Placebo and Nocebo Effects Across Symptoms: From Pain to Fatigue, Dyspnea, Nausea, and Itch

Abstract

Placebo and nocebo effects are, respectively, the helpful and harmful treatment effects that do not arise from active treatment components. These effects have thus far been researched most often in pain. It is not yet clear to what extent these findings from pain can be generalized to other somatic symptoms. This review investigates placebo and nocebo effects in four other highly prevalent symptoms: dyspnea, fatigue, nausea, and itch. The role of learning mechanisms (verbal suggestions, conditioning) in placebo and nocebo effects on various outcomes (self-reported, behavioral, and physiological) of these different somatic symptoms is explored. A search of experimental studies indicated that, as in pain, the combination of verbal suggestion and conditioning is generally more effective than suggestion alone for evoking placebo and nocebo effects. However, conditioning appears more and verbal suggestions less relevant in symptoms other than pain, with the exception of placebo effects on fatigue and nocebo effects on itch. Physiological measures, such as heart rate, lung function, or gastric activity, are rarely affected even when self-reported symptoms are. Neurobiological correlates are rarely investigated, and few commonalities appear across symptoms. Expectations generally predict placebo and nocebo effects for dyspnea and itch but seem less involved in fatigue and nausea. Individual characteristics do not consistently predict placebo or nocebo effects across symptoms or studies. In sum, many conclusions deriving from placebo and nocebo pain studies do appear to apply to other somatic symptoms, but a number of important differences exist. Understanding what type of learning mechanisms for which symptom are most likely to trigger placebo and nocebo effects is crucial for generalizing knowledge for research and therapies across symptoms and can help clinicians to optimize placebo effects in practice.

Open- and Closed-Label Placebo and Nocebo Suggestions About a Sham Transdermal Patch

“…Most studies on placebo and nocebo effects in pain and itch investigated placebo or nocebo effects with covert induction of effects (i.e., hidden or closed administration of an inert treatment, with participants being led to believe an active treatment is given (e.g., Refs. ( 23 , 24 )). Such an approach does not allow for an easy translation toward clinical practice, as it is simply not ethical to deceive patients ( 25 ).…”

Association of nocebo hyperalgesia and basic somatosensory characteristics in a large cohort

“…Pain is a multi-faceted phenomenon, with a large prevalence as a clinical symptom 1 , substantial impact on quality of life and high societal costs 2 . As with many subjective clinical symptoms, expectations substantially shape pain [3][4][5][6] . Implicit and explicit expectations can arise from sources as diverse as previous symptom experiences, verbal information or suggestions, or social observation 7 .…”

A virtual experimenter does not increase placebo hypoalgesia when delivering an interactive expectancy manipulation

“…We also opted against a within-person, cross-over design routinely employed in placebo research, which might have further reduced error variance, out of concerns for asymmetric carry-over effects 34 . The existence of a significant Expectancy effect is all the more noteworthy, as the simple expectancy manipulation we used (verbal suggestion of efficacy) is the most basic and arguably weakest form of manipulation employed in placebo mechanism studies 65,66 . While we have reinforced the placebo instruction intermittently (see Table 1), several other options exist to strengthen this protocol aspect now that basic efficacy was established 67 , the most obvious being to include some form of conditioning procedure (e.g.…”