Placebos and placebo effects

The last time Geneesmiddelenbulletin discussed the topic of placebos and placebo effects was in Gebu 1997; 31: 1-6. The article elaborated on a number of factors that may co-occur with the placebo effect, namely the interaction between care provider and patient and the natural course of the disorder. The present article adds to this a description of the various other factors that contribute to the placebo effect. The article in Gebu 1997; 31: 1-6 mainly discussed the use of placebos in clinical practice. The current state of affairs with regard to this use will be discussed in a future feature article. At the time of the 1997 article, calculations of the results of treatments in clinical research studies often did not include the influence of environmental factors on the natural course of disorders, which resulted in too high success rates being reported. Since then, much has been found out about the use of placebos in randomised trials, including the factors involved and their influence on the outcome in terms of the efficacy of the drug. The use of placebo-controlled research is now extensively discussed in various guidelines published by regulatory authorities. The differences between such guidelines show, however, that the debate on these matters has certainly not been finalised.

Not everyone knows the definitions of placebo response and placebo effect, and the two are often used interchangeably. The placebo effect is the effect that results from the treatment with a placebo, while the placebo response consists of the placebo effect plus other effects that may arise independent of the treatment. It is important to keep this distinction in mind when reading research reports on studies involving placebo and to critically analyse whether what is described in the report is what was actually studied. It is not only the placebo effect which can contribute to the placebo response, but also the effects of the interaction between care provider and patient, socially desirable behaviour, co-interventions and other non-specific effects. Some doubt has been raised as to whether the Hawthorne effect really exists, and the effects attributed to this factor in research studies could also be attributed to socially desirable behaviour or the interaction between care provider and patient. The placebo effect is largely caused by expectations and conditioning. All these factors may result not only in positive effects, but also in negative effects, the so-called nocebo effect.

There has been no well-designed and structured research to assess the degree to which the various factors contribute to the placebo response. Nor is it clear whether the additive model can be applied, and whether the pharmacological effect can be determined by subtracting the placebo response from the drug response. In other words, it is uncertain whether the placebo effect is the same in the drug response and the placebo response.

No unequivocal explanation can as yet be given for an increase in the placebo response over time. The regulatory authorities are aware of the fact that some disorders show a high and variable placebo response. There is a need for more research to determine what causes this and how it can be taken into account, in order to improve our understanding of the pharmacological effect of a drug. The FDA’s enrichment strategies designed for this purpose, including the placebo lead-in phase, appear to increase the risk that an ineffective drug is incorrectly authorised, and their use is thus to be discouraged.

Finally, the present article discusses registration studies of antidepressants. The response to antidepressants involves a variable and possibly increasing placebo response, which might provide one of the possible explanations for the fact that it is sometimes impossible to prove their efficacy. As regards the possible increase in the placebo response to antidepressants, as well as to antipsychotics and drugs to treat Crohn’s disease, colitis ulcerosa and epilepsy, the article mostly discusses the study design. Debatable aspects include the clinical relevance of the reported differences in outcome measures, the choice of scales used to measure the alleviation of symptoms and the use of placebo in the control arm. In any case, the use of enrichment strategies that increase the probability of favourable results is not the right method to find drugs with good and proven efficacy to add to the available treatment options.

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*The literature refers to the Dutch text