Minimizing nocebo effects by conditioning with verbal suggestion: A randomized clinical trial in healthy humans

Abstract

Nocebo effects, i.e., adverse treatment effects which are induced by patients’ expectations, are known to contribute to the experience of physical symptoms such as pain and itch. A better understanding of how to minimize nocebo responses might eventually contribute to enhanced treatment effects. However, little is known about how to reduce nocebo effects. In the current randomized controlled study, we tested whether nocebo effects can be minimized by positive expectation induction with respect to electrical and histaminic itch stimuli. First, negative expectations about electrical itch stimuli were induced by verbal suggestion and conditioning (part 1: induction of nocebo effect). Second, participants were randomized to either the experimental group or one of the control groups (part 2: reversing nocebo effect). In the experimental group, positive expectations were induced by conditioning with verbal suggestion. In the control groups either the negative expectation induction was continued or an extinction procedure was applied. Afterwards, a histamine application test was conducted. Positive expectation induction resulted in a significantly smaller nocebo effect in comparison with both control groups. Mean change itch NRS scores showed that the nocebo effect was even reversed, indicating a placebo effect. Comparable effects were also found for histamine application. This study is the first to demonstrate that nocebo effects can be minimized and even reversed by conditioning with verbal suggestion. The results of the current study indicate that learning via counterconditioning and verbal suggestion represents a promising strategy for diminishing nocebo responses.

Pain Modulation: From Conditioned Pain Modulation to Placebo and Nocebo Effects in Experimental and Clinical Pain

“…Nevertheless, as mentioned elsewhere, numerous studies reveal that expectancies also modulate placebo and nocebo effects (Bartels et al, 2014; Bartels, van Laarhoven, Heijmans, et al, 2017; Bartels, van Laarhoven, Stroo, et al, 2017; Bingel et al, 2011; Bräscher, Witthöft, & Becker, 2018; Fiorio et al, 2012). Expectancies are induced by verbal instructions, social observation (for reviews see, Colloca & Grillon, 2014; Medoff & Colloca, 2015) and distinct forms of learning (for example, Benedetti et al, 2003; Egorova et al, 2015; Morton, El-Deredy, & Jones, 2014; Reicherts, Gerdes, Pauli, & Wieser, 2016).…”

Incidence and characteristics of the nocebo response from meta‐analyses of the placebo arms of clinical trials of olanzapine for bipolar disorder

“…Nocebo and placebo responses have been attributed to expectancy, conditioning, learning, memory, motivation, somatic focus, reward, anxiety reduction, and “placebo by proxy” induced by clinician and family members . Conditioning was used to induce a nocebo response in one study and to minimize it using counterconditioning in another . Nocebo has been associated with neurobiological factors including decreased dopamine and opioid neurotransmission .…”

“…2 Conditioning was used to induce a nocebo response in one study 4 and to minimize it using counterconditioning in another. 5 Nocebo has been associated with neurobiological factors including decreased dopamine and opioid neurotransmission. 6 A nocebo response may occur as a result of a synergy of psychological and biological mechanisms.…”

What is new in the psychology of chronic itch?

“…For example, attention entails various processes that together regulate the selection and prioritization of incoming information . Psychological factors such as attentional focus, affect and expectancies are also shaped by our previous learning history, including past experiences of itch and scratching, which in turn can trigger future experiences, such as a worsening of itch . Based on these theoretical grounds, research has increasingly focused on the extent to which attention, affect and expectancies play a role in itch, both in healthy subjects and in patients.…”

“…A possible additional strategy for attenuating negative expectancies in itch is counterconditioning. In a recent experimental study in healthy volunteers, conditioned nocebo effects on itch could be reversed with a counterconditioning paradigm, in which the negative expectations were reversed into placebo effects of itch reduction . Another possible avenue for clinically applying placebo effects is by openly giving patients placebos, without deception.…”