Current Insights in the Placebo and Nocebo Phenomena

Clinical Therapeutics
March 2017 Volume 39, Issue 3, p451-664

Current Insights in the Placebo and Nocebo Phenomena
Seetal Dodd, PhD
We have arranged a series of review and original research reports that are both up-to-date and timely. The articles are from leading researchers in different countries, and they provide insight into the range of ongoing research investigating the placebo and nocebo phenomena.

The word placebo has a Latin origin and a long history of use; however, the context in which the word is used has changed over time. Nocebo is a modern word that has been made up from the word placebo. In common usage, a placebo or nocebo effect occurs when an inert substance creates a beneficial or harmful effect in a person who takes it. The concept is also extended beyond the administration of inert substances.1 In a research setting, active placebos are pharmacologically active controls that are not considered to be effective for the index symptoms being treated. Active placebos have also been used in clinical settings, where an active agent has been given to a patient even though the pharmacologic action of the active agent is not known to be beneficial for treating the patient’s diagnosed condition, typically to meet a patient’s expectation that he or she will receive a treatment. Similarly, a nocebo response can occur with an inert or noninert substance as a worsening of the diagnosed condition or as treatment-emergent adverse effects. Moreover, when indication-appropriate active treatment is administered, the therapeutic effect may be a combination of the pharmacologic activity of the treating agent and a placebo effect, as demonstrated in an experiment of open and hidden analgesic administration using an infusion pump where pain relief was significantly reduced when the patients were unaware that an analgesic was being administered.2

It is also common usage to refer to all improvement in a placebo arm of a randomized clinical trial (RCT) as a placebo response and all worsening and adverse events as a nocebo response, even though fluctuation of symptoms occurs with the natural progression of many illnesses. It is often impossible to discern between a genuine placebo response and fluctuation in symptom severity that may have occurred without administering a placebo or between a nocebo response and highly prevalent physical ailments, such as headache or nausea. Consequently, the terms placebo and nocebo are used differently by different authors or even by the same authors when reporting different studies.

In placebo-controlled RCTs, a mean change in the primary outcome from baseline to treatment end point is commonly described as the placebo response. For researchers whose objectives is to demonstrate efficacy of treatment in the active arm of the RCT, it does not matter whether the change from baseline for individuals in the placebo arm of an RCT is a genuine placebo response driven by expectancy and the treatment environment or is attributable to fluctuations in illness severity that may occur during the illness. What matters to these researchers is that there is a statistically significant difference in outcome between participants in the placebo and active arms of the RCT. Alternatively, for researchers investigating the placebo phenomenon itself, experiments are tightly controlled to measure only the response to the placebo itself, typically, in healthy participants.

There is a need for considerable further research investigating the placebo and nocebo phenomena that will increase our scientific and theoretical knowledge about these phenomena and broaden our understanding of their clinical relevance. This requires researchers working in a broad range of fields.

In this issue of Clinical Therapeutics, experts in nocebo and placebo research contribute new insights into the mechanisms and characteristics of the phenomena. The article by Weimer et al3 reports an experiment on the placebo effects for treating nausea, investigating whether altering the levels of expectation of receiving an active agent when actually receiving a placebo can influence treatment outcomes. The article by by Bartels et al4 reports an experiment in which cognitive schemas with regard to memory and expectations are assessed as moderators of placebo and nocebo responses.

Also in this issue, Enck et al5 contribute a review article that describes a wealth of recent research into placebo and nocebo effects but highlights the gaps in current research. Two other review articles are contributed by researchers in Australia, Spain, and Portugal, one reviewing current knowledge regarding the scientific and theoretical basis of the nocebo and placebo phenomena6 and the other investigating the importance and effect of the nocebo and placebo phenomena in clinical research and clinical practice.7

This issue accurately represents the current understanding of the nocebo and placebo phenomena and the limitation in the current knowledge. Gaps still exist in the way placebo and nocebo are conceptualized. As suggested by Enck et al,5 gaps exist in our understanding of the basic science of the placebo response, especially outside placebo analgesia research. In addition, within clinical populations, identifying placebo and nocebo responders remains problematic. I hope that readers enjoy this issue and find it informative.