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.

An exploration of the relationship between placebo and homeopathy and the implications for clinical trial design

“…Walach 4 recognizes that the individual psychological and psychosomatic receptive action on the part of the patient is relevant to therapeutic success.…”

Introduction to placebo effects in medicine: mechanisms and clinical implications

“…Harald Walach [44] introduces the reader to historical notes of the placebo effect when inert substances and procedures were introduced as control conditions. He then describes the efficacy paradox of sham interventions pointing to the fact that sham interventions frequently turn out to be more powerful than proved, evidence-based treatments.…”

“…During the pre-pharmacological age it was quite customary to distribute sugar pills or other pharmacologically inactive substances to sooth the patient, to test for 'real illness' or to placate people, when no real effective treatment was known [44]. Even nowadays, physicians and nurses use placebo interventions regularly in clinical practice for very similar reasons as the healers did before the rise of modern medicine [57].…”

“…Moreover, recent analyses suggest that placebo effects may vary considerably both between treatment arms and across studies [42][43][44]. For example, there is mounting evidence that an increased likelihood to receive active treatment-which may be regarded a proxy for the degree of expectation of improvement-is associated with better outcome in the respective placebo groups, thereby potentially affecting conclusions about the efficacy of active treatment [45][46][47][48][49].…”

“…This paradox, which has been theoretically described and termed the 'efficacy paradox' [44], has recently become reality in two large acupuncture studies [55,56]. Implications for clinical trial methodology need to be discussed [42,44].…”