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Developmental Medicine and Child... Oct 2023Placebo responses are frequently observed in research studies and clinical contexts, yet there is limited knowledge about the placebo effect among children with... (Review)
Review
Placebo responses are frequently observed in research studies and clinical contexts, yet there is limited knowledge about the placebo effect among children with neurodevelopmental disorders. Here, we review the placebo effect in autism spectrum disorder (ASD). Placebo responses are widely evident in ASD clinical trials and could partly operate via so-called placebo-by-proxy, whereby caregivers or clinicians indirectly shape patient outcomes. Understanding the role of placebo effects in ASD may help discern genuine treatment effects from contextual factors in clinical trials. The much less studied nocebo effect, or negative placebo, might contribute to the experience of side effects in ASD treatments but empirical data is missing. Better knowledge about placebo and nocebo mechanisms may contribute to the development of more effective research designs, such as three-armed designs that account for natural history, and improved treatments for ASD symptoms. At a clinical level, deeper knowledge about placebo and nocebo effects may optimize the delivery of care for individuals with ASD in the future. WHAT THIS PAPER ADDS: Placebo responses are evident in autism spectrum disorder (ASD) clinical trials. Placebo responses in ASD are likely dependent on a placebo-by-proxy mechanism.
Topics: Humans; Child; Placebo Effect; Autism Spectrum Disorder; Nocebo Effect
PubMed: 36917698
DOI: 10.1111/dmcn.15574 -
Pain Jan 2024This preregistered (CRD42021223379) systematic review and meta-analysis aimed to characterize the placebo and nocebo responses in placebo-controlled randomized clinical... (Meta-Analysis)
Meta-Analysis
This preregistered (CRD42021223379) systematic review and meta-analysis aimed to characterize the placebo and nocebo responses in placebo-controlled randomized clinical trials (RCTs) on painful diabetic neuropathy (PDN), updating the previous literature by a decade. Four databases were searched for PDN trials published in the past 20 years, testing oral medications, adopting a parallel-group design. Magnitude of placebo or nocebo responses, Cochrane risk of bias, heterogeneity, and moderators were evaluated. Searches identified 21 studies (2425 placebo-treated patients). The overall mean pooled placebo response was -1.54 change in the pain intensity from baseline [95% confidence interval (CI): -1.52, -1.56, I 2 = 72], with a moderate effect size (Cohen d = 0.72). The pooled placebo 50% response rate was 25% [95% CI: 22, 29, I 2 = 50%]. The overall percentage of patients with adverse events (AEs) in the placebo arms was 53.3% [95% CI: 50.9, 55.7], with 5.1% [95% CI: 4.2, 6] of patients dropping out due to AEs. The year of study initiation was the only significant moderator of placebo response (regression coefficient = -0.06, [95% CI: -0.10, -0.02, P = 0.007]). More recent RCTs tended to be longer, bigger, and to include older patients (N = 21, rs = 0.455, P = 0.038, rs = 0.600, P = 0.004, rs = 0.472, P = 0.031, respectively). Our findings confirm the magnitude of placebo and nocebo responses, identify the year of study initiation as the only significant moderator of placebo response, draw attention to contextual factors such as confidence in PDN treatments, patients' previous negative experiences, intervention duration, and information provided to patients before enrollment.
Topics: Humans; Nocebo Effect; Diabetic Neuropathies; Placebo Effect; Pain Measurement; Diabetes Mellitus
PubMed: 37530658
DOI: 10.1097/j.pain.0000000000003000 -
BioRxiv : the Preprint Server For... Feb 2024Placebo analgesia is a widely observed clinical phenomenon. Establishing a robust mouse model of placebo analgesia is needed for careful dissection of the underpinning...
Placebo analgesia is a widely observed clinical phenomenon. Establishing a robust mouse model of placebo analgesia is needed for careful dissection of the underpinning circuit mechanisms. However, previous studies failed to observe consistent placebo effects in rodent models of chronic pain. We wondered whether strong placebo analgesia can be reverse engineered using general anesthesia-activated neurons in the central amygdala (CeA ) that can potently suppress pain. Indeed, in both acute and chronic pain models, pairing a context with CeA -mediated pain relief produced robust context-dependent analgesia, exceeding that induced by morphine in the same paradigm. We reasoned that if the analgesic effect was dependent on reactivation of CeA neurons by conditioned contextual cues, the analgesia would still be an active treatment, rather than a placebo effect. CeA neurons indeed receive monosynaptic inputs from temporal lobe areas that could potentially relay contextual cues directly to CeA . However, in vivo imaging showed that CeA neurons were re-activated in the conditioned context, despite mice displaying a strong analgesic phenotype, supporting the notion that the cue-induced pain relief is true placebo analgesia. Our results show that conditioning with activation of a central pain-suppressing circuit is sufficient to engineer placebo analgesia, and that purposefully linking a context with an active treatment could be a means to harness the power of placebo for pain relief.
PubMed: 38405975
DOI: 10.1101/2024.02.12.579946 -
International Journal of Infectious... Aug 2023Unnecessary and inappropriate antibiotic use is an increasing global health challenge. In limited resource settings, prophylactic antibiotics are still often used in... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Unnecessary and inappropriate antibiotic use is an increasing global health challenge. In limited resource settings, prophylactic antibiotics are still often used in (adeno)tonsillectomy (AT), despite evidence against their effectiveness. This study aimed to investigate the effect of prophylactic amoxicillin, given after AT in children.
METHODS
This is a secondary analysis from a two-center, double-blinded, randomized controlled, non-inferiority trial to study the effect of prophylactic amoxicillin on post-AT morbidity. Children aged 2-14 years with recurrent chronic tonsillitis and/or obstructive sleep apnea were randomly assigned to receive either placebo or amoxicillin for 5 days after the operation. Pre- and postoperative samples were collected for polymerase chain reaction (PCR) analyses to detect the five most important pathogens known to be common causes of tonsillitis. PCR results were compared before and after surgery as well as between placebo and amoxicillin.
RESULTS
PCR results were obtained, 109 in the amoxicillin group and 115 in the placebo group. In the amoxicillin group, 91% of patients had at least one positive PCR test before surgery and 87% after surgery. In the placebo group, the respective percentages were 92% and 90%. In both groups, a decrease in the total number of pathogens was found after surgery.
CONCLUSION
Prophylactic amoxicillin given after AT in children did not show a clinically relevant effect with respect to the number of oropharyngeal microorganisms as compared to placebo.
Topics: Humans; Child; Tonsillectomy; Amoxicillin; Palatine Tonsil; Tonsillitis; Anti-Bacterial Agents
PubMed: 37116578
DOI: 10.1016/j.ijid.2023.04.409 -
Annals of Allergy, Asthma & Immunology... Sep 2023Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study, tezepelumab reduced exacerbations and improved lung... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study, tezepelumab reduced exacerbations and improved lung function, asthma control, and health-related quality of life compared with placebo in patients with severe, uncontrolled asthma. However, little is known about the impact of tezepelumab on healthcare utilization (HCU) in these patients.
OBJECTIVE
To evaluate to what extent tezepelumab reduces patients' HCU.
METHODS
In NAVIGATOR, patients were randomized to receive subcutaneous tezepelumab 210 mg or placebo, every 4 weeks for 52 weeks. For this analysis, the main outcomes of interest were asthma-related HCU. A blinded, systematic analysis of the symptoms and HCU recorded in the investigator-reported narratives describing exacerbation-related hospitalizations was also conducted; the narratives included blinded ratings of event intensity, recorded as mild, moderate, or severe.
RESULTS
Recipients of tezepelumab (n = 528) required fewer asthma-related unscheduled specialist visits (tezepelumab, 285 events; placebo, 406 events), telephone calls with a healthcare provider (tezepelumab, 234; placebo, 599), ambulance transports (tezepelumab, 5; placebo, 22), emergency department visits (without subsequent hospitalization; tezepelumab, 16; placebo, 37), hospitalizations (tezepelumab, 14; placebo, 78), and intensive care days (tezepelumab, 0; placebo, 31) than did recipients of placebo (n = 531). Among patients with asthma exacerbation-related hospitalizations, 38% of those hospitalized and receiving tezepelumab (5/13) had an event rated as severe, compared with 82% of those hospitalized and receiving placebo (32/39).
CONCLUSION
Tezepelumab substantially reduced HCU across all outcomes measured compared with placebo, in addition to the severity of asthma exacerbations requiring hospitalization. Tezepelumab can reduce the overall burden of disease of severe, uncontrolled asthma.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home), identifier: NCT03347279.
Topics: Humans; Anti-Asthmatic Agents; Quality of Life; Asthma; Patient Acceptance of Health Care; Double-Blind Method
PubMed: 37263380
DOI: 10.1016/j.anai.2023.05.028 -
International Forum of Allergy &... Mar 2024The placebo effect observed in clinical trials evaluating medical treatments for chronic rhinosinusitis (CRS) is not well understood. This systematic review and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The placebo effect observed in clinical trials evaluating medical treatments for chronic rhinosinusitis (CRS) is not well understood. This systematic review and meta-analysis sought to characterize the placebo effect present within CRS outcomes.
METHODS
A systematic review of PubMed, Scopus, and Cumulated Index in Nursing and Allied Health Nursing (CINAHL) was performed. Randomized controlled trials (RCTs) evaluating medical treatments for CRS versus placebo were included. We assessed patient-reported (sino-nasal outcome test 22 [SNOT-22], nasal obstruction, sense of smell, nasal obstruction visual analogue score [VAS], sense of smell VAS, anterior rhinorrhea, and postnasal drip) and objective (Lund-Mackay Computed tomography (CT) score, peak nasal inspiratory flow [PNIF], nasal polyp scores, 40-item Smell Identification Test, serum IgE, and blood eosinophil levels) outcomes.
RESULTS
Twenty-one RCTs were included, comprising 1437 patients (mean age 49.2 years). Biologics were the most common treatment investigated (n = 9). Eleven studies administered background steroids along with placebo. Following placebo administration, multiple patient-reported outcomes significantly decreased, including SNOT-22 (mean difference -9.49, 95% confidence interval [CI] [-11.26, -7.73]), nasal obstruction (-0.33 [-0.54, -0.13]), sense of smell (-0.22 [-0.33, -0.11]), nasal obstruction VAS (-2.47 [-2.87, -2.06]), and loss of smell VAS (-2.31 [-4.14, -0.47]) scores. For objective measures, significant changes occurred in Lund-Mackay CT score (-0.82, [-1.48, -0.16]) and PNIF (4.70, [4.76, 24.64]) with placebo. Placebo arms had the greatest impact when no background medications were used.
CONCLUSIONS
Placebo treatments have a statistically and potentially clinically significant effect on patient-reported and some objective CRS outcomes. Further investigation is required to fully understand placebo effect, which could improve assessment of RCTs and impact patient care.
Topics: Humans; Middle Aged; Nasal Obstruction; Rhinosinusitis; Rhinitis; Nasal Polyps; Sinusitis; Chronic Disease; Placebo Effect; Randomized Controlled Trials as Topic
PubMed: 37985206
DOI: 10.1002/alr.23302 -
Journal of Integrative Medicine Sep 2023The placebo response of sham acupuncture in patients with primary dysmenorrhea is a substantial factor associated with analgesia. However, the magnitude of the placebo... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The placebo response of sham acupuncture in patients with primary dysmenorrhea is a substantial factor associated with analgesia. However, the magnitude of the placebo response is unclear.
OBJECTIVE
This meta-analysis assessed the effects of sham acupuncture in patients with primary dysmenorrhea and the factors contributing to these effects.
SEARCH STRATEGY
PubMed, Embase, Web of Science, and Cochrane CENTRAL databases were searched from inception up to August 20, 2022.
INCLUSION CRITERIA
Randomized controlled trials (RCTs) using sham acupuncture as a control for female patients of reproductive age with primary dysmenorrhea were included.
DATA EXTRACTION AND ANALYSIS
Pain intensity, retrospective symptom scale, and health-related quality of life were outcome measures used in these trials. Placebo response was defined as the change in the outcome of interest from baseline to endpoint. We used standardized mean difference (SMD) to estimate the effect size of the placebo response.
RESULTS
Thirteen RCTs were included. The pooled placebo response size for pain intensity was the largest (SMD = -0.99; 95% confidence interval [CI], -1.31 to -0.68), followed by the retrospective symptom scale (Total frequency rating score: SMD = -0.20; 95% CI, -0.80 to -0.39. Average severity score: SMD = -0.35; 95% CI, -0.90 to -0.20) and physical component of SF-36 (SMD = 0.27; 95% CI, -0.17 to 0.72). Studies using blunt-tip needles, single-center trials, studies with a low risk of bias, studies in which patients had a longer disease course, studies in which clinicians had < 5 years of experience, and trials conducted outside Asia were more likely to have a lower placebo response.
CONCLUSION
Strong placebo response and some relative factors were found in patients with primary dysmenorrhea. PROSPERO registration number: CRD42022304215. Please cite this article as: Sun CY, Xiong ZY, Sun CY, Ma PH, Liu XY, Sun CY, Xin ZY, Liu BY, Liu CZ, Yan SY. Placebo response of sham acupuncture in patients with primary dysmenorrhea: A meta-analysis. J Integr Med. 2023; 21(5): 455-463.
Topics: Female; Humans; Dysmenorrhea; Acupuncture Therapy; Pain Management; Needles; Placebo Effect
PubMed: 37620224
DOI: 10.1016/j.joim.2023.08.005 -
Scientific Reports Oct 2023Multiple Sclerosis (MS) is a chronic demyelination disease of the central nervous system (CNS). The gut-brain axis involves communication between the nervous, endocrine,... (Randomized Controlled Trial)
Randomized Controlled Trial
Multiple Sclerosis (MS) is a chronic demyelination disease of the central nervous system (CNS). The gut-brain axis involves communication between the nervous, endocrine, and immune systems. Probiotics can positively impact immune and inflammatory responses by regulating gut microbiota. A total of 40 MS patients (average age of 34.38 ± 6.65) were examined to determine the effect of the Saccharomyces boulardii supplement for four months compared to a placebo. The results showed that the Saccharomyces boulardii significantly decreased the inflammatory marker high-sensitivity C-reactive protein (hs-CRP) compared to the placebo (P < 0.001). The serum antioxidant capacity (TAC) also increased significantly in the probiotic group compared to the placebo (p = 0.004). Both the probiotic and placebo groups showed a reduction in the oxidative stress indicator malondialdehyde (MDA), but there was no significant difference between the two groups. Pain intensity (measured by Visual Analogue Scale) and fatigue severity (measured by Fatigue Severity Scale) significantly decreased in the probiotic group compared to the placebo (p = 0.004 and p = 0.01, respectively). The probiotic group experienced significant improvement in some quality of life scales (measured by 36-Item Short Form Survey) and somatic and social dysfunction subscale of General Health Questionnaire scores compared to the placebo group (p = 0.01). The study suggests that the Saccharomyces boulardii probiotic supplement may benefit inflammatory markers, oxidative stress indicators, pain, fatigue, and quality of life in MS patients.
Topics: Humans; Adult; Multiple Sclerosis; Quality of Life; Probiotics; Dietary Supplements; Fatigue; Double-Blind Method
PubMed: 37903945
DOI: 10.1038/s41598-023-46047-6 -
Nutrients May 2024This study aimed to analyse the placebo effect associated with a high dose of caffeine (9 mg/kg) on heart rate and its variability and on strength tests. (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
This study aimed to analyse the placebo effect associated with a high dose of caffeine (9 mg/kg) on heart rate and its variability and on strength tests.
METHODS
18 participants experienced in strength training (19.7 ± 2.3 years; 72.2 ± 15.0 kg; 169.6 ± 9.0 cm) performed two days of trials (caffeine-informed/placebo-ingested (placebo) and non-ingested (control)). Firstly, heart rate and its variability were measured while participants lay down for 15 min. After that, bench press and squat tests were performed at 3 different loads (50%, 75% and 90% of 1RM). Perception of performance, effort and side effects were also evaluated.
RESULTS
no differences were found in the vast majority of strength variables analysed. Resting heart rate decreased in the placebo trial (60.39 ± 10.18 bpm control vs. 57.56 ± 9.50 bpm placebo, = 0.040), and mean RR increased (1020.1 ± 172.9 ms control vs. 1071.5 ± 185.7 ms placebo, = 0.032). Heart rate variability and perception of performance and effort were similar between conditions ( > 0.05 in all cases). Side effects such as activeness and nervousness were reported while consuming the placebo.
CONCLUSIONS
the placebo effect did not modify performance in the majority of the strength test variables, HRV and perception of performance and effort. However, resting heart rate was reduced, mean RR increased, and some side effects appeared in the placebo trial.
Topics: Humans; Caffeine; Heart Rate; Young Adult; Male; Placebo Effect; Female; Adult; Physical Functional Performance; Adolescent; Muscle Strength; Resistance Training
PubMed: 38794643
DOI: 10.3390/nu16101405 -
Journal of Affective Disorders Sep 2023The efficacy and safety of lurasidone monotherapy in patients with bipolar I depression with or without rapid cycling has not been previously investigated. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The efficacy and safety of lurasidone monotherapy in patients with bipolar I depression with or without rapid cycling has not been previously investigated.
METHODS
We performed subgroup analysis (rapid cycling/non-rapid cycling) of pooled data from two 6-week, randomized, double-blind, placebo-controlled trials of lurasidone monotherapy (20-60 mg/day or 80-120 mg/day). Analyses included mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Safety assessments included the number of treatment-emergent adverse events (TEAEs) and laboratory assessments.
RESULTS
Of 1024 patients randomized, 85 were rapid cycling. Mean change in MADRS total score in patients with non-rapid cycling and rapid cycling, respectively, was -14.8 (effect size = 0.47) and - 12.8 (effect size = 0.04) in the lurasidone 20-60 mg/day group, -14.3 (effect size = 0.41) and - 13.0 (effect size = 0.02) in the lurasidone 80-120 mg/day group and -10.6 and -13.3 in the placebo group. The most common TEAE in each subgroup was akathisia in both lurasidone groups. Treatment-emergent mania was reported only in a small number of rapid cycling and non-rapid cycling patients.
LIMITATIONS
This was a post-hoc analysis of a short-term study that excluded patients with ≥8 cycles in the past year.
CONCLUSIONS
In patients with non-rapid cycling bipolar depression, lurasidone monotherapy significantly improved depressive symptoms relative to placebo at both the 20-60 mg/day and 80-120 mg/day doses. In patients with rapid cycling, both doses of lurasidone displayed depressive symptom score reduction from baseline, but significant improvement was not observed likely due to high levels of improvement on placebo and small sample size.
Topics: Humans; Lurasidone Hydrochloride; Bipolar Disorder; Depression; Drug Therapy, Combination; Mania; Double-Blind Method; Antipsychotic Agents; Treatment Outcome
PubMed: 37245552
DOI: 10.1016/j.jad.2023.05.065