Counterconditioning as Treatment to Reduce Nocebo Effects in Persistent Physical Symptoms: Treatment Protocol and Study Design

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.Applied Ergonomics and Desig

Associations Between Interindividual Differences, Expectations and Placebo and Nocebo Effects in Itch

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.Applied Ergonomics and DesignHR Healt

Nocebo hyperalgesia and other expectancy-related factors in daily fibromyalgia pain: Combining experimental and electronic diary methods

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.Applied Ergonomics and Desig

Psychosocial barriers and facilitators for adherence to a healthy lifestyle among patients with chronic kidney disease: a focus group study

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.Applied Ergonomics and Desig

Conditioning of the Cortisol Awakening Response in Healthy Men: Study Protocol for a Randomized Controlled Trial

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.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Applied Ergonomics and Desig

Detecting and treating psychosocial and lifestyle-related difficulties in chronic disease: Development and treatment protocol of the e-goal ehealth care pathway

Many patients with lifestyle-related chronic diseases find it difficult to adhere to a healthy and active lifestyle, often due to psychosocial difficulties. The aim of the current study was to develop an eHealth care pathway aimed at detecting and treating psychosocial and lifestyle-related difficulties that fits the needs and preferences of individual patients across various lifestyle-related chronic diseases. Each intervention component was developed by (1) developing initial versions based on scientific evidence and/or the Behavior Change Wheel; (2) co-creation: acquiring feedback from patients and health professionals; and (3) refining to address users’ needs. In the final eHealth care pathway, patients complete brief online screening questionnaires to detect psychosocial and lifestyle-related difficulties, i.e., increased-risk profiles. Scores are visualized in personal profile charts. Patients with increased-risk profiles receive complementary questionnaires to tailor a 3-month guided web-based cognitive behavioral therapy intervention to their priorities and goals. Progress is assessed with the screening tool. This systematic development process with a theory-based framework and co-creation methods resulted in a personalized eHealth care pathway that aids patients to overcome psychosocial barriers and adopt a healthy lifestyle. Prior to implementation in healthcare, randomized controlled trials will be conducted to evaluate its cost-effectiveness and effectiveness on psychosocial, lifestyle, and health-related outcomes.Industrial Design EngineeringApplied Ergonomics and Desig

Increasing the Effectiveness of a Physical Activity Smartphone Intervention With Positive Suggestions: Randomized Controlled Trial

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.Applied Ergonomics and Desig

The Optimal Learning Cocktail for Placebo Analgesia: A Randomized Controlled Trial Comparing Individual and Combined Techniques

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.HR HealthApplied Ergonomics and Desig

eHealth to Improve Psychological Functioning and Self-Management of People With Chronic Kidney Disease: A Randomized Controlled Trial

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.Applied Ergonomics and Desig

Nocebo Hyperalgesia in Patients With Fibromyalgia and Healthy Controls: An Experimental Investigation of Conditioning and Extinction Processes at Baseline and 1-Month Follow-up

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.Applied Ergonomics and Desig