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  • Rémy Boussageon,
  • Jeremy Howick,
  • Raphael Baron,
  • florian naudet,
  • bruno falissard,
  • Ghina Harika-Germaneau,
  • Issa Wassouf,
  • François Gueyffier,
  • Nemat Jaafari,
  • Clara Blanchard
Rémy Boussageon
Université Claude Bernard Lyon 1

Corresponding Author:[email protected]

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Jeremy Howick
University of Oxford
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Raphael Baron
Universite Lyon 1 Faculte de Medecine Lyon-Est
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florian naudet
University Hospital Centre Rennes
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bruno falissard
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Ghina Harika-Germaneau
Centre Hospitalier Henri Laborit
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Issa Wassouf
Centre Hospitalier Henri Laborit
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François Gueyffier
Centre Hospitalier Universitaire de Lyon
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Nemat Jaafari
Centre Hospitalier Henri Laborit
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Clara Blanchard
University of Poitiers
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Aim: The placebo effect and the specific effect are often thought to add up (additive model). Whether this is true or whether there is an interaction between the two, can modify the external validity of a trial. This assumption of additivity was tested by Kleijnen et al. in 1994 but the data produced since then has not been synthetized. In this review, we aimed to systematically review the literature to determine whether additivity held. Methods: We searched Medline and Psychinfo up to 10/01/2019. Studies using the balanced placebo design (BPD), testing two different strengths of placebos, were included. The presence of interaction was evaluated by comparing each group in BPD with analysis of variance or covariance. Results: 30 studies were included and the overall risk of bias was high: four found evidence of additivity and 16 studies found evidence of interaction (seven had evidence of positive additivity). Conclusion: Evidence of additivity between placebo and specific features of treatments was rare in our sample. For ailments that are placebo-responsive, pragmatic trials should be preferred to increase their external validity.
29 Sep 2021Submitted to British Journal of Clinical Pharmacology
30 Sep 2021Submission Checks Completed
30 Sep 2021Assigned to Editor
02 Oct 2021Reviewer(s) Assigned
14 Oct 2021Review(s) Completed, Editorial Evaluation Pending
08 Nov 2021Editorial Decision: Revise Major
20 Jan 20221st Revision Received
21 Jan 2022Submission Checks Completed
21 Jan 2022Assigned to Editor
21 Jan 2022Review(s) Completed, Editorial Evaluation Pending
23 Jan 2022Reviewer(s) Assigned
24 Feb 2022Editorial Decision: Revise Minor
25 Mar 20222nd Revision Received
26 Mar 2022Submission Checks Completed
26 Mar 2022Assigned to Editor
26 Mar 2022Review(s) Completed, Editorial Evaluation Pending
27 Mar 2022Editorial Decision: Accept
Aug 2022Published in British Journal of Clinical Pharmacology volume 88 issue 8 on pages 3638-3656. 10.1111/bcp.15345