Summary Background: Vaccinations often elicit significant distress in school-aged children, which can impact pain perception and future medical experiences. This study examined the effects of three stages of a video-based magic intervention on self-reported distress and pain in children receiving HPV vaccinations. Methods: This cluster-randomized controlled trial randomized 412 children (aged 9–11 years) who received their first HPV vaccination at five mass-vaccination sites in The Netherlands. Based on vaccination date and time, children were assigned to one of four groups: 1. watching a magic trick video during the vaccination, 2. watching the trick with revelation of the secret, 3. watching the trick with revelation of the secret, followed by a brief post-vaccination video-training, and 4. a regular care control. Children completed questionnaires before (T0) and after (T1) the first vaccination in April 2024, and before the second vaccination six months later (T2) in September/October 2024. The primary outcome of child-reported distress was assessed at T0, T1, and T2 using the Facial Image Scale (FIS) and the short form of the State-Trait Anxiety Inventory (STAI-6). The study was preregistered on OSF (https://doi.org/10.17605/OSF.IO/5ASM9, registered April 4, 2024). Findings: All randomized participants were analyzed according to the intention-to-treat principle. Children in the combined magic-intervention groups (groups 1–3) reported less distress and lower pain after the first vaccination compared to the control group (group 4; distress: p < 0.0001, partial η2 = 0.11; pain: p = 0.0039, η2 = 0.02, 95% CI [0.002–0.058]). The most extensive magic intervention (group 3) showed the largest distress reduction as compared to all other groups (p < 0.0001). No significant differences in distress were observed preceding the second vaccination, indicating a lack of sustained effects. Interpretation: The video-based magic intervention reduced distress and pain immediately following the vaccination, with the largest effect found for the most elaborate intervention group involving active engagement. These findings suggest a promising, easily implementable intervention to improve children’s vaccination experiences during mass vaccinations. Funding: LUMC Foundation (non-profit).

Objectives: Placebo effects can relieve acute and chronic pain in both research and clinical treatments by learning mechanisms. However, the application of placebo-based treatment strategies in routine medical care is questioned. The current study investigated the opinions of patients with fibromyalgia and healthy controls regarding learning of placebo effects and their practical applications. Method: An online survey asked 158 age- and sex-matched adult patients and controls (79 per group) to rate the perceived influence of various placebo learning mechanisms on pain relief, and the acceptability and perceived effectiveness of placebo-based strategies (open-label, closed-label, dose-extending, and treatment-enhancing strategies). Respondents' knowledge about placebo effects was obtained through a 7-item quiz. Results: The groups did not differ in the perceived influence of placebo learning mechanisms on pain relief (p = 0.217). Controls considered closed-label and treatment-enhancing strategies more acceptable than patients (p = 0.003 and p < 0.001), whereas controls perceived all strategies more effective. In both groups, closed-label strategies were significantly less acceptable than any other strategy (p-values < 0.001), and treatment-enhancing or dose-extending strategies were most acceptable. Higher acceptability was predicted by higher perceived effectiveness ratings (p < 0.001). Also, increased placebo knowledge was related to higher acceptability (p = 0.03) and perceived effectiveness (p < 0.001). Discussion: This survey suggests that both the medical history of patients and knowledge about placebo effects affect the acceptability and perceived effectiveness of placebo-based strategies. Furthermore, strategies that are transparent, assumed effective, or combined with existing medical treatments are deemed most acceptable. Keeping these factors in mind is essential for the clinical implementation of placebo-based strategies in routine medical care.

Objective: Expectancies are known to shape pain experiences, but it remains unclear how different types of expectancies contribute to daily pain fluctuations in fibromyalgia. This combined experimental and diary study aims to provide insights into how experimentally-derived nocebo hyperalgesia and other, diary-derived, expectancy-related factors are associated with each other and with daily pain in fibromyalgia. Methods: Forty-one female patients with fibromyalgia first participated in a lab procedure measuring nocebo hyperalgesia magnitude, then filled out an electronic diary 3 times a day over 3 weeks regarding the expectancy-related factors of pain expectancy, anxiety, optimism, and pain-catastrophizing thoughts, and current pain intensity. Results: Our results indicate that experimentally-induced nocebo hyperalgesia was not significantly related to diary-assessed expectancy-related factors and did not predict daily fibromyalgia pain. Higher levels of the self-reported expectancy-related factors pain expectancy and pain catastrophizing, but not anxiety and optimism, predicted moment-to-moment pain increases in fibromyalgia, after controlling for current pain, moment-of-day and all other expectancy-related factors. Conclusion: Our exploratory research findings indicate that self-reported expectancy-related factors, particularly pain expectancy and pain catastrophizing, are potentially more relevant for predicting daily pain experience than experimentally-induced nocebo hyperalgesia. Further translation of nocebo hyperalgesia is needed from experimental to Ecological Momentary Assessment research. Our findings imply that targeting the decrease in pain expectancy and catastrophizing thoughts e.g., via Cognitive Behavioral Therapy, have potential for improving daily pain levels in fibromyalgia.

OBJECTIVES: The current paper explores the psychological predictors of nocebo hyperalgesia and whether the reduction of nocebo hyperalgesia can be predicted by susceptibility to nocebo hyperalgesia and psychological characteristics. METHODS: Nocebo effects on pressure pain were first experimentally induced in 83 healthy female participants through conditioning with open-label instructions about the pain-worsening function of a sham TENS device to assess susceptibility to nocebo hyperalgesia. Participants were then randomized to 1 out of 2 nocebo-reduction conditions (counterconditioning/extinction) or to continued nocebo-conditioning (control), each combined with open-label instructions about the new sham device function. Dispositional optimism, trait and state anxiety, pain catastrophizing, fear of pain, and body vigilance were assessed at baseline. RESULTS: The results showed that lower optimism and higher trait anxiety were related to a stronger induction of nocebo hyperalgesia. Moreover, a stronger induction of nocebo hyperalgesia and higher trait anxiety predicted a larger nocebo reduction across interventions. Also, nocebo hyperalgesia and optimism moderated the effects of the nocebo-reduction interventions, whereby larger nocebo hyperalgesia and lower optimism were associated with a larger nocebo reduction after counterconditioning, compared with control, and also extinction for larger nocebo hyperalgesia. DISCUSSION: Our findings suggest that open-label conditioning leads to stronger nocebo hyperalgesia when trait anxiety is high and dispositional optimism is low, while these psychological characteristics, along with larger nocebo hyperalgesia, also predict open-label counterconditioning to be an effective nocebo-reduction strategy. Susceptibility to nocebo hyperalgesia, trait anxiety, and dispositional optimism might be indicators of a flexible pain regulatory system.

Background: Nocebo effects can adversely affect the experience of physical symptoms, such as pain and itch. Nocebo effects on itch and pain have shown to be induced by conditioning with thermal heat stimuli and reduced by counterconditioning. However, open-label counterconditioning, in which participants are informed about the placebo content of the treatment, has not been investigated, while this can be highly relevant for clinical practice. Furthermore, (open-label) conditioning and counterconditioning has not been investigated for pain modalities relevant to musculoskeletal disorders, such as pressure pain. Methods: In a randomized controlled trial, we investigated in 110 healthy female participants whether nocebo effects on pressure pain combined with open-label verbal suggestions can be (1) induced via conditioning and (2) reduced via counterconditioning. Participants were allocated to either a nocebo- or sham-conditioning group. Next, the nocebo group was allocated to either counterconditioning, extinction or continued nocebo conditioning; sham conditioning was followed by placebo conditioning. Results: Nocebo effects were significantly larger after nocebo conditioning than sham conditioning (d = 1.27). Subsequently, a larger reduction of the nocebo effect was found after counterconditioning than after extinction (d = 1.02) and continued nocebo conditioning (d = 1.66), with effects similar to placebo conditioning (following sham conditioning). Conclusions: These results show that (counter)conditioning combined with open-label suggestions can modulate nocebo effects on pressure pain, which provides promise in designing learning-based treatments to reduce nocebo effects in patients with chronic pain disorders, particularly for musculoskeletal disorders. Significance: Few studies have investigated the efficacy counterconditioning to reduce nocebo effects. Whereas typically deceptive procedures are used, these are not ethically appropriate for use in clinical practice. The current study demonstrates that open-label counterconditioning in a pain modality relevant for many chronic pain conditions may be a promising new strategy for reducing nocebo effects in a non-deceptive and ethical manner, which provides promise in designing learning-based treatments to reduce nocebo effects in patients with chronic pain disorders.

Background: The hormone cortisol plays important roles in human circadian and stress physiology and is an interesting target for interventions. Cortisol varies not only in response to stress but also as part of a diurnal rhythm. It shows a particularly sharp increase immediately after awakening, the cortisol awakening response (CAR). Cortisol can be affected by medication, but it is less clear whether it can also be affected by learning. Animal studies have consistently shown that cortisol can be affected by pharmacological conditioning, but the results in humans have been mixed. Other studies have suggested that conditioning is also possible during sleep and that the diurnal rhythm can be conditioned, but these findings have not yet been applied to cortisol conditioning. Objective: The objective of our study was to introduce a novel avenue for conditioning cortisol: by using the CAR as an unconditioned response and using scent conditioning while the participant is asleep. This study investigates an innovative way to study the effects of conditioning on cortisol and the diurnal rhythm, using a variety of devices and measures to make measurement possible at a distance and at unusual moments. Methods: The study protocol takes 2 weeks and is performed from the participant’s home. Measures in week 1 are taken to reflect the CAR and waking under baseline conditions. For the first 3 nights of week 2, participants are exposed to a scent from 30 minutes before awakening until their normal time of awakening to allow the scent to become associated with the CAR. On the final night, participants are forced to wake 4 hours earlier, when cortisol levels are normally low, and either the same (conditioned group) or a different (control group) scent is presented half an hour before this new time. This allows us to test whether cortisol levels are higher after the same scent is presented. The primary outcome is the CAR, assessed by saliva cortisol levels, 0, 15, 30, and 45 minutes after awakening. The secondary outcomes are heart rate variability, actigraphy measures taken during sleep, and self-reported mood after awakening. To perform manipulations and measurements, this study uses wearable devices, 2 smartphone apps, web-based questionnaires, and a programmed scent device. Results: We completed data collection as of December 24, 2021. Conclusions: This study can provide new insights into learning effects on cortisol and the diurnal rhythm. If the procedure does affect the CAR and associated measures, it also has potential clinical implications in the treatment of sleep and stress disorders.

Rationale & Objective: Patients with chronic kidney disease (CKD) not receiving dialysis, including kidney transplant recipients, often experience difficulties regarding self-management. An important barrier for adherence to self-management recommendations may be the presence of psychological distress, consisting of depressive and anxiety symptoms. We investigated relationships between psychological distress and adherence to self-management recommendations. Study Design: Cross-sectional online questionnaire data as part of the E-GOAL study. Setting & Participants: Patients with CKD (estimated glomerular filtration rate, 20-89 mL/min/1.73 m²) were recruited from April 2018 to October 2020 at 4 hospitals in The Netherlands and completed online screening questionnaires. Exposures: Psychological distress, depressive symptoms, and anxiety symptoms. Outcomes: Dietary adherence, physical activity, medication adherence, smoking, body mass index, and a CKD self-management index (ie, the sum of 5 binary indicators of nonadherence to the recommended self-management factors). Analytical Approach: Adjusted multivariable regression and ordinal logistic regression analyses. Results: In our sample (N = 460), 27.2% of patients reported psychological distress, and 69.8% were nonadherent to 1 or more recommendations. Higher psychological distress was significantly associated with poorer dietary adherence (β^adj, −0.13; 95% CI, −0.23 to −0.04), less physical activity (β^adj, −0.13; 95% CI, −0.22 to −0.03), and lower medication adherence (β^adj, −0.15; 95% CI, −0.24 to −0.05), but not with smoking and body mass index. Findings were similar for depressive symptoms, whereas anxiety was only associated with poorer dietary and medication adherence. Every 1-point higher psychological distress was also associated with a higher likelihood of being nonadherent to an accumulating number of different recommendations (adjusted OR, 1.04; 95% CI, 1.02-1.07). Limitations: Cross-sectional design, possible residual confounding, and self-report. Conclusions: Many people with CKD experience psychological distress, of whom most have difficulties self-managing their CKD. Given the relationship between psychological distress and adherence to CKD self-management recommendations, behavioral interventions are needed to identify and treat psychological distress as a potential barrier to CKD self-management. Plain-Language Summary: This online questionnaire study investigated relationships between psychological distress and self-management among 460 people with chronic kidney disease. Over a quarter of them reported mild-to-severe psychological distress. Alarmingly, 4 out of 5 patients with psychological distress were also nonadherent to 1 or more self-management recommendations, and higher levels of psychological distress were associated with poorer dietary and medication adherence and lower physical activity. Moreover, patients who suffered from moderate-to-severe distress were relatively more often nonadherent to 3 or more recommendations compared with patients with no or mild distress symptoms. So, it seems that psychological distress can be a barrier for self-management. To support patients in managing chronic kidney disease, researchers and health professionals should not overlook patients’ mental health.

Objective Psychological distress is common among patients with chronic kidney disease and can interfere with disease self-management. We assessed the effectiveness of the personalized E-GOAL electronic health care pathway with screening and cognitive-behavioral therapy including self-management support, aimed to treat psychological distress and facilitate self-management among people with chronic kidney disease not on dialysis (N = 121). Methods Primary outcome of the open two-arm parallel randomized controlled trial in four Dutch hospitals was psychological distress at posttest directly after the intervention and at 3-month follow-up. Secondary outcomes were physical and mental health-related quality of life, self-efficacy, chronic disease self-management, and personalized outcomes, that is, perceived progress compared with the previous time point on functioning (e.g., mood or social functioning) and self-management (e.g., dietary or medication adherence) outcomes that were prioritized by each individual. Results Linear mixed-effects analyses showed no significant time-by-group interaction effects for psychological distress, health-related quality of life, self-efficacy, and chronic condition self-management, whereas analyses of covariance showed significantly more perceived progress in the intervention group at posttest on personally prioritized areas of functioning (b = 0.46, 95% confidence interval = 0.07-0.85) and self-management (b = 0.55, 95% confidence interval = 0.16-0.95), with Cohen d values of 0.46 and 0.54 (medium effects), respectively. Effects on personalized outcomes were maintained at follow-up. Conclusions Compared with regular care only, the electronic health intervention did not reduce psychological distress, whereas personalized outcomes did improve significantly after intervention. Future studies could consider personalized outcomes that reflect individually relevant areas and treatment goals, matching person-tailored treatments.

Aims: Implicit gender biases (IGBs) are unconscious evaluations about a person based on gender. IGBs of healthcare providers may affect medical decision making. This study investigated whether IGBs and genders of patients and general practitioners (GPs) influence diagnostics and treatment decisions in the context of diabetes type 2. Methods: Ninety-nine GPs participated in this randomized online study. Implicit Associations Tasks were used to measure two IGBs, related to lifestyle (women have a healthier lifestyle than men) and communication (men are less communicative than women). Clinical decisions regarding type 2 diabetes were measured with vignettes that included a fictional male or female patient case. Results: Female GPs exhibited a significant lifestyle IGB (p < 0.001). GPs of both genders exhibited a significant communication IGB (p < 0.001). Several associations between IGBs and clinical decisions were found. The gender of the vignette character affected several outcomes, for example GPs were less certain in the diabetes diagnosis when the character was a woman (p < 0.001). Conclusion: We demonstrated that GPs have IGBs and these biases as well as patient's gender affect decisions of GP's when they are solving a diabetes vignette case. Future research is needed to understand the most important consequences of IGBs in the context of type 2 diabetes.

This study investigated for the first time the effects of individual and combined application of 3 learning techniques (verbal suggestions, classical conditioning, and observational learning) on placebo analgesia and extinction. Healthy participants (N = 206) were assigned to 8 different groups in which they were taught through either a verbal suggestion, a conditioning paradigm, a video observing someone, or any combination thereof that a placebo device (inactive transcutaneous electric nerve stimulation [TENS]) was capable of alleviating heat pain, whereas one group did not (control). Placebo analgesia was quantified as the within-group difference in experienced pain when the placebo device was (sham) ‘activated’ or ‘inactivated’ during equal pain stimuli, and compared between groups. Placebo analgesia was induced in groups with 2 or 3 learning techniques. Significantly stronger placebo analgesia was induced in the combination of all 3 learning techniques as compared to the individual learning techniques or control condition, underlining the additional contribution of 3 combined techniques. Extinction did not differ between groups. Furthermore, pain expectancies, but not state anxiety or trust, mediated placebo analgesia. Our findings emphasize the added value of combining 3 learning techniques to optimally shape expectancies that lead to placebo analgesia, which can be used in experimental and clinical settings. Perspective: This unique experimental study compared the individual versus combined effects of 3 important ways of learning (verbal suggestions, classical conditioning, and observational learning) on expectation-based pain relief. The findings indicate that placebo effects occurring in clinical practice could be optimally strengthened if healthcare providers apply these techniques in combination.

Nocebo effects are adverse treatment outcomes that are not ascribed to active treatment components. Potentially, their magnitude might be higher in patients with chronic pain compared to healthy controls since patients likely experience treatment failure more frequently. The current study investigated group differences in the induction and extinction of nocebo effects on pressure pain at baseline (N = 69) and 1-month follow-up (N = 56) in female patients with fibromyalgia and matched healthy controls. Nocebo effects were first experimentally induced via classical conditioning combined with instructions on the pain-increasing function of a sham transcutaneous electrical nerve stimulation device, then decreased via extinction. One month later, the same procedures were repeated to explore their stability. Results suggest that nocebo effects were induced in the healthy control group during baseline and follow-up. In the patient group, nocebo effects were only induced during follow-up, without clear group differences. Extinction was only observed during baseline in the healthy control group. Further comparisons of nocebo effects and extinction indicated no significant changes across sessions, possibly suggesting their overall magnitudes were stable over time and across groups. In conclusion, contrary to our expectations, patients with fibromyalgia did not have stronger nocebo hyperalgesia; instead, they might be less responsive to nocebo manipulations than healthy controls. Perspective: The current study is the first to investigate group differences in experimentally manipulated nocebo hyperalgesia between chronic pain and healthy populations at baseline and 1-month follow-up. Since nocebo effects are common in clinical settings, their investigation in different populations is essential to explain and minimize their adverse effects during treatment.

Background: Progression of chronic kidney disease (CKD) may be delayed if patients engage in healthy lifestyle behaviors. However, lifestyle adherence is very difficult and may be influenced by problems in psychosocial functioning. This qualitative study was performed to gain insights into psychosocial barriers and facilitators for lifestyle adherence among patients with CKD not receiving dialysis. Methods: Eight semi-structured focus groups were conducted with a purposive sample of 24 patients and 23 health care professionals from four Dutch medical centers. Transcripts were analyzed using thematic analysis. Subsequently, the codes from the inductive analysis were deductively mapped onto the Theoretical Domains Framework (TDF). Results: Many psychosocial barriers and facilitators for engagement in a healthy lifestyle were brought forward, such as patients’ knowledge and intrinsic motivation, emotional wellbeing and psychological distress, optimism, and disease acceptance. The findings of the inductive analysis matched all fourteen domains of the TDF. The most prominent domains were ‘social influences’’and ‘environmental context and resources’, reflecting how patients’ environments hinder or support engagement in a healthy lifestyle. Conclusions: The results indicate a need for tailored behavioral lifestyle interventions to support disease self-management. The TDF domains can guide development of adequate strategies to identify and target individually experienced psychosocial barriers and facilitators.

BACKGROUND: eHealth interventions have the potential to increase the physical activity of users. However, their effectiveness varies, and they often have only short-term effects. A possible way of enhancing their effectiveness is to increase the positive outcome expectations of users by giving them positive suggestions regarding the effectiveness of the intervention. It has been shown that when individuals have positive expectations regarding various types of interventions, they tend to benefit from these interventions more. OBJECTIVE: The main objective of this web-based study is to investigate whether positive suggestions can change the expectations of participants regarding the effectiveness of a smartphone physical activity intervention and subsequently enhance the number of steps the participants take during the intervention. In addition, we study whether suggestions affect perceived app effectiveness, engagement with the app, self-reported vitality, and fatigue of the participants. METHODS: This study involved a 21-day fully automated physical activity intervention aimed at helping participants to walk more steps. The intervention was delivered via a smartphone-based app that delivered specific tasks to participants (eg, setting activity goals or looking for social support) and recorded their daily step count. Participants were randomized to either a positive suggestions group (69/133, 51.9%) or a control group (64/133, 48.1%). Positive suggestions emphasizing the effectiveness of the intervention were implemented in a web-based flyer sent to the participants before the intervention. Suggestions were repeated on days 8 and 15 of the intervention via the app. RESULTS: Participants significantly increased their daily step count from baseline compared with 21 days of the intervention (t107=-8.62; P<.001) regardless of the suggestions. Participants in the positive suggestions group had more positive expectations regarding the app (B=-1.61, SE 0.47; P<.001) and higher expected engagement with the app (B=3.80, SE 0.63; P<.001) than the participants in the control group. No effects of suggestions on the step count (B=-22.05, SE 334.90; P=.95), perceived effectiveness of the app (B=0.78, SE 0.69; P=.26), engagement with the app (B=0.78, SE 0.75; P=.29), and vitality (B=0.01, SE 0.11; P=.95) were found. Positive suggestions decreased the fatigue of the participants during the 3 weeks of the intervention (B=0.11, SE 0.02; P<.001). CONCLUSIONS: Although the suggestions did not affect the number of daily steps, they increased the positive expectations of the participants and decreased their fatigue. These results indicate that adding positive suggestions to eHealth physical activity interventions might be a promising way of influencing subjective but not objective outcomes of interventions. Future research should focus on finding ways of strengthening the suggestions, as they have the potential to boost the effectiveness of eHealth interventions. TRIAL REGISTRATION: Open Science Framework 10.17605/OSF.IO/CWJES; https://osf.io/cwjes.

Persistent physical symptoms have a high prevalence and a large impact for patients and society. To date, treatment effects for these symptoms are often limited. Nocebo effects (i.e., negative outcomes that are not attributable to active treatment components) have a substantial influence on treatment success and can be established via learning through classical conditioning. Therefore, interventions aimed at reducing nocebo effects by means of counterconditioning, in which an alternative association (inhibiting the previous association) is learned, could be a promising method for improving physical symptoms. In experimental studies, counterconditioning has been shown promising in reducing experimentally-induced nocebo effects on pain and itch. Application of counterconditioning procedures to reduce nocebo effects on clinical symptoms has yet to be researched. This paper provides a protocol of a 6-week counterconditioning intervention aimed at reducing nocebo effects and clinical pain in patients with fibromyalgia. A study in patients with fibromyalgia is proposed to examine the feasibility and potential effectiveness of this counterconditioning intervention as a novel treatment method for reducing nocebo effects and generalization to clinical pain symptoms. Results can help design an optimized treatment protocol for reducing nocebo effects, based on the experiences of participants and the first indications of treatment efficacy.

Introduction: Placebo and nocebo effects are positive and negative health outcomes that can be elicited by the psychosocial context. They can be mediated by expectations, and may emerge in somatic symptoms even when people are aware of these effects. Interindividual differences (e.g., in personality, affective states) could impact placebo and nocebo responding, but findings are inconsistent. Methods: The current work examined expectation as a mediator of the association between verbal placebo and nocebo suggestions (VSs) and histamine-induced itch across three experimental studies. Moreover, we examined whether interindividual differences (e.g., in optimism, neuroticism, behavioral activation system (BAS), body ignorance) modulated: (1) the direct association between VSs and itch (direct moderation), and (2) the indirect, expectation-mediated association between VSs and itch (moderated mediation). Positive VSs were compared to neutral instructions (Study 1; n = 92) or negative VSs (Studies 2+3; n = 203) in an open-label (i.e., explaining placebo and nocebo effects) or closed-label (concealed) context using PROCESS. First, mediation of VSs effects on itch by expectations was tested. Next, moderation by individual traits was explored using conditional process analyses. Results: The effects of VSs on itch were significantly mediated by expectation in Study 1 and in the open-label (but not closed-label) contexts of Studies 2 and 3. Ignorance of bodily signals marginally moderated the direct effects of VSs on itch when closed-label suggestions were given: at low levels of body ignorance, effects of positive and negative VSs were stronger. Moreover, moderated mediation was observed in the open-label groups of Studies 2 and 3: The expectation-mediated effects of VSs on itch were stronger when BAS drive was lower. Conclusion: Overall, the effects of VSs on itch were mediated by expectations in the open-label, but not the closed-label context. Moreover, the current work suggests that placebo and nocebo effects may be moderated by ignorance of bodily signals and the BAS. There was limited evidence that other interindividual differences modulated placebo and nocebo responding in itch.

Background and Objective: The current treatments of primary musculoskeletal low back pain (LBP) have a low to moderate efficacy, which might be improved by looking at the contribution of placebo effects. However, the size of true placebo effects in LBP is unknown. Therefore, a systematic review and meta-analysis were executed of randomized controlled trials investigating placebo effects in LBP. Databases and Data Treatment: The study protocol was registered in the international prospective register of systematic reviews Prospero (CRD42019148745). A literature search (in PubMed, Embase, The Cochrane Library, CINAHL and PsycINFO) up to 2021 February 16th yielded 2,423 studies. Two independent reviewers assessed eligibility and risk of bias. Results: Eighteen studies were eligible for the systematic review and 5 for the meta-analysis. Fourteen of the 18 studies were clinical treatment studies, and 4 were experimental studies specifically assessing placebo effects. The clinical treatment studies provided varying evidence for placebo effects in chronic LBP but insufficient evidence for acute and subacute LBP. Most experimental studies investigating chronic LBP revealed significant placebo effects. The meta-analysis of 5 treatment studies investigating chronic LBP depicted a significant moderate effect size of placebo for pain intensity (SMD = 0.57) and disability (SMD = 0.52). Conclusions: This review shows a significant contribution of placebo effects to chronic LBP symptom relief in clinical and experimental conditions. The meta-analysis revealed that placebo effects can influence chronic LBP intensity and disability. However, additional studies are required for more supporting evidence and evidence for placebo effects in acute or subacute LBP. Significance: This systematic review and meta-analysis provides evidence of true placebo effects in low back pain (LBP). It shows a significant contribution of placebo effects to chronic LBP symptom relief. The results highlight the importance of patient- and context-related factors in fostering treatment effects in this patient group. New studies could provide insight into the potential value of actively making use of placebo effects in clinical practice.

There is initial support for the effectiveness of approach-avoidance trainings in altering food-related health behaviors. Furthermore, outcome expectancies induced by verbal suggestions might optimize the effectiveness of these interventions, as shown in placebo research. The present study investigated the effectiveness of a gamified approach-avoidance training on food-related outcomes and whether verbal suggestions could strengthen those effects. A total of 120 participants were randomly assigned to 1 of 4 conditions: serious gaming only, verbal suggestions only, serious gaming combined with verbal suggestions, or a gaming control condition. Virtual food preference and food choice were assessed with a food choice task, with pairs differing in healthiness or in healthiness and attractiveness. Implicit food preference was assessed with an Implicit Association Test and food intake with a bogus taste test. Participants in both serious gaming conditions made healthier food choices for pairs differing in healthiness and attractiveness and had healthier implicit food preferences compared to gaming control. No effects were found on food intake. These findings provide the first preliminary support for the effects of a gamified approach-avoidance training on virtual food choice and implicit food preference. Future studies should further elucidate these effects, also in other health domains such as physical activity.