Chapter 2 – Meta-analysis 31 Introduction Negative expectations regarding the effects of a treatment can result in the aggravation of cutaneous sensations such as pain and itch 1–3. Such learned responses can be induced experimentally, allowing for the study of processes by which nocebo effects lead to symptom amplification 4– 10. In experimental studies, nocebo responses are defined as a significant increase in a sensation after a nocebo treatment, relative to no-treatment or a control treatment. Negative expectations leading to such responses are typically induced through classical conditioning, verbal suggestions, or their combination 4,5,10–13. Classical conditioning induces nocebo effects by building implicit associations between an (inert) treatment and the worsening of sensations such as pain or itch 14–16. Verbal suggestions explicitly provide negative information regarding the pain- or itchincreasing effects of a treatment 7. Because nocebo studies employ diverse methods, to better understand their potential impact on nocebo outcomes these methodological features warrant a systematic investigation. Learning has consistently been shown to underlie induced nocebo effects 5–7,9,17, and verbal suggestions seem to induce stronger nocebo responses when combined with conditioning 18. The positive counterpart to nocebo, placebo effects, also appear to be stronger when induced through a combination of conditioning with verbal suggestions, compared to conditioning alone, both on pain 19 and itch (Bartels et al., 2014; Blythe et al., 2019). One meta-analysis included results from ten nocebo experiments published up to 2013 and reports that the overall magnitude of the nocebo effect was moderate to large and effects were generally larger when verbal suggestions were used in combination with conditioning 18. That early meta-analysis had a limited sample of studies
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