Elsevier

Neuroscience

Volume 147, Issue 2, 29 June 2007, Pages 260-271
Neuroscience

Review
When words are painful: Unraveling the mechanisms of the nocebo effect

https://doi.org/10.1016/j.neuroscience.2007.02.020Get rights and content

Abstract

The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patient’s distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinson’s disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.

Section snippets

Placebo and nocebo effects

The placebo effect has been studied extensively from both a psychological and biological perspective, but in recent times placebo research has focused on the neural mechanisms, both from the neurochemical and the neuroanatomical viewpoint. Placebos are known to powerfully affect the brain in different pathological conditions, like pain, motor disorders and depression, and in different systems and apparatuses, such as the immune and endocrine system (Benedetti et al 2005, Colloca and Benedetti

Imaging the brain when expecting negative outcomes

Modern brain imaging techniques have been fundamental in the understanding of the neurobiology of negative expectations. It should be noted that no inert substance is given in these studies, and the experimenter typically uses verbal suggestions. Therefore, in this case it would be better to talk about nocebo-related effects. Typically, the experimenter tells the subject about the forthcoming pain so as to make the subject expect a painful stimulation, and both the anticipatory phase and the

Nocebo hyperalgesia and its biochemistry

Like placebo analgesia, nocebo hyperalgesia has represented the best model to study the mechanism of the nocebo effect. To obtain placebo analgesia, a placebo (inert treatment) is given along with verbal suggestions of improvement. Likewise, to obtain nocebo hyperalgesia, an inert treatment is given along with verbal suggestions of worsening.

A modulation of pain perception by placebo and nocebo that is dependent on expectation has been shown by Benedetti et al. (2003b). In this study, in one

The role of CCK in pain, cognition and emotion

Besides the understanding of the mechanisms of the nocebo effect, these studies on nocebo hyperalgesia have been useful to understand the role of CCK in both pain and some complex functions, such as cognition and emotion. In fact, in recent years CCK has been found to play a crucial role in many complex physiological and psychological functions (Hebb et al., 2005). For example, there has been accumulating evidence that CCK acts as a neuromodulator of pain and anxiety, although the exact

The nocebo effect in Parkinson’s disease

Whereas nocebo hyperalgesia and, more in general, negative expectations of pain increase have been studied from both a behavioral, neuroanatomical and biochemical point of view, the neural mechanisms of the nocebo effect in conditions other than pain are poorly understood. Recently, Parkinson’s disease, a disorder of movement characterized by tremor, muscle rigidity and bradykinesia (movements slow down), has represented an interesting model to investigate both the placebo and the nocebo

Open versus hidden interruption of treatments

One of the most interesting experimental approaches that emphasizes both the importance of positive and negative expectations and their clinical impact is represented by the open–hidden paradigm (Colloca et al 2004, Colloca and Benedetti 2005). The open (expected) administration of a medical treatment consists of the administration of a therapy by a doctor who tells the patient that his/her symptoms will improve, according to routine clinical practice. Therefore, in this condition, the patient

Conclusions

The concept of nocebo and nocebo-like effects is related to that of negative expectation of an outcome. Unfortunately, little is known about its neurobiology, although some neuroanatomical and neurochemical mechanisms have been unraveled for pain. In particular, anticipatory anxiety about the impending pain has been found to play an important role and to activate the CCKergic systems which, in turn, facilitate pain transmission. By taking the findings on nocebo and those on placebo together,

Acknowledgments

This work was supported by grants from Regione Piemonte and Istituto San Paolo di Torino. We thank all colleagues and technicians who participated in the works reviewed here.

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