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Pain Jan 2024This preregistered (CRD42021223379) systematic review and meta-analysis aimed to characterize the placebo and nocebo responses in placebo-controlled randomized clinical... (Meta-Analysis)
Meta-Analysis
This preregistered (CRD42021223379) systematic review and meta-analysis aimed to characterize the placebo and nocebo responses in placebo-controlled randomized clinical trials (RCTs) on painful diabetic neuropathy (PDN), updating the previous literature by a decade. Four databases were searched for PDN trials published in the past 20 years, testing oral medications, adopting a parallel-group design. Magnitude of placebo or nocebo responses, Cochrane risk of bias, heterogeneity, and moderators were evaluated. Searches identified 21 studies (2425 placebo-treated patients). The overall mean pooled placebo response was -1.54 change in the pain intensity from baseline [95% confidence interval (CI): -1.52, -1.56, I 2 = 72], with a moderate effect size (Cohen d = 0.72). The pooled placebo 50% response rate was 25% [95% CI: 22, 29, I 2 = 50%]. The overall percentage of patients with adverse events (AEs) in the placebo arms was 53.3% [95% CI: 50.9, 55.7], with 5.1% [95% CI: 4.2, 6] of patients dropping out due to AEs. The year of study initiation was the only significant moderator of placebo response (regression coefficient = -0.06, [95% CI: -0.10, -0.02, P = 0.007]). More recent RCTs tended to be longer, bigger, and to include older patients (N = 21, rs = 0.455, P = 0.038, rs = 0.600, P = 0.004, rs = 0.472, P = 0.031, respectively). Our findings confirm the magnitude of placebo and nocebo responses, identify the year of study initiation as the only significant moderator of placebo response, draw attention to contextual factors such as confidence in PDN treatments, patients' previous negative experiences, intervention duration, and information provided to patients before enrollment.
Topics: Humans; Nocebo Effect; Diabetic Neuropathies; Placebo Effect; Pain Measurement; Diabetes Mellitus
PubMed: 37530658
DOI: 10.1097/j.pain.0000000000003000 -
Gastroenterology Feb 2022Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may be associated with higher efficacy, especially in Crohn's disease (CD). (Meta-Analysis)
Meta-Analysis
Efficacy of Biologic Drugs in Short-Duration Versus Long-Duration Inflammatory Bowel Disease: A Systematic Review and an Individual-Patient Data Meta-Analysis of Randomized Controlled Trials.
BACKGROUND AND AIMS
Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may be associated with higher efficacy, especially in Crohn's disease (CD).
METHODS
This was a systematic review and individual-patient data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (October 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction of remission in patients with short-duration (≤18 months) vs long-duration disease (>18 months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients' characteristics on the primary outcome.
RESULTS
We included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab, or vedolizumab (6168 patients with CD and 3227 patients with UC). In CD, remission induction rates were higher in pooled placebo and patients in active arms with short-duration disease of ≤18 months (41.4% [244 of 589]) compared with disease duration of >18 months (29.8% [852 of 2857], meta-analytically estimated odds ratio, 1.33; 95% confidence interval, 1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction of remission, was not different in short-duration disease of ≤18 months (n = 589, odds ratio, 1.47; 95% confidence interval, 1.01-2.15) compared with longer disease duration (n = 2857, odds ratio, 1.43; 95% confidence interval, 1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable, regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cutoffs and when modeled for individual patient's covariates, including prior anti-tumor necrosis factor exposure.
CONCLUSIONS
There are higher rates of induction of remission with biologics and with placebo in early CD, resulting in a treatment to placebo effect ratio that is similar across disease durations. No such relationships between disease duration and outcomes was found in UC. PROSPERO registration: CRD42018041961.
Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biological Products; Certolizumab Pegol; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Humans; Immunologic Factors; Infliximab; Natalizumab; Randomized Controlled Trials as Topic; Tumor Necrosis Factor Inhibitors
PubMed: 34757139
DOI: 10.1053/j.gastro.2021.10.037 -
Sleep Medicine Reviews Apr 2018This systematic review and meta-analysis aimed to determine the size of the placebo effect for insomnia symptoms when comparing placebo treatment with no treatment.... (Review)
Review
This systematic review and meta-analysis aimed to determine the size of the placebo effect for insomnia symptoms when comparing placebo treatment with no treatment. PsycINFO, MEDLINE, and CINAHL databases were systematically searched for studies allocating participants with insomnia symptoms (diagnosed or self-reported) to receive a placebo that they were led to believe was an active treatment or to a no treatment control group. Thirteen independent studies (n = 566) met inclusion criteria. Meta-analysis indicated a reliable placebo effect whereby placebo treatment led to improved perceived sleep onset latency (SOL; Hedges g = 0.272), total sleep time (TST; Hedges g = 0.322), and global sleep quality (GSQ; Hedges' g = 0.581), when compared with no treatment. There was no effect on objective assessment of SOL, however only a few studies reported this outcome and there were insufficient sample sizes to meta-analyse other objective outcomes. Moderator analysis indicated that the placebo effect for perceived insomnia symptoms was quite consistent across different variables. The present findings provide strong evidence for placebo effects for perceived insomnia symptoms, but not on the only objective measurement with sufficient sample size to meta-analyse, namely objective SOL. This has important implications for the treatment of insomnia symptoms and the design and interpretation of clinical trials for insomnia symptoms.
Topics: Humans; Placebo Effect; Self Report; Sleep; Sleep Initiation and Maintenance Disorders
PubMed: 28554719
DOI: 10.1016/j.smrv.2017.03.006 -
Journal of Cosmetic Dermatology Apr 2022Some studies have shown that platelet-rich plasma (PRP) improves androgenetic alopecia (AGA), while others do not. We determined whether the placebo effect significantly...
The effect of placebo in split-scalp and whole-head platelet-rich plasma trials for androgenetic alopecia differs: Findings from a systematic review with quantitative evidence syntheses.
BACKGROUND
Some studies have shown that platelet-rich plasma (PRP) improves androgenetic alopecia (AGA), while others do not. We determined whether the placebo effect significantly varies between split-scalp and whole-head trials on PRP monotherapy for AGA. Our rationale was based on the plausibility of PRP diffusing to the control (i.e., "placebo") side of split-scalp trials. This is not possible in whole-head studies.
METHODS
We systematically searched the literature for available data. Our choice of analyses and outcomes were determined by the available data.
RESULTS
Our endpoint was change in total hair density 6 months after baseline. Our regression showed that total hair density after 6 months was significantly (p < 0.05) higher in the placebo arm of split-scalp trials, compared to whole-head studies, by 37 hairs/cm . Our one-arm meta-analyses showed that the pooled change in total hair density between the PRP side and placebo side in split-scalp studies was -3 hairs/cm (p = 0.37), that is, a slight decrease in hair density in the placebo side of the scalp. For whole-head studies, the corresponding difference in total hair density between patients receiving PRP and those on placebo was -30 hairs/cm (p = 0.000017), that is, a much larger decrease in hair density. Patients in the placebo group in whole-head trials lost significantly more hair than in the placebo side of the split-head trials where hair loss was comparatively reduced - presumably because of PRP diffusing from the treatment side of the scalp.
CONCLUSIONS
The association between design (i.e., split-scalp vs. whole-head) and outcome, in placebo arms of AGA trials on PRP monotherapy, had never been reported. This "design effect" could partly reconcile the incongruent conclusions across the PRP literature for AGA; furthermore, clinical guidelines can consider "design effect" when selecting evidence to base care practices on.
Topics: Alopecia; Hair; Humans; Platelet-Rich Plasma; Scalp; Treatment Outcome
PubMed: 35100488
DOI: 10.1111/jocd.14813 -
Journal of Clinical PsychopharmacologyIn the 1980s, the response rate of major depressive disorder with psychotic features (MDD-Psy) to placebo pills was reported to be close to 0%. To our knowledge, this... (Meta-Analysis)
Meta-Analysis
BACKGROUND
In the 1980s, the response rate of major depressive disorder with psychotic features (MDD-Psy) to placebo pills was reported to be close to 0%. To our knowledge, this placebo response rate has not been systematically reassessed. We undertook a systematic review of randomized controlled trials (RCTs) that have used a placebo or sham control group for MDD-Psy.
METHODS
We searched MEDLINE and identified 9 relevant publications reporting on 10 studies comparing a placebo or sham interventions versus an active intervention. We extracted reported rates of response or of dropout for all causes associated with placebo versus active intervention(s) and aggregated response and dropout rates across trials.
RESULTS
Two sham-controlled electroconvulsive therapy (ECT) trials did not provide response rates. In the 3 pharmacotherapy studies published in the 1980s, 0 of 12 participants (0%) responded to placebo versus 13 of 38 (34.2%) responding to the active interventions. In contrast, 5 RCTs published in the 2000s, 114 of 339 participants (33.6%) randomized to placebo responded versus 149 of 373 participants (39.9%) randomized to active interventions; dropout rates were 71/236 (30.1%) for placebo versus 84/282 (29.8%) for the active interventions.
CONCLUSIONS
As expected, response rates to placebo pills in RCTs for MDD-Psy increased markedly from the 1980s to the 2000s. Methodological issues in the design and conduct of more recent RCTs may have contributed to the high placebo response. However, one needs to consider this placebo response rate when interpreting the result of recent trials of MDD-Psy, which typically have not included a "pure" placebo condition.
Topics: Humans; Antidepressive Agents; Depressive Disorder, Major; Placebo Effect; Randomized Controlled Trials as Topic
PubMed: 35977030
DOI: 10.1097/JCP.0000000000001589 -
Medicine Apr 2016This systematic review was performed to investigate the ethical justification, methodological quality, validity and safety of placebo controls in randomized... (Meta-Analysis)
Meta-Analysis Review
This systematic review was performed to investigate the ethical justification, methodological quality, validity and safety of placebo controls in randomized placebo-controlled surgical trials.Central, MEDLINE, and EMBASE were systematically searched to identify randomized controlled trials comparing a surgical procedure to a placebo. "Surgical procedure" was defined as a medical procedure involving an incision with instruments. Placebo was defined as a blinded sham operation involving no change to the structural anatomy and without an expectable physiological response in the target body compartment.Ten randomized placebo-controlled controlled surgical trials were included, all of them published in high-ranking medical journals (mean impact factor: 20.1). Eight of 10 failed to show statistical superiority of the experimental intervention. Serious adverse events did not differ between the groups (rate ratio [RR] 1.38, 95% confidence interval [CI]: 0.92-2.06, P = 0.46). None of the trials had a high risk of bias in any domain. The ethical justification for the use of a placebo control remained unclear in 2 trials.Placebo-controlled surgical trials are feasible and provide high-quality data on efficacy of surgical treatments. The surgical placebo entails a considerable risk for study participants. Consequently, a placebo should be used only if justified by the clinical question and by methodological necessity. Based on the current evidence, a pragmatic proposal for the use of placebo controls in future randomized controlled surgical trials is made.
Topics: Patient Safety; Placebo Effect; Randomized Controlled Trials as Topic; Surgical Procedures, Operative
PubMed: 27124060
DOI: 10.1097/MD.0000000000003516 -
Neurology Jun 2017To estimate the placebo and nocebo responses in restless legs syndrome (RLS) and explore their determinants. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To estimate the placebo and nocebo responses in restless legs syndrome (RLS) and explore their determinants.
METHODS
Databases were searched up to October 2015. Randomized, double-blind, placebo-controlled trials of patients with RLS were included if quantitative data were extractable in the placebo arm. Placebo response was defined as the within-group change from baseline, using any scale measuring RLS severity or disability. Nocebo response was defined as the proportion of patients experiencing adverse events in the placebo arm. Random-effects meta-analysis was used to pool data. Statistical heterogeneity was assessed with statistic. Several predetermined subgroup and sensitivity analysis were performed. PROSPERO registration number is CRD42015027992.
RESULTS
We included 85 randomized controlled trials (5,046 participants). Pooled placebo response effect size was -1.41 (95% confidence interval [CI] -1.56 to -1.25, 64 trials, = 88.1%), corresponding to -6.58 points in the International RLS Study Group Scale (IRLS). Pooled nocebo response was 45.36% (95% CI 40.47%-50.29%, 72 trials; = 89.8%). The placebo and nocebo responses were greater in trials with longer duration, evaluating pharmacologic interventions and idiopathic RLS, and in industry-funded and unpublished studies. The placebo response was considerably smaller in objective as compared to subjective outcomes. In addition, the nocebo response increases proportionally with the placebo response, and has the same predictors.
CONCLUSIONS
The magnitude of the placebo response in RLS is above the threshold of minimal clinical important difference, and the frequency of adverse events is also considerable. These results are relevant to inform the design and interpretation of future clinical trials.
Topics: Humans; Placebo Effect; Randomized Controlled Trials as Topic; Restless Legs Syndrome
PubMed: 28490647
DOI: 10.1212/WNL.0000000000004004 -
Cardiovascular and Interventional... Jan 2021Objective To systematically review the published literature on genicular artery embolization (GAE) for osteoarthritis (OA) related knee pain. Materials and Methods Using... (Meta-Analysis)
Meta-Analysis
Objective To systematically review the published literature on genicular artery embolization (GAE) for osteoarthritis (OA) related knee pain. Materials and Methods Using three databases, a systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Outcome measures included the Visual Analog Scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Results Three single-arm studies were included from an initial search yielding 305 results. One hundred and eighty-six knees in 133 patients with either mild-to-moderate (174/186, 94%) or severe (12/186, 6%) OA underwent embolization with either imipenem/cilastatin sodium (159/186, 85%) or embozene (27/186, 15%). Technical success was 100%. Average VAS improved from baseline at 1 day, 1 week, 1 month, 3 months, 4 months, 6 months, 1 year and 2 years (66.5 at baseline vs 33.5, 32.7, 33.8, 28.9, 29.0, 22.3, 14.8 and 14.0, respectively). Average WOMAC scores improved from baseline at 1, 3, 4, 6, 12 and 24 months (45.7 at baseline vs 24.0, 31.0, 14.8, 14.6, 8.2 and 6.2). Severe OA in 12 cases showed initially improved VAS, but was not sustained. Minor adverse events such as erythema in the region of embolization (21/186, 11%), puncture-site hematoma (18/186, 10%), paresthesia (2/186, 1%) and fever (1/186, 0.5%) were reported. Conclusion Limited single-arm studies report GAE is promising for treating OA-related pain. Most treatments performed for mild-to-moderate OA demonstrated durable clinical responses from 6 months to 4 years. Limited data for severe OA suggest a non-durable response. Future studies should be standardized to facilitate comparison and control for placebo effect.
Topics: Arthralgia; Embolization, Therapeutic; Humans; Leg; Osteoarthritis, Knee; Pain Management; Pain Measurement; Treatment Outcome
PubMed: 33135117
DOI: 10.1007/s00270-020-02687-z -
International Forum of Allergy &... Mar 2024The placebo effect observed in clinical trials evaluating medical treatments for chronic rhinosinusitis (CRS) is not well understood. This systematic review and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The placebo effect observed in clinical trials evaluating medical treatments for chronic rhinosinusitis (CRS) is not well understood. This systematic review and meta-analysis sought to characterize the placebo effect present within CRS outcomes.
METHODS
A systematic review of PubMed, Scopus, and Cumulated Index in Nursing and Allied Health Nursing (CINAHL) was performed. Randomized controlled trials (RCTs) evaluating medical treatments for CRS versus placebo were included. We assessed patient-reported (sino-nasal outcome test 22 [SNOT-22], nasal obstruction, sense of smell, nasal obstruction visual analogue score [VAS], sense of smell VAS, anterior rhinorrhea, and postnasal drip) and objective (Lund-Mackay Computed tomography (CT) score, peak nasal inspiratory flow [PNIF], nasal polyp scores, 40-item Smell Identification Test, serum IgE, and blood eosinophil levels) outcomes.
RESULTS
Twenty-one RCTs were included, comprising 1437 patients (mean age 49.2 years). Biologics were the most common treatment investigated (n = 9). Eleven studies administered background steroids along with placebo. Following placebo administration, multiple patient-reported outcomes significantly decreased, including SNOT-22 (mean difference -9.49, 95% confidence interval [CI] [-11.26, -7.73]), nasal obstruction (-0.33 [-0.54, -0.13]), sense of smell (-0.22 [-0.33, -0.11]), nasal obstruction VAS (-2.47 [-2.87, -2.06]), and loss of smell VAS (-2.31 [-4.14, -0.47]) scores. For objective measures, significant changes occurred in Lund-Mackay CT score (-0.82, [-1.48, -0.16]) and PNIF (4.70, [4.76, 24.64]) with placebo. Placebo arms had the greatest impact when no background medications were used.
CONCLUSIONS
Placebo treatments have a statistically and potentially clinically significant effect on patient-reported and some objective CRS outcomes. Further investigation is required to fully understand placebo effect, which could improve assessment of RCTs and impact patient care.
Topics: Humans; Middle Aged; Nasal Obstruction; Rhinosinusitis; Rhinitis; Nasal Polyps; Sinusitis; Chronic Disease; Placebo Effect; Randomized Controlled Trials as Topic
PubMed: 37985206
DOI: 10.1002/alr.23302 -
Journal of Crohn's & Colitis May 2016Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them.
METHODS
MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool.
RESULTS
In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits.
CONCLUSIONS
Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.
Topics: Anti-Inflammatory Agents; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Induction Chemotherapy; Maintenance Chemotherapy; Models, Statistical; Placebo Effect; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome
PubMed: 26746169
DOI: 10.1093/ecco-jcc/jjw004