Background: Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching interdisciplinary field that is unravelling the neurobiological, behavioural and clinical underpinnings of these phenomena in a broad variety of medical conditions. As a consequence, there is an increasing demand from health professionals to develop expert recommendations about evidence-based and ethical use of placebo and nocebo effects for clinical practice. Methods: A survey and interdisciplinary expert meeting by invitation was organized as part of the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017. Twenty-nine internationally recognized placebo researchers participated. Results: There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects. Conclusions: The current paper forms a first step towards developing evidence-based and ethical recommendations about the implications of placebo and nocebo research for medical practice, based on the current state of evidence and the consensus of experts. Future research might focus on how to implement these recommendations, including how to optimize conditions for educating patients about placebo and nocebo effects and providing training for the implementation in clinical practice.

Patients' expectations are important predictors of the outcome of analgesic treatments, as demonstrated predominantly in research on placebo effects. Three commonly investigated interventions that have been found to induce expectations (verbal suggestion, conditioning, and mental imagery) entail promising, brief, and easy-to-implement adjunctive procedures for optimizing the effectiveness of analgesic treatments. However, evidence for their efficacy stems mostly from research on experimentally evoked pain in healthy samples, and these findings might not be directly transferable to clinical populations. The current meta-analysis investigated the effects of these expectation inductions on patients' pain relief. Five bibliographic databases were systematically searched for studies that assessed the effects of brief verbal suggestion, conditioning, or imagery interventions on pain in clinical populations, with patients experiencing experimental, acute procedural, or chronic pain, compared with no treatment or control treatment. Of the 15,955 studies retrieved, 30 met the inclusion criteria, of which 27 provided sufficient data for quantitative analyses. Overall, a medium-sized effect of the interventions on patients' pain relief was observed (Hedges g = 0.61, I = 73%), with varying effects of verbal suggestion (k = 18, g = 0.75), conditioning (always paired with verbal suggestion, k = 3, g = 0.65), and imagery (k = 6, g = 0.27). Subset analyses indicated medium to large effects on experimental and acute procedural pain and small effects on chronic pain. In conclusion, patients' pain can be relieved with expectation interventions; particularly, verbal suggestion for acute procedural pain was found to be effective.

Nocebo effects, i.e., adverse treatment effects which are induced by patients’ expectations, are known to contribute to the experience of physical symptoms such as pain and itch. A better understanding of how to minimize nocebo responses might eventually contribute to enhanced treatment effects. However, little is known about how to reduce nocebo effects. In the current randomized controlled study, we tested whether nocebo effects can be minimized by positive expectation induction with respect to electrical and histaminic itch stimuli. First, negative expectations about electrical itch stimuli were induced by verbal suggestion and conditioning (part 1: induction of nocebo effect). Second, participants were randomized to either the experimental group or one of the control groups (part 2: reversing nocebo effect). In the experimental group, positive expectations were induced by conditioning with verbal suggestion. In the control groups either the negative expectation induction was continued or an extinction procedure was applied. Afterwards, a histamine application test was conducted. Positive expectation induction resulted in a significantly smaller nocebo effect in comparison with both control groups. Mean change itch NRS scores showed that the nocebo effect was even reversed, indicating a placebo effect. Comparable effects were also found for histamine application. This study is the first to demonstrate that nocebo effects can be minimized and even reversed by conditioning with verbal suggestion. The results of the current study indicate that learning via counterconditioning and verbal suggestion represents a promising strategy for diminishing nocebo responses.

Expectancies can shape pain experiences. Attention for the influence of expectancies on pain has increased particularly due to research on placebo effects, of which expectancy is believed to be the core mechanism. In the current review, we provide a brief overview of the literature on the influence of expectancies on pain. We first discuss the central role of expectancy in the major psychological learning theories. Based on these theories, different kinds of expectancies can be distinguished. Pain experiences are influenced particularly by response expectancies directly pertaining to the pain experience itself, but can also be affected by self-efficacy expectancies regarding one's ability to cope with pain, and possibly by stimulus expectancies regarding external events. These different kinds of expectancies might interact with each other, and related emotions and cognitions, as reflected by various multifaceted constructs in which expectancies are incorporated. Optimism and pain catastrophizing, in particular, but also hope, trust, worry, and neuroticism have been found to be associated with pain outcomes. We conclude with recommendations for further advancing research on the influence of expectancies on pain and for harnessing expectancy effects in clinical practice.

Learning mechanisms in nocebo hyperalgesia: The role of conditioning and extinction processes. Thomaidou et al. Appendix 1. The TENS handout (translated from Dutch)Effectivity of electrical nerve stimulation (ENS) in increasing pain.Electrical nerve stimulation (ENS) is the administration of an electrical current produced by a

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.

Research into placebo effects has convincingly shown that inducing positive outcome expectations can reduce pain and other physical sensations. However, the comparative effects of different expectation inductions, such as verbal suggestion or mental imagery, and their generic effects on physical sensitivity, to different sensations such as pain, itch, and fatigue, are still largely unknown. In the current study, we assessed the individual and combined effects of verbal suggestion and imagery on pain, itch, and fatigue as indicators of physical sensitivity in a randomized study design. Healthy participants (n = 116) were given an inert (placebo) capsule that was said to be effective for reducing physical sensitivity in either the majority (positive verbal suggestion) or the minority (control verbal suggestion) of users. Subsequently, they imagined either their best possible health (positive imagery) or a typical day (control imagery). Sensitivity to pain, itch, and fatigue was tested using a cold pressor test, histamine iontophoresis, and a bicycle test, respectively. Heart rate and skin conductance were recorded continuously. Results showed that positive verbal suggestion and imagery successfully induced positive expectations, but they did not affect physical sensitivity, as indicated by sensitivity to pain, itch, or fatigue, or concurrent physiological responses. These results could indicate that the specificity and concreteness of expectation inductions might be important for their applicability in the treatment of physical symptoms.Trial RegistrationNederlands Trial Register NTR3641

Background: Information provision about prognosis, treatments, and side-effects is important in advanced cancer, yet also associated with impaired patient well-being. To counter potential detrimental effects, communication strategies based on placebo and nocebo effect mechanisms might be promising to apply in daily practice. This study aimed to provide more insight into how often and how oncologists use expectancy and empathy expressions in consultations with patients with advanced breast cancer. Methods: Forty-five consultations between oncologists and patients were audiotaped. To determine how often expectancy and empathy expressions were used, a coding scheme was created. Most consultations ( n = 33) were coded and discussed by two coders, and the remaining 13 were coded by one coder. To determine how expectancy and empathy expressions were used, principles of inductive content analysis were followed. Results: Discussed evaluation (i.e., scan) results were good ( n = 26,58%) or uncertain ( n = 12,27%) and less often bad ( n = 7,15%). Uncertain expectations about prognosis, treatment outcomes, and side effects occurred in 13, 38, and 27 consultations (29%, 85%, and 56%), followed by negative expectations in 8, 26, and 28 consultations (18%, 58%, and 62%) and positive expectations in 6, 34, and 17 consultations (13%, 76%, and 38%). When oncologists provided expectancy expressions, they tapped into three different dimensions: relational, personal, and explicit. Positive expectations emphasized the doctor–patient relationship, while negative expectations focused on the severity of the illness, and uncertainty was characterized by a balance between (potential) negative outcomes and hope. Observed generic or specific empathy expressions were regularly provided, most frequently understanding ( n = 29,64% of consultations), respecting ( n = 17,38%), supporting ( n = 16,36%), and exploring ( n = 16,36%). A lack of empathy occurred less often and contained, among others, not responding to patients’ emotional concerns ( n = 13,27% of consultations), interrupting ( n = 7,16%), and an absence of understanding ( n = 4,9%). Conclusion: In consultations with mainly positive or uncertain medical outcomes, oncologists predominantly made use of uncertain expectations ( hope for the best, prepare for the worst ) and used several empathic behaviors. Replication studies, e.g., in these and other medical situations, are needed. Follow-up studies should test the effect of specific communication strategies on patient outcomes, to counter potential negative effects of information provision. Studies should focus on uncertain situat...