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, 139, 407-441

Placebo and Active Treatment Additivity in Placebo Analgesia: Research to Date and Future Directions

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Placebo and Active Treatment Additivity in Placebo Analgesia: Research to Date and Future Directions

Matthew J Coleshill et al. Int Rev Neurobiol.

Abstract

Placebo analgesia is a robust experimental and clinical phenomenon. While our understanding of the mechanisms of placebo analgesia has developed rapidly, some central questions remain unanswered. Among the important questions is how placebo analgesia interacts with active analgesic effects. It is an assumption underlying double-blind randomized placebo-controlled trials (RCTs) that the true effect of a treatment can be determined by examining the effect of the active treatment arm and subtracting the response in the placebo group ("the assumption of additivity"). However, despite the importance of this assumption for the interpretation of RCTs, it has rarely been formally examined. This article reviews the assumption of additivity in placebo analgesia by examining studies employing factorial designs manipulating both the receipt of an active analgesic and instructions about the treatment being delivered. In reviewing the literature, we identified seven studies that allowed a test of additivity. Of these, four found evidence against additivity, while the remaining three studies found results consistent with additivity. While the limited available data are somewhat mixed, the evidence suggests that at least under some conditions the assumption of additivity does not hold in placebo analgesia. The concordance between mechanisms of the active analgesic and placebo analgesia may influence whether additivity occurs or not. However, more research using factorial designs is needed to disentangle the relationship between placebo analgesia and the active effect of analgesic treatments.

Keywords: Additivity; Drug interaction; Expectancy; Pain; Placebo analgesia; Placebo effect; Randomized controlled trials.

Figures

Fig. 1
Fig. 1
A graphical depiction of a placebo-controlled RCT.
Fig. 2
Fig. 2
Graphical representations of (A) additive, (B) subadditive, and (C) superadditive outcomes. In these outcomes, the first column indicates treatment efficacy when administered under normal circumstances (i.e., an active treatment is administered with the full awareness of the recipient). In contrast, the following two columns depict the isolated active treatment and placebo effects and the fourth column their summed total.
Fig. 3
Fig. 3
The four cells of the balanced placebo (A) and open-hidden (B) designs.
Fig. 4
Fig. 4
Flow chart depicting the study selection process.

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