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Perspectives in Biology and Medicine 2023The objective of this essay is to develop the argument that placebos are a species of metaphor and to demonstrate that an analysis of the figurative trope can help us...
The objective of this essay is to develop the argument that placebos are a species of metaphor and to demonstrate that an analysis of the figurative trope can help us elucidate the power of the placebo response. The cognitive and embodied responses to both metaphors and placebos stem from the transfer of meaning between two domains, each with rich allusive properties that in turn depend on highly ramified and interconnected neural webs. Metaphors and placebos require an appropriate cultural backdrop for their linguistic and cognitive work and are dependent on shared social forms of life. More specifically, metaphors rely on an intersubjective connection and imply that a relational entanglement between doctor and patient is necessary to the effect of placebos in the clinical setting.
Topics: Humans; Metaphor; Placebo Effect; Placebos; Physician-Patient Relations; Cognition
PubMed: 38661934
DOI: 10.1353/pbm.2023.a902033 -
International Review of Neurobiology 2020The power of placebos is commonly associated with the placebo effect. In contrast, detrimental effects related to the use of a placebo are little studied and less well... (Review)
Review
The power of placebos is commonly associated with the placebo effect. In contrast, detrimental effects related to the use of a placebo are little studied and less well recognized. This chapter covers the nocebo and lessebo effects defined, respectively, as expectation of harm in the form of adverse events in a placebo arm and reduction of therapeutic benefit due to the uncertainty of being allocated to placebo. The lessebo effect is a more recent concept and has been described only in depression, schizophrenia and Parkinson's disease. The nocebo response was evaluated in many neurological diseases, including epilepsy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, restless leg syndrome, among others. Meta-analyses of randomized controlled trials in these conditions reveal a significant variability of the magnitude of the nocebo response and that factors related to study design, study participants or neurological disease can be associated with a nocebo response, although with the opposing findings across conditions. The knowledge about neurobiological mechanisms of the nocebo effect is poor for neurological diseases, and most of the information has been generated in pain. Functional neuroimaging suggests the existence of a distinct network for the anticipation and the experience of a hyperalgesia nocebo response. Different types of neurotransmitters have been involved, including cholecystokinin, dopamine and opioids. Recognizing the potential impact of nocebo and lessebo effects, mitigating strategies are in development with application to clinical research and clinical practice, such as a contextualized informed consent process, alternative study designs and enhancement of patient-physician communication.
Topics: Anticipation, Psychological; Conditioning, Psychological; Controlled Clinical Trials as Topic; Humans; Informed Consent; Nervous System Diseases; Nocebo Effect; Patient Selection; Placebo Effect; Placebos
PubMed: 32563285
DOI: 10.1016/bs.irn.2020.04.005 -
Journal of Drugs in Dermatology : JDD Jan 2021Hair loss is a complex and multi-factorial problem that is associated with significant psychological morbidity in women. Menopausal women represent a significant... (Randomized Controlled Trial)
Randomized Controlled Trial
A Randomized, Double-Blind, Placebo-Controlled Study of a Nutraceutical Supplement for Promoting Hair Growth in Perimenopausal, Menopausal, and Postmenopausal Women With Thinning Hair.
Hair loss is a complex and multi-factorial problem that is associated with significant psychological morbidity in women. Menopausal women represent a significant percentage of those affected, since the menopausal hormonal transition can be a contributing factor. A novel nutraceutical supplement has been specifically formulated with phytoactives to improve hair growth and quality in menopausal women (Nutrafol® Women’s Balance Capsules). The objective of this 6-month, randomized, double-blind, placebo-controlled study was to assess the safety and efficacy of this oral supplement to promote hair growth in perimenopausal, menopausal, and postmenopausal women with self-perceived thinning. Subjects were randomized to the study supplement (n=40) or placebo (n=30). The primary endpoint was a statistically significant increase in the number of terminal and vellus hairs based on phototrichogram analysis. Daily intake of the nutraceutical supplement resulted in progressive and significant increase in terminal and total hair counts on days 90 (P<0.01) and 180 (P<0.01) compared to placebo. The vellus hair counts significantly increased for the active treatment group (P<0.05) by day 180 while significantly decreasing for the placebo group subjects. Hair shedding progressively and significantly decreased for the active group compared to placebo, culminating in a reduction of 32.41% by day 180 (P<0.01). The study supplement was well-tolerated. ClinicalTrials.gov Identifier: NCT04048031 J Drugs Dermatol. 2021;20(1):55-61. doi:10.36849/JDD.5701 THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.
Topics: Administration, Oral; Adult; Aged; Alopecia; Dermoscopy; Dietary Supplements; Double-Blind Method; Female; Hair; Humans; Menopause; Middle Aged; Photography; Phytochemicals; Placebos; Surveys and Questionnaires; Treatment Outcome
PubMed: 33400421
DOI: 10.36849/JDD.5701 -
The Lancet. Infectious Diseases Mar 2020Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to established guidelines. Therefore, we aimed to investigate the... (Randomized Controlled Trial)
Randomized Controlled Trial
Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial.
BACKGROUND
Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to established guidelines. Therefore, we aimed to investigate the efficacy of the combination drug device Amikacin Inhale as an adjunctive therapy to intravenous standard-of-care antibiotics for pneumonia caused by Gram-negative pathogens in intubated and mechanically ventilated patients.
METHODS
INHALE was a prospective, double-blind, randomised, placebo-controlled, phase 3 study comprising two trials (INHALE 1 and INHALE 2) done in 153 hospital intensive-care units in 25 countries. Eligible patients were aged 18 years or older; had pneumonia that had been diagnosed by chest radiography and that was documented as being caused by or showing two risk factors for a Gram-negative, multidrug-resistant pathogen; were intubated and mechanically ventilated; had impaired oxygenation within 48 h before screening; and had a modified Clinical Pulmonary Infection Score of at least 6. Patients were stratified by region and disease severity (according to their Acute Physiology and Chronic Health Evaluation [APACHE] II score) and randomly assigned (1:1) via an interactive voice-recognition system to receive 400 mg amikacin (Amikacin Inhale) or saline placebo, both of which were aerosolised, administered every 12 h for 10 days via the same synchronised inhalation system, and given alongside standard-of-care intravenous antibiotics. All patients and all staff involved in administering devices and monitoring outcomes were masked to treatment assignment. The primary endpoint, survival at days 28-32, was analysed in all patients who received at least one dose of study drug, were infected with a Gram-negative pathogen, and had an APACHE II score of at least 10 at diagnosis. Safety analyses were done in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, numbers NCT01799993 and NCT00805168.
FINDINGS
Between April 13, 2013, and April 7, 2017, 807 patients were assessed for eligibility and 725 were randomly assigned to Amikacin Inhale (362 patients) or aerosolised placebo (363 patients). 712 patients received at least one dose of study drug (354 in the Amikacin Inhale group and 358 in the placebo group), although one patient assigned to Amikacin Inhale received placebo in error and was included in the placebo group for safety analyses. 508 patients (255 in the Amikacin Inhale group and 253 in the placebo group) were assessed for the primary endpoint. We found no between-group difference in survival: 191 (75%) patients in the Amikacin Inhale group versus 196 (77%) patients in the placebo group survived until days 28-32 (odds ratio 0·841, 95% CI 0·554-1·277; p=0·43). Similar proportions of patients in the two treatment groups had a treatment-emergent adverse event (295 [84%] of 353 patients in the Amikacin Inhale group vs 303 [84%] of 359 patients in the placebo group) or a serious treatment-emergent adverse event (101 [29%] patients vs 97 [27%] patients).
INTERPRETATION
Our findings do not support use of inhaled amikacin adjunctive to standard-of-care intravenous therapy in mechanically ventilated patients with Gram-negative pneumonia.
FUNDING
Bayer AG.
Topics: Administration, Inhalation; Administration, Intravenous; Adult; Aged; Amikacin; Anti-Bacterial Agents; Double-Blind Method; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Gram-Negative Bacterial Infections; Hospitals; Humans; Male; Middle Aged; Placebos; Pneumonia, Ventilator-Associated; Prospective Studies; Standard of Care; Survival Analysis; Treatment Outcome; Young Adult
PubMed: 31866328
DOI: 10.1016/S1473-3099(19)30574-2 -
The Journal of Clinical Endocrinology... Jan 2022Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism.
OBJECTIVE
This work aimed to investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism.
METHODS
This phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension enrolled 59 individuals with hypoparathyroidism. Interventions included TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 22-week extension during which TransCon PTH dose was titrated (6-60 µg PTH[1-34]/day).
RESULTS
By Week 26, 91% of participants treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 μg/day and calcium [Ca] ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while normal serum Ca (sCa) was maintained and serum phosphate and serum calcium-phosphate product fell within the normal range. By Week 26, mean scores on the generic 36-Item Short Form Health Survey domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale symptom and impact scores improved through 26 weeks. TransCon PTH was well tolerated with no treatment-related serious or severe adverse events.
CONCLUSION
TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most participants, achieving normal sCa, serum phosphate, uCa, serum calcium-phosphate product, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.
Topics: Adult; Aged; Calcium; Delayed-Action Preparations; Double-Blind Method; Drug Administration Schedule; Female; Hormone Replacement Therapy; Humans; Hypoparathyroidism; Male; Middle Aged; Parathyroid Hormone; Patient Reported Outcome Measures; Placebos; Prodrugs; Quality of Life; Treatment Outcome; Vitamin D
PubMed: 34347093
DOI: 10.1210/clinem/dgab577 -
JAMA Oct 2021Smoking cessation medications are routinely used in health care. Research suggests that combining varenicline with the nicotine patch, extending the duration of... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Smoking cessation medications are routinely used in health care. Research suggests that combining varenicline with the nicotine patch, extending the duration of varenicline treatment, or both, may increase cessation effectiveness.
OBJECTIVE
To compare combinations of varenicline plus the nicotine or placebo patch vs combinations used for either 12 weeks (standard duration) or 24 weeks (extended duration).
DESIGN, SETTINGS, AND PARTICIPANTS
Double-blind, 2 × 2 factorial randomized clinical trial conducted from November 11, 2017, to July 9, 2020, at 1 research clinic in Madison, Wisconsin, and at 1 clinic in Milwaukee, Wisconsin. Of the 5836 adults asked to participate in the study, 1251 who smoked 5 cigarettes/d or more were randomized.
INTERVENTIONS
All participants received cessation counseling and were randomized to 1 of 4 medication groups: varenicline monotherapy for 12 weeks (n = 315), varenicline plus nicotine patch for 12 weeks (n = 314), varenicline monotherapy for 24 weeks (n = 311), or varenicline plus nicotine patch for 24 weeks (n = 311).
MAIN OUTCOMES AND MEASURES
The primary outcome was carbon monoxide-confirmed self-reported 7-day point prevalence abstinence at 52 weeks.
RESULTS
Among 1251 patients who were randomized (mean [SD] age, 49.1 [11.9] years; 675 [54.0%] women), 751 (60.0%) completed treatment and 881 (70.4%) provided final follow-up. For the primary outcome, there was no significant interaction between the 2 treatment factors of medication type and medication duration (odds ratio [OR], 1.03 [95% CI, 0.91 to 1.17]; P = .66). For patients randomized to 24-week vs 12-week treatment duration, the primary outcome occurred in 24.8% (154/622) vs 24.3% (153/629), respectively (risk difference, -0.4% [95% CI, -5.2% to 4.3%]; OR, 1.01 [95% CI, 0.89 to 1.15]). For patients randomized to varenicline combination therapy vs varenicline monotherapy, the primary outcome occurred in 24.3% (152/625) vs 24.8% (155/626), respectively (risk difference, 0.4% [95% CI, -4.3% to 5.2%]; OR, 0.99 [95% CI, 0.87 to 1.12]). Nausea occurrence ranged from 24.0% to 30.9% and insomnia occurrence ranged from 24.4% to 30.5% across the 4 groups.
CONCLUSIONS AND RELEVANCE
Among adults smoking 5 cigarettes/d or more, there were no significant differences in 7-day point prevalence abstinence at 52 weeks among those treated with combined varenicline plus nicotine patch therapy vs varenicline monotherapy, or among those treated for 24 weeks vs 12 weeks. These findings do not support the use of combined therapy or of extended treatment duration.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03176784.
Topics: Carbon Monoxide; Combined Modality Therapy; Confidence Intervals; Double-Blind Method; Female; Humans; Male; Middle Aged; Nausea; Nicotinic Agonists; Odds Ratio; Placebos; Self Report; Sleep Initiation and Maintenance Disorders; Smoking Cessation; Temperance; Time Factors; Tobacco Use Cessation Devices; Varenicline; Wisconsin
PubMed: 34665204
DOI: 10.1001/jama.2021.15333 -
RMD Open Feb 2020Biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs are used in patients with psoriatic arthritis (PsA), but few studies directly... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
Biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs are used in patients with psoriatic arthritis (PsA), but few studies directly compare their clinical efficacy. In such situations, network meta-analysis (NMA) can inform evidence-based decision-making.
OBJECTIVE
To evaluate the comparative efficacy and safety of approved bDMARDs in patients with PsA.
METHODS
Bayesian NMA was conducted to compare the clinical efficacy of bDMARDs at weeks 12‒16 in bDMARD-naïve patients with PsA in terms of American College of Rheumatology (ACR) criteria, Psoriatic Arthritis Response Criteria (PsARC) and Psoriasis Area and Severity Index (PASI). Safety end points were evaluated in the overall mixed population of bDMARD-naive and bDMARD-experienced patients.
RESULTS
For ACR, all treatments except abatacept were statistically superior to placebo. Infliximab was most effective, followed by golimumab and etanercept, which were statistically superior to most other treatments. Ixekizumab 80 mg every 2 weeks (Q2W) was statistically superior to abatacept subcutaneous, apremilast and both regimens of ustekinumab; similar findings were observed for ixekizumab 80 mg Q4W. For PsARC response, ixekizumab did not significantly differ from other therapies, except for golimumab, infliximab and etanercept, which were superior to most other agents including ixekizumab. For PASI response, infliximab was numerically most effective, but was not statistically superior to ixekizumab, which was the next best performing agent. Analysis of safety end points identified few differences between treatments.
CONCLUSION
Our NMA confirms the efficacy and acceptable safety profile of bDMARDs in patients with active PsA. There were generally few statistically significant differences between most treatments.
Topics: Abatacept; Adult; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Psoriatic; Biological Products; Clinical Decision-Making; Humans; Immune Checkpoint Inhibitors; Interleukin-17; Network Meta-Analysis; Placebos; Safety; Severity of Illness Index; Treatment Outcome
PubMed: 32094304
DOI: 10.1136/rmdopen-2019-001117 -
International Review of Neurobiology 2020The placebo effect in many areas of neurological therapeutics is common and prominent. The importance of the response means that any new treatment must account for the... (Review)
Review
The placebo effect in many areas of neurological therapeutics is common and prominent. The importance of the response means that any new treatment must account for the placebo effect, but this in turn raises major challenges as to how to conduct scientifically meaningful research in an ethically acceptable fashion. Basic principles that may be in tension with one another are those of beneficence and respect for autonomy. It may be challenging to respect autonomy if the scientific design of a study depends upon the use of deception, but this is often mitigated by the information provided to trial participants as part of the informed consent process. Deception is a particular challenge if placebos are to be used in a clinical/therapeutic setting, outside the context of a clinical trial. While practice-based placebo use may on occasion be both beneficial and ethically acceptable, close attention must then be paid to ensuring that basic ethical principles are respected and that placebos are either prescribed in an open and honest fashion, or that any deception is authorized.
Topics: Deception; Ethics, Medical; Humans; Informed Consent; Nervous System Diseases; Placebo Effect; Placebos
PubMed: 32563286
DOI: 10.1016/bs.irn.2020.03.030 -
American Journal of Respiratory and... Mar 2020Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. To evaluate the... (Clinical Trial)
Clinical Trial
Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56-0.97; = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro-brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil-assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12-60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).
Topics: Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; Double-Blind Method; Epoprostenol; Female; Humans; Male; Middle Aged; Placebos; Pulmonary Arterial Hypertension; Young Adult
PubMed: 31765604
DOI: 10.1164/rccm.201908-1640OC -
The Lancet. Gastroenterology &... Jul 2020Bifidobacterium bifidum MIMBb75 is one of a few probiotic strains that have been shown to be effective in the treatment of irritable bowel syndrome (IBS) and its... (Randomized Controlled Trial)
Randomized Controlled Trial
Heat-inactivated Bifidobacterium bifidum MIMBb75 (SYN-HI-001) in the treatment of irritable bowel syndrome: a multicentre, randomised, double-blind, placebo-controlled clinical trial.
BACKGROUND
Bifidobacterium bifidum MIMBb75 is one of a few probiotic strains that have been shown to be effective in the treatment of irritable bowel syndrome (IBS) and its symptoms. Non-viable strains might have advantages over viable bacteria for product stability and standardisation, as well as for tolerability because safety concerns have been raised for specific patient groups who are susceptible to infection. We aimed to assess the efficacy of non-viable, heat-inactivated (HI) B bifidum MIMBb75 (SYN-HI-001) in the treatment of IBS and its symptoms.
METHODS
We did a double-blind, placebo-controlled trial in which patients with IBS were recruited from 20 study sites in Germany and randomly assigned to receive either two placebo capsules or two capsules with a combined total of 1 × 10 non-viable B bifidum HI-MIMBb75 cells to be taken orally once a day for 8 weeks. Eligible patients were diagnosed with IBS according to Rome III criteria and had abdominal pain (≥4 on an 11-point numerical rating scale) on at least 2 days during a 2-week run-in phase. Patients with chronic inflammatory bowel diseases, systemic diseases, cancer, autoimmune diseases, with an intake of antipsychotic medications 3 months before study start, or with an intake of systemic corticosteroids within 1 month before study start were excluded. Randomisation was in a 1:1 ratio according to a computer-generated blocked list. Patients, investigators, clinical monitors, project managers, and statisticians were masked to the randomisation. The primary composite endpoint was the combination of at least 30% improvement of abdominal pain and adequate relief of overall IBS symptoms being fulfilled in at least 4 of 8 weeks during treatment. Analysis of the primary endpoint included all randomly assigned patients receiving at least one dose of study medication and who had no severe protocol violation. Safety analysis included all patients who had taken at least one dose of the study medication and was based on frequency and severity of adverse events, laboratory evaluation, and global assessment of tolerability. This trial is registered with the ISRCTN registry, ISRCTN14066467, and is completed: the results shown here represent the final analysis.
FINDINGS
Patients were screened between April 15, 2016, and Feb 3, 2017, and 443 patients were allocated to the placebo group (n=222) or the B bifidum HI-MIMBb75 group (n=221). The composite primary endpoint was reached by 74 (34%) of 221 patients in the B bifidum HI-MIMBb75 group compared with 43 (19%) of 222 in the placebo group (risk ratio 1·7, 95% CI 1·3-2·4; p=0·0007). No serious adverse events occurred in the B bifidum HI-MIMBb75 group; seven adverse events suspected to be related to the study product were reported in the B bifidum HI-MIMBb75 group as were eight in the placebo group. No deaths were reported in this study. The most common reported adverse event with a suspected relationship to the study product was abdominal pain, which was reported in two (<1%) patients in the B bifidum HI-MIMBb75 group and one (<1%) in the placebo group. Tolerability was rated as very good or good by 200 (91%) patients in the B bifidum HI-MIMBb75 group compared with 191 (86%) in the placebo group.
INTERPRETATION
This study shows that B bifidum HI-MIMBb75 substantially alleviates IBS and its symptoms in a real-life setting. These results indicate that specific beneficial bacterial effects are mediated independently of cell viability.
FUNDING
Synformulas.
Topics: Abdominal Pain; Adult; Bifidobacterium bifidum; Case-Control Studies; Double-Blind Method; Female; Germany; Humans; Intestines; Irritable Bowel Syndrome; Male; Middle Aged; Pain Measurement; Placebos; Probiotics; Safety; Treatment Outcome
PubMed: 32277872
DOI: 10.1016/S2468-1253(20)30056-X