placebo Treatments:  A Systematic Review of Migraine Prophylaxis FREE

Karin Meissner, MD1,2; Margrit Fässler, MD1,3; Gerta Rücker, PhD4; Jos Kleijnen, PhD5,6; Asbjorn Hróbjartsson, PhD7; Antonius Schneider, MD1; Gerd Antes, MD4; Klaus Linde, MD1
[+] Author Affiliations
1Institute of General Practice, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
2Institute of Medical Psychology, Ludwig-Maximilians-University Munich, Munich, Germany
3Institute of Biomedical Ethics, University of Zurich, Zurich, Switzerland
4Department for Medical Biometry and Medical Informatics, University of Freiburg, Freiburg, Germany
5Kleijnen Systematic Reviews Ltd, Unit 6, York, England
6School for Public Health and Primary Care, Maastricht University, Maastricht, the Netherlands
7Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark
JAMA Intern Med. 2013;173(21):1941-1951. doi:10.1001/jamainternmed.2013.10391.
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Published online

Importance  When analyzing results of randomized clinical trials, the treatment with the greatest specific effect compared with its placebo control is considered to be the most effective one. Although systematic variations of improvements in placebo control groups would have important implications for the interpretation of placebo-controlled trials, the knowledge base on the subject is weak.

Objective  To investigate whether different types of placebo treatments are associated with different responses using the studies of migraine prophylaxis for this analysis.

Design, Setting, and Participants  We searched relevant sources through February 2012 and contacted the authors to identify randomized clinical trials on the prophylaxis of migraine with an observation period of at least 8 weeks after randomization that compared an experimental treatment with a placebo control group. We calculated pooled random-effects estimates according to the type of placebo for the proportions of treatment response. We performed meta-regression analyses to identify sources of heterogeneity. In a network meta-analysis, direct and indirect comparisons within and across trials were combined. Additional analyses were performed for continuous outcomes.

Exposure  Active migraine treatment and the placebo control conditions.

Main Outcomes and Measures  Proportion of treatment responders, defined as having an attack frequency reduction of at least 50%. Other available outcomes in order of preference included a reduction of 50% or greater in migraine days, the number of headache days, or headache score or a significant improvement as assessed by the patients or their physicians.

Results  Of the 102 eligible trials, 23 could not be included in the meta-analyses owing to insufficient data. Sham acupuncture (proportion of responders, 0.38 [95% CI, 0.30-0.47]) and sham surgery (0.58 [0.37-0.77]) were associated with a more pronounced reduction of migraine frequency than oral pharmacological placebos (0.22 [0.17-0.28]) and were the only significant predictors of response in placebo groups in multivariable analyses (P = .005 and P = .001, respectively). Network meta-analysis confirmed that more patients reported response in sham acupuncture groups than in oral pharmacological placebo groups (odds ratio, 1.88 [95% CI, 1.30-2.72]). Corresponding analyses for continuous outcomes showed similar findings.

Conclusions and Relevance  Sham acupuncture and sham surgery are associated with higher responder ratios than oral pharmacological placebos. Clinicians who treat patients with migraine should be aware that a relevant part of the overall effect they observe in practice might be due to nonspecific effects and that the size of such effects might differ between treatment modalities.

Figures in this Article

Placebo controls are important when evaluating the effectiveness of medical treatments. They separate specific and nonspecific effects (including placebo effects, regression to the mean, natural course of the disease, etc) and reduce bias by enabling blinding of participants (and, if possible, of providers and outcome assessors). Although placebo-controlled trials may not be possible for ethical or technical reasons in certain instances, they are an important tool when investigating whether a treatment truly works, in the sense that the postulated mechanism of action makes a clinically relevant difference.

Placebo controls are crucial in many evaluations of health care. However, for theoretical reasons and based on empirical evidence, responses to placebo treatments can be quite variable depending on several factors, such as the type of placebo treatment,13 how such treatments are provided (eg, in an enthusiastic or a neutral manner),4 and whether informed consent is obtained.5 Although these issues might be of little relevance for some conditions, they could be of major importance for those conditions in which cognitive and emotional processes play a central role, such as chronic pain or depression or when the symptoms evaluated are mostly of a subjective nature.

Differential responses to different types of placebo controls would challenge the classic interpretation of randomized clinical trials that the treatment with the greatest specific effect compared with its placebo control is also the most effective one.6 Rather, a direct comparison of the different types of treatments would be necessary to find out the best treatment option for a certain disease. Otherwise, a complex intervention with a small specific effect but a large placebo effect, for example, would be considered of little value while still being more effective than a simple drug application with a moderate specific effect but only a small placebo effect. This paradox has been termed the efficacy paradox (Figure 1).6

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Figure 1.
The Efficacy Paradox Demonstrated by a Hypothetical 4-Arm Study to Compare Specific and Placebo Effects of Different Types of Treatments

Patients are randomized to 1 of 4 arms, each 2 of which represent a double-blind substudy with an active treatment arm and a corresponding placebo arm. Regression to the mean and spontaneous changes are assumed to be equal in all groups. Treatment arm 2 has a smaller specific effect than treatment arm 1, but its total (specific + placebo) effect is larger because it is associated with a larger placebo effect. Adapted from Walach.6

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Although systematic variations of improvements in placebo control groups would have important implications for the interpretation of placebo-controlled trials, the knowledge base on the subject is weak. Trials with a direct comparison of different types of placebo treatments are relatively rare, dispersed over a variety of conditions, and difficult to identify.3 For these reasons, systematic reviews making indirect comparisons are warranted. In this review, we collected randomized clinical trials on the prophylaxis of migraine that included a placebo control group. We focused on migraine because this disease has high prevalence and economic relevance, a variety of treatment strategies have been investigated, and diagnostic criteria and outcome measures are relatively well defined. An influence of contextual factors on clinical outcomes also seems plausible on theoretical grounds. The primary aim of this review was to determine whether different types of placebo treatments are associated with different effect sizes.

Literature Search

We searched MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and PsychINFO (from inception to February 2012) using a combination of keywords and text words related to migraine and placebo controls, combined with validated filters for controlled clinical trials.7 The search strategy for MEDLINE is shown in the Supplement (eTable 1).

Study Selection

We included randomized placebo-controlled trials of the prophylactic treatment of migraine in adults with observation periods of at least 8 weeks after randomization. Studies had to report at least 1 clinical outcome related to migraine (eg, response, frequency, pain intensity, headache scores, or analgesic use). Migraine had to be diagnosed according to the International Headache Society criteria, or criteria for migraine diagnosis had to be in close agreement with the International Headache Society classification. We excluded crossover studies except when the results of the first administration were given separately. We also excluded studies in which migraine was associated with other neurological disorders, studies of daily or converted migraine, studies with single-blind placebo run-in periods, studies with changes in prophylactic migraine treatment (except for titration of study medication therapy), and studies with experimental cointerventions (except for acute migraine attacks).

We screened all abstracts identified by the literature search and removed irrelevant hits (eg, duplicate studies, studies that were not randomized clinical trials, studies of conditions other than migraine, and treatment of acute migraine). All other articles were obtained in full text and checked by 2 reviewers (K.M. and M.F.) for eligibility according to our selection criteria. Disagreements were resolved by discussion.

Data Collection

The 2 reviewers extracted information on patients, methods, interventions, outcomes, and results using a pretested standard form. In particular, we extracted the bibliographic details of the study; exact diagnoses and headache classifications used; number and type of centers; age and sex of the patients; duration of disease; number of patients undergoing randomization, treatment, and analysis; special inclusion criteria; resistance to previous treatment; number of and reasons for dropouts; duration of baseline, treatment, and follow-up periods; type, duration, and frequency of experimental and sham treatments; description of other groups (if any); handling of acute migraine attacks; cointerventions; informed consent procedure; definition of primary outcomes; adverse events; success of blinding; type of analysis (ie, intent to treat or per protocol); and randomization ratio of placebo to active treatment (eg, 1:1, 1:2).

Outcome Measures

The primary outcome measure was the proportion of responders. We preferably defined responders as patients with a reduction in attack frequency of at least 50%. If these data were not available, we used (in descending order of preference) patients with at least a 50% reduction in the number of migraine days, with at least a 50% reduction in the number of headache days, with at least a 50% reduction in headache scores, and with significant improvement as assessed by the patients or their physicians. As a secondary outcome measure, we preferably extracted the frequency of migraine attacks (means and SDs) per month at baseline and follow-up or (in descending order of preference) the number of migraine days per month, number of headache days per month, migraine index, headache index, headache scores, headache intensity, or frequency of analgesic use. The following time windows were applied: 8 weeks or 2 months after randomization, 3 to 4 months after randomization, 5 to 6 months after randomization, and more than 6 months after randomization. The analysis considered preferably the data 3 to 4 months after randomization; otherwise, the presented data closest to 3 to 4 months were used. All outcomes relied on patient reports, mainly collected in headache diaries. If a study contained multiple treatment groups that differed only in the dosage, we pooled the values.

Risk of Bias Assessment

Risk of bias was assessed using the risk of bias tool of the Cochrane Collaboration.8 We considered adequate sequence generation, allocation concealment, patient blinding, addressing incomplete outcome data at 4 months and at 5 to 12 months after randomization, and absence of selective reporting. At least 2 reviewers K.M., M.F., or K.L.) independently judged whether the risk of bias for each criterion was considered low, high, or unclear. Disagreements were resolved by discussion.

Statistical Analysis

The proportion of responders in the placebo and active treatment groups with the associated 95% confidence intervals and the relative risk between the percentage of responders in the placebo and active treatment groups (responder ratio [RR]) were calculated for each study, and results were pooled using random-effects models. To evaluate the effects of different types of placebo treatments, we performed stratified analyses (for descriptive purposes) and meta-regression analyses using the inverse variance method (Freeman-Tukey arcsine transformation). In explorative analyses, we investigated the effects of 15 covariates on outcome separately and then in a multivariable meta-regression analysis (Supplement [eTables 3 and 4]). Because a strong overlap between the factors “type of placebo treatment” and “type of blinding” was present, we tested 2 models for multivariable analyses, in each of which only one of these factors was involved. Responder data in the active treatment groups, placebo control groups, and no-treatment groups were then subjected to a network analysis using a fixed-effects method based on logistic regression to enable indirect comparisons between studies while preserving within-group randomization.912

Secondary analyses were performed on continuous outcomes. The changes from baseline to after treatment (pretreatment to posttreatment changes) were analyzed by calculating standardized mean differences in the placebo and active treatment groups with the associated 95% CIs. Posttreatment data were analyzed by calculating standardized mean differences between placebo and active treatment groups with the associated 95% CIs. For both types of continuous outcomes, individual study results were pooled using the inverse variance method and a random-effects model. Network analyses were performed by adapting the method originally developed for logistic regression912 for continuous outcomes.13

We assessed heterogeneity between trials using the I2 statistic.14 All analyses were performed with the R packages meta15 and metafor.16

A total of 102 studies (reported in 118 publications) met the inclusion criteria. At least 1 outcome could be included in the meta-analyses from 79 studies (Figure 2).

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Figure 2.
Flowchart

This flowchart depicts the selection of the 79 studies.

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Characteristics of Included Studies

The individual characteristics of the 79 studies1793 included in the meta-analyses are given in the Supplement (eTable 2). Dichotomous and/or continuous data were retrieved from 56 and 55 studies, respectively, and 32 studies provided both types of data. The 79 trials had randomly allocated a total of 9278 patients to an experimental treatment, a placebo treatment, no treatment, or an active control treatment. The mean age of study patients was 39 years, they experienced migraine for a mean of 18 years, and most of the study participants (79.8%) were female. Twenty-four studies had a clearly predefined outcome measure and 21 had a partly predefined primary outcome measure (such as predefinition of the outcome but not of the time point). Fifty-one trials were double blind; 26, single blind; and 2, not specified. In 49 trials, the randomization ratio (placebo to active treatment) was 1:1; in 30 trials, 1:2 or less.

In 35 studies, the placebo treatment was an orally administered placebo for a pharmacological drug; in 13 studies, sham acupuncture (typically superficial needling at nonacupuncture points); in 10 studies, a pharmacological sham injection; in 8 studies, an orally administered placebo for an herbal remedy, a homeopathic remedy, or a vitamin supplement; in 8 studies, a sham cognitive-behavioral treatment; in 3 studies, a sham electromagnetic device; and in 2 studies, sham surgery (skin incision in the groin43 and exposure of cranial nerves and muscles at trigger sites56). In 4 studies, only the placebo arms were analyzed owing to different types of treatments in the placebo and active treatment groups.44,55,85,89 Four studies included a no-treatment group.24,49,52,64 One acupuncture study40 included a group that received guideline-oriented standard drug therapy.

Most studies had considerable weaknesses in relation to the details of sequence generation (51 studies with a high or unclear risk of bias), allocation concealment (68 studies with a high or unclear risk of bias), and blinding (48 studies with a high or unclear risk of bias). In 39 studies, the dropout rates at 4 months were substantial (>15%) and could have led to distortions. Although study results were often presented in a suboptimal manner, we considered the risk of selective reporting in most studies (n = 70) to be low.

Results of Included Studies

The overall pooled proportion of responders in the active treatment groups was 0.42 (95% CI, 0.38-0.45), whereas it was 0.26 (0.22-0.30) in the placebo groups. On average, active treatment was significantly more effective than placebo treatment (RR, 1.40 [95% CI, 1.23-1.59]). Heterogeneity between trials was substantial (for placebo and active treatment groups, I2 = 80.8% and 80.7%, respectively [both P < .001]; for placebo vs active treatment groups, I2 = 60.5% [P < .001]).

Stratified analyses according to type of placebo treatment showed wide variations in the proportions of responders in the placebo groups (Tables 1, 2, 3, 4, and 5). On average, sham surgery and sham acupuncture (Table 4) were associated with the greatest responder proportions (0.58 [95% CI, 0.37-0.77] and 0.38 [0.30-0.47], respectively), whereas oral pharmacological placebos (Table 1) were associated with clearly smaller ones (0.22 [95% CI, 0.17-0.28]). The pooled proportions of responders for other placebo treatments ranged from 0.23 to 0.27 (Tables 2, 3, and 5). Subgroup analyses according to the type of placebo confirmed significant differences between different types of placebo treatments (Q = 22.02 [P = .001]), with substantial heterogeneity across trials (I2 = 80.8% [P < .001]). The proportions of responders in the sham acupuncture and sham surgery subgroups were significantly greater than those in the subgroup of oral pharmacological placebos (P = .004 and P = .03, respectively).

Table Graphic Jump LocationTable 1.  Basic Results for the 26 Studies Providing Proportion of Responders and RRs for Oral Pharmacological Placebo Treatmenta
Table Graphic Jump LocationTable 2.  Basic Results for the 8 Studies Providing Proportion of Responders and RRs for Herbal, Vitamin, and Homeopathic Placebo Treatmenta
Table Graphic Jump LocationTable 3.  Basic Results for the 6 Studies Providing Proportion of Responders and RRs for Pharmacological Placebo Injectiona
Table Graphic Jump LocationTable 4.  Basic Results for the 12 Studies Providing Proportion of Responders and RRs for Sham Surgery and Sham Acupuncturea
Table Graphic Jump LocationTable 5.  Basic Results for the 4 Studies Providing Proportion of Responders and RRs for Sham Electromagnetic Device and Sham CBTa

In addition to type of placebo treatment, separate subgroup analyses revealed that studies with sample sizes larger than 100 patients, patients unresponsive to previous prophylactic treatments, parallel-group design, and single blinding were associated with significantly greater placebo RRs (Supplement [eTable 3]). Explorative multivariable analyses showed the placebo treatments of sham surgery and sham acupuncture to be the only independent predictors of placebo RRs in model 1 (Supplement [eTable 4]). In model 2, blinding emerged as the only independent predictor of placebo RRs, with single-blinded studies associated with greater RRs.

Forty trials with dichotomous outcomes were included in a network meta-analysis, which allowed comparisons among sham acupuncture, oral pharmacological placebos, sham cognitive-behavioral treatment, their corresponding active treatments, and no treatment (Figure 3). Results are summarized in Figure 4. Sham acupuncture was associated with greater effects than were oral pharmacological placebos and no treatment (odds ratio, 1.88 [95% CI, 1.30-2.72] and 4.57 [2.34-8.92], respectively). Meta-analyses of continuous outcomes and the corresponding network meta-analyses broadly confirmed the findings for the dichotomous data (Supplement [eTables 5 through 8]).

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Figure 3.
Network Based on Studies Providing Proportions of Response

Numbers and solid lines indicate studies with direct comparisons between active treatment and placebo groups; dashed lines, studies with direct comparisons with an additional group. Three-armed studies are displayed as triangles (the sources are given in the figure).

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Figure 4.
Results of the Network Meta-analysis Based on Responder Ratios

Results are displayed in text and graphically. CBT indicates cognitive-behavioral treatment; OR, odds ratio.

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In the studies included in this review, the amount of reduction in migraine frequency varied systematically between different types of placebo. We found consistent evidence across analyses that sham acupuncture was associated with a more pronounced frequency reduction than were oral pharmacological placebos. Sham surgery also appeared to be more effective, but data on this subject were sparse. Oral placebos for herbs, vitamins, or homeopathic drugs; injected placebos for pharmacological drugs; a sham electromagnetic device; and sham cognitive-behavioral treatment were associated with effects similar to oral pharmacological placebos.

By focusing on a single condition with well-defined diagnostic criteria and outcome measures, we were able to confirm and extend earlier findings that suggested physical placebo treatments in general and acupuncture in particular were associated with greater effects than were pharmacological placebo treatments.1,94,95 Experimental placebo research in the past decades has provided ample evidence that treatments without active ingredients can relieve pain and other symptoms, and the underlying mechanisms are increasingly understood.96 The context and meaning of a placebo treatment are more important than the placebo vehicle itself.4,97 However, the context and meaning of surgery, for example, differ considerably from those of an oral drug. Patients may develop greater expectations about treatments such as acupuncture and surgery because of the more elaborate and impressive treatment rituals.98 The higher level of attention and physical contact may also play a role.99 The most probable explanation for the apparently greater effectiveness of sham acupuncture and possibly sham surgery compared with placebo pills is thus their systematic association with contextual factors that are known to enhance placebo effects. Part of the enhanced placebo effect, however, may also result from the physiological effects of skin injury during sham acupuncture and sham surgery.100,101

Our results suggest that the response to sham acupuncture and sham surgery can be as great as the mean response to active drugs. The other placebo treatments in our data set showed RRs comparable to those of oral pharmacological placebos. The finding that studies with pharmacological sham injections as placebo controls did not show greater effects than oral placebo pills is in contrast to the results of 2 earlier meta-analyses2,102 reporting an enhanced placebo effect of injected vs oral placebos for the treatment of acute migraine attacks. The discrepancy with the literature may be due in part to the fact that, in our review, the placebo injections controlled for botulinum toxin, which induces persistent physical change due to muscle relaxation, whereas in the other reviews the placebo treatment controlled for analgesics without such adverse effects. The absence of physical changes in placebo-treated patients in botulinum toxin studies may have led to the unblinding of patients and physicians, thereby decreasing the placebo effect. The absence of a difference between the responses to a sham electromagnetic device and oral pharmacological placebos is in agreement with a recent meta-analysis that detected no difference between the placebo response for oral pharmacological placebos and repetitive transcranial magnetic stimulation.103

The multivariable analyses indicated that the placebo response was greater in single-blinded than in double-blinded designs (Supplement [eTable 4, model 2]). This response most probably results from a strong overlap of the factors blinding and type of treatment in that the placebo treatments associated with the greatest improvements (ie, sham acupuncture and sham surgery) can usually only be performed in a single-blinded manner. In contrast to what would be expected, single blinding apparently did not decrease the placebo response.

Our data cannot prove that the differences in migraine frequency reduction are caused by the different types of placebos and their associated context and meaning. In the first part of our analyses, we compared the outcome of control groups of separate trials receiving different types of placebo treatments. This comparison of uncontrolled case series is prone to biases. Although we investigated a variety of covariates, we cannot rule out the risk of spurious positive associations due to the high number of covariates and the possibility that we missed an important factor. Although our main results could be confirmed by network analyses, the connections in our networks did not allow us to include all studies of our data set, and the heterogeneity of patients, settings, and treatment modalities further limit the conclusiveness of the network meta-analyses. One potential explanation for our findings could be differential response bias.104 The use of patient diaries in migraine trials probably reduces the risk of response bias but does not eliminate it. Regression to the mean and spontaneous improvements also could vary between subgroups of studies. Our data suggest that baseline headache frequency was slightly lower in acupuncture trials compared with pharmacological trials, making larger regression to the mean less likely. However, this reduced frequency could also imply that patients in acupuncture trials were easier to treat.

Our results suggest that some types of placebo treatments can be, on average, associated with greater improvements than others. Although our study cannot prove that this association is causal, the results support the notion that some placebo treatments can trigger clinically relevant responses. Our findings warrant further studies testing different types of placebo as well as active treatments directly against each other. We also suggest that treatment options whose contexts vary strongly should be investigated in placebo-controlled trials and head-to-head comparisons. Otherwise, treatments with small specific effects greater than those of their sham controls are withheld from patients even though they work better than standard treatment. Clinicians who treat patients with migraine should be aware that a relevant part of the overall effect they observe in practice might be the result of nonspecific effects and that the size of such effects might differ between treatment modalities. In other words, the method of treatment delivery might have an important influence on outcome. Although our analyses focused on migraine, the same conclusion could well be true for other conditions.

Submitted for Publication: December 13, 2012; final revision received May 16, 2013; accepted May 19, 2013.

Corresponding Author: Karin Meissner, MD, Institute of Medical Psychology, Ludwig-Maximilians-University Munich, Goethestrasse 31, 80336 Munich, Germany (karin.meissner@med.lmu.de).

Published Online: October 14, 2013. doi:10.1001/jamainternmed.2013.10391.

Author Contributions: Drs Meissner and Linde had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Meissner, Fässler, Kleijnen, Hróbjartsson, Antes, Linde.

Acquisition of data: Meissner, Fässler, Linde.

Analysis and interpretation of data: Meissner, Fässler, Rücker, Kleijnen, Hróbjartsson, Schneider, Linde.

Drafting of the manuscript: Meissner, Rücker.

Critical revision of the manuscript for important intellectual content: Fässler, Rücker, Kleijnen, Hróbjartsson, Schneider, Antes, Linde.

Statistical analysis: Meissner, Rücker, Kleijnen.

Obtaining funding: Meissner, Kleijnen, Linde.

Administrative, technical, or material support: Schneider, Fässler, Antes.

Study supervision: Kleijnen, Antes, Linde.

Conflicts of Interest Disclosures: None reported.

Funding/Support: This study was supported by grant 01KG0924 from the German Ministry of Education and Research.

Role of the Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Kaptchuk  TJ, Stason  WB, Davis  RB,  et al.  Sham device v inert pill: randomised controlled trial of two placebo treatments. BMJ. 2006;332(7538):391-397.
PubMed   |  Link to Article
de Craen  AJ, Tijssen  JG, de Gans  J, Kleijnen  J.  Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos. J Neurol. 2000;247(3):183-188.
PubMed   |  Link to Article
Kaptchuk  TJ, Goldman  P, Stone  DA, Stason  WB.  Do medical devices have enhanced placebo effects? J Clin Epidemiol. 2000;53(8):786-792.
PubMed   |  Link to Article
Di Blasi  Z, Harkness  E, Ernst  E, Georgiou  A, Kleijnen  J.  Influence of context effects on health outcomes: a systematic review. Lancet. 2001;357(9258):757-762.
PubMed   |  Link to Article
Bergmann  JF, Chassany  O, Gandiol  J,  et al.  A randomised clinical trial of the effect of informed consent on the analgesic activity of placebo and naproxen in cancer pain. Clin Trials Metaanal. 1994;29(1):41-47.
PubMed
Walach  H.  The efficacy paradox in randomized controlled trials of CAM and elsewhere: beware of the placebo trap. J Altern Complement Med. 2001;7(3):213-218.
PubMed   |  Link to Article
Watson  RJ, Richardson  PH.  Identifying randomized controlled trials of cognitive therapy for depression: comparing the efficiency of EMBASE, MEDLINE and PsycINFO bibliographic databases. Br J Med Psychol. 1999;72(pt 4):535-542.
PubMed   |  Link to Article
Higgins JPT, Altman DG, Sterne JAC. Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [Updated September 2009]. Cochrane Collaboration; 2011. http://handbook.cochrane.org/. Accessed November 10, 2009.
Li  T, Puhan  MA, Vedula  SS, Singh  S, Dickersin  K; Ad Hoc Network Meta-analysis Methods Meeting Working Group.  Network meta-analysis—highly attractive but more methodological research is needed. BMC Med. 2011;9(1):79. doi:10.1186/1741-7015-9-79.
PubMed   |  Link to Article
Mills  EJ, Bansback  N, Ghement  I,  et al.  Multiple treatment comparison meta-analyses: a step forward into complexity. Clin Epidemiol. 2011;3:193-202.
PubMed   |  Link to Article
Puhan  MA, Bachmann  LM, Kleijnen  J, Ter Riet  G, Kessels  AG.  Inhaled drugs to reduce exacerbations in patients with chronic obstructive pulmonary disease: a network meta-analysis. BMC Med. 2009;7:2. doi:10.1186/1741-7015-7-2.
PubMed   |  Link to Article
Salanti  G, Higgins  JP, Ades  AE, Ioannidis  JP.  Evaluation of networks of randomized trials. Stat Methods Med Res. 2008;17(3):279-301.
PubMed   |  Link to Article
Wolff  RF, Bala  MM, Westwood  M, Kessels  AG, Kleijnen  J.  5% Lidocaine–medicated plaster vs other relevant interventions and placebo for post-herpetic neuralgia (PHN): a systematic review. Acta Neurol Scand. 2011;123(5):295-309.
PubMed   |  Link to Article
Higgins  JP, Thompson  SG, Deeks  JJ, Altman  DG.  Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.
PubMed   |  Link to Article
Schwarzer  G.  meta: An R package for meta-analysis. R News.2007;7(3):40-45.
Viechtbauer  W.  Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36(3):1-48.
Adly  C, Straumanis  J, Chesson  A.  Fluoxetine prophylaxis of migraine. Headache. 1992;32(2):101-104.
PubMed   |  Link to Article
Alecrim-Andrade  J, Maciel-Júnior  JA, Carné  X, Correia-Filho  HR, Machado  HC, Vasconcelos  GMS.  Efficacy of acupuncture in migraine attack prophylaxis: a randomized sham-controlled trial. Cephalalgia. 2005;25(10):942.
Alecrim-Andrade  J, Maciel-Júnior  JA, Carnè  X, Severino Vasconcelos  GM, Correa-Filho  HR.  Acupuncture in migraine prevention: a randomized sham controlled study with 6-months posttreatment follow-up. Clin J Pain. 2008;24(2):98-105.
PubMed   |  Link to Article
Alecrim-Andrade  J, Maciel-Júnior  JA, Cladellas  XC, Correa-Filho  HR, Machado  HC.  Acupuncture in migraine prophylaxis: a randomized sham-controlled trial. Cephalalgia. 2006;26(5):520-529.
PubMed   |  Link to Article
Anand  KS, Prasad  A, Singh  MM, Sharma  S, Bala  K.  Botulinum toxin type A in prophylactic treatment of migraine. Am J Ther. 2006;13(3):183-187.
PubMed   |  Link to Article
Andersson  PG, Dahl  S, Hansen  JH,  et al.  Prophylactic treatment of classical and non-classical migraine with metoprolol: a comparison with placebo. Cephalalgia. 1983;3(4):207-212.
PubMed   |  Link to Article
Baust  W, Stürtzbecher  KH.  Management of migraine using acupuncture in a double-blind study [in German]. Med Welt. 1978;29(16):669-673.
PubMed
Blanchard  EB, Appelbaum  KA, Radnitz  CL,  et al.  A controlled evaluation of thermal biofeedback and thermal biofeedback combined with cognitive therapy in the treatment of vascular headache. J Consult Clin Psychol. 1990;58(2):216-224.
PubMed   |  Link to Article
Blanchard  EB, Peters  ML, Hermann  C,  et al.  Direction of temperature control in the thermal biofeedback treatment of vascular headache. Appl Psychophysiol Biofeedback. 1997;22(4):227-245.
PubMed
Bousser  MG, Chick  J, Fuseau  E, Soisson  T, Thevenet  R.  Combined low-dose acetylsalicylic acid and dihydroergotamine in migraine prophylaxis: a double-blind, placebo-controlled crossover study. Cephalalgia. 1988;8(3):187-192.
PubMed   |  Link to Article
Boutouyrie  P, Corvisier  R, Ong  KT,  et al.  Acute and chronic effects of acupuncture on radial artery: a randomized double blind study in migraine. Artery Res. 2010;4(1):7-14.
Link to Article
Brandes  JL, Saper  JR, Diamond  M,  et al; MIGR-002 Study Group.  Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291(8):965-973.
PubMed   |  Link to Article
Brown  JM.  Imagery coping strategies in the treatment of migraine. Pain. 1984;18(2):157-167.
PubMed   |  Link to Article
Cady  R, Schreiber  C.  Botulinum toxin type A as migraine preventive treatment in patients previously failing oral prophylactic treatment due to compliance issues. Headache. 2008;48(6):900-913.
PubMed   |  Link to Article
Cady  RK, Mathew  N, Diener  H-C, Hu  P, Haas  M, Novak  GP; Study Group.  Evaluation of carisbamate for the treatment of migraine in a randomized, double-blind trial. Headache. 2009;49(2):216-226.
PubMed   |  Link to Article
Carasso  RL, Yehuda  S.  The prevention and treatment of migraine with an analgesic combination. Br J Clin Pract. 1984;38(1):25-27.
PubMed
Carrieri  P, Orefice  G, Sorge  F.  Indobufen, a new antiaggregant drug, in the treatment of migraine: a double-blind study compared with placebo. Cephalalgia. 1985;5(suppl 3):546-547.
Ceccherelli  F, Ambrosio  F, Avila  M, Duse  G, Munari  A, Giron  GP.  Acupuncture vs placebo in the common migraine: a double blind study. Cephalalgia. 1987;7(suppl 6):499-500.
Chankrachang  S, Arayawichanont  A, Poungvarin  N,  et al.  Prophylactic botulinum type A toxin complex (Dysport®) for migraine without aura. Headache. 2011;51(1):52-63.
PubMed   |  Link to Article
Cruz  A, Bühling  M, Seibel  K.  Double blind study of migraine therapy with etilefrine pivalate [in German]. Arzneimittelforschung. 1985;35(7):1086-1089.
PubMed
de Tommaso  M, Marinazzo  D, Nitti  L,  et al.  Effects of levetiracetam vs topiramate and placebo on visually evoked phase synchronization changes of alpha rhythm in migraine. Clin Neurophysiol. 2007;118(10):2297-2304.
PubMed   |  Link to Article
Di Trapani  G, Mei  D, Marra  C, Mazza  S, Capuano  A.  Gabapentin in the prophylaxis of migraine: a double-blind randomized placebo-controlled study. Clin Ter. 2000;151(3):145-148.
PubMed
Diener  HC, Föh  M, Iaccarino  C,  et al.  Cyclandelate in the prophylaxis of migraine: a randomized, parallel, double-blind study in comparison with placebo and propranolol: the study group. Cephalalgia. 1996;16(6):441-447.
PubMed   |  Link to Article
Diener  HC, Kronfeld  K, Boewing  G,  et al; GERAC Migraine Study Group.  Efficacy of acupuncture for the prophylaxis of migraine: a multicentre randomised controlled clinical trial. Lancet Neurol. 2006;5(4):310-316.
PubMed   |  Link to Article
Diener  HC, Pfaffenrath  V, Schnitker  J, Friede  M, Henneicke-von Zepelin  HH.  Efficacy and safety of 6.25 mg t.i.d. Feverfew CO2-extract (MIG-99) in migraine prevention: a randomized, double-blind, multicentre, placebo-controlled study. Cephalalgia. 2005;25(11):1031-1041.
PubMed   |  Link to Article
Diener  H-C, Tfelt-Hansen  P, Dahlöf  C,  et al; MIGR-003 Study Group.  Topiramate in migraine prophylaxis: results from a placebo-controlled trial with propranolol as an active control. J Neurol. 2004;251(8):943-950.
PubMed   |  Link to Article
Dowson  A, Mullen  MJ, Peatfield  R,  et al.  Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache [published correction appears in Circulation. 2009;120(9):e71-e72]. Circulation. 2008;117(11):1397-1404.
PubMed   |  Link to Article
Dowson  DI, Lewith  GT, Machin  D.  The effects of acupuncture versus placebo in the treatment of headache. Pain. 1985;21(1):35-42.
PubMed   |  Link to Article
D’Souza  PJ, Lumley  MA, Kraft  CA, Dooley  JA.  Relaxation training and written emotional disclosure for tension or migraine headaches: a randomized, controlled trial. Ann Behav Med. 2008;36(1):21-32.
PubMed   |  Link to Article
Edwards  KR, Potter  DL, Wu  S-C, Kamin  M, Hulihan  J.  Topiramate in the preventive treatment of episodic migraine: a combined analysis from pilot, double-blind, placebo-controlled trials. CNS Spectr. 2003;8(6):428-432.
PubMed
Elkind  AH, O’Carroll  P, Blumenfeld  A, DeGryse  R, Dimitrova  R; BoNTA-024-026-036 Study Group.  A series of three sequential, randomized, controlled studies of repeated treatments with botulinum toxin type A for migraine prophylaxis. J Pain. 2006;7(10):688-696.
PubMed   |  Link to Article
Evers  S, Vollmer-Haase  J, Schwaag  S, Rahmann  A, Husstedt  IW, Frese  A.  Botulinum toxin A in the prophylactic treatment of migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia. 2004;24(10):838-843.
PubMed   |  Link to Article
Facco  E, Liguori  A, Petti  F,  et al.  Traditional acupuncture in migraine: a controlled, randomized study. Headache. 2008;48(3):398-407.
PubMed   |  Link to Article
Freitag  FG, Collins  SD, Carlson  HA,  et al; Depakote ER Migraine Study Group.  A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. 2002;58(11):1652-1659.
PubMed   |  Link to Article
Gauthier  J, Bois  R, Allaire  D, Drolet  M.  Evaluation of skin temperature biofeedback training at two different sites for migraine. J Behav Med. 1981;4(4):407-419.
PubMed   |  Link to Article
Gauthier  J, Doyon  J, Lacroix  R, Drolet  M.  Blood volume pulse biofeedback in the treatment of migraine headache: a controlled evaluation. Biofeedback Self Regul. 1983;8(3):427-442.
PubMed   |  Link to Article
Goadsby  PJ, Ferrari  MD, Csanyi  A, Olesen  J, Mills  JG; Tonabersat TON-01-05 Study Group.  Randomized, double-blind, placebo-controlled, proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in migraine prophylaxis. Cephalalgia. 2009;29(7):742-750.
PubMed   |  Link to Article
Grossman  W, Schmidramsl  H.  An extract of Petasites hybridus is effective in the prophylaxis of migraine. Altern Med Rev. 2001;6(3):303-310.
PubMed
Guyuron  B, Kriegler  JS, Davis  J, Amini  SB.  Comprehensive surgical treatment of migraine headaches. Plast Reconstr Surg. 2005;115(1):1-9.
PubMed
Guyuron  B, Reed  D, Kriegler  JS, Davis  J, Pashmini  N, Amini  S.  A placebo-controlled surgical trial of the treatment of migraine headaches. Plast Reconstr Surg. 2009;124(2):461-468.
PubMed   |  Link to Article
Hauge  AW, Asghar  MS, Schytz  HW, Christensen  K, Olesen  J.  Effects of tonabersat on migraine with aura: a randomised, double-blind, placebo-controlled crossover study. Lancet Neurol. 2009;8(8):718-723.
PubMed   |  Link to Article
Henry  P. Headaches and acupuncture. In: Pfaffenrath  V, Lundberg  PO, Sjaastad  O, eds. Updating in Headache. Berlin, Germany: Springer-Verlag; 1985:208-216.
Høivik  HO, Laurijssens  BE, Harnisch  LO,  et al.  Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. Cephalalgia. 2010;30(12):1458-1467.
PubMed   |  Link to Article
Holroyd  KA, Cottrell  CK, O’Donnell  FJ,  et al.  Effect of preventive (β blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial. BMJ. 2010;341:c4871. doi:10.1136/bmj.c4871.
PubMed   |  Link to Article
Kewman  D, Roberts  AH.  Skin temperature biofeedback and migraine headaches: a double-blind study. Biofeedback Self Regul. 1980;5(3):327-345.
Link to Article
Kubiena  G, Nissel  H, Porenta  G, Veitl  M, Wessely  P.  Acupuncture in migraine: follow-up study [in German]. Deutsche Zeitschrift fur Akupunktur.1992;35(6):140-148.
Leandri  M, Rigardo  S, Schizzi  R, Parodi  CI.  Migraine treatment with nicardipine. Cephalalgia. 1990;10(3):111-116.
PubMed   |  Link to Article
Linde  K, Streng  A, Jürgens  S,  et al.  Acupuncture for patients with migraine: a randomized controlled trial. JAMA. 2005;293(17):2118-2125.
PubMed   |  Link to Article
Lipton  RB, Göbel  H, Einhäupl  KM, Wilks  K, Mauskop  A.  Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology. 2004;63(12):2240-2244.
PubMed   |  Link to Article
Louis  P.  A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Headache. 1981;21(6):235-239.
PubMed   |  Link to Article
Maizels  M, Blumenfeld  A, Burchette  R.  A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache. 2004;44(9):885-890.
PubMed   |  Link to Article
Mei  D, Capuano  A, Vollono  C,  et al.  Topiramate in migraine prophylaxis: a randomised double-blind versus placebo study. Neurol Sci. 2004;25(5):245-250.
PubMed   |  Link to Article
Mendenopoulos  G, Manafi  T, Logothetis  I, Bostantjopoulou  S.  Flunarizine in the prevention of classical migraine: a placebo-controlled evaluation. Cephalalgia. 1985;5(1):31-37.
PubMed   |  Link to Article
Mikkelsen  B, Pedersen  KK, Christiansen  LV.  Prophylactic treatment of migraine with tolfenamic acid, propranolol and placebo. Acta Neurol Scand. 1986;73(4):423-427.
PubMed   |  Link to Article
Mullinix  JM, Norton  BJ, Hack  S, Fishman  MA.  Skin temperature biofeedback and migraine. Headache. 1978;17(6):242-244.
PubMed   |  Link to Article
Orholm  M, Honoré  PF, Zeeberg  I.  A randomized general practice group-comparative study of femoxetine and placebo in the prophylaxis of migraine. Acta Neurol Scand. 1986;74(3):235-239.
PubMed   |  Link to Article
Osterman  PO.  A comparison between placebo, pizotifen and 1-isopropyl-3-hydroxy-5-semicarbazono-6-oxo-2.3.5.6-tetrahydroindol (Divascan) in migraine prophylaxis. Acta Neurol Scand. 1977;56(1):17-28.
PubMed   |  Link to Article
Peikert  A, Wilimzig  C, Köhne-Volland  R.  Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 1996;16(4):257-263.
PubMed   |  Link to Article
Petri  S, Tölle  T, Straube  A, Pfaffenrath  V, Stefenelli  U, Ceballos-Baumann  A; Dysport Migraine Study Group.  Botulinum toxin as preventive treatment for migraine: a randomized double-blind study. Eur Neurol. 2009;62(4):204-211.
PubMed   |  Link to Article
Pfaffenrath  V, Diener  HC, Fischer  M, Friede  M, Henneicke-von Zepelin  HH; Investigators.  The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis: a double-blind, multicentre, randomized placebo-controlled dose-response study. Cephalalgia. 2002;22(7):523-532.
PubMed   |  Link to Article
Pfaffenrath  V, Wessely  P, Meyer  C,  et al.  Magnesium in the prophylaxis of migraine: a double-blind placebo-controlled study. Cephalalgia. 1996;16(6):436-440.
PubMed   |  Link to Article
Saper  JR, Mathew  NT, Loder  EW, DeGryse  R, VanDenburgh  AM; BoNTA-009 Study Group.  A double-blind, randomized, placebo-controlled comparison of botulinum toxin type A injection sites and doses in the prevention of episodic migraine. Pain Med. 2007;8(6):478-485.
PubMed   |  Link to Article
Silberstein  S, Mathew  N, Saper  J, Jenkins  S; BOTOX Migraine Clinical Research Group.  Botulinum toxin type A as a migraine preventive treatment. Headache. 2000;40(6):445-450.
PubMed   |  Link to Article
Silberstein  SD, Hulihan  J, Karim  MR,  et al.  Efficacy and tolerability of topiramate 200 mg/d in the prevention of migraine with/without aura in adults: a randomized, placebo-controlled, double-blind, 12-week pilot study. Clin Ther. 2006;28(7):1002-1011.
PubMed   |  Link to Article
Silberstein  SD, Neto  W, Schmitt  J, Jacobs  D; MIGR-001 Study Group.  Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol. 2004;61(4):490-495.
PubMed   |  Link to Article
Siniatchkin  M, Andrasik  F, Kropp  P,  et al.  Central mechanisms of controlled-release metoprolol in migraine: a double-blind, placebo-controlled study. Cephalalgia. 2007;27(9):1024-1032.
PubMed   |  Link to Article
Sjaastad  O, Stensrud  P.  Appraisal of BC-105 in migraine prophylaxis. Acta Neurol Scand. 1969;45(5):594-600.
PubMed   |  Link to Article
Somerville  BW, Herrmann  WM.  Migraine prophylaxis with Lisuride hydrogen maleate—a double blind study of Lisuride versus placebo. Headache. 1978;18(2):75-79.
PubMed   |  Link to Article
Spigt  MG, Kuijper  EC, Schayck  CP,  et al.  Increasing the daily water intake for the prophylactic treatment of headache: a pilot trial. Eur J Neurol. 2005;12(9):715-718.
PubMed   |  Link to Article
Storey  JR, Calder  CS, Hart  DE, Potter  DL.  Topiramate in migraine prevention: a double-blind, placebo-controlled study. Headache. 2001;41(10):968-975.
PubMed   |  Link to Article
Straumsheim  P, Borchgrevink  C, Mowinckel  P, Kierulf  H, Hafslund  O.  Homeopathic treatment of migraine: a double blind, placebo controlled trial of 68 patients. Br Homeopath J. 2000;89(1):4-7.
PubMed   |  Link to Article
Teepker  M, Hötzel  J, Timmesfeld  N,  et al.  Low-frequency rTMS of the vertex in the prophylactic treatment of migraine. Cephalalgia. 2010;30(2):137-144.
PubMed
Tuchin  PJ, Pollard  H, Bonello  R.  A randomized controlled trial of chiropractic spinal manipulative therapy for migraine. J Manipulative Physiol Ther. 2000;23(2):91-95.
PubMed   |  Link to Article
Vahedi  K, Taupin  P, Djomby  R,  et al; DIAMIG Investigators.  Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomised placebo-controlled trial. J Neurol. 2002;249(2):206-211.
PubMed   |  Link to Article
Vo  AH, Satori  R, Jabbari  B,  et al.  Botulinum toxin type-a in the prevention of migraine: a double-blind controlled trial. Aviat Space Environ Med. 2007;78(5)(suppl):B113-B118.
PubMed
Weber  RB, Reinmuth  OM.  The treatment of migraine with propranolol. Neurology. 1972;22(4):366-369.
PubMed   |  Link to Article
Weinschütz  T, Niederberger  U, Johnsen  S, Schreiber  C, Kropp  P.  The neuroregulative effects of acupuncture in patients with headache [in German]. Deutsche Zeitschrift fur Akupunktur.1994;37(5):106-117.
Hróbjartsson  A, Gøtzsche  PC.  Placebo interventions for all clinical conditions. Cochrane Database Syst Rev. 2010;(1):CD003974.
PubMed
Linde  K, Niemann  K, Meissner  K.  Are sham acupuncture interventions more effective than (other) placebos? a re-analysis of data from the Cochrane review on placebo effects. Forsch Komplementmed. 2010;17(5):259-264.
PubMed   |  Link to Article
Meissner  K, Bingel  U, Colloca  L, Wager  TD, Watson  A, Flaten  MA.  The placebo effect: advances from different methodological approaches. J Neurosci. 2011;31(45):16117-16124.
PubMed   |  Link to Article
Benedetti  F, Amanzio  M.  The placebo response: how words and rituals change the patient’s brain. Patient Educ Couns. 2011;84(3):413-419.
PubMed   |  Link to Article
Kaptchuk  TJ.  Placebo studies and ritual theory: a comparative analysis of Navajo, acupuncture and biomedical healing. Philos Trans R Soc Lond B Biol Sci. 2011;366(1572):1849-1858.
PubMed   |  Link to Article
Kerr  CE, Shaw  JR, Conboy  LA, Kelley  JM, Jacobson  E, Kaptchuk  TJ.  Placebo acupuncture as a form of ritual touch healing: a neurophenomenological model. Conscious Cogn. 2011;20(3):784-791.
PubMed   |  Link to Article
Birch  S.  A review and analysis of placebo treatments, placebo effects, and placebo controls in trials of medical procedures when sham is not inert. J Altern Complement Med. 2006;12(3):303-310.
PubMed   |  Link to Article
Lund  I, Lundeberg  T.  Are minimal, superficial or sham acupuncture procedures acceptable as inert placebo controls? Acupunct Med. 2006;24(1):13-15.
PubMed   |  Link to Article
Macedo  A, Farré  M, Baños  JE.  A meta-analysis of the placebo response in acute migraine and how this response may be influenced by some of the characteristics of clinical trials. Eur J Clin Pharmacol. 2006;62(3):161-172.
PubMed   |  Link to Article
Brunoni  AR, Lopes  M, Kaptchuk  TJ, Fregni  F.  Placebo response of non-pharmacological and pharmacological trials in major depression: a systematic review and meta-analysis. PLoS One. 2009;4(3):e4824.
PubMed   |  Link to Article
Hróbjartsson  A, Kaptchuk  TJ, Miller  FG.  Placebo effect studies are susceptible to response bias and to other types of biases. J Clin Epidemiol. 2011;64(11):1223-1229.
PubMed   |  Link to Article

Figures

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Figure 1.
The Efficacy Paradox Demonstrated by a Hypothetical 4-Arm Study to Compare Specific and Placebo Effects of Different Types of Treatments

Patients are randomized to 1 of 4 arms, each 2 of which represent a double-blind substudy with an active treatment arm and a corresponding placebo arm. Regression to the mean and spontaneous changes are assumed to be equal in all groups. Treatment arm 2 has a smaller specific effect than treatment arm 1, but its total (specific + placebo) effect is larger because it is associated with a larger placebo effect. Adapted from Walach.6

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Figure 2.
Flowchart

This flowchart depicts the selection of the 79 studies.

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Figure 3.
Network Based on Studies Providing Proportions of Response

Numbers and solid lines indicate studies with direct comparisons between active treatment and placebo groups; dashed lines, studies with direct comparisons with an additional group. Three-armed studies are displayed as triangles (the sources are given in the figure).

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Figure 4.
Results of the Network Meta-analysis Based on Responder Ratios

Results are displayed in text and graphically. CBT indicates cognitive-behavioral treatment; OR, odds ratio.

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Tables

Table Graphic Jump LocationTable 1.  Basic Results for the 26 Studies Providing Proportion of Responders and RRs for Oral Pharmacological Placebo Treatmenta
Table Graphic Jump LocationTable 2.  Basic Results for the 8 Studies Providing Proportion of Responders and RRs for Herbal, Vitamin, and Homeopathic Placebo Treatmenta
Table Graphic Jump LocationTable 3.  Basic Results for the 6 Studies Providing Proportion of Responders and RRs for Pharmacological Placebo Injectiona
Table Graphic Jump LocationTable 4.  Basic Results for the 12 Studies Providing Proportion of Responders and RRs for Sham Surgery and Sham Acupuncturea
Table Graphic Jump LocationTable 5.  Basic Results for the 4 Studies Providing Proportion of Responders and RRs for Sham Electromagnetic Device and Sham CBTa

References

Kaptchuk  TJ, Stason  WB, Davis  RB,  et al.  Sham device v inert pill: randomised controlled trial of two placebo treatments. BMJ. 2006;332(7538):391-397.
PubMed   |  Link to Article
de Craen  AJ, Tijssen  JG, de Gans  J, Kleijnen  J.  Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos. J Neurol. 2000;247(3):183-188.
PubMed   |  Link to Article
Kaptchuk  TJ, Goldman  P, Stone  DA, Stason  WB.  Do medical devices have enhanced placebo effects? J Clin Epidemiol. 2000;53(8):786-792.
PubMed   |  Link to Article
Di Blasi  Z, Harkness  E, Ernst  E, Georgiou  A, Kleijnen  J.  Influence of context effects on health outcomes: a systematic review. Lancet. 2001;357(9258):757-762.
PubMed   |  Link to Article
Bergmann  JF, Chassany  O, Gandiol  J,  et al.  A randomised clinical trial of the effect of informed consent on the analgesic activity of placebo and naproxen in cancer pain. Clin Trials Metaanal. 1994;29(1):41-47.
PubMed
Walach  H.  The efficacy paradox in randomized controlled trials of CAM and elsewhere: beware of the placebo trap. J Altern Complement Med. 2001;7(3):213-218.
PubMed   |  Link to Article
Watson  RJ, Richardson  PH.  Identifying randomized controlled trials of cognitive therapy for depression: comparing the efficiency of EMBASE, MEDLINE and PsycINFO bibliographic databases. Br J Med Psychol. 1999;72(pt 4):535-542.
PubMed   |  Link to Article
Higgins JPT, Altman DG, Sterne JAC. Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [Updated September 2009]. Cochrane Collaboration; 2011. http://handbook.cochrane.org/. Accessed November 10, 2009.
Li  T, Puhan  MA, Vedula  SS, Singh  S, Dickersin  K; Ad Hoc Network Meta-analysis Methods Meeting Working Group.  Network meta-analysis—highly attractive but more methodological research is needed. BMC Med. 2011;9(1):79. doi:10.1186/1741-7015-9-79.
PubMed   |  Link to Article
Mills  EJ, Bansback  N, Ghement  I,  et al.  Multiple treatment comparison meta-analyses: a step forward into complexity. Clin Epidemiol. 2011;3:193-202.
PubMed   |  Link to Article
Puhan  MA, Bachmann  LM, Kleijnen  J, Ter Riet  G, Kessels  AG.  Inhaled drugs to reduce exacerbations in patients with chronic obstructive pulmonary disease: a network meta-analysis. BMC Med. 2009;7:2. doi:10.1186/1741-7015-7-2.
PubMed   |  Link to Article
Salanti  G, Higgins  JP, Ades  AE, Ioannidis  JP.  Evaluation of networks of randomized trials. Stat Methods Med Res. 2008;17(3):279-301.
PubMed   |  Link to Article
Wolff  RF, Bala  MM, Westwood  M, Kessels  AG, Kleijnen  J.  5% Lidocaine–medicated plaster vs other relevant interventions and placebo for post-herpetic neuralgia (PHN): a systematic review. Acta Neurol Scand. 2011;123(5):295-309.
PubMed   |  Link to Article
Higgins  JP, Thompson  SG, Deeks  JJ, Altman  DG.  Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.
PubMed   |  Link to Article
Schwarzer  G.  meta: An R package for meta-analysis. R News.2007;7(3):40-45.
Viechtbauer  W.  Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36(3):1-48.
Adly  C, Straumanis  J, Chesson  A.  Fluoxetine prophylaxis of migraine. Headache. 1992;32(2):101-104.
PubMed   |  Link to Article
Alecrim-Andrade  J, Maciel-Júnior  JA, Carné  X, Correia-Filho  HR, Machado  HC, Vasconcelos  GMS.  Efficacy of acupuncture in migraine attack prophylaxis: a randomized sham-controlled trial. Cephalalgia. 2005;25(10):942.
Alecrim-Andrade  J, Maciel-Júnior  JA, Carnè  X, Severino Vasconcelos  GM, Correa-Filho  HR.  Acupuncture in migraine prevention: a randomized sham controlled study with 6-months posttreatment follow-up. Clin J Pain. 2008;24(2):98-105.
PubMed   |  Link to Article
Alecrim-Andrade  J, Maciel-Júnior  JA, Cladellas  XC, Correa-Filho  HR, Machado  HC.  Acupuncture in migraine prophylaxis: a randomized sham-controlled trial. Cephalalgia. 2006;26(5):520-529.
PubMed   |  Link to Article
Anand  KS, Prasad  A, Singh  MM, Sharma  S, Bala  K.  Botulinum toxin type A in prophylactic treatment of migraine. Am J Ther. 2006;13(3):183-187.
PubMed   |  Link to Article
Andersson  PG, Dahl  S, Hansen  JH,  et al.  Prophylactic treatment of classical and non-classical migraine with metoprolol: a comparison with placebo. Cephalalgia. 1983;3(4):207-212.
PubMed   |  Link to Article
Baust  W, Stürtzbecher  KH.  Management of migraine using acupuncture in a double-blind study [in German]. Med Welt. 1978;29(16):669-673.
PubMed
Blanchard  EB, Appelbaum  KA, Radnitz  CL,  et al.  A controlled evaluation of thermal biofeedback and thermal biofeedback combined with cognitive therapy in the treatment of vascular headache. J Consult Clin Psychol. 1990;58(2):216-224.
PubMed   |  Link to Article
Blanchard  EB, Peters  ML, Hermann  C,  et al.  Direction of temperature control in the thermal biofeedback treatment of vascular headache. Appl Psychophysiol Biofeedback. 1997;22(4):227-245.
PubMed
Bousser  MG, Chick  J, Fuseau  E, Soisson  T, Thevenet  R.  Combined low-dose acetylsalicylic acid and dihydroergotamine in migraine prophylaxis: a double-blind, placebo-controlled crossover study. Cephalalgia. 1988;8(3):187-192.
PubMed   |  Link to Article
Boutouyrie  P, Corvisier  R, Ong  KT,  et al.  Acute and chronic effects of acupuncture on radial artery: a randomized double blind study in migraine. Artery Res. 2010;4(1):7-14.
Link to Article
Brandes  JL, Saper  JR, Diamond  M,  et al; MIGR-002 Study Group.  Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291(8):965-973.
PubMed   |  Link to Article
Brown  JM.  Imagery coping strategies in the treatment of migraine. Pain. 1984;18(2):157-167.
PubMed   |  Link to Article
Cady  R, Schreiber  C.  Botulinum toxin type A as migraine preventive treatment in patients previously failing oral prophylactic treatment due to compliance issues. Headache. 2008;48(6):900-913.
PubMed   |  Link to Article
Cady  RK, Mathew  N, Diener  H-C, Hu  P, Haas  M, Novak  GP; Study Group.  Evaluation of carisbamate for the treatment of migraine in a randomized, double-blind trial. Headache. 2009;49(2):216-226.
PubMed   |  Link to Article
Carasso  RL, Yehuda  S.  The prevention and treatment of migraine with an analgesic combination. Br J Clin Pract. 1984;38(1):25-27.
PubMed
Carrieri  P, Orefice  G, Sorge  F.  Indobufen, a new antiaggregant drug, in the treatment of migraine: a double-blind study compared with placebo. Cephalalgia. 1985;5(suppl 3):546-547.
Ceccherelli  F, Ambrosio  F, Avila  M, Duse  G, Munari  A, Giron  GP.  Acupuncture vs placebo in the common migraine: a double blind study. Cephalalgia. 1987;7(suppl 6):499-500.
Chankrachang  S, Arayawichanont  A, Poungvarin  N,  et al.  Prophylactic botulinum type A toxin complex (Dysport®) for migraine without aura. Headache. 2011;51(1):52-63.
PubMed   |  Link to Article
Cruz  A, Bühling  M, Seibel  K.  Double blind study of migraine therapy with etilefrine pivalate [in German]. Arzneimittelforschung. 1985;35(7):1086-1089.
PubMed
de Tommaso  M, Marinazzo  D, Nitti  L,  et al.  Effects of levetiracetam vs topiramate and placebo on visually evoked phase synchronization changes of alpha rhythm in migraine. Clin Neurophysiol. 2007;118(10):2297-2304.
PubMed   |  Link to Article
Di Trapani  G, Mei  D, Marra  C, Mazza  S, Capuano  A.  Gabapentin in the prophylaxis of migraine: a double-blind randomized placebo-controlled study. Clin Ter. 2000;151(3):145-148.
PubMed
Diener  HC, Föh  M, Iaccarino  C,  et al.  Cyclandelate in the prophylaxis of migraine: a randomized, parallel, double-blind study in comparison with placebo and propranolol: the study group. Cephalalgia. 1996;16(6):441-447.
PubMed   |  Link to Article
Diener  HC, Kronfeld  K, Boewing  G,  et al; GERAC Migraine Study Group.  Efficacy of acupuncture for the prophylaxis of migraine: a multicentre randomised controlled clinical trial. Lancet Neurol. 2006;5(4):310-316.
PubMed   |  Link to Article
Diener  HC, Pfaffenrath  V, Schnitker  J, Friede  M, Henneicke-von Zepelin  HH.  Efficacy and safety of 6.25 mg t.i.d. Feverfew CO2-extract (MIG-99) in migraine prevention: a randomized, double-blind, multicentre, placebo-controlled study. Cephalalgia. 2005;25(11):1031-1041.
PubMed   |  Link to Article
Diener  H-C, Tfelt-Hansen  P, Dahlöf  C,  et al; MIGR-003 Study Group.  Topiramate in migraine prophylaxis: results from a placebo-controlled trial with propranolol as an active control. J Neurol. 2004;251(8):943-950.
PubMed   |  Link to Article
Dowson  A, Mullen  MJ, Peatfield  R,  et al.  Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache [published correction appears in Circulation. 2009;120(9):e71-e72]. Circulation. 2008;117(11):1397-1404.
PubMed   |  Link to Article
Dowson  DI, Lewith  GT, Machin  D.  The effects of acupuncture versus placebo in the treatment of headache. Pain. 1985;21(1):35-42.
PubMed   |  Link to Article
D’Souza  PJ, Lumley  MA, Kraft  CA, Dooley  JA.  Relaxation training and written emotional disclosure for tension or migraine headaches: a randomized, controlled trial. Ann Behav Med. 2008;36(1):21-32.
PubMed   |  Link to Article
Edwards  KR, Potter  DL, Wu  S-C, Kamin  M, Hulihan  J.  Topiramate in the preventive treatment of episodic migraine: a combined analysis from pilot, double-blind, placebo-controlled trials. CNS Spectr. 2003;8(6):428-432.
PubMed
Elkind  AH, O’Carroll  P, Blumenfeld  A, DeGryse  R, Dimitrova  R; BoNTA-024-026-036 Study Group.  A series of three sequential, randomized, controlled studies of repeated treatments with botulinum toxin type A for migraine prophylaxis. J Pain. 2006;7(10):688-696.
PubMed   |  Link to Article
Evers  S, Vollmer-Haase  J, Schwaag  S, Rahmann  A, Husstedt  IW, Frese  A.  Botulinum toxin A in the prophylactic treatment of migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia. 2004;24(10):838-843.
PubMed   |  Link to Article
Facco  E, Liguori  A, Petti  F,  et al.  Traditional acupuncture in migraine: a controlled, randomized study. Headache. 2008;48(3):398-407.
PubMed   |  Link to Article
Freitag  FG, Collins  SD, Carlson  HA,  et al; Depakote ER Migraine Study Group.  A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. 2002;58(11):1652-1659.
PubMed   |  Link to Article
Gauthier  J, Bois  R, Allaire  D, Drolet  M.  Evaluation of skin temperature biofeedback training at two different sites for migraine. J Behav Med. 1981;4(4):407-419.
PubMed   |  Link to Article
Gauthier  J, Doyon  J, Lacroix  R, Drolet  M.  Blood volume pulse biofeedback in the treatment of migraine headache: a controlled evaluation. Biofeedback Self Regul. 1983;8(3):427-442.
PubMed   |  Link to Article
Goadsby  PJ, Ferrari  MD, Csanyi  A, Olesen  J, Mills  JG; Tonabersat TON-01-05 Study Group.  Randomized, double-blind, placebo-controlled, proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in migraine prophylaxis. Cephalalgia. 2009;29(7):742-750.
PubMed   |  Link to Article
Grossman  W, Schmidramsl  H.  An extract of Petasites hybridus is effective in the prophylaxis of migraine. Altern Med Rev. 2001;6(3):303-310.
PubMed
Guyuron  B, Kriegler  JS, Davis  J, Amini  SB.  Comprehensive surgical treatment of migraine headaches. Plast Reconstr Surg. 2005;115(1):1-9.
PubMed
Guyuron  B, Reed  D, Kriegler  JS, Davis  J, Pashmini  N, Amini  S.  A placebo-controlled surgical trial of the treatment of migraine headaches. Plast Reconstr Surg. 2009;124(2):461-468.
PubMed   |  Link to Article
Hauge  AW, Asghar  MS, Schytz  HW, Christensen  K, Olesen  J.  Effects of tonabersat on migraine with aura: a randomised, double-blind, placebo-controlled crossover study. Lancet Neurol. 2009;8(8):718-723.
PubMed   |  Link to Article
Henry  P. Headaches and acupuncture. In: Pfaffenrath  V, Lundberg  PO, Sjaastad  O, eds. Updating in Headache. Berlin, Germany: Springer-Verlag; 1985:208-216.
Høivik  HO, Laurijssens  BE, Harnisch  LO,  et al.  Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. Cephalalgia. 2010;30(12):1458-1467.
PubMed   |  Link to Article
Holroyd  KA, Cottrell  CK, O’Donnell  FJ,  et al.  Effect of preventive (β blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial. BMJ. 2010;341:c4871. doi:10.1136/bmj.c4871.
PubMed   |  Link to Article
Kewman  D, Roberts  AH.  Skin temperature biofeedback and migraine headaches: a double-blind study. Biofeedback Self Regul. 1980;5(3):327-345.
Link to Article
Kubiena  G, Nissel  H, Porenta  G, Veitl  M, Wessely  P.  Acupuncture in migraine: follow-up study [in German]. Deutsche Zeitschrift fur Akupunktur.1992;35(6):140-148.
Leandri  M, Rigardo  S, Schizzi  R, Parodi  CI.  Migraine treatment with nicardipine. Cephalalgia. 1990;10(3):111-116.
PubMed   |  Link to Article
Linde  K, Streng  A, Jürgens  S,  et al.  Acupuncture for patients with migraine: a randomized controlled trial. JAMA. 2005;293(17):2118-2125.
PubMed   |  Link to Article
Lipton  RB, Göbel  H, Einhäupl  KM, Wilks  K, Mauskop  A.  Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology. 2004;63(12):2240-2244.
PubMed   |  Link to Article
Louis  P.  A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Headache. 1981;21(6):235-239.
PubMed   |  Link to Article
Maizels  M, Blumenfeld  A, Burchette  R.  A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache. 2004;44(9):885-890.
PubMed   |  Link to Article
Mei  D, Capuano  A, Vollono  C,  et al.  Topiramate in migraine prophylaxis: a randomised double-blind versus placebo study. Neurol Sci. 2004;25(5):245-250.
PubMed   |  Link to Article
Mendenopoulos  G, Manafi  T, Logothetis  I, Bostantjopoulou  S.  Flunarizine in the prevention of classical migraine: a placebo-controlled evaluation. Cephalalgia. 1985;5(1):31-37.
PubMed   |  Link to Article
Mikkelsen  B, Pedersen  KK, Christiansen  LV.  Prophylactic treatment of migraine with tolfenamic acid, propranolol and placebo. Acta Neurol Scand. 1986;73(4):423-427.
PubMed   |  Link to Article
Mullinix  JM, Norton  BJ, Hack  S, Fishman  MA.  Skin temperature biofeedback and migraine. Headache. 1978;17(6):242-244.
PubMed   |  Link to Article
Orholm  M, Honoré  PF, Zeeberg  I.  A randomized general practice group-comparative study of femoxetine and placebo in the prophylaxis of migraine. Acta Neurol Scand. 1986;74(3):235-239.
PubMed   |  Link to Article
Osterman  PO.  A comparison between placebo, pizotifen and 1-isopropyl-3-hydroxy-5-semicarbazono-6-oxo-2.3.5.6-tetrahydroindol (Divascan) in migraine prophylaxis. Acta Neurol Scand. 1977;56(1):17-28.
PubMed   |  Link to Article
Peikert  A, Wilimzig  C, Köhne-Volland  R.  Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 1996;16(4):257-263.
PubMed   |  Link to Article
Petri  S, Tölle  T, Straube  A, Pfaffenrath  V, Stefenelli  U, Ceballos-Baumann  A; Dysport Migraine Study Group.  Botulinum toxin as preventive treatment for migraine: a randomized double-blind study. Eur Neurol. 2009;62(4):204-211.
PubMed   |  Link to Article
Pfaffenrath  V, Diener  HC, Fischer  M, Friede  M, Henneicke-von Zepelin  HH; Investigators.  The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis: a double-blind, multicentre, randomized placebo-controlled dose-response study. Cephalalgia. 2002;22(7):523-532.
PubMed   |  Link to Article
Pfaffenrath  V, Wessely  P, Meyer  C,  et al.  Magnesium in the prophylaxis of migraine: a double-blind placebo-controlled study. Cephalalgia. 1996;16(6):436-440.
PubMed   |  Link to Article
Saper  JR, Mathew  NT, Loder  EW, DeGryse  R, VanDenburgh  AM; BoNTA-009 Study Group.  A double-blind, randomized, placebo-controlled comparison of botulinum toxin type A injection sites and doses in the prevention of episodic migraine. Pain Med. 2007;8(6):478-485.
PubMed   |  Link to Article
Silberstein  S, Mathew  N, Saper  J, Jenkins  S; BOTOX Migraine Clinical Research Group.  Botulinum toxin type A as a migraine preventive treatment. Headache. 2000;40(6):445-450.
PubMed   |  Link to Article
Silberstein  SD, Hulihan  J, Karim  MR,  et al.  Efficacy and tolerability of topiramate 200 mg/d in the prevention of migraine with/without aura in adults: a randomized, placebo-controlled, double-blind, 12-week pilot study. Clin Ther. 2006;28(7):1002-1011.
PubMed   |  Link to Article
Silberstein  SD, Neto  W, Schmitt  J, Jacobs  D; MIGR-001 Study Group.  Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol. 2004;61(4):490-495.
PubMed   |  Link to Article
Siniatchkin  M, Andrasik  F, Kropp  P,  et al.  Central mechanisms of controlled-release metoprolol in migraine: a double-blind, placebo-controlled study. Cephalalgia. 2007;27(9):1024-1032.
PubMed   |  Link to Article
Sjaastad  O, Stensrud  P.  Appraisal of BC-105 in migraine prophylaxis. Acta Neurol Scand. 1969;45(5):594-600.
PubMed   |  Link to Article
Somerville  BW, Herrmann  WM.  Migraine prophylaxis with Lisuride hydrogen maleate—a double blind study of Lisuride versus placebo. Headache. 1978;18(2):75-79.
PubMed   |  Link to Article
Spigt  MG, Kuijper  EC, Schayck  CP,  et al.  Increasing the daily water intake for the prophylactic treatment of headache: a pilot trial. Eur J Neurol. 2005;12(9):715-718.
PubMed   |  Link to Article
Storey  JR, Calder  CS, Hart  DE, Potter  DL.  Topiramate in migraine prevention: a double-blind, placebo-controlled study. Headache. 2001;41(10):968-975.
PubMed   |  Link to Article
Straumsheim  P, Borchgrevink  C, Mowinckel  P, Kierulf  H, Hafslund  O.  Homeopathic treatment of migraine: a double blind, placebo controlled trial of 68 patients. Br Homeopath J. 2000;89(1):4-7.
PubMed   |  Link to Article
Teepker  M, Hötzel  J, Timmesfeld  N,  et al.  Low-frequency rTMS of the vertex in the prophylactic treatment of migraine. Cephalalgia. 2010;30(2):137-144.
PubMed
Tuchin  PJ, Pollard  H, Bonello  R.  A randomized controlled trial of chiropractic spinal manipulative therapy for migraine. J Manipulative Physiol Ther. 2000;23(2):91-95.
PubMed   |  Link to Article
Vahedi  K, Taupin  P, Djomby  R,  et al; DIAMIG Investigators.  Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomised placebo-controlled trial. J Neurol. 2002;249(2):206-211.
PubMed   |  Link to Article
Vo  AH, Satori  R, Jabbari  B,  et al.  Botulinum toxin type-a in the prevention of migraine: a double-blind controlled trial. Aviat Space Environ Med. 2007;78(5)(suppl):B113-B118.
PubMed
Weber  RB, Reinmuth  OM.  The treatment of migraine with propranolol. Neurology. 1972;22(4):366-369.
PubMed   |  Link to Article
Weinschütz  T, Niederberger  U, Johnsen  S, Schreiber  C, Kropp  P.  The neuroregulative effects of acupuncture in patients with headache [in German]. Deutsche Zeitschrift fur Akupunktur.1994;37(5):106-117.
Hróbjartsson  A, Gøtzsche  PC.  Placebo interventions for all clinical conditions. Cochrane Database Syst Rev. 2010;(1):CD003974.
PubMed
Linde  K, Niemann  K, Meissner  K.  Are sham acupuncture interventions more effective than (other) placebos? a re-analysis of data from the Cochrane review on placebo effects. Forsch Komplementmed. 2010;17(5):259-264.
PubMed   |  Link to Article
Meissner  K, Bingel  U, Colloca  L, Wager  TD, Watson  A, Flaten  MA.  The placebo effect: advances from different methodological approaches. J Neurosci. 2011;31(45):16117-16124.
PubMed   |  Link to Article
Benedetti  F, Amanzio  M.  The placebo response: how words and rituals change the patient’s brain. Patient Educ Couns. 2011;84(3):413-419.
PubMed   |  Link to Article
Kaptchuk  TJ.  Placebo studies and ritual theory: a comparative analysis of Navajo, acupuncture and biomedical healing. Philos Trans R Soc Lond B Biol Sci. 2011;366(1572):1849-1858.
PubMed   |  Link to Article
Kerr  CE, Shaw  JR, Conboy  LA, Kelley  JM, Jacobson  E, Kaptchuk  TJ.  Placebo acupuncture as a form of ritual touch healing: a neurophenomenological model. Conscious Cogn. 2011;20(3):784-791.
PubMed   |  Link to Article
Birch  S.  A review and analysis of placebo treatments, placebo effects, and placebo controls in trials of medical procedures when sham is not inert. J Altern Complement Med. 2006;12(3):303-310.
PubMed   |  Link to Article
Lund  I, Lundeberg  T.  Are minimal, superficial or sham acupuncture procedures acceptable as inert placebo controls? Acupunct Med. 2006;24(1):13-15.
PubMed   |  Link to Article
Macedo  A, Farré  M, Baños  JE.  A meta-analysis of the placebo response in acute migraine and how this response may be influenced by some of the characteristics of clinical trials. Eur J Clin Pharmacol. 2006;62(3):161-172.
PubMed   |  Link to Article
Brunoni  AR, Lopes  M, Kaptchuk  TJ, Fregni  F.  Placebo response of non-pharmacological and pharmacological trials in major depression: a systematic review and meta-analysis. PLoS One. 2009;4(3):e4824.
PubMed   |  Link to Article
Hróbjartsson  A, Kaptchuk  TJ, Miller  FG.  Placebo effect studies are susceptible to response bias and to other types of biases. J Clin Epidemiol. 2011;64(11):1223-1229.
PubMed   |  Link to Article

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eTable 1. Search strategy for MEDLINE

eTable 2. Characteristics of the 79 studies included in the meta-analyses

eTable 3. Subgroup analyses for proportion of placebo responders

eTable 4. Multivariable analyses for proportions of placebo responders

eTable 5. Subgroup analyses according to type of placebo treatment for the 17 studies reporting pretreatment to posttreatment changes of continuous outcomes

eTable 6. Subgroup analyses according to type of placebo treatment for the specific effects in the 38 studies reporting posttreatment values of continuous outcomes

eTable 7. Results of the network meta-analysis from 7 studies reporting pretreatment to posttreatment changes of continuous outcomes

eTable 8. Results of the network meta-analysis from 11 studies reporting posttreatment values of continuous outcomes

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