Placebo and nocebo effects constitute a major part of treatment success in medical interventions; there is interest in optimizing placebo effects to improve existing treatments and in examining ways to minimize nocebo effects to improve clinical outcome

Psychobiological Mechanisms of Placebo and Nocebo Effects: Pathways to Improve Treatments and Reduce Side Effects. Keith J. Petrie and Winfried Rief, Annual Review of Psychology, Vol. 70:- (Volume publication date January 2019). https://doi.org/10.1146/annurev-psych-010418-102907

Abstract: Placebo effects constitute a major part of treatment success in medical interventions. The nocebo effect also has a major impact, as it accounts for a significant proportion of the reported side effects for many treatments. Historically, clinical trials have aimed to reduce placebo effects; however, currently, there is interest in optimizing placebo effects to improve existing treatments and in examining ways to minimize nocebo effects to improve clinical outcome. To achieve these aims, a better understanding of the psychological and neurobiological mechanisms of the placebo and nocebo response is required. This review discusses the impact of the placebo and nocebo response in health care. We also examine the mechanisms involved in the placebo and nocebo effects, including the central mechanism of expectations. Finally, we examine ways to enhance placebo effects and reduce the impact of the nocebo response in clinical practice and suggest areas for future research.

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Open-Label Placebos

There has been recent interest in the use of open-label placebos, i.e., placebos that patients take knowing that they do not contain active medicine. Open-label placebos avoid the ethical issues involved in the deceptive prescription of placebos, which violates informed consent and may compromise the clinician–patient relationship. In the studies that have used open-label placebos, positive expectations are typically established by describing the power of the placebo effect as being established through conditioning and expectations and working through mind–body processes to improve health. The patient is informed that, even though they are not taking any active medicine, a placebo may still help improve health.

An initial RCT of 80 patients with IBS assigned patients to open-label placebo pills described as being “made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvements in IBS symptoms through mind-body self-healing processes” (Kaptchuk et al. 2010, p. 1) or to a no-treatment control group with the same amount ofprovider contact. Findings revealed significant improvements in symptoms at the 3-week follow-up.

The study demonstrated that open-label placebos delivered with a convincing rationale can improve subjective symptom reports in IBS. This prompted other researchers to investigate whether open-label placebos could improve outcomes in other conditions. Positive effects from open-label placebos have now been demonstrated in low-back pain (Carvalho et al. 2016), allergic rhinitis (Schaefer et al. 2016), and cancer-related fatigue (Hoenemeyer et al. 2018). A review of five open-label placebo studies found a positive medium effect size on subjective symptoms (Charlesworth et al. 2017).

While the initial results of studies of open-label placebos have been positive, there are some reasons to be cautious about the findings. A recent study evaluated the effect of open-label placebos on an objective, measurable physiological outcome, wound healing, and found no effect (Mathur et al. 2018), suggesting that the main benefit from open-label placebos could be restricted to subjective symptoms. The participants recruited into the initial studies for a mind–body treatment are also more likely to be receptive to open-label placebos than individuals with a preference for more traditional medical treatments. A further question at this stage is whether open-label placebo treatment will be acceptable to doctors and therefore more widely adopted.

To summarize, initial attempts to make use of placebo mechanisms to improve treatment outcomes indicate that this strategy could have enormous potential to improve clinical care. A number of the factors that have been found to improve placebo response could be easily incorporated into current treatments to maximize outcomes. These include optimizing patient’s expectations prior to treatment, using a positive role model to demonstrate treatment effectiveness, and inducing positive pretreatment experiences with similar drug treatments. Improving aspects of the clinical interaction, such empathy, shared decision making, and patient perceptions of physician competence, is also likely to lead to improved outcomes, although future research in this area is needed. It is likely that open-label placebos will also play a role in treatment in the future as an adjunct to standard therapies, either to reduce side effects or to maximize response to treatment, but the exact niche of open-label placebos has yet to be established.