REVIEW
The placebo–nocebo response: Controversies and challenges from clinical and research perspective

https://doi.org/10.1016/j.euroneuro.2013.11.014Get rights and content

Abstract

Placebo and nocebo responses fascinate, confuse, mystify and challenge. They are genuine social, cultural and psychobiological phenomena which can significantly modify the overall treatment outcome. The placebo–nocebo phenomenon represents a very good model for our better understanding the role of treatment context and how the words, indices, symbols and icons act on our brains. Placebo response is associated with reward expectancy and relief of anticipatory anxiety, while nocebo response is related to lack of reward/positive expectancy and to increase of anticipatory anxiety. Placebo–nocebo responses are mediated through changes in various cortico-subcortical networks and psychophysiological systems. In spite of many existing complementary theories and still growing research on placebo and nocebo response, the implementation of our current knowledge to benefit basic research, clinical trials and routine clinical practice is still so scarce.

Introduction

“Fortis imaginatio generat casum”

A powerful imagination generates the event

(Michel de Montaigne)

The placebo–nocebo phenomenon is subject to an increasing and heated debate, and extensive controversial research. For time being it represents a huge challenge to contemporary psychiatry as well as to medicine in general. Although “the history of medicine is the history of placebo” (Czerniak and Davidson, 2012), it is not only a conundrum (Jubb and Bensing, 2013), but a big puzzle wrapped into the great mystery of human body, brain and mind relationships. In modern clinical psychopharmacology neutral substance wrongly called placebo has been mainly used as a comparison factor rather than being studied while phenomenon of nocebo has been studied even less extensively than placebo. Placebo–nocebo challenge includes quite a number of conceptual, explanatory and moral questions and dilemmas. Conceptual questions are related to the cacophony regarding various definitions and meanings of terms like fake, slam or dummy treatment; pharmaceuticals and neutraceuticals; placebo treatment; multiple placebo effects; inert and active placebo, true and perceived placebo; pure and impure placebo, placebogenic and nocebogenic effects; placebo and nocebo effect or response; placebo and nocebo induction; negative placebo effect, placebo adverse reaction, placebo induced side-effect, negative placebo response, reverse placebo effect, antiplacebo; iatrogenic effects due to diagnosis and treatment, context effects and meaning responses. Questions concerning the function of neutral control treatment in research are very important from both ethical and methodological perspective. Explanatory or epistemological questions are relevant to mechanisms underlying placebo–nocebo phenomenon related to mind-body operating systems and psychosomatic networks, treatment context, doctor–patient relationship, suggestion and auto-suggestion, deception and self-deception and self-fulfilling prophecies, interactions between specific and nonspecific mechanisms of change and therapeutic action. Placebo–nocebo phenomenon is multifactorial, multidimensional and etiologically complex and that is why explanatory models should refer mostly to explanatory pluralism rather than to reductionism. Moral or ethical questions are about the supposed use of neutral or fake treatment should be used. These questions, although very important, are beyond the scope of this article.

The use of imprecise thinking and language in mind-body medicine associated with conceptual cacophony, mythology and misconceptions (see Table 1) has been leading to a confusion in placebo–nocebo research and understanding as well as to a widespread disconnect between clinical practice guidelines, patients’ attitudes, and physicians’ practice (Hull et al., 2013). As there is no consensus regarding terminology, this review focuses first on conceptual chaos and different connotations in placebo–nocebo medicine, then on some new perspectives on placebo–nocebo phenomenon in the frame of creative psychopharmacotherapy and transdisciplinary integrative psychiatry.

Section snippets

Contradicting definitions: What's in the name?

The words placebo and nocebo are used with many different meanings associated with a lot of controversies. Regarding the neutral, inert, pharmacologically/biologically inactive, fake or deceptive treatment, given as if it was a real treatment, the very fundamental question is what is more appropriate to talk about “the effect of” or “response to” the such kind of treatment. Today an interchangeable use of the terms ‘placebo effect’ and ‘placebo response’ as synonyms is a trend (Benedeti, 2013).

Two sides of the same coin or different currency?

“If patients can't imagine a good result, they won't experience a good result” (Vertosick, 2000).

Any medical or psychosocial treatment has two components, one related to the specific effects of a treatment itself (so called “characteristic constituents of a treatment”) and the other related to the individual perception, imagination and subjective meaning and experience. The latter is labeled as incidental constituents of a treatment (see McQueen et al., 2013) including placebogenic and

How words, beliefs and rituals change the human brain: The role of suggestion, deception and self-deception

Faith has always played a strong role as a popular measure of cure

Sir William Osler

History of psychiatry, as well as of medicine in general, in some way is a history of placebo or nocebo rituals or remedies and “a humiliating memorial of the credulity and infatuations of the physicians” who recommended and prescribed remedies which were not known to be inert or event dangerous (Jopling, 2008). Our “belief system”, an important part of our mental model, which “programs” us how to deal with any

The evidence-based medicine, clinical trials and placebo–nocebo phenomenon

Evidence based medicine has become the gospel of truth in modern psychiatry, the double-blind randomized clinical trial despite its limitations has obtained a status of the golden standard in clinical psychopharmacology, while inactive or neutral comparator wrongly called placebo “has turned into an indispensable instrument” (Stein, 2008, Touwen and Engberts, 2012). Placebo and nocebo responses occur in both active and non-active treatment groups, since they are related to the treatment context

The placebo–nocebo phenomenon in everyday clinical practice

“He cures most successfully in whom the people have the most confidence” (Galen)

Psychopharmacotherapy is a context dependent practice because different treatment contexts may affect the meaning of biological variables in different ways. Patients are not just neurobiological objects who respond only neurochemically to medications, but also subjects who respond to the meaning that prescribed medications have for them and their psychiatrists (Mintz, 2005). Treatment outcome depends on a complex

The placebo–nocebo response to informed consent

“Medications are guilty until proven innocent”

(Oliver Wendel Holmes 1861)

In contrast to paternalism, one of the fundamental principles of professionalism in psychiatry and health care (see Jakovljevic, 2012a) is to obtain informed consent from patients before any treatment. In addition, informed consent is a precondition for patients’ inclusion in randomized controlled clinical trials. However, the informed consent has also two sides, positive one and negative one. The bad news here is that

Creative psychopharmacotherapy, good clinical practice and placebo–nocebo response

“The practice of medicine is an art based on science”

Sir William Osler

Modern psychiatry and medicine in general tend to disregard the idea of deliberately maximizing the placebo response linking it with pre-scientific medicine and with unethical and deceitful practices (Verhulst et al., 2013). There is a lack of conceptual frameworks that integrate placebo healing into standard clinical practice as well as medical education programs that specifically teach this (Verhulst et al., 2013). It has

Conclusions

Any medical or psychosocial treatment has two components, one associated with the specific effects of the treatment itself and the other related to the treatment context, individual perception, imagination, subjective meaning and psychobiological response. Understanding the placebo and nocebo phenomenon and its psychobiological underpinnings, as well as mastering placebo–nocebo responses in everyday clinical practice and the use of comparative treatments in clinical trials represent a great

Role of funding source

There is no funding source regarding the article.

Contributors

There are no contributors to the article.

Conflict of interest

There is no conflict of interest regarding the article.

Acknowledgement

There are no acknowledgements regarding the article.

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