Implications of Placebo and Nocebo Effects

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Placebo and nocebo effects are the effects of patients’ positive and negative expectations, respectively, concerning their state of health. These effects occur in many clinical contexts, including treatment with an active agent or a placebo in clinical practice or in a clinical trial, the informed consent process, the provision of information about medical treatments, and public health campaigns. Placebo effects cause beneficial outcomes, and nocebo effects cause harmful and dangerous outcomes.

Placebo effects have been shown to be associated with the release of substances such as endogenous opioids, endocannabinoids, dopamine, oxytocin, and vasopressin.
Exacerbation of experimentally produced pain through verbal suggestion, a nocebo effect, has been shown to be mediated by the neuropeptide cholecystokinin and blocked by proglumide, a mixed cholecystokinin type A and type B receptor antagonist.

Implications of Placebo and Nocebo Effects for Research, Clinical Practice, and Clinical Trials

Laboratory, genetic, and other investigations

  • Assess placebo and nocebo effects and include the appropriate control groups (including a no-intervention group when feasible) in designing laboratory studies
  • Explore the molecular and genetic mechanisms underlying placebo and nocebo effects (e.g., use genomic investigations and animal models)
  • Conduct large studies that allow clustering and machine-learning approaches to better understand the driving factors for individual placebo and nocebo responsiveness
  • Recommend replication studies and data sharing for creating large data sets to improve phenotype discoveries

Clinical practice

  • Become familiar with the mechanisms of placebo and nocebo effects
  • Present patients with the mechanisms of placebo and nocebo effects as a basis for promoting healing processes
  • Favor positive associations and minimize negative associations between the therapeutic intervention and contextual factors
  • Consider administering interventions in a positive context, suggesting coping strategies and providing multisensory cues (e.g., sight, smell, and taste stimulations associated with the active medication) to promote conditioning
  • Encourage patients to recount their previous positive or negative experiences with interventions
  • Present patients with realistic possible effects of the intervention to avoid a discrepancy between what is expected and what actually occurs
  • Collect information about patients’ expectations concerning treatment and outcomes as part of the medical history
  • Encourage discussion to align patients’ expectations with anticipated therapeutic outcomes
  • Frame information about side effects in such a way as to minimize nocebo effects
  • Use communication strategies to reduce the likelihood of nonadherence to the treatment regimen or discontinuation of the drug
  • Consider using educational strategies (e.g., video clips of patients recounting positive treatment experiences) to improve outcomes

Clinical trials

  • Ask patients at baseline how much improvement they would expect from the active treatment
  • Ask patients whether they believe they received the active treatment (assessment of group assignment)
  • Standardize the language used to present the benefit–risk profile of the intervention under investigation
  • Standardize the duration and number of therapeutic visits across study sites
  • Standardize framing strategies used to present information about side effects
  • Standardize questions and use structured checklists to collect data on side effects

 

References:

  1. Colloca L, Barsky AJ. Placebo and Nocebo Effects. N Engl J Med. 2020;382(6):554–561. [Medline]
  2. Evers AWM, Colloca L, Blease C, et al. Implications of Placebo and Nocebo Effects for Clinical Practice: Expert Consensus. Psychother Psychosom. 2018;87(4):204–210. [Medline]

Created Feb 12, 2020.

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