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

<div><p>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.</p></div

Means and standard deviations for itch VAS scores in the learning phase for the different groups.

<p>Means (M) and standard deviations (SD) of the visual analogue scale (VAS) scores for itch in the verbal suggestion group (<i>n = 23</i>), conditioning group (<i>n = 24</i>), conditioning with verbal suggestion group (<i>n = 23</i>) and control group (<i>n = 25</i>) in the learning phase.</p

Experimental design.

<p>The study started with negative expectation induction: participants were told that the purple light (conditioned cue) indicated an increase in the itch stimulus, and that the yellow light (neutral cue) indicated no change in the itch stimulus. In accordance with the verbal suggestion, the purple and yellow lights were repeatedly paired with high and medium electrical itch stimulus intensities, respectively. Subsequently, participants were randomized over the three groups in which 1) positive expectations were induced; 2) continued negative expectations were induced; or 3) an extinction procedure was applied. In the learning phases verbal suggestion and conditioning procedures depended on the experimental group. In the testing phase the verbal suggestion corresponded to the verbal suggestion provided in the learning phase, while all participants received electrical itch stimuli of medium intensity. Next, generalization of reduced nocebo effects to histamine application was tested. The verbal suggestion corresponded to the verbal suggestion provided in part 2 and the purple light (conditioned cue) was displayed during the histamine application. The intensity of the histamine application was identical for all groups. Note that for half of the participants the conditioned cue was a purple light and the neutral cue a yellow light (like in this example); for the other half of the participants the conditioned cue was yellow and the neutral purple.</p

Means (±<i>SD)</i> for itch NRS scores in the learning and testing phase in part 1 (induction of negative expectations).

<p>Means (±<i>SD)</i> for itch NRS scores in the learning and testing phase in part 1 (induction of negative expectations).</p

Participant characteristics.

<p>Participant characteristics.</p

Flow diagram showing the experimental procedures of the study in chronological order.

<p>Flow diagram showing the experimental procedures of the study in chronological order.</p

Means and standard error of the mean of the visual analogue scale (VAS) itch scores for the nocebo effect (change VAS score between the red and yellow cues) of the four groups in the testing phase.

<p>The asterisks show the level of significance related to the post hoc Dunnett comparison of the nocebo effect between the experimental groups and the control group (**<i>p</i><0.01; *<i>p</i><0.05; <i>t</i> = <i>p</i><0.10).</p

Means (<i>±SD)</i> for itch NRS scores in the testing phase for the different groups in part 2.

<p>Means (<i>±SD)</i> for itch NRS scores in the testing phase for the different groups in part 2.</p

Means (<i>±SD)</i> for itch NRS scores in the learning phase for the different groups in part 2.

<p>Means (<i>±SD)</i> for itch NRS scores in the learning phase for the different groups in part 2.</p

Experimental design.

<p>Subjects were randomly assigned to one of four groups: verbal suggestion; conditioning; verbal suggestion with conditioning; and control. In the learning phase verbal suggestion and conditioning procedures depended on the experimental group. In the testing phase the verbal suggestion was in correspondence with the verbal suggestion applied in the learning phase, while all participants received itch stimuli of a medium intensity.</p