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Review
. 2018 Dec 11;19(1):674.
doi: 10.1186/s13063-018-3042-4.

Rapid overview of systematic reviews of nocebo effects reported by patients taking placebos in clinical trials

Jeremy Howick  1 , Rebecca Webster  2 , Nigel Kirby  3 , Kerry Hood  4
Affiliations
Review

Rapid overview of systematic reviews of nocebo effects reported by patients taking placebos in clinical trials

Jeremy Howick et al. Trials. .

Abstract

Background: Trial participants in placebo groups report experiencing adverse events (AEs). Existing systematic reviews have not been synthesized, leaving questions about why these events occur as well as their prevalence across different conditions unanswered.

Objectives: (1) To synthesize the evidence of prevalence of AEs in trial placebo groups across different conditions. (2) To compare AEs in trial placebo groups with AEs reported in untreated groups within a subset of randomized trials.

Search methods: We searched PubMed for records with the word "nocebo" in the title and "systematic" in any field. We also contacted experts and hand-searched references of included studies.

Study eligibility: We included any systematic review of randomized trials where nocebo effects were reported. We excluded systematic reviews of non-randomized studies.

Participants and interventions: We included studies in any disease area.

Study appraisal and synthesis methods: We appraised the quality of the studies using a shortened version of the Assessment of Multiple Systematic Reviews tool (AMSTAR) tool. We reported medians and interquartile ranges (IQRs) of AEs. Among the trials within the review that included untreated groups, we compared the prevalence of AEs in untreated groups with the prevalence of AEs in placebo groups.

Results: We identified 20 systematic reviews. These included 1271 randomized trials and 250,726 placebo-treated patients. The median prevalence of AEs in trial placebo groups was 49.1% (IQR 25.7-64.4%). The median rate of dropouts due to AEs was 5% (IQR 2.28-8.4%). Within the 15 of trials that reported AEs in untreated groups, we found that the AE rate in placebo groups (6.51%) was higher than that reported in untreated groups (4.25%).

Limitations: This study was limited by the quality of included reviews and the small number of trials that included untreated groups.

Conclusions and implications of key findings: AEs in trial placebo groups are common and cannot be attributed entirely to natural history. Trial methodologies that reduce AEs in placebo groups while satisfying the requirement of informed consent should be developed and implemented.

Keywords: Adverse events; Nocebo; Placebo; Randomized trial; Systematic review.

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Conflict of interest statement

Authors’ information

Rebecca Webster is affiliated to the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emergency Preparedness and Response at King’s College London in partnership with Public Health England (PHE), in collaboration with the University of East Anglia and Newcastle University. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. The funders had no input in the writing of and the decision to submit this article.

Ethics approval and consent to participate

This is a systematic review; consent not required.

Consent for publication

The corresponding and all other authors give consent to Trials to publish this manuscript.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
PRISMA diagram records
See this image and copyright information in PMC

References

    1. Jensen KB, Kaptchuk TJ, Chen X, Kirsch I, Ingvar M, Gollub RL, et al. A neural mechanism for nonconscious activation of conditioned placebo and nocebo responses. Cereb Cortex. 2014;25(10):3903–10. - PMC - PubMed
    1. Jensen KB, Kaptchuk TJ, Kirsch I, Raicek J, Lindstrom KM, Berna C, et al. Nonconscious activation of placebo and nocebo pain responses. Proc Natl Acad Sci U S A. 2012;109(39):15959–15964. doi: 10.1073/pnas.1202056109. - DOI - PMC - PubMed
    1. Howick J. Saying things the “right” way: avoiding “nocebo” effects and providing full informed consent. Am J Bioeth. 2012;12(3):33–34. doi: 10.1080/15265161.2012.656799. - DOI - PubMed
    1. Mercado R, Constantoyannis C, Mandat T, Kumar A, Schulzer M, Stoessl AJ, et al. Expectation and the placebo effect in Parkinson’s disease patients with subthalamic nucleus deep brain stimulation. Mov Disord. 2006;21(9):1457–1461. doi: 10.1002/mds.20935. - DOI - PubMed
    1. Whitford HS, Olver IN. When expectations predict experience: the influence of psychological factors on chemotherapy toxicities. J Pain Symptom Manag. 2012;43(6):1036–1050. doi: 10.1016/j.jpainsymman.2011.06.026. - DOI - PubMed

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