Chapter 8 – General discussion 255 conditioning was found to be more powerful than verbally delivered negative information, showing that experienced adversity may be more powerful in inducing negative expectations, as compared to verbal suggestions. In examining what moderates effect sizes of nocebo responses between different studies, however, we found no significant moderating factors within our data. It should be noted that several factors were not systematically measured, such as fear of the pain stimulations or specific contextual factors, which may potentially account for some of the variability in nocebo magnitudes. More systematic and comparable studies on these aspects are needed. Chapter 2 thus leaves little doubt regarding the potency of learned effects on pain perception, but raises a number of questions and points to knowledgegaps regarding the potential cognitive-emotional and biobehavioral moderating and mediating factors in nocebo hyperalgesia. Chapter 2 also highlighted nocebo effects as being present across the different sensations and types of pain, which led us, in chapter 3, to dive deeper into the diverse literature on the neurobiological correlates of nocebo hyperalgesia. To summarize and further utilize current knowledge, a comprehensive review of the neurobiological nocebo literature on pain was conducted. Twenty-two studies were included based on exhaustive database searches. A narrative review of these experiments highlighted the nocebo effect as a top-down phenomenon based on learned effects. Nocebo effects were shown to be influenced by basic nociceptive signal conduction in the spinal cord, as well as by higher cognitive functions such as emotional processing and expectations. Importantly, a marked inconsistency in methods used and results yielded between nocebo studies, led to a motivation for using consistent and comparable methods in the experimental work of this PhD project. We suggest that the field as whole attempts reproduction and replication of experimental methods, in order to reach a robust and reliable knowledge base for nocebo effects. Finally, with this review of the literature, the central question emerged which exact learning
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