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Homeopathy : the Journal of the Faculty... Jul 2014Samuel Hahnemann (1755-1843) known today as the founder of homoeopathy, was - as far as we know - the first physician who administrated placebos to his patient on a...
Samuel Hahnemann (1755-1843) known today as the founder of homoeopathy, was - as far as we know - the first physician who administrated placebos to his patient on a systematic and regular basis. This study is based upon unpublished documents (e.g. patients' letters) in the Archives of the Institute for the History of Medicine of the Robert Bosch Foundation in Stuttgart. It also profited from the critical edition of Hahnemann's case journals and the editorial comments which have also been published in this series. Hahnemann differentiated clearly between homeopathic drugs and pharmaceutical substances which he considered as sham medicine (e.g. milk sugar). A close look at Hahnemann's case journals reveals that the percentage of placebo prescriptions was very high (between 54 and 85 percent). In most instances Hahnemann marked placebos with the paragraph symbol (§). The rationale behind this practice was that Hahnemann had encountered the well-known problem that patients were used to taking medicine on a daily basis as it was typical for the age of heroic medicine. The main reason for giving placebo was therefore to please the impatient patient who was used to frequent medications in allopathic medicine, not only every day but sometimes also hourly.
Topics: Famous Persons; Germany; History, 18th Century; History, 19th Century; Homeopathy; Humans; Male; Materia Medica; Pharmaceutical Preparations; Placebo Effect; Placebos
PubMed: 24931754
DOI: 10.1016/j.homp.2014.03.003 -
International Review of Neurobiology 2020A critical issue facing the therapeutic area of neurological diseases is the large number of failed randomized clinical trials, especially when moving from promising... (Review)
Review
A critical issue facing the therapeutic area of neurological diseases is the large number of failed randomized clinical trials, especially when moving from promising Phase 2 trials to failed Phase 3 trials. A common cited reason for these failures is a high placebo response rate that thereby reduces the observed treatment effect. Explanations for this higher than anticipated placebo response include small sample sizes, inadequate study designs and/or analytic methods, baseline characteristics of the trial sample, possible investigator bias and a participant's own expectations and conditional learning. Several innovative study designs and new methodological approaches to statistical analyses have been proposed to handle placebo effects anticipated or observed in double blind, randomized clinical trials (RCT's). This chapter examines current study designs being used to reduce the observed placebo response and statistical analysis methods being employed for addressing this problem in neuroscience clinical trials.
Topics: Data Interpretation, Statistical; Humans; Nervous System Diseases; Placebo Effect; Placebos; Randomized Controlled Trials as Topic; Research Design
PubMed: 32563284
DOI: 10.1016/bs.irn.2020.04.004 -
International Review of Neurobiology 2018The placebo effect is closely related to many other constructs, including most prominently, conditioning and expectancy, but also natural history, regression to the... (Review)
Review
The placebo effect is closely related to many other constructs, including most prominently, conditioning and expectancy, but also natural history, regression to the mean, priming, mindset, context effects, the meaning response, specific and non-specific clinical effects, placebo-related effects, the patient-clinician relationship, and the common factors in psychotherapy. How are these various terms related to one another? To what degree do they overlap, and to what degree do they diverge? To form a better theoretical understanding of these constructs and to foster improved empirical research, is it better to lump these terms together in some fashion? Or will progress best be served by maintaining the splits between the constructs? Or would it perhaps be most effective to employ some mixture of lumping and splitting? I will address these and related questions with two major goals: (1) to delineate and clarify the relationship between these various terms and (2) to suggest some possible re-alignments in the way in which we conceptualize the relationships among these constructs that might prove useful in fostering research on placebo and related effects. In addition, clarifying the interconnections between the placebo effect and other related terms has the potential to spark innovative cross-fertilizations between related areas of research.
Topics: Classification; Conditioning, Psychological; Humans; Physician-Patient Relations; Placebo Effect; Placebos
PubMed: 30146051
DOI: 10.1016/bs.irn.2018.07.011 -
Psychoneuroendocrinology Jul 2019Placebos are usually employed deceptively in clinical trials in order to control for non-specific effects. However, since placebos themselves have been found to cause... (Review)
Review
Placebos are usually employed deceptively in clinical trials in order to control for non-specific effects. However, since placebos themselves have been found to cause clinically relevant changes and in some cases are indistinguishable from the verum they are tested against, this theoretically inert, but practically effective intervention has become a scientific discipline in its own right. In this review, it is argued that placebos are generic and genuine biopsychosocial interventions and as such are highly interesting candidates for a psychoneuroendocrinological perspective. Yet, despite a considerable conceptual proximity between explanatory models of placebos and their effects with psychoneuroendocrine models and findings, placebos have thus far not been subject to systematic psychoneuroendocrine examination. Consequently, it would be highly interesting and informative to make placebos the target of psychoneuroendocrine scrutiny.
Topics: Conditioning, Psychological; Humans; Neuroendocrinology; Placebo Effect; Placebos
PubMed: 30098833
DOI: 10.1016/j.psyneuen.2018.08.008 -
International Review of Neurobiology 2020The placebo effect is a widely recognized phenomenon in clinical research, with a negative perception that it could hide the "true" drug effect. In clinical care its... (Review)
Review
The placebo effect is a widely recognized phenomenon in clinical research, with a negative perception that it could hide the "true" drug effect. In clinical care its positive potential to increase known drug effects has been neglected for too long. The placebo and nocebo responses have been described in many neurologic disorders such as Parkinson's, Huntington's and Alzheimer's diseases, restless leg syndrome, tics, essential tremor, dystonia, functional movement disorders, neuropathic pain, headaches, migraine, amyotrophic lateral sclerosis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis and epilepsy. Knowledge regarding placebo mechanisms and their consequences on clinical outcome have greatly improved over the last two decades. This evolution has led to reconsiderations of the importance of placebo response in the clinic and has given several clues on how to improve it in daily practice. In this chapter, we first illustrate "why," e.g. the reasons (relevance to clinical practice, help in differential diagnosis/treatment of psychogenic movements, clinical impact, proven neurobiological grounds, health economic potential), and "how," e.g. the means (increase patients' knowledge, increase learning, improve patient-doctor relationship, increase Hawthorne effect, increase positive/decrease negative expectations (the Rosenthal effect), personalize placebo response), the placebo should be maximized (and nocebo avoided) in neurological clinical practice. Future studies regarding more specific neurobiological mechanisms will allow a finer tuning of placebo response in clinical practice. The use of placebo in clinical practice raises ethical issues, and a recent expert consensus regarding placebo use in the clinic is a first step to future guidelines necessary to this field.
Topics: Humans; Nervous System Diseases; Personality; Placebo Effect; Placebos
PubMed: 32563294
DOI: 10.1016/bs.irn.2020.04.003 -
Clinical Gastroenterology and... Jun 2024Coconut water (CW) is anti-inflammatory, can manipulate the gut microbiome, and is a rich source of potassium. Gut microbiome modulation improves outcomes in ulcerative... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Coconut water (CW) is anti-inflammatory, can manipulate the gut microbiome, and is a rich source of potassium. Gut microbiome modulation improves outcomes in ulcerative colitis (UC), and potassium possesses in vitro anti-inflammatory property. We evaluated the effect of CW as an adjunct therapy for patients with mild-moderate UC.
METHODS
This single-center, double-blind, placebo-controlled trial randomized patients with mild to moderate (Simple Clinical Colitis Activity Index [SCCAI]: 3-9) endoscopically active UC (Ulcerative Colitis Endoscopic Index of Severity [UCEIS] >1) in 1:1 ratio to CW + standard medical therapy (SMT) vs placebo + SMT. Four hundred mL of CW was administered for 8 weeks. Primary outcome measure was clinical remission (SCCAI ≤2), and secondary outcome measures were clinical response (SCCAI decline ≥3) and adverse events at 8 weeks. Microbiome was analyzed at baseline and 8 weeks.
RESULTS
Of 121 patients screened, 95 were included for modified intention to treat analysis (CW, n = 49; placebo, n = 46) (mean age, 37.2 ± 11.2 years; males, 54.1%; disease duration, 48 months [interquartile range (IQR), 24-90 months]; pancolitis, 26.1%; SCCAI, 5 [IQR, 4-6]; UCEIS, 4 [IQR, 3-5]). Clinical response (57.1% vs 28.3%; odds ratio [OR], 3.4; 95% confidence interval [CI], 1.4-7.9; P = .01), remission (53.1% vs 28.3%; OR, 2.9; 95% CI, 1.2-6.7; P = .02), and proportion of patients with fecal calprotectin (FCP) <150 μg/g (30.6% vs 6.5%; OR, 6.3; 95% CI, 1.7-23.6; P = .003) were significantly higher in CW. The relative abundance of bacterial taxa that had a significant or trend towards negative correlation with SCCAI, UCEIS, or FCP increased at 8 weeks in CW, and this effect was independent of disease activity and dietary fiber. Adverse events were comparable, and no patient developed hyperkalemia.
CONCLUSIONS
CW was more effective than placebo for induction of clinical remission in patients with mild to moderate UC. The trial was prospectively registered on Clinical Trials Registry of India (ctri.nic.in, Number: CTRI/2019/03/01827).
Topics: Humans; Colitis, Ulcerative; Male; Female; Double-Blind Method; Adult; Middle Aged; Treatment Outcome; Cocos; Placebos; Young Adult; Gastrointestinal Microbiome; Aged; Remission Induction; Anti-Inflammatory Agents; Severity of Illness Index
PubMed: 38278200
DOI: 10.1016/j.cgh.2024.01.013 -
The Cochrane Database of Systematic... May 2017Osteoarthritis (OA) is the most common form of arthritis and is caused by degeneration of the joint cartilage and growth of new bone, cartilage and connective tissue. It... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Osteoarthritis (OA) is the most common form of arthritis and is caused by degeneration of the joint cartilage and growth of new bone, cartilage and connective tissue. It is often associated with major disability and impaired quality of life. There is currently no consensus on the best treatment to improve OA symptoms. Celecoxib is a selective non-steroidal anti-inflammatory drug (NSAID).
OBJECTIVES
To assess the clinical benefits (pain, function, quality of life) and safety (withdrawals due to adverse effects, serious adverse effects, overall discontinuation rates) of celecoxib in osteoarthritis (OA).
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and clinical trials registers up to April 11, 2017, as well as reference and citation lists of included studies. Pharmaceutical companies and authors of published articles were contacted.
SELECTION CRITERIA
We included published studies (full reports in a peer reviewed journal) of prospective randomized controlled trials (RCTs) that compared oral celecoxib versus no intervention, placebo or another traditional NSAID (tNSAID) in participants with clinically- or radiologically-confirmed primary OA of the knee or hip, or both knee and hip.
DATA COLLECTION AND ANALYSIS
Two authors independently performed data extraction, quality assessment, and compared results. Main analyses for patient-reported outcomes of pain and physical function were conducted on studies with low risk of bias for sequence generation, allocation concealment and blinding of participants and personnel.
MAIN RESULTS
We included 36 trials that provided data for 17,206 adults: 9402 participants received celecoxib 200 mg/day, and 7804 were assigned to receive either tNSAIDs (N = 1869) or placebo (N = 5935). Celecoxib was compared with placebo (32 trials), naproxen (6 trials) and diclofenac (3 trials). Studies were published between 1999 and 2014. Studies included participants with knee, hip or both knee and hip OA; mean OA duration was 7.9 years. Most studies included predominantly white participants whose mean age was 62 (± 10) years; most participants were women. There were no concerns about risk of bias for performance and detection bias, but selection bias was poorly reported in most trials. Most trials had high attrition bias, and there was evidence of selective reporting in a third of the studies. Celecoxib versus placeboCompared with placebo celecoxib slightly reduced pain on a 500-point Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain scale, accounting for 3% absolute improvement (95% CI 2% to 5% improvement) or 12% relative improvement (95% CI 7% to 18% improvement) (4 studies, 1622 participants). This improvement may not be clinically significant (high quality evidence).Compared with placebo celecoxib slightly improved physical function on a 1700-point WOMAC scale, accounting for 4% absolute improvement (95% CI 2% to 6% improvement), 12% relative improvement (95% CI 5% to 19% improvement) (4 studies, 1622 participants). This improvement may not be clinically significant (high quality evidence).There was no evidence of an important difference for withdrawals due to adverse events (Peto OR 0.99, 95% CI 0.85 to 1.15) (moderate quality evidence due to study limitations).Results were inconclusive for numbers of participants experiencing any serious AEs (SAEs) (Peto OR 0.95, 95% CI 0.66 to 1.36), gastro-intestinal events (Peto OR 1.91, 95% CI 0.24 to 14.90) and cardiovascular events (Peto OR 3.40, 95% CI 0.73 to 15.88) (very low quality evidence due to serious imprecision and study limitations). However, regulatory agencies have warned of increased cardiovascular events for celecoxib. Celecoxib versus tNSAIDsThere were inconclusive results regarding the effect on pain between celecoxib and tNSAIDs on a 100-point visual analogue scale (VAS), showing 5% absolute improvement (95% CI 11% improvement to 2% worse), 11% relative improvement (95% CI 26% improvement to 4% worse) (2 studies, 1180 participants, moderate quality evidence due to publication bias).Compared to a tNSAID celecoxib slightly improved physical function on a 100-point WOMAC scale, showing 6% absolute improvement (95% CI 6% to 11% improvement) and 16% relative improvement (95% CI 2% to 30% improvement). This improvement may not be clinically significant (low quality evidence due to missing data and few participants) (1 study, 264 participants).Based on low or very low quality evidence (downgraded due to missing data, high risk of bias, few events and wide confidence intervals) results were inconclusive for withdrawals due to AEs (Peto OR 0.97, 95% CI 0.74 to 1.27), number of participants experiencing SAEs (Peto OR 0.92, 95% CI 0.66 to 1.28), gastro-intestinal events (Peto OR 0.61, 0.15 to 2.43) and cardiovascular events (Peto OR 0.47, 95% CI 0.17 to 1.25).In comparisons of celecoxib and placebo there were no differences in pooled analyses between our main analysis with low risk of bias and all eligible studies. In comparisons of celecoxib and tNSAIDs, only one outcome showed a difference between studies at low risk of bias and all eligible studies: physical function (6% absolute improvement in low risk of bias, no difference in all eligible studies).No studies included in the main comparisons measured quality of life. Of 36 studies, 34 reported funding by drug manufacturers and in 34 studies one or more study authors were employees of the sponsor.
AUTHORS' CONCLUSIONS
We are highly reserved about results due to pharmaceutical industry involvement and limited data. We were unable to obtain data from three studies, which included 15,539 participants, and classified as awaiting assessment. Current evidence indicates that celecoxib is slightly better than placebo and some tNSAIDs in reducing pain and improving physical function. We are uncertain if harms differ among celecoxib and placebo or tNSAIDs due to risk of bias, low quality evidence for many outcomes, and that some study authors and Pfizer declined to provide data from completed studies with large numbers of participants. To fill the evidence gap, we need to access existing data and new, independent clinical trials to investigate benefits and harms of celecoxib versus tNSAIDs for people with osteoarthritis, with longer follow-up and more direct head-to-head comparisons with other tNSAIDs.
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Diclofenac; Female; Humans; Male; Middle Aged; Naproxen; Osteoarthritis, Hip; Osteoarthritis, Knee; Pain Measurement; Placebos; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 28530031
DOI: 10.1002/14651858.CD009865.pub2 -
Gastroenterology Feb 2021Pruritus may seriously impair quality of life in patients with cholestatic diseases such as primary or secondary sclerosing cholangitis (PSC, SSC) and primary biliary... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
Pruritus may seriously impair quality of life in patients with cholestatic diseases such as primary or secondary sclerosing cholangitis (PSC, SSC) and primary biliary cholangitis (PBC). Pharmacologic strategies show limited efficacy and can provoke serious side effects. We hypothesized that bezafibrate, a broad peroxisome proliferator-activated receptor (PPAR) agonist, relieves cholestasis-associated itch by alleviating hepatobiliary injury. The aim of this investigator-initiated FITCH trial (Fibrates for cholestatic ITCH) was to assess effects of bezafibrate on pruritus in patients with PSC, PBC, and SSC.
METHODS
Patients with moderate to severe pruritus (≥5 of 10 on visual analog scale [VAS]) due to PSC, PBC, or SSC were recruited for this double-blind, randomized, placebo-controlled trial between 2016 and 2019. Patients received once-daily bezafibrate (400 mg) or placebo for 21 days. The primary end point was ≥50% reduction of pruritus (VAS; intention-to-treat).
RESULTS
Of 74 randomized patients, 70 completed the trial (95%; 44 PSC, 24 PBC, 2 SSC). For the primary end point, bezafibrate led in 45% (41% PSC, 55% PBC) and placebo in 11% to ≥50% reduction of severe or moderate pruritus (P = .003). For secondary end points, bezafibrate reduced morning (P = .01 vs placebo) and evening (P = .007) intensity of pruritus (VAS) and improved the validated 5D-Itch questionnaire (P = .002 vs placebo). Bezafibrate also reduced serum alkaline phosphatase (-35%, P = .03 vs placebo) correlating with improved pruritus (VAS, P = .01) suggesting reduced biliary damage. Serum bile acids and autotaxin activity remained unchanged. Serum creatinine levels tended to mildly increase (3% bezafibrate, 5% placebo, P = .14).
CONCLUSIONS
Bezafibrate is superior to placebo in improving moderate to severe pruritus in patients with PSC and PBC.
TRIAL REGISTRATION
Netherlands Trial Register, ID: NTR5436 (August 3, 2015), ClinicalTrials.gov ID: NCT02701166 (March 2, 2016).
Topics: Adult; Bezafibrate; Cholangitis, Sclerosing; Double-Blind Method; Female; Humans; Liver Cirrhosis, Biliary; Male; Middle Aged; Placebos; Pruritus; Quality of Life; Severity of Illness Index; Treatment Outcome; Visual Analog Scale
PubMed: 33031833
DOI: 10.1053/j.gastro.2020.10.001 -
Monash Bioethics Review Mar 2016The concept of clinical equipoise restricts the use of placebo controls in clinical trials when there already exists a proven effective treatment. Several critics of... (Review)
Review
The concept of clinical equipoise restricts the use of placebo controls in clinical trials when there already exists a proven effective treatment. Several critics of clinical equipoise have put forward alleged counter-examples to this restriction-describing instances of ethical placebo-controlled trials that apparently violate clinical equipoise. In this essay, we respond to these examples and show that clinical equipoise is not as restrictive of placebos as these authors assume. We argue that a subtler appreciation for clinical equipoise-in particular the distinction between de facto and de jure interpretations of the concept-allows the concept to explain when and why a placebo control may be necessary to answer a question of clinical importance.
Topics: Biomedical Research; Control Groups; Ethics, Research; Humans; Placebo Effect; Placebos; Randomized Controlled Trials as Topic
PubMed: 27188301
DOI: 10.1007/s40592-016-0057-z -
PLoS Medicine Sep 2020Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their...
BACKGROUND
Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their delivery have been shown to affect study outcomes, placebo and sham controls are rarely reported and often not matched to those of the active comparator. This can influence how beneficial or harmful the active intervention appears to be. Without adequate descriptions of placebo or sham controls, it is difficult to interpret results about the benefits and harms of active interventions within placebo-controlled trials. To overcome this problem, we developed a checklist and guide for reporting placebo or sham interventions.
METHODS AND FINDINGS
We developed an initial list of items for the checklist by surveying experts in placebo research (n = 14). Because of the diverse contexts in which placebo or sham treatments are used in clinical research, we consulted experts in trials of drugs, surgery, physiotherapy, acupuncture, and psychological interventions. We then used a multistage online Delphi process with 53 participants to determine which items were deemed to be essential. We next convened a group of experts and stakeholders (n = 16). Our main output was a modification of the existing Template for Intervention Description and Replication (TIDieR) checklist; this allows the key features of both active interventions and placebo or sham controls to be concisely summarised by researchers. The main differences between TIDieR-Placebo and the original TIDieR are the explicit requirement to describe the setting (i.e., features of the physical environment that go beyond geographic location), the need to report whether blinding was successful (when this was measured), and the need to present the description of placebo components alongside those of the active comparator.
CONCLUSIONS
We encourage TIDieR-Placebo to be used alongside TIDieR to assist the reporting of placebo or sham components and the trials in which they are used.
Topics: Checklist; Humans; Placebos; Research Design; Research Personnel; Research Report; Surveys and Questionnaires
PubMed: 32956344
DOI: 10.1371/journal.pmed.1003294