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\begin{document}

\title{HOW DO THEY ADD UP? THE INTERACTION BETWEEN THE PLACEBO AND TREATMENT
EFFECT : A SYSTEMATIC REVIEW.}



\author[1]{Rémy Boussageon}%
\author[2]{Jeremy Howick}%
\author[3]{Raphael Baron}%
\author[4]{florian naudet}%
\author[5]{bruno falissard}%
\author[6]{Ghina Harika-Germaneau}%
\author[6]{Issa Wassouf}%
\author[7]{François Gueyffier}%
\author[6]{Nemat Jaafari}%
\author[8]{Clara Blanchard}%
\affil[1]{Université Claude Bernard Lyon 1}%
\affil[2]{University of Oxford}%
\affil[3]{Universite Lyon 1 Faculte de Medecine Lyon-Est}%
\affil[4]{University Hospital Centre Rennes}%
\affil[5]{INSERM}%
\affil[6]{Centre Hospitalier Henri Laborit}%
\affil[7]{Centre Hospitalier Universitaire de Lyon}%
\affil[8]{University of Poitiers}%


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  \date{June 17, 2024}


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\begin{abstract}
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.%
\end{abstract}%



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