-
Clinical Orthopaedics and Related... Apr 2022Tennis elbow is a common painful enthesopathy of the lateral elbow that limits upper limb function and frequently results in lost time at work. Surgeons often recommend... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Tennis elbow is a common painful enthesopathy of the lateral elbow that limits upper limb function and frequently results in lost time at work. Surgeons often recommend surgery if symptoms persist despite nonsurgical management, but operations for tennis elbow are inconsistent in their efficacy, and what we know about those operations often derives from observational studies that assume the condition does not continue to improve over time. This assumption is largely untested, and it may not be true; meta-analyzing results from the control arms of tennis elbow studies can help us to evaluate this premise, but to our knowledge, this has not been done.
QUESTIONS/PURPOSES
The aims of this systematic review were to describe the course of (1) global improvement, (2) pain, and (3) disability in participants who received no active treatment (placebo or no treatment) in published randomized controlled trials (RCTs) on tennis elbow. We also assessed (4) whether the duration of symptoms or placebo effect is associated with differences in symptom trajectories.
METHODS
We searched MEDLINE, Embase, and CENTRAL from database inception to August 12, 2019, for trials including participants with tennis elbow and a placebo or a no-treatment arm and a minimum follow-up duration of 6 months. There were no language restrictions or exclusion criteria. We extracted global improvement, pain, and disability outcomes. We used the Cochrane Risk of Bias tool to assess the risk of bias of included trials. To estimate the typical course of tennis elbow without active treatment, we pooled global improvement (the proportion of participants who reported feeling much better or completely recovered), mean pain, and mean disability using baseline, 1-month, 3-month, 6-month, and 12-month follow-up data. We transformed pain and disability data from the original papers so that at each timepoint the relevant outcome was expressed as change relative to baseline to account for different baseline values. We used meta-regression to assess whether the placebo effect or duration of symptoms before enrollment was associated with differences in symptom trajectories. We included 24 trials with 1085 participants who received no active treatment.
RESULTS
The number of patients who were not improved decreased exponentially over time. The half-life of global improvement was between 2.5 and 3 months (that is, every 2.5 to 3 months, 50% of the remaining symptomatic patients reported complete recovery or greatly improved symptoms). At 1 year, 89% (189 of 213; 95% CI 80% to 97%) of patients experienced global improvement. The mean pain and disability followed a similar pattern, halving every 3 to 4 months. Eighty-eight percent of pain (95% CI 70% to 100%) and 85% of disability (95% CI 60% to 100%) had resolved by 1 year. The mean duration of symptoms before trial enrollment was not associated with differences in symptom trajectories. The trajectories of the no-treatment and placebo arms were similar, indicating that the placebo effect of the studied active treatments likely is negligible.
CONCLUSION
Based on the placebo or no-treatment control arms of randomized trials, about 90% of people with untreated tennis elbow achieve symptom resolution at 1 year. The probability of resolution appears to remain constant throughout the first year of follow-up and does not depend on previous symptom duration, undermining the rationale that surgery is appropriate if symptoms persist beyond a certain point of time. We recommend that clinicians inform people who are frustrated with persisting symptoms that this is not a cause for apprehension, given that spontaneous improvement is about as likely during the subsequent few months as it was early after the symptoms first appeared. Because of the high likelihood of spontaneous recovery, any active intervention needs to be justified by high levels of early efficacy and little or no risk to outperform watchful waiting.
LEVEL OF EVIDENCE
Level I, therapeutic study.
Topics: Elbow; Humans; Pain; Prognosis; Tennis Elbow
PubMed: 34874323
DOI: 10.1097/CORR.0000000000002058 -
World Journal of Gastroenterology Mar 2017To determine the placebo response rate associated with different types of placebo interventions used in psychological intervention studies for irritable bowel syndrome. (Review)
Review
AIM
To determine the placebo response rate associated with different types of placebo interventions used in psychological intervention studies for irritable bowel syndrome.
METHODS
Randomized controlled trials comparing psychological interventions (stress management/relaxation therapy (cognitive) behavioral therapy, short-term psychodynamic therapy, and hypnotherapy) for the treatment of adult patients with irritable bowel syndrome (IBS) diagnosed with the Manning or Rome criteria with an adequate placebo control treatment and reporting data on IBS symptom severity were identified by searching PubMed, Embase, the Cochrane Library, CINAHL and PsycINFO databases. Full-text articles that were written in English and published between 1966 and February 2016 in peer-reviewed journals were selected for the present review. Placebo interventions were considered to be adequate if the number of sessions and the amount of time spent with the therapist were the same as in the active treatment. The placebo response rate (PRR) was computed for IBS symptom severity (primary outcome measure) as well as for anxiety, depression and quality of life (secondary outcome measures).
RESULTS
Six studies, with a total of 555 patients met the inclusion criteria. Four studies used an educational intervention, whereas two studies used a form of supportive therapy as the placebo intervention. The PRR for IBS symptom severity ranged from 25% to 59%, with a pooled mean of 41.4%. The relative PRR for the secondary outcome measures ranged from 0% to 267% for anxiety, 6% to 52% for depression 20% to 125% for quality of life. The PRR associated with pharmacological treatments, treatment with dietary bran and complementary medicine ranged from 37.5% to 47%. Contrary to our expectations, the PRR in studies on psychological interventions was comparable to that in studies on pharmacological, dietary and alternative medical interventions.
CONCLUSION
The PRR is probably determined to a larger extent by patient-related factors, such as expectations and desire for the treatment to be effective, than the content of the placebo intervention.
Topics: Adult; Aged; Cognitive Behavioral Therapy; Female; Humans; Irritable Bowel Syndrome; Male; Middle Aged; Placebo Effect; Psychotherapy, Psychodynamic; Quality of Life; Randomized Controlled Trials as Topic; Stress, Psychological; Treatment Outcome; Young Adult
PubMed: 28405151
DOI: 10.3748/wjg.v23.i12.2223 -
Progress in Neuro-psychopharmacology &... Feb 2018Although several studies indicate that placebo response is large to antidepressant pharmacotherapy in major depressive disorder (MDD), no updated meta-analysis has... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Although several studies indicate that placebo response is large to antidepressant pharmacotherapy in major depressive disorder (MDD), no updated meta-analysis has quantified the magnitude of the placebo (sham) response to repetitive transcranial magnetic stimulation (rTMS) in MDD yet.
OBJECTIVE
To conduct a systematic review and meta-analysis on this issue in randomized controlled trials (RCTs) involving participants with MDD; and to explore potential moderators.
METHODOLOGY
PubMed/MEDLINE, Embase, PsycINFO, and Web of Science electronic databases were searched from inception up to March 15, 2017 for RCTs that investigated the efficacy of any rTMS modality compared to sham intervention in participants with acute depressive episodes. Cochrane Risk of Bias Tool was used to estimate risks. We estimated the placebo effect size (Hedges's g, random-effects model) response using placebo groups baseline and endpoint depressive symptom scores. Meta-regressions have been employed to explore potential moderators of response.
RESULTS
Sixty-one studies met eligibility criteria (N=1328; mean age, 47years; 57% females). Placebo response was large (g=0.8, 95% CI=0.65-0.95, p<0.01) regardless of the modality of intervention. Placebo response was directly associated with publication year and depression improvement of the active group, and inversely associated with higher levels of treatment-resistant depression. Other moderators, including gender, age, and stimulator type, were not associated with the outcome. Overall, 24.6%, 67.2%, and 8.2% of studies had an overall low, unclear, and high bias risk, respectively.
CONCLUSION
Placebo response in rTMS depression trials was large and associated with depression improvement of the active treatment group. Such result suggests that excluding placebo responders with a run-in phase may not confer advantage since response to 'active' rTMS may decrease as well. Moreover, placebo response may be a component of therapeutic response to rTMS in MDD. In addition, placebo response increase over time could indicate improvement in rTMS trial designs, including better sham rTMS methods.
Topics: Depressive Disorder, Major; Humans; Placebo Effect; Randomized Controlled Trials as Topic; Transcranial Magnetic Stimulation
PubMed: 29111404
DOI: 10.1016/j.pnpbp.2017.10.016 -
Neuroscience and Biobehavioral Reviews Dec 2020Microdosing psychedelic drugs-that is, taking sub-behavioral doses of lysergic acid diethylamide (LSD) or psilocybin-is a growing practice in Western societies. Taken... (Review)
Review
Microdosing psychedelic drugs-that is, taking sub-behavioral doses of lysergic acid diethylamide (LSD) or psilocybin-is a growing practice in Western societies. Taken mainly for creative or mood-enhancing purposes, thousands of users are increasingly being exposed to (micro)doses of psychedelic drugs. In this systematic review, we searched the available evidence from human studies, focusing our results in terms of three main axes: efficacy, safety, and the influence of the placebo effect in microdosing practices. While the available evidence has some strengths (e.g. large sample sizes, robust methodologies) there are also remarkable limitations (e.g. gender bias, heterogeneity of dosing schedules and drugs used). Highly contradictory results have been found, showing both the benefits and detriments of microdosing in terms of mood, creative processes, and energy, among other regards. This review provides a general overview of the methods and approaches used, which could be useful for improving future studies.
Topics: Female; Hallucinogens; Humans; Male; Pharmaceutical Preparations; Placebo Effect; Psilocybin; Sexism
PubMed: 33031815
DOI: 10.1016/j.neubiorev.2020.09.035 -
Frontiers in Physiology 2020Placebo/nocebo effects involve the autonomic nervous system, including cardiac activity, but studies have reported inconsistent findings on how cardiac activity is...
Placebo/nocebo effects involve the autonomic nervous system, including cardiac activity, but studies have reported inconsistent findings on how cardiac activity is modulated following a placebo/nocebo effect. However, no systematic review has been conducted to provide a clear picture of cardiac placebo responses. The main goal of the present study is to review the effects of placebo analgesia and nocebo hyperalgesia on cardiac activity as measured by blood pressure, heart rate, and heart rate variability. Using several Boolean keyword combinations, the PubMed, EMBASE, PsycINFO, Cochrane Review Library, and ISI Web of Knowledge databases were searched until January 5, 2020, to find studies that analyzed blood pressure, heart rate, or heart rate variability indexes following a placebo analgesic/nocebo hyperalgesic effect. Nineteen studies were found, with some reporting more than one index of cardiac activity; eight studies were on blood pressure, 14 studies on heart rate, and six on heart rate variability. No reliable association between placebo/nocebo effects and blood pressure or heart rate was found. However, placebo effects reduced, and nocebo effects increased low-frequency heart rate variability, and heart rate variability significantly predicted placebo effects in two studies. Placebo/nocebo effects can have reliable effects on heart rate variability, but not on heart rate and blood pressure.
PubMed: 33101048
DOI: 10.3389/fphys.2020.549807 -
The Journal of Clinical Psychiatry Apr 2008Cognitive-behavioral therapy (CBT) is frequently used for various adult anxiety disorders, but there has been no systematic review of the efficacy of CBT in randomized... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Cognitive-behavioral therapy (CBT) is frequently used for various adult anxiety disorders, but there has been no systematic review of the efficacy of CBT in randomized placebo-controlled trials. The present study meta-analytically reviewed the efficacy of CBT versus placebo for adult anxiety disorders.
DATA SOURCES
We conducted a computerized search for treatment outcome studies of anxiety disorders from the first available date to March 1, 2007. We searched MEDLINE, PsycINFO, PubMed, Scopus, the Institute of Scientific Information, and Dissertation Abstracts International for the following terms: random*, cognitive behavior*therap*, cognitive therap*, behavior*therap*, GAD, generalized anxiety disorder, OCD, obsessive compulsive disorder, social phobia, social anxiety disorder, specific phobia, simple phobia, PTSD, post-traumatic stress disorder, and acute stress disorder. Furthermore, we examined reference lists from identified articles and asked international experts to identify eligible studies.
STUDY SELECTION
We included studies that randomly assigned adult patients between ages 18 and 65 years meeting DSM-III-R or DSM-IV criteria for an anxiety disorder to either CBT or placebo. Of 1165 studies that were initially identified, 27 met all inclusion criteria.
DATA EXTRACTION
The 2 authors independently identified the eligible studies and selected for each study the continuous measures of anxiety severity. Dichotomous measures reflecting treatment response and continuous measures of depression severity were also collected. Data were extracted separately for completer (25 studies for continuous measures and 21 studies for response rates) and intent-to-treat (ITT) analyses (6 studies for continuous measures and 8 studies for response rates).
DATA SYNTHESIS
There were no significant differences in attrition rates between CBT and placebo. Random-effects models of completer samples yielded a pooled effect size (Hedges' g) of 0.73 (95% CI = 0.88 to 1.65) for continuous anxiety severity measures and 0.45 (95% CI = 0.25 to 0.65) for depressive symptom severity measures. The pooled odds ratio for completer treatment response rates was 4.06 (95% CI = 2.78 to 5.92). The strongest effect sizes were observed in obsessive-compulsive disorder and acute stress disorder, and the weakest effect size was found in panic disorder. The advantage of CBT over placebo did not depend on placebo modality, number of sessions, or study year.
CONCLUSIONS
Our review of randomized placebo-controlled trials indicates that CBT is efficacious for adult anxiety disorders. There is, however, considerable room for improvement. Also, more studies need to include ITT analyses in the future.
Topics: Adult; Anxiety Disorders; Cognitive Behavioral Therapy; Humans; Randomized Controlled Trials as Topic
PubMed: 18363421
DOI: 10.4088/jcp.v69n0415 -
Annals of Internal Medicine Sep 2015Placebo controls are essential in evaluating the effectiveness of medical treatments. Although it is unclear whether different placebo interventions for osteoarthritis... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Placebo controls are essential in evaluating the effectiveness of medical treatments. Although it is unclear whether different placebo interventions for osteoarthritis vary in efficacy, systematic differences would substantially affect interpretation of the results of placebo-controlled trials.
OBJECTIVE
To evaluate the effects of alternative placebo types on pain outcomes in knee osteoarthritis.
DATA SOURCES
MEDLINE, EMBASE, Web of Science, Google Scholar, and Cochrane Database from inception through 1 June 2015 and unpublished data.
STUDY SELECTION
149 randomized trials of adults with knee osteoarthritis that reported pain outcomes and compared widely used pharmaceuticals against oral, intra-articular, topical, and oral plus topical placebos.
DATA EXTRACTION
Study data were independently double-extracted; study quality was assessed by using the Cochrane risk of bias tool.
DATA SYNTHESIS
Placebo effects that were evaluated by using a network meta-analysis with 4 separate placebo nodes (differential model) showed that intra-articular placebo (effect size, 0.29 [95% credible interval, 0.09 to 0.49]) and topical placebo (effect size, 0.20 [credible interval, 0.02 to 0.38]) had significantly greater effect sizes than did oral placebo. This differential model showed marked differences in the relative efficacies and hierarchy of the active treatments compared with a network model that considered all placebos equivalent. In the model accounting for differential effects, intra-articular and topical therapies were superior to oral treatments in reducing pain. When these differential effects were ignored, oral nonsteroidal anti-inflammatory drugs were superior.
LIMITATIONS
Few studies compared different placebos directly. The study could not decisively conclude whether disease severity and co-interventions systematically differed between trials evaluating different placebos.
CONCLUSION
All placebos are not equal, and some can trigger clinically relevant responses. Differential placebo effects can substantially alter estimates of the relative efficacies of active treatments, an important consideration for the design of clinical trials and interpretation of their results.
PRIMARY FUNDING SOURCE
Agency for Healthcare Research and Quality.
Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Humans; Hyaluronic Acid; Osteoarthritis, Knee; Pain; Placebo Effect; Randomized Controlled Trials as Topic
PubMed: 26215539
DOI: 10.7326/M15-0623 -
Clinical Orthopaedics and Related... Feb 2020To improve ankle stability in patients who have experienced an ankle sprain with residual symptoms of instability and/or objective joint laxity, external supports (such... (Meta-Analysis)
Meta-Analysis
BACKGROUND
To improve ankle stability in patients who have experienced an ankle sprain with residual symptoms of instability and/or objective joint laxity, external supports (such as taping, bracing, and orthotic insoles) are used sometimes. However, available randomized trials have disagreed on whether restraints improve balance in those individuals. In this situation, a network meta-analysis can help because it allows for comparing multiple treatments simultaneously, taking advantage not only of direct but also indirect evidence synthesis.
QUESTIONS/PURPOSES
The aim of this network meta-analysis was to assess (1) the impact of taping and orthotic devices on dynamic postural control in individuals with ankle instability and (2) the presence of a placebo effect in participants treated with sham taping and complications resulting from the administered treatments.
METHODS
We searched the PubMed, Scopus, and CENTRAL databases up to February 13, 2019 for completed studies. Randomized trials assessing the results of real and/or sham taping, wait-and-see protocols, ankle bracing, and foot orthotics for ankle instability as determined by one or more ankle sprains followed by ongoing subjective symptoms and/or mechanical laxity were included. We evaluated dynamic postural control in terms of the Star Excursion Balance Test in the posteromedial direction (SEBT-PM), which is considered the most representative of balance deficits in patients with ankle instability. Standardized mean differences were re-expressed to percentage differences in SEBT-PM, with higher scores representing possible improvement. Subsequently, those data were checked against the established minimal detectable change of 14% for this scale to make judgements on clinical importance. We also assessed the presence of a placebo effect by comparing the results of sham taping with no treatment and complications resulting from the administered treatments. Additionally, we judged the quality of trials using the Cochrane risk of bias tool and quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. A total of 22 trials met our inclusion criteria, 18 of which were deemed to be at a low risk of bias. A network of treatments consisting of 13 studies was created, and the level of evidence was judged to be high. As far as participants' allocation to treatment arms, 85 patients followed a wait-and-see protocol, 29 received placebo taping, 99 were treated with taping, 16 were treated with bracing, 27 were administered insoles, and six individuals were offered a combination of insoles with bracing. Of note, with statistical power set at 80%, a minimum of 16 patients per treatment group was required to provide sufficient statistical power and detect a SEBT-PM percentage difference of 14%.
RESULTS
A network meta-analysis did not demonstrate a benefit of taping or bracing over no treatment (percentage difference in SEBT-PM between taping and bracing versus control: -2.4 [95% CI -6 to 1.1]; p = 0.18, and -7.5 [95% CI -15.9 to 1]; p = 0.08, respectively). This was also the case for sham taping because the measurement increase failed to exceed the minimal detectable change (percentage difference in SEBT-PM between sham taping and untreated control: -1.1 [95% CI -6.9 to 4.7]; p = 0.72). Importantly, there were no reported adverse events after treatment application.
CONCLUSIONS
Evidence of moderate strength indicated that external supports of any type were no more effective than controls in improving dynamic postural control in patients with at least one ankle sprain and residual functional or mechanical deficits. Therefore, implementing those tools as a standalone treatment does not appear to be a viable strategy for the primary management of ankle instability. It is conceivable that combinations of rehabilitation and external supports could be more effective than external supports alone, and future trials should evaluate the potential of such combinations in enhancing not only clinician-reported but also patient-oriented outcomes using long-term follow-up measurements.
LEVEL OF EVIDENCE
Level I, therapeutic study.
Topics: Ankle Injuries; Ankle Joint; Athletic Tape; Biomechanical Phenomena; Chronic Disease; Equipment Design; Humans; Joint Instability; Network Meta-Analysis; Orthopedic Procedures; Orthotic Devices; Postural Balance; Randomized Controlled Trials as Topic; Range of Motion, Articular; Recovery of Function; Treatment Outcome
PubMed: 31625960
DOI: 10.1097/CORR.0000000000000946 -
Defining and evaluating the Hawthorne effect in primary care, a systematic review and meta-analysis.Frontiers in Medicine 2022In 2015, we conducted a randomized controlled trial (RCT) in primary care to evaluate if posters and pamphlets dispensed in general practice waiting rooms enhanced...
In 2015, we conducted a randomized controlled trial (RCT) in primary care to evaluate if posters and pamphlets dispensed in general practice waiting rooms enhanced vaccination uptake for seasonal influenza. Unexpectedly, vaccination uptake rose in both arms of the RCT whereas public health data indicated a decrease. We wondered if the design of the trial had led to a Hawthorne effect (HE). Searching the literature, we noticed that the definition of the HE was unclear if stated. Our objectives were to refine a definition of the HE for primary care, to evaluate its size, and to draw consequences for primary care research. We designed a Preferred Reporting Items for Systematic reviews and Meta-Analyses review and meta-analysis between January 2012 and March 2022. We included original reports defining the HE and reports measuring it without setting limitations. Definitions of the HE were collected and summarized. Main published outcomes were extracted and measures were analyzed to evaluate odds ratios (ORs) in primary care. The search led to 180 records, reduced on review to 74 for definition and 15 for quantification. Our definition of HE is "an aware or unconscious complex behavior change in a study environment, related to the complex interaction of four biases affecting the study subjects and investigators: selection bias, commitment and congruence bias, conformity and social desirability bias and observation and measurement bias." Its size varies in time and depends on the education and professional position of the investigators and subjects, the study environment, and the outcome. There are overlap areas between the HE, placebo effect, and regression to the mean. In binary outcomes, the overall OR of the HE computed in primary care was 1.41 (95% CI: [1.13; 1.75]; = 97%), but the significance of the HE disappears in well-designed studies. We conclude that the HE results from a complex system of interacting phenomena and appears to some degree in all experimental research, but its size can considerably be reduced by refining study designs.
PubMed: 36425097
DOI: 10.3389/fmed.2022.1033486 -
Seizure Feb 2017Nocebo is very prevalent among neurological diseases resulting in low adherence and treatment outcome. We sought to examine the AEs following placebo administration in... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Nocebo is very prevalent among neurological diseases resulting in low adherence and treatment outcome. We sought to examine the AEs following placebo administration in Randomized Controlled Studies (RCTs) for Epilepsy.
METHOD
After a systematic Medline search for RCTs for Epilepsy pharmacological treatments, we assessed the number of discontinuations because of placebo intolerance.
RESULTS
Data were extracted from 4 RCTs fulfilling our search criteria. Three out of 5 placebo-treated patients (60.8%) reported at least one AE and 4.0% discontinued placebo treatment because of AEs. All patients participating in the epilepsy RCTs reported similar AEs independently of the study arm they belonged.
CONCLUSION
Very limited epilepsy RCTs with pure placebo groups are available and all are in treatment resistant patients during pre-surgical monitoring. However, our study indicates a significant nocebo effect in trials for epilepsy treatment adversely affecting adherence and efficacy of current treatments in clinical practice, with additional implications for trial designing.
Topics: Drug Resistant Epilepsy; Humans; MEDLINE; Nocebo Effect; Preoperative Care; Randomized Controlled Trials as Topic
PubMed: 27978485
DOI: 10.1016/j.seizure.2016.12.003