The Placebo Effect in Medicine and Clinical Practice: A Narrative Review.

Placebo effects are complex psychobiological phenomena driven by patients' expectations, conditioning, and contextual cues. In clinical practice, placebo effects are mediated by endogenous opioid, dopaminergic, and cholecystokinin (CCK) pathways and are accompanied by characteristic alterations in brain connectivity. Functional imaging and neurochemical investigations converge to demonstrate that these are genuine neurophysiological phenomena rather than mere responses. These effects are documented across pharmacologic, surgical, and physiotherapy and rehabilitation settings, including sham pills, surgery, and acupuncture. However, attributing observed improvements solely to placebo is challenging, as they may reflect natural history, regression to the mean, concomitant care, or active effects from control conditions. This narrative review highlights the measurable influence and clinical relevance of placebo effects across interventions. Research should continue to clarify their mechanisms and triggers to strengthen causal inference in randomized trials and guide their ethical use in practice. Accordingly, within an evidence-based and ethically sound framework, clinicians may purposefully leverage placebo-enhancing mechanisms to improve therapeutic outcomes, particularly in conditions where contextual and psychosocial factors strongly influence recovery. In practice, this entails transparent, constructive expectation-setting, minimization of nocebo cues, and, in selected contexts, the ethical use of open-label placebos alongside active treatment.