Risk factors associated with nocebo effects: A review of reviews

Objective: This meta-review aims to identify and categorize the risk factors that are associated with nocebo effects. The nocebo effect can exert a negative impact on treatment outcomes and have detrimental outcomes on health. Learning more about its potential predictors and risk factors is a crucial step to mitigating it. Methods: Literature review studies about the risk factors for nocebo effects were searched through five databases (PubMed, Scopus, The Cochrane Library, PsycINFO, and Embase) and through grey literature. Methodological validity and risk of bias were assessed. We conducted a thematic analysis of the results of the forty-three included reviews. Results: We identified nine categories of risk factors: prior expectations and learning; socio-demographic characteristics; personality and individual differences; neurodegenerative conditions; inflammatory conditions; communication of information and patient-physician relationship; drug characteristics; setting; and selfawareness. We also highlighted the main biochemical and neurophysiological mechanisms underlying nocebo effects. Conclusions: Nocebo effects arise from expectations of adverse symptoms, particularly when triggered by previous negative experiences. A trusting relationship with the treating physician and clear, tailored treatment instructions can act as protective factors against a nocebo effect. Clinical implications are discussed.