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Placebo 2.0: the impact of expectations on analgesic treatment outcome.

U. Bingel

Published 2020 in Pain

ABSTRACT

Experimental and clinical evidence from the past decades indicates that patients’ expectations about treatment benefits are crucial modulators of health and treatment outcomes (for comprehensive reviews see Refs. 12, 31, 37, 43, 58, and 95). The pivotal role of expectation is best illustrated by experimental or clinical trials involving placebo (inactive) treatments. Changes in health outcomes (eg, pain) after a placebo treatment cannot be explained by specific properties of a drug. Instead, as seminal work by Donald Price, Irving Kirsch, and other pioneers in the field were able to demonstrate, they are critically determined by patients’ expectations regarding the (drug) treatment in addition to natural fluctuations (ie, natural course) of the underlying condition. Meta-analyses of placebo-controlled randomized clinical trials in different diseases have shown that a large proportion of symptom improvement can be attributed to placebo effects. Placebo effects have been observed in various physiological systems and medical conditions, but their effect size seems to vary between systems and conditions. The effects of positive expectations are particularly strong in studies on pain and depression, where up to 70% of overall treatment effects can be attributed to placebo effects. Meta-analyses of experimental placebo analgesia studies that allow for a dissociation of expectation effects and natural fluctuations in pain, which is not feasible using a classic randomized controlled trial design, corroborate large and clinically relevant effect sizes of positive expectation on pain. Importantly, expectations can also have a negative effect on treatment outcome, which is commonly referred to as nocebo effect. The role of negative expectations in driving the occurrence of unwanted side effects in placebo groups is being increasingly acknowledged. In fact, large proportions of adverse events and symptoms reported by patients in clinical trials may not be caused by the drug itself. This is suggested by the observation that adverse events in placebo arms of drug trials not only resemble those of active treatments in frequency of occurrence, but also in the nature of the symptoms. The key role of negative expectations in pain perception is corroborated by experimental nocebo studies, indicating that the mere expectation of more intense or more frequent pain can modulate pain sensitivity at the behavioural and neural level. Negative expectations also play a key role in the development and maintenance of new symptoms, as highlighted in a recent study by the Benedetti group on pain at high altitude. Study volunteers who were informed by a fellow participant that the high altitude may lead to hypobaric hypoxia headache showed a significant increase in the prevalence and intensity of headache and salivary cyclooxygenase activity, a core factor in prostaglandin synthesis. Similarly, expectations of increasing sensitivity to pain over time can counter the naturally occurring habituation to repetitive painful stimulation in healthy volunteers.

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