Chapter 2 – Meta-analysis 53 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 speculate of the reasons why none of the factors collected in the nocebo literature appear to consistently explain variations in the magnitudes of learned nocebo effects on pain and itch. In experimental inductions of nocebo effects on pain, we found the magnitudes of responses across studies to be moderate to large, with a moderate heterogeneity. Often conceptualized as the counterpart of nocebo responses, placebo effects appear to be comparable in magnitude to the overall nocebo magnitude found in the current metaanalysis, but heterogeneity in placebo responses may be higher 19. In a more recent meta-analysis, placebo responses were found to yield small to moderate effects, with moderate to large heterogeneity in results 32. We speculate that this may indicate that the negativity of suggestions and experiences in nocebo paradigms may result in stronger learned effects, as compared to the positive expectations induced in placebo excrements. Indeed, aversive learning has consistently be shown to be prioritized over the learning of neutral or positive information in the brain 33–36, something that is thought to have an evolutionary basis 37. Magnitudes of nocebo responses were found to be moderate to large in pain studies when looking at both verbal suggestions and combination with conditioning. As expected, in pain experiments the addition of classical conditioning yielded somewhat larger nocebo responses, suggesting that learning by experience during behavioral conditioning may be more potent than mere negative suggestions regarding pain outcomes. For itch, however, verbal suggestions alone yielded moderate effects whereas combination with conditioning resulted in small effects across studies. The number of studies included in each of the two itch conditions (k = 4 in each) may be insufficient to allow for further conclusions to be drawn regarding this apparent distinction between learned pain and itch effects.
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