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BMJ Evidence-based Medicine Mar 2024The placebo effect is the 'effect of the simulation of treatment that occurs due to a participant's belief or expectation that a treatment is effective'. Although the... (Meta-Analysis)
Meta-Analysis
The placebo effect is the 'effect of the simulation of treatment that occurs due to a participant's belief or expectation that a treatment is effective'. Although the effect might be of little importance for some conditions, it can have a great role in others, mostly when the evaluated symptoms are subjective. Several characteristics that include informed consent, number of arms in a study, the occurrence of adverse events and quality of blinding may influence response to placebo and possibly bias the results of randomised controlled trials. Such a bias is inherited in systematic reviews of evidence and their quantitative components, pairwise meta-analysis (when two treatments are compared) and network meta-analysis (when more than two treatments are compared). In this paper, we aim to provide red flags as to when a placebo effect is likely to bias pairwise and network meta-analysis treatment effects. The classic paradigm has been that placebo-controlled randomised trials are focused on estimating the treatment effect. However, the magnitude of placebo effect itself may also in some instances be of interest and has also lately received attention. We use component network meta-analysis to estimate placebo effects. We apply these methods to a published network meta-analysis, examining the relative effectiveness of four psychotherapies and four control treatments for depression in 123 studies.
Topics: Humans; Network Meta-Analysis; Placebo Effect; Meta-Analysis as Topic
PubMed: 37385716
DOI: 10.1136/bmjebm-2022-112197 -
Movement Disorders : Official Journal... Sep 2023The outcome of clinical trials in neurodegeneration can be highly uncertain due to the presence of a strong placebo effect. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The outcome of clinical trials in neurodegeneration can be highly uncertain due to the presence of a strong placebo effect.
OBJECTIVES
To develop a longitudinal model that can enhance the success of future Parkinson's disease trials by quantifying trial-to-trial variations in placebo and active treatment response.
METHODS
A longitudinal model-based meta-analysis was conducted on the total score of Unified Parkinson's Disease Rating Scale (UPDRS) Parts 1, 2, and 3. The analysis included aggregate data from 66 arms (observational [4], placebo [28], or investigational-drug-treated [34]) from 4 observational studies and 17 interventional trials. Inter-study variabilities in key parameters were estimated. Residual variability was weighted by the size of study arms.
RESULTS
The baseline total UPDRS was estimated to average at 24.5 points. Disease score was estimated to worsen by 3.90 points/year for the duration of the treatments; whilst notably, arms with a lower baseline progressed faster. The model captured the transient nature of the placebo response and sustained symptomatic drug effect. Both placebo and drug effects peaked within 2 months; although, 1 year was needed to observe the full treatment difference. Across these studies, the progression rate varied by 59.4%, the half-life for offset of placebo response varied by 79.4%, and the amplitude for drug effect varied by 105.3%.
CONCLUSION
The longitudinal model-based meta-analysis describes UPDRS progression rate, captures the dynamics of the placebo response, quantifies the effect size of the available therapies, and sets the expectation of uncertainty for future trials. The findings provide informative priors to enhance the rigor and success of future trials of promising agents, including potential disease modifiers. © 2023 GSK. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; Research Design; Clinical Trials as Topic
PubMed: 37400277
DOI: 10.1002/mds.29514 -
American Journal of Respiratory and... May 2024Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models.
RATIONALE
Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models.
OBJECTIVES
We aimed to determine whether anastrozole improved six-minute walk distance (6MWD) at six months in pulmonary arterial hypertension (PAH).
METHODS
We performed a randomized, double-blind, placebo-controlled Phase II clinical trial of anastrozole in subjects with PAH at seven centers. Eighty-four post-menopausal women and men with PAH were randomized in a 1:1 ratio to receive anastrozole 1 mg or placebo by mouth daily, stratified by sex using permuted blocks of variable sizes. All subjects and study staff were masked. The primary outcome was the change from baseline in 6MWD at six months. Using intent-to-treat analysis, we estimated the treatment effect of anastrozole using linear regression models adjusted for sex and baseline 6MWD. Assuming 10% loss to follow-up, we anticipated having 80% power to detect a difference in the change in 6MWD of 22 meters.
MEASUREMENTS AND MAIN RESULTS
Forty-one subjects were randomized to placebo and 43 to anastrozole and all received the allocated treatment. Three subjects in the placebo group and two in the anastrozole group discontinued study drug. There was no significant difference in the change in 6MWD at six months (placebo-corrected treatment effect -7.9 m, 95%CI -32.7 - 16.9, p = 0.53). There was no difference in adverse events between the groups.
CONCLUSIONS
Anastrozole did not show a significant effect on 6MWD compared to placebo in post-menopausal women and men with PAH. Anastrozole was safe and did not show adverse effects. Clinical trial registration available at www.
CLINICALTRIALS
gov, ID: NCT03229499.
PubMed: 38747680
DOI: 10.1164/rccm.202402-0371OC -
Journal of Medical Ethics Oct 2023A growing body of cross-cultural survey research shows high percentages of clinicians report using placebos in clinical settings. One motivation for clinicians using...
A growing body of cross-cultural survey research shows high percentages of clinicians report using placebos in clinical settings. One motivation for clinicians using placebos is to help patients by capitalising on the placebo effect's reported health benefits. This is not surprising, given that placebo studies are burgeoning, with increasing calls by researchers to ethically harness placebo effects among patients. These calls propose placebos/placebo effects offer clinically significant benefits to patients. In this paper, we argue many findings in this highly cited and 'hot' field have not been independently replicated. Evaluating the ethicality of placebo use in clinical practice involves first understanding whether placebos are efficacious clinically. Therefore, it is crucial to consider placebo research in the context of the replication crisis and what can be learnt to advance evidence-based knowledge of placebos/placebo effects and their clinical relevance (or lack thereof). In doing so, our goal in this paper is to motivate both increased awareness of replication issues and to help pave the way for advances in scientific research in the field of placebo studies to better inform ethical evidence-based practice. We argue that, only by developing a rigorous evidence base can we better understand how, if at all, placebos/placebo effects can be harnessed ethically in clinical settings.
Topics: Humans; Placebo Effect; Clinical Relevance; Informed Consent; Ethics, Medical
PubMed: 36609361
DOI: 10.1136/jme-2022-108672 -
The Cochrane Database of Systematic... Jan 2024Clinical practice guidelines recommend testosterone replacement therapy (TRT) for men with sexual dysfunction and testosterone deficiency. However, TRT is commonly... (Review)
Review
BACKGROUND
Clinical practice guidelines recommend testosterone replacement therapy (TRT) for men with sexual dysfunction and testosterone deficiency. However, TRT is commonly promoted in men without testosterone deficiency and existing trials often do not clearly report participants' testosterone levels or testosterone-related symptoms. This review assesses the potential benefits and harms of TRT in men presenting with complaints of sexual dysfunction.
OBJECTIVES
To assess the effects of testosterone replacement therapy compared to placebo or other medical treatments in men with sexual dysfunction.
SEARCH METHODS
We performed a comprehensive search of CENTRAL (the Cochrane Library), MEDLINE, EMBASE, and the trials registries ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform, with no restrictions on language of publication or publication status, up to 29 August 2023.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) in men (40 years or over) with sexual dysfunction. We excluded men with primary or secondary hypogonadism. We compared testosterone or testosterone with phosphodiesterase-5 inhibitors (PDEI5I) to placebo or PDE5I alone.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the literature, assessed the risk of bias, extracted data, and rated the certainty of evidence (CoE) according to GRADE using a minimally contextualized approach. We performed statistical analyses using a random-effects model and interpreted them according to standard Cochrane methodology. Predefined primary outcomes were self-reported erectile dysfunction assessed by a validated instrument, sexual quality of life assessed by a validated instrument, and cardiovascular mortality. Secondary outcomes were treatment withdrawal due to adverse events, prostate-related events, and lower urinary tract symptoms (LUTS). We distinguished between short-term (up to 12 months) and long-term (> 12 months) outcomes.
MAIN RESULTS
We identified 43 studies with 11,419 randomized participants across three comparisons: testosterone versus placebo, testosterone versus PDE5I, and testosterone with PDE5I versus PDE5I alone. This abstract focuses on the most relevant comparison of testosterone versus placebo. Testosterone versus placebo (up to 12 months) Based on a predefined sensitivity analysis of studies at low risk of bias, and an analysis combing data from the similar International Index of Erectile Function (IIEF-EF) and IIEF-5 instruments, TRT likely results in little to no difference in erectile function assessed with the IIEF-EF (mean difference (MD) 2.37, 95% confidence interval (CI) 1.67 to 3.08; I² = 0%; 6 RCTs, 2016 participants; moderate CoE) on a scale from 6 to 30 with larger values reflecting better erectile function. We assumed a minimal clinically important difference (MCID) of greater than or equal to 4. TRT likely results in little to no change in sexual quality of life assessed with the Aging Males' Symptoms scale (MD -2.31, 95% CI -3.63 to -1.00; I² = 0%; 5 RCTs, 1030 participants; moderate CoE) on a scale from 17 to 85 with larger values reflecting worse sexual quality of life. We assumed a MCID of greater than or equal to 10. TRT also likely results in little to no difference in cardiovascular mortality (risk ratio (RR) 0.83, 95% CI 0.21 to 3.26; I² = 0%; 10 RCTs, 3525 participants; moderate CoE). Based on two cardiovascular deaths in the placebo group and an assumed MCID of 3%, this would correspond to no additional deaths per 1000 men (95% CI 1 fewer to 4 more). TRT also likely results in little to no difference in treatment withdrawal due to adverse events, prostate-related events, or LUTS. Testosterone versus placebo (later than 12 months) We are very uncertain about the longer-term effects of TRT on erectile dysfunction assessed with the IIEF-EF (MD 4.20, 95% CI -2.03 to 10.43; 1 study, 42 participants; very low CoE). We did not find studies reporting on sexual quality of life or cardiovascular mortality. We are very uncertain about the effect of testosterone on treatment withdrawal due to adverse events. We found no studies reporting on prostate-related events or LUTS.
AUTHORS' CONCLUSIONS
In the short term, TRT probably has little to no effect on erectile function, sexual quality of life, or cardiovascular mortality compared to a placebo. It likely results in little to no difference in treatment withdrawals due to adverse events, prostate-related events, or LUTS. In the long term, we are very uncertain about the effects of TRT on erectile function when compared to placebo; we did not find data on its effects on sexual quality of life or cardiovascular mortality. The certainty of evidence ranged from moderate (signaling that we are confident that the reported effect size is likely to be close to the true effect) to very low (indicating that the true effect is likely to be substantially different). The findings of this review should help to inform future guidelines and clinical decision-making at the point of care.
Topics: Male; Humans; Erectile Dysfunction; Prostatic Hyperplasia; Testosterone; Prostate; Lower Urinary Tract Symptoms; Cardiovascular Diseases
PubMed: 38224135
DOI: 10.1002/14651858.CD013071.pub2 -
BMJ Open Nov 2023Given the high prevalence of mental health disorders and their significant socioeconomic burden, there is a need to develop improved treatments, and to evaluate them...
INTRODUCTION
Given the high prevalence of mental health disorders and their significant socioeconomic burden, there is a need to develop improved treatments, and to evaluate them through placebo-controlled trials. However, the magnitude of the placebo response in randomised controlled trials to test medications may be substantial, affecting their interpretation. Therefore, improved understanding of the patient, trial and mental disorder factors that influence placebo responses would inform clinical trial design to better detect active treatment effects. There is a growing literature exploring the placebo response within specific mental health disorders, but no overarching synthesis of this research has been produced to date. We present a protocol for an umbrella review of systematic reviews and/or meta-analyses in which we aim to understand the effect size and potential predictors of placebo response within, and across, mental health disorders.
METHODS AND ANALYSIS
We will systematically search databases (Medline, PsycINFO, EMBASE+EMBASE Classic, Web of Knowledge) for systematic reviews and/or meta-analyses that report placebo effect size in clinical trials in patients with mental health disorders (initial search date 23 October 2022). Screening of abstracts and full texts will be done in pairs. We will extract data to qualitatively examine how placebo effect size varies across mental health disorders. We also plan to qualitatively summarise predictors of increased placebo response identified either quantitatively (eg, through meta-regression) or qualitatively. Risk of bias will be assessed using the AMSTAR-2 tool. We aim to not only summarise the current literature but also to identify gaps in knowledge and generate further hypotheses.
ETHICS AND DISSEMINATION
We do not believe there are any specific ethical considerations relevant to this study. We will publish the results in a peer-reviewed journal.
Topics: Humans; Mental Disorders; Mental Health; Placebo Effect; Systematic Reviews as Topic; Review Literature as Topic
PubMed: 38035741
DOI: 10.1136/bmjopen-2023-073946 -
Acta Neurologica Belgica Jan 2024Placebo control plays an important role in evaluating the effectiveness of interventions. Specifying differential effects of various placebo controls on migraine... (Review)
Review
BACKGROUND
Placebo control plays an important role in evaluating the effectiveness of interventions. Specifying differential effects of various placebo controls on migraine prevention would be essential in the explanation of preventive treatment for migraine and the indirect comparison between different prophylactic therapeutics.
OBJECTIVES
To access the impact of different non-pharmacologic placebo types on different outcomes in migraine patients.
METHODS
We searched PubMed, Cochrane Controlled Register of Trials, Embase, and Web of Science databases from the date of creation to June 19, 2023. Randomized controlled trials of migraine that included sham intervention of acupuncture or cognitive behavioural therapy (CBT) or non-invasive Vagus Nerve Stimulation (nVNS) or repetitive Transcranial Magnetic Stimulation (rTMS) or transcranial Direct Current Stimulation (tDCS) were conducted. The primary outcome was the migraine days, and the secondary outcomes were the number of migraine attacks, headache days, headache frequency, and responder's rate. Placebo effects were assessed using five individual placebos for network meta-analysis, using mean differences to measure the relative effect of pair-wise comparisons between interventions.
RESULT
A total of 50 trials with 4880 subjects were included. Twenty-seven trials were evaluated for low risk of bias. The results of indirect comparisons show that sham rTMS and sham tDCS had optimal and similar effects in reducing migraine days; sham acupuncture has the greatest effect on reducing the number of migraine attacks and relieving headache frequency; sham rTMS had a highly significant advantage in reducing headache days compared with the other placebo controls.
CONCLUSION
Based on the network meta-analysis results, we found that sham acupuncture had the greatest effect on migraine prophylaxis. The strong placebo effect of sham acupuncture should be considered when assessing the therapeutic effect.
PubMed: 38245660
DOI: 10.1007/s13760-023-02460-2 -
Nature. Mental Health Nov 2023Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials. We present a single-center,...
Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials. We present a single-center, parallel-arm, triple-masked, randomized, placebo-controlled trial assessing the antidepressant efficacy of intravenous ketamine masked by surgical anesthesia (ClinicalTrials.gov, NCT03861988). Forty adult patients with major depressive disorder who were scheduled for routine surgery were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during usual anesthesia. All participants, investigators, and direct patient care staff were masked to treatment allocation. The primary outcome was depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received. A mixed-effects model showed no evidence of effect of treatment assignment on the primary outcome (-5.82, 95% CI -13.3 to 1.64, p=0.13). 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions. In conclusion, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. Although this masking strategy is impractical for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias.
PubMed: 38188539
DOI: 10.1038/s44220-023-00140-x -
The Cochrane Database of Systematic... Jan 2024Cocaine is a psychostimulant used by approximately 0.4% of the general population worldwide. Cocaine dependence is a chronic mental disorder characterised by the... (Review)
Review
BACKGROUND
Cocaine is a psychostimulant used by approximately 0.4% of the general population worldwide. Cocaine dependence is a chronic mental disorder characterised by the inability to control cocaine use and a host of severe medical and psychosocial complications. There is current no approved pharmacological treatment for cocaine dependence. Some researchers have proposed disulfiram, a medication approved to treat alcohol use disorder. This is an update of a Cochrane review first published in 2010.
OBJECTIVES
To evaluate the efficacy and safety of disulfiram for the treatment of cocaine dependence.
SEARCH METHODS
We updated our searches of the following databases to August 2022: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and PsycINFO. We also searched for ongoing and unpublished studies via two trials registries. We handsearched the references of topic-related systematic reviews and included studies. The searches had no language restrictions.
SELECTION CRITERIA
We included randomised controlled trials that evaluated disulfiram alone or associated with psychosocial interventions versus placebo, no intervention, other pharmacological interventions, or any psychosocial intervention for the treatment of cocaine dependence.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
Thirteen studies (1191 participants) met our inclusion criteria. Disulfiram versus placebo or no treatment Disulfiram compared to placebo may increase the number of people who are abstinent at the end of treatment (point abstinence; risk ratio (RR) 1.58, 95% confidence interval (CI) 1.05 to 2.36; 3 datasets, 142 participants; low-certainty evidence). However, compared to placebo or no pharmacological treatment, disulfiram may have little or no effect on frequency of cocaine use (standardised mean difference (SMD) -0.11 standard deviations (SDs), 95% CI -0.39 to 0.17; 13 datasets, 818 participants), amount of cocaine use (SMD -0.00 SDs, 95% CI -0.30 to 0.30; 7 datasets, 376 participants), continuous abstinence (RR 1.23, 95% CI 0.80 to 1.91; 6 datasets, 386 participants), and dropout for any reason (RR 1.20, 95% CI 0.92 to 1.55; 14 datasets, 841 participants). The certainty of the evidence was low for all these outcomes. We are unsure about the effects of disulfiram versus placebo on dropout due to adverse events (RR 12.97, 95% CI 0.77 to 218.37; 1 study, 67 participants) and on the occurrence of adverse events (RR 3.00, 95% CI 0.35 to 25.98), because the certainty of the evidence was very low for these outcomes. Disulfiram versus naltrexone Disulfiram compared with naltrexone may reduce the frequency of cocaine use (mean difference (MD) -1.90 days, 95% CI -3.37 to -0.43; 2 datasets, 123 participants; low-certainty evidence) and may have little or no effect on amount of cocaine use (SMD 0.12 SDs, 95% CI -0.27 to 0.51, 2 datasets, 123 participants; low-certainty evidence). We are unsure about the effect of disulfiram versus naltrexone on dropout for any reason (RR 0.86, 95% CI 0.56 to 1.32, 3 datasets, 131 participants) and dropout due to adverse events (RR 0.50, 95% CI 0.07 to 3.55; 1 dataset, 8 participants), because the certainty of the evidence was very low for these outcomes.
AUTHORS' CONCLUSIONS
Our results show that disulfiram compared to placebo may increase point abstinence. However, disulfiram compared to placebo or no pharmacological treatment may have little or no effect on frequency of cocaine use, amount of cocaine use, continued abstinence, and dropout for any reason. We are unsure if disulfiram has any adverse effects in this population. Caution is required when transferring our results to clinical practice.
Topics: Humans; Disulfiram; Cocaine-Related Disorders; Naltrexone; Alcoholism; Cocaine
PubMed: 38180268
DOI: 10.1002/14651858.CD007024.pub3 -
Current Journal of Neurology Jul 2023Recent research shows that most of the patients with multiple sclerosis (MS) have cognitive-like disorders. Due to the beneficial effects of atomoxetine on improving...
Recent research shows that most of the patients with multiple sclerosis (MS) have cognitive-like disorders. Due to the beneficial effects of atomoxetine on improving cognition in limited animal and human surveys, the aim of the present study was to investigate the effect of the atomoxetine on improving cognitive disorders of MS. This study was a parallel, randomized clinical trial, designed to investigate the effect of atomoxetine drug on the improvement of cognitive impairment (CI) in MS, from April 2021 to March 2022. According to the inclusion and exclusion criteria, a total of 52 participants were involved in the study and then randomly divided in two groups of 26. Experimental group was treated with atomoxetine and the control group was treated with placebo. The Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) test was performed for assessment at the beginning and after 3 months. The California Verbal Learning Test (CVLT), the CVLT-delay, the Brief Visuospatial Memory Test-Revised (BVMT-R), and the Symbol Digit Modalities Test (SDMT) were used to evaluate the CI and changes following medication. Finally, data were analyzed by SPSS software at significance level of 0.05. The mean age of patients in the experimental group was 37.7 ± 8.5 and in the placebo group was 37.8 ± 7.6 (P = 0.32). The results showed significant changes in cognitive levels before and after the use of atomoxetine and also in comparison to the placebo group (P < 0.05). This study showed that atomoxetine improved the cognitive domains after administration compared to placebo.
PubMed: 38011451
DOI: 10.18502/cjn.v22i3.13792