Placebo Effect Research Articles

Alterations in brain activity and functional connectivity originating residual inhibition of tinnitus induced by tailor-made notched music training.

Tinnitus arises from the intricate interplay of multiple, parallel but overlapping networks, involving at least neuroplastic changes in the auditory and non-auditory activity. Tailor-made notched music training (TMNMT) is a promising therapy for tinnitus. Residual inhibition (RI) is one of the rare interventions capable of temporarily alleviating tinnitus, which is a useful technique that can be applied to tinnitus research and explore tinnitus mechanisms. To our knowledge, this study is the first to investigate the neural mechanisms underlying the RI effect of TMNMT through analysis of neural source activity and functional connectivity of EEG. Forty-four participants with tinnitus were divided into TMNMT group (twenty-two participants; ECnm, NMnm, RInm represent that EEG recordings with eyes closed stimuli-pre, stimuli-ing, stimuli-post by TMNMT music, respectively) and Placebo control group (twenty-two participants; ECpb, PBpb, RIpb represent that EEG recordings with eyes closed stimuli-pre, stimuli-ing, stimuli-post by Placebo music, respectively) in a single-blind manner. Source localization analysis revealed that RI effect of TMNMT significantly increased in current density at the delta band for the insula, subgenual anterior cingulate cortex (sgACC), parahippocampus (PHC), and secondary auditory cortex (AⅡ), and significantly increased in current density at the theta band for the sgACC, and significantly decreased in current density at the alpha band for the precuneus, PHC, primary and secondary auditory cortex (AⅠ and AⅡ). Meanwhile, RI effect of Placebo significantly decreased in current density at the alpha band for the PHC. Functional connectivity analysis demonstrated that RI effect of TMNMT significantly increased in phase coherence between the left AⅡ and the right sgACC; and between the left PHC and the left retrosplenial cortex (RSC) at the theta band. It significantly decreased in phase coherence between the left PHC and the right precuneus, the right posterior cingulate cortex (PCC), the right AⅡ; between the right PHC and the right PCC; and between the right PCC and the right AⅡ at the alpha band. RI effect of Placebo significantly increased in phase coherence between the left insula and the right precuneus, the left PHC, the right PHC, the left AⅠ, the left AⅡ; between the left sgACC and the right PHC; between the left AⅡ and the right PHC, the left PCC at the delta band. It was also found that the current density of sgACC was significant positively correlated with the tinnitus evaluation indicators (Loudness, VAS, THI, TFI) at the alpha band in TMNMT group. These results suggested that TMNMT, a novel music therapy for tinnitus, had a stronger ability of residual inhibition (RI), which RI effect of TMNMT not only participated in the activity of auditory network (AⅠ, AⅡ), but also extends to non-auditory network, particularly higher-level auditory association cortices such as the sgACC, PHC and PCC. The current study provided valuable experimental evidence and practical prospects for the potential applications of TMNMT in tinnitus treatment.

Comprehensive analysis of ocrelizumab's efficacy across different forms of multiple sclerosis: a multi-dimensional approach

BackgroundMultiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system. MS usually affects individuals between the ages of 20 and 40 and is 3 times more common among women than among men. This disease presents with a vast range of neurological symptoms and, in some cases, cognitive impairment. Aim of the studyThe purpose of this review was to assess whether the anti-CD20 antibody ocrelizumab has proven effective in treating MS since its introduction.Material and methodsThe PubMed database was searched for original papers on the effects of ocrelizumab in the treatment of MS. The inclusion criterion was a comparison of the clinical or radiological effectiveness of ocrelizumab versus placebo or other MS therapies. For this purpose, the phrase "Ocrelizumab AND Multiple Sclerosis" was used, marking only studies such as "Randomised Clinical Trial" and "Clinical Trial". The cut-off point for publishing the work was 2016.Results43 works were found, of which 15 met the conditions for inclusion in the work. The analysed studies investigated the efficacy and safety of ocrelizumab in Relapsing Multiple Sclerosis, Primary Progressive Multiple SclerosisConclusionsThe effectiveness of ocrelizumab treatment shows that the use of newly developed targeted factors may significantly improve the clinical status of MS patients. Preliminary real-world data on the efficacy of ocrelizumab are promising and align with clinical trial findings. Although ocrelizumab is generally well tolerated, it is essential to monitor and assess its long-term safety.

Neural mechanisms underlying placebo and nocebo effects in tonic muscle pain

Pain is a highly subjective and multidimensional experience, significantly influenced by various psychological factors. Placebo analgesia and nocebo hyperalgesia exemplify this influence, where inert treatments result in pain relief or exacerbation, respectively. While extensive research has elucidated the psychological and neural mechanisms behind these effects, most studies have focused on transient pain stimuli. To explore these mechanisms in the context of tonic pain, we conducted a study using a 15-minute tonic muscle pain induction procedure, where hypertonic saline was infused into the left masseter of healthy participants. We collected real-time Visual Analogue Scale (VAS) scores and functional magnetic resonance imaging (fMRI) data during the induction of placebo analgesia and nocebo hyperalgesia via conditioned learning. Our findings revealed that placebo analgesia was more pronounced and lasted longer than nocebo hyperalgesia. Real-time pain ratings correlated significantly with neural activity in several brain regions. Notably, the putamen was implicated in both effects, while the caudate and other regions were differentially involved in placebo and nocebo effects. These findings confirm that the tonic muscle pain paradigm can be used to investigate the mechanisms of placebo and nocebo effects and indicate that placebo analgesia and nocebo hyperalgesia may have more distinct than common neural bases.

Population pharmacokinetic and dose-response models of nepadutant, a selective antagonist of the NK2 receptors, in infants with colic.

The aim of the current analyses was to develop a population pharmacokinetic model for nepadutant in infants with colic, and a pharmacokinetic-pharmacodynamic model based on observations of duration of crying and fussing following oral nepadutant administration in infants (3-25 weeks) with colic. The models were developed based on data obtained at baseline and following treatment with placebo, nepadutant 0.1mg/kg or nepadutant 0.5mg/kg administered for 7days. A continuous response variable, duration of crying and fussing in minutes within 2h interval, was assembled based on records from "baby's day" diary. The pharmacokinetics of nepadutant was described by a one-compartment model with first-order absorption and elimination with body weight as a structural covariate incorporated allometrically. For an infant weighing 5.3kg, the estimated apparent clearance was 68.6L/h (12% relative standard error) and exhibited large variability (78% coefficient of variation). The pharmacokinetic-pharmacodynamic model described (i) a circadian rhythm in the response with lowest and highest observations at 4a.m. and 9p.m., respectively, (ii) a placebo effect increasing and flattening out with time in an exponential manner, and (iii) a statistically significant (P < .01) linearly increasing response with dose. The observed and model predicted relative change in response from baseline was -35% and -28% (95% prediction interval -36%; -19%) following placebo, and -44% and -36% (-46%; -27%) after 0.5mg/kg. Population pharmacokinetic and dose-response models were successfully developed characterizing the available nepadutant pharmacokinetics and duration of crying and fussing data in infants.

Placebo effects beyond dopamine.

The role of dopamine in reward expectancy has led to the hypothesis that it is crucial for forming treatment expectations and placebo effects. However, a new study in PLOS Biology presents robust evidence against the causal role of dopamine in these processes.

Opioids Diminish the Placebo Antidepressant Response: A Post Hoc Analysis of a Randomized Controlled Ketamine Trial.

The endogenous opioid system is thought to play a role in the placebo antidepressant response. A recent trial comparing the rapid antidepressant effects of ketamine versus placebo in surgical patients, some of whom were on chronic opioid therapy, revealed a substantial placebo effect. This finding provided an opportunity to test the hypothesis that opioid agonist exposure interacts with placebo antidepressant responses. This post hoc analysis utilized data from a previously reported randomized, anesthesia-blinded, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery. Mixed-effects models were used to determine whether baseline opioid use influenced antidepressant responses to the trial interventions, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) over 1 to 14 days post-treatment. The analysis showed that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, baseline pain intensity, and ethnicity. Additionally, there was negligible correlation between postoperative pain intensity and depression severity. This analysis was unregistered and conducted on a small sample; the findings need to be confirmed by prospective controlled studies. Opioid use at baseline attenuated the placebo antidepressant response independently of pain in depressed patients who received the study treatment under general anesthesia for routine surgery. The antidepressant response was preserved in opioid users who received intravenous ketamine.

Dopamine has no direct causal role in the formation of treatment expectations and placebo analgesia in humans.

Dopamine-based reward and learning mechanisms have been suggested to contribute to placebo effects. However, the exact role of dopaminergic neurotransmission in their generation and maintenance is still unclear. This study aimed to shed light on the causal role of dopamine in establishing positive treatment expectations, as well as on the magnitude and duration of their effect on pain. To this end, we used an established placebo analgesia paradigm in combination with 2 opposing pharmacological modulations of dopaminergic tone, i.e., the dopamine antagonist sulpiride and the dopamine precursor L-dopa which were both applied in an experimental, double-blind, randomized, placebo-controlled trial with a between-subject design in N = 168 healthy volunteers. The study medication successfully altered dopaminergic tone during the conditioning procedure. Contrary to our hypotheses, the medication did not modulate the formation of positive treatment expectation and placebo analgesia tested 1 day later. Placebo analgesia was no longer detectable on day 8 after conditioning. Using a combined frequentist and Bayesian approach, our data provide strong evidence against a direct dopaminergic influence on the generation and maintenance of placebo effects. Further exploration of the neurochemical mechanisms underlying placebo analgesia remains paramount in the quest to exploit these effects for optimal treatment outcomes. Trial registration: ClinicalTrials.gov German Clinical Trials Register, ID: DRKS00029366, https://drks.de/search/en/trial/DRKS00029366.

Caffeine Placebo Effect in Sport and Exercise: A Systematic Review.

The objective of this review article is to systematically identify the caffeine placebo effect in sport and exercise activities. We selected randomized controlled trial studies to better understand the impact of caffeine and its placebo effect on sports performance. We extracted a set of articles that refer strictly to the topics of caffeine and its placebo effect in sport and exercise, considering the databases integrated to the Core Collection Web of Science and Scopus, as well as the registration of the documents in PubMed®, a system with a selection process aligned with the guidelines for the PRISMA methodology, establishing the eligibility criteria of the articles with the PICOS tool, to which a systematic review is applied. Finally, the results show that caffeine improves anaerobic capacity and endurance, while placebo perceived as caffeine can also increase performance by reducing pain and improving concentration. This finding underscores the influence of expectations and placebo on physical performance, suggesting that managing these expectations may be an effective strategy for improving athletic performance.

Randomised control trial indicates micronutrient supplementation may support a more robust maternal microbiome for women with antenatal depression during pregnancy

Background and AimsWe investigated the effects of high dose dietary micronutrient supplementation or placebo on the human gut microbiome in pregnant women who had moderate symptoms of antenatal depression. There is a significant absence of well-controlled clinical studies that have investigated the dynamic changes of the microbiome during pregnancy and the relationship among diet, microbiome and antenatal depression. This research is among the first to provide an insight into this area of research. MethodsThis 12 - week study followed a standard double blinded randomised placebo-controlled trial (RCT) design with either high dose micronutrients or active placebo. Matching stool microbiome samples and mood data were obtained at baseline and post-treatment, from participants between 12 and 24 weeks gestation. Stool microbiome samples from 33 participants (17 in the placebo and 16 in the treatment group) were assessed using 16s rRNA sequencing. Data preparation and statistical analysis was predominantly performed using the QIIME2 bioinformatic software tools for 16s rRNA analysis. ResultsMicrobiome community structure became increasingly heterogenous with decreased diversity during the course of the study, which was represented by significant changes in alpha and beta diversity. This effect appeared to be mitigated by micronutrient administration. There were less substantial changes at the genus level, where Coprococcus decreased in relative abundance in response to micronutrient administration. We also observed that a higher abundance of Coprococcus and higher alpha diversity correlated with higher antenatal depression scores. ConclusionsMicronutrient treatment appeared to support a more diverse (alpha diversity) and stable (beta diversity) microbiome during pregnancy. This may aid in maintaining a more resilient or adaptable microbial community, which would help protect against decreases or fluctuations that are observed during pregnancy.

Impact of empagliflozin on cardiac structure and function assessed by echocardiography after myocardial infarction: a post-hoc sub-analysis of the emmy trial

Abstract Background Empagliflozin administered after acute myocardial infarction proofed to improve cardiometabolic parameters and biomarkers, but the impact on cardiac function is still largely unknown. The aim of this post-hoc echocardiographic sub-analysis of the EMMY trial was to provide in-depth echocardiographic analysis on the effects of empagliflozin versus placebo on standard and novel echocardiographic structural and functional parameters after acute myocardial infarction. Methods In this post-hoc analysis of the EMMY trial a subset of 313 patients (157 empagliflozin vs. 156 placebo) was enrolled for post-processing analysis of echocardiographic structural and functional parameters. On top of two-dimensional and Doppler parameters, myocardial deformation analyses were performed to assess ventricular and atrial strain values. Results Left ventricular volumes showed significant differences in favor of empagliflozin over the course of the trial (change in left ventricular end-diastolic volume median [interquartile range] 8 [−3;19]% versus 13 [0;29]%, p = 0.048; left ventricular end-systolic volume −3 [−15;12]% versus 4 [−12;18]%, p = 0.044). This effect persisted after adjusting for baseline values, age, and sex. Left ventricular systolic and diastolic function overall improved over the course of the trial and parameters for diastolic function showed a distinct trend between groups but did not meet statistical significance in this cohort. Conclusion In this post-hoc analysis among patients with acute myocardial infarction, treatment with empagliflozin resulted in a significant beneficial effect on left ventricular end-diastolic and end-systolic volume, without significantly improving left ventricular or right ventricular functional parameters compared to placebo after 26 weeks. ClinicalTrials.gov registration NCT03087773. Graphical abstract

Associations with early vomiting when using intranasal fentanyl and nitrous oxide for procedural sedation in children: A secondary analysis of a randomised controlled trial.

Intranasal (IN) fentanyl and nitrous oxide (N2O) can be combined to provide procedural sedation and analgesia to children. This combination is advantageous because of rapid onset of action and non-parenteral administration, but is associated with increased vomiting. We sought to describe the associations of demographic and procedural factors with early vomiting when using this combination in children. This was a planned secondary analysis of a randomised controlled trial comparing the effect of oral ondansetron versus placebo at a single paediatric hospital. Children aged 3 to <18 years with planned procedural sedation with IN fentanyl and N2O were randomised to receive oral ondansetron or placebo prior to N2O administration. Vomiting was defined as early if occurring during or up to 1 h after N2O delivery. We assessed the relationship between early vomiting, demographic and procedural characteristics. Participants were recruited between October 2016 and January 2019 and 62 out of 436 (14%) had early vomiting. The risk of early vomiting was 30% higher with higher total dose of fentanyl, risk ratio = 1.3 (95% confidence interval = 1.004-1.59). There was little evidence of a relationship between the occurrence of early vomiting and sex, age, weight, type of procedure, fasting duration, time between fentanyl administration and start of procedure, and procedure duration. We found that higher doses of IN fentanyl were associated with higher risk of early vomiting when administered with N2O in children. Other factors did not appear to be associated with vomiting.

Dapagliflozin in Heart Failure: A Comprehensive Meta-analysis on Functional Capacity, Symptoms, and Safety Outcomes.

To evaluate the comparative effects of dapagliflozin versus placebo in patients with heart failure (HF), focusing on functional capacity, symptoms, and safety outcomes. Despite advancements in heart failure (HF) therapy, HF is still a significant cause of recurrent hospitalization and death worldwide. Dapagliflozin has demonstrated potential in lowering hospitalizations and mortality associated with heart failure; however, its impact on functional capacity, particularly the 6-min walk distance (6MWD), and the comprehensive assessment of safety outcomes in diverse HF populations, including those with preserved or reduced ejection fraction (HFpEF and HFrEF, respectively), requires further investigation. PubMed, Web of Science, Cochrane Library, and Scopus databases were comprehensively searched to identify randomized controlled trials (RCTs) investigating the efficacy of dapagliflozin in comparison with control interventions for heart failure. The primary outcome was a change in the 6MWD, KCCQ score, and safety measures included hospitalization, all-cause mortality, and adverse events. In our meta-analysis of ten studies involving 12,695 patients with heart failure, dapagliflozin showed significantly improved Kansas City Cardiomyopathy Questionnaire (KCCQ) scores [risk ratio (RR) of 2.75, 95% confidence interval (CI) (1.95-3.569), p < 0.00001] and no significant differences in 6-min walk distance [6MWD; RR of 3.59, 95% CI (- 1.44 to 8.63), p = 0.16]. Dapagliflozin demonstrated a notable reduction in hospitalization for heart failure [RR of 0.76, 95% CI (0.68-0.84), p < 0.00001], significant overall reduction on the effect of any cause mortality [RR of 0.90, 95% CI (0.83-0.99), p = 0.03). There was, however, no significant effect on adverse events [RR of 0.96, 95% CI (0.98-1.03), p = 0.39). Our meta-analysis of ten trials concluded that dapagliflozin significantly improved KCCQ scores in both HFrEF and HFpEF. The improvement in 6MWD was not statistically significant but trended toward dapagliflozin. Dapagliflozin also showed a mortality benefit in patients with reduced ejection fraction; however, in patients with preserved ejection fraction, the result was not statistically significant. There was also a statistically significant reduction in heart failure hospitalizations across all classes.

Naldemedine for Opioid-Induced Constipation in Patients With Cancer: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial.

Opioid-induced constipation is the most frequent and non-self-limiting adverse effect of opioid analgesia, reducing adherence and interfering with pain relief. This clinical trial aimed to clarify the preventive effect of naldemedine versus placebo for constipation in patients with cancer starting regularly dosed strong opioids therapy. This multicenter, double-blinded, randomized, placebo-controlled, confirmatory trial was conducted between July 2021 and May 2023 at four academic hospitals in Japan (ClinicalTrials.gov identifier: jRCTs031200397). Patients with cancer starting a first-time regularly dosed strong opioid for cancer pain and age 20+ years were included. Eligible patients were randomly assigned to the naldemedine (Symproic 0.2 mg) or placebo group in a 1:1 ratio for 14 days with protocol treatment. The primary end point was the proportion of patients with a Bowel Function Index (BFI) of <28.8 on day 14. The secondary end points included frequency of spontaneous bowel movements (SBM), quality of life (QOL), and frequency of opioid-induced nausea and vomiting (OINV). Of the 103 patients assessed for eligibility, 99 received either naldemedine (n = 49) or placebo (n = 50). A BFI of <28.8 on day 14 was significantly more likely to occur in the naldemedine group (64.6%; 95% CI, 51.1 to 78.1) versus placebo (17.0%; 95% CI, 6.3 to 27.8), and the difference between groups was 47.6% (95% CI, 30.3 to 64.8; P < .0001). The frequency of SBM, QOL, and the severity of OINV were nominally significant in the naldemedine group than in the control group. Naldemedine prevented constipation and improved constipation-related QOL, with possible preventive effect on OINV in patients with cancer starting regularly dosed opioids therapy.

Do Audible Sounds during a Lumbar Spine Thrust Manipulation Have an Impact on Brainwave Activity?

To manage pain and stiffness of the lumbar spine, thrust manipulation is commonly used. High-velocity, small-amplitude thrust manipulation often elicits audible sounds. What causes this audible sound remains unclear, and its clinical significance has not been shown. This study aimed to identify how audible sound affects brainwave activity following a side-lying right rotatory thrust manipulation in a group of healthy individuals. This was a quasi-experimental repeated measures study design in which 44 subjects completed the study protocol. A portable Bluetooth EEG device was used to capture brainwave activity. The environment was controlled during testing to minimize any factors influencing the acquisition of real-time EEG data. After a short accommodation period, initial brainwaves were measured. Following this, each subject underwent a lumbar 4-5 side-lying right rotatory thrust manipulation, immediately followed by a second brainwave measurement. A third measurement took place one minute later, followed by a fourth one at the three-minute mark. 21 subjects did not experience audible sounds, while 23 subjects experienced audible sounds. Both groups had significant changes measured by the 14 electrodes (p < 0.05). The audible group had more significant changes, which lasted only two minutes. The lack of brainwave response differences between the audible and non-audible groups implies no direct, measurable placebo or beneficial effect from the audible sound. This study could not identify a benefit from the audible sound during an HVLA manipulation of the subjects.

Effects of fremanezumab on migraine-associated symptoms and medication use in Japanese and Korean patients with episodic migraine: Exploratory endpoint analysis of a multicenter, randomized, double-blind, placebo-controlled trial.

To describe exploratory endpoints from a previous phase 2b/3 placebo-controlled trial conducted in Japan and Korea, specifically investigating the effect of fremanezumab or placebo on migraine-associated symptoms and acute headache medication use in patients with episodic migraine (EM). EM is associated with non-head pain symptoms, including nausea, vomiting, photophobia, or phonophobia, which contribute substantially to the disease burden, healthcare resource utilization, and impaired quality of life. Current EM treatments include a mix of nonspecific/migraine-specific acute headache medications, but medication overuse can induce headaches and progression from EM to chronic migraine (CM). In multiple phase 2b/3 trials, the monoclonal antibody fremanezumab significantly reduced the average number of monthly migraine days experienced by patients with EM/CM compared with placebo. This was a prespecified analysis of exploratory endpoints in a multicenter, randomized, double-blind, placebo-controlled, phase 2b/3 trial conducted in Japanese and Korean patients with EM (NCT03303092). Patients were randomized to receive fremanezumab, either monthly or quarterly, or matching placebo, administered subcutaneously at 4-week/28-day ("monthly") intervals to maintain blinding. Exploratory endpoints reported here were the mean change from baseline in the number of days/month with (i) the use of any acute headache medication, (ii) the use of any migraine-specific acute headache medication, (iii) nausea or vomiting, and (iv) photophobia and phonophobia. Overall, 357 Japanese and Korean patients with EM received either monthly (n = 121) or quarterly (n = 119) fremanezumab or placebo (n = 117). Compared with placebo, fremanezumab administered monthly or quarterly was associated with a significant reduction from baseline in the average number of days/month with acute headache medication use over three months (difference vs. placebo -2.81 [95% confidence interval (CI) -3.52, -2.11]; p < 0.001 and -2.79 [95% CI -3.50, -2.08]; p < 0.001, respectively). Similar findings were observed in the monthly average number of days with migraine-specific acute headache medications (difference vs. placebo with monthly and quarterly fremanezumab, -2.63 [95% CI -3.31, -1.95] for both; p < 0.001), the average number of days/month with nausea or vomiting (difference vs. placebo -1.09 [95% CI -1.60, -0.58]; p < 0.001 for monthly fremanezumab and -1.37 [95% CI -1.88, -0.86]; p < 0.001 for quarterly fremanezumab), and the average number of days with photophobia and phonophobia (difference vs. placebo -1.22 [95% CI -1.80, -0.65]; p < 0.001 and -1.64 [95% CI -2.22, -1.06]; p < 0.001, respectively). Monthly and quarterly administered fremanezumab effectively prevented EM in Japanese and Korean patients. Fremanezumab also improved other disease aspects including the need for acute headache medications and the frequency of migraine-associated symptoms.

Pulmonary Vein Isolation vs Sham Intervention in Symptomatic Atrial Fibrillation

There are concerns that pulmonary vein isolation for atrial fibrillation may have a profound placebo effect, but no double-blind randomized clinical trials have been conducted. To determine whether pulmonary vein isolation is more effective than a sham procedure for improving outcomes in atrial fibrillation. Double-blind randomized clinical trial conducted at 2 tertiary centers in the UK between January 2020 and March 2024 among patients with symptomatic paroxysmal or persistent atrial fibrillation. Major exclusion criteria included long-standing persistent atrial fibrillation, prior left atrium ablation, other arrhythmias requiring ablative therapy, a left atrium of 5.5 cm or larger, and ejection fraction of less than 35%. Participants were randomly assigned to receive pulmonary vein isolation with cryoablation (n = 64) or a sham procedure with phrenic nerve pacing (n = 62). The primary end point was atrial fibrillation burden at 6 months, excluding a 3-month blanking period. Secondary outcomes included quality-of-life measures, time to events, and safety. Atrial fibrillation burden was measured by an implantable loop recorder. A total of 126 participants were randomized (mean age, 66.8 years; 89 men [70.63%]; 20.63% with paroxysmal atrial fibrillation). The absolute mean atrial fibrillation burden change from baseline to 6 months was 60.31% in the ablation group and 35.0% in the sham group (geometric mean difference, 0.25; 95% CI, 0.15-0.42; P < .001). The estimated difference in the overall Atrial Fibrillation Effect on Quality of Life score at 6 months, favoring catheter ablation, was 18.39 points (95% CI, 11.48-25.30 points). The Short Form 36 general health score also improved substantially more with ablation, with an estimated difference of 9.27 points at 6 months (95% CI, 3.78-14.76 points). Pulmonary vein isolation resulted in a statistically significant and clinically important decrease in atrial fibrillation burden at 6 months, with substantial improvements in symptoms and quality of life, compared with a sham procedure. ClinicalTrials.gov Identifier: NCT04272762.

Balancing Placebo Use with Evidence-Based Treatments: The Placebo Effect in Clinical Practice and Research

The placebo effect has notable implications for clinical practice and research, demonstrating its ability to enhance therapeutic outcomes through psychological and physiological mechanisms. Evidence shows that placebos can impact treatment responses by influencing patients’ expectations and mental states, with mechanisms including neurobiological changes such as endogenous opioid release and brain activity alterations. However, their use raises ethical concerns, especially regarding patient trust and autonomy. Psychological factors like belief, expectation, and mindset play a significant role in placebo efficacy, affecting mental and physical health outcomes. In clinical settings, integrating placebo effects requires careful management to enhance patient care without replacing evidence-based treatments. Ethical integration involves boosting placebo responses transparently and maintaining adherence to ethical standards to prevent misuse, such as non-disclosure or substituting proven therapies, which can damage trust and patient autonomy. Future research aims to refine placebo mechanisms, including genetic factors and biomarkers—to personalize medicine and improve therapeutic efficacy—and evaluate the long-term effects of placebo responses on patient care. Placebos are essential in drug development and approval. Placebo-controlled trials help differentiate between active drug effects and psychological influences. However, ethical concerns, especially about withholding effective treatments, remain. Guidelines by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are crucial for upholding ethical standards in these trials. While the placebo effect offers valuable insights, its application must be managed with transparency and rigor to balance its benefits with high ethical standards in medical practice.

Conclusions Regarding the Role of Expectations in Placebo Analgesia Studies May Depend on How We Investigate It: A Meta-Analysis, Systematic Review, and Proposal for Methodological Discussions.

Expectations are highlighted as a key component in placebo effects. However, there are different approaches to whether and how placebo studies should account for expectations, and the direct contribution has yet to be estimated in meta-analyses. Using different methodological approaches, this meta-analysis and systematic review examines the extent to which expectations contribute to pain in placebo studies. The databases PubMed, PsycINFO, Embase, and Web of Science were searched for placebo analgesia mechanism studies with numerical measures of both expectations and pain. Thirty-one studies, comprising 34 independent study populations (1566 subjects: patients and healthy participants) were included. Two meta-analyses were conducted: meta-analysis 1, using study-level data, estimated the effect of expectation interventions without taking measures of expectations into account (expectations assumed); and meta-analysis 2, using individual-level data, estimated the direct impact of participants' expectations on pain (expectations assessed). Risk of bias was assessed using the Cochrane risk-of-bias tool. Meta-analysis 1 showed a moderate effect of expectation interventions over no expectation intervention on pain intensity (Hedges g = 0.45, I2 = 54.19). Based on 10 studies providing individual-level data, meta-analysis 2 showed that expectations predicted pain intensity in placebo and control groups ( b = 0.36, SE = 0.05), although inconsistently across study methodologies. Participants' expectations contributed moderately to pain in placebo analgesia studies. However, this may largely be influenced by how we measure expectations and how their contribution is conceptualized and analyzed-both within and across studies.

Microfragmented Adipose Tissue Injection Reduced Pain Compared With a Saline Control Among Patients With Symptomatic Osteoarthritis of the Knee During 1-Year Follow-Up: A Randomized Controlled Trial

PurposeTo evaluate the effectiveness of microfragmented adipose tissue (MFAT) for pain relief and improved joint functionality in knee OA in a randomized, controlled clinical trial with 1-year follow-up. MethodsSeventy-five patients were stratified by baseline pain level, and randomized to one of three treatment groups: MFAT, corticosteroid (CS), or saline control (C) injection. Patients 18 years of age or older, diagnosed with symptomatic knee osteoarthritis, with radiographic evidence of knee osteoarthritis and a visual analog pain scale (VAS) score of 3/10 or greater were included. Patients were excluded if they had any prior intra-articular knee injection, current knee ligamentous instability or an allergy to lidocaine/corticosteroid. The VAS pain scale, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Knee Injury and Osteoarthritis Outcome score (KOOS) were recorded pre-procedure and at 2 weeks, 6 weeks, 3 and 6 months, and 1 year follow-up. ResultsMFAT demonstrated consistent and statistically significant improvements across all primary outcome measures for joint pain and functionality compared to C. For MFAT, there was a significant improvement over baseline at each follow-up, with median (95% CI) KOOS Pain score changes of 18.1 (11.1, 26.4) at week 2 to 27.8 (19.4, 37.5) at 1 year. For CS, the median KOOS pain score reached a maximum of 22.2 (15.3, 30.6) at week 2, only to level off to 13.9 (-2.8, 29.2), a level not statistically different from baseline, at 1 year. The median changes for C hovered around 6-11 points, with statistically significant improvements over baseline indicating a placebo effect. Similar trends were seen for the WOMAC Pain score and VAS Pain score. ConclusionsIn this study, MFAT demonstrated a clinically significant improvement in primary outcome scores compared with a saline control group, while the corticosteroid group only showed statistically significant improvement compared to the control group at 2 and 6 weeks. This finding indicates that MFAT may be a viable alternative treatment for patients with knee OA that fall into the orthopaedic treatment gap.

Roles of tranexamic acid on bleeding in percutaneous nephrolithotomy procedure: A systematic review and meta-analysis

Purpose: Bleeding is the most common percutaneous nephrolithotomy (PCNL) complication. We investigated the role of tranexamic acid (TXA), which has numerous benefits in trauma and elective surgery, in PCNL. Materials and methods: Systematic reviews were performed using PubMed, Science Direct, Scopus, and Google Scholar. This study included randomized clinical trials that compared the effects of TXA and placebo during PCNL. The publication date, which was a limitation of the study, was disregarded. The analysis only included studies published in English that were available in full text. Patients with kidney stones who underwent PCNL were also enrolled. The outcomes comprised blood loss, hemoglobin decrease, blood transfusion rate, and length of hospital stay. Results: A total of 1377 patients from 8 studies were included. TXA was correlated with a low rate of blood transfusion (odds ratio = 0.35 [0.22–0.56]; P &lt; 0.00001), blood loss (mean difference [MD] = −66.88 mL [−101.54 to −32.23]; P = 0.0002), decreased hemoglobin levels (MD = −0.67 g/dL [−0.96 to −0.38]; P &lt; 0.00001), and reduced length of hospital stay (MD = −0.61 day [−1.04 to −0.18]; P = 0.005). Conclusion: The promising roles of TXA in PCNL procedures have been revealed. Further studies involving additional clinical trials, particularly those that assess interactions and adaptations to patients’ comorbidities, are suggested.