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

Abstract

ObjectivesThis review aimed to summarise the existing knowledge about placebo and nocebo effects associated with pharmacological interventions and their mechanisms.DesignUmbrella review, adopting the Assessment of Multiple Systematic Reviews 2 tool for critical appraisal.Data sourcesMEDLINE/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 measuresMechanisms underlying placebo/nocebo effects and/or their effect sizes.ResultsThe 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.ConclusionsThis study provides a valuable tool for clinicians and researchers, identifying both results ready for clinical practice and gaps to address in the near future.FundingUniversità Cattolica del Sacro Cuore, Milan, Italy with the ‘Finanziamento Ponte 2022’ grant.PROSPERO registration numberCRD42023392281.

Belief That Caffeine Ingestion Improves Performance in a 6-Minute Time Trial Test without Affecting Pacing Strategy

“…Indeed, a dose-response relationship was found in a 10 km TT test, with cyclists reducing performance by 1.4% when they believed they had ingested a placebo and increasing performance by 1.3% when they believed they had ingested 4.5 mg/kg caffeine and 3.1% when they believed they had ingested 9.0 mg/kg caffeine [22]. According to our data and other previous research, the placebo effect could improve endurance performance by around ≈2-3%, and this could be explained by a variety of factors, such as fatigue endurance, pain tolerance, and motivation [1].…”

“…The placebo effect (i.e., an improvement derived from something that has no effect by itself) has been broadly studied in medicine and psychology in various clinical conditions [ 1 ]. In recent decades, an increasing interest has emerged in sports sciences research, where previous reviews have found small to moderate exercise performance improvements [ 2 , 3 ].…”

Risk factors associated with nocebo effects: A review of reviews

“… Prior Expectations and Learning Personality and individual differences Communication of information and patient-physician relationship 42. E. Frisaldi et al (2023) To summarize the current understanding of placebo and nocebo effects linked to pharmacological interventions, along with an exploration of their underlying mechanisms. N = 158 312 The characterization of mechanisms associated with placebo and/or nocebo effects in various medical conditions was demonstrated.…”

“…Meanwhile, previous positive experiences may enhance placebo analgesic effects, while negative experiences can induce nocebo effects ( Colloca and Benedetti, 2016 ). This category receives additional validation from a recent umbrella review conducted by Frisaldi et al (2023) . Their extensive analysis has demonstrated that, in the context of nocebo effects, the manipulation of expectations, conditioning, or a combination of both has proven effective in eliciting nocebo responses across diverse domains, such as pain perception, skin dryness, nausea, and cognitive performance ( Frisaldi et al, 2023 ).…”

“…Several immune-related mechanisms contribute to the manifestation of nocebo responses. This includes the release of pro-inflammatory cytokines, the bidirectional communication between the nervous and immune systems (neuroimmune interactions), and the field of psychoneuroimmunology, which explores the connections between psychological processes and immune responses ( Frisaldi et al, 2015 , 2023 ). The release of inflammatory mediators and the neurobiology-associated nocebo effects also play a role ( Zhang et al, 2022 ).…”