Citrus supplementation in subjective cognitive decline: results of a 36-week, randomized, placebo-controlled trial.

BACKGROUND: Developing interventions for older adults with subjective cognitive decline (SCD) has the potential to prevent dementia in this at-risk group. Preclinical models indicate that Citrus-derived phytochemicals could benefit cognition and inflammatory processes, but results from clinical trials are still preliminary. The aim of this study is to determine the effects of long-term supplementation with Citrus peel extract on cognitive performance and inflammation in individuals with SCD. METHODS: Eighty participants were randomly assigned to active treatment (400 mg of Citrus peel extract containing 3.0 mg of naringenin and 0.1 mg of auraptene) or placebo at 1:1 ratio for 36 weeks. The primary endpoint was the change in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score across the 36-week trial period. Other cognitive outcomes included tests and scales evaluating verbal memory, attention, executive and visuospatial functions, and memory concerns. The secondary endpoint was the change of interleukin-8 (IL-8) levels over the 36-week trial period in a subsample of 60 consecutive participants. An Intention-to-treat approach with generalized linear mixed models was used for data analysis. RESULTS: The RBANS total score showed significant improvement in both Citrus peel extract and placebo groups at 36 weeks (p for time < .001, d = 0.36, p time x treatment = .910). Significant time effects were also found in cognitive domains of short- and long-term verbal memory (p < .001) and scales of subjective memory (p < .01), with no significant time x treatment interaction. The largest effect sizes were observed in verbal memory in the placebo group (d = 0.69 in short-term, and d = 0.78 in long-term verbal memory). Increased IL-8 levels were found at 36-week follow-up in both Citrus peel extract and placebo groups (p for time = .010, d = 0.21, p time x treatment = .772). Adverse events were balanced between groups. CONCLUSIONS: In this randomized clinical trial, long-term Citrus peel extract supplementation did not show cognitive benefits over placebo in participants with SCD, possibly due to high placebo response. These findings might have specific implications for designing future nutraceutical trials in individuals experiencing SCD. TRIAL REGISTRATION: The trial has been registered at the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 ( https://www. CLINICALTRIALS: gov/ct2/show/NCT04744922 ).

Placebo rates in Crohn's disease randomized clinical trials: An individual patient data meta-analysis.

BACKGROUND & AIMS: Understanding placebo rates is critical for efficient clinical trial design. We assessed placebo rates and associated factors using individual patient data (IPD) from Crohn's disease (CD) trials. METHODS: We conducted a meta-analysis of phase 2/3 placebo-controlled trials evaluating advanced therapies in moderate-to-severe CD (2010-2021). Deidentified IPD were obtained through Vivli Inc. and Yale University Open Data Access Project. Primary outcomes were clinical response and remission. Pooled placebo rates and 95% confidence intervals (CIs) were estimated using one- and two-stage meta-analytical approaches. Regression analyses identified patient-level factors associated with placebo rates. RESULTS: Using IPD from eight induction (n=1147) and four maintenance (n=524) trials, overall placebo clinical response and remission rates for induction were 27% (95%CI=23-32%) and 10% (95%CI=8-14%) respectively, and 32% (95%CI=23-42%) and 22% (95%CI=14-33%) for maintenance, respectively. Among bio-naïve patients, placebo response and remission rates during induction were 29% (95%CI=24-35%) and 11% (95%CI=8-15%) respectively, and 26% (95% CI=20-33%) and 10% (95% CI=8-14%) for bio-exposed, respectively. During maintenance, bio-naïve response and remission rates were 41% (95%CI=34-48%) and 32% (95%CI=24-40%), respectively, and 29% (95%CI=24-34%) and 16% (95%CI=13-21%) for bio-exposed, respectively. Higher baseline C-reactive protein concentration predicted lower placebo rates, while higher baseline albumin levels and body mass index increased the odds of placebo outcomes. Increased baseline Crohn's Disease Activity Index and 2-item patient-reported outcome scores predicted higher response rates in induction, lower response rates in maintenance, and lower remission rates in induction and maintenance. CONCLUSION: Patient- and trial-level characteristics influence placebo rates in CD trials. Careful implementation of eligibility criteria, outcome definitions, and patient stratification may reduce placebo rates.

Ultra-overt therapy: a novel medical approach centered on patient consciousness.

Within the realms of human and artificial intelligence, the concepts of consciousness and comprehension are fundamental distinctions. In the clinical sphere, patient awareness regarding medication and its physiological processes plays a crucial role in determining drug efficacy and outcomes. This article introduces a novel perspective on prescription practices termed "Ultra-Overt Therapy" (UOT). A review of current supporting evidence was conducted through a non-systematic search in PubMed and Google Scholar, focusing on concepts such as the "mind-body relationship," "placebo response," "neuroscience," and "complementary medicine." Our findings, rooted in the mechanisms of the "placebo effect," the intricacies of "intersubjective therapy," the potency of "interoceptive awareness," and other domains of medical science, suggest that UOT holds theoretical promise. Future research endeavors focusing on these areas may elucidate the global impact of this method on medical treatment and patient care.

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.

Report of similar placebo response in one internet versus onsite randomised controlled trials from the literature.

Objective: The aim of this study was to compare the magnitude and the predictors of the placebo response in an internet versus onsite randomised controlled trials (RCTs) in people with hand osteoarthritis (HOA). Method: This study is a post-hoc analysis based on one internet RCT (RADIANT) and previously published onsite RCTs for HOA identified through a rigorous searching and selection strategy. The magnitude of the placebo response in the two different types of RCTs were compared using heterogeneity statistics and forest plots visualisation. Classic placebo predictors as well as a combined model, defined with data from onsite RCTs, were tested to predict the placebo response. Results: We analysed the dataset from RADIANT and fourteen previously published onsite RCTs. None of the analyses showed a significant difference between the placebo response for the internet versus onsite RCTs. The "classic" placebo predictors combined in a multivariate predictive model correlated significantly with the placebo response measured in RADIANT study. Conclusion: Despite the absence of face-to-face interactions with the study personnel, there is no evidence that either the magnitude or the predictors of the placebo response of this internet RCT differ from those of onsite RCTs. This analysis is considered as a first step towards evaluating the difference between these designs and strengthens the argument that internet RCTs remain an acceptable alternative way to assess the efficacy of an active treatment in comparison to a placebo.

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.

Current and Emerging Technologies to Address the Placebo Response Challenge in CNS Clinical Trials: Promise, Pitfalls, and Pathways Forward.

Excessive placebo response rates have long been a major challenge for central nervous system (CNS) drug discovery. As CNS trials progressively shift toward digitalization, decentralization, and novel remote assessment approaches, questions are emerging about whether innovative technologies can help mitigate the placebo response. This article begins with a conceptual framework for understanding placebo response. We then critically evaluate the potential of a range of innovative technologies and associated research designs that might help mitigate the placebo response and enhance detection of treatment signals. These include technologies developed to directly address placebo response; technology-based approaches focused on recruitment, retention, and data collection with potential relevance to placebo response; and novel remote digital phenotyping technologies. Finally, we describe key scientific and regulatory considerations when evaluating and selecting innovative strategies to mitigate placebo response. While a range of technological innovations shows potential for helping to address the placebo response in CNS trials, much work remains to carefully evaluate their risks and benefits.

Hype or hope? High placebo response in major depression treatment with ketamine and esketamine: a systematic review and meta-analysis.

Background: Ketamine and esketamine offer a novel approach in the pharmacological treatment of major depressive disorder (MDD). This meta-analysis aimed to investigate the placebo response in double-blind, randomized controlled studies (RCTs) on patients with MDD receiving ketamine or esketamine. Methods: For this systematic review and meta-analysis Medline (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), PsycInfo and Embase databases were systematically searched for citations published up to March 17, 2023. A total number of 5017 abstracts was identified. Quality of the included trials was assessed with the Cochrane risk-of-bias tool. The meta-analysis was performed using a restricted maximum likelihood model. This study is registered with PROSPERO, number CRD42022377591. Results: A total number of 14 studies and 1100 participants (593 in the medication group and 507 in the placebo group) meeting the inclusion criteria were selected. We estimated the pooled effect sizes of the overall placebo (d pl = -1.85 [CI 95%: -2.9 to -0.79] and overall treatment (dtr = -2.57; [CI 95% -3.36 to -1.78]) response. The overall placebo response accounts for up to 72% of the overall treatment response. Furthermore, we performed subgroup analysis of 8 studies for the for the 7 days post-intervention timepoint. Seven days post-intervention the placebo response (d pl 7d = -1.98 [CI 95%: -3.26 to -0.69]) accounts for 66% of the treatment response (d tr 7d = - 3.01 [CI 95%, -4.28 to -1.74]). Conclusion: Ketamine and esketamine show large antidepressant effects. However, our findings suggest that the placebo response plays a significant role in the antidepressant response and should be used for the benefit of the patients in clinical practice. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022377591.

Placebo response to sham electroacupuncture in patients with chronic functional constipation: A secondary analysis.

BACKGROUND: Chronic severe functional constipation is a common disease that requires novel and effective treatment strategies. Acupuncture might constitute a promising therapeutic approach for chronic constipation, but it reportedly engenders an enhanced placebo response. Herein, we aimed to determine the magnitude of the placebo responses to electroacupuncture for constipation and identify its influencing factors. METHODS: In this secondary analysis of a multicenter randomized trial, patients were randomized to a sham electroacupuncture group, which was administered for 8 weeks in 24 sessions of superficial needling at nonacupoints. The placebo response rates were assessed using three responder criteria: ≥3 complete spontaneous bowel movements per week (CSBMs/week), overall CSBM, and sustained CSBM. Logistic regression with backward selection method was employed to identify the potential factors that affected the placebo response. KEY RESULTS: Overall, 539 patients were included in the study. The placebo response rate was 10.58%, 9.46%, and 9.09% according to the three aforementioned criteria, respectively. Those who exhibited more CSBMs/week at baseline were more likely to respond to sham electroacupuncture. Among patients with more than one CSBM per week at baseline, the response rates for achieving the criteria of ≥3 CSBMs per week, overall CSBM, and sustained CSBM were 25.40%, 30.16%, and 22.22%. CONCLUSIONS AND INFERENCE: Electroacupuncture did not demonstrate a large placebo response in functional constipation treatment. The number of CSBMs at baseline may be a moderator of the placebo response to sham electroacupuncture. Thus, superficial needling sham acupuncture may be considered an ideal sham control for clinical trials of chronic constipation.

Placebo and Nocebo Responses in Pharmacological Trials of Tic Disorders: A Meta-Analysis.

BACKGROUND: Clinical trials of new drugs for tic disorders (TD) often fail to yield positive results. Placebo and nocebo responses play a vital role in interpreting the outcomes of randomized controlled trials (RCTs), yet these responses in RCTs of TD remain unexplored. OBJECTIVE: The aim was to assess the magnitude of placebo and nocebo responses in RCTs of pharmacological interventions for TD and identify influencing factors. METHODS: A systematic search of the Embase, Medline, Cochrane Central Register of Controlled Trials, and PsycINFO databases was conducted. Eligible studies were RCTs that compared active pharmacological agents with placebos. Placebo response was defined as the change from baseline in TD symptom severity in the placebo group, and nocebo response as the proportion experiencing adverse events (AEs) in this group. Subgroup analysis and meta-regression were performed to explore modifying factors. RESULTS: Twenty-four trials involving 2222 participants were included in this study. A substantial placebo response in TD symptom severity was identified, with a pooled effect size of -0.79 (95% confidence interval [CI] -0.99 to -0.59; I2 = 67%). Forty-four percent (95% CI 27% to 63%; I2 = 92%) of patients experienced AEs while taking inert pills. Sample size, study design, and randomization ratio were correlated with changes in placebo and nocebo responses. CONCLUSION: There were considerable placebo and nocebo responses in TD clinical trials. These results are of great relevance for the design of future trials and for clinical practice in TD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration ID CRD42023388397. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Endoscopic and Histological Placebo Rates in Crohn's Disease Clinical Trials: A Systematic Review and Meta-analysis.

BACKGROUND: Precise estimates of placebo response rates help efficient clinical trial design. In this systematic review and meta-analysis, we assessed contemporary placebo endoscopic and histological response rates in Crohn's disease (CD) clinical trials. METHODS: MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to April 2022 to identify placebo-controlled studies of pharmacological interventions for CD. Endoscopic response, remission, and mucosal healing rates for participants assigned to placebo in induction and maintenance studies were pooled using a random-effects model. Point estimates and associated 95% confidence intervals (CIs) were calculated. RESULTS: In total, 16 studies (11 induction, 3 maintenance, 2 induction and maintenance) that randomized 1646 participants to placebo were eligible. For induction trials, the pooled placebo endoscopic response, endoscopic remission, and mucosal healing rates in participants assigned to placebo were 13% (95% CI, 10-16; I2 = 14.1%; P = .14), 6% (95% CI, 3-11; I2 = 74.7%; P < .001), and 6% (95% CI, 4-9; I2 = 26.9%; P = .29), respectively. The pooled endoscopic remission rate in patients who were bio-naïve was 10% (95% CI, 4-23) compared with only 4% (95% CI, 3-7) in bio-experienced patients. For maintenance trials, the pooled endoscopic response, remission, and mucosal healing rates were 7% (95% CI, 1-31; I2 = 78.2%; P = .004), 11% (95% CI, 4-27; I2 = 70.8%; P = .06), and 7% (95% CI, 3-15; I2 = 29.7; P = .23), respectively. Only 3 trials assessed histological outcomes. CONCLUSIONS: Endoscopic placebo rates vary according to trial phase and prior biologic exposure. These contemporary data will serve to inform CD trial design, sample size calculation, and end point selection for future trials.

Methylphenidate dose-response in children with ADHD: evidence from a double-blind, randomized placebo-controlled titration trial.

Methylphenidate (MPH) is highly efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) in children. Generally increased doses are found to result in better symptom control; however, it remains unclear whether this pattern can be observed at the individual level, given the large heterogeneity in individual dose-response relationships and observed placebo responses. A double-blind, randomized, placebo-controlled cross-over trial was used to compare weekly treatment with placebo and 5, 10, 15 and 20 mg of MPH twice daily on parent and teacher ratings of child ADHD symptoms and side effects. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). MPH response was assessed at group and individual levels and predictors of individual dose-response curves were examined. Mixed model analysis showed positive linear dose-response curves at group level for parent and teacher rated ADHD symptoms and parent rated side effects, but not for teacher rated side effects. Teachers reported all dosages to improve ADHD symptoms compared to placebo, while parents only reported > 5 mg/dose as effective. At the individual level, most (73-88%) children, but not all, showed positive linear dose-response curves. Higher severity of hyperactive-impulsive symptoms and lower internalizing problems, lower weight, younger age and more positive opinions towards diagnosis and medication partly predicted steeper linear individual dose-response curves. Our study confirms that increased doses of MPH yield greater symptom control at a group level. However, large interindividual variation in the dose-response relationship was found and increased doses did not lead to greater symptom improvement for all children. This trial was registered in the Netherlands trial register (# NL8121).

Comparison of low-level laser therapy and standard treatment for temporomandibular disorders: An assessment of therapeutic and placebo effects.

BACKGROUND: Despite extensive research on the use of low-power lasers for TMD treatment, the extent of their effectiveness remains uncertain. OBJECTIVE: This study aimed to investigate the therapeutic or placebo effect of LLLT for TMD, and to compare it with standard treatment methods. A unique aspect of this study was the inclusion of a control group that received only standard treatment, allowing for an assessment of the placebo effect of LLLT. METHODS: A total of 42 patients with TMD were referred to Kerman Dental School Pain Clinic and were randomly assigned to three groups: group A received LLLT, group B was a placebo group and group C was a control group that received only standard treatment. The laser groups received gallium-aluminium-arsenide laser treatment twice a week for 10 sessions. Patients' jaw movement rate indicators and VAS index were evaluated at the start of treatment, and indicators were re-recorded every week for 5 weeks. SPSS 21 was used for statistical analysis, including ANOVA and Tukey's post hoc tests for inter-group comparisons. The repeated measurement test was used to analyse the data. RESULTS: All groups showed significant improvement in VAS indicators (p = .0001), lateral jaw movements (p = .0001), forward jaw movement (p = .007) but not for maximum mouth opening. No significant difference was observed between the groups at the end of the study (p = .000). CONCLUSION: Our study provides insights into LLLT's effectiveness for TMD, suggesting it cannot replace standard treatment alone. These findings contribute to the literature and emphasise the importance of including a control group in future studies to assess the placebo effect of LLLT.

A Mini Review of the Impact of Baseline Disease Severity on Clinical Outcomes: Should We Compare Atopic Dermatitis Clinical Trials?

Based on clinical trials of systemic treatments in adults with moderate-to-severe atopic dermatitis (AD) reported between 2014 and 2023, we used linear regression to investigate relationships between baseline Eczema Area and Severity Index (EASI) scores and (1) study start date, (2) EASI response, and (3) rescue medication rates. Analysis 1 was conducted with all patients from monotherapy and combination therapy trials; analyses 2 and 3 used monotherapy trial placebo arms. Across 32 trials with a baseline inclusion criterion of EASI ≥ 16, baseline mean EASI scores decreased with study start date. The lowest and highest baseline mean EASI scores were 25.1 and 33.6 (median 21.1 and 30.5), reported for the WW001 Phase 2 trial of rademikibart (formerly CBP-201; start date, July 2020) and the SOLO1 Phase 3 trial of dupilumab (start date, December 2014), respectively. In placebo arms, lower baseline EASI scores tended to be associated with greater percent reductions in EASI scores at Week 16 and less rescue medication usage. The WW001 trial placebo arm had the lowest baseline EASI score (mean 25.2; median 22.1), lowest rescue medication rate (14.3%), and a large reduction in least squares mean EASI scores (- 39.7%) at Week 16. In summary, baseline mean EASI scores have decreased across clinical trials conducted during the last decade. Less severe AD at baseline tended to be associated with greater placebo response and less use of rescue medications in placebo arms. Intertrial differences in variables, such as baseline AD severity, limit the validity of indirectly comparing clinical trials.

To respond or not to respond: exploring empathy-related psychological and structural brain differences between placebo analgesia responders and non-responders.

Introduction: Placebo responsiveness is highly variable across individuals. In the domain of pain, it may range from pronounced hypoalgesia to no response at all. Which factors predict such variation awaits clarification, as the available literature is characterized by mixed and inconclusive results. Particularly interesting in this case are social factors such as empathy or prosocial behavior, as prior work has stressed the connection between feeling pain yourself and empathizing with pain observed in others. Methods: In a mixed confirmatory and exploratory approach, this study investigated potential psychological and structural brain differences between placebo responders and non-responders in the domain of pain. We aggregated data of four behavioral and neuroimaging studies that had been designed to investigate the effects of placebo analgesia on empathy. Results: Analyses comparing groups of placebo responders and non-responders showed significant group differences in trait characteristics, with responders reporting increased helping behavior and lower psychopathic traits compared to non-responders. Uncorrected results further showed higher pain-related empathic concern in responders vs. non-responders. These results were accompaniedby tentative group differences in brain structure: placebo analgesia non-responders exhibited increased gray matter volume in left inferior temporal and parietal supramarginal cortical areas, and an increased cortical surface area in bilateral middle temporal cortex. Discussion: Together, our findings suggest that modifiability of one's pain perception by means of placebo effects is linked to personality traits characterizing social emotions and behavior. They also hint that these psychological as well as brain structural characteristics might be beneficial for the identification of placebo responders. At the same time, they stress the importance of considering contextual factors such as the study setting or paradigm when investigating the association between individual characteristics and placebo responding.

Placebo response in sham-acupuncture-controlled trials for migraine: A systematic review and meta-analysis.

AIM: To understand the placebo response of acupuncture and its effect on migraine and optimize the design of future acupuncture clinical trials on migraine treatment. METHODS: Randomized controlled trials with sham acupuncture as a control in migraine treatment were searched in four English databases from inception to September 1, 2022. The primary outcome was placebo response rate. Secondary outcomes were migraine symptoms, emotional condition, and quality of life. Factors associated with placebo response were also explored. Results were combined using risk difference (RD) or standardized mean difference (SMD) and 95% confidence interval (CI) with a random effects model. RESULTS: The final analysis included 21 studies involving 1177 patients. The pooled response rate of sham acupuncture was 0.34 (RD, 95% CI 0.23-0.45, I2 89.8%). The results (SMD [95% CI]) showed significant improvements in migraine symptoms (pain intensity -0.56 [-0.73 to -0.38], and episode conditions -0.55 [-0.75 to -0.35]); emotional condition (anxiety scale -0.49 [-0.90 to -0.08] and depression scale -0.21 [-0.40 to -0.03]); and quality of life on the Migraine-Specific Quality-of-Life Questionnaire (restrictive 0.78 [0.61-0.95]; preventive 0.52 [0.35-0.68]; and emotional 0.45 [0.28-0.62]) and on the Medical Outcomes Study Short-Form (physical 0.48 [0.34-0.62] and mental 0.21 [0.02-0.41]). Only acupuncture treatment frequency had a significant impact on the placebo response rate (RD 0.49 vs. 0.14; p = 0.00). CONCLUSIONS: The effect sizes for placebo response of sham acupuncture varied across migraine treatment trials. Further studies should routinely consider adjusting for a more complete set of treatment factors.

Placebo Response among Different Types of Sham Acupuncture for Low Back Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Low back pain (LBP) is a prevalent and debilitating condition that poses a significant burden on healthcare systems. Acupuncture has been proposed as a promising intervention for LBP, but the evidence supporting its specific effect is insufficient, and the use of sham acupuncture as a control in clinical trials presents challenges due to variations in sham acupuncture techniques and the magnitude of the placebo effect. OBJECTIVE: To investigate the magnitude of the placebo response of sham acupuncture in trials of acupuncture for nonspecific LBP, and to assess whether different types of sham acupuncture are associated with different responses. METHODS: Four databases including PubMed, EMBASE, MEDLINE, and the Cochrane Library were searched through April 15, 2023, and randomized controlled trials (RCTs) were included if they randomized patients with LBP to receive acupuncture or sham acupuncture intervention. The main outcomes included the placebo response in pain intensity, back-specific function and quality of life. Placebo response was defined as the change in these outcome measures from baseline to the end of treatment. Random-effects models were used to synthesize the results, standardized mean differences (SMDs, Hedges'g) were applied to estimate the effect size. RESULTS: A total of 18 RCTs with 3,321 patients were included. Sham acupuncture showed a noteworthy pooled placebo response in pain intensity in patients with LBP [SMD -1.43, 95% confidence interval (CI) -1.95 to -0.91, I2=89%]. A significant placebo response was also shown in back-specific functional status (SMD -0.49, 95% CI -0.70 to -0.29, I2=73%), but not in quality of life (SMD 0.34, 95% CI -0.20 to 0.88, I2=84%). Trials in which the sham acupuncture penetrated the skin or performed with regular needles had a significantly higher placebo response in pain intensity reduction, but other factors such as the location of sham acupuncture did not have a significant impact on the placebo response. CONCLUSIONS: Sham acupuncture is associated with a large placebo response in pain intensity among patients with LBP. Researchers should also be aware that the types of sham acupuncture applied may potentially impact the evaluation of the efficacy of acupuncture. Nonetheless, considering the nature of placebo response, the effect of other contextual factors cannot be ruled out in this study. (PROSPERO registration No. CRD42022304416).

A new method for analyzing clinical trials in depression based on individual propensity to respond to placebo estimated using artificial intelligence.

One of the major reasons for trial failures in major depressive disorders (MDD) is the presence of unpredictable levels of placebo response as the individual baseline propensity to respond to placebo is not adequately controlled by the current randomization and statistical methodologies. The individual propensity to respond to any treatment or intervention assessed at baseline was considered as a major non-specific prognostic and confounding effect. The objective of this paper was to apply the propensity score methodology to control for potential imbalance at baseline in the propensity to respond to placebo in clinical trials in MDD. Individual propensity was estimated using artificial intelligence (AI) applied to observations collected in two pre-randomization occasions. Cases study are presented using data from two randomized, placebo-controlled trials to evaluate the efficacy of paroxetine in MDD. AI models were used to estimate the individual propensity probability to show a treatment non-specific placebo effect. The inverse of the estimated probability was used as weight in the mixed-effects analysis to assess treatment effect. The comparison of the results obtained with and without propensity weight indicated that the weighted analysis provided an estimate of treatment effect and effect size significantly larger than the conventional analysis.

Magnitude of placebo response in clinical trials of paroxetine for vasomotor symptoms: a meta-analysis.

Introduction: Vasomotor symptoms, or hot flashes, are among the most common complaints for menopausal and postmenopausal women. As an alternative to hormone replacement therapy, paroxetine mesylate became the only non-hormonal treatment approved by the U.S. Food and Drug Administration (FDA), despite limited evidence for its efficacy. More specifically, there is uncertainty around paroxetine's unique benefit and the magnitude of the placebo response in clinical trials of paroxetine. Methods: Relevant databases were searched to identify randomized clinical trials examining the efficacy of paroxetine to treat hot flashes. The primary outcomes of interest were hot flash frequency and hot flash severity scores. Data was extracted from the published results, and risk of bias assessments were conducted. Results: Six randomized clinical trials that included a total of 1,486 women were coded and analyzed. The results demonstrated that 79% of the mean treatment response for hot flash frequency is accounted for by a placebo response, resulting in a mean true drug effect of 21% at most. Additionally, 68% of the mean treatment response for hot flash severity is accounted for by a placebo response, resulting in a maximum true drug effect of 32%. Discussion: The results herein call into question the actual efficacy of the only FDA approved, non-hormonal treatment for hot flashes by demonstrating that a placebo response accounts for the majority of treatment responses for reductions in both hot flash frequency and severity. The findings provide evidence to reevaluate the use of paroxetine to treat postmenopausal hot flashes and emphasize the importance of considering effective, alternative treatments for vasomotor symptoms.

Placebo response of sham acupuncture in patients with primary dysmenorrhea: A meta-analysis.

BACKGROUND: The placebo response of sham acupuncture in patients with primary dysmenorrhea is a substantial factor associated with analgesia. However, the magnitude of the placebo response is unclear. OBJECTIVE: This meta-analysis assessed the effects of sham acupuncture in patients with primary dysmenorrhea and the factors contributing to these effects. SEARCH STRATEGY: PubMed, Embase, Web of Science, and Cochrane CENTRAL databases were searched from inception up to August 20, 2022. INCLUSION CRITERIA: Randomized controlled trials (RCTs) using sham acupuncture as a control for female patients of reproductive age with primary dysmenorrhea were included. DATA EXTRACTION AND ANALYSIS: Pain intensity, retrospective symptom scale, and health-related quality of life were outcome measures used in these trials. Placebo response was defined as the change in the outcome of interest from baseline to endpoint. We used standardized mean difference (SMD) to estimate the effect size of the placebo response. RESULTS: Thirteen RCTs were included. The pooled placebo response size for pain intensity was the largest (SMD = -0.99; 95% confidence interval [CI], -1.31 to -0.68), followed by the retrospective symptom scale (Total frequency rating score: SMD = -0.20; 95% CI, -0.80 to -0.39. Average severity score: SMD = -0.35; 95% CI, -0.90 to -0.20) and physical component of SF-36 (SMD = 0.27; 95% CI, -0.17 to 0.72). Studies using blunt-tip needles, single-center trials, studies with a low risk of bias, studies in which patients had a longer disease course, studies in which clinicians had < 5 years of experience, and trials conducted outside Asia were more likely to have a lower placebo response. CONCLUSION: Strong placebo response and some relative factors were found in patients with primary dysmenorrhea. PROSPERO registration number: CRD42022304215. Please cite this article as: Sun CY, Xiong ZY, Sun CY, Ma PH, Liu XY, Sun CY, Xin ZY, Liu BY, Liu CZ, Yan SY. Placebo response of sham acupuncture in patients with primary dysmenorrhea: A meta-analysis. J Integr Med. 2023; 21(5): 455-463.