Medication regimens using conditioning via variable reinforcement have shown similar or improved therapeutic effects as full pharmacological treatment, but evidence in patient populations is scarce... Show moreMedication regimens using conditioning via variable reinforcement have shown similar or improved therapeutic effects as full pharmacological treatment, but evidence in patient populations is scarce. This proof-of-principle double-blind randomized clinical trial examined whether treatment effects in recent-onset rheumatoid arthritis (RA) can be optimized through pharmacological conditioning. After four months of standardized treatment (n = 46), patients in clinical remission (n = 19) were randomized to the Control group (C), continuing standardized treatment (n = 8), or the Pharmacological Conditioning (PC) group, receiving variable treatment according to conditioning principles (n = 11). After eight months, treatment was tapered and discontinued linearly (C) or variably (PC). Standard treatment led to large improvements in disease activity and HRQoL in both groups. The groups did not differ in the percentage of drug-free clinical remission obtained after conditioning or continued standard treatment. The PC group did show a larger decrease in self-reported disease activity (Cohen's d = 0.9) and a smaller increase in TNF-alpha levels (Cohen's d = 0.7) than the C group. During all phases, more differences between groups were found for the patients who followed protocol than for the intention-to-treat sample. Although the results are not conclusive, pharmacological conditioning may have some advantages in terms of disease progression and stability, especially during the conditioning phase, compared with standard clinical treatment. The effects may be particularly beneficial for patients who show a good initial response to increased medication dosages. Show less
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... Show moreThis 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.(R) 2023 The Author(s). Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
ObjectiveIssues regarding clinician communication remain an important source of complaints within healthcare. This systematic review aims to determine cancer patients' and their family caregivers'... Show moreObjectiveIssues regarding clinician communication remain an important source of complaints within healthcare. This systematic review aims to determine cancer patients' and their family caregivers' views on which clinicians' communication behaviors can harm (i.e. eliciting negative feelings/consequences for patients/family caregivers).MethodsWe searched for all types of peer-reviewed studies that determined adult (>= 18 years) cancer patients' and/or family caregivers' perspectives on which clinicians' communication behaviors can harm in several databases (PubMed, Embase, Web of Science, Cochrane Library, Emcare, PsycINFO and Academic Search Premier), supplemented by expert-consultation. Studies were screened using the Artificial intelligence screening tool of ASReview and data was analyzed using Thematic Analysis. To assess the quality of the studies the Qualsyst critical appraisal tool was used.ResultsA total of 47 studies were included. Four main themes of harmful communication behaviors were identified: (1) Lack of tailored information provision (e.g. giving too little or too much/specific information) (2) Lack of tailored decision making (ranging from; patient exclusion, to the patients' responsibility, and/or haste) (3) Lack of feeling seen and heard (seen as a disease, not as a human being; not listened to concerns and emotions) (4) Lack of feeling held and remembered (forgotten agreements; lack of care continuity).ConclusionsOur results reveal an overview of patients' and family caregivers' perspectives on which clinicians' communication behaviors can harm. Harm could be prevented when information and decision involvement are tailored and patients' and family caregivers' needs to feel seen, heard, held and remembered are met. Show less
Cardol, C.K.; Meuleman, Y.; Middendorp, H. van; Boog, P.J. van der; Hilbrands, L.B.; Navis, G.; ... ; E-GOAL Study Grp 2023
Rationale & Objective: Patients with chronic kid-ney disease (CKD) not receiving dialysis, including kidney transplant recipients, often experience diffi-culties regarding self-management. An... Show moreRationale & Objective: Patients with chronic kid-ney disease (CKD) not receiving dialysis, including kidney transplant recipients, often experience diffi-culties 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 question-naire data as part of the E-GOAL study. Setting & Participants: Patients with CKD (esti-mated 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 pa-tients reported psychological distress, and 69.8% were nonadherent to 1 or more recommendations. Higher psychological distress was significantly associated with poorer dietary adherence (3adj, -0.13; 95% CI, -0.23 to -0.0 4), less phys-ical activity (3adj, -0.13; 95% CI, -0.22 to -0.03), and lower medication adherence (3adj, -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 re-sidual confounding, and self-report. Conclusions: Many people with CKD experience psychological distress, of whom most have diffi-culties 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. Show less
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... Show moreNocebo 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. Show less
Nocebo effects on pain are widely thought to be driven by negative expectations. This suggests that anticipatory processing, or some other form of top-down cognitive activity prior to the... Show moreNocebo effects on pain are widely thought to be driven by negative expectations. This suggests that anticipatory processing, or some other form of top-down cognitive activity prior to the experience of pain, takes place to form sensory-augmenting expectations. However, little is known about the neural markers of anticipatory processing for nocebo effects. In this event-related potential study on healthy participants (n = 42), we tested whether anticipatory processing for classically conditioned nocebo-augmented pain differed from pain without nocebo augmentation using stimulus preceding negativity (SPN), and Granger Causality (GC). SPN is a slow-wave ERP component thought to measure top-down processing, and GC is a multivariate time series analysis used to measure functional connectivity between brain regions. Fear of pain was assessed with the Fear of Pain Questionnaire-III and tested for correlation with SPN and GC metrics. We found evidence that both anticipatory processing measured with SPN and functional connectivity from frontal to temporoparietal brain regions measured with GC were increased for nocebo pain stimuli relative to control pain stimuli. Other GC node pairs did not yield significant effects, and a lag in the timing of nocebo pain stimuli limited interpretation of the results. No correlations with trait fear of pain measured after the conditioning procedure were detected, indicating that while differences in neural activity could be detected between the anticipation of nocebo and control pain trials, they likely were not related to fear. These results highlight the role that top-down processes play in augmenting sensory perception based on negative expectations before sensation occurs. Show less
ObjectiveThe objective of this study was to investigate whether placebo effect induced by pharmacological conditioning with intranasal insulin can affect glucose, insulin, C-peptide, hunger, and... Show moreObjectiveThe objective of this study was to investigate whether placebo effect induced by pharmacological conditioning with intranasal insulin can affect glucose, insulin, C-peptide, hunger, and memory in patients with diabetes type 2 and healthy controls.MethodsPlacebo effect was induced by pharmacological conditioning. Thirty-two older patients (mean age = 68.3 years) with diabetes type 2 and age- and sex-matched thirty-two healthy older adults (mean age = 67.8 years) were randomly assigned to a conditioned or a control group. On day 1, conditioned group received six administrations of intranasal insulin with a conditioned stimulus (CS; smell of rosewood oil), whereas the control group received a placebo with the CS. On day 2, both groups received a placebo spray with the CS. Glucose, insulin, and C-peptide were repeatedly measured in blood. Hunger and memory were assessed with validated measures.ResultsIntranasal insulin stabilized dropping glucose levels in patients (B = 0.03, SE = 0.02, p = .027) and healthy men (B = 0.046, SE = 0.02, p = .021), and decreased C-peptide levels in healthy controls (B = 0.01, SE = 0.001, p = .008). Conditioning also prevented the drop of glucose levels but only in men (both healthy and patients; B = 0.001, SE = 0.0003, p = .024). Conditioning significantly decreased hunger in healthy participants (B = 0.31, SE = 0.09, p < .001). No effects were found on other measures.ConclusionsPlacebo effect induced by conditioning with intranasal insulin modifies blood glucose levels and decreases hunger in older adults, but its effects depend on health status and sex. Insulin conditioning might be beneficial for groups suffering from intensive hunger but seems not be particularly suitable for blood glucose reduction. Show less
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... Show moreObjectives: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. Show less
Hulst, A.M. van; Akker, E.L.T. van den; Verwaaijen, E.J.; Fiocco, M.; Rensen, N.; Litsenburg, R.R.L. van; ... ; Heuvel-eibrink, M.M. van den 2023
Background: Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who... Show moreBackground: Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who suffer most from neurobehavioural side-effects might benefit from physiological hydrocortisone in addition to dexamethasone treatment. This study aimed to validate this finding.Methods: Our phase three, double-blind, randomised controlled trial with cross-over design included ALL patients (3-18 years) during medium-risk maintenance therapy in a national tertiary hospital between 17th May 2018 and 5th August 2020. A baseline measurement before and after a 5-day dexamethasone course was performed, whereafter 52 patients with clinically relevant neurobehavioural problems were randomised to receive an intervention during four subsequent dexamethasone courses. The intervention consisted of two courses hydrocortisone (physiological dose 10 mg/m2/d in circadian rhythm), followed by two courses placebo, or vice versa. Neurobehavioural problems were assessed before and after each course using the parent-reported Strengths and Difficulties Questionnaire (SDQ) as primary end-point. Secondary end-points were sleep problems, health-related quality of life (HRQoL), hunger feeling, and parental stress, measured with questionnaires and actigraphy. A generalised mixed model was estimated to study the intervention effect.Results: The median age was 5.5 years (range 3.0-18.8) and 61.5% were boys. The SDQ filled in by 51 primary caregivers showed no difference between hydrocortisone and placebo in reducing dexamethasone-induced neurobehavioral problems (estimated effect-2.05 (95% confidence interval (CI)-6.00-1.90). Also, no benefit from hydrocortisone compared to pla-cebo was found for reducing sleep problems, hunger, parental stress or improving HRQoL.Conclusions: Hydrocortisone, when compared to placebo, had no additional effect in redu-cing clinically relevant dexamethasone-induced neurobehavioural problems. Therefore, hy-drocortisone is not advised as standard of care for children with ALL who experience dexamethasone-induced neurobehavioural problems. Trial registration: NetherlandsTrial Register NTR6695/NL6507 (https://trialsearch.who.int/) and EudraCT 2017-002738-22 (https://eudract.ema.europa.eu/).(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/). Show less
Meijer, S.; Karacaoglu, M.; Middendorp, H. van; Veldhuijzen, D.S.; Jensen, K.B.; Peerdeman, K.J.; Evers, A.W.M. 2023
BackgroundNocebo 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... Show moreBackgroundNocebo 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. MethodsIn 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. ResultsNocebo 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). ConclusionsThese 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. SignificanceFew 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. Show less
AimsImplicit 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... Show moreAimsImplicit 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.MethodsNinety-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.ResultsFemale 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).ConclusionWe 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. Show less
Cardol, C.K.; Middendorp, H. van; Dusseldorp, E.; Boog, P.J.M. van der; Hilbrands, L.B.; Navis, G.; ... ; E GOAL Study Grp 2023
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... Show moreObjective: 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. Show less
Wolters, F.; Middendorp, H. van; Bergh, O. van den; Biermasz, N.R.; Meijer, O.C.; Evers, A.W.M. 2023
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... Show moreBackground: 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. Trial Registration: Netherlands Trial Register NL58792.058.16; https://trialsearch.who.int/Trial2.aspx?TrialID=NL7791 International Registered Report Identifier (IRRID): DERR1-10.2196/38087 Show less
Kitselaar, W.M.; Büchner, F.L.; Vaart, R. van der; Sutch, S.P.; Bennis, F.C.; Evers, A.W.M.; Numans, M.E. 2023
Contagious itch can be evoked by observing people scratching. Verbal suggestions about to-be-received itch can influence itch intensity, as shown by placebo research, but it is unknown whether this... Show moreContagious itch can be evoked by observing people scratching. Verbal suggestions about to-be-received itch can influence itch intensity, as shown by placebo research, but it is unknown whether this extends to contagious itch. The current study aimed to replicate prior findings that listening to scratching and rubbing sounds elicits contagious itch, and to investigate whether suggestions can modulate this process. Healthy participants (n = 140) received positive or negative suggestions about itch in response to the sounds (aimed to decrease or increase expected itch, respectively), or no specific suggestions as a control. Participants listened to a number of audio fragments with scratching and rubbing sounds. The amount of expected itch as well as itch sensation after each audio fragment were measured by self-report. Suggestions had no effect on the expected itch. Both rubbing and scratching sounds significantly elicited itch in all groups. Scratching sounds induced more itch than rubbing sounds exclusively in the control group. These findings indicate that short suggestions might be not effective enough to modify the expectations of people regarding contagious itch. Furthermore, suggestions modulate contagious itch to some degree, but not in the hypothesized direction. Potential similarities and differences in the neurobiological mechanisms of contagious itch and nocebo effects are discussed. Show less
BackgroundNocebo and placebo effects, i.e., adverse or beneficial treatment effects, respectively, putatively due to expectancies can modulate pain and itch. These effects can generalize within the... Show moreBackgroundNocebo and placebo effects, i.e., adverse or beneficial treatment effects, respectively, putatively due to expectancies can modulate pain and itch. These effects can generalize within the pain or itch modality. Predicting the induction and generalization of these effects can be helpful in clinical practice. This study aims to investigate whether psychological characteristics related to the fear-avoidance model predict the induction and generalization of nocebo and placebo effects on pain and itch in young healthy participants. MethodsData from two previous experiments were analyzed. In Experiment 1, we induced nocebo and placebo effects on heat pain and tested generalization to pressure pain and to cowhage-evoked itch (n = 33 in a nocebo group, n = 32 in a placebo group). In Experiment 2, we induced nocebo effects on cowhage-evoked itch and tested generalization to mechanical itch and to mechanical touch (n = 44). Potential predictors were anxiety- and stress symptoms, attention to pain/itch, and pain/itch catastrophizing. Multiple regression analyses were performed. ResultsFor nocebo effects, none of the individual psychological characteristics significantly predicted induction of nocebo effects nor their generalization. For placebo effects, only less stress symptoms, lower attention to pain, and higher pain catastrophizing weakly predicted a stronger generalization of placebo effects from heat pain to pressure pain. ConclusionThe tested psychological characteristics may not play an important role in the induction and generalization of nocebo and placebo effects in healthy individuals. However, firm conclusions cannot be drawn with the current sample. Future studies should validate findings in larger and more diverse samples. Show less
Meijer, S.; Middendorp, H. van; Peerdeman, K.J.; Evers, A.W.M. 2022
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... Show morePersistent 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. Show less
Pain and other somatosensory sensations, such as itch, can be effectively decreased by placebo effects and increased by nocebo effects. There are indications that placebo effects on pain generalize... Show morePain and other somatosensory sensations, such as itch, can be effectively decreased by placebo effects and increased by nocebo effects. There are indications that placebo effects on pain generalize to other sensations and that nocebo effects generalize within itch modalities. However, it has not yet been investigated whether learned effects can generalize within pain stimulus modalities or from pain to itch. Our aims were to test whether placebo and nocebo effects can generalize within pain modalities, ie, from heat pain to pressure pain, and across somatosensory sensations with psychophysiological similarities, ie, from heat pain to cowhage-evoked itch. For this purpose, 65 healthy participants were randomized to either a placebo or nocebo group. All participants first underwent a conditioning and verbal suggestion procedure with heat pain stimuli. Subsequently, responses to heat pain, pressure pain, and cowhage-evoked itch stimuli were tested. Results showed altered levels of heat and pressure pain with the conditioned cue in both placebo and nocebo groups in the expected directions, but no significant difference in itch in both groups. In conclusion, placebo and nocebo effects on pain may generalize within but not across stimulus modalities. This study provides a novel perspective on the role that response generalization plays in physical symptoms. Show less
Nocebo effects, that is, negative treatment outcomes due to negative expectancies, can increase itch. Moreover, indirect evidence has shown that nocebo hyperknesis can generalize to another itch... Show moreNocebo effects, that is, negative treatment outcomes due to negative expectancies, can increase itch. Moreover, indirect evidence has shown that nocebo hyperknesis can generalize to another itch modality. Knowledge on response generalization can help to prevent and decrease negative effects. The aims of this study were to investigate (1) the efficacy of inducing nocebo effects on cowhage-evoked itch via verbal suggestions and (2) whether these effects can generalize to (2a) mechanically evoked touch and (2b) mechanically evoked itch. Forty-four healthy participants watched a video suggesting that a nocebo solution increases cowhage-evoked itch and that a control solution does not affect itch. Subsequently, cowhage, mechanical itch, and mechanical touch stimuli were applied. Nocebo effects were measured as the difference in both mean and peak of the outcomes itch and urge to scratch between nocebo and control trials. Main analyses revealed significant nocebo effects on mean and peak itch for all stimuli. For urge to scratch, a significant nocebo effect was only observed for mechanical touch (peak). As mechanical stimuli did not induce pure sensations as planned, posthoc sensitivity analyses were run for mechanical stimuli that individually induced either touch or itch at baseline. These analyses showed similar results for generalization to mechanical itch, but generalization to mechanical touch was non-significant. This study showed that merely verbal suggestion can induce nocebo effects on cowhage-evoked itch and that these effects can generalize to another itch modality. Future studies may examine how to prevent negative experiences from generalizing to subsequent encounters. Show less
Smits, R.M.; Veldhuijzen, D.S.; Middendorp, H. van; Heijden, M.J.E. van der; Dijk, M. van; Evers, A.W.M. 2022
Objectives: Placebo effects, beneficial treatment outcomes due to non-active treatment components, play an important role in the overall treatment response. To facilitate these beneficial effects... Show moreObjectives: Placebo effects, beneficial treatment outcomes due to non-active treatment components, play an important role in the overall treatment response. To facilitate these beneficial effects it is important to explore the perspectives of health care professionals (HCPs) on the integration of placebo effects in clinical care. Three themes were investigated: knowledge about placebo effects and factors that contribute to these, frequency of placebo use, and attitudes toward acceptability and transparency of placebo use in treatment.Methods: A cross-sectional survey, according to the Checklist for Reporting Results of Internet E-Surveys guidelines and STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE), was conducted in the Netherlands in 2020. The survey was conducted in two samples: a (nested) short survey in 78 nurses during working shifts (sample 1) and an extended online survey in 47 general HCPs e.g., medical psychologists, oncologists, surgeons (sample 2).Results: Respondents from both samples reported to be somewhat or quite familiar with placebo effects (24.0 and 47.2%, respectively). From the six placebo mechanisms that were presented, mind-body interaction, positive expectations, and brain activity involved in placebo effects were rated as the most influential factors in placebo effects [F-(5,F-119) = 20.921, p < 0.001]. The use of placebo effects was reported in 53.8% (n = 42) of the nurses (e.g., by inducing positive expectations), and 17.4% of the HCPs (n = 8 reported to make use of pure placebos and 30.4% of impure placebos (n = 14). Attitudes toward placebo use in treatment were acceptant, and transparency was highly valued (both up to 51%).Conclusions: The findings from this study address knowledge gaps in placebo effects in practice and provide insights in attitudes toward the integration of placebo effects from HCPs. Altogether, integrating these findings may potentially optimize treatment outcomes. Show less
