Our understanding of the mechanisms mediating or moderating the placebo response to medicines has grown substantially over the past decade and offers the opportunity to capitalize on its benefits in future drug development as well as in clinical practice. In this article, we discuss three strategies that could be used to modulate the placebo response, depending on which stage of the drug development process they are applied. In clinical trials the placebo effect should be minimized to optimize drug–placebo differences, thus ensuring that the efficacy of the investigational drug can be truly evaluated. Once the drug is approved and in clinical use, placebo effects should be maximized by harnessing patients' expectations and learning mechanisms to improve treatment outcomes. Finally, personalizing placebo responses — which involves considering an individual's genetic predisposition, personality, past medical history and treatment experience — could also maximize therapeutic outcomes.
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All authors are participants of a collaborative research group dedicated to studying placebo and nocebo mechanisms across different physiological systems in health and disease. This work was supported by grants from the German Research Foundation (DFG) for the Research Unit FOR 1328 (BI 89/2-1; EN 50/30-1; RI 574/21-1; RI 574-22-1; SCHE 341/17-1), the Volkswagen Foundation Germany (P.E.: I/83 805; M.S.: I/83 806) and the German Federal Ministry of Education and Research (U.B.: 01GQ0808).
The authors declare no competing financial interests.
- Active placebo
A substance or treatment that mimics the side effects of the active compound under investigation and is thus, by definition, not an inert substance. In clinical trials, active placebos are administered to avoid un-blinding owing to different side-effect profiles of drugs and placebo treatments.
- Assay sensitivity
The ability of a clinical trial to differentiate between an effective treatment (for example, a drug) and a less effective or ineffective treatment (for example, placebo).
- CER trial
A comparative effectiveness research (CER) trial is performed to analyse the efficacy of a novel pharmacological agent or treatment in comparison with standard treatments or approved drugs. Patients are therefore randomly allocated to receive the treatment under investigation or one or more standard treatments.
- Declaration of Helsinki
A statement, developed by the World Medical Association (WMA), of ethical principles for medical research involving human participants, identifiable human material and data.
- Health locus of control
The extent to which individuals believe that they can control events that affect their personal health.
- Open/hidden study
An experimental approach undertaken to separate the effects of the psychosocial context (placebo) from the pharmacodynamic effects of a drug under investigation. The pharmacological agent is administered either in an open condition (by a physician in a visible way) or in a hidden condition, in which the patient is unaware of the timing of the administration of the medication (for example, the drug is administered using computer-controlled infusion).
A method of application in which both the patients (or participants) and the investigators know which pharmacological agent or treatment is being administered. This design contrasts the single- or double-blind study designs.
- Patient-reported outcomes
(PROs). A method of measuring treatment efficacy via the states of symptom severity and health from the patient's perspective, instead of physician's reports or biomarkers of clinical outcome. PROs are typically analysed via questionnaires or interviews, providing insight into how patients perceive the impact of a treatment on their health and quality of life.
Latin term for “I shall please”. Used to indicate sham treatments or inert substances such as sugar pills or saline infusions.
- Placebo effects
Defined as any improvements in a symptom or physiological condition of individuals following a placebo treatment. There are different mechanisms underlying this phenomenon, including spontaneous remission, regression to the mean, natural course of a disease, biases and placebo responses.
- Placebo responses
The outcomes caused by a placebo manipulation. The placebo response reflects the neurobiological and psychophysiological response of an individual to an inert substance or sham treatment and is mediated by various factors that make up the treatment context. Importantly, placebo responses are not restricted to placebo treatments and can also modulate the outcome of any active treatment.
- Randomized double-blind placebo-controlled trials
(RCTs). The most commonly used clinical trial design for testing the efficacy of a treatment within a patient population. Patients are randomly allocated to a treatment or placebo group. Patients and investigators are blinded to group allocation. The design aims to control for confounding factors such as suggestion, imagination and biases for the patient and investigator, as well as spontaneous fluctuation of diseases and symptoms.
- Regression to the mean
A statistical phenomenon; individuals tend to have extreme values in symptom severity or physiological parameters when enrolled into a clinical trial. These values tend to be lower and closer to the average at subsequent assessments, because they are more likely to change in the direction of the mean score, instead of developing even more extreme scores. This phenomenon in part explains the improvement observed in placebo groups in clinical trials.
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Enck, P., Bingel, U., Schedlowski, M. et al. The placebo response in medicine: minimize, maximize or personalize?. Nat Rev Drug Discov 12, 191–204 (2013). https://doi.org/10.1038/nrd3923
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