Placebo controls: historical, methodological and general aspects

Abstract

Control conditions were introduced through the trial of Mesmerism in Paris. Placebo controls became codified standard in 1946. Although seemingly unchallenged, there are various problems with this received view. The notion of a placebo is only defined from the negative. A positive notion proposed that placebo effects are effects owing to the meaning an intervention has for an individual. Thus, placebo effects are individualized, whereas standard research paradigms reveal only grossly averaged behaviour. Also, placebo effects are context sensitive, dependent on psychological factors such as expectancy, relief of stress and anxiety, and hence can generate strong and long-lasting treatment effects. These, however, are not predictable. Such a situation can lead to the efficacy paradox: sometimes, sham interventions can be more powerful than proved, evidence-based treatments. This situation has methodological consequences. Placebo-controlled randomized trials reveal only part of the answer, whether an intervention is effective. This is valuable information for regulators, but not necessarily also for patients and of limited value for providers. Hence, I have argued that we need to complement the hierarchical model of evidence by a circular one, in which various methods are employed on equal footing to answer different questions.

Figure 1.

Cause–effect relationship between pharmacological agent and effect. Individual factors are conceived as perturbations that need to be controlled or clarified. The relationship between cause and effect is bivalent with only two elements.

Figure 2.

Triadic semiotic relationship. What is a dyadic relationship between cause and effect in the mechanistic model becomes a triadic relationship. The cause–effect relationship is mediated by the meaning that the intervention has as a sign.

Figure 3.

The Efficacy Paradox. A trial might prove one intervention (treatment y) as efficacious, because it is superior to a placebo control, yet this efficacious treatment might be ineffective compared with another treatment (treatment x), which is indistinguishable from its own placebo (placebo x), because the non-specific effects in treatment x are larger.