The impact of an illness perception conversation on open-label placebo response in knee osteoarthritis: A randomised controlled trial.

OBJECTIVE: To compare the effect of an illness perception conversation (IPC), relative to a research participation conversation (RPC), on 2-week changes in knee pain in patients with knee osteoarthritis. METHOD: This was a randomised single-blind trial. Patients were randomised to two matched conversations. An IP conversation concerning the participant's knee pain-related illness perception (IP) or an RPC concerning the participant's motivation for participating in research. Both conversations were followed by an open-label intraarticular saline injection in the most symptomatic knee. The primary outcome was change in knee pain from baseline to 2 weeks follow-up on a 100 mm visual analogue scale (VAS). Key secondary outcomes included the Knee injury and Osteoarthritis Outcome Score (KOOS) subscales: Activities of daily living (ADL) and Quality of life (QoL). Main analyses were based on the intention-to-treat population using repeated measures mixed effects linear models. RESULTS: 103 patients were randomised to the IPC group (n = 52) and the RPC group (n = 51). VAS knee pain scores changed statistically significantly from baseline to end of treatment in both groups, -13.7 (standard error [SE]: 3.2) in the IPC group and -13.0 (SE: 3.1) in the RPC group with an adjusted between-group difference of -0.7 (95% CI: -8.3 to 6.9; P = 0.85). Likewise, no group differences were seen in KOOS ADL and KOOS QoL. CONCLUSION: A conversation concerning knee pain-related IP did not augment the pain-relieving effect of an open-label placebo injection when compared to a similar control conversation concerning motivations for participating in research. TRIAL REGISTRATION: NCT05225480.

Effects of (non)deceptive placebos on reported sleep quality and food cue reactivity.

A lack of sleep can increase appetite, particularly for high-calorie food. The current study tested the effects of an open-label placebo for improving sleep quality and reducing food cue reactivity. In open-label placebo interventions, placebo recipients are informed that they are receiving a placebo without a pharmacologically active substance. Participants (n = 150) were randomly allocated to one of three groups that received either an open-label placebo to improve sleep quality, a deceptive placebo ("melatonin"), or no placebo. The placebo was administered daily before bedtime for 1 week. Sleep quality and reactivity to high-calorie food cues (appetite, visual attention to food images) were assessed. The deceptive placebo (but not the open-label placebo) reduced reported sleep-onset latency. The open-label placebo decreased perceived sleep efficiency. The placebo interventions did not change food cue reactivity. This study demonstrated that open-label placebos do not present an alternative to deceptive placebos for improving sleep quality. The undesirable open-label placebo effects found warrant further exploration.

A Fictionalist Account of Open-Label Placebo.

The placebo effect is now generally defined widely as an individual's response to the psychosocial context of a clinical treatment, as distinct from the treatment's characteristic physiological effects. Some researchers, however, argue that such a wide definition leads to confusion and misleading implications. In response, they propose a narrow definition restricted to the therapeutic effects of deliberate placebo treatments. Within the framework of modern medicine, such a scope currently leaves one viable placebo treatment paradigm: the non-deceptive and non-concealed administration of "placebo pills" or open-label placebo (OLP) treatment. In this paper, I consider how the placebo effect occurs in OLP. I argue that a traditional, belief-based account of OLP is paradoxical. Instead, I propose an account based on the non-doxastic attitude of pretence, understood within a fictionalist framework.

Exercise and education vs intra-articular saline for knee osteoarthritis: a 1-year follow-up of a randomized trial.

OBJECTIVE: To assess the longer-term effect of the Good Life with osteoarthritis in Denmark (GLAD) exercise and education program relative to open-label placebo (OLP) on changes from baseline in core outcomes in individuals with knee osteoarthritis (OA). METHODS: In this 1-year follow-up of an open-label, randomized trial, patients with symptomatic and radiographically confirmed knee OA were monitored after being randomized to either the 8-week GLAD program or OLP given as 4 intra-articular saline injections over 8 weeks. The primary outcome was the change from baseline in the Knee injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale after 1 year in the intention-to-treat population. Key secondary outcomes were the KOOS function and quality of life subscales, and Patients' Global Assessment of disease impact. RESULTS: 206 adults were randomly assigned: 102 to GLAD and 104 to OLP, of which only 137 (63/74 GLAD/OLP) provided data at 1 year. At one year the mean changes in KOOS pain were 8.4 for GLAD and 7.0 for OLP (Difference: 1.5 points; 95% CI -2.6 to 5.5). There were no between-group differences in any of the secondary outcomes. CONCLUSIONS: In this 1-year follow-up of individuals with knee OA, the 8-week GLAD program and OLP both provided minor longer-term benefits with no group difference. These results require confirmation given the significant loss to follow-up. TRIAL REGISTRATION NUMBER: NCT03843931.

Who are likely to benefit from the Good Life with osteoArthritis in Denmark (GLAD) exercise and education program? An effect modifier analysis of a randomised controlled trial.

OBJECTIVE: To identify contextual factors that modify the treatment effect of the 'Good Life with osteoArthritis in Denmark' (GLAD) exercise and education programme compared to open-label placebo (OLP) on knee pain in individuals with knee osteoarthritis (OA). METHODS: Secondary effect modifier analysis of a randomised controlled trial. 206 participants with symptomatic and radiographic knee OA were randomised to either the 8-week GLAD programme (n = 102) or OLP given as 4 intra-articular saline injections over 8 weeks (n = 104). The primary outcome was change from baseline to week 9 in the Knee injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale (range 0 (worst) to 100 (best)). Subgroups were created based on baseline information: BMI, swollen study knee, bilateral radiographic knee OA, sports participation as a young adult, sex, median age, a priori treatment preference, regular use of analgesics (NSAIDs or paracetamol), radiographic disease severity, and presence of constant or intermittent pain. RESULTS: Participants who reported use of analgesics at baseline seem to benefit from the GLAD programme over OLP (subgroup contrast: 10.3 KOOS pain points (95% CI 3.0 to 17.6)). Participants with constant pain at baseline also seem to benefit from GLAD over OLP (subgroup contrast: 10.0 points (95% CI 2.8 to 17.2)). CONCLUSIONS: These results imply that patients who take analgesics or report constant knee pain, GLAD seems to yield clinically relevant benefits on knee pain when compared to OLP. The results support a stratified recommendation of GLAD as management of knee OA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03843931. EudraCT number 2019-000809-71.

Experiences of Patients Taking Conditioned Open-Label Placebos for Reduction of Postoperative Pain and Opioid Exposure After Spine Surgery.

BACKGROUND: Pain after spine surgery is difficult to manage, often requiring the use of opioid analgesics. While traditional "deceptive" or concealed placebo has been studied in trials and laboratory experiments, the acceptability and patient experience of taking honestly prescribed placebos, such as "open-label" placebo (non-deceptive placebo), or conditioned placebo (pairing placebo with another active pharmaceutical) is relatively unexamined. METHODS: Qualitative thematic analysis was performed using semi-structured, post-treatment interviews with spine surgery patients (n = 18) who had received conditioned open-label placebo (COLP) during the first 2-3 weeks after surgery as part of a RCT. Interview transcripts were reviewed by 3 investigators using an immersion/crystallization approach, followed by iterative large-group discussions with additional investigators, to identify, refine, and codify emergent themes. RESULTS: Patients' experiences and perceptions of COLP efficacy varied widely. Some emergent themes included the power of the mind over pain, how COLP might provide distraction from or agency over pain, bandwidth required and engagement with COLP, and its modulation of opioid tapering, as well as negative attitudes toward opioids and pill taking in general. Other themes included uncertainty about COLP efficacy, observations of how personality may relate to COLP efficacy, and a recognition of the greater impact of COLP on reduction of opioid use rather than on pain itself. Interestingly, participant uncertainty, disbelief, and skepticism were not necessarily associated with greater opioid consumption or worse pain. CONCLUSION: Participants provided insights into the experience of COLP which may help to guide its future utilization to manage acute pain and tapering from opioids.

Beliefs About Medicines Predict Side-Effects of Placebo Modafinil.

BACKGROUND: Patients receiving placebo in clinical trials often report side-effects (nocebo effects), but contributing factors are still poorly understood. PURPOSE: Using a sham trial of the cognition-enhancing "smart pill" Modafinil we tested whether medication beliefs and other psychological factors predicted detection and attribution of symptoms as side-effects to placebo. METHODS: Healthy students (n = 201) completed measures assessing beliefs about medication, perceived sensitivity to medicines, negative affectivity, somatization, and body awareness; 66 were then randomized to receive Deceptive Placebo (told Modafinil-given placebo, 67 to Open Placebo (told placebo-given placebo, and 68 to No Placebo. Memory and attention tasks assessed cognitive enhancement. Nocebo effects were assessed by symptom checklist. RESULTS: More symptoms were reported in the Deceptive Placebo condition (M = 2.65; SD = 2.27) than Open Placebo (M = 1.92; SD = 2.24; Mann-Whitney U = 1,654, z = 2.30, p = .022) or No Placebo (M = 1.68; SD = 1.75, Mann-Whitney U = 1,640, z = 2.74, p = .006). Participants were more likely to attribute symptoms to Modafinil side-effects if they believed pharmaceuticals to be generally harmful (incidence rate ratio [IRR] = 1.70, p = .019), had higher perceived sensitivity to medicines (IRR = 1.68, p = .011), stronger concerns about Modafinil (IRR = 2.10, p < .001), and higher negative affectivity (IRR = 2.37, p < .001). CONCLUSIONS: Beliefs about medication are potentially modifiable predictors of the nocebo effect. These findings provide insight into side-effect reports to placebo and, potentially, active treatment.

No increased suggestibility to placebo in functional neurological disorder.

BACKGROUND AND PURPOSE: On the basis of occasional strong placebo responses, increased susceptibility to placebo has been proposed as a characteristic of functional neurological disorder (FND). The aim of this study was to clarify whether people with FND have a stronger placebo analgesic response than healthy controls. METHODS: A study using a classic placebo paradigm, with additional conditioning and open-label components, was performed in 30 patients with FND, and in 30 healthy controls. Ratings of mildly to moderately painful electrotactile stimuli were compared before and after the application of a placebo "anaesthetic" cream versus a control cream, after an additional conditioning exposure, and after full disclosure (open-label component). RESULTS: Pain intensity ratings at the placebo compared to the control site were similarly reduced in both groups. The conditioning exposure had no additional effect. After placebo disclosure a residual analgesic effect remained. CONCLUSION: Patients with FND did not have stronger placebo responses than healthy controls. The notion of generally increased suggestibility or increased suggestibility to placebo in FND seems mistaken. Instead, occasional dramatic placebo responses may occur because functional symptoms are inherently more changeable than those due to organic disease.

Nocebo effects by providing informed consent in shared decision making? Not necessarily: a randomized pilot-trial using an open-label placebo approach.

BACKGROUND: Thorough information of the patient is an integral part of the process of shared decision making. We aimed to investigate if detailed information about medication may induce nocebo (or placebo) effects. METHODS: We conducted a randomized, single-blind, pilot-study including n = 51 psychiatric in-patients aged between 18 and 80 years with a depressive disorder and accompanying sleeping disorders. In the intervention group we provided thorough information about adverse effects, while the control group received only a simple consent procedure. In both groups, patients received an open-label placebo pill instead of their sleeping medication. RESULTS: No statistically significant differences between the intervention group and the control group were found regarding the main outcome parameter (a visual analogue scale indicating impairment by the new pill). CONCLUSION: In this study, we were not able detect an effect of informed consent vs. simple consent on the emergence of placebo or nocebo effects. This finding is contrary to most assumptions and publications about this topic. TRIAL REGISTRATION: Trial registration number: DRKS00017653, registered August 30th 2018. Retrosprectively registered.

[Placebos and placeboids in clinical practice: conceptual and ethical considerations]. / Placebos und Placeboide in der therapeutischen Praxis ­ begriffliche und ethische Überlegungen.

Reflecting on results of recent placebo research, this article analyzes relevant key concepts and ethical positions. "Placeboids" and possibly open-label placebo treatments should replace any deceptive use of sham medication. Their use should give rise to a critical consideration of the modern patient-physician relationship.

[Placebo effects in pain therapy]. / Placeboeffekte in der Schmerztherapie.

In the past few decades, research on pain and placebo analgesia has gained importance both scientifically and clinically. In this article, the current findings and focus of research as well as the significance of placebo research for assessing the effectiveness of pain medication are illustrated. The underlying mechanisms of placebo analgesia not only have implications for theoretical models but also offer clinically relevant guidelines for everyday interventions in pain treatment. However, many placebo phenomena are not fully understood and have to be investigated further in order to exploit the full potential of placebo effects. Interindividual differences and their inclusion in treatment will play a major role in this aspect.

Open-label placebo reduces fatigue in cancer survivors: a randomized trial.

PURPOSE: Cancer-related fatigue (CRF) is a common and challenging late effect for many cancer survivors. Clinical trials demonstrate robust placebo effects on CRF in blinded trials. Recently, open-label placebo (OLP) has been shown to improve a variety of symptoms in other populations. We conducted a randomized controlled trial to investigate the effect of OLP on CRF in cancer survivors, and to explore biologic and psychological correlates of placebo efficacy. METHODS: Forty cancer survivors (92.5% female; mean age 47.3 years) were randomized to OLP or no treatment control. OLP participants were prescribed two placebo tablets twice daily, for 3 weeks. All participants completed assessments at Baseline, Day 8, and Day 22. The primary endpoint was change in CRF (FACIT-F), and secondary outcomes included exercise frequency, mood, and quality of life. We examined whether personality characteristics or a genetic variation important in dopamine catabolism (catechol-O-methyltransferase; COMT) affected the placebo response. RESULTS: The OLP group reported significantly improved CRF at both Day 8 (p = 0.005) and Day 22 (p = .02), while the control group did not (ps > .05). CRF improvement differed by COMT genotype, but was not associated with personality characteristics. Marginal improvements were noted in the placebo group for some secondary outcomes (exercise frequency and quality of life), but not in the control group. CONCLUSIONS: Results demonstrate that even when administered openly, placebos improve CRF in cancer survivors and dopaminergic systems may be associated with this response. This novel research has meaningful implications for the use of OLP in symptom management for cancer survivors.

No acute effects of placebo or open-label placebo treatments on strength, voluntary activation, and neuromuscular fatigue.

PURPOSE: Recent evidence suggests that deception may not be necessary for placebos to improve clinical outcomes. We tested the hypothesis that placebo and open-label placebo (OLP) treatments would acutely improve strength and voluntary activation, as well as minimize neuromuscular fatigue, in untrained participants. METHODS: Twenty-one males (n = 11) and females (n = 10) visited the laboratory on three occasions (placebo, OLP, control) to receive each treatment in a randomized, counter-balanced manner. Trials involved a pretest, a 15-min intervention, and posttests. For the placebo trial, participants were informed that they would be ingesting a capsule that would improve their performance and make them feel more energetic. For the OLP intervention, participants were told that the capsules would have no effects. In "Experiment #1", knee extensor maximal voluntary contraction (MVC) peak torque and percent voluntary activation were evaluated. In "Experiment #2", participants performed 20 consecutive MVCs while surface electromyographic signals were detected from the vastus lateralis. Subjective assessments of energy and perceived exertion were examined. RESULTS: The interventions had no effect on strength or voluntary activation, but energy levels increased following treatments (p = 0.016, η2 = 0.257). Neither treatment influenced neuromuscular fatigue. Though some variables showed moderate-to-large effect sizes, these results were consistent for individuals with lower voluntary activation. CONCLUSION: Placebo and OLP treatments had minimal influence on strength, voluntary activation, and fatigue resistance. As these findings differ from recent reports, we speculate that placebos and OLPs are more likely to enhance muscle function in patient populations seeking medical care.

Open-label placebos enhance test performance and reduce anxiety in learner drivers: a randomized controlled trial.

Passing the driving school test can be very challenging, especially in big cities, where up to 52% of all students fail this test. Consequently, many learner drivers experience stress and anxiety. For some learner drivers these feelings can be extreme and negatively affect the performance in the driving test. Different strategies to face anxiety and stress are known, including, for example, psychological or pharmacological approaches and even placebo pills. Recent intriguing findings have also demonstrated that placebos without deception, so-called open-label placebos, successfully reduce anxiety. Here we aimed to test effects of this novel treatment for learner drivers. We investigated whether open-label placebos affect test performance and feelings of anxiety in learner drivers. Sixty-eight healthy participants (mean age 21.94 years, 26 females) were randomized into two groups. The open-label placebo group received placebo pills two weeks before the driving test (two pills each day). The control group received no treatment. Results revealed that the open-label placebo group experienced significantly less anxiety than the control group before the test (measured with the State-Trait-Anxiety-Inventory, STAI-S, and the German Test Anxiety Inventory, PAF). Moreover, in the open-label placebo group less learner drivers failed the driving test (29.41% vs. 52.95%). The results suggest that open-label placebos may provide an ethical unproblematic way to experience less anxiety and might also enhance the probability to pass the driving test. We discuss possible mechanisms of open-label placebos and limitations of our findings.

Open-label placebos reduce weight in obesity: a randomized controlled trial.

Obesity is a major public health problem worldwide. Different approaches are known to face this problem, for example, dieting, surgery, or drug interventions. It has also been shown that placebos may help to reduce weight and hunger feelings, but the use of placebos is linked to problems with respect to the patient-healthcare-provider relationship. However, recent studies demonstrated that even placebos without deception (open-label placebos) affect symptoms such as pain, anxiety, or emotional distress. Here we aimed to examine whether an open-label placebo may help to lose weight in obesity. Our study included fifty-seven overweight and obese patients who aimed to lose weight using a combination of diet and sports. Patients were randomly divided into two groups. Participants in the open-label placebo group received two placebos each day. A treatment-as-usual group received no pills. Primary outcome included changes of body weight. Secondary outcomes were change of eating behavior and self-management abilities. After 4 weeks we found that participants in the open-label placebo condition lost more weight than the treatment-as-usual group. Furthermore, OLP treatment affected eating behavior. No effects for self-management abilities were found. Although further research is necessary, open-label placebos might help individuals to lose weight.

The pill you don't have to take that is still effective: neural correlates of imaginary placebo intake for regulating disgust.

A commonly established protocol for the administration of open-label placebos (OLPs)-placebos honestly prescribed-emphasizes the necessity of ingesting the pill for the placebo effect to manifest. The current functional magnetic resonance imaging study used a novel approach to OLP administration: the imaginary intake of an OLP pill for regulating disgust. A total of 99 females were randomly allocated to one of three groups that either swallowed a placebo pill (OLP Pill), imagined the intake of a placebo pill (Imaginary Pill) or passively viewed (PV) repulsive and neutral images. The imaginary pill reduced reported disgust more effectively than the OLP pill and was also perceived as a more plausible method to reduce emotional distress. Relative to the OLP pill, the imaginary pill lowered neural activity in a region of interest involved in disgust processing: the pallidum. No significant differences in brain activation were found when comparing the OLP pill with PV. These findings highlight that imagining the intake of an OLP emerged as a superior method for regulating feelings of disgust compared to the actual ingestion of a placebo pill. The study's innovative approach sheds new light on the potential of placebo interventions in emotion regulation.

Reducing Emotional Distress with Open-Label Placebos: Assessing the Role of Motor Engagement in Pill Consumption.

It has been posited that ingesting a pill constitutes a pivotal action that facilitates the effects of open-label placebos (OLPs: placebos honestly prescribed). In the present OLP experiment, the motor components of a placebo treatment were systematically varied. The participants (n = 183) were randomly allocated to one of four groups that all viewed aversive pictures. The 'active OLP' group took a placebo pill with specific instructions concerning the sequence of motor actions for the intake. The 'usual OLP' group swallowed the pill (without specific motor instructions), while the third group received an 'imaginary OLP' (no pill intake). The fourth group applied cognitive reappraisal (CR; active control group) to reduce emotional distress. The participants rated their affective state as well as the efficacy and plausibility of the treatment approach. Moreover, blood pressure and pulse were recorded as indicators of bodily arousal. The four groups did not differ in their valence ratings and physiological measures. The 'imaginary OLP' received higher ratings for both effectiveness and plausibility than the 'usual OLP'. CR was rated as superior relative to all OLP conditions. In conclusion, reducing emotional distress with OLPs does not necessitate the consumption of a placebo pill. In terms of acceptability and ease of implementation, CR stands as a well-established alternative.

The effect of open-label placebo on allergic rhinitis symptoms: A systematic review and meta-analysis of randomized controlled trials.

KEY POINTS: The evidence regarding the open-label placebo effect on allergic rhinitis symptoms remains uncertain. Open-label placebo significantly reduced the frequency of symptoms in allergic rhinitis patients with similar safety profiles; however, there was no effect on the severity of symptoms and impairment due to symptoms. The statistically significant impact on symptom frequency can be considered not clinically significant.

Boosting open-label placebo effects in acute induced pain in healthy adults (BOLPAP-study): study protocol of a randomized controlled trial.

Introduction: Pain is a highly prevalent symptom in the hospital setting, but treatment options remain limited. Harnessing the placebo effect in an ethical manner could provide a new possibility to reduce pain in clinical practice. So called open-label placebos (OLP) have been shown to elicit significant effects in reducing acute pain. But, before implementation, more knowledge concerning the properties of OLPs is needed. This study aims to assess the duration of analgesic effects from OLP and to determine the possibility of boosting such effects. Methods and analysis: This is the protocol of an ongoing (first patient enrolled in March 2023) single-site randomized trial investigating OLPs in two parts (i.e., substudies). In both parts, pain will be induced in healthy adults using an intradermal electrical stimulation model. Participants in Part 1 will have two study visits: An interventional visit with one OLP injection accompanied by an evidence-based treatment rationale and a control visit with no treatment. For Part 2, participants will be randomized into three groups: (1) A fixed-time "Booster" group including one single repetition of the OLP injection at a fixed time point, (2) an on-demand "Booster" group including one single repetition of the OLP injection on-demand, and (3) a control group who will receive just one OLP injection. Differences in pain ratings over time (using the Numeric Rating Scale) will be analyzed with several two-sample t-tests. The time point for a fixed-time "Booster" in Part 2 will be derived from Part 1 with additional statistical tools such as a broken-stick mixed-effect model. Discussion: This study aims to further characterize the analgesic effects of OLPs. In doing so, it will provide valuable information needed for later implementation of OLPs in clinical practice, where they could play a role in multimodal analgesic concepts. Ethics and dissemination: The "Ethikkommission Nordwest- und Zentralschweiz" (BASEC 2023-00296) approved the study protocol. Results of the analysis will be submitted for publication in a peer-reviewed journal. Clinical Trial Registration: This study is registered at ClinicalTrials.gov (NCT05819476) and is listed in the Swiss National Registry at kofam.ch (SNCTP000005470).

Open-label placebo treatment for reducing overeating in children: A study protocol for a randomized clinical trial with an app-assisted approach.

Food advertising has become almost ubiquitous in Western societies. In adults as well as in children this omnipresence of food cues has been shown to trigger cravings and overeating, which can lead to overweight or even obesity. This is concerning because obesity is a leading cause of preventable diseases. The planned project aims at reducing craving and overeating in overweight/obese children using a placebo treatment. A total of 80 children (40 girls, 40 boys; aged between 8 and 12 years; body mass index >90th percentile) will take part in the study. A randomized controlled cross-over design will be implemented, which will include four weeks with daily placebo treatment and four weeks without placebo treatment. The placebo will be introduced without deception as an open-label placebo (OLP), that can help to control food cravings. The study will use an app-assisted approach: The children will rate the intensity of their cravings, the occurrence of binge-eating episodes, their emotional state, and placebo usage via a smartphone application. It is expected that the OLP will help the children to reduce cravings and body weight. If effective, this OLP approach could be implemented in weight-control programs for children.