We're unable to sign you in at this time. Please try again in a few minutes.
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
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.
Text Size: A A A
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

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal


Place holder to copy figure label and caption
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

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

This flowchart depicts the selection of the 79 studies.

Graphic Jump Location
Place holder to copy figure label and caption
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).

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location




Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment


Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 5

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles