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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.


The strange truth about medicine and the brain is that they often interact in completely unpredictable and counterintuitive ways. Nowhere is this more true than with the bewildering phenomenon known as the nocebo effect.

Last week, researchers from the Technical University of Munich in Germany published one of the most thorough reviews to date on the nocebo effect. Breaking down 31 empirical studies that involved the phenomenon, they examined the underlying biological mechanisms and the problems it causes for doctors and researchers in clinical practice. Their conclusion: although perplexing, the nocebo effect is surprisingly common and ought to be taken into consideration by medical professionals on an everyday basis.

The nocebo effect might even be powerful enough to kill. In one case study, researchers noted an individual who attempted to commit suicide by swallowing 26 pills. Although they were merely placebo tablets without a biological mechanism to harm the patient even at such a high dose, he experienced dangerously low blood pressure and required injections of fluids to be stabilized, based solely on the belief that the overdose of tablets would be deadly. After it was revealed that they were sugar pills, the symptoms went away quickly.

In modern medicine, the placebo response or placebo effect has often been regarded as a nuisance in basic research and particularly in clinical research. The latest scientific evidence has demonstrated, however, that the placebo effect and the nocebo effect, the negative effects of placebo, stem from highly active processes in the brain that are mediated by psychological mechanisms such as expectation and conditioning. These processes have been described in some detail for many diseases and treatments, and we now know that they can represent both strength and vulnerability in the course of a disease as well as in the response to a therapy. However, recent research and current knowledge raise several issues that we shall address in this review. We will discuss current neurobiological models like expectation-induced activation of the brain reward circuitry, Pavlovian conditioning, and anxiety mechanisms of the nocebo response. We will further explore the nature of the placebo responses in clinical trials and address major questions for future research such as the relationship between expectations and conditioning in placebo effects, the existence of a consistent brain network for all placebo effects, the role of gender in placebo effects, and the impact of getting drug-like effects without drugs.

Nocent has been in the English language as a word for "harmful" since the 15th century. It comes from Latin nocēre, meaning "to harm." Latin nocebo is a close relative that means "I will be harmful" and that contrasts with placebo, meaning "I shall please." People in medicine began using "placebo" for inert preparations prescribed solely for a patient's mental relief, and not for relieving a disorder, in the late 18th century. As doctors began to observe the effects of placebos, some noticed that the harmless preparations actually sometimes caused detrimental effects on the patient's health. English speakers began using the word nocebo for substances causing such adverse reactions in patients in 1961.

Despite the increasing research on placebos in recent times, little is known about the nocebo effect, a phenomenon that is opposite to the placebo effect and whereby expectations of symptom worsening play a crucial role. By studying experimental ischemic arm pain in healthy volunteers and by using a neuropharmacological approach, we found that verbally induced nocebo hyperalgesia was associated to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by means of adrenocorticotropic hormone and cortisol plasma concentrations. Both nocebo hyperalgesia and HPA hyperactivity were antagonized by the benzodiazepine diazepam, suggesting that anxiety played a major role in these effects. The administration of the mixed cholecystokinin (CCK) type-A/B receptor antagonist proglumide blocked nocebo hyperalgesia completely but had no effect on HPA hyperactivity, which suggests a specific involvement of CCK in the hyperalgesic but not in the anxiety component of the nocebo effect. Importantly, both diazepam and proglumide did not show analgesic properties on basal pain, because they acted only on the nocebo-induced pain increase. These data indicate a close relationship between anxiety and nocebo hyperalgesia, in which the CCKergic systems play a key role in anxiety-induced hyperalgesia. These results, together with previous findings showing that placebo analgesia is mediated by endogenous opioids, suggest that the analgesic placebo/hyperalgesic nocebo phenomenon may involve the opposite activation of endogenous opioidergic and CCKergic systems.

Placebo and nocebo effects are embodied psycho-neurobiological responses capable of modulating pain and producing changes at different neurobiological, body at perceptual and cognitive levels. These modifications are triggered by different contextual factors (CFs) presented in the therapeutic encounter between patient and healthcare providers, such as healing rituals and signs. The CFs directly impact on the quality of the therapeutic outcome: a positive context, that is a context characterized by the presence of positive CFs, can reduce pain by producing placebo effects, while a negative context, characterized by the presence of negative CFs, can aggravate pain by creating nocebo effects. Despite the increasing interest about this topic; the detailed study of CFs as triggers of placebo and nocebo effects is still lacked in the management of musculoskeletal pain.

By definition, CFs are physical, psychological and social elements that characterize the therapeutic encounter with the patient [17, 18]. CFs are actively interpreted by the patient and are capable of eliciting expectations, memories and emotions that in turn can influence the health-related outcome, producing placebo or nocebo effects [19]. In other words, the CFs represent the context that accompany any healthcare treatment: the exposure of a patient to a positive context (positive CFs) very often produces a placebo effect that is the occurrence of symptoms improvement (e.g. analgesia), whereas a negative context (negative CFs) can generate a nocebo effect, with a worsening of the pain condition (e.g. hyperalgesia) [20, 21]. In the following review, we use the term CFs instead of placebo, avoiding the misleading interpretation of placebo as inert treatment given to comfort or please the patient and following the recent conceptualization of the placebo as the psychosocial context that accompanies any medical intervention, be it active or sham [22,23,24,25,26,27,28,29,30,31].

If we aim to implement an aware use of CFs along the clinical routine, the understanding of how they work has a capital importance. The CFs shape placebo and nocebo effects through different sources. Historically, the most important models include classical conditioning and expectation processes.

A robust body of knowledge, especially acquired in the field of pain, has identified the neural networks activated by the CFs. Indeed, a crucial question that catch the attention of neuroscientists and clinicians is whether the subjective changes in the outcome after the exposure to a specific therapeutic context are associated with specific neurobiological activities [10]. Pharmacological studies, as well as neuroimaging studies, have address this question using different experimental approaches based on classical conditioning and modulation of expectations. Taken together, these studies demonstrated that different changes in the pain processing network occurs when positive or negative CFs trigger placebo or nocebo effects, respectively. In particular, pain reduction is associated with decreased activity in the classical pain-matrix areas, such as the thalamus, insula, somatosensory cortex, and mid-cingulate regions [55,56,57,58,59,60]. Interestingly, positron emission tomography (PET) studies showed that the analgesic effect induced by the administration of a real mu-agonist, such as remifentanil, and the analgesic effect triggered by verbal suggestions determined similar activation of different brain regions, such as rostral anterior cingulate cortex and the orbital cortex [61, 62]. Separating the pain anticipation phase and the pain perception phase, a meta-analysis of brain imaging data using the activation likelihood estimation method, identified the involvement of different brain regions: during expectation, areas of activation are found in the anterior cingulate, precentral and lateral prefrontal cortex, and in the periaqueductal gray, whereas during pain inhibition, deactivations are found in the mid- and posterior cingulate cortex, superior temporal and precentral gyri, in the anterior and posterior insula, in the claustrum and putamen, and in the thalamus and caudate body [63]. On the other hand, pain increase is associated with signal increases in several regions including anterior cingulate cortex, insula, left frontal and parietal operculum [64,65,66,67]. Also, high temporal resolution techniques, such as electroencephalography (EEG), have confirmed that the amplitude of specific evoked potentials, both related to pain anticipation and to pain perception, are affected by the CFs [68,69,70,71]. Thus, both early and late sensory components of pain processing are affected by the exposure to positive and negative CFs. 041b061a72


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