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JAMA Network Open Dec 2018Several reports have associated the placebo effect with objective response and improvement of a clinical condition in oncology, but only a few studies have analyzed the... (Meta-Analysis)
Meta-Analysis
Incidence of Placebo Adverse Events in Randomized Clinical Trials of Targeted and Immunotherapy Cancer Drugs in the Adjuvant Setting: A Systematic Review and Meta-analysis.
IMPORTANCE
Several reports have associated the placebo effect with objective response and improvement of a clinical condition in oncology, but only a few studies have analyzed the adverse events (AEs) in the placebo groups of the clinical trials.
OBJECTIVE
To determine the incidence of placebo AEs reported in randomized clinical trials of modern cancer drugs in the adjuvant setting.
DATA SOURCES
Based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, a systematic literature search of English-language publications from January 1, 2000, through April 15, 2018, was performed using MEDLINE (PubMed). The following search terms were used to retrieve all trials from the PubMed library: adjuvant, maintenance, consolidation, and placebo, in addition to specific cancer type-related keywords.
STUDY SELECTION
A double-blind, randomized, placebo-controlled, phase 3 design was mandatory for study inclusion. Only studies enrolling patients who had undergone macroscopically complete resections were included. No other anticancer treatments in addition to placebo were allowed in the control group. Only trials involving a targeted therapy (tyrosine kinase, BRAF, or MEK inhibitors) or immunotherapy-related drugs were included. Trials using chemotherapy, interferon, and endocrine therapy were excluded. Two authors (D.H.E. and F.D.W.) independently reviewed the studies for inclusion.
DATA EXTRACTION AND SYNTHESIS
Data were extracted by investigators, and random-effects meta-analysis was performed to estimate the proportion of grade 3 to 4 placebo AEs in the included studies.
MAIN OUTCOMES AND MEASURES
Incidence of grade 3 to 4 placebo AEs in the placebo groups.
RESULTS
Of 731 studies screened, 10 eligible trials were found including 4 tumor types (melanoma, non-small cell lung cancer, gastrointestinal stromal tumor, and renal cell carcinoma). Overall, 11 143 patients (6270 [56.3%] in the treatment group with mean [SD] age of 55.6 [4.2] years and 4873 patients [43.7%] in the placebo group with mean [SD] age of 55.9 [4.3] years) were included. The mean incidence of any-grade placebo AEs was 85.1% (95% CI, 79.2%-91.0%). The most frequent (mean [SD]) grade 3 to 4 placebo AEs in patients were hypertension (2.8% [2.2%]), fatigue (1.0% [0.9%]), and diarrhea (0.8% [0.6%]). The overall, random-effects pooled incidence of grade 3 to 4 placebo AEs was 18% (95% CI, 15%-21%), with a high level of heterogeneity (I2 = 86%). Frequency of grade 3 to 4 placebo AEs was found to be correlated in the treatment and placebo groups (ρ = 0.7; P = .03). Mean study drug discontinuation owing to placebo AEs was 3.9% (95% CI, 2.7%-5.2%).
CONCLUSIONS AND RELEVANCE
Placebo administration was associated with a substantial incidence of grade 3 to 4 placebo AEs in modern cancer adjuvant trials. This finding should be considered by investigators, sponsors, regulatory authorities, and patient support groups.
Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Fatigue; Humans; Hypertension; Immunotherapy; Middle Aged; Neoplasms; Placebos; Randomized Controlled Trials as Topic
PubMed: 30646278
DOI: 10.1001/jamanetworkopen.2018.5617 -
American Journal of Physical Medicine &... Feb 2010Compared with other specialties, the field of physical and rehabilitation medicine has not received the deserved recognition from clinicians and researchers in the...
Challenges and recommendations for placebo controls in randomized trials in physical and rehabilitation medicine: a report of the international placebo symposium working group.
Compared with other specialties, the field of physical and rehabilitation medicine has not received the deserved recognition from clinicians and researchers in the scientific community. One of the reasons is the lack of sound evidence to support the traditional physical and rehabilitation medicine treatments. The best way to change this disadvantage is through a well conducted clinical research, such as standard placebo- or sham-controlled randomized clinical trials. Therefore, having placebo groups in clinical trials is essential to improve the level of evidence-based practice in physical and rehabilitation medicine that ultimately translates to better clinical care. To address the challenges for the use of placebo in physical and rehabilitation medicine and randomized clinical trials and to create useful recommendations, we convened a working group during the inaugural International Symposium in Placebo (February 2009, in Sao Paulo, Brazil) in which the following topics were discussed: (1) current status of randomized clinical trials in physical and rehabilitation medicine, (2) challenges for the use of placebo in physical and rehabilitation medicine, (3) bioethics, (4) use of placebo in acupuncture trials and for the treatment of low-back pain, (5) mechanisms of placebo, and (6) insights from other specialties. The current article represents the consensus report from the working group.
Topics: Adult; Child; Humans; Patient Selection; Physical and Rehabilitation Medicine; Placebos; Professional-Patient Relations; Randomized Controlled Trials as Topic; Rehabilitation
PubMed: 20090428
DOI: 10.1097/PHM.0b013e3181bc0bbd -
International Review of Neurobiology 2018
Topics: Animals; History, 19th Century; Humans; Neurobiology; Placebo Effect; Placebos; Translational Research, Biomedical
PubMed: 30146061
DOI: 10.1016/S0074-7742(18)30087-4 -
EuroIntervention : Journal of EuroPCR... Dec 2017
Topics: Angina, Stable; Clinical Trials as Topic; Humans; Percutaneous Coronary Intervention; Placebos; Treatment Outcome
PubMed: 29208573
DOI: 10.4244/EIJV13I12A217 -
Journal of Psychiatric Research Nov 2017In a study of recent antidepressant clinical trial data, it was found placebo response had grown significantly over time and that contrary to expectations, trial outcome...
In a study of recent antidepressant clinical trial data, it was found placebo response had grown significantly over time and that contrary to expectations, trial outcome measures and success rate were not impacted. The aim of this paper was to evaluate if this trend of increasing placebo response and stable outcome measures could be seen in clinical trial data for Attention-Deficit Hyperactivity Disorder, a different psychiatric condition with susceptibility to placebo response. For this reason, we evaluated efficacy data reported in the FDA Medical and Statistical reviews for 10 ADHD medication programs (4917 patients, 17 trials, 29 treatment arms). Placebo and medication response were measured as percent symptom reduction and effect sizes and drug-placebo differences were calculated for each treatment arm and analyzed in relation to year of approval. We also investigated the potential role of age and medication class on trends and outcomes. Results showed a similar pattern to antidepressants wherein the placebo response is rising significantly over time (r = 0.636, p = 0.006) and effect size (r < 0.0001, p = 1.0), drug-placebo difference (r = -0.238, p = 0.214), and success rate (28/29 97%) have remained unaffected, likely due to a parallel, although not statistically significant increase in medication response (r = 0.326, p = 0.085). Age and medication class did not alter these observed time trends but pediatric trials and stimulants were found to have more robust treatment effects than adult trials and non-stimulants. The results of this study suggest that like antidepressants, the relationship between placebo response and the outcomes of ADHD clinical trials is weak at best.
Topics: Adolescent; Adrenergic alpha-2 Receptor Agonists; Adult; Age Factors; Aged; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Controlled Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Placebo Effect; Placebos; United States; United States Food and Drug Administration; Young Adult
PubMed: 28755620
DOI: 10.1016/j.jpsychires.2017.07.018 -
American Journal of Pharmaceutical... Jun 2017To review published educational interventions focusing on medication non-adherence. A literature search was performed of educational articles on the topic of... (Review)
Review
To review published educational interventions focusing on medication non-adherence. A literature search was performed of educational articles on the topic of medication adherence. Data on interventions and learning assessments were abstracted for relevant studies meeting search criteria. Twenty studies met inclusion criteria. Sixteen included pill-taking experiences with regimens of candies or placebos and varied in their inclusion of novel elements to highlight issues such as stigma, regimen complexity, and adherence measurement. Three studies involved interacting with the public. Qualitative and quantitative methods were used to assess a variety of learning outcomes. Pill-taking experiences can help future providers appreciate the complex logistics of medication-taking, but are less capable of addressing the psychosocial aspects of adherence. A promising area for learning is to interact with actual medication users to understand their experiences and perspectives.
Topics: Education, Pharmacy; Health Occupations; Humans; Medication Adherence; Placebos; Students, Health Occupations
PubMed: 28720923
DOI: 10.5688/ajpe81595 -
Scientific Reports Oct 2016Considered an antidepressant and anti-anxiety agent, Hypericum perforatum affects multiple neurotransmitters in a non-competitive synergistic manner, and may have... (Meta-Analysis)
Meta-Analysis Review
Considered an antidepressant and anti-anxiety agent, Hypericum perforatum affects multiple neurotransmitters in a non-competitive synergistic manner, and may have nootropic potential. We quantitatively reviewed the pre-clinical literature to examine if there is a cognitive-enhancing effect of H. perforatum in healthy rodents. Additionally, within these studies, we compared the effects observed in intact rodents versus those whose performance has been impaired, mostly through stress manipulations. The meta-analysis incorporated studies that examined the effect of H. perforatum versus placebo on memory indices of task performance. All analyses were based on weighting different studies according to their inverse variance. Thirteen independent studies (published 2000-2014) involving 20 experimental comparisons met our inclusion criteria. The results showed a large positive effect of H. perforatum on cognitive performance for intact, healthy rodents (d = 1.11), though a larger effect emerged for stress-impaired rodents (d = 3.10 for restraint stress). The positive effect on intact rodents was observed in tasks assessing reference memory as well as working memory, and was not moderated by the type of memory or motivation (appetitive versus aversive). Thus, while primarily considered as a medication for depression, H. perforatum shows considerable nootropic potential in rodents.
Topics: Animals; Hypericum; Memory; Nootropic Agents; Placebos; Rodentia
PubMed: 27762349
DOI: 10.1038/srep35700 -
The Journal of Neuroscience : the... Nov 2021Pain perception can be powerfully influenced by an individual's expectations and beliefs. Although the cortical circuitry responsible for pain modulation has been...
Pain perception can be powerfully influenced by an individual's expectations and beliefs. Although the cortical circuitry responsible for pain modulation has been thoroughly investigated, the brainstem pathways involved in the modulatory phenomena of placebo analgesia and nocebo hyperalgesia remain to be directly addressed. This study used ultra-high-field 7 tesla functional MRI (fMRI) to accurately resolve differences in brainstem circuitry present during the generation of placebo analgesia and nocebo hyperalgesia in healthy human participants ( = 25, 12 male). Over 2 successive days, through blinded application of altered thermal stimuli, participants were deceptively conditioned to believe that two inert creams labeled lidocaine (placebo) and capsaicin (nocebo) were acting to modulate their pain relative to a third Vaseline (control) cream. In a subsequent test phase, fMRI image sets were collected while participants were given identical noxious stimuli to all three cream sites. Pain intensity ratings were collected and placebo and nocebo responses determined. Brainstem-specific fMRI analysis revealed altered activity in key pain modulatory nuclei, including a disparate recruitment of the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway when both greater placebo and nocebo effects were observed. Additionally, we found that placebo and nocebo responses differentially activated the parabrachial nucleus but overlapped in engagement of the substantia nigra and locus coeruleus. These data reveal that placebo and nocebo effects are generated through differential engagement of the PAG-RVM pathway, which in concert with other brainstem sites likely influences the experience of pain by modulating activity at the level of the dorsal horn. Understanding endogenous pain modulatory mechanisms would support development of effective clinical treatment strategies for both acute and chronic pain. Specific brainstem nuclei have long been known to play a central role in nociceptive modulation; however, because of the small size and complex organization of the nuclei, previous neuroimaging efforts have been limited in directly identifying how these subcortical networks interact during the development of antinociceptive and pro-nociceptive effects. We used ultra-high-field fMRI to resolve brainstem structures and measure signal change during placebo analgesia and nocebo hyperalgesia. We define overlapping and disparate brainstem circuitry responsible for altering pain perception. These findings extend our understanding of the detailed organization and function of discrete brainstem nuclei involved in pain processing and modulation.
Topics: Adult; Analgesics; Brain Stem; Female; Humans; Hyperalgesia; Magnetic Resonance Imaging; Male; Nocebo Effect; Pain Perception; Placebos
PubMed: 34697093
DOI: 10.1523/JNEUROSCI.0806-21.2021 -
Schizophrenia Bulletin Nov 2013Fluphenazine, a phenothiazine derivative, was one of the first drugs to be classed as an "antipsychotic" and was approved by the Food and Drug Administration in 1959. In... (Comparative Study)
Comparative Study Review
Fluphenazine, a phenothiazine derivative, was one of the first drugs to be classed as an "antipsychotic" and was approved by the Food and Drug Administration in 1959. In Britain, it was first used for the relief of anxiety. The American reports, however, were the first to indicate its value in psychotic illness. Fluphenazine is an inexpensive and widely accessible antipsychotic drug that has been available to treat people with schizophrenia for five decades. We updated our original search (from September 2006) using The Cochrane Schizophrenia Group Trials register (May 2012); we found no new relevant studies. Seven randomized controlled trials (RCTs) were included with a total of N = 439 participants. Results, based on this small selection of studies, suggested that there was no significant difference between oral fluphenazine and placebo for most outcomes, including global state and leaving the study early. Results did suggest a statistically significant effect favoring oral fluphenazine in the short term for levels of relapse (n = 38, 1 RCT, RR 0.25 CI 0.06-1.03) with levels of extrapyramidal adverse effects more frequent with oral fluphenazine. The findings in this review confirm much that clinicians and recipients of care already know, but they provide quantification to support clinical impression. In this review, for perhaps the first time, we objectively quantified the effects of oral administration of fluphenazine in comparison with placebo. It is indeed a potent antipsychotic but with considerable adverse effects. Other drugs may well be preferable.
Topics: Antipsychotic Agents; Fluphenazine; Humans; Placebos; Schizophrenia
PubMed: 24072807
DOI: 10.1093/schbul/sbt140 -
The Cochrane Database of Systematic... Jul 2020Behavioural activation is a brief psychotherapeutic approach that seeks to change the way a person interacts with their environment. Behavioural activation is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Behavioural activation is a brief psychotherapeutic approach that seeks to change the way a person interacts with their environment. Behavioural activation is increasingly receiving attention as a potentially cost-effective intervention for depression, which may require less resources and may be easier to deliver and implement than other types of psychotherapy.
OBJECTIVES
To examine the effects of behavioural activation compared with other psychological therapies for depression in adults. To examine the effects of behavioural activation compared with medication for depression in adults. To examine the effects of behavioural activation compared with treatment as usual/waiting list/placebo no treatment for depression in adults.
SEARCH METHODS
We searched CCMD-CTR (all available years), CENTRAL (current issue), Ovid MEDLINE (1946 onwards), Ovid EMBASE (1980 onwards), and Ovid PsycINFO (1806 onwards) on the 17 January 2020 to identify randomised controlled trials (RCTs) of 'behavioural activation', or the main elements of behavioural activation for depression in participants with clinically diagnosed depression or subthreshold depression. We did not apply any restrictions on date, language or publication status to the searches. We searched international trials registries via the World Health Organization's trials portal (ICTRP) and ClinicalTrials.gov to identify unpublished or ongoing trials.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of behavioural activation for the treatment of depression or symptoms of depression in adults aged 18 or over. We excluded RCTs conducted in inpatient settings and with trial participants selected because of a physical comorbidity. Studies were included regardless of reported outcomes.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened all titles/abstracts and full-text manuscripts for inclusion. Data extraction and 'Risk of bias' assessments were also performed by two review authors in duplicate. Where necessary, we contacted study authors for more information.
MAIN RESULTS
Fifty-three studies with 5495 participants were included; 51 parallel group RCTs and two cluster-RCTs. We found moderate-certainty evidence that behavioural activation had greater short-term efficacy than treatment as usual (risk ratio (RR) 1.40, 95% confidence interval (CI) 1.10 to 1.78; 7 RCTs, 1533 participants), although this difference was no longer evident in sensitivity analyses using a worst-case or intention-to-treat scenario. Compared with waiting list, behavioural activation may be more effective, but there were fewer data in this comparison and evidence was of low certainty (RR 2.14, 95% CI 0.90 to 5.09; 1 RCT, 26 participants). No evidence on treatment efficacy was available for behavioural activation versus placebo and behavioural activation versus no treatment. We found moderate-certainty evidence suggesting no evidence of a difference in short-term treatment efficacy between behavioural activation and CBT (RR 0.99, 95% CI 0.92 to 1.07; 5 RCTs, 601 participants). Fewer data were available for other comparators. No evidence of a difference in short term-efficacy was found between behavioural activation and third-wave CBT (RR 1.10, 95% CI 0.91 to 1.33; 2 RCTs, 98 participants; low certainty), and psychodynamic therapy (RR 1.21, 95% CI 0.74 to 1.99; 1 RCT,60 participants; very low certainty). Behavioural activation was more effective than humanistic therapy (RR 1.84, 95% CI 1.15 to 2.95; 2 RCTs, 46 participants; low certainty) and medication (RR 1.77, 95% CI 1.14 to 2.76; 1 RCT; 141 participants; moderate certainty), but both of these results were based on a small number of trials and participants. No evidence on treatment efficacy was available for comparisons between behavioural activation versus interpersonal, cognitive analytic, and integrative therapies. There was moderate-certainty evidence that behavioural activation might have lower treatment acceptability (based on dropout rate) than treatment as usual in the short term, although the data did not confirm a difference and results lacked precision (RR 1.64, 95% CI 0.81 to 3.31; 14 RCTs, 2518 participants). Moderate-certainty evidence did not suggest any difference in short-term acceptability between behavioural activation and waiting list (RR 1.17, 95% CI 0.70 to 1.93; 8 RCTs. 359 participants), no treatment (RR 0.97, 95% CI 0.45 to 2.09; 3 RCTs, 187 participants), medication (RR 0.52, 95% CI 0.23 to 1.16; 2 RCTs, 243 participants), or placebo (RR 0.72, 95% CI 0.31 to 1.67; 1 RCT; 96 participants; low-certainty evidence). No evidence on treatment acceptability was available comparing behavioural activation versus psychodynamic therapy. Low-certainty evidence did not show a difference in short-term treatment acceptability (dropout rate) between behavioural activation and CBT (RR 1.03, 95% CI 0.85 to 1.25; 12 RCTs, 1195 participants), third-wave CBT (RR 0.84, 95% CI 0.33 to 2.10; 3 RCTs, 147 participants); humanistic therapy (RR 1.06, 95% CI 0.20 to 5.55; 2 RCTs, 96 participants) (very low certainty), and interpersonal, cognitive analytic, and integrative therapy (RR 0.84, 95% CI 0.32 to 2.20; 4 RCTs, 123 participants). Results from medium- and long-term primary outcomes, secondary outcomes, subgroup analyses, and sensitivity analyses are summarised in the text.
AUTHORS' CONCLUSIONS
This systematic review suggests that behavioural activation may be more effective than humanistic therapy, medication, and treatment as usual, and that it may be no less effective than CBT, psychodynamic therapy, or being placed on a waiting list. However, our confidence in these findings is limited due to concerns about the certainty of the evidence. We found no evidence of a difference in short-term treatment acceptability (based on dropouts) between behavioural activation and most comparison groups (CBT, humanistic therapy, waiting list, placebo, medication, no treatment or treatment as usual). Again, our confidence in all these findings is limited due to concerns about the certainty of the evidence. No data were available about the efficacy of behaioural activation compared with placebo, or about treatment acceptability comparing behavioural activation and psychodynamic therapy, interpersonal, cognitive analytic and integrative therapies. The evidence could be strengthened by better reporting and better quality RCTs of behavioural activation and by assessing working mechanisms of behavioural activation.
Topics: Adult; Antidepressive Agents; Anxiety; Behavior Therapy; Cognitive Behavioral Therapy; Confidence Intervals; Depression; Humans; Placebos; Psychotherapy, Psychodynamic; Quality of Life; Randomized Controlled Trials as Topic; Social Adjustment; Waiting Lists
PubMed: 32628293
DOI: 10.1002/14651858.CD013305.pub2