Placebo and nocebo effects and mechanisms associated with pharmacological interventions: An umbrella review

Objectives This review aimed to summarise the existing knowledge about placebo and nocebo effects associated with pharmacological interventions and their mechanisms. Design Umbrella review, adopting the Assessment of Multiple Systematic Reviews 2 tool for critical appraisal. Data sources MEDLINE/PubMed, Scopus, Web of Science, PsycINFO, Cochrane Central Register of Controlled Trial were searched in September 2022, without any time restriction, for systematic reviews, narrative reviews, original articles. Results were summarised through narrative synthesis, tables, 95% CI. Outcome measures Mechanisms underlying placebo/nocebo effects and/or their effect sizes. Results The databases search identified 372 studies, for a total of 158 312 participants, comprising 41 systematic reviews, 312 narrative reviews and 19 original articles. Seventy-three per cent of the examined systematic reviews were of high quality. Our findings revealed that mechanisms underlying placebo and/or nocebo effects have been characterised, at least in part, for: pain, non-noxious somatic sensation, Parkinson's disease, migraine, sleep disorders, intellectual disability, depression, anxiety, dementia, addiction, gynaecological disorders, attention-deficit hyperactivity disorder, immune and endocrine systems, cardiovascular and respiratory systems, gastrointestinal disorders, skin diseases, influenza and related vaccines, oncology, obesity, physical and cognitive performance. Their magnitude ranged from 0.08 to 2.01 (95% CI 0.37 to 0.89) for placebo effects and from 0.32 to 0.90 (95% CI 0.24 to 1.00) for nocebo effects. Conclusions This study provides a valuable tool for clinicians and researchers, identifying both results ready for clinical practice and gaps to address in the near future. Funding Università Cattolica del Sacro Cuore, Milan, Italy with the 'Finanziamento Ponte 2022' grant. PROSPERO registration number CRD42023392281.