University of Oulu

Karjalainen T, Heikkinen J, Busija L, et al. Use of Placebo and Nonoperative Control Groups in Surgical Trials: A Systematic Review and Meta-analysis. JAMA Netw Open. 2022;5(7):e2223903. doi:10.1001/jamanetworkopen.2022.23903

Use of placebo and nonoperative control groups in surgical trials : a systematic review and meta-analysis

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Author: Karjalainen, Teemu1,2,3; Heikkinen, Juuso4; Busija, Ljoudmila5;
Organizations: 1Department of Surgery, Hospital Nova Central Finland, Jyvaskyla, Finland
2Monash Department of Clinical Epidemiology, Cabrini Institute, Malvern, Australia
3School of Public Health and Preventive Medicine, Department of Epidemiology and Preventive Medicine, Monash University, Malvern, Australia
4Department of Orthopaedics, Oulu University Hospital, Oulu, Finland
5Biostatistical Consulting Platform, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
6Tampere University and Tampere University Hospital, Tampere, Finland
7Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, UNSW Sydney, Liverpool, New South Wales, Australia
8South Western Sydney Clinical School, UNSW, Liverpool Hospital, New South Wales, Australia
9Sydney Orthopaedic Trauma and Reconstructive Surgery, Kogarah, New South Wales, Australia
10Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University
11Monash Department of Musculoskeletal Health and Clinical Epidemiology, Cabrini Health, Melbourne, Australia
12St George and Sutherland Clinical School, UNSW Sydney, Kogarah, New South Wales, Australia
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1 MB)
Persistent link:
Language: English
Published: American Medical Association, 2022
Publish Date: 2023-07-07


Importance: Nonspecific effects, particularly placebo effects, are thought to contribute significantly to the observed effect in surgical trials.

Objective: To estimate the proportion of the observed effect of surgical treatment that is due to nonspecific effects (including the placebo effect).

Data Sources: Published Cochrane reviews and updated, extended search of MEDLINE, Embase, and CENTRAL until March 2019.

Study Selection: Published randomized placebo-controlled surgical trials and trials comparing the effect of the same surgical interventions with nonoperative controls (ie, no treatment, usual care, or exercise program).

Data Extraction and Synthesis: Pairs of authors independently screened the search results, assessed full texts to identify eligible studies and the risk of bias of included studies, and extracted data. The proportion of all nonspecific effects was calculated as the change in the placebo control divided by the change in the active surgery and pooled in a random-effect meta-analysis. To estimate the magnitude of the placebo effect, we pooled the difference in outcome between placebo and nonoperative controls and used metaregression to estimate the association between the type of control group and the treatment effect (difference between the groups), adjusting for risk of bias, sample size, and type of outcome.

Main Outcomes and Measures: Between- and within-group effect sizes expressed as Hedges g.

Results: In this review, 100 trials were included comprising data from 62 trials with placebo controls (3 also included nonoperative controls), and 38 trials with nonoperative controls (32 interventions; 10 699 participants). Risk of bias across trials was comparable except for performance and detection bias, which was high in trials with nonoperative controls. The mean nonspecific effects accounted for 67% (95% CI, 61% to 73%) of the observed change after surgery; however, this varied widely between different procedures. The estimated surgical placebo effect had a standardized mean difference (SMD) of 0.13 (95% CI, −0.26 to 0.51). Trials with placebo and nonoperative controls found comparable treatment effects (SMD, −0.09 [95% CI, −0.35 to 0.18]; 15 interventions; 73 between-group effects; adjusted analysis: SMD, −0.11 [95% CI, −0.37 to 0.15]).

Conclusions and Relevance: In this review, the change in health state after surgery was composed largely of nonspecific effects, but no evidence supported a large placebo effect. Placebo-controlled surgical trials may be redundant when trials with nonoperative controls consistently report no substantial association from surgery compared with nonoperative treatment.

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Series: JAMA network open
ISSN: 2574-3805
ISSN-E: 2574-3805
ISSN-L: 2574-3805
Volume: 5
Issue: 7
Article number: e2223903
DOI: 10.1001/jamanetworkopen.2022.23903
Type of Publication: A2 Review article in a scientific journal
Field of Science: 3126 Surgery, anesthesiology, intensive care, radiology
Funding: Dr Karjalainen reported receiving grants from the Finnish Medical Foundation during the conduct of the study. Dr Buchbinder reported receiving support from an Australian National Health and Medical Research fellowship during the conduct of the study. Dr Busija reported receiving consulting fees from the Charité Universitätsmedizin Berlin, Jesuit Social Services Victoria, and Swinburne University of Technology outside the submitted work. No other disclosures were reported.
Copyright information: © 2022 Karjalainen T et al. JAMA Network Open. This is an open access article distributed under the terms of the CC-BY License.