Placebo Effect Research Articles

Effect of Finerenone on the KCCQ in Patients With HFmrEF/HFpEF: A Prespecified Analysis of FINEARTS-HF

BackgroundPatients with heart failure (HF) are limited by symptoms and have impaired quality of life. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a patient-reported outcome measure that enables evaluation of the effect of HF and the impact of new therapies on health status in patients with HF. ObjectivesThis prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) assessed the efficacy and safety of finerenone according to baseline KCCQ Total Symptom Score (TSS) and the effect of finerenone on KCCQ-TSS. MethodsFINEARTS-HF tested the efficacy of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone, compared with placebo, in patients with HF with mildly reduced ejection fraction/preserved ejection fraction. The primary endpoint was the composite of cardiovascular death and total worsening HF events. The KCCQ was completed by patients at randomization and at 6, 9, and 12 months after randomization. Change in KCCQ-TSS was a key secondary endpoint. Patients were stratified by KCCQ-TSS tertiles at baseline. The association between KCCQ tertile and clinical outcomes was evaluated using semiparametric proportional-rates models for total events and Cox models for time-to-first-event data, and the effects of finerenone vs placebo on the primary endpoint were assessed across tertiles of KCCQ-TSS. ResultsOf the 6,001 participants in FINEARTS-HF, 5,986 (99.8%) had baseline KCCQ-TSS recorded (median score 69.8 of a possible 100; higher score = better health status). Lower (worse) KCCQ-TSS was associated with a higher risk of the primary endpoint. Finerenone, compared with placebo, reduced the risk of the primary endpoint across the range of KCCQ-TSS: tertile 1 (score 0-<57): RR: 0.82 (95% CI: 0.68-1.00); tertile 2 (57-<81): 0.88 (95% CI: 0.70-1.11); tertile 3 (81-100): 0.88 (95% CI: 0.69-1.14) (Pinteraction = 0.89). Compared with placebo, finerenone significantly improved KCCQ-TSS from baseline with a mean difference at 12 months of 1.62 points (95% CI: 0.69-2.56 points) (P < 0.001). Numerically fewer finerenone-treated patients experienced clinically meaningful deterioration, and more had improvements in KCCQ-TSS. ConclusionsFinerenone significantly reduced HF events and improved health status in patients with HF and mildly reduced ejection fraction/preserved ejection fraction across the spectrum of KCCQ-TSS at baseline. (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone on Morbidity [Events Indicating Disease Worsening] & Mortality [Death Rate] in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF], NCT04435626; Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure; EudraCT 2020-000306-29)

Reverse-engineering placebo analgesia

Placebo analgesia is a widely observed clinical phenomenon. Establishing a robust mouse model of placebo analgesia is needed for careful dissection of the underpinning circuit mechanisms. However, previous studies failed to observe consistent placebo effects in rodent models of chronic pain. We wondered whether strong placebo analgesia can be reverse engineered using general-anesthesia-activated neurons in the central amygdala (CeAGA) that can potently suppress pain. Indeed, in both acute and chronic pain models, pairing a context with CeAGA-mediated pain relief produced robust context-dependent analgesia, exceeding that produced by morphine in the same paradigm. CeAGA neurons receive monosynaptic inputs from temporal lobe areas that could potentially relay contextual cues directly to CeAGA neurons. However, invivo imaging showed that CeAGA neurons were not reactivated in the conditioned context, despite mice displaying a strong analgesic phenotype. This finding suggests that the placebo-context-induced pain relief engages circuits beyond CeAGA neurons and relies on plasticity in other analgesic and/or nociceptive circuits. Our results show that conditioning with the activation of a central pain-suppressing circuit is sufficient to engineer placebo analgesia and that purposefully linking a context with an active treatment could be a means to harness the power of placebo for pain relief.

Metformin and small for gestational age babies: findings of a randomised placebo-controlled clinical trial of metformin in gestational diabetes (EMERGE).

Gestational diabetes mellitus (GDM) is associated with adverse perinatal outcomes because of suboptimal glucose management and glucose control and excessive weight gain. Metformin can offset these factors but is associated with small for gestational age (SGA) infants. We sought to identify risk factors for SGA infants, including the effect of metformin exposure on SGA status. In this prespecified secondary analysis of the EMERGE trial, which evaluated the effectiveness of metformin vs placebo in treating GDM and found reduced gestational weight gain and longer time to insulin initiation with metformin use, we included women with a live-born infant and known infant birthweight and gestational age at delivery. We compared the numbers of SGA infants in both groups and explored baseline predictive factors to help identify those at highest risk of delivering an SGA infant. Baseline maternal characteristics were similar between SGA and non-SGA pregnancies. On multivariable-adjusted regression, no baseline maternal variables were associated with SGA status. Mothers of SGA infants were more likely to develop pre-eclampsia or gestational hypertension (18.2% vs 2.0%, p=0.001; 22.7% vs 5.4%, p=0.005, respectively); after multivariable adjustment, pre-eclampsia was positively associated with SGA status). Among SGA pregnancies, important perinatal outcomes including preterm birth, Caesarean delivery and neonatal care unit admission did not differ between the metformin and placebo groups (20.0% vs 14.3%, p=1.00; 50.0% vs 28.6%, p=0.25; 13.3% vs 42.9%, p=0.27, respectively). Pre-eclampsia was strongly associated with SGA infants. Metformin-exposed SGA infants did not display a more severe SGA phenotype than infants treated with placebo. Clinical Trials.gov NCT02980276; EudraCT number: 2016-001644-19.

Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure

BackgroundObesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown. ObjectivesIn this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function. MethodsEchocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values. ResultsOverall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, −6.13 mL; 95% CI: −9.85 to −2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: −1.99 cm2; 95% CI: −3.60 to −0.38 cm2; P = 0.016; EMD in RV end-systolic area: −1.41 cm2; 95% CI: −2.42 to −0.40] cm2; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: −5.63 cm/s; 95% CI: −9.42 to −1.84 cm/s; P = 0.0037), E/A (early/late mitral inflow velocity) ratio (EMD: −0.14; 95% CI: −0.24 to −0.04; P = 0.0075), and E/e′ (early mitral inflow velocity/early diastolic mitral annular velocity) average (EMD: −0.79; 95% CI: −1.60 to 0.01; P = 0.05). These associations were not modified by diabetes or atrial fibrillation status. Semaglutide did not significantly affect left ventricular dimensions, mass, or systolic function. Greater weight loss with semaglutide was associated with greater reduction in LA volume (Pinteraction = 0.033) but not with changes in E-wave velocity, E/e′ average, or RV end-diastolic area. ConclusionsIn the STEP-HFpEF Program echocardiography substudy, semaglutide appeared to improve adverse cardiac remodeling compared with placebo, further suggesting that treatment with semaglutide may be disease modifying among patients with obesity-related HFpEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470)

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

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

Non-surgical interventions for preventing contralateral tissue loss and amputation in dysvascular patients with a primary major lower limb amputation.

Major lower limb amputation (LLA, above the ankle) is performed for people with intractable pain, life-threatening infections, or non-functional limbs. Of 7500 LLAs carried out in England between 2015 and 2018, the majority of these were performed in dysvascular patients. Dysvascularity is the absence of adequate blood supply to maintain a limb's usual function (ischaemia, usually caused by peripheral arterial disease or diabetes mellitus), ultimately leading to pain and tissue injury (ulcers, gangrene, sometimes referred to as tissue loss). Among those who undergo dysvascular LLA, 5.7% and 11.5% will likely undergo contralateral LLA at one and five years respectively, which is associated with greater disability and lower likelihood of returning to work, increasing the psychological burden to the patient and socioeconomic cost to the patient and health service. While extensive research has been carried out in the management of peripheral arterial disease and the care of diabetic feet, there are no guidelines for practice on prevention of contralateral amputation. To assess the effects of non-surgical interventions versus placebo, no intervention, or other non-surgical interventions on contralateral limb (CLL) tissue loss and amputation in dysvascular patients with a primary major LLA. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and PEDro databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers until 20 March 2023. We also checked the references of identified studies and contacted study authors and manufacturers of relevant products. We aimed to include all randomised controlled trials (RCTs) and quasi-RCTs (e.g. randomised by birthdate) comparing the effectiveness of a non-surgical intervention with placebo, no intervention, or other non-surgical intervention, in adults with a primary major LLA due to dysvascularity. Interventions could be physical, pharmacological, educational, behavioural, or organisational, and delivered by a healthcare professional or carer. Our critical and important outcomes of interest were as follows. Critical outcomes • Incidence of new localised tissue injury or ulceration (tissue loss) of the CLL, regardless of stage or classification at given time points. • Time to the development of any localised tissue injury or ulceration (tissue loss) of the CLL, regardless of stage or classification. • Incidence of new minor amputation (through the ankle, foot, or toe(s)) of the CLL at given time points. • Time to new minor amputation (through the ankle, foot, or toe(s)) of the CLL. • Incidence of new major amputation (whole limb or partial limb, above the ankle) of the CLL at given time points. • Time to new major amputation (whole limb or partial limb, above the ankle) of the CLL. Important outcomes • Survival (time to death from all causes) at 12 months. • Patient-reported outcome measures of health-related quality of life (HRQoL) using validated scales such as the 12-item Short Form Health Survey (SF-12) and EQ-5D. • Adverse events (e.g. infections in the CLL). • Hospital readmission. We used Cochrane's RoB 1 tool to assess risk of bias in the included study. We were only able to perform a narrative review due to lack of data. We reported risk ratios (RR) with 95% CIs for dichotomous outcomes. We used GRADE to assess the certainty of evidence for each outcome. We found one eligible study, which compared electrostimulation of the gastrocnemius muscle and standard rehabilitation against standard rehabilitation in 50 dysvascular amputees. There was no new incidence of tissue loss reported. The following outcomes were not reported: time to new tissue loss; time to and incidence of minor amputation; HRQoL outcomes; adverse events; and hospital readmissions. Electrostimulation was associated with a three-fold reduction in the incidence of new major amputation of the CLL (RR 0.33, 95% CI 0.04 to 2.99), although time to new major amputation was not reported. There was no difference between groups in 12-month survival (RR 1.0, 95% CI 0.85 to 1.18). We judged the overall certainty of the evidence (GRADE) as very low across all outcomes, with unclear risk of selection and detection bias and high risk of performance bias. Despite the care of the CLL being identified as a key research priority by two separate consensus papers, there is insufficient high-quality evidence to address this priority to date. We found only a single RCT suitable for inclusion, and this study was subject to risk of bias. Contralateral limb outcomes should be recorded in future research on dysvascular amputees. Until better evidence and clearer recommendations are available, this topic is likely to remain a research priority. This Cochrane review had no dedicated funding. Protocol available via DOI 10.1002/14651858.CD013857.

Comparative efficacy of subcutaneous versus intravenous natalizumab on annualized relapse rate: A post-hoc analysis of the REFINE study

BackgroundThe non-inferiority of the efficacy of subcutaneous (SC) vs intravenous (IV) administration of natalizumab (NTZ) once every 4 weeks in relapsing-remitting multiple sclerosis (RRMS) was recently demonstrated on the primary outcome of the REFINE study, i.e. MRI “combined unique active lesions number” (CUAL). To provide further evidence on the comparative efficacy of the two NTZ formulations, the effect of NTZ-SC vs NTZ-IV on annualized relapse rate (ARR) was investigated re-analysing the REFINE dataset. MethodsPost-hoc analysis of the REFINE study dataset aimed at exploring the non-inferiority of the efficacy of NTZ-SC vs NTZ-IV on ARR, i.e. the main secondary outcome of the REFINE study. Robustness of the non-inferiority analysis on CUAL with respect to the presence of cases from the SC arm who received a rescue treatment, including NTZ-IV, was also assessed by sensitivity analyses. Three non-inferiority margins were selected, corresponding to 25 %, 33 %, and 50 % fractions of the effect size of NTZ-IV vs placebo observed in the AFFIRM study on ARR (i.e. 0.125, 0.170, and 0.250). ResultsNinety-nine RRMS patients were included. The mean difference in the effect of NTZ-SC vs NTZ-IV on ARR was close to 0. The lower bound of the 95 % confidence interval (worst case scenario) was –0.119, corresponding to 25 % (p = 0.025) of the effect of NTZ-IV vs placebo on ARR. Sensitivity analyses confirmed the results of the primary non-inferiority analysis on the outcome CUAL. ConclusionsNTZ-SC resulted not inferior to NTZ-IV on ARR for all the non-inferiority margins. The non-inferiority analysis of the efficacy of NTZ-SC vs NTZ-IV on CUAL was demonstrated to be robust with respect to rescued patients.

Analysis of placebo effect of acupuncture.

Acupuncture is a comprehensive therapy which takes the theory of traditional Chinese medicine as the core. Currently, there is much controversy surrounding the "placebo effect" of acupuncture： some people argue that acupuncture is a "super placebo", while others believe that the so-called placebo effect is just part of the therapeutic effect of acupuncture. To solve the controversy, this article clarified the definition, composition, and research purposes of "placebo acupuncture", pointed out its differences from "sham acupuncture", elucidated the relationship between the placebo effect and the intrinsic efficacy of acupuncture, distinguished the differences between the "observed placebo effect" and the "real placebo effect" in acupuncture clinical trials, and proposed the dilemmas and prospects of implementing "placebo acupuncture" and "sham acupuncture" contrasts at the current stage, in order to provide clues for optimizing randomized controlled trials of acupuncture.

Extracellular vesicles for the treatment of ulcerative colitis: A systematic review and meta-analysis of animal studies

BackgroundExtracellular vesicles (EVs) are being considered as a potential therapeutic option for ulcerative colitis (UC), and numerous preclinical studies have been conducted on the use of EVs for UC. MethodsA systematic review was conducted to compare the therapeutic effects of mammalian EVs and placebo on UC in animal models, along with a meta-analysis comparing naïve (unmodified) EVs and placebo. The search was performed in four databases (PubMed, Web of Science, Scopus, and EMBASE) up to September 13th, 2023. The primary outcomes included disease activity index (DAI), colonic mucosal damage index (CMDI), and adverse effects (PROSPERO ID: CRD42023458039). ResultsA total of 69 studies were included based on pre-determined criteria, involving 1271 animals. Of these studies, 51 measured DAI scores, with 98 % reporting that EVs could reduce DAI scores. Additionally, 5 studies reported CMDI and all showed that EVs could significantly reduce CMDI. However, only 3 studies assessed adverse effects and none reported any significant adverse effects. The meta-analysis of these studies (40 studies involving 1065 animals) revealed that naïve EVs could significantly decrease the DAI score (SMD = −3.00; 95 % CI: −3.52 to −2.48) and CMDI (SMD = −2.10; 95 % CI: −2.85 to −1.35). ConclusionThe results indicate that mammalian EVs have demonstrated therapeutic benefits in animal models of UC; however, the safety profile of EVs remains inadequate which highlights the need for further research on safety outcomes.

Acute effects of R-MDMA, S-MDMA, and racemic MDMA in a randomized double-blind cross-over trial in healthy participants.

Racemic 3,4-methylenedioxymethamphetamine (MDMA) acutely increases mood, feelings of empathy, trust, and closeness to others and is investigated to assist psychotherapy. Preclinical research indicates that S-MDMA releases monoamines and oxytocin more potently than R-MDMA, whereas R-MDMA more potently stimulates serotonin 5-hydroxytryptamine-2A receptors. S-MDMA may have more stimulant properties, and R-MDMA may be more psychedelic-like. However, acute effects of S- and R-MDMA have not been examined in a controlled human study. We used a double-blind, randomized, placebo-controlled, crossover design to compare acute effects of MDMA (125 mg), S-MDMA (125 mg), R-MDMA (125 mg and 250 mg), and placebo in 24 healthy participants. Outcome measures included subjective, autonomic, and adverse effects, pharmacokinetics, and plasma oxytocin, prolactin, and cortisol concentrations. S-MDMA (125 mg) induced greater subjective effects ("stimulation," "drug high," "happy," "open") and higher increases in blood pressure than R-MDMA (both 125 and 250 mg) and MDMA (125 mg). Unexpectedly, R-MDMA did not produce more psychedelic-like effects than S-MDMA. S-MDMA increased plasma prolactin more than MDMA, and S-MDMA increased plasma cortisol and oxytocin more than MDMA and R-MDMA. The plasma elimination half-life of S-MDMA was 4.1 h after administration. The half-life of R-MDMA was 12 and 14 h after the administration of 125 and 250 mg, respectively. Half-lives for S-MDMA and R-MDMA were 5.1 h and 11 h, respectively, after racemic MDMA administration. Concentrations of the CYP2D6-formed MDMA-metabolite 4-hydroxy-3-methoxymethamphetamine were lower after R-MDMA administration compared with S-MDMA administration. The pharmacokinetic findings are consistent with the R-MDMA-mediated inhibition of CYP2D6. Stronger stimulant-like effects of S-MDMA in the present study may reflect the higher potency of S-MDMA rather than qualitative differences between S-MDMA and R-MDMA. Equivalent acute effects of S-MDMA, MDMA, and R-MDMA can be expected at doses of 100, 125, and 300 mg, respectively, and need to be investigated.Trial registration: ClinicalTrials.gov identifier: NCT05277636.

Health-related quality of life with gilteritinib vs placebo posttransplant for FLT3-ITD+ acute myeloid leukemia

AbstractThe Blood and Marrow Transplant (BMT) Clinical Trials Network conducted a phase 3 randomized trial comparing gilteritinib with placebo after allogeneic hematopoietic cell transplantation (HCT) for FLT3-ITD+ acute myeloid leukemia (AML). The primary analysis demonstrated no statistically significant difference in relapse-free survival (RFS); however, patients with FLT3-ITD measurable residual disease (MRD) peri-HCT had significantly longer RFS with gilteritinib. This analysis investigates the effect of post-HCT gilteritinib vs placebo on health-related quality of life (HRQOL). HRQOL was measured with Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), FACT-Leukemia (FACT-Leu), and EuroQOL-5 Dimensions (EQ-5D-5L) at post-HCT randomization; day 29; months 3, 6, 12, 18, 24; and/or end of therapy. HRQOL and clinically meaningful differences were summarized using descriptive statistics and compared using mixed model repeated measures to evaluate longitudinal change from baseline and stratified Cox model to evaluate time to improvement. HRQOL completion rate was acceptable (>70%) across all time points and measures. There were no differences in HRQOL scores at any time point between cohorts. Clinically meaningful and time to improvement in HRQOL were similar in both arms. Despite higher treatment-emergent adverse effects with gilteritinib, response to the question of being “bothered by side effects of treatment” did not differ between groups. Subgroup analysis of MRD-positive and negative patients demonstrated no differences in HRQOL between arms. For patients with FLT3-ITD+ AML undergoing HCT, gilteritinib maintenance was not associated with any difference in HRQOL or patient-reported impact of side effects. This trial was registered at www.ClinicalTrials.gov as #NCT02997202.

Placebo Effects on the Enjoyment of Physical Activity and Performance among Kindergarten Children: A Randomized Controlled Trial.

Studies with adults and school children have shown that placebos can enhance motivation and performance in physical activities. This study aimed to investigate whether similar effects are present in kindergarten-aged children. A total of 101 children (58 girls, 43 boys) aged 3 to 6 years were randomly assigned to one of two groups that either received a deceptive placebo (DP: "magic potion") or a nondeceptive placebo (NDP: "water") to enhance physical abilities. Each child completed three tasks (sprinting; balancing: standing on a balance board; strength: using a handheld dynamometer) both with and without the placebo. The variables assessed included task performance, enjoyment, and expected and perceived placebo efficacy (measured with nonverbal pictorial rating scales). Results showed that both the DP and NDP increased speed. For strength, balance, and task enjoyment (which was very high), no placebo-induced changes were observed. Expected efficacy was higher for the DP; perceived efficacy did not differ between DP and NDP. In conclusion, reported outcome expectations indicated that kindergarten-aged children were already able to differentiate between the two types of placebos which exhibited positive effects concerning running performance. This encourages further research on using nondeceptive placebos to enhance physical activity, which is crucial for children's overall health.

Esketamine vs. placebo combined with erector spinae plane block vs. intercostal nerve block on quality of recovery following thoracoscopic lung resection: A randomized controlled factorial trial.

Multimodal analgesic strategy is pivotal for enhanced recovery after surgery. The objective of this trial was to assess the effect of subanesthetic esketamine vs. placebo combined with erector spinae plane block (ESPB) vs. intercostal nerve block (ICNB) on postoperative recovery following thoracoscopic lung resection. This randomized, controlled, 2×2 factorial trial was conducted at a university hospital in Suzhou, China. One hundred adult patients undergoing thoracoscopic lung surgery were randomized to one of four groups (esketamine-ESPB, esketamine-ICNB, placebo-ESPB, and placebo-ICNB) to receive i.v. esketamine 0.3mg/kg or normal saline placebo combined with ESPB or ICNB using 0.375% ropivacaine 20mL. All patients received flurbiprofen axetil and patient-controlled fentanyl. The primary outcome was quality of recovery (QoR) at 24 h postoperatively, assessed using the QoR-15 scale, with a minimal clinically important difference of 6.0. The median age was 57 years and 52% were female. No significant interaction effect was found between esketamine and regional blocks on QoR (P=0.215). The QoR-15 score at 24 h was 111.5±5.8 in the esketamine group vs. 105.4±4.5 in the placebo group (difference=6.1, 95% CI, 4.0-8.1; P<0.001); 109.7±6.2 in the ESPB group vs. 107.2±5.6 in the ICNB group (difference=2.5, 95% CI, 0.2-4.9; P=0.033; not statistically significant after Bonferroni correction). Additionally, esketamine resulted in higher QoR-15 scores at 48 h (difference=4.6) and hospital discharge (difference=1.6), while ESPB led to a higher QoR-15 score at 48 h (difference=3.0). For patients undergoing thoracoscopic lung resection, subanesthetic esketamine improved QoR after surgery, while ICNB can be used interchangeably with ESPB as a component of multimodal analgesia.

Effect of Fermented Soybean (FSB) Supplementation on Gastroesophageal Reflux Disease (GERD).

Gastroesophageal reflux disease (GERD) is a prevalent chronic condition affecting the well-being of both adults and children in general medical practice. Research on the effects of fermented soybean (SB) supplementation in managing GERD is relatively new, with limited studies available. The existing research often lacks sufficient dosing regimens and study durations to differentiate between transient placebo effects and sustained benefits. In this study, the beneficial effects of FSB supplementation were investigated in 110 voluntary participants (NCT06524271). The participants were required to take 1 g of FSB supplement once daily for 12 weeks. GERD symptoms were evaluated using the Reflux Disease Questionnaire (RDQ), while inflammatory markers, including interleukin-4 (IL-4), interleukin-6 (IL-6), and interleukin-8 (IL-8), were measured to assess inflammation. The Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire was used to evaluate participants' quality of life. The results indicated that FSB supplementation significantly (p < 0.05) alleviated heartburn and regurgitation symptoms and reduced levels of IL-4, IL-6, and IL-8, indicating a notable anti-inflammatory effect. Additionally, significant (p < 0.05) improvements were observed in QOLRAD scores, particularly in vitality, emotional distress, and physical/social functioning. Collectively, our findings support the use of FSB as an adjuvant approach in managing GERD, with notable improvements in patients' quality of life.

Placebo effect in clinical practice

The term placebo poses challenges in definition, language and use in research and clinical settings. Placebo extends beyond inactive substances, and modern exploration has revealed complex neurobiological, psychological, and social factors influencing placebo mechanisms. With knowledge of the placebo effect, clinicians can assess and enhance the effectiveness of the most optimal treatments. Future research should explore ethical ways of promoting placebo effects, aligning with broader goals in medical practice, as argued in this review.

Effects of open and hidden administration of treatment-related information; a multi-experiment study

Background Two experiments (E1 and E2; N = 44 and N = 52, respectively) investigated the effect of positive (PI) and neutral information (NI) about a dental procedure, and if the delivery of the information by the treatment team (open administration) or unbeknownst to the treatment team (hidden administration), affected pain. Methods Using a mixed design, patients undergoing drilling in a molar were randomized to the NI or PI groups. Before, during, and after treatment, patients reported their pain and stress levels. In E1 the treatment team delivered the information. In E2, an assistant not engaged in the treatment delivered the information. Results In the PI group in E1, pain was reduced by 50 % compared to the NI group, and the effects of stress on pain were mitigated. These effects were abolished in E2. The dentist reported having displayed positive nonverbal behaviours (e.g. smiling and longer eye contact) in the PI group in E1, but not in E2. Discussion Positive information reduced pain only when administrated openly. There was no effect of positive information administrated hidden from the treatment team. As information was similar in both experiments, factors other than the information most likely reduced pain in the PI group in E1. Conclusion Delivering positive information by the treatment team may generate behavioural cues which generate placebo effects.

A Pilot Phase 2 Randomized Trial to Evaluate the Safety and Potential Efficacy of Etravirine in Friedreich Ataxia Patients.

A drug repositioning effort supported the possible use of the anti-HIV drug etravirine as a disease-modifying drug for Friedreich ataxia (FRDA). Etravirine increases frataxin protein and corrects the biochemical defects in cells derived from FRDA patients. Because of these findings, and since etravirine displays a favorable safety profile, we conducted a pilot open-label phase 2 clinical trial assessing the safety and potential efficacy of etravirine in FRDA patients. Thirty-five patients were stratified into three severity groups and randomized to etravirine 200 mg/day or 400 mg/day. They were treated for 4 months. Safety endpoints were the number and type of adverse events and number of dropouts. Efficacy endpoints were represented by changes in peak oxygen uptake and workload as measured by incremental exercise test, SARA score, cardiac measures, measures of QoL and disability. Data were collected 4 months before the start of the treatment (T - 4), at the start (T0), at the end (T4) and 4 months after the termination of the treatment (T + 4). Etravirine was reasonably tolerated, and adverse events were generally mild. Four months of etravirine treatment did not significantly increase the peak oxygen uptake but was associated with a change in the progression of the SARA score (p value < 0.001), compared to the 4 months pre- and post-treatment. It also significantly increased peak workload (p value = 0.021). No changes in the cardiac measures were observed. Health and QoL measures showed a worsening at the suspension of the drug. In this open trial etravirine treatment was safe, reasonably well tolerated and appreciably improved neurological function and exercise performance. Even though a placebo effect cannot be ruled out, these results suggest that etravirine may represent a potential therapeutic agent in FRDA deserving testing in a randomized placebo-controlled clinical trial.

Placebo Effect in the Treatment of Patellar Tendinopathy and Its Influencing Factors: Systematic Review With Meta-analysis and Meta Regression of Randomized Controlled Trials.

The effectiveness of nonsurgical treatment of patellar tendinopathy is questioned due to the conflicting results of placebo-controlled randomized controlled trials (RCTs) in which placebo arms often show impressive results. To quantify the magnitude of placebo effect of the different nonsurgical treatments of patellar tendinopathy. We also evaluated the influence of patients and treatments characteristics on the response to the placebo. Systematic review; Level of evidence, 1. We searched PubMed, Web of Science, Embase, Scopus, Cochrane Library, and gray literature databases on May 10, 2023, with no time limitation. RCTs on nonoperative treatment of patellar tendinopathy, including a placebo control arm reporting the evolution of symptoms after placebo administration, were included. A single-arm meta-analysis was performed with the Victorian Institute of Sport Assessment-Patella (VISA-P) at mid-term follow-up (3-6 months) as the primary outcome. The VISA-P score at short-term (1-3 months) and long-term (6-12 months) follow-ups, as well as visual analog scale (VAS) for pain at all 3 time points were also analyzed. A subanalysis based on the type of placebo and a meta-regression were conducted to look for potential determinants of the placebo effect. Risk of bias and level of evidence were also analyzed using the revised tool for risk of bias in randomized trials and Grading of Recommendations Assessment, Development and Evaluation. In total, 14 studies (251 patients) were included. VISA-P score at mid-term follow-up (3-6 months) showed statistically significant improvements of 13 of 100 points (P = .001). The change at short-term follow-up (1-3 months) was not statistically significant, whereas at long-term follow-up (6-12 months) it was 27 of 100 points (P < .001). Regarding VAS, results were statistically significant only at mid-term (MD = -1.5/10; P = .02) and long-term (MD = -3.2/10; P < .001) follow-ups. The meta-regression showed positive correlations between the response to placebo and the follow-up length (P < .001) and the effect size in the experimental group (P = .006). The level of evidence was moderate for mid- and long-term results and low for short-term results. The placebo effect for nonsurgical treatments of patellar tendinopathy is long-lasting (up to 12 months) and statistically and clinically significant. It has a perceived and true component and differs among treatments. The duration of follow-up and the effect size of experimental groups correlate with the magnitude of the placebo component, underlining the importance of RCTs to determine the effectiveness of new treatments of patellar tendinopathy.

A systematic review and meta-analysis of the placebo effect on both semen quality and male infertility.

Placebo influence on such objective indicators, as sperm quality and infertility, has not been studied previously, but some studies report that placebo may distort even objective outcomes. The aim of current study is to assess the placebo effect on fertility in patients suffering from sperm abnormalities and/or infertility. We conducted a search of two databases (Scopus and MEDLINE) and identified placebo-controlled clinical trials which focused on sperm abnormalities and/or male infertility treatment. Primary outcomes included changes in semen parameters (volume, total count, sperm concentration in semen, progressive motility, morphology (normal cells)). Secondary outcomes included DNA fragmentation and change in pregnancy rate. Seventy-seven articles published from 1983 to 2022 were included. Statistically significant changes were observed for the following values: total sperm count, mean change 0.16 (95% CI 0.05, 0.26); P=0.004, I2=75.1%; and progressive motility, mean change 0.13 (95% CI 0.02, 0.24); P=0.026, I2=84.9%. In contrast, placebo did not affect sperm concentration, sperm volume, sperm morphology or DNA fragmentation index. The publication bias for all the values measured with Egger's test and funnel plots was low. The current meta-analysis indicated a statistically significant increase of total sperm count and progressive motility in the placebo group. In contrast, placebo did not affect sperm concentration, sperm volume, sperm morphology and DNA fragmentation index. These findings should be considered while planning or analyzing placebo-controlled clinical trials.

Is microdosing a placebo? A rapid review of low-dose LSD and psilocybin research.

Some recent research and commentary have suggested that most or all the effects reported by people who microdose psychedelics may be explained by expectations or placebo effects. In this rapid review, we aimed to evaluate the strength of evidence for a placebo explanation of the reported effects of microdosing. We conducted a PubMed search for all studies investigating psychedelic microdosing with controlled doses and a placebo comparator. We identified 19 placebo-controlled microdosing studies and summarised all positive and null findings across this literature. Risk of bias was assessed using the Cochrane risk-of-bias tool for randomised trials. The reviewed papers indicated that microdosing with LSD and psilocybin leads to changes in neurobiology, physiology, subjective experience, affect, and cognition relative to placebo. We evaluate methodological gaps and challenges in microdosing research and suggest eight reasons why current claims that microdosing is predominately a placebo are premature and possibly wrong: (1) there have been only a small number of controlled studies; (2) studies have had small sample sizes; (3) there is evidence of dose-dependent effects; (4) studies have only investigated the effects of a small number of doses; (5) the doses investigated may have been too small; (6) studies have looked only at non-clinical populations; (7) studies so far have been susceptible to selection bias; and (8) the measured impact of expectancy is small. Considering the available evidence, we conclude that it is not yet possible to determine whether microdosing is a placebo.