Curiosities in a Table: Learning Points for Responsible Clinical Rating.

This article presents a table containing redacted data from a real study. The table contains three curiosities: statistical significance in the absence of clinical significance, narrow standard deviations, and the absence of a placebo effect. The data in the table had been obtained by an inexperienced rater; how the inexperience compromised the data is explained. Action points for rater experience, rater training, and rating procedures are suggested.

Case report: Tremor in the placebo condition of a blinded clinical trial of intermittent theta-burst stimulation for cocaine use disorder.

We report a case of a new-onset, persistent tremor that developed during a clinical trial (NCT02927236) of intermittent theta burst stimulation [iTBS, a form of repetitive magnetic transcranial magnetic stimulation (rTMS)] for cocaine use disorder. Although the participant exhibited an exceptionally strong clinical response, subsequent unblinding revealed that they received sham iTBS. This case highlights the potential for strong functional neurological placebo responses in rTMS trials, and functional disorders might be a marker of a placebo response. Additionally, we note the possibility that the weak e-fields produced by some sham rTMS systems may induce clinically relevant effects.

Assessing the longevity of attribute framing in attenuating the nocebo effect to brand and generic medication.

The perception of taking a generic, relative to brand, medication has been demonstrated to exacerbate the nocebo effect. Conversely, positive attribute framing has been shown to attenuate the nocebo effect. However, little is known about the longevity of positive attribute framing nor how it interacts with generic versus brand treatment cues. Healthy participants (N = 205) were randomised to receive either sham-modafinil capsules with a brand or generic appearance, in conjunction with standard negative side effect framing (brand-negative: N = 42; generic-negative: N = 41) or positive side effect framing (brand-positive: N = 40; generic-positive: N = 40). The remainder were randomised to a no-treatment control (N = 42). Participants were informed that modafinil could enhance alertness and cognitive performance and reduce fatigue. Critically, modafinil was described as having several potential side effects. Treatment-related side effects, alertness, fatigue and cognitive performance were measured at baseline, 30-min post-treatment and 24 h later. Nocebo and placebo effects were observed across modafinil-treated participants relative to control. Positive framing significantly reduced warned side effects for 24 h. Perceived side effect likelihood, severity, and worry mediated the nocebo, but not framing, effect. Results have important implications for the presentation of side effect information, providing a potential route to reduce unwanted negative effects of generic medication.

Optimizing placebo and minimizing nocebo effects through communication: e-learning and virtual reality training development.

BACKGROUND: The effects of many treatments in healthcare are determined by factors other than the treatment itself. Patients' expectations and the relationship with their healthcare provider can significantly affect treatment outcomes and thereby play a major role in eliciting placebo and nocebo effects. We aim to develop and evaluate an innovative communication training, consisting of an e-learning and virtual reality (VR) training, for healthcare providers across all disciplines, to optimize placebo and minimize nocebo effects through healthcare provider-patient communication. The current paper describes the development, mid-term evaluation, optimization, and final evaluation of the communication training, conducted in The Netherlands. METHODS: The development of both the e-learning and the VR training consisted of four phases: 1) content and technical development, 2) mid-term evaluation by healthcare providers and placebo/communication researchers, 3) optimization of the training, and 4) final evaluation by healthcare providers. To ensure the success, applicability, authenticity, and user-friendliness of the communication training, there was ongoing structural collaboration with healthcare providers as future end users, experts in the field of placebo/communication research, and educational experts in all phases. RESULTS: Placebo/communication researchers and healthcare providers evaluated the e-learning positively (overall 7.9 on 0-10 scale) and the content was perceived as useful, accessible, and interesting. The VR training was assessed with an overall 6.9 (0-10 scale) and was evaluated as user-friendly and a safe method for practicing communication skills. Although there were some concerns regarding the authenticity of the VR training (i.e. to what extent the virtual patient reacts like a real patient), placebo and communication researchers, as well as healthcare providers, recognized the significant potential of the VR training for the future. CONCLUSIONS: We have developed an innovative and user-friendly communication training, consisting of an e-learning and VR training (2D and 3D), that can be used to teach healthcare providers how to optimize placebo effects and minimize nocebo effects through healthcare provider-patient communication. Future studies can work on improved authenticity, translate the training into other languages and cultures, expand with additional VR cases, and measure the expected effects on providers communication skills and subsequently patient outcomes.

Factors associated with a placebo effect in Parkinson's disease in clinical trials: a meta-analysis.

OBJECTIVES: Outcomes of clinical trials of treatment in patients with Parkinson's disease (PD) may be influenced by placebo effects. The aim of this study was to determine the factors associated with placebo effects in Parkinson's disease (PD) for guidance with design of future clinical trials. METHODS: Factors associated with placebo effects in PD were examined in a meta-analysis using a random effects model with pooling of placebo effects on the Unified Parkinson's Disease Rating Scale part III (UPDRS III) or Movement Disorder Society sponsored revision of UPDRS III (MDS-UPDRS III). The following prespecified variables were included in the analyses: with or without drug at baseline, with or without a placebo run-in phase, with or without motor fluctuation, published year, number of study sites, placebo administration period, age, sex, disease duration, and daily levodopa dose. Publication bias was assessed by visual inspection of funnel plots and adjusted using the trim-and-fill method. RESULTS: Thirty-eight articles with a total of 4828 subjects satisfied the inclusion criteria. There was a significant placebo effect using UPDRS III or MDS-UPDRS III (SMD = - 0.25; 95% CI - 0.35 to - 0.14; p < 0.001, I2 = 92%). Subgroup and/or multivariate meta-regression analyses revealed that placebo effects were associated with advanced PD (p = 0.04), drug exposure at baseline (p < 0.001), placebo administration period (p < 0.001), and disease duration (p < 0.01). CONCLUSIONS: The results of this study are important as guidance in design of future clinical trials in which the influence of placebo effects is minimized.

¿Influye la comunicación con el paciente sobre la kinesiofobia? Una revisión sistemática / Does patient communication influence kinesiophobia? A systematic review

El objetivo de la presente revisión sistemática consistió en determinar el efecto de la comunicación en el ámbito sanitario sobre la kinesiofobia. Para ello, se realizó una búsqueda bibliográfica en siete bases de datos entre noviembre de 2022 y febrero de 2023. La revisión se efectuó acorde a la declaración Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) y para el análisis de la calidad metodológica se utilizaron: la escala Physiotherapy Evidence Database (PEDro), los criterios de Van Tulder y el análisis del riesgo de sesgo de la Colaboración Cochrane. Se incluyeron un total de 13 artículos que presentaron una calidad metodológica media de 7,1 sobre 10. Se obtuvieron resultados significativos para al menos una variable (kinesiofobia, discapacidad o nivel de actividad física) en 12 trabajos. Existe evidencia sólida de que la comunicación puede influir sobre la kinesiofobia del sujeto. Es más probable que esta influencia ocurra en un sentido negativo o discapacitante, pero también puede actuar en sentido positivo disminuyendo la misma. (AU)

The aim of the present systematic review was to determine the effect of communication in the health care setting on kinesiophobia. To this end, a literature search was conducted in seven databases between November 2022 and February 2023. The review was carried out following the PRISMA statement and for the analysis of methodological quality we used: PEDro Scale, Van Tulder criteria and risk of bias analysis of the Cochrane Collaboration. A total of 13 articles were included with a mean methodological quality of 7.1 out of 10. Significant results were obtained for at least one variable (kinesiophobia, disability or level of physical activity) in 12 articles. There is strong evidence that communication can influence a subject's kinesiophobia. This influence is most likely to be in a negative or disabling sense, but it can also act in a positive sense by decreasing it. (AU)

Mulligan manual therapy added to exercise improves headache frequency, intensity and disability more than exercise alone in people with cervicogenic headache: a randomised trial.

QUESTION: What is the effect of a 4-week regimen of Mulligan manual therapy (MMT) plus exercise compared with exercise alone for managing cervicogenic headache? Is MMT plus exercise more effective than sham MMT plus exercise? Are any benefits maintained at 26 weeks of follow-up? DESIGN: A three-armed, parallel-group, randomised clinical trial with concealed allocation, blinded assessment of some outcomes and intention-to-treat analysis. PARTICIPANTS: Ninety-nine people with cervicogenic headache as per International Classification of Headache Disorders (ICHD-3). INTERVENTIONS: Participants were randomly allocated to 4 weeks of: MMT with exercise, sham MMT with exercise or exercise alone. OUTCOME MEASURES: The primary outcome was headache frequency. Secondary outcomes were headache intensity, headache duration, medication intake, headache-related disability, upper cervical rotation range of motion, pressure pain thresholds and patient satisfaction. Outcome measures were collected at baseline and at 4, 13 and 26 weeks. RESULTS: MMT plus exercise reduced headache frequency more than exercise alone immediately after the intervention (MD between groups in change from baseline: 2 days/month, 95% CI 2 to 3) and this effect was still evident at 26 weeks (MD 4 days, 95% CI 3 to 4). There were also benefits across all time points in several secondary outcomes: headache intensity, headache duration, headache-related disability, upper cervical rotation and patient satisfaction. Pressure pain thresholds showed benefits at all time points at the zygapophyseal joint and suboccipital areas but not at the upper trapezius. The outcomes in the sham MMT with exercise group were very similar to those of the exercise alone group. CONCLUSIONS: In people with cervicogenic headache, adding MMT to exercise improved: headache frequency, intensity and duration; headache-related disability; upper cervical rotation; and patient satisfaction. These benefits were not due to placebo effects. TRIAL REGISTRATION: CTRI/2019/06/019506.

Social Learning of Placebo Effects in Pain: A Critical Review of the Literature and a Proposed Revised Model.

Relatively recently, in 2009, experimental studies were undertaken to determine the role of social observational learning in forming hypoalgesic, analgesic and hyperalgesic responses to a placebo. The research findings obtained in studies published before 2018 were integrated and formed the basis of the theoretical model of social learning of placebo effects in pain proposed by Bajcar and Babel. This model considered the involvement of different types of modeling (ie, behavioral modeling, symbolic modeling, and verbal modeling) in shaping placebo hypoalgesia/analgesia and nocebo hyperalgesia. The model assumed that pain expectancies might be involved in observationally induced placebo effects in pain and that the effectiveness of observational learning in shaping placebo effects could be moderated by the observer's dispositions, especially empathy. Based on the latest research data, we propose a modified and significantly extended version of this model. The revised model includes the involvement of particular types of modeling in placebo effects and their role in shaping conscious pain-related expectancies. It explains the role of dispositional empathy in shaping observationally induced placebo effects. Notably, the extended version of the model considers the contribution of the characteristics of the observed person to the magnitude of placebo effects induced by social learning. PERSPECTIVE: The paper proposes a comprehensive theoretical approach to explaining the role of observational learning in shaping placebo effects in pain. The proposed model emphasizes the potential of this form of learning in shaping placebo responses and indicates factors that can modify the effectiveness of observational learning.

Imagining flying increases jumping performance in volleyball players: A pilot study.

OBJECTIVE: The study aimed to examine the effect of mental imagery on sports performance. Specifically, it was tested whether imagining flying (i.e., air travel) increases jumping performance in a group of female volleyball players. METHODS: The study included 46 female young athletes (mean age = 15.23 years; standard deviation = 2.4) divided into two groups: the experimental group viewed a three-dimensional video that simulated a flying experience, while the control group watched neutral footage. The jump performance of both groups was measured before and after viewing the videos, using the Vertec Like® instrument to assess jump height. Participants were assessed for their flow disposition, mental imagery skills, and image vividness. RESULTS: Comparing pre-post jump performance scores, the experimental group showed a significant improvement over the control group, with a medium-large effect size (d = 0.634). There was no significant association between flow disposition, mental imagery skills, image vividness, and pre-post jumping performance differences (respectively: ß = -0.107, p = .484; ß = -0.008, p = .957; ß = 0.024, p = .913). CONCLUSIONS: These findings suggest that the experience of imagining flying, enhanced with an immersive video, has a positive effect on jumping performance in a one-session study with young female volleyball players. This effect does not appear to be associated with pre-existing characteristics or the vividness of the image itself.

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

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

Negative expectations (nocebo phenomenon) in clinical interventions: A scoping review.

Unpredictable, undesirable, and confusing reactions in the face of psychological or medical interventions make the clinical presentation more complicated and may represent clinically unexplained symptoms and also disturbed the doctor-patients relationship and decrease patients' benefits of treatment. It seems that negative expectations from the treatment (nocebo phenomenon) can explain such reactions. The aim of the current study is a scoping review and investigate different aspects of the nocebo phenomenon (negative expectations) in clinical interventions. This paper follows a scoping review of the existence, importance, and multidimensions of the nocebo phenomenon in medical and psychological interventions. Data sources include literature databases (ProQuest, PubMed, Google Scholar, and Scopus) reviewed from inception dates to 2023, and the terms negative expectations, nocebo effect, placebo effect, negative placebo, and clinical interventions were searched. The review of the available articles showed that negative expectations play an important role in the process and effectiveness of clinical interventions. Negative expectations (here named nocebo effect) can significantly interfere with rapport and treatment processes. Some underlying components of the nocebo effect include negative expectancies, conditioning, social learning, memory, cognitive distortions, meaning, motivation, somatic focus, negative reinforcements, personality, anxiety, and neurophysiological factors such as CCK, dopamine, and cortisol are proposed for development and presence of nocebo phenomenon in clinical practice. Negative expectations with its biopsychosocial aspects play an important and amazing role in disorganizing medical and psychological interventions. Using appropriate methods to reduce nocebo effects in therapeutic interventions may increase treatment compliance and adherence and increase the effectiveness of interventions.

Re-evaluating the placebo response in recent canine dietary epilepsy trials.

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.

[Should fire cutters be thrown into the fire ?] / Faut-il jeter au feu les coupeurs de feu ?

Spirituality (in addition to laughter) is inherent to humans. When their health deteriorates, especially in the field of oncology, people often seek help through it. Prayer is the most commonly used tool and is sometimes entrusted to a particular person believed to possess certain powers referred to as a «fire cutter¼. It is then used in a targeted manner against specific symptoms such as burns. No biophysical effects are known. This intercession brings secondary benefits (positive effects on anxiety, stress, placebo effect) that can improve the patients' health. It is not the healthcare provider's mission to prescribe these spiritual practices, but they should be able to recognize them and openly discuss with patient who choose to use them, knowing that a benefit is likely to be reached.

La spiritualité (en plus du rire) est le propre de l'homme. Quand son état de santé se dégrade, en particulier en cancérologie, il y cherche souvent une aide. La prière est l'outil le plus souvent utilisé. Elle est parfois confiée à une personne particulière dotée de certains pouvoirs appelée «coupeur de feu¼. La prière est alors utilisée de manière ciblée contre une symptomatologie spécifique type brûlure. Aucun effet biophysique n'est connu. Cette intercession amène des bénéfices secondaires (effet sur l'anxiété, le stress, effet placebo) à même d'améliorer l'état de santé des patients. Le soignant n'a pas pour mission de prescrire ces accompagnements qui relèvent du spirituel, mais doit savoir les reconnaître et en discuter de manière ouverte avec le patient y ayant recours, sachant qu'un bénéfice sera vraisemblablement au rendez-vous.

Contextual Factors-Enriched Standard Care on mechanical neck pain (ContextualizAR trial): Protocol for a randomised controlled trial.

BACKGROUND: Understanding the influence of contextual factors (CFs) on interventions for mechanical neck pain (MNP) is essential for evidence-based practice in physical therapy. However, the specific effects and synergies of combining different CFs remain unclear. OBJECTIVE: The primary purpose of this study will be to determine if a CFs-Enriched Standard Care (SC) approach is an effective treatment for MNP in terms of reducing pain and improving function. METHODS: This will be an assessor-blinded, 2-group (1:1) randomised clinical trial (RCT) aiming to enrol 94 participants with neck pain persisting for more than 4 weeks. Both groups will undergo 4 weeks of SC twice weekly, following established clinical practice guidelines. In the intervention group, CFs will be enhanced, encompassing the physical, psychological, and social elements inherent in the clinical encounter, based on existing evidence. The primary outcomes will encompass changes in pain and disability after 4 weeks of treatment, with a follow-up reassessment at week 12 post-treatment. Secondary outcomes will include changes in Active Range of Motion, Global Rating of Change, and Satisfaction with treatment. The change between groups after treatment and at the 12-week follow-up will be reported for all outcomes, considering the difference from scores recorded at baseline. RESULTS: We hypothesise that a 4-week CFs-Enriched SC approach will be superior to SC alone in terms of patient-reported disability and pain, with measurements conducted using the Northwick Park Neck Pain Questionnaire and the Numeric Pain Rating Scale, respectively. CONCLUSION: This RCT rigorously assesses the effect of purposeful manipulation of CFs during MNP treatment. By elucidating the role of these factors, our findings have the potential to significantly refine clinical practice in managing MNP, thereby enhancing patient care, and advancing the fields of physical therapy and rehabilitation.

Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalized Anxiety.

BACKGROUND: Anxiety disorders are highly prevalent and socio-economically costly. Novel pharmacological treatments for these disorders are needed because many patients do not respond to current agents or experience unwanted side effects. However, a barrier to treatment development is the variable and large placebo response rate seen in trials of novel anxiolytics. Despite this, the mechanisms that drive placebo responses in anxiety disorders have been little investigated, possibly due to low availability of convenient experimental paradigms. We aimed to develop and test a novel protocol for inducing placebo anxiolysis in the 7.5% CO2 inhalational model of generalized anxiety in healthy volunteers. METHODS: Following a baseline 20-minute CO2 challenge, 32 healthy volunteers were administered a placebo intranasal spray labelled as either the anxiolytic "lorazepam" or "saline." Following this, participants surreptitiously underwent a 20-minute inhalation of normal air. Post-conditioning, a second dose of the placebo was administered, after which participants completed another CO2 challenge. RESULTS: Participants administered sham "lorazepam" reported significant positive expectations of reduced anxiety (P = .001), but there was no group-level placebo effect on anxiety following CO2 challenge post-conditioning (Ps > .350). Surprisingly, we found many participants exhibited unexpected worsening of anxiety, despite positive expectations. CONCLUSIONS: Contrary to our hypothesis, our novel paradigm did not induce a placebo response, on average. It is possible that effects of 7.5% CO2 inhalation on prefrontal cortex function or behavior in line with a Bayesian predictive coding framework attenuated the effect of expectations on subsequent placebo response. Future studies are needed to explore these possibilities.

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.

Effects of deep brain stimulation and verbal suggestions on pain in Parkinson's disease.

BACKGROUND AND OBJECTIVES: In Parkinson's disease (PD) patients, verbal suggestions have been shown to modulate motor and clinical outcomes in treatment with subthalamic deep brain stimulation (DBS). Furthermore, DBS may alleviate pain in PD. However, it is unknown if verbal suggestions influence DBS' effects on pain. METHODS: Twenty-four people with PD and DBS had stimulation downregulated (80-60 to 20%) and upregulated (from 20-60 to 80%) in a blinded manner on randomized test days: (1) with negative and positive suggestions of pain for down- and upregulation, respectively, and (2) with no suggestions to effect (control). Effects of DBS and verbal suggestions were assessed on ongoing and evoked pain (hypertonic saline injections) via 0-10 numerical rating scales along with motor symptoms, expectations, and blinding. RESULTS: Stimulation did not influence ongoing and evoked pain but influenced motor symptoms in the expected direction. Baseline and experimental pain measures showed no patterns in degree of pain. There was a trend toward negative suggestions increasing pain and positive suggestions decreasing pain. Results show significant differences in identical stimulation with negative vs positive suggestions (60% conditions AUC 38.75 vs 23.32, t(13) = 3.10, p < 0.001). Expectations to pain had small to moderate effects on evoked pain. Patients estimated stimulation level correctly within 10 points. CONCLUSION: Stimulation does not seem to influence ongoing and evoked pain, but verbal suggestions may influence pain levels. Patients appear to be unblinded to stimulation level which is an important consideration for future studies testing DBS in an attempted blind fashion.

Efficacy of a stannous fluoride dentifrice for relieving dentinal hypersensitivity in Chinese population: an 8-week randomized clinical trial.

OBJECTIVES: To compare the effectiveness of using a 0.454% stannous fluoride-containing dentifrice twice daily in relieving dentinal hypersensitivity (DH) in a Chinese population. MATERIALS AND METHODS: This was a single-centre, randomized, controlled, examiner-blind, three-treatment-arm, parallel-group study in participants with clinically diagnosed DH. Subjects who met inclusion criteria (n = 197) were randomly allocated into 3 groups: test group (n = 66)-using a 0.454% stannous fluoride-containing dentifrice twice daily; positive control group (n = 64)-using a 5.0% calcium sodium phosphosilicate-containing dentifrice twice daily; negative control group (n = 67)-using a 1150 ppm of NaF dentifrice twice daily. Status of DH was assessed at week 4 and week 8 by the same independent examiner. Changes from baseline in Schiff sensitivity score, tactile threshold and Dentine Hypersensitivity Experience Questionnaire (DHEQ) score were analysed using analysis of covariance models. The DHEQ evaluated subject-perceived oral health-related quality of life (OHRQoL). RESULTS: Statistically significant improvements in mean Schiff scores (p < 0.0001 for all products at Weeks 4 and 8), tactile threshold (p < 0.0001 for test and negative control at Weeks 4 and 8: Week 4 p = 0.0040 and Week 8 p < 0.0001 for positive control) and all DHEQ scores (p < 0.01 for all groups) were observed. No statistically significant differences were observed in the adjusted mean between all dentifrices at both timepoints, potentially driven by a placebo effect. Forty-two treatment-emergent adverse events (TEAEs) were reported (n = 32 subjects), with 2 serious AEs (n = 1) in the test group. TEAEs were not considered treatment-related. CONCLUSIONS: All groups demonstrated statistically significant improvements in Schiff score, tactile threshold and OHRQoL. However, due to a possible placebo effect in the negative control, there were no statistically significant differences between the dentifrices. CLINICAL RELEVANCE: This study adds to the growing research exploring why the placebo effect is a common phenomenon in DH studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04950465.

Factors That Predict Magnitude, Timing, and Persistence of Placebo-Like Response in Patients With Irritable Bowel Syndrome.

BACKGROUND AND AIMS: Placebo response impedes the development of novel irritable bowel syndrome (IBS) therapies and the interpretability of randomized clinical trials. This study sought to characterize the magnitude, timing, and durability of IBS symptom relief in patients undergoing a non-drug placebo-like control. METHODS: One hundred forty-five Rome III-diagnosed patients (80% F, M age = 42 years) were assigned to education/nondirective support delivered over a 10-week acute phase. Treatment response was based on the IBS version of the Clinical Global Improvement Scale completed 2 weeks after treatment ended. Candidate predictors were assessed at baseline (eg, emotion regulation, pain catastrophizing, distress, neuroticism, stress, somatization, gastrointestinal-specific anxiety) or clinically relevant points during treatment (patient-provider relationship, treatment expectancy/credibility). RESULTS: Midtreatment response was associated with lower levels of stress and somatization at baseline and greater patient-provider agreement on treatment tasks (P < .001). Treatment response was associated with baseline gastroenterologist-rated IBS severity, anxiety, ability to reappraise emotions to reduce their impact [cognitive reappraisal], and agreement that provider and patient shared goals from provider perspective (P < .001). The day-to-day ability to reappraise emotions at baseline distinguished rapid from delayed placebo responders (P = .011). CONCLUSION: Patient beliefs (eg, perceived stress, cognitive reappraisal) impacted the magnitude, timing, and persistence of placebo response measured at midway point of acute phase and 2 weeks after treatment discontinuation. Baseline beliefs that patients could alter the impact of stressful events by rethinking their unpleasantness distinguished rapid vs delayed placebo responders. Collaborative agreement between doctor and patient around shared tasks/goals from the clinician perspective predicted placebo response.

The Local Route of Administration of Dexamethasone in Impacted Mandibular Third Molar Surgery: A Systematic Review and Meta-analysis of Randomised Controlled Trials and a Critical Narrative Review on the Claimed Advantages of the Local Route.

Introduction: The proponents of local route of Dexamethasone (DXM) administration for impacted mandibular 3rd molar (MM3) surgeries claim advantages over the traditional systemic routes. This systematic review and meta-analysis were aimed to determine whether the route of perioperative administration of DXM influences the inflammatory outcomes of MM3 surgeries. Methodology: An electronic database search over a 25 year period of randomised trials of DXM in MM3 surgeries was conducted. The mean differences or standardised mean differences were extracted and pooled using the fixed or random-effects model. Results: Of the sixteen selected trials, four were considered for a meta-analysis. There were no statistically significant differences in the inflammatory outcomes between the local and systemic routes of DXM. Conclusion: The claimed advantages of the local route of DXM do not appear to be scientifically valid. Clinical trials supported with DXM plasma measurements are needed to confirm the absence of a systemic effect when DXM is administered locally.