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Journal of Medical Ethics Aug 2015It is widely supposed that the prescription of placebo treatments to patients for therapeutic purposes is ethically problematic on the grounds that the patient cannot... (Review)
Review
It is widely supposed that the prescription of placebo treatments to patients for therapeutic purposes is ethically problematic on the grounds that the patient cannot give informed consent to the treatment, and is therefore deceived by the physician. This claim, I argue, rests on two confusions: one concerning the meaning of 'informed consent' and its relation to the information available to the patient, and another concerning the relation of body and mind. Taken together, these errors lead naturally to the conclusion that the prescription of placebos to unwitting patients is unethical. Once they are dispelled, I argue, we can see that providing 'full' information against a background of metaphysical confusion may make a patient less informed and that the 'therapeutic' goal of relieving the patient of such confusions is properly the duty of the philosopher rather than the physician. Therapeutic placebos therefore do not violate the patient's informed consent or the ethical duties of the doctor.
Topics: Disclosure; Ethical Theory; Humans; Informed Consent; Moral Obligations; Personal Autonomy; Physician-Patient Relations; Placebos
PubMed: 25323316
DOI: 10.1136/medethics-2014-102332 -
Antimicrobial Agents and Chemotherapy Oct 2017Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the... (Randomized Controlled Trial)
Randomized Controlled Trial
Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination processes should be evaluated in more detail. Finafloxacin exhibited a favorable safety and tolerability profile. (This study has been registered at ClinicalTrials.gov under registration no. NCT01910883.).
Topics: Administration, Intravenous; Anti-Bacterial Agents; Double-Blind Method; Female; Fluoroquinolones; Healthy Volunteers; Humans; Male; Placebos
PubMed: 28784673
DOI: 10.1128/AAC.01122-17 -
Scientific Reports Jan 2018Among the serious consequences of alcohol abuse is the reduced ability to process visual information. Diminished vision from excessive consumption of alcohol has been... (Randomized Controlled Trial)
Randomized Controlled Trial
Among the serious consequences of alcohol abuse is the reduced ability to process visual information. Diminished vision from excessive consumption of alcohol has been implicated in industrial, home, and automobile accidents. Alcohol is also generally recognized as an inhibitor in the brain by potentiating GABA-ergic transmission. In this study, we focused on visual motion processing and explored whether moderate alcohol intoxication induced changes in inhibitory mediated motion repulsion in a center-surround configuration. We conducted a double-blind, placebo-controlled, within-subjects study on the effect of alcohol on visual motion repulsion. Each subject underwent three experimental conditions (no alcohol, placebo and moderate alcohol) on separate days. The order of the placebo and moderate alcohol conditions was counterbalanced. The results showed that the effects of the surround context on the perception of the center motion direction were similar in both the sober (no alcohol) and placebo conditions. However, contextual modulations were significantly stronger during intoxication compared to both the sober and placebo conditions. These results demonstrate that moderate alcohol consumption is associated with altered neural function in visual cortical areas and that motion repulsion deficits might reflect the inhibitory effects of alcohol on the central nervous system.
Topics: Adult; Alcoholic Intoxication; Alcohols; Double-Blind Method; Female; Healthy Volunteers; Humans; Male; Motion Perception; Placebos; Visual Cortex; Young Adult
PubMed: 29371672
DOI: 10.1038/s41598-018-19932-8 -
Dermatologic Surgery : Official... Aug 2021ATX-101 is indicated for submental fat treatment. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
ATX-101 is indicated for submental fat treatment.
OBJECTIVE
Evaluate ATX-101 versus placebo for reducing submental fat.
MATERIALS AND METHODS
Adults with unwanted submental fat across 6 global sites were randomized to ATX-101 (0.5%, 1.0%, or 2.0%) or placebo for ≤4 treatments every 28 days. Outcomes included safety (adverse events and pain visual analog scale) throughout the study and efficacy (submental fat rating, patient satisfaction, and submental fat improvements) at Week 16.
RESULTS
Eighty-four of 85 enrolled patients received ≥1 ATX-101 treatment (0.5% [n = 20], 1.0% [n = 20], 2.0% [n = 22] or placebo [n = 22]). Most patients (n = 82) experienced adverse events, which were mostly mild/moderate, seemed to be dose-related, and led to no study discontinuations. The mean pain scores were highest in the ATX-101 1.0% and 2.0% groups. Week-16 change from baseline in the submental fat rating scale was significantly greater for ATX-101 0.5% and 1.0% versus placebo (p ≤ .05). At Week 16, 71%, 74%, 53%, and 40% of patients in the ATX-101 0.5%, 1.0%, 2.0%, and placebo groups, respectively, achieved a ≥1-grade reduction in submental fat from baseline. Satisfaction with appearance and patient-assessed global improvement ratings increased in all ATX-101 treatment groups versus placebo.
CONCLUSION
All ATX-101 concentrations were safe and efficacious for moderate/severe submental fat reduction.
Topics: Adult; Chin; Deoxycholic Acid; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Pain Measurement; Pain, Procedural; Patient Satisfaction; Placebos; Rhytidoplasty; Subcutaneous Fat; Treatment Outcome
PubMed: 34115682
DOI: 10.1097/DSS.0000000000003092 -
Pain Nov 2018Network meta-analysis uses direct comparisons of interventions within randomized controlled trials and indirect comparisons across them. Network meta-analysis uses more... (Review)
Review
Network meta-analysis uses direct comparisons of interventions within randomized controlled trials and indirect comparisons across them. Network meta-analysis uses more data than a series of direct comparisons with placebo, and theoretically should produce more reliable results. We used a Cochrane overview review of acute postoperative pain trials and other systematic reviews to provide data to test this hypothesis. Some 261 trials published between 1966 and 2016 included 39,753 patients examining 52 active drug and dose combinations (27,726 given active drug and 12,027 placebo), in any type of surgery (72% dental). Most trials were small; 42% of patients were in trials with arms <50 patients, and 27% in trials with arms ≥100 patients. Response to placebo in third molar extraction fell by half in studies over 30 to 40 years (171 trials, 7882 patients given placebo). Network meta-analysis and Cochrane analyses provided very similar results (average difference 0.04 number needed to treat units), with no significant difference for almost all comparisons apart from some with small patient numbers or small effect size, or both. Network meta-analysis did not detect significant differences between effective analgesics. The similarity between network meta-analysis and Cochrane indirect analyses probably arose from stringent quality criteria in trials accepted in Cochrane reviews (with consequent low risk of bias) and consistency in methods and outcomes. Network meta-analysis is a useful analytical tool that increases our confidence in estimates of efficacy of analgesics in acute postoperative pain, in this case by providing similar results.
Topics: Adult; Analgesics; Female; Humans; Male; Network Meta-Analysis; Pain, Postoperative; Placebos; Retrospective Studies; Treatment Outcome
PubMed: 29965830
DOI: 10.1097/j.pain.0000000000001322 -
The Cochrane Database of Systematic... Jun 2020Gestational diabetes mellitus (GDM) is carbohydrate intolerance first recognised during pregnancy and associated with complications for mothers and babies. Probiotics... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Gestational diabetes mellitus (GDM) is carbohydrate intolerance first recognised during pregnancy and associated with complications for mothers and babies. Probiotics are naturally occurring micro-organisms, which when ingested in adequate amounts, may confer health benefits. Evidence of the role of probiotics as treatment for GDM is limited.
OBJECTIVES
To evaluate the safety and effectiveness of probiotics in treating women with GDM on maternal and infant outcomes.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth's Trials Register ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (24 July 2019), and reference lists of retrieved studies.
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing the use of probiotics versus placebo/standard care for the treatment of GDM.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed study eligibility, extracted data, checked data accuracy, and assessed risk of bias of included trials. The certainty of evidence for selected maternal and infant/child outcomes was assessed using GRADE.
MAIN RESULTS
Nine RCTs (695 pregnant women with GDM) comparing probiotics versus placebo were identified. The overall risk of bias in the nine RCTs was low to unclear and the evidence was downgraded for imprecision due to the small numbers of women participating in the trials. The trials were carried out in hospitals and universities in Iran (seven trials), Thailand (one trial) and Ireland (one trial). All trials compared probiotics with placebo. Maternal outcomes We are uncertain if probiotics have any effect compared with placebo on hypertensive disorders of pregnancy, (risk ratio (RR) 1.50, 95% confidence interval (CI) 0.64 to 3.53; participants = 256; studies = 3; low-certainty evidence) and mode of birth as caesareans (average RR 0.64, 95% CI 0.30 to 1.35; participants = 267; studies = 3; low-certainty evidence) because the certainty of evidence is low and the 95% CIs span possible benefit and possible harm. No trials reported primary outcomes of: mode of birth as vaginal/assisted and subsequent development of type 2 diabetes. We are uncertain if probiotics have any effect compared with placebo on induction of labour (RR 1.33, 95% CI 0.74 to 2.37; participants = 127; studies = 1; very low-certainty evidence). For other secondary maternal outcomes, we are uncertain if there are differences between probiotics and placebo for: postpartum haemorrhage; weight gain during pregnancy intervention and total gestational weight gain; fasting plasma glucose and need for extra pharmacotherapy (insulin). Probiotics may be associated with a slight reduction in triglycerides and total cholesterol. In probiotics compared with placebo, there was evidence of reduction in markers for insulin resistance (HOMA-IR) and HOMA-B; and insulin secretion. There was also an increase in quantitative insulin sensitivity check index (QUICKI). Probiotics were associated with minor benefits in relevant bio-markers with evidence of a reduction in inflammatory markers high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and marker of oxidative stress malondialdehyde; and an increase in antioxidant total glutathione, but we are uncertain if there is any difference in total antioxidant capacity. No trials reported secondary outcomes: perineal trauma, postnatal weight retention or return to pre-pregnancy weight and postnatal depression. Infant/child/adult outcomes We are uncertain if probiotics have any effect, compared with placebo, on the risk of large-for-gestational-age babies (RR 0.73, 95% CI 0.35 to 1.52; participants = 174; studies = 2; low-certainty evidence) or infant hypoglycaemia (RR 0.85, 95% CI 0.39 to 1.84; participants = 177; studies = 3; low-certainty evidence) because the certainty of evidence is low and the 95% CIs span possible benefit and possible harm. No trials reported primary outcomes of: perinatal (fetal/neonatal) mortality; or neurosensory disability. For other secondary outcomes, we are uncertain if there is any difference between probiotics and placebo in gestational age at birth, preterm birth, macrosomia, birthweight, head circumference, length, infant hypoglycaemia, and neonatal intensive care unit (NICU) admissions. There was evidence of a reduction in infant hyperbilirubinaemia with probiotics compared with placebo. No trials reported secondary outcomes: infant adiposity, and later childhood adiposity. There were no adverse events reported by any of the trials.
AUTHORS' CONCLUSIONS
Low-certainty evidence means we are not certain if there is any difference between probiotic and placebo groups in maternal hypertensive disorders of pregnancy, caesareans; and large-for-gestational-age babies. There were no adverse events reported by the trials. Due to the variability of probiotics used and small sample sizes of trials, evidence from this review has limited ability to inform practice. Well-designed adequately-powered trials are needed to identify whether probiotics may improve maternal blood glucose levels and/or infant/child/adult outcomes; and whether they can be used to treat GDM.
Topics: Adult; Child; Confidence Intervals; Diabetes, Gestational; Female; Humans; Hypertension, Pregnancy-Induced; Infant, Newborn; Infant, Postmature; Labor, Induced; Odds Ratio; Placebos; Pregnancy; Probiotics; Randomized Controlled Trials as Topic
PubMed: 32575163
DOI: 10.1002/14651858.CD012970.pub2 -
JAMA Psychiatry Nov 2015High placebo responses have been observed across a wide range of pathologies, severely impacting drug development. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
High placebo responses have been observed across a wide range of pathologies, severely impacting drug development.
OBJECTIVE
To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder (MDD).
DESIGN, SETTING, AND PARTICIPANTS
In this study involving 2 placebo lead-in phases followed by an open antidepressant administration, we performed a single-blinded 2-week crossover randomized clinical trial of 2 identical oral placebos (described as having either active or inactive fast-acting antidepressant-like effects) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor or, in some cases, another agent as clinically indicated. The volunteers (35 medication-free patients with MDD at a university health system) were studied with positron emission tomography and the µ-opioid receptor-selective radiotracer [11C]carfentanil after each 1-week inactive and active oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect.
MAIN OUTCOMES AND MEASURES
Changes in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of µ-opioid receptor binding.
RESULTS
Higher baseline µ-opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment (r = 0.48; P = .02). Reductions in depressive symptoms after 1 week of active placebo treatment, compared with the inactive, were associated with increased placebo-induced µ-opioid neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely, the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala (nucleus accumbens: r = 0.6; P < .001). Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response, predicting 43% of the variance in symptom improvement at the end of the antidepressant trial.
CONCLUSIONS AND RELEVANCE
These data demonstrate that placebo-induced activation of the µ-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses, conferring illness resiliency, during open administration.
TRIAL REGISTRATION
clinicaltrials.gov Identifier:NCT02178696.
Topics: Adult; Analgesics, Opioid; Depressive Disorder, Major; Female; Fentanyl; Humans; Male; Middle Aged; Nucleus Accumbens; Placebo Effect; Placebos; Positron-Emission Tomography; Receptors, Opioid, mu; Selective Serotonin Reuptake Inhibitors; Single-Blind Method; Treatment Outcome; Young Adult
PubMed: 26421634
DOI: 10.1001/jamapsychiatry.2015.1335 -
JAMA Psychiatry Jan 2022Single-blind placebo run-in (PRI) periods are common in randomized clinical trials (RCTs) of treatment for depression. They aim to increase sensitivity to detect drug... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Single-blind placebo run-in (PRI) periods are common in randomized clinical trials (RCTs) of treatment for depression. They aim to increase sensitivity to detect drug effects; however, the association of PRI periods with study outcomes remains unclear. This is concerning given the costs of PRI periods to patients and investigators.
OBJECTIVE
To examine the association of the use of PRI periods with the placebo response, drug response, and drug-placebo difference among RCTs of antidepressants.
DATA SOURCES
MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and PsycINFO, as well as repositories of unpublished studies, were systematically searched up to July 2021.
STUDY SELECTION
Included studies were double-blind, placebo-controlled RCTs of antidepressant medication among adults with depressive disorders.
DATA EXTRACTION AND SYNTHESIS
Data were extracted into a coding sheet, including the characteristics of studies, the characteristics of PRI periods, and the outcomes of studies.
MAIN OUTCOMES AND MEASURES
Study outcomes were the primary depression symptom measure reported by the RCT. These outcomes were used to calculate effect sizes (Hedges g) of the within-group drug response and placebo response as well as the drug-placebo difference. Random-effects meta-analysis was used to calculate effect sizes, and subgroup analyses were used to compare outcomes depending on use of PRI periods.
RESULTS
A total of 347 trials (representing 89 183 participants) were included; 174 studies (50%) reported using a single-blind PRI period. Response outcome data were available for 189 studies. Studies using PRI periods reported a smaller placebo response (g = 1.05 [95% CI, 0.98-1.11]; I2 = 82%) than studies that did not use a PRI period (g = 1.15 [95% CI, 1.09-1.21]; I2 = 81%; P = .02). Subgroup analysis showed a larger drug response size among studies that did not use a PRI period (g = 1.55 [95% CI, 1.49-1.61]; I2 = 85%) than those that did use a PRI period (g = 1.42 [95% CI, 1.36-1.48]; I2 = 81%; P = .001). The drug-placebo difference did not differ by use of PRI periods (g = 0.33 [95% CI, 0.29-0.38]; I2 = 47% for use of a PRI period vs g = 0.34 [95% CI, 0.30-0.38]; I2 = 54% for no use of PRI periods; P = .92). The likelihood of response to drug vs placebo also did not differ between studies that used a PRI period (odds ratio, 1.89 [95% CI, 1.76-2.03]) and those that did not use a PRI period (odds ratio, 1.77 [95% CI, 1.65-1.89]; P = .18).
CONCLUSIONS AND RELEVANCE
This study suggests that RCTs using PRI periods yield smaller within-group changes across both placebo and drug groups compared with RCTs without PRI periods. The reduction in effect size across groups was equivalent in magnitude. Consequently, PRI studies do not observe larger drug-placebo differences, suggesting that they do not increase trial sensitivity. As such, given the resources and probable deception required and risk to external validity, the practice of using PRI periods in RCTs of antidepressants should be ended.
Topics: Antidepressive Agents; Humans; Placebos; Randomized Controlled Trials as Topic; Single-Blind Method
PubMed: 34757405
DOI: 10.1001/jamapsychiatry.2021.3204 -
Journal of the European Academy of... Jun 2020A growing number of clinical trials of biological and systemic therapies have been conducted within adult atopic dermatitis (AD). No study has yet examined and... (Meta-Analysis)
Meta-Analysis
A growing number of clinical trials of biological and systemic therapies have been conducted within adult atopic dermatitis (AD). No study has yet examined and meta-analysed the pooled placebo response in AD. We performed a systematic review and meta-analysis to examine the placebo response in clinical trials evaluating the effect of systemic and biological therapies in adult AD and compared it to results from clinical trials in psoriasis. Two screeners independently searched the databases ClinicalTrials.gov, Embase, Pubmed and Web of Science. A total of 2058 articles were identified, of which 78 were full-text reviewed. Overall, 25 trials were included in the qualitative analysis, of which 24 were further included in the quantitative analysis. At 12-week follow-up, EASI50, EASI75 and EASI90 placebo responses were 39.9% [95% confidence interval (CI), 36.7-43.2], 20.9% (95% CI, 18.2-23.8) and 9.0% (95% CI, 6.7-11.6), respectively. At week 12, the pooled proportion of placebo-treated AD patients that obtained EASI50, EASI75 and EASI90 was significantly higher than the pooled proportion of placebo-treated psoriasis patients obtaining PASI50, PASI75 and PASI90 (P < 0.05). Our findings emphasize the fluctuating nature of AD and show that correct and consistent use of topical treatments strongly reduces disease severity.
Topics: Biological Products; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dermatitis, Atopic; Humans; Placebos; Psoriasis; Severity of Illness Index
PubMed: 31856331
DOI: 10.1111/jdv.16163 -
American Journal of Infection Control Apr 2017Preoperative bathing with 4% chlorhexidine is recommended as a measure to prevent surgical site infection (SSI) despite uncertainty regarding the effectiveness of the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Preoperative bathing with 4% chlorhexidine is recommended as a measure to prevent surgical site infection (SSI) despite uncertainty regarding the effectiveness of the intervention. This review aimed to assess the effect of bathing with 4% chlorhexidine on the prevention of SSIs in clean surgeries compared with bathing with placebo solution or soap.
METHODS
Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for systematic reviews and the Cochrane manual were followed. Sources were MEDLINE and Latin American and Caribbean Health Sciences Literature databases and manual search of references from evaluated studies. We included randomized studies evaluating clean surgical wounds and reporting SSIs after preoperative bathing with 4% chlorhexidine.
RESULTS
A total of 243 primary studies were identified and 8 were considered methodologically appropriate based on the Jadad Scale. Data were gathered from 10,655 patients. The global SSI rate was 7.2%. The SSI rate for chlorhexidine bathing, placebo, and soap without antiseptic groups was 7.1%, 9.1%, and 5.1%, respectively. A significant reduction in the infection rates was not found in the comparison between patients subjected to preoperative bathing with 4% chlorhexidine versus placebo solution (relative risk, 0.91; 95% confidence interval, 0.76-1.09). The same absence of benefit was observed comparing chlorhexidine bathing with soap (relative risk, 1.06; 95% confidence interval, 0.68-1.66).
CONCLUSIONS
Controlled clinical trials are needed to assess the effect of preoperative chlorhexidine bathing on infection rates following clean surgery before the incorporation of this intervention in health care services.
Topics: Anti-Infective Agents, Local; Baths; Chlorhexidine; Disinfection; Humans; Incidence; Placebos; Preoperative Care; Surgical Wound Infection; Treatment Outcome
PubMed: 28109628
DOI: 10.1016/j.ajic.2016.12.003