title: The magnitude and temporal changes of response in the placebo arm of surgical randomized controlled trials: a systematic review and meta-analysis.
abstract: Understanding changes in the placebo arm is essential for correct design and interpretation of randomized controlled trials (RCTs). It is assumed that placebo response, defined as the total improvement in the placebo arm of surgical trials, is large; however, its precise magnitude and properties remain to be characterized. To the best of our knowledge, the temporal changes in the placebo arm have not been investigated. The aim of this paper was to determine, in surgical RCTs, the magnitude of placebo response and how it is affected by duration of follow-up.
  
  
  
  The databases of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched from their inception to 20 October 2015 for studies comparing the efficacy of a surgical intervention with placebo. Inclusion was not limited to any particular condition, intervention, outcome or patient population. The magnitude of placebo response was estimated using standardized mean differences (SMDs). Study estimates were pooled using random effects meta-analysis. Potential sources of heterogeneity were evaluated using stratification and meta-regression.
  
  
  
  Database searches returned 88 studies, but for 41 studies SMDs could not be calculated, leaving 47 trials (involving 1744 participants) eligible for inclusion. There were no temporal changes in placebo response within the analysed trials. Meta-regression analysis showed that duration of follow-up did not have a significant effect on the magnitude of the placebo response and that the strongest predictor of placebo response was subjectivity of the outcome. The pooled effect in the placebo arm of studies with subjective outcomes was large (0.64, 95% CI 0.5 to 0.8) and remained significantly different from zero regardless of the duration of follow-up, whereas for objective outcomes, the effect was small (0.11, 95% CI 0.04 to 0.26) or non-significant across all time points.
  
  
  
  This is the first study to investigate the temporal changes of placebo response in surgical trials and the first to investigate the sources of heterogeneity of placebo response. Placebo response in surgical trials was large for subjective outcomes, persisting as a time-invariant effect throughout blinded follow-up. Therefore, placebo response cannot be minimized in these types of outcomes through their appraisal at alternative time points. The analyses suggest that objective outcomes may be preferable as trial end-points. Where subjective outcomes are of primary interest, a placebo arm is necessary to control for placebo response.
authors.affiliation: Oxford NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK. karolina.wartolowska@ndorms.ox.ac.uk.|Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. karolina.wartolowska@ndorms.ox.ac.uk.
authors.forename: Karolina A
authors.initials: KA
authors.lastname: Wartolowska
authors.affiliation: Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Feakins
authors.affiliation: Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.|Centre for Statistics in Medicine, University of Oxford, Oxford, UK.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Collins
authors.affiliation: Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cook
authors.affiliation: Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.|MRC Lifecourse Epidemiology Unit, University of Southampton, Oxford, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Judge
authors.affiliation: Oxford NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK.|Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Ines
authors.initials: I
authors.lastname: Rombach
authors.affiliation: Oxford NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK.|Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Benjamin J F
authors.initials: BJ
authors.lastname: Dean
authors.affiliation: Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Oxford NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK.|Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carr
mesh_terms: D023381:Endpoint Determination; D006801:Humans; D015990:Placebo Effect; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D013514:Surgical Procedures, Operative; D013997:Time Factors; D016896:Treatment Outcome
keywords: Meta-analysis; Placebos; Randomized controlled trials; Surgery; Systematic review