Mia Thomaidou

30 Abstract In past decades, the field of nocebo research has focused on studying how sensory perception can be shaped by learning. Behavioral conditioning processes as well as mere verbal suggestions of a negative treatment outcome may aggravate pain and itch perception. Gaining a comprehensive view of the magnitude of nocebo effects and the factors that contribute to their formation will help steer nocebo research towards fruitful directions for better understanding complex sensory phenomena. We conducted a systematic review and meta-analysis of a total of 37 distinct experimental nocebo studies on healthy participants, with four separate meta-analyses for nocebo effects on pain or itch, induced with classical conditioning and verbal suggestion, or verbal suggestion alone. We conducted subgroup analyses and meta-regression on factors such as the type and intensity of sensory stimuli, and the length of learning paradigms. This meta-analysis showed that on average, effect sizes of nocebo effects were moderate to large (Hedges g between 0.26-0.71 for the four primary outcomes). The combination of conditioning and verbal suggestions yielded stronger nocebo responses on pain in particular. Subgroup analyses, including factors such as the type of sensory stimulation, did not explain the moderate heterogeneity in nocebo magnitudes between different studies. Risk of bias was generally low and was not related to nocebo magnitudes either. We discuss these results in relation to the role of conditioning as well as aversive learning, and we recommend more consistency in designing and reporting nocebo experiments.

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