Chapter Fifteen - Nocebo Effects: Neurobiological Mechanisms and Strategies for Prevention and Optimizing Treatment

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Abstract

Psychosocial and contextual factors, such as patient–physician relationship, prior treatment experience, and treatment expectation, can either improve or compromise treatment efficacy. These phenomena are commonly specified as placebo and nocebo effects. As placebo and nocebo effects can influence symptom development, adverse event rate, and treatment efficacy, it is crucial to be aware of these effects and to develop strategies for prevention to optimize treatment outcomes. While experimental studies have made substantial progress in elucidating the psychosocial and neurobiological mechanisms underlying placebo effects, the detailed mechanisms of nocebo effects remain largely unexplored. A better understanding of these mechanisms promises to facilitate the development of easy-to-use strategies in clinical care to improve overall treatment outcomes and patient satisfaction.

Introduction

The psychosocial context is an essential and inevitable part of most medical treatments. Evidence gained in the recent past highlights the importance of the various mechanisms involved in shaping this therapeutic context, such as patients’ expectations, learning mechanisms, and the patient–physician relationship. Positive physiological or psychological effects induced by the treatment context are referred to as placebo effects or placebo responses and are known to represent complex psychoneurobiological phenomena (Benedetti et al., 2005; Enck et al., 2013). Importantly, placebo effects are not restricted to placebo treatments; rather, we know that they can substantially modulate the efficacy and tolerability of active pharmacological therapies, for example.

On the other hand, the negative effects the treatment context induces—defined as nocebo effects (nocere, lat. = to hurt)—can impair medical (treatment) outcomes on various levels including the development and maintenance of new symptoms (Crichton & Petrie, 2015), as well as the efficacy and tolerability of medical treatments including pharmacotherapy. However, despite their potentially detrimental effects on treatment outcomes, the neurobiological and neurochemical mechanisms involved in nocebo effects are largely unknown and much less studied than placebo effects. In this chapter, we highlight the levels at which different nocebo effects interfere negatively with medical and treatment outcomes, and propose strategies for preventing or even overcoming their influence so as to optimize treatment outcomes.

Section snippets

Psychosocial Mechanisms

From a psychological point of view, nocebo effects are induced and/or moderated by several factors that ultimately converge to negative treatment outcome expectations. These include, among others, negative prior information regarding a treatment or health outcome provided by healthcare professionals, the media or a social peer, or negative personal experiences as evidence following treatment failure. These latter learning mechanisms are not restricted to first-hand experiences. Negative

Neurobiological Correlates

Despite their potentially detrimental clinical consequences, the mechanisms underlying nocebo effects including nocebo hyperalgesia have received very little attention so far. Initial fMRI studies have shown that nocebo hyperalgesia is associated with increased activity in pain-processing areas (Keltner et al., 2006; Sawamoto et al., 2000), but the specific mechanisms underlying this amplification of nociceptive information have not been adequately explored. Placebo analgesia is known to be

Symptom Development

A well-known nocebo effect is symptom augmentation, as Benedetti, Durando, and Vighetti (2014) showed recently in a study investigating nocebo and placebo effects in hypobaric hypoxia headache. As a symptom of acute mountain sickness, hypobaric hypoxia headache results from a rise in the concentration of prostaglandins due to hypoxia at high altitudes (Benedetti et al., 2014). In this trial, negative information (i.e., the induction of a negative expectation) from other study volunteers (social

Treatment Efficacy and Course of Disease

A recent meta-analysis involving studies with experimental, acute (e.g., procedural or postoperative), and chronic pain (e.g., chronic back pain) settings reveals that different positive (placebo-)expectations—either verbally induced, by conditioning or by imagery—can lead to pain relief, especially in case of acute pain, therefore improving pain therapy and its outcome (Peerdeman et al., 2016). In contrast, negative expectations are not just able to augment symptoms. It has long been suggested

Unwanted/Adverse Events

Aside from the harm nocebo effects have on treatment efficacy, negative expectations or prior experiences may also facilitate the occurrence and development of side effects during drug and other therapies. This is well demonstrated by Rief et al. (2009), who studied the reported adverse effects in 12,742 patients randomized to the placebo arm of RCTs investigating tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors. Although all patients analyzed in this meta-analysis

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