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BackgroundNocebo effect, the occurrence of adverse symptoms fallowing an inactive treatment, is much less understood than its opposite, placebo effect. This systematic review of contemporary studies exploring the nocebo effect focuses on (1) the mechanisms underlying the nocebo effect, (2) the characteristics of participants exhibiting a more intensive nocebo response, and (3) the circumstances that might reduce or prevent the nocebo effect.MethodWe included experimental nocebo studies published in English that examined the occurrence of nocebo in various domains (i.e., types of sensations and symptoms) and different levels of nocebo response (e.g., performance, self-assessment) and in different populations of participants (healthy and clinical). Using Web of Science, PsycInfo and PubMed, we identified 25 papers (35 studies) that met our criteria with a total of N = 2614 participants, mostly healthy volunteers.ResultsNocebo was invoked by manipulating expectations, conditioning or both. A narrative content synthesis was conducted. Nocebo was successfully invoked in a range of domains (e.g., pain, nausea, itch, skin dryness) and levels (sensory, affective, psychological, and behavioral). Various characteristics of the conditioning procedure and participants’ emotions, expectations, and dispositions are found to be related to the nocebo response, which sheds insight into the possible mechanisms of the nocebo effect. Strategies successful and unsuccessful in diminishing the nocebo response are identified. Limitations of this review include a small sample of studies.ConclusionThese findings point to the universality of nocebo as well as to the importance of participant characteristics and experimental circumstances in invoking the nocebo effect. Further research should examine the nocebo effect in clinical populations.

Placebo and nocebo effects (effects of patients’ positive and negative expectations) are powerful and pervasive in clinical practice. Neurobiologic mechanisms, information offered about treatment, prior encounters with a drug or procedure, and the therapeutic milieu can all generate these effects.

IntroductionNon-coeliac gluten/wheat sensitivity (NCGS) is characterized by gastrointestinal and extra-intestinal symptoms triggered by gluten/wheat ingestion in patients without coeliac disease (CD) or wheat allergy. There are controversies on the mechanism leading to this phenomenon, including media influence and the presence of a nocebo effect. The only treatment available is a gluten/wheat-free diet (GFD), yet long-term outcomes are poorly understood. This study aimed to evaluate long-term GFD adherence in patients with NCGS. The secondary goals are the assessment of the perceived efficacy of GFD and the need of further medical/nutritional support.MethodsPatients with self-reported NCGS referred to a tertiary center clinic from 2006 to 2018 completed a questionnaire regarding their dietary habits and further need of medical advice for symptoms related to their diagnosis. The Biagi score was used to assess their adherence to a GFD. We compared the dietary adherence scores to age and sex matched controls cohort of patients with CD to validate the results using a chi-square test.ResultsOut of 186 patients with NCGS, 101 answered the questionnaire (response rate 54.3%, female 82.2%, average age 54±14years). Of these, 47 patients (46.5%) were following a GFD but only 25 (53.3%) strictly (Biagi score 3-4), 1 had a Biagi score of 2 (2.2%) indicating poor adherence to a gluten free diet, and 20 (43.4%) voluntarily ate gluten (Biagi 1-0). The average time patients remained on a gluten free diet was 140±55 months. The remaining 54 patients (53.5%) did not follow a GFD, although 14.8% reduced wheat consumption and 22.2% tried a GFD previously. Half (50%) reported no symptom improvement on a GFD. Compared to patients with CD those with NCGS on a GFD showed a significantly lower adherence to a GFD (Biagi score of 0-1 NCGS: 44.7% vs CD: 19,1%, χ2 = 5.92, p=0.02; Biagi score 3-4, NCGS: 53.2% vs CD: 76.6%, χ2 =4.67, p=0.03). After being discharged from medical services, 56.4% of patients tried other dietary regimens (54.3% lactose free, 31.6% low FODMAP) and 35.6% sought further medical advice. No significant correlation was found between the adherence to a GFD and need for further medical intervention.ConclusionsUnlike CD, the vast majority of patients with self-reported NCGS do not continue a gluten free diet or significantly reduce their level of adherence. Half of the patients who have tried a gluten exclusion regimen report the GFD did not help their symptoms. However, over a third sought further medical advice to manage their symptoms or other ways to manage their symptoms by other exclusion diets. These findings underline the need of a better understanding of this condition and the challenges in the management of these patients.

Harnessing placebo and nocebo effects has significant implications for research and medical practice. Placebo analgesia and nocebo hyperalgesia, the most well-studied placebo and nocebo effects, are thought to initiate from the dorsal lateral prefrontal cortex (DLPFC) and then trigger the brain’s descending pain modulatory system and other pain regulation pathways. Combining repeated transcranial direct current stimulation (tDCS), an expectancy manipulation model, and functional MRI, we investigated the modulatory effects of anodal and cathodal tDCS at the right DLPFC on placebo analgesia and nocebo hyperalgesia using a randomized, double-blind and sham-controlled design. We found that compared with sham tDCS, active tDCS could 1) boost placebo and blunt nocebo effects and 2) modulate brain activity and connectivity associated with placebo analgesia and nocebo hyperalgesia. These results provide a basis for mechanistic manipulation of placebo and nocebo effects and may lead to improved clinical outcomes in medical practice.

•Attention plays an important role in pain modulation.•Changing the excitability at the rDLPFC through tDCS can modulate the placebo effect.•Repeated tDCS at the rDLPFC can modulate the functional connectivity of the FPN and DAN.•DAN connectivity changes after tDCS are correlated with the placebo analgesia. Literature suggests that attention is a critical cognitive process for pain perception and modulation and may play an important role in placebo and nocebo effects. Here, we investigated how repeated transcranial direct current stimulation (tDCS) applied at the dorsolateral prefrontal cortex (DLPFC) for three consecutive days can modulate the brain functional connectivity (FC) of two networks involved in cognitive control: the frontoparietal network (FPN) and dorsal attention network (DAN), and its association with placebo and nocebo effects. 81 healthy subjects were randomized to three groups: anodal, cathodal, and sham tDCS. Resting state fMRI scans were acquired pre- and post- tDCS on the first and third day of tDCS. An Independent Component Analysis (ICA) was performed to identify the FPN and DAN. ANCOVA was applied for group analysis. Compared to sham tDCS, 1) both cathodal and anodal tDCS increased the FC between the DAN and right parietal operculum; cathodal tDCS also increased the FC between the DAN and right postcentral gyrus; 2) anodal tDCS led to an increased FC between the FPN and right parietal operculum, while cathodal tDCS was associated with increased FC between the FPN and left superior parietal lobule/precuneus; 3) the FC increase between the DAN and right parietal operculum was significantly correlated to the placebo analgesia effect in the cathodal group. Our findings suggest that both repeated cathodal and anodal tDCS could modulate the FC of two important cognitive brain networks (DAN and FPN), which may modulate placebo / nocebo effects.

Sex has been speculated to be a predictor of the placebo and nocebo effect for many years, but whether this holds true or not has rarely been investigated. We utilized a placebo literature database on various aspects of the genuine placebo/nocebo response. In 2015, we had extracted 75 systematic reviews, meta-analyses, and meta-regressions performed in major medical areas (neurology, psychiatry, internal medicine). These meta-analyses were screened for whether sex/gender differences had been noted to contribute to the placebo/nocebo effect: in only 3 such analyses female sex was associated with a higher placebo effect, indicating poor evidence for a contribution of sex to it in RCTs. This was updated with another set of meta-analyses for the current review, but did not change the overall conclusion. The same holds true for 18 meta-analyses investigating adverse event (nocebo) reporting in RCT in the placebo arm of trials. We also screened our database for papers referring to sex/gender and the placebo effect in experimental studies, and identified 28 papers reporting 29 experiments. Their results can be summarized as follows: (a) Despite higher sensitivity of pain in females, placebo analgesia is easier to elicit in males; (b) It appears that conditioning is effective specifically eliciting nocebo effects; (c) Conditioning works specifically well to elicit placebo and nocebo effects in females and with nausea; (d) Verbal suggestions are not sufficient to induce analgesia in women, but work in men. These results will be discussed with respect to the question why nausea and pain may be prone to be responsive to sex/gender differences, while other symptoms are less. Lastly, we will discuss the apparent discrepancy between RCT with low relevance of sex, and higher relevance of sex in specific experimental settings. We argue that the placebo response is predominantly the result of a conditioning (learning) response in females, while in males it predominantly may be generated via (verbal) manipulating of expectancies. In RCT therefore, the net outcome of the intervention may be the same despite different mechanisms generating the placebo effect between the sexes, while in experimental work when both pathways are separated and explicitly explored, such differences may surface.

Observation of another’s treatment side effects can elicit side effects in the observer, even when the treatment is a placebo. This study investigated whether these socially acquired side effects can generalise to similar treatments. Healthy volunteers ( N  = 120) participated in a study ostensibly comparing the effect of two cognitive enhancers (placebos). Participants were randomised to one of four experimental groups. The three treatment groups comprised: social modelling of side effects associated with the same treatment; social modelling of side effects associated with the different treatment; and a verbal suggestion only group (i.e., no social modelling). The fourth group was a no-treatment control group. The primary outcome was severity of side effects reported. Groups that received placebos reported increased symptom severity, i.e., showed a nocebo effect. Surprisingly, primary outcome analysis revealed no significant enhancement of the nocebo effect due to social modelling. However, there was an additive effect of social modelling on general side effects (planned secondary outcome) and specifically for headaches and dizziness (exploratory analysis), both of which generalised across treatments. Therefore, preliminary findings suggest that socially induced nocebo side effects may not always occur, but when they do, they can generalise beyond identical treatments. This warrants replication and raises significant concern given the widespread sharing of treatment-related information, potentially contributing to the societal burden of nocebo effects.

Background Adverse events of chemotherapy may be caused by pharmacodynamics or psychological factors such as negative expectations, which constitute nocebo effects. In a randomized controlled trial, we examined whether educating patients about the nocebo effect is efficacious in reducing the intensity of self-reported adverse events. Methods In this proof-of-concept study, N  = 100 outpatients (mean age: 60.2 years, 65% male, 54% UICC tumour stage IV) starting first-line, de novo chemotherapy for gastrointestinal cancers were randomized 1:1 to a nocebo education ( n  = 49) or an attention control group ( n  = 51). Our primary outcome was patient-rated intensity of four chemotherapy-specific and three non-specific adverse events (rated on 11-point Likert scales) at 10-days and 12-weeks after the first course of chemotherapy. Secondary outcomes included perceived control of adverse events and tendency to misattribute symptoms. Results General linear models indicated that intensity of adverse events differed at 12-weeks after the first course of chemotherapy (mean difference: 4.04, 95% CI [0.72, 7.36], p  = .02, d  = 0.48), with lower levels in the nocebo education group. This was attributable to less non-specific adverse events (mean difference: 0.39, 95% CI [0.04, 0.73], p  = .03, d  = 0.44) and a trend towards less specific adverse events in the nocebo education group (mean difference: 0.36, 95% CI [− 0.02, 0.74], p  = .07, d  = 0.37). We found no difference in adverse events at 10-days follow-up, perceived control of adverse events, or tendency to misattribute non-specific symptoms to the chemotherapy. Conclusions This study provides first proof-of-concept evidence for the efficacy of a brief information session in preventing adverse events of chemotherapy. However, results regarding patient-reported outcomes cannot rule out response biases. Informing patients about the nocebo effect may be an innovative and clinically feasible intervention for reducing the burden of adverse events. Trial registration Retrospectively registered on March 27, 2018 to the German Clinical Trial Register (ID: DRKS00009501).

This overview focuses on placebo and nocebo effects in clinical trials and routine care. Our goal was to propose strategies to improve outcomes in clinical practice, maximizing placebo effects and reducing nocebo effects, as well as managing these phenomena in clinical trials. A narrative literature search of PubMed was conducted (January 1980–September 2016). Systematic reviews, randomized controlled trials, observational studies, and case series that had an emphasis on placebo or nocebo effects in clinical practice were included in the qualitative synthesis. Search terms included: placebo, nocebo, clinical, clinical trial, clinical setting, placebo effect, nocebo effect, adverse effects, and treatment outcomes. This search was augmented by a manual search of the references of the key articles and the related literature. Placebo and nocebo effects are psychobiological events imputable to the therapeutic context. Placebo is defined as an inert substance that provokes perceived benefits, whereas the term nocebo is used when an inert substance causes perceived harm. Their major mechanisms are expectancy and classical conditioning. Placebo is used in several fields of medicine, as a diagnostic tool or to reduce drug dosage. Placebo/nocebo effects are difficult to disentangle from the natural course of illness or the actual effects of a new drug in a clinical trial. There are known strategies to enhance clinical results by manipulating expectations and conditioning. Placebo and nocebo effects occur frequently and are clinically significant but are underrecognized in clinical practice. Physicians should be able to recognize these phenomena and master tactics on how to manage these effects to enhance the quality of clinical practice.

Summary Dropout from placebo arms in randomized-controlled trials is a surrogate for nocebo responses, resulting from patients’ negative expectations to treatment. Among 16,460 placebo-treated patients in oral anti-osteoporotic drug trials, nocebo dropouts were 8% on average, being higher in older patients. This implies that nocebo may contribute to the osteoporosis treatment gap in clinical practice. Purpose Osteoporosis is a common disease requiring long-term treatment. Despite the availability of effective anti-osteoporotic drugs, adherence to treatment is low. Nocebo, a behavior mostly related to the negative expectations to a certain treatment, decreases adherence and negatively affects treatment outcomes and health-related care costs in chronic diseases. Since in double-blind placebo-controlled randomized trials any unfavorable outcome leading to discontinuation in placebo arms is considered as nocebo, we aimed to investigate the size of nocebo response in patients participating in osteoporosis trials. Methods We searched MEDLINE, EMBASE, SCOPUS, and Cochrane databases for dropouts due to reported adverse events in the placebo arms (nocebo dropouts) in all double-blind trials investigating anti-osteoporotic drugs published between January 1993 and March 2022. Only data on bisphosphonates and selective estrogen receptor modulators (SERMs) were analyzed (Prospero registration number CRD42020212843). Results Data from 44 trials were extracted. In 16,460 placebo-treated patients, the pooled nocebo-dropout was 8% both for bisphosphonates (average: 0.08; range 0.01–0.27; 95%CI 0.06–0.10) and SERMs (average: 0.08; range 0.03–0.15; 95%CI 0.05–0.13). Nocebo-dropouts were higher in bisphosphonate trials enrolling individuals ≥ 65 years (11%) ( n  = 18) compared to trials enrolling younger individuals (6%) ( n  = 18) (average: 0.11; 95%CI 0.08–0.13 vs. average: 0.06; 95%CI 0.05–0.08, respectively, p  = 0.001). Participants’ sex, dosing-intervals, publication year, or severity of osteoporosis had no impact on the nocebo-dropouts. Conclusion Almost 1 in 10 osteoporosis patients receiving placebo in trials of bisphosphonates and SERMs experiences AEs leading to dropout, implying that nocebo contributes to treatment-discontinuation in clinical practice. Efforts to identify and minimize nocebo, especially in older patients, are warranted.