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
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
Cardol, C.K.; Meuleman, Y.; Middendorp, H. van; Boog, P.J.M. van der; Hilbrands, L.B.; Navis, G.; ... ; Dijk, S. van 2023
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
Karacaoglu, M.; Meijer, S.; Peerdeman, K.J.; Dusseldorp, E.M.L.; Veldhuijzen, D.S.; Middendorp, H. van; 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
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
Background: Chronic pain has a large individual and societal burden. Previous reviews have shown that internetbased cognitive-behavioral therapy (iCBT) can support patients' pain coping. However,... Show moreBackground: Chronic pain has a large individual and societal burden. Previous reviews have shown that internetbased cognitive-behavioral therapy (iCBT) can support patients' pain coping. However, factors related to participant experience of iCBT and effective and safe iCBT delivery for chronic pain have not recently been summarized. Objective: The aim of this review was to give an overview of the efficacy of guided iCBT for chronic pain on psychological, physical, and impact on daily life outcomes, including factors that inform optimal delivery. Methods: Cochrane, Emcare, Web of Science, PubMed, PsycINFO, and Embase were systematically searched from inception to 11 February 2022. Randomized controlled trials on guided iCBTs for adults with chronic pain were included with a broad range of outcomes. Results: The search yielded 7406 studies of which 33 studies were included totaling 5133 participants. ICBT was more effective than passive control conditions for psychological (ES = 0.34-0.47), physical (ES = 0.26-0.29), and impact outcomes (ES = 0.38-0.41). ICBT was more effective than active control conditions for distress (ES = 0.40), pain acceptance (ES = 0.15), and pain interference after outlier removal (ES = 0.30). Longer treatments were associated with larger effects for anxiety and quality of life than shorter treatments. Mode of therapist contact (synchronous, asynchronous or a mix of both) was not related to differences in effect sizes in most outcomes. However, studies with mixed and synchronous contact modes had higher effects on pain self-efficacy than studies with asynchronous contact modes. Treatment satisfaction was high and adverse events were minor. Dropout was related to time, health, technical issues, and lack of computer skills. Conclusions: Guided iCBT is an effective and potentially safe treatment for chronic pain. Future research should more consistently report on iCBT safety and detail the effectiveness of individual treatment components to optimize iCBT in clinical practice. Show less
Meijer, S.; Middendorp, H. van; Peerdeman, K.J.; Evers, A.W.M. 2022
