The role of anxiety in nocebo hyperalgesia and its impact on pain perception

Understanding the mechanisms and impact of nocebo effects is crucial, as negative treatment expectations can worsen health outcomes and undermine therapeutic efficacy. In this pilot study, we aimed to develop an approach to investigate how negative affect, particularly anxiety, influence nocebo hyperalgesia. A nocebo manipulation using verbal suggestions combined with a sham infusion and cold pressor test was employed to induce negative expectations and anxiety. Importantly, one of the nocebo groups received the anxiolytic drug midazolam to examine the role of anxiety in nocebo hyperalgesia, which may represent in important clinical target to mitigate nocebo effects. Our paradigm succeeded in inducing more pronounced negative treatment expectations regarding the impact of sham infusion on pain perception in the nocebo groups as compared to the control group; however, these expectations were already evident even at baseline, indicating they were not solely induced by the verbal suggestions. Against our hypothesis, our nocebo manipulation did not lead to increased anxiety. On the contrary, the nocebo groups reported lower stress and arousal levels compared to the control group. As intended, pain sensitivity was elevated in the nocebo group, as evident in higher pain intensity ratings and lower pain tolerance. However, this effect was not statistically significant, possibly due to a far too small sample-size. The pilot study delivered important methodological considerations for future research. The baseline differences in treatment expectations may stem from different informed consent forms used for nocebo and control conditions. As the cold pressor test gave participants a certain control over the duration of the pain stimulus and reusing it at test phase reduced unpredictability of the setting, reflected in the lower stress and arousal ratings in the nocebo group. Potential confounding factors—such as the administration of two drugs and the presence of a peripheral venous line—may have further attenuated anxiogenic responses specific to the sham naloxone infusion and their effect should be further examined in future studies. Overall, this pilot study offers valuable insights to key methodological challenges and refining the experimental approach, laying a critical foundation for future, larger-scale studies.