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Original Investigation |

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

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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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.

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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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