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Datablitz sessions

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Datablitz I:
Computational and Psychological Mechanisms Underlying Placebo Effects

Jana Aulenkamp

Negative pain-related expectations shape the presence and the future: Unraveling modality-specific nocebo mechanisms in experimental visceral versus somatic pain

Dynamic changes in negative expectations underlying nocebo effects in visceral pain remain incompletely understood. In model of repeated pain experiences from the visceral and somatic modalities, we elucidated modality-specific expectations, experience and pain recall in healthy volunteers.Visceral (rectal distensions) and somatic pain (thermal pain applied to abdomen) stimuli were matched to perceived intensity. On two study days (7 days apart) a pseudorandomized series of stimuli from both modalities was implemented. Negative pain-related expectations were greater for the visceral modality, and visceral pain was experienced as more intense and unpleasant (trial-by-trial ratings). Visceral pain recall at end of day 1 was more negative, and correlated with greater negative visceral pain-related expectations 1 week later. While pain experience on day 1 was not associated with expectations on day 2 for visceral modality, pain experience and future expectations matched for somatic modality. Dynamic changes in pain-related negative expectations are modality-specific, suggesting distinct and more pronounced modulation of visceral pain by nocebo effects. Biased short-term pain recall may trigger long-term expectation bias, with implications for chronic visceral pain.

Friederike Thams

Attention and prefrontal regulation modulate positive treatment effects on emotional processing

Positive treatment expectations substantially influence treatment outcomes. This highly potent placebo effect has been shown in the context of pain as well as in the emotional domain with regard to antidepressant-treatment outcomes. Here, we are interested in attentional top-down modulation of beneficial treatment expectation effects in the affective system.  We performed a controlled cross-over study using positive expectation induction for alleged intranasal oxytocin treatment in N = 49 healthy participants who completed an attentional emotion-interference task (modified Posner paradigm) during functional magnetic resonance imaging. 
Behavioral findings show an enhanced bias toward positive versus negative stimuli during the positive expectation compared to the control condition. This effect emerged only when the attention to emotional stimuli was high. The effect was paralleled by neural activations in cognitive control network regions such as the dorsolateral prefrontal cortex. Taken together our results indicate that affective treatment effects are modulated by attentional control and higher-order prefrontal regulation. 

Funding: We gratefully acknowledge funding from the German Research Foundation (DFG) - Project-ID 422744262—TRR 289.

Rotem Botvinik-Nezer

The integration of multiple social cues into expectations and their effect on perception in pain and vision

Expectations about upcoming stimuli shape their perception. When integrating over multiple cues, the mean value across cues has been shown to shape expectations and subsequent perception. Some studies have found that this effect is weaker when the variance (uncertainty) across cues is higher, in accordance with a Bayesian predictive-coding framework, but others have found that uncertainty increases pain irrespective of the mean cue value or has no effect. To test whether these mixed findings result from over-weighting of extreme pain cues, N=45 participants were presented with 10 simultaneous lines indicating purported ratings by other participants, followed by either a hot stimulus or a flickering checkerboard with varying intensities. The mean, variance and skewness of the cues were experimentally manipulated. Expectation and perception were indeed higher following cues with higher mean value, but effects of variance were weak. Computational models revealed that more fine-grained features of the distribution matter: Healthy young adults overweight outliers in both modalities, and also smaller values, specifically in pain. fMRI data revealed that expectation-related effects are a combination of modality-specific and modality-general processes. Our results explain previous mixed findings regarding the variance based on over-weighting of extreme values.

Nick Augustat

Uncertainty enhances treatment expectation effects on reinforcement learning

The placebo-reward hypothesis suggests that placebo and reward processing share similar cognitive resources. Moreover, experiments in humans and animals indicate that uncertainty enhances striatal dopamine, which is presumably involved in placebo responses and reward learning. Therefore, the probability of receiving active treatment may affect reward learning after placebo treatment. Here, we address whether different degrees of uncertainty regarding the efficacy of a sham treatment affect reward learning. In an online between-subjects experiment with N = 141 participants, we systematically varied the provided efficacy instructions (0-100% in steps of 25%) before participants first received a sham treatment that consisted of listening to binaural beats and then performed a probabilistic reinforcement learning task. We fitted a Q-learning model including two different learning rates for positive (gain) and negative (loss) prediction errors and an inverse gain parameter to behavioral decision data in the reinforcement learning task. Our results yielded an inverted-U-shape relationship between provided treatment efficacy probability and learning rates for gain, suggesting that treatment uncertainty, rather than net efficacy, affects presumably dopamine-related reward learning. These findings support the placebo-reward hypothesis and suggest harnessing uncertainty in placebo treatment in order to recover reward learning capabilities.

Justyna Braczyk

The effectiveness of medically and non-medically connoted placebos in inducing placebo hypoalgesia by operant conditioning

Recent studies have shown that placebo hypoalgesia can be induced by operant conditioning. The aim of the study is to compare the placebo hypoalgesia induced by operant conditioning with the use of medically and non-medically connoted placebo. Participants will be randomly allocated to one of the two experimental groups: medically connoted placebo, non-medically connoted placebo; and three control groups: random medically connoted, random non-medically connoted, natural history.  In the medically connoted placebo groups, a TENS device alleged activation will serve as placebo intervention. In non-medically connoted placebo groups, a white circle on the screen will be a placebo. In both experimental groups, in the operant conditioning phase, during every series of electrical stimulation participants will have an option: to take or reject the placebo. If they choose the placebo, they will be reinforced with lowered pain intensity. If they choose to reject the placebo, the pain intensity will stay at the same level. In the posttest phase, participants will still have the choice between taking or rejecting the placebo, however no reinforcement will be distributed.  The data collection is ongoing, and the results will be presented during the conference.

Datablitz II:
Animal Models in Placebo Research

Aleksandrina Skvortsova

The role of cholecystokinin in nocebo hyperalgesia in mice.

Conditioned hyperalgesia was found in mice and humans after a pairing of an environmental context with pain. This study investigated the neurochemical mediation of this phenomenon focusing on cholecystokinin (CCK), a neurotransmitter that affects nocebo hyperalgesia in humans.Post-operative pain was used as an unconditioned stimulus. Mice underwent an incision surgery on their paw. Right after the surgery they were placed in a particular testing context for 5 hours (conditioned stimulus). Testing day took place six days later, when the incision wound recovered. Mice were tested for mechanical pain sensitivity either in the same or in a different context. Additionally, mice received either CCK-2 antagonist LY-225910 (1 mg/kg) or saline immediately before the surgery and at the start of the test day. A significant increase in pain sensitivity was observed in saline-treated mice tested in the same context on the test day. This conditioned hyperalgesia was blocked by LY-225910. Mice tested in a new context did not exhibit hyperalgesia. One pairing of pain with context is enough to cause conditioned hyperalgesia in mice. LY-225910 blocks conditioned hyperalgesia, indicating that CCK-2 receptors are involved in mediating this phenomenon.

Maria Willadsen

Effects of positive and negative treatment expectation on antidepressant treatment efficacy in rats

In rats, juvenile social isolation leads to a depression-like phenotype. This rodent model of affective disorders in turn can be used to examine how positive vs. negative treatment experience as a function of the treatment context affects the placebo and nocebo responses compared to pharmacological treatment with selective serotonin reuptake inhibitors (SSRIs). Hereby, ultrasonic vocalizations (USV) are of special interest. For one, as a marker of affective states in general, and as indicator of altered emotional processing in depression-like phenotypes specifically. Different types of USV accompany a range of appetitive and aversive contexts, and their emission is known to be influenced by juvenile social isolation. A balanced placebo design is applied to test how positive and negative prior treatment experiences affect the response to placebo and pharmacological antidepressant treatment (SSRIs). Furthermore, treatment outcome is evaluated by several standard tests, e.g. open field and elevated plus maze.
Preliminary results indicate context dependent effects on USV.
In a series of experiments, it is investigated how positive vs. negative treatment experience (treatment context) affects the response to placebo and SSRIs, as assessed by depression-related behavioral phenotypes, such as ultrasonic vocalization deficits, social impairments, and anhedonia.

Kirsten Dombrowski

The bittersweet taste of sickness: induction of negative treatment expectation in an animal model of endotoxin-induced sickness

Despite broad clinical implications, the neurobiological mechanisms underlying negative treatment expectation are largely unknown. For ethical reasons, such mechanistic insights are difficult to obtain in humans. This calls for translational animal models that mimic clinically relevant features of negative treatment expectation. Here we present results from an animal model of endotoxin-induced sickness aimed at inducing a negative treatment expectation in rats.Using a conditioned taste aversion (CTA) paradigm, we combined the presentation of a novel taste (saccharin) with the injection of bacterial endotoxin as sickness-inducing agent. This was done either once, twice or three times, to vary the amount of learning experiences. After consolidation, animals were re-exposed to the taste alone, and the consumed amount of saccharin was quantified as a measure of the CTA. Additionally, neural activation markers (c-fos, arc) and stress hormone levels were assessed. Conditioned animals developed a pronounced CTA that was greater in individuals with more learning trials. Moreover, re-exposure to the taste stimulus induced a conditioned increase in plasma corticosterone levels.Our findings show successful induction of a negative treatment expectation as well as a conditioned stress response, which both were strongly correlated with the number of prior treatment experiences.

Laura Heiß-Lückemann

Effects of taste-immune associative learning on experimentally induced glioblastoma in rats

Mechanistic target of rapamycin (mTOR)-signaling is one key driver in glioblastoma (GBM) tumor growth by promoting the shift to an anti-inflammatory, pro-cancerogenic microenvironment. In fact, mTOR inhibitors such as rapamycin have been shown to interfere with GBM disease progression in both animal models and patients. However, therapy is frequently chaperoned by toxic drug side effects. Since latest findings document that taste-immune associative learning with rapamycin induces pharmacological placebo responses in the immune system, the present report analyzed its applicability in a syngeneic GBM rat model. Following repeated pairings of a novel gustatory stimulus and injections of therapeutically effective rapamycin (5 mg/kg), learned immunopharmacological effects were retrieved in GBM-bearing animals when re-exposed to the gustatory stimulus together with administering only 10 % amount of the initial drug dose (0.5 mg/kg). This procedure promoted the development of a pro-inflammatory, anti-tumor microenvironment thereby effectively prevented tumor growth to an almost identical outcome obtained after full dose treatment (5 mg/kg). This proof-of-concept study document that taste-immune associative learning strategies may be utilized as supportive treatment strategy, allowing the reduction of required drug doses and side effects without losing treatment efficacy.

Datablitz III:
Placebo Effects in Clinical Trials

Amke Müller

Combined N-of-1 trials to assess open-label placebo treatment for antidepressant discontinuation symptoms.

Antidepressant discontinuation is associated with negative side-effects, contributing to unnecessary long-term intake. Negative expectations towards discontinuation likely influence discontinuation symptoms (nocebo effect). Our objective is to determine the effect of open-label placebo (OLP) treatment in reducing discontinuation symptoms, examining the role of expectations.
A series of N-of-1 trials is conducted in 20 patients with remitted depressive disorder reporting moderate discontinuation symptoms following antidepressant discontinuation. During the eight-week trials, patients go through two cycles each containing two-week periods of OLP and no treatment in random order. Discontinuation symptoms and expectations thereof are rated twice daily via smartphone (StudyU application). Analysis employ a Bayesian multilevel random effects model yielding posterior estimates of the overall and individual treatment effects. 
Individual trajectories of four completed N-of-1 trials show that negative expectations at the previous assessment are related to more discontinuation symptoms at the following assessment (r=.52 to r=.71). Visual inspection of individual trajectories shows variation in the expression and course of discontinuation symptoms and expectations (range: 0-10). Preliminary analyses suggest that treatment expectations can influence the severity of discontinuation symptoms, indicating the need for interventions to target expectations.

Maria Lalouni

Placebo controlled surgery for sacroiliac joint pain, a double blind randomized controlled trial

Sacroiliac (SI) joint pain is prevalent and debilitating. Evidence for non-operative treatments is limited. Studies of minimally-invasive surgical fusion show promising results. However, many studies are industry-sponsored and lack placebo-controls.Patients aged 35-60 years, n=23 (22 females), with SI-joint pain were randomized to SI-joint fusion or sham operation in a double-blind trial at Karolinska University Hospital, Sweden. Measures included resting-state functional magnetic resonance imaging and quantitative sensory testing (QST), before surgery and at six months follow up. Last week’s average pain and treatment expectation were self-assessed on a VAS scale (0-100). QST included pressure pain thresholds and supra threshold pain (4/10 NRS) on the thigh and the SI-joint pain site. 
Last week’s average pain was reduced from baseline to follow-up for fusion compared with placebo (P=0.031). Functional connectivity between S1 (hip/back area) and default mode network was decreased in the fusion group compared with placebo. There were no differences in QST change between groups. There was a trend for higher treatment expectations in responders compared with non-responders. Because of the small sample, results need to be interpreted with causion.

Moa Ponten

Expectancy effects in online versus face-to-face psychological interventions – an individual participant data meta-analysis

Online treatments are increasing in number and currently available for a wide range of clinical problems. Little is known about the role of treatment expectations and other placebo-like mechanisms in online settings. MEDLINE and PsycINFO were last searched Feb 2, 2021. Randomized clinical trials of therapist guided online versus face-to-face psychological interventions for psychiatric or somatic conditions were included. Authors of matching trials were contacted for individual participant data. Ratings from the Credibility and Expectancy Questionnaire (CEQ) and the primary outcome measure from each trial were used to estimate the association between expectation ratings and treatment outcomes in online versus face-to-face interventions, using a mixed-effects model. Of 7045 screened studies, 62 full-text articles were retrieved whereof six studies fulfilled the criteria and provided individual participant data (n=491). Overall, CEQ ratings predicted clinical outcomes (β=0,27) at end of treatment with no moderating effect of treatment modality (online versus face-to-face). Online treatment appears to be equally susceptible to expectancy effects as face-to-face therapy. This furthers our understanding of the importance of placebo-like factors in online treatment and may aid the improvement of healthcare in online settings.

Stefan Schmidt

Treatment Effects in Pharmacological Clinical Randomized Controlled Trials are Mainly Due to Placebo

The placebo response in clinical trials has four components: regression to the mean (RTM), measurement artefacts, the natural tendency (NT) of the disease, and the genuine placebo effect. We assessed predictors of the placebo response in clinical trials. For five diagnoses where NT rates were available (osteoarthritis of the knee, irritable bowel syndrome, depression, sleep disorders, migraine) 150 placebo-controlled RCTs were searched. We extracted study descriptors and fitted two meta-regressions to predict improvement in treatment and placebo-groups. Both models were significant, explaining 73% and 72% variance. The improvement in the placebo-group can be predicted by improvement in the treatment-group (β= .84), by application of intention-to-treat analysis (β=-.10) and multicenter trial (β=.12). The improvement in the treatment-group can be explained by improvement in the placebo-group (β=.83), multicenter trial (β=-.16), and by RTM (β=-.18). The correlation of r=.73 between placebo and treatment improvement rates is genuine and not explainable by trial or disease characteristics. We conclude from out data that the placebo-response is the major driver of treatment effects in clinical trials. Context effects are more important than pharmacological effects in the conditions studied here.

Datablitz IV:
Patient Physician Interaction and Communication

Anna Seewald

How to change negative outcome expectations in psychotherapy? The role of the therapist's warmth and competence

Negative outcome expectations of psychological treatments predict unfavorable treatment outcomes. Therefore, therapists should approach negative outcome expectations and transform them into more positive outcome expectations. We investigated the therapist's interpersonal behavior in two studies to induce positive outcome expectations. In two online experiments, we presented videos of therapist-patient interactions to induce positive outcome expectations. While we kept the expectation-forming information constant, we manipulated the therapist's warmth and competence in the videos.  Results confirmed a significant influence of the therapist's warmth and competence on outcome expectations, leading to the most positive outcome expectations when the therapist was warm and competent. Furthermore, warmth and competence influenced alliance, therapy motivation, and help-seeking.In contrast to former correlational analyses, our experimental studies confirm the causal role of the therapist's interpersonal behavior and its impact on changing patients' outcome expectations. We discuss the clinical implication of these results and further research ideas.

Dasha Sandra

Presenting a Sham Treatment as Personalised Increases its Effectiveness

Tailoring interventions to patient subgroups can improve treatment outcomes for various conditions. Yet, it is unclear how much of this improvement is due to the pharmacological personalisation itself versus the related contextual factors, such as the therapeutic interaction. Here, we tested whether presenting a placebo machine as personalised would improve its effectiveness. We recruited 102 adults in two samples (N1 = 17, N2 = 85) to receive painful heat stimulations on their forearm. During half of the stimulations, a placebo machine purportedly delivered an electric current to reduce their pain. The participants were either told that the machine was personalised to their genetics, or that it was effective in reducing pain generally. Participants receiving the sham personalisation reported more relief in pain intensity than the control group in the feasibility study (standardised B = -0.50 [-1.08, 0.08]) and the pre-registered double-blind confirmatory study (B = -0.20, [-0.36, -0.04]). We found similar effects on pain unpleasantness and various personality moderators. We present the first evidence that precision treatments may benefit from the contextual factors associated with the personalisation process. Isolating these factors could help improve control in clinical trials or potentially boost treatment effects in clinical settings.

Justine Schmidt

Effects of positive treatment expectation on psychological and bodily sickness symptoms during experimental endotoxemia: A randomized controlled study in healthy volunteers

Inflammatory mediators released during inflammatory conditions induce unspecific physical and psychological sickness symptoms. It remains unclear whether sickness symptoms can be modulated by expectation. We employed human experimental endotoxemia to induce sickness symptoms in healthy volunteers in combination with a placebo-controlled anti-inflammatory drug treatment, aiming to test for treatment expectation effects on inflammation-mediated sickness symptom. In this ongoing study, all healthy volunteers received 0.8ng/kg lipopolysaccharide (LPS) to induce sickness symptoms. We herein report on N=47 volunteers who received a placebo pill, randomly combined with positive or neutral treatment-related information, before LPS-injection. Inflammatory markers and sickness symptoms were repeatedly assessed up to six hours post LPS-injection. LPS application induced transient increases in inflammatory markers and in self-reported sickness symptoms in all participants (all p<.001, time effect). Compared to neutral treatment expectation, participants in the positive condition reported significantly less bodily symptoms (p<.05) and - as a trend - decreased symptoms of negative mood in response to LPS.
Our findings indicate a beneficial effect of verbally induced positive expectation on sickness symptoms, suggesting that expectation effects may enhance treatment efficacy in the context of immune-mediated sickness symptoms.

Arvina Grahl

Treatment adherence and the patient-clinician relationship: a longitudinal fMRI hyperscan study in chronic pain patients

A warm-empathic/augmented patient-clinician relationship can substantially boost clinical outcomes. In this longitudinal study, fibromyalgia patients (N=23) were randomly assigned to an Augmented (N=11) or Limited (N=12) patient-clinician dyadic interaction style (trained acupuncturists). Each dyad underwent synchronized fMRI between two scanners, with a live video connection and evoked pressure pain/treatment before and after acupuncture therapy (3 weeks, 6 sessions). Patients rated Therapeutic Alliance, Trust, and clinicians’ Warmth higher for the Augmented vs. Limited group (p<0.001). Pain catastrophizing was significantly reduced after acupuncture therapy in the Augmented, ∆A=-7.45, but not Limited group, ∆L=0.59 (time-group-interaction p=0.004). For both groups, acupuncture decreased clinical pain (no pain relief group difference: ∆A=-1.04, ∆L=-1.33) and reduced patients’ fMRI response to evoked pressure pain in nociceptive processing areas. However, the Augmented group reported a higher likelihood of continuing acupuncture with their assigned clinician after the study, i.e., were willing to seek further care for their chronic pain. Our study supports the potential importance of the patient-clinician relationship to treatment adherence and suggests brain mechanisms supporting the influence of this relationship on clinically relevant outcomes.

Datablitz V:
Social Aspects of Placebo Effects

Antonia Borcherding

Treatment of chronic low back pain: can social observation improve effects of pain medication or placebos?

Experimental and clinical studies suggest that positive expectations regarding pain treatment have a relevant pain-reducing effect in pain patients. The aim of our study is to investigate the optimization of treatment expectation in chronic low backpain (CLBP) patients by observing others. In our clinical trial (2x2 factorial design) we randomize CLBP patients to either a 3-week treatment with an analgesic, Metamizole (ANA), or to a 3-week treatment with open-label placebos (OLP). Treatment expectations are built through social observation, and their impact on these two treatments will be analysed. Accordingly, patients watch a positive or a neutral video. We assess patient’s treatment expectations before and after their 3-week treatment. We test effects of these expectations on subjective and objective outcome. An initial analysis with two-sided t-testing of 46 patients shows a significant decline in pain ratings in both OLP-groups and in the ANA-group without social observation. The ANA-group with social learning shows no significant pain reduction. The initial results may suggest that social observation has a better effect in the OLP-group than in the ANA-group. However, this result should be interpreted with caution.

Charlotte Krahe (virtual)

Updating beliefs about pain following advice: Trustworthiness of social advice predicts pain expectations and experience

Prior expectations about pain influence pain experience. Although social context is critical in shaping pain, previous research has mainly focused on the pain-modulatory role of own rather than social expectations. We studied effects of explicitly communicated social expectations (‘advice’) on pain. N = 72 female participants undertook a cold water task before and after receiving advice about their likely pain tolerance from a confederate. We examined how participants changed (1) their own pain expectations and pain tolerance based on the advice, and (2) their future pain expectations (prospective posterior beliefs) based on the combined effect of the advice on their expectations, and their experience. Further, we manipulated perceived trustworthiness of the confederate (high; low) to investigate how varying the uncertainty of advice would impact the above measures. Participants adjusted their pain expectations towards the social advice more in the high vs. low trustworthiness condition, and greater advice taking predicted greater pain tolerance. In the high trustworthiness condition, advice increased the precision of prior beliefs relative to precision of new sensory evidence, and less learning was achieved by new sensory evidence. Conversely, advice from a less trustworthy source rendered prior beliefs more uncertain, and more learning was achieved from sensory evidence.

Ilenia Ceccarelli

Sharing pain: nocebo and placebo effects in a group context

Social context plays a crucial role in both placebo and nocebo responses. In a social shared aversive condition, this study investigated the contribution of individual (i.e. pain expectations, social and pain-related personality factors) and group features (i.e. pain tolerance, level of group identification, the quality and strength of the relationship between members, level of trust) in shaping pain perception.
Sixty-one university students (33 women) of the same class were randomly subdivided in 10 groups and underwent an experimental pain induction (i.e. cold pressure test). Pain tolerance, pain threshold, pain intensity and autonomic reactivity to nociceptive stimulation were assessed. The average pain intensity was significantly higher when participants were members of a group where at least one person stopped the procedure before its end. Regression analysis indicated that individual pain expectations and the strength of the relationship with group members are significant predictors of pain intensity. Individual’s fear of pain and group relationship predicted mean heart rate and sympathovagal balance during procedure.
Sharing with meaningful others an experience of pain seems to be able to influence individual pain perception and the general adaptation to the aversive condition.

Stefanie Meeuwis

Placebo stories: people’s experiences with placebo effects in daily life

Experimental studies show that placebo effects can improve somatic symptoms including pain. In these studies, suggestions or learning procedures are often applied that explicitly trigger effects. Little is known about situations outside of the laboratory, for instance, whether people notice and utilize placebo effects in daily life. This semistructured survey study aimed to evaluate people’s experiences with placebo effects in daily life. Qualitative and quantitative questions mapped multiple aspects of placebo effects, including their frequency, their affected symptoms/conditions and purported cause.

192 respondents completed the survey, of whom 110 (57.3%) indicated they experienced a placebo effect before and 19 (10.2%) observed it in others. Effects were reported most often in somatic symptoms (76.2%; eg, immediate pain relief after taking a painkiller) or wellbeing (68.5%; eg, feeling less stressed). Possible explanations that people provided for the placebo effects included information from others (eg, parents advising home-remedies), hope for pain relief, a positive mindset and trust in the healthcare professional.

Over half of the respondents indicated that they experienced/observed placebo effects in daily life. This provides opportunities for translating experimental effects into ecologically valid methods to maintain placebo effects, for instance in clinical practice.

Datablitz VI:
Open-label Placebo: A Critical Evaluation

Kirsten Barnes

The Role of Positive Information Provision and Baseline Symptomology on Open-Label Placebo Effects

The efficacy of open-label placebos (OLPs) appears robust among clinical samples. However, evidence regarding OLPs in non-clinical samples, as well as without a convincing rationale, appears equivocal. Methods: Healthy participants (N=102) completed a 6-day course of OLP pills with information provision (OLP-plus: N=35), without information (OLP-only: N=35), or were assigned no-treatment (N=32). OLP pills were described as enhancing physical (symptoms and sleep) and psychological (positive and negative emotional) wellbeing. Wellbeing was assessed at baseline and day 6. Expectancies and adherence were measured. OLP administration interacted with baseline wellbeing. The OLP-plus group demonstrated increased wellbeing on all outcomes except positive emotions, but only when they reported decreased baseline wellbeing. OLP-only and control groups did not differ. The OLP-plus group demonstrated elevated expectancies, that mediated the OLP effect on physical symptoms relative to control, but when wellbeing was lower than average at baseline (i.e., moderated-mediation). Conclusions: Results demonstrate the importance of information provided with OLPs. The moderating effect of baseline outcomes may reconcile inconsistent results concerning clinical and non-clinical samples.

Marco Valerio

Rituals and open-label placebo effects

Rituals, defined as sequences of repeated actions with symbolic value for the performer, are ubiquitous in every aspect of human life. Even health treatments, whether traditional, alternative, or evidence-based, present important ritualistic features (e.g., taking a pill at the same time and with the same actions) that may enhance the placebo effect associated with these treatments. Two studies, involving 294 participants and delivered remotely, investigated whether performing a ritual could increase open-label placebo (OLP) effects in wellbeing. Three groups were compared: OLPs taken with a ritual; OLPs taken without any ritual; and no treatment control. Mental wellbeing, emotional distress, vigour-fatigue, and sleep quality were assessed at baseline and after six days of OLP treatment. In both studies, participants consuming OLPs reported greater well-being compared to the control group. Moreover, participants taking OLPs with a ritual reported greater sleep quality compared with participants taking OLPs without ritual. Only in the second study, performing the ritual also led to a reduction in emotional distress. Therefore, adding rituals to OLPs consumption may enhance placebo effects in sleep and emotional distress. These results provide useful insights to improve the placebo effect component of both placebo and active medical treatments.

Octavia Zahrt

Effects of Wearable Fitness Trackers and Activity Adequacy Mindsets on Affect, Behavior and Health: A Longitudinal Randomized Controlled Trial

Initial evidence suggests that mindsets about the adequacy and health consequences of one’s physical activity (activity adequacy mindsets, AAMs) can shape health through placebo effects. This research examined how fitness trackers and meta-mindset interventions influence AAMs, affect, behavior and health.  162 participants received fitness trackers for 5 weeks. After a baseline week without step count feedback, participants were randomly assigned to receive either accurate step count, 40% deflated step count, 40% inflated step count, or accurate step count + a meta-mindset intervention encouraging more positive AAMs. Participants receiving accurate steps adopted more positive AAMs and healthier diets, experienced improved mental health and aerobic capacity, but also reduced functional health. Participants receiving deflated steps adopted more negative AAMs and unhealthier diets, experienced more negative affect and mental health, increased blood pressure and heart rate (compared to participants receiving accurate steps). Inflated steps had no systematic effects. Participants receiving the meta-mindset intervention experienced improved AAM, affect, functional health, and self-reported physical activity (compared to participants receiving accurate steps only). Actual step count remained unchanged across conditions.AAMs - induced by trackers or adopted deliberately - can influence affect, behavior, and health, independent of actual physical activity.

Biya Tang

Choice Over Placebo Administration Enhances Open-label Placebo Analgesia

Research suggests that placebos have been frequently used without patients' knowledge in clinical practice, which raises ethical concerns as deception violates patient autonomy. A growing body of research revealed that open-label placebos (OLPs) are also effective in the treatment of several medical conditions, including chronic back pain, showing that OLPs can be an ethical alternative to deceptive placebos. Yet, important questions remains regarding how we can capitalize on OLPs to improve patient outcomes. Choice is shown to have the capacity of enhancing the placebo effect when placebos are delivered deceptively, but the potential benefit of choice on OLPs is unknown. This study thus investigated whether and to what extent choice over placebo administration facilitated OLP analgesia using a electro-cutaneous pain paradigm. Healthy participants were randomly assigned to either receive a placebo treatment and have choice over placebo administration, receive a placebo treatment without choice, or a Natural History control group. The most important finding was that participants who chose when to initiate the placebo treatment exhibited significantly greater OLP analgesia than those without choice. Our findings suggest when OLPs are involved in treatment plans, choice has the potential to improve clinical pain outcomes by enhancing OLP analgesia.

Matthijs de Leeuw

Open-Label Placebo Treatment for Acute Postoperative Pain: Preliminary Results of a Randomized Controlled Trial

Opioids are the primary pharmacotherapy for postoperative analgesia. Therefore, minimization of opioid-related side effects remains a key challenge. Open-label placebos (OLP) have been studied and found to be efficacious in various conditions. However, evidence on OLP effects in acute pain is limited. This talk presents the design and results of an ongoing RCT (NCT04339023), investigating the effect of OLPs on acute postoperative pain and corresponding opioid consumption. Two OLP-injections are added for two days to treatment-as-usual (TAU; i.e., morphine patient-controlled analgesia pump) and compared to TAU alone in patients suffering from postoperative pain following dorsal lumbar interbody fusion. Primary outcome is assessed by the amount of self-administered morphine during the first two postoperative days. Until May 2023, 70 participants are expected to be enrolled. Preliminary findings will be reported. 
Conclusion: In the light of the current challenges in postoperative pain management and the promising results of experimental OLP studies in acute pain, an OLP intervention could provide a means of harnessing analgesic placebo effects. Thereby, adding OLP to TAU could lead to a reduction in postoperative opioid consumption and related side-effects, without any loss in pain management efficacy.

Datablitz VII:
Placebos beyond the horizon

Roni Shafir

Virtual reality for pain reduction – simply a distraction?

Virtual Reality (VR) appears to be a promising analgesic tool. This talk will summaries recent findings from our lab, showing the analgesic effects of VR in both healthy participants and patients suffering from orofacial pain (temporomandibular disorder, TMD). Specifically, among healthy participants, we found that VR resulted in better pain tolerance, as well as reduced pain unpleasantness and state anxiety. These findings were replicated with a cohort of TMD patients, where VR improved experientially-induced pain tolerance, as well as pain unpleasantness, mood, and anxiety ratings. Furthermore, when testing the effectiveness of VR in a clinical trial conducted remotely at home, we found improvement in TMD pain outcomes. These findings support the notion that VR is an effective intervention for both acute and chronic pain. Yet, its underlying psychological mechanisms are not well understood. One important question that remains relatively unexplored is whether VR differs from cognitive attentional distraction. To test that, VR must be compared to a positively valanced attentional distraction. I will present new data comparing between the analgesic effects of a VR ocean environment and attentional distraction that involves imagining the same VR ocean contents, with the goal of better understanding whether VR transcends attentional distraction.

Jana Kraft

Relationship between hope, confidence, and anxiety and the success of infertility treatment with IVF-Naturelle® - a prospective cohort study

In addition to biological factors, psychological factors such as stress also play a role for the success of infertility treatments. This ongoing study investigates the influence of treatment expectancy and emotional states of women undergoing in vitro fertilization treatment in natural cycle (IVF-Naturelle®) on pregnancy outcome. A prospective cohort study of 100 women (37,0 ± 3,3 years) who undergo IVF-Naturelle® treatment is conducted. Depression, anxiety, stress (DASS), state anxiety (STAI), current state of mood (ASTS), fertility-related quality of life (FertiQoL) and treatment expectations (TEX-Q) are examined at baseline. Emotional states are recorded daily up to 17 days until biochemical pregnancy is evaluated. Biochemical pregnancy was so far documented in 13 of 51 women. Preliminary analyses revealed significantly lower anxiety levels, higher infertility-treatment related QoL, and increased hope, confidence and satisfaction in women who later got pregnant compared to non-responding women. Logistic regressions revealed confidence and anxiety as independent predictors for biochemical pregnancy. Our study yields preliminary evidence that a positive attitude may favor the success of infertility treatment with IVF-Naturelle®. However, this is an ongoing study and complete results will be presented at the conference.

Sigrid Juhl Lunde

Implementing control interventions in studies on music-induced analgesia: Which methodological standards should apply?

There is a growing interest in the pain-relieving effect of music listening, i.e. music-induced analgesia. Yet, this line of research is accompanied by methodological challenges that may cause us to overestimate the specific effect of music. For instance, due to lack of blinding or rigorous control interventions, the impact of treatment expectations may be skewed or is unaccounted for. 
Based on the newly developed CoPPS statement, this presentation will discuss the implementation of control interventions within the framework of music-induced analgesia. This is exemplified by recent experimental work that tested the pain-relieving effect of music against matched, auditory controls to test the contribution of non-specific, contextual factors (e.g., expectations for pain relief) and employed pharmacological manipulations to investigate the involvement of neurotransmitters (i.e., endogenous opioids and dopamine). Importantly, results from the study showed that music-induced analgesia—as well as pain levels in auditory controls—was primarily mediated by the participants’ expectations for pain relief rather than opioid and dopamine-dependent mechanisms. These findings underline the importance of determining how expectations influence trial outcomes and encourage the application of new guidelines and methodological standards for control conditions when examining music-induced analgesia.

Jens Gaab

Deceptive and open-label placebo effects in experimentally induced guilt: a randomized controlled trial in healthy subjects

Placebos are known to yield significant effects in many conditions. We examined deceptive and open-label placebo effects on guilt, which is important for self-regulation and a symptom of mental disorders. Following an experimental induction of guilt, healthy subjects were randomized to deceptive placebo (DP; n = 35), open-label placebo (OLP; n = 35), or no treatment (NT; n = 39). The primary outcome was guilt responses assessed in area under the curve (AUC). Secondary outcomes were shame, guilt, and affect. We hypothesized that DP and OLP would reduce guilt compared to NT. Guilt responses were higher in the NT group than in the placebo groups (estimate = 2.03, 95% CI = 0.24–3.82, d = 0.53), whereas AUC guilt did not differ significantly between the placebo groups (estimate = −0.38, 95% CI = −2.52–1.76, d = −0.09). Placebos are efficacious in reducing acute guilt responses, regardless of the placebo administration (i.e., open vs. deceptive). Furthermore, we observed narrative-specific effects with significant changes of guilt but not shame, pride, or affect. These results indicate not only that guilt is amenable to placebos but also that placebos can be administered in an ethical and potentially emotion-specific manner.

Recent updates as of 05/04/2023