Does the model of additive effect in placebo research still hold true? A narrative review.

Personalised and contextualised care has been turned into a major demand by people involved in healthcare suggesting to move toward person-centred medicine. The assessment of person-centred medicine can be most effectively achieved if treatments are investigated using 'with versus without' person-centredness or integrative study designs. However, this assumes that the components of an integrative or person-centred intervention have an additive relationship to produce the total effect. Beecher's model of additivity assumes an additive relation between placebo and drug effects and is thus presenting an arithmetic summation. So far, no review has been carried out assessing the validity of the additive model, which is to be questioned and more closely investigated in this review. Initial searches for primary studies were undertaken in July 2016 using Pubmed and Google Scholar. In order to find matching publications of similar magnitude for the comparison part of this review, corresponding matches for all included reviews were sought. A total of 22 reviews and 3 clinical and experimental studies fulfilled the inclusion criteria. The results pointed to the following factors actively questioning the additive model: interactions of various effects, trial design, conditioning, context effects and factors, neurobiological factors, mechanism of action, statistical factors, intervention-specific factors (alcohol, caffeine), side-effects and type of intervention. All but one of the closely assessed publications was questioning the additive model. A closer examination of study design is necessary. An attempt in a more systematic approach geared towards solutions could be a suggestion for future research in this field.