Learned Nocebo Effects on Cutaneous Sensations of Pain and Itch: A Systematic Review and Meta-analysis of Experimental Behavioral Studies on Healthy Humans

Objective: In past decades, the field of nocebo research has focused on studying how sensory perception can be shaped by learning. Nocebo effects refer to aggravated sensory experiences or increased sensitivity to sensations such as pain and itch resulting from treatment-related negative experiences. Behavioral conditioning and verbal suggestions of a negative treatment outcome may aggravate pain and itch perception. Gaining a comprehensive view of the magnitude of nocebo effects and contributing factors will help steer nocebo research toward fruitful directions for understanding complex sensory phenomena. Methods: We conducted a systematic review and meta-analysis of a total of 37 distinct experimental nocebo studies on healthy participants (all published in English between 2008 and 2021), with four separate meta-analyses for nocebo effects on pain or itch. We conducted subgroup analyses and meta-regression on factors such as type and intensity of sensory stimuli, and length of conditioning paradigms. Results: This meta-analysis showed that, on average, effect sizes of nocebo effects were moderate to large (Hedges g between 0.26 and 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. Conclusions: We discuss these results in relation to the role of conditioning and aversive learning, and we recommend more consistency in designing and reporting nocebo experiments.

Mia A Thomaidou, Joseph S Blythe, Kaya J Peerdeman, Antoinette I M Van Laarhoven, Myrthe M E Van Schothorst, Dieuwke S Veldhuijzen, Andrea W M Evers