Learning by observing: a systematic exploration of modulatory factors and the impact of observationally induced placebo and nocebo effects on treatment outcomes.

Introduction: Observational learning (OL) refers to learning through observing other people's behavior. OL has been suggested as an effective and simple tool to evoke treatment expectations and corresponding placebo and nocebo effects. However, the exact mechanisms by which OL shapes treatment outcomes, its moderating factors and possible areas of application remain unclear. We thus reviewed the existing literature with two different literature searches to answer the following questions: Which influencing factors contribute to OL-induced placebo and nocebo effects (in healthy volunteers and patients) and how large are these effects (search 1)? In which medical fields has OL been used so far to modulate treatment expectancy and treatment outcomes in patients, their caregivers, and at-risk groups (search 2)? We also aimed to explore whether and how the assessment of treatment expectations has been incorporated. Methods: We conducted two independent and comprehensive systematic literature searches, both carried out on September 20, 2022. Results: We identified 21 studies that investigated OL-mediated placebo and nocebo effects for pain and itch, the (placebo) efficacy of sham treatment on anxiety, and the (nocebo) induction of medication side effects (search 1). Studies showed that OL can efficiently induce placebo and nocebo effects across different presentation modes, with medium effect sizes on average: placebo effects, d = 0.79 (range: d = -0.36-1.58), nocebo effects, d = 0.61 (range: d = 0.04-1.5). Although several moderating factors have been investigated, their contribution to OL-induced effects remains unclear because of inconsistent results. Treatment expectation was assessed in only four studies. Regarding medical applications of OL (search 2), we found 12 studies. They showed that OL was effectively applied in preventive, therapeutic and rehabilitative interventions and that it was mainly used in the field of psychosomatics. Discussion: OL effects on treatment outcomes can be both positive and negative. Future research should investigate which individuals would benefit most from OL and how OL can be implemented most effectively to induce placebo and avoid nocebo effects in clinical settings. Systematic review registration: This work was preregistered at the Center for Open Science as open-ended registration (doi: 10.17605/OSF.IO/FVHKE). The protocol can be found here: https://archive.org/details/osf-registrations-fvhke-v1.

Translating knowledge on placebo and nocebo effects into clinical practice.

Introduction: Positive and negative treatment expectations are powerful modulators of health and treatment outcomes. A substantial part of treatment success is due to contextual factors modulating patient's expectations towards a treatment. Consequently, treatment expectations should be a target of therapeutic interventions themselves. Objectives: This article highlights the neurobiological underpinnings of treatment expectations as well as strategies to modulate contextual factors to optimize treatment outcomes in daily clinical settings. Methods: This clinical update aligns with the 2022 IASP Global Year Translating Pain Knowledge into Practice and selectively reviews the best available evidence and practice. Results: The effects of treatment expectations, also known as placebo and nocebo effects, are observed in various clinical conditions and physiological systems. However, most of our knowledge comes from the field of pain, where expectation effects substantially contribute to overall analgesic treatment outcomes. Experimental placebo analgesia paradigms provide the best illustration of how analgesic effects can be attributed not only to a pharmacological or specific treatment, but instead are the result of the expectation towards the treatment. The impact of expectations on treatment outcome is highly variable between individuals, and the identification of factors predicting an individual's response has proven to be challenging. Further research is required to provide personalized treatment strategies for the daily clinical practice. Conclusion: Patient's previous experiences and expectations are powerful modulators of treatment efficacy, tolerability, and adherence. By providing a comprehensive overview of recent advances in this field, this review offers valuable insights for clinicians and researchers seeking to improve patient-clinician interaction.

EFFects of Exposure and Cognitive behavioral Therapy for chronic BACK pain ("EFFECT-BACK"): study protocol for a randomized controlled trial.

INTRODUCTION: Chronic back pain is a widespread medical condition associated with high socioeconomic costs and increasing prevalence. Despite the advanced implementation of multidisciplinary approaches, providing a satisfactory treatment offer for those affected is often not possible. Exposure therapy (EXP) promises to be an effective and economical form of treatment and in a previous pilot study showed to be superior to cognitive behavioral therapy (CBT) in reducing perceived limitations of movement. The current study aims to further compare the efficacy of both treatment methods and identify those patient groups that particularly benefit from EXP. METHODS: The general objective of this randomized multicenter clinical trial (targeted N = 380) is to improve and expand the range of treatments available to patients with chronic back pain. As the primary objective of the study, two different psychological treatments (EXP and CBT) will be compared. The primary outcome measure is a clinically significant improvement in pain-related impairment, measured by the QPBDS, from baseline to 6-month follow-up. Secondary outcome measures are absolute changes and clinically significant improvements in variables coping, psychological flexibility, depressiveness, catastrophizing, exercise avoidance and fear of exercise, and intensity of pain. Participants are recruited in five psychological and medical centers in Germany and receive ten sessions of manualized therapy by trained licensed CBT therapists or clinical psychologists, who are currently in their post-gradual CBT training. Potential predictors of each treatment's efficacy will be explored with a focus on avoidance and coping behavior. CONCLUSION: This study will be the first RCT to compare CBT and EXP in chronic back pain in a large sample, including patients from different care structures due to psychological and medical recruitment centers. By identifying and exploring potential predictors of symptom improvement in each treatment group, this study will contribute to enable a more individualized assignment to treatment modalities and thus improves the care situation for chronic back pain and helps to create a customized treatment program for subgroups of pain patients. If our findings confirm EXP to be an efficacious and efficient treatment concept, it should gain more attention and be further disseminated. TRIAL REGISTRATION: ClinicalTrials.gov NCT05294081. Registered on 02 March 2022.

Hydrocortisone Differentially Affects Reinstatement of Pain-related Responses in Patients With Chronic Back Pain and Healthy Volunteers.

Despite the crucial role of effective and sustained extinction of conditioned pain-related fear in cognitive-behavioral treatment approaches for chronic pain, experimental research on extinction memory retrieval in chronic pain remains scarce. In healthy populations, extinction efficacy of fear memory is affected by stress. Therefore, we investigated the effects of oral hydrocortisone administration on the reinstatement of pain-related associations in 57 patients with non-specific chronic back pain (CBP) and 59 healthy control (HC) participants in a differential pain-related conditioning paradigm within a placebo-controlled, randomized, and double-blind design. Participants' skin conductance responses indicate hydrocortisone-induced reinstatement effects in HCs but no observable reinstatement in HCs receiving placebo treatment. Interestingly, these effects were reversed in patients with CBP, that is, reinstatement responses were only observed in the placebo and not in the hydrocortisone group. Our findings corroborate previous evidence of stress-induced effects on extinction efficacy and reinstatement of fear memory in HCs, extending them into the pain context, and call for more research to clarify the role of stress in fear extinction and return of fear phenomena possibly contributing to treatment failure in chronic pain treatment. PERSPECTIVE: Opposing effects in HCs and patients with non-specific CBP may be associated with changes in the patients' stress systems. These findings could be of relevance to optimizing psychological, extinction-based treatment approaches.

Open-label placebo treatment does not enhance cognitive abilities in healthy volunteers.

The use of so-called 'smart drugs' such as modafinil to improve cognitive performance has recently attracted considerable attention. However, their side effects have limited user enthusiasm. Open-label placebo (OLP) treatment, i.e., inert treatments that are openly disclosed to individuals as having no active pharmacological ingredient, has been shown to improve various medical symptoms and conditions, including those related to cognitive performance. OLP treatment could therefore be an exciting alternative to pharmacological cognitive enhancers. Here, we used a randomized-controlled design to investigate the effect of a 21-day OLP treatment on several sub-domains of cognitive performance in N = 78 healthy volunteers. Subjective and objective measures of cognitive performance as well as different measures of well-being were obtained before and after the treatment period. Using a combination of classic Frequentist and Bayesian analysis approaches showed no additional benefit from OLP treatment in any of the subjective or objective measures of cognitive performance. Our study thus highlights possible limitations of OLP treatment in boosting cognitive performance in healthy volunteers. These findings are discussed in the light of expectancy-value considerations that may determine OLP efficacy.

The influence of psychological traits and prior experience on treatment expectations.

BACKGROUND: Placebo and nocebo responses are modulated by the treatment expectations of participants and patients. However, interindividual differences predicting treatment expectations and placebo responses are unclear. In this large-scale pooled analysis, we aim to investigate the influence of psychological traits and prior experiences on treatment expectations. METHODS: This paper analyses data from six different placebo studies (total n = 748). In all studies, participants' sociodemographic information, treatment expectations and prior treatment experiences and traits relating to stress, somatization, depression and anxiety, the Big Five and behavioral inhibition and approach tendencies were assessed using the same established questionnaires. Correlation coefficients and structural equation models were calculated to investigate the relationship between trait variables and expectations. RESULTS: We found small positive correlations between side effect expectations and improvement expectations (r = 0.187), perceived stress (r = 0.154), somatization (r = 0.115), agitation (r = 0.108), anhedonia (r = 0.118), and dysthymia (r = 0.118). In the structural equation model previous experiences emerged as the strongest predictors of improvement (ß = 0.32, p = .005), worsening (ß = -0.24, p = .005) and side effect expectations (ß = 0.47, p = .005). Traits related to positive affect (ß = - 0.09; p = .007) and negative affect (ß = 0.04; p = .014) were associated with side effect expectations. DISCUSSION: This study is the first large analysis to investigate the relationship between traits, prior experiences and treatment expectations. Exploratory analyses indicate that experiences of symptom improvement are associated with improvement and worsening expectations, while previous negative experiences are only related to side effect expectations. Additionally, a proneness to experience negative affect may be a predictor for side effect expectation and thus mediate the occurrence of nocebo responses.

Study protocol: effects of treatment expectation toward repetitive transcranial magnetic stimulation (rTMS) in major depressive disorder-a randomized controlled clinical trial.

BACKGROUND: Patients' expectations toward any given treatment are highly important for the effectiveness of such treatment, as has been demonstrated for several disorders. In particular, in major depressive disorder (MDD), one of the most frequent and most serious mental disorders with severe consequences for the affected, the augmentation of available treatment options could mean a ground-breaking success. Repetitive transcranial magnetic stimulation (rTMS), a new, non-invasive, and well-tolerated intervention with proven effects in the treatment of MDD, appears particularly suitable in this context as it is assumed to exert its effect via structures implicated in networks relevant for both expectation and depression. METHODS: All patients will receive rTMS according to its approval. Half of the patients will be randomized to a psychological intervention, which is a comprehensive medical consultation aiming to improve positive treatment expectations; the control group will receive a conventional informed consent discussion (in the sense of a treatment-as-usual condition). As outcome parameters, instruments for both self-assessment and external assessment of depression symptoms will be applied. Furthermore, psycho-immunological parameters such as inflammation markers and the cortisol awakening response in saliva will be investigated. Resting-state functional magnetic resonance imaging (rs fMRI) will be performed to analyze functional connectivity, including the cerebellum, and to identify neuronal predictors of expectation effects. In addition, possible cerebellar involvement will be assessed based on a cerebellar-dependent motor learning paradigm (i.e., eyeblink conditioning). DISCUSSION: In this study, the effects of treatment expectations towards rTMS are investigated in patients with MDD. The aim of this study is to identify the mechanisms underlying the expectation effects and, beyond that, to expand the potential of non-invasive and well-tolerated treatments of MDD. TRIAL REGISTRATION: German Registry of Clinical Studies (DRKS DRKS00028017. Registered on 2022/03/07. URL: https://www.drks.de/drks_web/ .

Neural underpinnings of preferential pain learning and the modulatory role of fear.

Due to its unique biological relevance, pain-related learning might differ from learning from other aversive experiences. This functional magnetic resonance imaging study compared neural mechanisms underlying the acquisition and extinction of different threats in healthy humans. We investigated whether cue-pain associations are acquired faster and extinguished slower than cue associations with an equally unpleasant tone. Additionally, we studied the modulatory role of stimulus-related fear. Therefore, we used a differential conditioning paradigm, in which somatic heat pain stimuli and unpleasantness-matched auditory stimuli served as US. Our results show stronger acquisition learning for pain- than tone-predicting cues, which was augmented in participants with relatively higher levels of fear of pain. These behavioral findings were paralleled by activation of brain regions implicated in threat processing (insula, amygdala) and personal significance (ventromedial prefrontal cortex). By contrast, extinction learning seemed to be less dependent on the threat value of the US, both on the behavioral and neural levels. Amygdala activity, however, scaled with pain-related fear during extinction learning. Our findings on faster and stronger (i.e. "preferential") pain learning and the role of fear of pain are consistent with the biological relevance of pain and may be relevant to the development or maintenance of chronic pain.

Brain morphology predicts individual sensitivity to pain: a multicenter machine learning approach.

ABSTRACT: Sensitivity to pain shows a remarkable interindividual variance that has been reported to both forecast and accompany various clinical pain conditions. Although pain thresholds have been reported to be associated to brain morphology, it is still unclear how well these findings replicate in independent data and whether they are powerful enough to provide reliable pain sensitivity predictions on the individual level. In this study, we constructed a predictive model of pain sensitivity (as measured with pain thresholds) using structural magnetic resonance imaging-based cortical thickness data from a multicentre data set (3 centres and 131 healthy participants). Cross-validated estimates revealed a statistically significant and clinically relevant predictive performance (Pearson r = 0.36, P < 0.0002, R2 = 0.13). The predictions were found to be specific to physical pain thresholds and not biased towards potential confounding effects (eg, anxiety, stress, depression, centre effects, and pain self-evaluation). Analysis of model coefficients suggests that the most robust cortical thickness predictors of pain sensitivity are the right rostral anterior cingulate gyrus, left parahippocampal gyrus, and left temporal pole. Cortical thickness in these regions was negatively correlated to pain sensitivity. Our results can be considered as a proof-of-concept for the capacity of brain morphology to predict pain sensitivity, paving the way towards future multimodal brain-based biomarkers of pain.

Needs and Demands for eHealth Pain Management Interventions in Chronic Pain Patients.

Although chronic pain is a global health problem, the current care situation is often inadequate. eHealth offers many advantages as an additional option for treating chronic pain. Yet, an intervention's efficacy can only be fully exhausted if patients intend to use it. This study aims to identify the needs and demands of patients with chronic pain regarding intervention concepts and frameworks to develop specifically tailored eHealth pain management interventions. A cross-sectional study was conducted, including 338 individuals with chronic pain. Within the cohort, a distinction between a high- and a low-burden group was made. Respondents generally preferred a permanently accompanying mobile app, but the preferred content varied with group. According to the majority, interventions should be made available on smartphones, offer sessions once per week with a duration from 10 to 30 min, and be recommended by experts. These results can provide the basis for future eHealth pain management interventions tailored to the patients' needs and demands.

Measuring Patient Experience and Patient Satisfaction-How Are We Doing It and Why Does It Matter? A Comparison of European and U.S. American Approaches.

(1) Background: Patients' experiences and satisfaction with their treatment are becoming increasingly important in the context of quality assurance, but the measurement of these parameters is accompanied by several disadvantages such as poor cross-country comparability and methodological problems. The aim of this review is to describe and summarize the process of measuring, publishing, and utilizing patient experience and satisfaction data in countries with highly developed healthcare systems in Europe (Germany, Sweden, Finland, Norway, the United Kingdom) and the USA to identify possible approaches for improvement. (2) Methods: Articles published between 2000 and 2021 that address the topics described were identified. Furthermore, patient feedback in social media and the influence of sociodemographic and hospital characteristics on patient satisfaction and experience were evaluated. (3) Results: The literature reveals that all countries perform well in collecting patient satisfaction and experience data and making them publicly available. However, due to the use of various different questionnaires, comparability of the results is difficult, and consequences drawn from these data remain largely unclear. (4) Conclusions: Surveying patient experience and satisfaction with more unified as well as regularly updated questionnaires would be helpful to eliminate some of the described problems. Additionally, social media platforms must be considered as an increasingly important source to expand the range of patient feedback.

[Placebo effects in analgesia : Influence of expectations on the efficacy and tolerability of analgesic treatment]. / Placeboeffekte in der Schmerztherapie : Einfluss der Erwartung auf die Wirksamkeit und Verträglichkeit schmerzmedizinischer Behandlungen.

Expectations of patients influence the perception and neuronal processing of acute and chronic pain and modulate the effectiveness of analgesic treatment. The expectation of treatment is not only the most important determinant of placebo analgesia. Expectations of treatment also influence the efficacy and tolerability of "active" pharmacological and non-pharmacological treatment of pain. Recent insights into the psychological and neurobiological mechanisms underlying the clinically relevant effects of treatment expectations enable and call for the systematic integration and modulation of treatment expectations into analgesic treatment concepts. Such a strategy promises to optimize analgesic treatment and to prevent or reduce the burden of unwanted side effects and the misuse of analgesics, particularly of opioids. This review highlights the current concepts, recent achievements and also challenges and key open research questions.

No long-term effects after a 3-week open-label placebo treatment for chronic low back pain: a 3-year follow-up of a randomized controlled trial.

ABSTRACT: Chronic low back pain is prevalent, highly disabling, and a relevant socioeconomic health concern. Although allocated to placebo groups, patients in randomized controlled trials show significant pain relief, pointing to the relevance of placebo effects. Overcoming ethical and legal concerns related to deceptive placebos, recent studies have demonstrated the efficacy of short-term treatments for chronic low back pain with open-label (ie, nondeceptive) placebos. However, data on long-term efficacy of open-label placebos are sparse. Here, we report a 3-year follow-up of our previously published randomized controlled trial demonstrating pain reduction, improvement in disability, and depressive symptoms after a 3-week treatment with open-label placebos. Including records from 89 previously enrolled patients, we investigated changes between the groups with and without previous open-label placebo treatment in pain intensity (primary outcome), disability and mood (secondary outcomes), biopsychosocial factors and lifestyle (exploratory outcomes) from parent baseline to follow-up. Over the 3-year period, there were no differences in any outcome between groups with and without open-label placebo treatment. Therefore, our follow-up data do not support the previously suggested assumption that a 3-week open-label placebo treatment has long-term effects. This study was preregistered on April 14, 2020, in the German Clinical Trials Register (registration number DRKS00021405).

Savor the flavor: A randomized double-blind study assessing taste-enhanced placebo analgesia in healthy volunteers.

Placebo effects substantially contribute to analgesic treatment outcomes and might be leveraged to enhance gold-standard treatments. The taste of oral medications has been proposed to boost placebo effects. Here, we aimed at estimating how far the taste of an oral medication enhances placebo analgesia. We conducted a randomized, double-blind, between-group, single-visit study, with pre-treatment baseline. Over the course of three substudies, 318 healthy volunteers (297 included) were tested in a clinical trial setting. Participants were subjected to experimental tonic cold water pain (cold pressor test) before and after receiving taste-neutral (water), or bitter (quinine), or sweet (saccharin), or no placebo drops. Pre- versus post-treatment changes in area under the pain rating curve, the main outcome, indicated that placebo treatment showed a small analgesic effect versus no treatment. Added taste induced placebo enhancement in the very small effect size range, but accounted for a substantial portion of the overall placebo effect. No noteworthy advantage of sweet over bitter placebo was observed. An exploration of heart rate (HR) recordings indicated that placebo treatments were associated with an increase in peak HR-response to cold water, but these were not associated with placebo analgesia at an individual level. Placebo treatments were associated with minimal side effects. These results indicate that added taste may be an easy-to-implement, cost-effective, and safe way to optimize treatment outcomes and that taste-neutral preparations may reduce placebo-related outcome variance in clinical trials. Further studies are needed to test if these findings can be translated into clinical scenarios.

Determining the Influencing Factors on Acceptance of eHealth Pain Management Interventions Among Patients With Chronic Pain Using the Unified Theory of Acceptance and Use of Technology: Cross-sectional Study.

BACKGROUND: Chronic pain is a complex disease with high prevalence rates, and many individuals who are affected do not receive adequate treatment. As a complement to conventional therapies, eHealth interventions could provide many benefits to a multimodal treatment approach for patients with chronic pain, whereby future use is associated with the acceptance of these interventions. OBJECTIVE: This study aims to assess the acceptance of eHealth pain management interventions among patients with chronic pain and identify the influencing factors on acceptance. A further objective of the study is to evaluate the viability of the Unified Theory of Acceptance and Use of Technology (UTAUT) model and compare it with its extended version in terms of explained variance of acceptance. METHODS: We performed a cross-sectional web-based study. In total, 307 participants with chronic pain, as defined according to the International Association for the Study of Pain criteria, were recruited through flyers, posters, and web-based inquiries between December 2020 and July 2021. In addition to sociodemographic and medical data, the assessment included validated psychometric instruments and an extended version of the well-established UTAUT model. For statistical analyses, group comparisons and multiple hierarchical regression analyses were performed. RESULTS: The acceptance of eHealth pain management interventions among patients with chronic pain was overall moderate to high (mean 3.67, SD 0.89). There was significant difference in acceptance among age groups (W=9674.0; r=0.156; P=.04). Effort expectancy (ß=.37; P<.001), performance expectancy (ß=.33; P<.001), and social influence (ß=.34; P<.001) proved to be the most important predictors of acceptance. The extended UTAUT (including the original UTAUT factors as well as sociodemographic, medical, and eHealth-related factors) model explained 66.4% of the variance in acceptance, thus supporting the viability of the model. Compared with the original UTAUT model (performance expectancy, effort expectancy, and social influence), the extended model explained significantly more variance (F25,278=1.74; P=.02). CONCLUSIONS: Given the association between acceptance and future use, the knowledge of the influencing factors on acceptance should be used in the development and promotion of eHealth pain management interventions. Overall, the acceptance of eHealth pain management interventions was moderate to high. In total, 8 predictors proved to be significant predictors of acceptance. The UTAUT model is a valuable instrument for determining acceptance as well as the factors that influence acceptance of eHealth pain management interventions among patients with chronic pain. The extended UTAUT model provided the greatest predictive value for acceptance.

Influence on study outcomes of an inpatient study by the behavior of the study staff (PINgPOng): study protocol for a randomized clinical trial.

BACKGROUND: The placebo effect as the symptom improvement following inert treatments is a fixed component of RCTs to differentiate between specific effects of the tested pharmacological substance from other unspecific effects. The PINgPOng study was set up to analyze the influence of a study team trained to either minimize the placebo response and optimize drug-placebo differences or to maximize the placebo response to increase drug efficacy by unspecific factors on the study results of a RCT in a classical early clinical trial setting. METHODS/DESIGN: PINgPOng is a single-center, prospective, randomized, double-blind, placebo-controlled study in a 3-group, 2-sequence, 2-period cross-over design. The study is conducted according to the principles of ICH-GCP and the Declaration of Helsinki on the Phase I-Unit of the University Hospital Bonn. The primary endpoint is the pain intensity in the cold pressor test before and after the administration of 15 mg oxycodone or placebo. The pain intensity is compared between three study conditions: 32 healthy volunteers in each study arm will be treated either by an untrained study team (arm A), by a study team trained to maximize (arm B), or to minimize placebo responses (arm C). Neuroendocrine factors (alpha-amylase activity, salivary cortisol), characteristic traits (anxiety, depression, stress), and somatic reactions are analyzed as covariates of the pain perception. DISCUSSION: The PINgPOng study will allow to answer the question whether and to what extent the behavior of a trained study team (neutral vs. maximize vs. minimize placebo responses) will differentially affect placebo responses in a setting of a highly standardized early clinical trial. The results will help to control the placebo effects by education of the clinical study team and to avoid unnecessary high placebo effects in clinical development. TRIAL REGISTRATION: German Clinical Trials Register DRKS00013586 . Registered on December 22, 2017.