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Manfred Schedlowski is Professor of Medical Psychology and Behavioral Immunology at the University Hospital Essen. He is director of the Institute for Medical Psychology and Behavioral Immunology at the University Hospital Essen. The focus of his research is the analysis of the functional connections between the nervous system, the endocrine system and the immune system. Against this background, he and his research groups on the one hand deal with the phenomenon of classical conditioning of immune functions in the context of the placebo response and analyze the neurobiological and biochemical mechanisms as well as the clinical significance of the placebo and nocebo response. On the other hand, they analyze the effects of inflammatory processes in the body on neurocognitive and affective functions in the context of the pathophysiological processes of neuropsychiatric disorders such as depression or schizophrenia.
Over the past decade, candidate gene analyses and genome-wide association studies (GWAS) have been used to examine the role of genetics in placebo response. Critical to any genetic association finding is reproducibility. While the finding of COMT association with placebo response in irritable bowel syndrome clinical trials has been replicated, findings in other diseases and experimental models have not been reproduced. This is in part because most placebo GWAS are conducted as secondary analyses of failed trials which because of cost and futility are not likely to be repeated. One way around the challenge of replicating expensive studies is to conduct GWAS of combined placebo arms from multiple studies in one disease area. While this approach has yielded several interesting findings in areas like major depressive disorder and asthma, further utilization of the findings still requires replication. Similarly, gene expression studies that examine how changes in gene expression influence placebo response have also yielded interesting findings, these studies also need replication before these findings can be translated to practice.
An overview of the brain predictive and responsive circuitry to placebo manipulations in the laboratory setting in comparison to the clinical setting will be presented. I will then discuss mechanistic differences between the two types of placebo and their implications regarding practical decision making for clinical trials.
Background: Placebo effects are highly variable between individuals, but it is unclear whether dispositional psychological traits influence responsiveness to placebo. This preregistered meta-analysis and systematic review synthesized the literature investigating the association between personality traits and placebo effects.We collected published and nonpublished reports of correlation coefficients between placebo effects and personality trait scores. Based on 19 studies with 712 participants, we performed random-effects meta-analysis for 10 different traits, including behavioral inhibition, fun-seeking, goal-drive persistence, reward responsiveness, empathic concern, empathic fantasy, perspective-taking, personal distress, optimism, and anxiety. We followed up nonsignificant results with two one-sided tests for statistical equivalence to evaluate evidence for the null hypothesis. We did not find evidence of associations between any of these traits and magnitude of placebo effects, which was supported by equivalence tests. Furthermore, we did not find evidence for moderating factors placebo manipulation type (Conditioning, non-conditioning) or condition (pain, non-pain). Our meta-analysis did not support an association between personality traits and placebo effects, suggesting individual variability in placebo responding may be better explained by situational and learning factors, or dispositional factors beyond personality (e.g. genetic or brain phenotypes).
Pre-treatment expectations regarding beneficial treatment effects and symptom worsening are important modulators of treatment outcome. Thus, manipulations of these treatment expectations can be valuable additions to standard clinical care. For the development of efficient expectation manipulations, it is important to explore how individual differences shape these expectations. We will present data from n = 748 participants from k = 7 studies involving assessments of expectations regarding a manipulation of pain or affective distress (funded by Deutsche Forschungsgemeinschaft (DFG) – 422744262). We assessed the influence of somatization tendency, perceived stress, state depression, and state anxiety on expectations of symptom improvement and symptom worsening. Our results show that perceived stress (b = .228, p < .001) and somatization (b = -.202, p < .001) predict improvement expectancy. Expected worsening of symptoms was not significantly predicted (F = 1.289, p = .214). As expected, higher levels of somatization are linked to reduced positive treatment expectations. However, surprisingly, high levels of perceived stress are associated with increased positive expectations.
The healthcare workforce in the United States is becoming increasingly diverse. However, given the long-standing underrepresentation of people of color and women in the medical field, patients may still associate the concept of doctors with White men and may be physiologically less responsive to treatment administered by providers from other backgrounds. To investigate this, we varied the race and gender of the provider from which White patients received an identical placebo treatment for allergic reactions and measured patients’ improvement in response. A total of 187 White patients experiencing a laboratory-induced allergic reaction interacted with a healthcare provider who applied a placebo cream to the reaction. Interactions were completely standardized except for the provider’s race and gender. Patients were randomly assigned to interact with a provider who was a man or a woman and Asian, Black, or White. A fully blinded research assistant measured the change in the size of patients’ allergic reaction after cream administration. Results indicated that White patients showed a weaker placebo response when it was administered by women or Black providers. We explore several potential explanations and discuss the implications of problematic race and gender dynamics that can endure "under the skin."
Katja Weimer is a postdoc at Ulm University Hospital and scientific coordinator of the Translational Research WG. Her research includes the effects of chronic stress and traumatic experiences as risk factors for later psychosomatic and somatic diseases, such as depression, anxiety and pain disorders, cardiovascular dysfunction and systemic inflammatory reactions. In addition, the research group is concerned with the effects of expectations and learning mechanisms on psychosomatic symptoms such as pain, stress, and anxiety.
The management and control of pain are one of medicine's biggest challenges in rehabilitation medicine. Overall, opioid usage in patients hospitalized in the Comprehensive Rehabilitation Program still is high due to the complexity of their injuries, including polytrauma, burn injuries, amputations or other severe injuries, which require appropriate and aggressive pain management. Moreover, these side effects have a detrimental impact for the recovery of these patients.
The use of placebos in the clinical arena represents an ethical challenge as deception or concealment is usually thought to be necessary; an alternative strategy to harness placebo effects is the use of open-label prescribed placebos. Pharmacological conditioning dose extension capitalizes on classic conditioning mechanisms and differential reinforcement rates of the medication. The reinforcement rate is gradually decreased (i.e., the pharmacological agent is intermittently replaced by a placebo). Therefore, placebo effects can contribute to the pharmacological effects of a drug and help to sustain therapeutic responses.
In this workshop, data from conditioning open-label placebo (COLP) for opioid dose reduction will be presented. Models for clinical implementation, and mechanisms behind pharmacological conditioning in severe pain are going to be also discussed.
Background. Studying placebo/nocebo effects in special populations such as children requires to adjust or newly develop experimental designs. Yet, failures to experimentally demonstrate such effects are rarely reported. However, such trials combined with a detailed methodological scrutiny may provide important information about possible determinants of placebo/nocebo effects. Methods. A novel hand-withdrawal method we had developed for children was first successfully validated in adults. Subsequently, this method was then tested in school-aged children. In a second series of experiments, an adapted version of this method was piloted in kindergarten children. In both series, hypoalgesia was tested using heat pain. Subjective pain intensity, pain threshold or tolerance served as outcome. Results. We identified several procedural aspects such as the potential influence of the control condition, differences in children’s handling the apparatus, behavioral vs. verbal measures, or subtle effects of instructions and the setting which impact on obtaining a placebo effects in children, especially very young ones. Conclusions. Our findings suggest that experimentally inducing placebo effects in children relies on several rather fundamental design features. Implications with regard to the robustness of the obtained effects, replication, and the demonstration of age-related differences will be discussed.
Most children experience anxiety, stress, and pain during hospital procedures. Placebo-related treatment applications could be added-on to regular treatment to improve hospital experiences. What pediatric healthcare providers know and think about placebo effects and placebo-related applications to optimize child healthcare was examined in an online questionnaire study in 150 healthcare professionals(87% female;40% physicians,31% nurses,11% medical psychologists,5% pedagogical staff). Higher placebo knowledge (M6.1±0.9 of 7 items) was associated with higher acceptability(r=.30,p<.001). Acceptability (M7.6±1.3 on 0-10NRS) and expected effectiveness (M7.3±1.5) increased after reading about placebo-related applications(p-values≤.004). Nurses had lower placebo knowledge, acceptability, and expected effectivity than physicians and psychologists(p-values≤.04). Acceptability was higher for chronic than acute conditions(p<.001), with no consistent differences for child gender and age. This study showed relatively positive opinions about placebo-related applications in child hospital care by pediatric healthcare providers, which decreased towards more ‘misleading’ applications. The results suggest the potential effectiveness of education on optimization of placebo and minimization of nocebo effects in children, especially for nurses.
Placebos prescribed as 'regular' medication can reduce symptoms of depression. However, using a placebo without patients' informed consent presents ethical issues. Therefore, the present study assessed the efficacy of an open-label placebo (OLP), which was administered concurrently with cognitive-behavioral therapy (CBT).
Sixty patients (mean age: 48 years) diagnosed with major depressive disorder were randomly assigned to a 4-week CBT outpatient program with or without daily OLP treatment. The patients were assessed directly before and after the program as well as three months after the therapy.
Compared to the CBT group, the CBT + OLP group showed a greater reduction in symptoms of depression at the end of the program. Changes in categories pertaining to severity of depression did not differ between groups. All patients completed the program. Noncompliance with the follow-up appointment differed significantly between CBT + OLP (27%) and CBT (7%). Noncompliance was associated with a negative evaluation of the OLP.
The OLP intervention reduced symptoms of depression, however, these changes were not clinically meaningful. The OLP increased the risk for loss to follow-up. The high dropout rate in the present study raises questions concerning the acceptance of OLPs in the treatment of depression.
In recent years, numerous studies investigated the potential of open-label placebos (OLPs). However, it is unclear whether the effects are different across (1) clinical vs. nonclinical populations, (2) comparators, (3) modalities and (4) expectation. Therefore, network meta-analyses (NMA) were conducted to evaluate distinct magnitudes of effects.
Systematic searches were carried out. RCTs comparing OLPs to controls were included. 6’832 records were screened. Two networks were created and assessed in random-effects models. Either primary or most informative outcomes were extracted.Twelve trials were eligible for the nonclinical, 25 trials for the clinical network. In the nonclinical network, deceptive placebos (DP) and OLPs nasal were more (SMD=0.49;0.43) and OLPs without expectation less efficacious than NT (SMD=-0.62). In the clinical network, psychological intervention, conditioned OLP-pills, DP, and OLP-pills outperformed NT (SMD=0.46–1.96). OLP-pills and DPs showed higher effects as OLPs without expectations (SMD=0.49;0.79).NMAs revealed that OLPs are more beneficial for clinical populations compared to nonclinical. The kind of comparator and administration route had no substantial impact on effects. Treatment expectations were found to be essential for OLP efficacy.
So far, no study has examined the effect of an open-label placebo (OLP) intervention on premenstrual syndrome (PMS), although PMS appears considerably susceptible to placebo effects. We conducted a randomized controlled trial with 150 women with PMS, examining the effect of an OLP intervention on PMS. The study entailed a treatment as usual (TAU; N=50), an OLP intervention without a treatment rationale (OLP-; N=50), and an OLP intervention with a treatment rationale group (OLP+; N=50). Primary outcomes were symptom intensity and interference assessed across three menstrual cycles.
Symptom intensity decreased significantly between groups (b = -7.42, SE = 1.97, p<.001), showing a large effect (d=1.10). OLP+ showed the highest decrease of symptom intensity, followed by OLP-, while TAU exhibited the smallest decrease. Interference decreased significantly between groups (b = -0.92, SE = 0.36, p=.011), showing a large effect (d=0.88). OLP+ showed the highest decrease of interference, followed by OLP-, while TAU exhibited the smallest decrease.
Our findings indicate that women with PMS benefit from an OLP intervention, while the treatment rationale effect highlights the potential of comprehensive patient elucidation in clinical practice.
Julian Kleine-Borgmann is an assistant physician in the Department of Neurology at the University Medical Center Essen and part of the research group led by Prof. Dr. Bingel. His research focuses on the influence of cognitive processes on the development and processing of pain. and the role of cognition in analgesic treatment outcomes and open-label placebo treatments.
Beyond legal and ethical purposes, informed consent has the potential to influence treatment expectations. Trials investigating informed consent procedures for psychotherapy are missing. We determine the efficacy and safety of a newly developed optimized informed consent consultation (OIC).
In this randomized trial, 122 adults with mental disorders, confirmed by structured interview, were randomized to treatment as usual (TAU; n=61) or TAU plus a one-session OIC (n=61) utilizing expectation-management and framing. Primary outcome was treatment expectations at 2-week follow-up.Participants receiving OIC showed greater increases in positive treatment expectations compared to TAU (mean difference: 0.70, 95%CI, 0.35 to 1.05, d=0.73). Likewise, OIC positively influenced motivation, adherence intention, and capacity to consent with medium and decisional conflicts, and knowledge with high effect sizes. No significant group differences resulted for adverse events, except for fear of negative effects at post-intervention (OIC: 15.00% vs. TAU: 3.45%).Explaining to patients how psychotherapy works via a short consultation was effective in strengthening treatment expectations and decision-making in a non-harmful way. Further trials should clarify whether this effectively translates to better psychotherapy outcomes.
Significant progress has been made in the investigation of the placebo effects. Most of our knowledge about the neurobiology and neuropsychology of this phenomenon comes from the field of pain and analgesia. A critical impetus for the clinical implications of placebo research is the closer examination of treatment expectations, as these play a critical mediating role in the formation of placebo effects. Positive treatment expectations appear to significantly improve pain treatment outcomes. The question here, however, is (1) whether a positive treatment expectation leads to a positive treatment outcome in general or can also have opposite effects when associated with "bad" treatments, (2) how to adequately design positive expectation management and (3) whether there is clinical evidence for this approach. The goal of this workshop is to identify ways of positively, but realistically, aligning pain patients' expectations regarding their pain management.
Upon completion of this session, attendees will be able to understand and bring together three different aspects (a) analysis of the most relevant psychological strategies to induce expectation and bodily placebo-related changes; (b) best evidence of significant placebo analgesic effects due to treatment expectation and (c) implications for clinical practice.
Specifically designed control interventions (also known as ‘placebo controls’) can account for expectation effects in clinical trials and test treatment mechanisms. How control interventions are designed, conducted, and reported is fundamental when interpreting efficacy and mechanistic clinical trials of physical, psychological, and self-management interventions. The newly developed CoPPS statement establishes a quality standard in the field and provides a reporting checklist for control interventions to enhance research transparency, usefulness, and rigour. This guideline was developed using a three-round Delphi study with 64 experts in placebo research and/or clinical trials of physical, psychological, and self-management interventions for pain. Development also involved a systematic review, interviews with people experiencing pain, and consensus meetings.
This presentation will focus on communicating the core recommendations of CoPPS, such as a design principle for control interventions, and best-practice approaches to the conceptual design of control interventions, pre-trial testing, stakeholder involvement, and quality assurance during implementation. Briefly, the guideline’s practical application will be discussed by means examples from a study of psychologically-informed manual therapy for people with painful diabetic neuropathy, and several student projects from the manual therapy field.
Knee osteoarthritis is a common and debilitating disease associated with knee pain and stiffness. Interestingly, the pain one experiences does not correlate with physiological osteoarthritis severity as determined by imaging. The relationship between osteoarthritis and knee symptoms is related to physical factors, such as co-morbidities and BMI, and psychological factors, such as beliefs about osteoarthritis and pain. Our work has shown that mindsets about osteoarthritis, which include these beliefs and assumptions and orient individuals to a set of attributions, expectations, and goals, are related to symptoms and whether one engages in physical activity as a management strategy. Aiming to now change mindsets, we developed a digital, scalable mindset intervention for individuals with knee osteoarthritis. In pilot testing of the intervention, mindsets about osteoarthritis and exercise significantly increased to more adaptive mindsets. We then further evaluated if this intervention improves pain and engagement in physical activity more than typically provided educational content in patients with knee osteoarthritis in a clinical trial. We will share the development, testing, and results of this study and the promising notion that by changing the beliefs and expectations about osteoarthritis, we can improve one’s experience with osteoarthritis, its symptoms, and engagement in its management.
Placebo studies has undergone one successful revolution and it now needs another one. Over the last 10 years, the number of studies on placebos has roughly doubled, while researchers in the area have organized themselves into the international Society for Interdisciplinary Placebo Studies (SIPS), whose membership has mushroomed from eight to more than 500. Many initial controversies surrounding placebo effects, most notably the controversy about whether placebo effects exist have been resolved in favour of placebo researchers. In parallel, high-profile trials on placebos have been published in eminent journals such as the BMJ, The Lancet, and the New England Journal of Medicine. Collectively, these successes can be dubbed the 1st revolution in placebo studies. Because of its success, the knowledge gained by placebo researchers can now be used to benefit patients (and avoid “nocebo” harms). Yet, relatively little effort is being placed putting the knowledge into practice. In this presentation I argue that the failure to put the knowledge “to work” borders on being unethical and spell out a plan to put the research into practice. The needed 2nd revolution in placebo studies is one that focuses on putting placebo research for patient benefit.
Spinal cord stimulation (SCS) is a neuromodulation treatment which is increasingly used in several chronic neuropathic pain conditions. Despite its widespread clinical use, a recent Cochrane review showed that the evidence base of SCS is uncertain, and a recent randomized clinical trial showed no significant differences between SCS and placebo stimulation. This study aims to investigate clinical effects of active SCS treatment separately from placebo effects. Methods: A repeated-measures study using the balanced placebo design will be used to investigate placebo and active treatment effects, separately and in combination. Twenty-five patients will evaluate their clinical pain, in a 2x2 design with paresthesia-free stimulation activated and deactivated and suggestions about activation and deactivation. Furthermore, patients will be interviewed about their experience and pain relief with SCS.The study estimates whether the clinical effect of SCS outperform potential effects of placebo treatment on chronic neuropathic pain, while including the perspective and experience of patients. Preliminary study results will be presented at the SIPS 2023 conference in Duisburg, Germany. The study presents the first application of the balanced placebo design to test effects of SCS and placebo on chronic pain.
Tamas Spisak is Junior Research Group Leader and Head of the Laboratory of Predictive Neuroimaging at the University Hospital Essen. He is working on whether imaging techniques can predict treatment expectancy on therapy success. In the future, it should be possible to use them to predict the influence of treatment expectancy and to optimize therapy on an individual basis.
Clinical conditions such as inflammatory diseases, pain, or depression often require continuous treatment with respective drugs to diminish symptoms, whereas the amount of unwanted drug side effects detrimentally affects the patients’ quality of life. In the search to overcome the disadvantage of these side effects, reframing continuous drug intake as a learning process may open a new path for treatment optimization. Against this background, the growing knowledge about the neuropsychological mechanisms of associative learning and memory provides a number of fascinating challenges and opportunities which allow the optimal use of the still largely under-studied phenomenon of “learned” placebo responses. Employing the efferent and afferent communication pathways between the brain and other physiological systems, together with end-organ functions as hardware (to borrow IT terminology) and sophisticated associative learning protocols as software, behavioral conditioning of pharmacological responses might serve as an activator of the body-own pharmacy and thus a valuable supportive treatment tool for the patient’s benefit. This talk outlines the development and application of paradigms in experimental animals, healthy subjects, and patient populations with a focus on learned placebo responses in the immune system.
Unlike human studies, animal models of placebo analgesia can inspect the underlying neurobiology at cellular levels. Placebo analgesic responses have been demonstrated in nerve-injured rats using pharmacological-conditioning. Whether placebo analgesia can be elicited from nerve-injured rats using clinically relevant response-conditioning techniques is unknown. 96 rats received sciatic nerve injuries or sham surgery. Rats underwent a 5-day response-conditioning procedure, whereby contextual cues were paired with either a high, low or moderate intensity thermal stimulus using a hot/cold plate. The following day (Test Day), all rats were tested at the moderate intensity stimulus.
On Test Day, rats conditioned to the low intensity stimulus performed reduced pain behaviours, while rats conditioned to the high intensity stimulus performed increased pain behaviours (p=0.004, d=1.43, Welch’s unpaired t-test), indicating placebo and nocebo effects, respectively. Here we present a novel animal model of response-conditioned placebo analgesia and nocebo hyperalgesia in the context of chronic pain. This model can now be used to further investigate the cellular mechanisms underlying these phenomena, while also providing an essential preclinical resource for the development of novel treatments that exploit placebo analgesia.
Pain is a multidimensional experience with sensory, emotional and cognitive components. Although the neural circuits and dynamics underlying the sensory and emotional dimensions of pain have been elucidated by us (Corder, Ahanonu, et al., Science, 2019) and others, our understanding of the cognitive dimension of pain remains comparatively limited. We created a behavioral assay that models placebo analgesia by conditioning mice to expect pain relief when moving from a chamber with a heated floor to another chamber. In this assay, an expectation of pain relief induces analgesia that is mediated by endogenous opioids. Calcium imaging of neural activity in freely moving mice revealed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Physiologically, this conditioning unbalances the excitation and inhibition of rACC→Pn neurons, impairing feedforward inhibition, and facilitating burst firing and postsynaptic potentiation. Transcriptomic studies of Pn neurons revealed an extraordinary abundance of opioid receptors in these cells, consistent with their newfound key role in pain modulation. Inhibition of either rACC→Pn or postsynaptic opioid receptor-expressing Pn neurons disrupts placebo analgesia and increases pain. Collectively, these findings uncover circuit and synaptic mechanisms underlying placebo analgesia and open the possibility of acting on this rACC→Pn pathway to produce pain relief.
Placebo effects can be induced in various ways. Verbal instruction and conditioning procedures alone or in combination represent the most commonly used approaches in experimental settings, whereby conditioning procedures consistently enhance the efficacy of placebo treatments. However, the underlying neural mechanisms are less well understood. Using a systematic meta-analysis of individual participant data from 16 within-subject placebo neuroimaging studies (total n = 409, we aimed to identify differences in placebo analgesia (PA)-associated brain activity based on whether conditioning was used in the PA induction or not. Analyzing rank-harmonized individual-level data in a permutation testing framework (i) replicated our previous meta-analytic findings of typical placebo-related brain activity changes with a different subsample and methodology and (ii) revealed distinct neural correlates of conditioned as compared to verbally induced analgesia. Conditioned PA was associated with stronger activity in prefrontal, anterior cingulate, and cerebellar regions, and reduced activity in primary somatosensory cortex, supramarginal gyrus, and posterior insula as compared to verbally induced PA. Importantly, these results controlled for behavioral placebo ratings, thus potentially reflecting differences in the underlying neural mechanisms over and above the differences in magnitude of behavioural analgesia evoked by the different strategies to induced PA.
Expectation effects play a crucial role in pain perception. The most precise expectation about an upcoming stimulus can be generated if its intensity can be self-controlled. If stimulus intensities are externally controlled, but still predictable, expectations get more uncertain but remain directed. In case of uncontrollable and unpredictable stimulus intensities, expectations are most variable. By now, predictability and controllability effects on pain perception were confounded in most studies. In a new experimental paradigm we were able to disentangle those effects by employing a design with the following conditions: Painful stimuli were either (1) controllable and predictable, (2) uncontrollable and predictable, or (3) uncontrollable and unpredictable. Healthy participants rated pre-calibrated stimuli applied to their forearm using a visual analogue scale. One sample was tested in the behavioral lab (N = 55) and a second sample in the MR-scanner (N = 60) while recording brain activity. We show in both samples that ratings of uncontrollable and unpredictable heat pain stimuli follow Bayesian magnitude estimation mechanisms and that the ability to control and predict a painful stimulus interacts with pain intensity in subjective pain ratings. In addition, we report neural correlates of the influence of controllability and predictability on pain processing.