Dopamine has no direct causal role in the formation of treatment expectations and placebo analgesia in humans.

Dopamine-based reward and learning mechanisms have been suggested to contribute to placebo effects. However, the exact role of dopaminergic neurotransmission in their generation and maintenance is still unclear. This study aimed to shed light on the causal role of dopamine in establishing positive treatment expectations, as well as on the magnitude and duration of their effect on pain. To this end, we used an established placebo analgesia paradigm in combination with 2 opposing pharmacological modulations of dopaminergic tone, i.e., the dopamine antagonist sulpiride and the dopamine precursor L-dopa which were both applied in an experimental, double-blind, randomized, placebo-controlled trial with a between-subject design in N = 168 healthy volunteers. The study medication successfully altered dopaminergic tone during the conditioning procedure. Contrary to our hypotheses, the medication did not modulate the formation of positive treatment expectation and placebo analgesia tested 1 day later. Placebo analgesia was no longer detectable on day 8 after conditioning. Using a combined frequentist and Bayesian approach, our data provide strong evidence against a direct dopaminergic influence on the generation and maintenance of placebo effects. Further exploration of the neurochemical mechanisms underlying placebo analgesia remains paramount in the quest to exploit these effects for optimal treatment outcomes. Trial registration: ClinicalTrials.gov German Clinical Trials Register, ID: DRKS00029366, https://drks.de/search/en/trial/DRKS00029366.

The effects of experimental pain on episodic memory and its top-down modulation: a preregistered pooled analysis.

Introduction: Pain can automatically interfere with ongoing cognitive processes such as attention and memory. The extent of pain's negative effects on cognitive functioning seems to depend on a balance between top-down and bottom-up factors. Objectives: In this large, preregistered, pooled reanalysis of 8 studies, we investigated the robustness of the detrimental effect of acute pain on recognition memory and whether top-down mechanisms such as pain-related expectations or cognitions (pain-related fear, pain catastrophizing) modulate this effect. Methods: Two hundred forty-seven healthy participants underwent similar experimental paradigms, including a visual categorization task with images randomly paired with (or without) concomitant painful stimulation and a subsequent unannounced recognition task. Recognition memory (ie, d', recollection, and familiarity) and categorization performance (ie, reaction time, accuracy) served as proxies for the effect of pain on cognitive performance. Results: Acute painful stimulation significantly impaired recognition performance (d', familiarity). However, recognition performance was not significantly modulated by participants' expectations regarding the effect of pain on task performance or pain-related cognitions in this sample of healthy participants. Conclusion: Our results corroborate the negative effects of pain on (visual) memory encoding reported in previous studies and reports of "memory problems" from patients with chronic pain. To characterize the role of bottom-up and top-down factors for the detrimental effects of pain, large-scale studies with more nuanced study designs are necessary. Future studies in patient cohorts must unravel the interaction of maladaptive pain-related cognitions and the often-reported impaired cognitive performance in chronic pain patients.

Setting the stage for pain relief: how treatment setting impacts interdisciplinary multimodal pain treatment for patients with chronic back pain.

ABSTRACT: While interdisciplinary multimodal pain treatment (IMPT) is an effective treatment option for chronic low back pain, it is usually accomplished as an inpatient treatment incurring substantial healthcare costs. Day hospital IMPT could be a resource-saving alternative approach, but whether treatment setting is associated with differences in treatment outcomes has not yet been studied. In a retrospective matched cohort study including data from N = 595 patients diagnosed with chronic back pain and undergoing IMPT at the back pain center in Essen, Germany, we investigated the association between treatment setting (ie, inpatient or day patient of an otherwise identical IMPT) and pain intensity, disability, and self-efficacy after treatment. Outcomes were assessed by questionnaires used in clinical routine, collected at pre-IMPT, post-IMPT, and at 3-, 6-, and 12-month follow-up. The results indicate that day patients showed greater improvements in pain-related disability at 3-month post-IMPT (d = 0.74) and in pain intensity at 6-month post-IMPT (d = 0.79), compared to a matched sample of inpatients. Moreover, day patients achieved higher scores in pain-related self-efficacy at discharge, 3- and 6-month post-IMPT (d = 0.62, 0.99, and 1.21, respectively) and reported fewer incapacity-for-work days than inpatients at 6-month post-IMPT (d = 0.45). These data suggest that day hospital IMPT can be as effective as inpatient treatment and might even be more effective for the less afflicted patients. Further research regarding treatment setting and indication could guide optimized and cost-efficient treatments that are more closely tailored to the individual patient's needs.

An externally validated resting-state brain connectivity signature of pain-related learning.

Pain can be conceptualized as a precision signal for reinforcement learning in the brain and alterations in these processes are a hallmark of chronic pain conditions. Investigating individual differences in pain-related learning therefore holds important clinical and translational relevance. Here, we developed and externally validated a novel resting-state brain connectivity-based predictive model of pain-related learning. The pre-registered external validation indicates that the proposed model explains 8-12% of the inter-individual variance in pain-related learning. Model predictions are driven by connections of the amygdala, posterior insula, sensorimotor, frontoparietal, and cerebellar regions, outlining a network commonly described in aversive learning and pain. We propose the resulting model as a robust and highly accessible biomarker candidate for clinical and translational pain research, with promising implications for personalized treatment approaches and with a high potential to advance our understanding of the neural mechanisms of pain-related learning.

Media coverage of COVID-19 vaccination-associated cerebral venous sinus thrombosis was followed by a surge in emergency presentations due to headache - observations from a university hospital in Germany.

Nocebo effects describe all negative outcomes for well-being brought about by negative health-related expectations. Media coverage of drug side effects can fuel nocebo effects and lead to increased symptom reports. This retrospective observational analysis of emergency reports at the neurological emergency room at University Hospital Essen, Germany, examines whether media communication about a cumulation of very rare cases of cerebral venous sinus thrombosis (CVST) after COVID-19 vaccination with the AstraZeneca compound (ChAdOx-1 nCoV-19) was followed by an increase in weekly presentation rates of patients with the main complaint of headache, a symptom commonly occurring as a vaccination reaction but also communicated as a warning symptom for CVST. The rate of headache presentations increased by 171.7% during the five weeks after the first announcement of CVSTs in Germany on 11 March 2021, compared to the five weeks immediately prior. Furthermore, more young women sought consultation for headache, reflecting the communicated at-risk profile for CVST. The increased rate of headache presenters contributed to a 32.1% rise in total neurological emergency cases, causing an increased strain on the emergency facility after the side effect risk was publicized. We discuss a causal role of negative side effect expectations after vaccination with AstraZeneca as a driver for this increase. While transparent communication about benefits and potential side effects is crucial for vaccination acceptance, increased vigilance toward nocebo effects in health-related media communication is needed due to its potential harm to the individual and society, especially when emergency medical resources are stretched thin.

Working with patients' treatment expectations - what we can learn from homeopathy.

The usual homeopathic remedy, "globules," does not contain any pharmacologically active ingredient. However, many patients and practitioners report beneficial effects of homeopathic treatment on various health outcomes. Experimental and clinical research of the last two decades analyzing the underlying mechanisms of the placebo effect could explain this phenomenon, with patients' treatment expectations as the predominant mechanism. Treatment expectations can be optimized through various factors, such as prior information, communication, and treatment context. This narrative review analyses how homeopathy successfully utilizes these factors. Subsequently, it is discussed what evidence-based medicine could learn from homeopathic practice to optimize treatment expectations (e.g., using an empathic, patient-centered communication style, deliberately selecting objects in practice rooms, or using clear treatment rituals and salient contextual stimuli) and thereby treatment effectiveness. Homeopathic remedy does not work beyond the placebo effect but is recommended or prescribed as an active treatment by those who believe in it. Thus, practitioners need to understand the manner in which homeopathy (as an example of inert treatment) works and are advised to reintegrate its underlying effective placebo mechanisms into evidence-based medicine. This promises to increase treatment efficacy, tolerability, satisfaction, and compliance with evidence-based treatments, and addresses the desires patients are trying to satisfy in homeopathy in an ethical, fully informed way that is grounded in evidence-based medicine.

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.

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.

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.

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.