Placebo and nocebo responses and effects influence treatment outcomes across a variety of conditions. The current scoping review aims to synthesise evidence from systematic reviews and meta-analyses in both clinical and healthy populations, elucidating key determinants of placebo and nocebo responses and effects, including individual, clinical, psychological and contextual factors. Among the 306 publications identified, 83% were meta-analyses and 17% systematic reviews, with a predominance of research in medical specialties (81.7%) such as psychiatry and neurology. Placebo responses were significantly more studied than nocebo responses. Individual determinants (e.g., age), clinical determinants (e.g., baseline symptom severity) and psychological determinants (e.g., expectations) were found to influence placebo and nocebo outcomes. Contextual determinants, including trial design and the method of treatment administration, also played critical roles. Several key underinvestigated areas in the current body of systematic reviews and meta-analyses were also identified. This scoping review highlights valuable insights into the determinants of placebo and nocebo responses and effects on a group level, potentially offering practical implications for optimising clinical trial designs and enhancing patient care strategies in clinical practice. However, to fully leverage these benefits, it is crucial to address the underexplored topics through more rigorous investigations using a person-centred perspective.

Placebo is a term to define physiologically inactive compounds used in treatment that causes physical and emotional changes. The placebo effect, driven by expectation and conditioning, plays a significant role in various conditions like pain, depression, and Parkinson's disease, while the nocebo effect can hinder treatment outcomes. Understanding mechanisms such as neuromodulation and genetics has gained importance in modern medicine. This review aims to explore the clinical relevance of placebo responses, particularly in neuropsychiatric disorders, and their potential in personalized medicine. By integrating placebo research into healthcare, it highlights opportunities to enhance treatment efficacy, improve patient well-being, and reduce reliance on pharmacological interventions.

A comprehensive literature search was conducted in PubMed, Scopus, and Google Scholar databases. Recent studies were reviewed to evaluate placebo effects, and the variability of the placebo response in neuropsychiatric disorders was summarized.

Placebo effects significantly impact treatment outcomes across various conditions, including Parkinson's disease, depression, pain syndromes, and epilepsy. The mechanisms involve neurobiological and psychological factors, with evidence suggesting that placebo interventions can modulate neurotransmitter activity and improve patient well-being.

Integrating placebo research into clinical practice may enhance treatment outcomes, reduce drug dependency, and support personalized medicine by tailoring interventions to individual placebo responsiveness. Understanding placebo and nocebo mechanisms can optimize therapeutic strategies while minimizing unnecessary pharmacological treatments.

Ethical research follows numerous rules and regulations to ensure that all human subjects are protected during the collection and dissemination of research outcomes. Nevertheless, there is often a critical distinction drawn between human subjects research and non-human subjects research (NHSR). The latter can also be described as non-research activities, which typically reduces any oversight even if human subjects are involved. Despite the need to conduct ethical NHSR or non-research activities in an applied setting, there are several ways this determination can be used to circumvent regulatory oversight. In particular, the problem arises because one or more of several key functions become conflated in an applied setting, whereas they would be compartmentalized and independent in controlled or experimental settings. These functions include: 1) ethical oversight; 2) funding; 3) execution; and 4) peer review. The current discussion outlines how NHSR in an applied setting can allow these functions to overlap, and how personnel might stretch the boundaries of ethical conduct even while following existing regulations. As such, the goal is to guide future practices when conducting or reviewing NHSR in an applied setting so that unethical practices do not bias the results.

Background: The surge in scientific publications during the COVID-19 pandemic has heightened the need for reliable secondary studies such as Systematic Reviews, synthesising evidence to guide clinical and public health decisions. This study aimed to analyse the current practices, preferences, and challenges faced by researchers conducting secondary studies and assess the impact of the COVID-19 pandemic on these practices. Methods: An online survey was conducted among researchers actively involved in secondary research. Email addresses were collected from PubMed for publications related to COVID-19 secondary studies between 2020 and 2022. The survey comprised 24 questions, including single- and multiple-choice formats, covering general information, Systematic Review processes, and changes during the pandemic. Statistical analysis, including Pearson's Chi2 test, was performed on key responses to identify significant correlations. Results: This study highlights that only 26.9% of respondents use keyword-generation tools. However, those using PubMed were more likely to utilise MeSH (p = 0.01486, df = 1, Chi2 = 5.932568). Systematic Review software adoption was prevalent, particularly for Rapid Reviews, with Covidence being commonly used (p = 0.00843, df = 1, Chi2 = 6.938953), especially during the screening stage (p = 0.02400, df = 1, Chi2 = 5.094851). Despite this, many researchers still reported that they did not use any software. A total of 94.9% of respondents reported adherence to PRISMA guidelines, and protocol registration was strongly associated with following these guidelines (p = 0.00320, df = 2, Chi2 = 11.48858). Researchers using Embase were significantly more likely to incorporate RCTs (p = 0.00360, df = 1, Chi2 = 8.476092), while Cochrane reviewers showed a lower reliance on non-randomised trials (p = 0.02601, df = 1, Chi2 = 4.955580). During the COVID-19 pandemic, 64.3% of respondents observed a significant increase in secondary studies. Conclusions: This study highlights key trends in secondary research, emphasising adherence to established guidelines and the growing reliance on software tools. However, gaps remain in protocol registration and keyword generation practices. Addressing these gaps through targeted training may improve the quality of future secondary studies, particularly during global health crises.

This study investigated the effects of caffeine supplementation, carbohydrate mouth rinsing, and combined caffeine supplementation with carbohydrate mouth rinsing on the pulling performance and ratings of perceived exertion in indoor tug-of-war athletes. Eighteen tug-of-war athletes were recruited as participants. They underwent four supplementation protocols in a double-blind, single-factor, repeated-measures design: caffeine supplementation (CAF), carbohydrate solution mouth rinsing (CHO), combined caffeine supplementation with carbohydrate mouth rinsing (CAF-CHO), and a placebo (PLA). Each participant performed a maximal pulling test at 80% of their maximum pulling force, and the duration was recorded. Ratings of perceived exertion were also assessed. Data were analyzed using SPSS version 25.0 for Windows, and effect sizes (ES) were calculated. The main findings were as follows: (1) The CAF-CHO group showed a significantly longer pulling duration than the PLA and CHO groups (165.0 ± 69.2 s vs. 137.4 ± 48.9 s vs. 135.6 ± 66.6 s). (2) The CAF group also demonstrated a significantly longer pulling duration than the CHO group (162.0 ± 14.1 s vs. 135.6 ± 66.6 s). (3) Both the CAF-CHO and CAF groups exhibited large effect sizes (ω2 > 0.14) compared to the PLA and CHO groups. Both caffeine supplementation combined with carbohydrate mouth rinsing and caffeine supplementation alone can significantly enhance the duration of 80% maximal pulling performance in indoor tug-of-war athletes, with the primary effect attributed to caffeine. These results provide practical strategies for coaches and athletes to suppress fatigue and improve pulling performance during competitions or training sessions for indoor tug-of-war.

The recent publication of the second Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina trial has renewed debate surrounding the indications and benefits of percutaneous coronary intervention (PCI) in stable angina. The second Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina results show that PCI improves anginal symptoms in the absence of antianginal medications. Taken together with the first Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina and Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation trial results, proponents argue that in contrast to current guidance, PCI and aggressive medical therapy are both equally acceptable initial antianginal strategies and subject to patient preference. Drawing on the history of randomized studies of interventional management for stable angina, we detail our reservations with this interpretation. More broadly, we highlight the merits of elegantly designed sham-controlled trials in answering lingering clinical questions. Finally, we offer select frameworks for more conclusive trials designed to answer the looming question that cardiologists face: does the landscape of randomized evidence support a medication-first, PCI-first, or shared decision-making treatment paradigm in stable angina?

The placebo effect has been widely documented across various medical conditions, demonstrating its ability to influence both subjective and objective outcomes. Placebo responses can significantly improve symptoms in these different conditions, such as pain, Parkinson's disease, depression, anxiety, and addiction. Psychological mechanisms, particularly the power of patient expectations, appear to play a central role, with neurobiological evidence supporting the activation of dopamine, endogenous opioids, and endocannabinoids in response to placebo interventions. Studies have demonstrated that placebo injections and more complex procedures, including sham surgeries, can produce therapeutic effects comparable to real treatments, particularly in pain management and neurological disorders. Moreover, placebo responses could be amplified when patients are aware of receiving treatment, as shown by research on open-label placebos and open versus hidden medical treatments. The effectiveness of 0.9% sodium chloride solution as a placebo in clinical trials is debated, with some studies indicating its potential to induce clinical improvements, though it may not be an ideal control in inflammatory pain conditions. Advances in neuroimaging have revealed that placebo treatments trigger tangible biological processes in the brain and body and are supported by psychological and physiological mechanisms that interact, suggesting real biological processes are involved in the observed effects. Overall, the growing understanding of placebo mechanisms suggests that incorporating placebo-based strategies, with patient awareness and appropriate ethical considerations, may offer significant potential for improving patient outcomes, particularly in chronic pain, mental health, and neurological conditions.

The goal of this paper is to explore a set of epistemological and ontological issues regarding the historical and philosophical role of placebos in the contested history of antidepressants. Starting from an account of the dual nature of the placebo as both an epistemic and a therapeutic tool, and against the background of the heated debates on the efficacy of second-generation antidepressants, I propose two related arguments. First, I argue that placebos as controls played a crucial but paradoxical role in the rise of so-called evidence-based approaches to depression. Second, I discuss how current research on placebo effects puts into question some of the most crucial assumptions of psychiatric technoscience regarding the ontology of affective experiences. Ultimately, this paper aims to probe discussions around placebos, placebo effects, and the status of depression both as a diagnostic category and a lived experience.

Thousands of essays and studies have been published on placebo and nocebo. Yet, despite this plethora of information, we are not much closer to a comprehensive understanding of the fundamental mechanism producing placebo and nocebo effects than we were in 1946, when participants in the Cornell Conferences on Therapy speculated on the roles of authority, belief and expectancy. In this paper, we examine the weaknesses in current placebo and nocebo definitions and theories. We also propose a more concise and comprehensive definition and theory of placebo and nocebo by introducing the Law of Identification and the Generic Placebo Instruction (GPI). The latter being the placebo/nocebo information expressed or implied in virtually every clinical encounter and trial; the former (i.e., the Law of Identification), being what drives the GPI to actualization. Further, we demonstrate the explanatory power of this new theory and suggest clinical studies that test predictions arising from it - studies whose results, if positive, would translate universally into clinical practice.

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

The placebo effect can induce physiological or clinical neurological and organic responses despite the recipient receiving no active ingredients; these responses are based instead on the recipient's perceptions. Placebo effects come from the rostral anterior cingulate cortex, pontine nucleus, and cerebellum of the brain; this information provides a better understanding of placebo effects and can also help us understand the mechanism of the modulation of neurotransmitters from the use of psychedelic substances, activity of selective serotonin reuptake inhibitors, the process of transcranial magnetic stimulation, and deep brain stimulation, as well as aid in developing novel therapies, challenging the validity of controlled clinical trials (RCTs) that the regulatory agencies now appreciate. Education about how placebo effects bring in social, political, and religious beliefs and whether these can be modulated may help reduce global confrontations.

Communication between medical staff and patients about treatment efficacy elicits expectations of benefit and improves treatment outcomes. While demonstrated in multiple studies via different research methodologies, uniform communication protocols have not been adopted in clinical practice. Here, we summarize the results of two sister studies aimed at bridging this gap.

Women undergoing C-section (study 1, randomized controlled trial) and patients undergoing general or otolaryngologic surgeries (study 2, control group design) were recruited and assigned to the "regular communication" (RC) or "enhanced communication" (EC) arms. The EC arm received positive information about treatment, while the RC arm received no such information. In both studies, the primary outcome was change in pain intensity; in study 2, an additional outcome was morphine consumption.

Eighty women successfully completed study 1, and 102 patients successfully completed study 2. In both studies, significant time*group interactions were observed (p < 0.001). The analgesic effect was virtually twice as large in the EC arm compared to the RC arm. In study 2, in the last two timepoints of assessment, participants in the EC arm also consumed fewer doses of opioids than participants in the RC arm (p < 0.001). No significant differences were found in vital signs.

We provide ecological evidence that positive information about treatment significantly decreases pain and opioid consumption during routine clinical care. This study and others could encourage healthcare providers to harness the powerful effects of patients' expectations of benefit to improve analgesics outcomes and, potentially, the outcomes of other symptoms.

Communication between medical staff and patients about treatment efficacy elicits expectations of benefit and improves treatment outcomes. While demonstrated in multiple studies via different research methodologies, uniform communication protocols have not been adopted in clinical practice. Here, we summarize the results of two sister studies aimed at bridging this gap.

Women undergoing C-section (study 1, randomized controlled trial) and patients undergoing general or otolaryngologic surgeries (study 2, control group design) were recruited and assigned to the "regular communication" (RC) or "enhanced communication" (EC) arms. The EC arm received positive information about treatment, while the RC arm received no such information. In both studies, the primary outcome was change in pain intensity; in study 2, an additional outcome was morphine consumption.

Eighty women successfully completed study 1, and 102 patients successfully completed study 2. In both studies, significant time*group interactions were observed (p < 0.001). The analgesic effect was virtually twice as large in the EC arm compared to the RC arm. In study 2, in the last two timepoints of assessment, participants in the EC arm also consumed fewer doses of opioids than participants in the RC arm (p < 0.001). No significant differences were found in vital signs.

We provide ecological evidence that positive information about treatment significantly decreases pain and opioid consumption during routine clinical care. This study and others could encourage healthcare providers to harness the powerful effects of patients' expectations of benefit to improve analgesics outcomes and, potentially, the outcomes of other symptoms.

This article first describes the mechanism of any self-fulfilling prophecy through discussion of its four conditions: credibility, employment, employment sensitivity, and realization. Each condition is illustrated with examples specific to the medical context. The descriptive account ends with the definition of self-fulfilling prophecy and an expansion on collective self-fulfilling prophecies. Second, the normative account then discusses the moral relevance of self-fulfilling prophecies in medicine. A self-fulfilling prophecy is typically considered problematic when the prediction itself changes the predicted outcome to match the prediction (transformative self-fulfillment). I argue that also self-fulfilling prophecies that do not change the outcome but change the ways in which the outcome was realized (operative self-fulfillment), have significant ethical and epistemic ramifications. Because it is difficult to distinguish, retrospectively, between a transformative and an operative self-fulfilling prophecy, and thus between a false or true positive, it becomes equally difficult to catch mistakes. Moreover, since the prediction necessarily turns out true, there is never an error signal warning that a mistake might have been made. On the contrary, accuracy is seen as the standard for quality assurance. As such, self-fulfilling prophecies inhibit our ability to learn, inviting repetition and exacerbation of mistakes. With the rise of automated diagnostic and prognostic procedures and the increased use of machine learning and artificial intelligence for the development of predictive algorithms, attention to self-fulfilling feedback loops is especially warranted. This account of self-fulfilling prophecies is practically relevant for medical research and clinical practice. With it, researchers and practitioners can detect and analyze potential self-fulfilling mechanisms in any medical case and take responsibility for their ethical and epistemic implications.

Changes in performance caused by positive and negative expectations (i.e., placebo and nocebo responses) were found to play an important role in many aspects of motor performance. This study aimed to test the impact of placebo/nocebo responses and the assumed moderating role of dispositional optimism and anxiety on proprioceptive accuracy, an essential aspect of motor functions. 78 undergraduate university students completed questionnaires assessing dispositional optimism, state anxiety, and motivation to cooperate, then were randomly assigned to three experimental groups. A sham subliminal electric stimulation was applied with claimed positive (placebo group, n = 26), negative (nocebo group, n = 26) or neutral (control group, n = 26) impact on proprioceptive accuracy. Proprioceptive accuracy was measured with active and passive versions of the Joint Position Reproduction task before and after the intervention. Expected and perceived changes in performance were also assessed; changes in state anxiety, optimism, and motivation to cooperate were used as control variables (covariates). Mixed analyses of variance indicated that the experimental manipulation did not affect actual proprioceptive accuracy but impacted expected and perceived performance. Adding the covariates to the models did not substantially change the results. Further, no significant association emerged between actual and perceived change in performance in the active test, and only a weak correlation was found in the passive test. Expected performance did not predict actual performance but predicted perceived performance in both tasks. The results suggest that only perceived (subjective) aspects of proprioceptive accuracy are susceptible to placebo and nocebo interventions.

This paper proposes a new model of stress that integrates earlier models and adds insights from developmental psychology. Previous models describe the behavioral and physical effects of stress events, but have not explained the translation of experiences into stress itself. The Developmental Model of Stress shows how psychosocial developmental challenges in childhood create persistent negative beliefs and behaviors that increase threat perception and maladaptive stress responses. These developmental challenges produce early psychological and physiological predispositions for increased stress responses over time. Ongoing stress leads to dysregulation of physical stress-response systems (allostatic load), which is associated with multiple diseases. High allostatic load provides the necessary preconditions for the diathesis-stress model, which says the addition of an acute stressor to a weakened or predisposed system can lead to disease development. The paper also documents the evolving measurement of stress to better understand the stress-disease relationship, helping to resolve conflicting results between studies. The Developmental Model of Stress was combined with clinician insight and patient reports to build an integrative framework for understanding the role of stress in the development and progression of multiple sclerosis (MS). It includes the first mapping of maladaptive beliefs and behaviors arising from developmental challenges that are common to people with MS. An initial comparison shows these may be distinct from those of people with other chronic diseases. These beliefs and behaviors form the predisposing factors and contribute to the triggering factors, which are the acute stressors triggering disease onset. These often took two forms, a prolonged incident experienced as feeling trapped or stuck, and threat of a breach in a relationship. The reinforcing factors add the stress of a chronic disease with a poor prognosis and seemingly random symptom fluctuation, still managed with the same beliefs and behaviors developed in childhood, increasing physiological dysregulation and symptom severity. A pilot study is described in which these three categories of stress factors in MS were explicitly addressed. This study noted clinically important improvements in physical and mental well-being, providing preliminary support for the Developmental Model. Future research might expand on the pilot using a more robust sample and design.

Six decades ago the world learned that thalidomide, a seemingly non-toxic sedative and hypnotic, caused severe birth defects including the flipper-like deformity of the arms known as phocomelia. When thalidomide was tested against placebo by the trialist Louis Lasagna in 1960 (while the drug was banned from the U.S. marketplace), he found the 100-mg dosage equivalent to placebo, as well as greatly inferior to the 200-mg dosage, in producing sleep. Even as these findings were made known, a 100-mg dose of thalidomide was in general use as a sleep aid for pregnant women. It appears that unbeknownst to themselves, an untold number of pregnant women around the world who were prescribed thalidomide incurred the risks of a teratogen in return for the benefits of a sugar pill.

Negative symptoms and cognitive impairments are highly frequent in schizophrenia spectrum disorders (SSD), associated with adverse functional outcomes and quality of life. Repetitive transcranial magnetic stimulation (rTMS) has been considered a promising therapeutic option in SSD. However, placebo effects of rTMS on these symptoms remained unclear.

To investigate placebo effects of rTMS on alleviating negative symptoms and cognitive impairment in patients with SSD and to explore potential moderators.

We systematically searched five electronic databases up to 15 July 2023. Randomized, double-blind, sham-controlled trials investigating effects of rTMS on negative symptoms or cognition in patients with SSD were included. The pooled placebo effect sizes, represented by Hedges' g, were estimated using the random-effects model. Potential moderators were explored through subgroup analysis and meta-regression.

Forty-four randomized controlled trials with 961 patients (mean age 37.53 years; 28.1% female) in the sham group were included. Significant low-to-moderate pooled placebo effect sizes were observed for negative symptoms (g=0.44, p<0.001), memory (g=0.31, p=0.010), executive function (g=0.35, p<0.001), working memory (g=0.26, p=0.004), and processing speed (g=0.36, p=0.004). Subgroup analysis indicated that placebo effects were affected by sham stimulation methods, rTMS targeting approaches, and stimulation frequency.

Placebo effects of rTMS on negative symptoms and cognition in patients with SSD are significant in a small-to-moderate magnitude, which might be mediated by rTMS parameters. Our findings will provide new insights for practitioners to further optimize and establish standardized rTMS protocols for future RCTs tackling cardinal symptoms in SSD.

https://www.crd.york.ac.uk/prospero/, identifier CRD42023390138.

The placebo response is a common phenomenon. Limited evidence is available about its magnitude in canine epilepsy trials, even though it can significantly influence the efficacy evaluation of new treatments. It was hypothesised that the placebo response is diminished when epilepsy trials are conducted in a prospective crossover design. Seizure data spanning six months from three previous multicenter epilepsy studies were analysed. The monthly seizure frequency of 60 dogs diagnosed with idiopathic epilepsy was calculated, comparing baseline data with placebo treatment. Furthermore, differentiation was made between dogs randomised to the placebo group early (Phase 1: first 3 months) or later during the study (Phase 2: second 3 months).The analysis did not reveal any placebo response in terms of monthly seizure frequency. Instead, an increase was noted during the placebo treatment period, with a mean of 2.95 seizures per month compared to 2.30 seizures per month before study entry (p = 0.0378). Additionally, a notable phase effect was observed. Dogs receiving the placebo in the second study phase exhibited a significant increase in monthly seizure frequency compared to baseline (p = 0.0036). Conversely, no significant difference from baseline was observed for dogs receiving the placebo in the first study phase. These findings underscore the considerable variability in placebo responses observed in trials for canine epilepsy, contrasting with previous limited data. The identified phase effect should be carefully considered in the design and evaluation of canine epilepsy trials to ensure a more accurate assessment of efficacy for new treatments.

Ecuador stands as a nation inheriting a profound ancestral legacy in the utilization of medicinal plants, reflective of the rich biodiversity embraced by various ethnic groups. Despite this heritage, many of these therapeutic resources remain insufficiently explored concerning their toxicity and potential pharmacological effects. This study focused on a comprehensive evaluation of cytotoxicity and the potential subcellular targets within various extracts and nine isolated metabolites from carefully selected medicinal plants. Assessing their impact on the breast cancer cell line (MCF7), we subsequently examined the most active fractions for effects on the cell cycle, microtubule network, centrosome duplication, γH2AX foci, and E-cadherin. The investigated crude extracts and isolated compounds from Ecuadorian medicinal plants demonstrated cytotoxic effects, influencing diverse cellular pathways. These findings lend credence to the traditional uses of Ecuadorian medicinal plants, which have served diverse therapeutic purposes. Moreover, they beckon the exploration of the specific chemicals, whether in isolation or combination, responsible for these observed activities.

Contextual effects (e.g. patient expectations) may play a role in treatment effectiveness. This study aimed to estimate the magnitude of contextual effects for conservative, non-pharmacological interventions for musculoskeletal pain conditions. A systematic review and meta-analysis of randomized controlled trials (RCTs) that compared placebo conservative non-pharmacological interventions to no treatment for musculoskeletal pain. The outcomes assessed included pain intensity, physical functioning, health-related quality of life, global rating of change, depression, anxiety and sleep at immediate, short-, medium- and/or long-term follow-up.

MEDLINE, EMBASE, CINAHL, Web of Science Core Collection, CENTRAL and SPORTDiscus were searched from inception to September 2021. Trial registry searches, backward and forward citation tracking and searches for prior systematic reviews were completed. The Cochrane risk of bias 2 tool was implemented.

The study included 64 RCTs (N = 4314) out of 8898 records. For pain intensity, a mean difference of (MD: -5.32, 95% confidence interval (CI): -7.20, -3.44, N = 57 studies with 74 outcomes, GRADE: very low) was estimated for placebo interventions. A small effect in favour of the placebo interventions for physical function was estimated (SMD: -0.22, 95% CI: -0.35, -0.09; N = 37 with 48 outcomes, GRADE: very low). Similar results were found for a broad range of patient-reported outcomes. Meta-regression analyses did not explain heterogeneity among analyses.

The study found that the contextual effect of non-pharmacological conservative interventions for musculoskeletal conditions is likely to be small. However, given the known effect sizes of recommended evidence-based treatments for musculoskeletal conditions, it may still contribute an important component.

Contextual effects of non-pharmacological conservative interventions for musculoskeletal conditions are likely to be small for a broad range of patient-reported outcomes (pain intensity, physical function, quality of life, global rating of change and depression). Contextual effects are unlikely, in isolation, to offer much clinical care. But these factors do have relevance in an overall treatment context as they provide almost 30% of the minimally clinically important difference.

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.

The placebo effect is the 'effect of the simulation of treatment that occurs due to a participant's belief or expectation that a treatment is effective'. Although the effect might be of little importance for some conditions, it can have a great role in others, mostly when the evaluated symptoms are subjective. Several characteristics that include informed consent, number of arms in a study, the occurrence of adverse events and quality of blinding may influence response to placebo and possibly bias the results of randomised controlled trials. Such a bias is inherited in systematic reviews of evidence and their quantitative components, pairwise meta-analysis (when two treatments are compared) and network meta-analysis (when more than two treatments are compared). In this paper, we aim to provide red flags as to when a placebo effect is likely to bias pairwise and network meta-analysis treatment effects. The classic paradigm has been that placebo-controlled randomised trials are focused on estimating the treatment effect. However, the magnitude of placebo effect itself may also in some instances be of interest and has also lately received attention. We use component network meta-analysis to estimate placebo effects. We apply these methods to a published network meta-analysis, examining the relative effectiveness of four psychotherapies and four control treatments for depression in 123 studies.

Oxygen toxicity has been defined as acute central nervous system (CNS), acute pulmonary, and chronic pulmonary oxygen toxicity. This study identifies acute and chronic CNS oxygen toxicity under 2.0 atmospheres absolute (ATA) pressure of oxygen. Methods: The authors' medical records from September 29, 1989 to January 20, 2023 and correspondence to the authors (9/1994 to 1/20.2023) from patients with signs and/or symptoms historically identified as acute CNS oxygen toxicity and those with neurological deterioration receiving hyperbaric oxygen for neurological conditions were reviewed. Acute cases were those occurring with ≤5 HBOTs and chronic cases >5 HBOTs. Chronic cases were separated into those at 1.5 ATA, > 1.5 ATA, or < 1.5 ATA oxygen. Cumulative dose of oxygen in atmosphere-hours (AHs) was calculated at symptom onset.

Seven acute cases, average 4.0 ± 2.7 AHs, and 52 chronic cases were identified: 31 at 1.5 ATA (average 116 ± 106 AHs), 12 at >1.5 ATA (103 ± 74 AHs), and 9 at <1.5 ATA (114 ± 116 AHs). Second episodes occurred at 81 ± 55, 67 ± 49, and 22 ± 17 AHs, and three or more episodes at 25 ± 18, 83 ± 7.5, and 5.4 ± 6.0 AHs, respectively. Most cases were reversible. There was no difference between adults and children (p = 0.72). Acute intervention in cases (<3 months) was more sensitive than delayed intervention (21.1 ± 8.8 vs. 123 ± 102 AHs, p = 0.035). Outside sources reported one acute and two chronic exposure deaths and one patient institutionalized due to chronic oxygen toxicity. A withdrawal syndrome was also identified.

Hyperbaric oxygen therapy-generated acute and chronic cases of CNS oxygen toxicity in chronic neurological conditions were identified at <2.0 ATA. Chronic CNS oxygen toxicity is idiosyncratic, unpredictable, and occurred at an average threshold of 103-116 AHs with wide variability. There was no difference between adults and children, but subacute cases were more sensitive than chronic intervention cases. When identified early it was reversible and an important aid in proper dosing of HBOT. If ignored permanent morbidity and mortality resulted with continued HBOT.

The placebo effect observed in clinical trials evaluating medical treatments for chronic rhinosinusitis (CRS) is not well understood. This systematic review and meta-analysis sought to characterize the placebo effect present within CRS outcomes.

A systematic review of PubMed, Scopus, and Cumulated Index in Nursing and Allied Health Nursing (CINAHL) was performed. Randomized controlled trials (RCTs) evaluating medical treatments for CRS versus placebo were included. We assessed patient-reported (sino-nasal outcome test 22 [SNOT-22], nasal obstruction, sense of smell, nasal obstruction visual analogue score [VAS], sense of smell VAS, anterior rhinorrhea, and postnasal drip) and objective (Lund-Mackay Computed tomography (CT) score, peak nasal inspiratory flow [PNIF], nasal polyp scores, 40-item Smell Identification Test, serum IgE, and blood eosinophil levels) outcomes.

Twenty-one RCTs were included, comprising 1437 patients (mean age 49.2 years). Biologics were the most common treatment investigated (n = 9). Eleven studies administered background steroids along with placebo. Following placebo administration, multiple patient-reported outcomes significantly decreased, including SNOT-22 (mean difference -9.49, 95% confidence interval [CI] [-11.26, -7.73]), nasal obstruction (-0.33 [-0.54, -0.13]), sense of smell (-0.22 [-0.33, -0.11]), nasal obstruction VAS (-2.47 [-2.87, -2.06]), and loss of smell VAS (-2.31 [-4.14, -0.47]) scores. For objective measures, significant changes occurred in Lund-Mackay CT score (-0.82, [-1.48, -0.16]) and PNIF (4.70, [4.76, 24.64]) with placebo. Placebo arms had the greatest impact when no background medications were used.

Placebo treatments have a statistically and potentially clinically significant effect on patient-reported and some objective CRS outcomes. Further investigation is required to fully understand placebo effect, which could improve assessment of RCTs and impact patient care.

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.

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.

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.

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.

This study is registered at ClinicalTrials.gov (NCT05819476) and is listed in the Swiss National Registry at kofam.ch (SNCTP000005470).

Fibromyalgia (FM) is a complex, chronic, widespread pain syndrome that can cause significant health and economic burden. Emerging evidence has shown that neuroinflammation is an underlying pathological mechanism in FM. Toll-like receptors (TLRs) are key mediators of the immune system. TLR4 is expressed primarily in microglia and regulates downstream signaling pathways, such as MyD88/NF-κB and TRIF/IRF3. It remains unknown whether electroacupuncture (EA) has therapeutic benefit in attenuating FM pain and what role the TLR4 pathway may play in this effect. We compared EA with sham EA to eliminate the placebo effect due to acupuncture. We demonstrated that intermittent cold stress significantly induced an increase in mechanical and thermal FM pain in mice (mechanical: 2.48 ± 0.53 g; thermal: 5.64 ± 0.32 s). EA but not sham EA has an analgesic effect on FM mice. TLR4 and inflammatory mediator-related molecules were increased in the thalamus, medial prefrontal cortex, somatosensory cortex (SSC), and amygdala of FM mice, indicating neuroinflammation and microglial activation. These molecules were reduced by EA but not sham EA. Furthermore, a new chemogenetics method was used to precisely inhibit SSC activity that displayed an anti-nociceptive effect through the TLR4 pathway. Our results imply that the analgesic effect of EA is associated with TLR4 downregulation. We provide novel evidence that EA modulates the TLR4 signaling pathway, revealing potential therapeutic targets for FM pain.

Neither psychological nor neuroscientific investigations have been able to fully explain the paradox that placebo is designed to be inert in randomized controlled trials (RCTs), yet appears to be effective in evaluations of clinical interventions in all fields of medicine and alternative medicine. This article develops the Neuroplasticity Placebo Theory, which posits that neuroplasticity in fronto-limbic areas is the unifying factor in placebo response (seen in RCTs) and placebo effect (seen in clinical interventions) where it is not intended to be inert. Depression is the disorder that has the highest placebo response of any medical condition and has the greatest potential for understanding how placebos work: recent developments in understanding of the pathophysiology of depression suggest that fronto-limbic areas are sensitized in depression which is associated with a particularly strong placebo phenomenon. An innovative linkage is made between diverse areas of the psychology and the translational psychiatry literature to provide supportive evidence for the Neuroplasticity Placebo Theory. This is underpinned by neuro-radiological evidence of fronto-limbic change in the placebo arm of antidepressant trials. If placebo stimulates neuroplasticity in fronto-limbic areas in conditions other than depression - and results in a partially active treatment in other areas of medicine - there are far reaching consequences for the day-to-day use of placebo in clinical practice, the future design of RCTs in all clinical conditions, and existing unwarranted assertions about the efficacy of antidepressant medications. If fronto-limbic neuroplasticity is the common denominator in designating placebo as a partially active treatment, the terms placebo effect and placebo response should be replaced by the single term "placebo treatment."

This chapter describes the placebo effect in the context of physical activity and mental health. Following a brief historical overview, definitions for placebos, placebo effects, and related terminology are discussed. Next, three major methodological challenges posed from studying the placebo effect in the context of exercise are described. Additionally, the role of a primary psychological mechanism of placebo and nocebo effects - expectations - will be summarized through the lens of key terminology. Findings from relevant chronic and acute exercise studies that have measured or manipulated exercise-associated expectations will be presented. The chapter concludes with recommendations for controlling or quantifying the placebo effect in exercise and mental health research and its implications in clinical practice.

Pelvic floor myofascial pain (PFMP) is a common but underrecognized component of chronic pelvic pain and pelvic floor disorders symptoms with limited, well-studied treatment modalities. Our objective was to determine the effect of vaginal cryotherapy on PFMP with palpation.

Following a standardized PFMP screening examination, individuals with a pain score ≥4/10 in ≥1 of four muscle groups were invited to participate in a randomized controlled trial comparing patients undergoing vaginal cryotherapy with controls. Participants in both arms could choose to participate in a single in-office treatment; a 2-week, at-home daily treatment; or both.

Between March 2019 and September 2021, a total of 163 participants were enrolled and randomized: 80 to cryotherapy, and 83 to the control group. Sixty-three (28 cryotherapy; 35 controls) completed in-office treatment and 56 (32 cryotherapy; 24 controls) completed at-home therapy. In the in-office comparison, mean pain scores decreased significantly in both arms: cryotherapy (5.13 vs 4.10; p=0.02) and controls (5.60 vs 4.72; p<0.01), with a similar magnitude of reduction between arms (p=0.75). In the at-home comparison, mean pain scores decreased significantly in the cryotherapy arm (6.34 vs 4.75; p<0.01), and nonsignificantly in the control arm (5.41 vs 4.66; p=0.07), resulting in a nonsignificant difference between arms (p=0.14).

Pelvic floor myofascial pain with palpation improved following both a single cryotherapy session and 2 weeks of daily cryotherapy. Interestingly, pain scores also improved with room temperature therapy. Whether these findings reflect a therapeutic effect of both cold and room temperature intravaginal therapy or a placebo effect is unclear but should be explored in larger studies.

Placebo and nocebo effects have been well documented for nearly two centuries. However, research has only relatively recently begun to explicate the neurobiological underpinnings of these phenomena. Similarly, research on the broader social implications of placebo/nocebo effects, especially within healthcare delivery settings, is in a nascent stage. Biological and psychosocial outcomes of placebo/nocebo effects are of equal relevance. A common pathway for such outcomes is the endogenous opioid system. This chapter describes the history of placebo/nocebo in medicine; delineates the current state of the literature related to placebo/nocebo in relation to pain modulation; summarizes research findings related to human performance in sports and exercise; discusses the implications of placebo/nocebo effects among diverse patient populations; and describes placebo/nocebo influences in research related to psychopharmacology, including the relevance of endogenous opioids to new lines of research on antidepressant pharmacotherapies.

Given the high prevalence of mental health disorders and their significant socioeconomic burden, there is a need to develop improved treatments, and to evaluate them through placebo-controlled trials. However, the magnitude of the placebo response in randomised controlled trials to test medications may be substantial, affecting their interpretation. Therefore, improved understanding of the patient, trial and mental disorder factors that influence placebo responses would inform clinical trial design to better detect active treatment effects. There is a growing literature exploring the placebo response within specific mental health disorders, but no overarching synthesis of this research has been produced to date. We present a protocol for an umbrella review of systematic reviews and/or meta-analyses in which we aim to understand the effect size and potential predictors of placebo response within, and across, mental health disorders.

We will systematically search databases (Medline, PsycINFO, EMBASE+EMBASE Classic, Web of Knowledge) for systematic reviews and/or meta-analyses that report placebo effect size in clinical trials in patients with mental health disorders (initial search date 23 October 2022). Screening of abstracts and full texts will be done in pairs. We will extract data to qualitatively examine how placebo effect size varies across mental health disorders. We also plan to qualitatively summarise predictors of increased placebo response identified either quantitatively (eg, through meta-regression) or qualitatively. Risk of bias will be assessed using the AMSTAR-2 tool. We aim to not only summarise the current literature but also to identify gaps in knowledge and generate further hypotheses.

We do not believe there are any specific ethical considerations relevant to this study. We will publish the results in a peer-reviewed journal.

No specific methods have been officially proposed for the prevention and improvement of oral hypofunction. Therefore, in this randomized controlled trial, we aimed to develop a gum-chewing training program and determine its effects in older adults. A total of 218 older adults, aged 65-85 years, were randomly allocated to the intervention or control groups. The intervention group chewed the experimental gum daily, whereas the control group consumed the experimental granular food daily. The outcome assessments measured the maximum bite force, occlusal contact areas, oral dryness, tongue pressure, tongue and lip functions, masticatory function, and gum-chewing time. The measured values for each outcome were compared between groups using the Mann-Whitney U test and within groups pre- and post-intervention using the Wilcoxon signed-rank test. A total of 211 participants completed the study. After 2 months, the intervention group had a significantly higher maximum bite force than the control group (p = 0.01), indicating that gum-chewing training improved maximum bite force in older adults. This was determined using one type of bite force measuring device. Therefore, it is suggested that gum-chewing training has a high potential to improve oral hypofunction.

The randomized controlled trial (RCT) research design assumes that a drug's "specific" effect can be isolated, added, and subtracted from the "nonspecific" effect of context and person. While RCTs are helpful in assessing the added benefit of a novel drug, they tend to obscure the curative potential of extra-pharmacological variables, known as "the placebo effect." Ample empirical evidence suggests that person/context-dependent physical, social, and cultural variables not only add to, but also shape drug effects, making them worth harnessing for patient benefits. Nevertheless, utilizing placebo effects in medicine is challenging due to conceptual and normative obstacles. In this article, we propose a new framework inspired by the field of psychedelic science and its employment of the "set and setting" concept. This framework acknowledges that drug and nondrug factors have an interactive and synergistic relationship. From it, we suggest ways to reintegrate nondrug variables into the biomedical toolbox, to ethically harness the placebo effect for improved clinical care.

This review aims to identify the magnitude of the placebo effect in people with type 2 diabetes mellitus. Literature research was conducted Medline, Embase and Virtual Health Library for studies published between the date of inception and June 2021. The eligibility criteria included randomized controlled trials, showing comparison to placebo, having participants with type 2 diabetes mellitus, and having glycated hemoglobin (HbA1c) as the primary outcome. Meta-analysis was conducted with the effect of changing HbA1c in relation to the baseline. Exploration of heterogeneity was performed.The meta-analysis showed an increase in the average of HbA1c compared to the baseline of 0.14% (95% CI: 0.07-0.21). There was a significant difference between follow-up times (p = 0.03) and between administration routes (p = 0.01), with an increase in HbA1c in the oral route [0.15% (95% CI: 0.07-0.23)]. The meta-regression of the year of publication showed a significant downward trend (p = 0.01) of the increase in HbA1c compared to the baseline.In this study, the expected placebo effect of Hba1c reduction was not found; instead, higher Hba1c levels were observed in the control groups, although this effect was reduced over the years. Registration: PROSPERO ID CRD42020172797.

Placebo effects are known for numerous clinical symptoms. Until recently, deception of placebos was thought to be essential for placebo effects, but intriguing new studies suggest that even placebos without concealment (open-label placebos) may help patients with various clinical disorders. Most of those studies compared open-label placebo treatments with no treatment conditions (or treatment "as usual"). Given that open-label placebo studies obviously cannot be blinded, additional control studies are important to assess the efficacy of open-label placebos. The current study aimed to fil this gap by comparing open-label with conventional double-blind placebos and treatment as usual. Patients with seasonal allergic rhinitis were randomly divided in different groups. The first group received open-label placebos, the second double-blind placebos, and the third was treated as usual. After 4 weeks, results demonstrated that open-label placebos improved allergic symptoms more than treatment-as-usual and even more as double-blind placebos. In addition, we observed that allergic symptoms in general (and also the open-label placebo effects) were reduced by the Covid-19 pandemic. The results suggest that seasonal allergic symptoms may be relieved by open-label placebos. We discuss these results by addressing possible different mechanisms of open-label and conventionally concealed placebo treatments.

This study aimed to assess the effect sizes, changes over time, and ethnic differences in placebo effects on urinary function among Japanese patients participating in clinical trials.

A meta-analysis of 30 Japanese placebo-controlled clinical trials was conducted to determine the placebo effects on three functions: daily urinary frequency, nocturnal urinary frequency, and average urine volume per void.

The I-square heterogeneity values for the basic values of the three functions ranged from 84.5% to 97.9%, with differences among trials. Longitudinal analysis (1 to 12 weeks) indicated an enhanced placebo effect for up to 8 weeks and no consistency among trials on nocturnal urinary frequency (p < 0.01), unlike those on daily urinary frequency and average urine volume per void (p = 1.0). Based on the random-effects model, the mean differences in urinary frequency at 4, 8, and 12 weeks were -0.70 (-0.80; -0.60), -1.06 (-1.16; -0.96), and -1.18 (-1.34; -1.01), respectively. Furthermore, the mean difference (95% confidence interval) in nocturnal urinary frequency and volume of urination per void at 12 weeks was -0.63 (-0.94; -0.31) and 9.67 (7.25; 12.1), respectively.

My findings suggest an increase in the strength of placebo effects over time (up to 8 weeks). A comparison of my results to those published in previous global reports showed no meaningful differences in placebo effects among ethnic groups. The consistent placebo effect size on urinary function could be an external indicator in clinical trials.

The use of open-label placebos (OLPs) has shown to be effective in clinical trials. We conducted a systematic review and meta-analysis to examine whether OLPs are effective in experimental studies with non-clinical populations. We searched five databases on April 15, 2021. We conducted separate analyses for self-reported and objective outcomes and examined whether the level of suggestiveness of the instructions influenced the efficacy of OLPs. Of the 3573 identified records, 20 studies comprising 1201 participants were included, of which 17 studies were eligible for meta-analysis. The studies investigated the effect of OLPs on well-being, pain, stress, arousal, wound healing, sadness, itchiness, test anxiety, and physiological recovery. We found a significant effect of OLPs for self-reported outcomes (k = 13; standardized mean difference (SMD) = 0.43; 95% CI = 0.28, 0.58; I2 = 7.2%), but not for objective outcomes (k = 8; SMD =  - 0.02; 95% CI =  - 0.25, 0.21; I2 = 43.6%). The level of suggestiveness of the instructions influenced the efficacy of OLPs for objective outcomes (p = 0.02), but not for self-reported outcomes. The risk of bias was moderate for most studies, and the overall quality of the evidence was rated low to very low. In conclusion, OLPs appear to be effective when examined in experimental studies. However, further research is needed to better understand the mechanisms underlying OLPs.

Preoperative expectations influence postoperative outcomes. Patients with lumbar degenerative spondylolisthesis have especially high expectations of pain relief and overall functional well-being compared to patients with lumbar stenosis.

The primary objective was to analyze preoperative expectations of lumbar DS patients with respect to the type of surgery proposed (decompression vs decompression and fusion). Secondarily, we aimed to assess the associations between preoperative expectations and patient and clinical factors as well as postoperative expectations fulfillment.

Patients were prospectively enrolled in a multicenter, prospective cohort study evaluating the assessment and management of degenerative spondylolisthesis utilizing the infrastructure of the Canadian Spine Outcomes and Research Network (CSORN) surgical registry.

Patients with a diagnosis of degenerative spondylolisthesis with symptoms of neurogenic claudication or radiculopathy with or without back pain, unresponsive to nonoperative management over at least 3 months were included. Patients who underwent decompression, decompression and posterolateral fusion or decompression and interbody fusion at Canadian spine centers between January 2015 and September 2021 were included.

The North American Spine Society Lumbar Spine Questionnaire was utilized for expectations measurement. The expectation questionnaire was completed following consent and before surgery and at 1 year.

Expectations for pain relief and improvements in overall functional well-being were rated on a scale of 0 to 100. Preoperative expectation in terms of pain relief and functional well-being score were calculated. Multivariate linear regression was used to evaluate the association between expected preoperative patient factors and pain relief and functional well-being. The factors associated with the most important expectation were evaluated using multivariable multinomial logistic regression.

Three hundred fifty-two patients were included with 100 patients undergoing decompression and 252 patients also undergoing fusion. The seven items of preoperative expectations did not differ between the procedure groups nor did expected change. The mean pain relief and overall functional well-being expectation scores did not significantly differ between procedures. Higher expectations were associated with having more comorbidities [β=-2.0 (SE 0.8), p=.020], being physically active [β=8.4 (SE 3.2), p=.010] and having more leg pain [β=1.6 (SE 0.7), p=.015]. Better perceived physical health measured by SF12 PCS was associated with lower expectation of pain relief [β= -0.4 (SE 0.2), p=.039] and functional well-being [β=-0.84 (SE 0.2), p=.001]. Better perceived mental health measured by SF12 MCS was associated with lower expectation of functional well-being [β=-0.8 (SE 0.2), p=.001]. Postoperative expectations fulfillment did not differ between procedures.

Preoperative expectations in terms of pain relief and functional well-being were similar between the two most common procedures performed, decompression ± fusion. Secondarily, higher preoperative expectations were associated with greater pain, disability and being physically active. Expectations fulfillment did not differ between procedures.

Placebo responses to an apparently inactive intervention are of interest from a scientific perspective as they suggest possible mechanism(s) at work beyond the intervention itself. They are also of interest from a clinical trials perspective since high rates of placebo response limit the potential to demonstrate worthwhile efficacy of a new intervention. This mini-review was motivated by the work of Bosman and colleagues(Neurogastroenterol Motil, 2022, and e14474) that is published in this issue of the journal in which they report on a systematic review and meta-analysis of placebo response in functional dyspepsia clinical trials. The review sets the scene for their work by putting it in the context of other disorders of brain-gut interaction and extra-gastrointestinal disorders. The review canvasses potential mechanisms of placebo response.

While placebo effects are well-known, research in the last decade revealed intriguing effects that placebos may have beneficial effects even when given without deception. At first glance, this seems paradoxical, but several studies have reported improvements in pain, depression, or anxiety. However, it still remains unclear whether these results represent objective biological effects or simply a bias in response and what neural underpinnings are associated with the open-label placebo effects. In two studies, we address this gap by demonstrating that open-label placebos reduce self-reported emotional distress when viewing highly arousing negative pictures. This reduced emotional distress was associated with an activation of brain areas known to modulate affective states such as the periaqueductal gray, the bilateral anterior hippocampi, and the anterior cingulate cortex. We did not find any prefrontal brain activation. Furthermore, brain activation was not associated with expectation of effects. In contrast, we found that brain responses were linked to general belief in placebos. The results demonstrate that the neural mechanisms of open-label placebo effects are partly identical to the neurobiological underpinnings of conventional placebos, but our study also highlights important differences with respect to a missing engagement of prefrontal brain regions, suggesting that expectation of effects may play a less prominent role in open-label placebos.

Our objectives were to examine the magnitude of the proportion attributable to contextual effects (PCE), which shows what proportion of the treatment arm response can be achieved by the placebo arm across various interventions, and to examine PCE variability by outcome type and condition.

We conducted a meta-epidemiological study.

We searched the Cochrane Database of Systematic Reviews with the keyword 'placebo' in titles, abstracts and keywords on 1 January 2020.

We included reviews that showed statistically significant beneficial effects of the intervention over placebo for the first primary outcome.

We performed a random-effects meta-analysis to calculate PCEs based on the pooled result of each included review, grouped by outcome type and condition. The PCE quantifies how much of the observed treatment response can be achieved by the contextual effects.

No patient or member of the public was involved in conducting this research.

We included 328 out of 3175 Cochrane systematic reviews. The results of meta-analyses showed that PCEs varied greatly depending on outcome type (I²=98%) or condition (I²=98%), but mostly lie between 0.40 and 0.95. Overall, the PCEs were 0.65 (95% CI 0.59 to 0.72) on average. Subjective outcomes were 0.50 (95% CI 0.41 to 0.59), which was significantly smaller than those of semiobjective (PCE 0.78; 95% CI 0.72 to 0.85) or objective outcomes (PCE 0.94; 95% CI 0.91 to 0.97).

The results suggest that much of the observed benefit is not just due to the specific effect of the interventions. The specific effects of interventions may be larger for subjective outcomes than for objective or semiobjective outcomes. However, PCEs were exceptionally variable. When we evaluate the magnitude of PCEs, we should consider each PCE individually, for each condition, intervention and outcome in its context, to assess the importance of an intervention for each specific clinical setting.

Whether and to which extent placebo treatment in double-blinded randomized controlled clinical trials is effective in chronic arthritic diseases has not been studied before. Therefore, a systematic literature search was undertaken to detect eligible trials. Demographic data of the placebo groups as well as concomitant and previous disease outcomes were collected. Analyses of significant bivariate correlations and linear regression between clinical endpoints and characteristics of the placebo groups were performed. A total of 152 double-blinded randomized controlled studies, including 21,616 participants in the placebo groups, was analyzed. The results of bivariate correlations and linear regressions revealed significant positive associations between responses in the placebo groups and the following factors: (i) naïvety of previous treatment and (ii) early stage of disease. In addition to the clinical relevance, the results support the importance of the placebo effect on study size calculations, and will allow an optimized calculation of patients' numbers for early placebo-controlled trials conducted in patients with chronic arthritic diseases.

Asthma in obese patients represents a specific phenotype that is associated with increased symptoms, more frequent and severe exacerbations, reduced responsiveness to treatment, and decreased quality of life. Marketing and placebos have been shown to alter subjective responses to interventions in both asthma and obesity. We evaluated obesity as a potential treatment effect modifier of the effects enhanced drug messaging or placebos on subjective asthma outcomes.

We conducted a secondary analysis of a multicenter, randomized clinical trial that studied the effect of messaging and placebos on asthma outcomes. A total of 601 participants were randomized (1:1:1:1:1) to one of 5 groups: enhanced messaging with montelukast or placebo, neutral messaging with montelukast or placebo, or usual care and followed for 4 weeks after randomization. We compared baseline characteristics by obesity status for 600 participants with data on body weight. Obesity was evaluated as an effect modifier for enhanced messaging (versus neutral messaging) and on placebo effects (versus usual care) in 362 participants assigned to a placebo group or usual care for three asthma questionnaires: Asthma Control Questionnaire, Asthma Quality of Life Questionnaire and Asthma Symptoms Utility Index.

Overall, 227 (37%) of participants were obese. Obese participants were older (mean age 41 vs 34), more likely female (82% vs 67%) and self-identified as Black (44% vs 25%) than non-obese participants. As previously published, enhanced messaging was associated with improvements in patient-reported asthma scores, but there was no evidence for a placebo effect. Obesity status did not influence the message effects nor did it modify responses to placebo.

Obesity has been shown to be an important factor associated with asthma outcomes and an effect modifier of drug treatment effects. We conducted a post hoc, subgroup analysis of data from a multicenter randomized trial of enhanced messaging and placebo associated with drug treatment on asthma outcomes. Our findings suggest that observed differences in treatment effects between obese and non-obese patients sometimes seen in trials of asthma treatments are unlikely to be due to different "placebo" effects of treatment and may reflect differential physiologic effects of active agents.

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.

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.

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.

Participants provided insights into the experience of COLP which may help to guide its future utilization to manage acute pain and tapering from opioids.