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The Journal of Orthopaedic and Sports... Jun 2024We aimed to quantify the proportion not attributable to the specific effects (PCE) of physical therapy interventions for musculoskeletal pain. Intervention systematic... (Meta-Analysis)
Meta-Analysis Review
Which Portion of Physiotherapy Treatments' Effect Is Not Attributable to the Specific Effects in People With Musculoskeletal Pain? A Meta-Analysis of Randomized Placebo-Controlled Trials.
We aimed to quantify the proportion not attributable to the specific effects (PCE) of physical therapy interventions for musculoskeletal pain. Intervention systematic review with meta-analysis. We searched Ovid, MEDLINE, EMBASE, CINAHL, Scopus, PEDro, Cochrane Controlled Trials Registry, and SPORTDiscus databases from inception to April 2023. Randomized placebo-controlled trials evaluating the effect of physical therapy interventions on musculoskeletal pain. Risk of bias was evaluated using the Cochrane risk-of-bias tool for randomized trials (RoB 2). The proportion of physical therapy interventions effect that was not explained by the specific effect of the intervention was calculated, using the proportion not attributable to the specific effects (PCE) metric, and a quantitative summary of the data from the studies was conducted using the random-effects inverse-variance model (Hartung-Knapp-Sidik-Jonkman method). Sixty-eight studies were included in the systematic review (participants: n = 5238), and 54 placebo-controlled trials informed our meta-analysis (participants: n = 3793). Physical therapy interventions included soft tissue techniques, mobilization, manipulation, taping, exercise therapy, and dry needling. Placebo interventions included manual, nonmanual interventions, or both. The proportion not attributable to the specific effects of mobilization accounted for 88% of the immediate overall treatment effect for pain intensity (PCE = 0.88, 95% confidence interval [CI]: 0.57, 1.20). In exercise therapy, this proportion accounted for 46% of the overall treatment effect for pain intensity (PCE = 0.46, 95% CI: 0.41, 0.52). The PCE in manipulation excelled in short-term pain relief (PCE = 0.81, 95% CI: 0.62, 1.01) and in mobilization in long-term effects (PCE = 0.86, 95% CI: 0.76, 0.96). In taping, the PCE accounted for 64% of disability improvement (PCE = 0.64, 95% CI: 0.48, 0.80). The outcomes of physical therapy interventions for musculoskeletal pain were significantly influenced by factors not attributable to the specific effects of the interventions. Boosting these factors consciously to enhance therapeutic outcomes represents an ethical opportunity that could benefit patients. .
Topics: Humans; Musculoskeletal Pain; Randomized Controlled Trials as Topic; Physical Therapy Modalities; Exercise Therapy
PubMed: 38602164
DOI: 10.2519/jospt.2024.12126 -
Neurology Apr 2024The recently published results of the 18-month randomized controlled trial of lecanemab, reporting the efficacy of the drug in slowing the progression of early Alzheimer... (Comparative Study)
Comparative Study
The recently published results of the 18-month randomized controlled trial of lecanemab, reporting the efficacy of the drug in slowing the progression of early Alzheimer disease, quickly led to approval by the FDA and widespread acceptance of lecanemab treatment. However, there are a number of matters that deserve further consideration. The success of blinding was not assessed, even as infusion reactions and the cerebral pathology underlying amyloid-related imaging abnormalities could have signaled to many participants that they were on drug, potentially exerting a potent placebo effect. The value of the outcome to participants is not defined in the absolute terms necessary for clinical decision-making, and the difference attributable to lecanemab was between 18% and 46% of estimates of the minimal clinically important difference on the Clinical Dementia Rating Scale Sum of Boxes. The attenuation of change on the Alzheimer's Disease Assessment Scale-Cognitive 14 achieved by lecanemab at 18 months was 50% of that achieved by donepezil at 6 months. Lecanemab treatment imposes a high treatment burden. The fact that the burden commences at the initiation of lecanemab treatment, whereas the benefit accrues years later requires us to take into account value discounting over time, which would significantly reduce the benefit/burden ratio. Finally, treatment with monoclonal antibodies to cerebral amyloid has consistently been associated with progressive cerebral atrophy. At the least, these issues should be raised in treatment discussions with patients. They also suggest a need to very seriously reconsider how we evaluate clinical trial results preparatory to translating them into clinical practice. Some suggestions are provided.
Topics: Humans; Alzheimer Disease; Antibodies, Monoclonal, Humanized; Cognition; Donepezil; Randomized Controlled Trials as Topic
PubMed: 38484213
DOI: 10.1212/WNL.0000000000209320 -
Medicine and Science in Sports and... Oct 2023Our purpose was to examine the effects of 2 yr of creatine monohydrate supplementation and exercise on bone health in postmenopausal women. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Our purpose was to examine the effects of 2 yr of creatine monohydrate supplementation and exercise on bone health in postmenopausal women.
METHODS
Two hundred and thirty-seven postmenopausal women (mean age, 59 yr) were randomized to receive creatine (0.14 g·kg -1 ·d -1 ) or placebo during a resistance training (3 d·wk -1 ) and walking (6 d·wk -1 ) program for 2 yr. Our primary outcome was the femoral neck bone mineral density (BMD), with lumbar spine BMD and proximal femur geometric properties as the secondary outcomes.
RESULTS
Compared with placebo, creatine supplementation had no effect on BMD of the femoral neck (creatine: 0.725 ± 0.110 to 0.712 ± 0.100 g·cm -2 ; placebo: 0.721 ± 0.102 to 0.706 ± 0.097 g·cm -2 ), total hip (creatine: 0.879 ± 0.118 to 0.872 ± 0.114 g·cm -2 ; placebo: 0.881 ± 0.111 to 0.873 ± 0.109 g·cm -2 ), or lumbar spine (creatine: 0.932 ± 0.133 to 0.925 ± 0.131 g·cm -2 ; placebo: 0.923 ± 0.145 to 0.915 ± 0.143 g·cm -2 ). Creatine significantly maintained section modulus (1.35 ± 0.29 to 1.34 ± 0.26 vs 1.34 ± 0.25 to 1.28 ± 0.23 cm 3 (placebo), P = 0.0011), predictive of bone bending strength, and buckling ratio (10.8 ± 2.6 to 11.1 ± 2.2 vs 11.0 ± 2.6 to 11.6 ± 2.7 (placebo), P = 0.011), predictive of reduced cortical bending under compressive loads, at the narrow part of the femoral neck. Creatine reduced walking time over 80 m (48.6 ± 5.6 to 47.1 ± 5.4 vs 48.3 ± 4.5 to 48.2 ± 4.9 s (placebo), P = 0.0008) but had no effect on muscular strength (i.e., one-repetition maximum) during bench press (32.1 ± 12.7 to 42.6 ± 14.1 vs 30.6 ± 10.9 to 41.4 ± 14 kg (placebo)) and hack squat (57.6 ± 21.6 to 84.4 ± 28.1 vs 56.6 ± 24.0 to 82.7 ± 25.0 kg (placebo)). In the subanalysis of valid completers, creatine increased lean tissue mass compared with placebo (40.8 ± 5.7 to 43.1 ± 5.9 vs 40.4 ± 5.3 to 42.0 ± 5.2 kg (placebo), P = 0.046).
CONCLUSIONS
Two years of creatine supplementation and exercise in postmenopausal women had no effect on BMD; yet, it improved some bone geometric properties at the proximal femur.
Topics: Female; Humans; Middle Aged; Bone Density; Creatine; Postmenopause; Osteoporosis, Postmenopausal; Femur Neck; Dietary Supplements; Double-Blind Method
PubMed: 37144634
DOI: 10.1249/MSS.0000000000003202 -
The Journal of Clinical Psychiatry Oct 2023Some individuals with attention-deficit/hyperactivity disorder (ADHD) may not tolerate or adequately respond to currently available treatments. This study examined... (Randomized Controlled Trial)
Randomized Controlled Trial
Some individuals with attention-deficit/hyperactivity disorder (ADHD) may not tolerate or adequately respond to currently available treatments. This study examined whether solriamfetol could have a favorable pattern of effects and tolerability as a treatment for ADHD in adults. Sixty adults with ADHD participated from August 2021 through January 2023 in a remotely conducted, randomized, double-blind, placebo-controlled, 6-week dose-optimization trial of 75 mg or 150 mg of solriamfetol. Measures included the Adult ADHD Investigator Symptom Rating Scale (AISRS), which was our primary outcome measure, as well as the Clinical Global Impressions scale (CGI), vital signs, the Global Assessment of Functioning (GAF), the Behavior Rating Inventory of Executive Function-Adult Form (BRIEF-A), the Epworth Sleepiness Scale (ESS), the Pittsburgh Sleep Quality Index (PSQI), and a modified Adult ADHD Self-Report Scale (MASRS). Solriamfetol was well tolerated, with no significant effect on mean heart rate (+3.7 vs +2.2 bpm, = .5609), systolic blood pressure (+2.4 vs +1.5 mm Hg, = .6474), or diastolic blood pressure (+1.1 vs +1.5 mm Hg, = .8117). There was no statistically significant treatment effect on occurrence of adverse events. Compared to individuals on placebo, individuals on solriamfetol treatment experienced adverse events at a rate of at least 10 percentage points higher in the categories of decreased appetite, headache, gastrointestinal, insomnia, increased energy, cardiovascular, and neurologic. Compared to individuals on placebo, by study endpoint, a greater proportion of individuals in the treatment group met the a priori-defined treatment response (CGI score indicating much or very much improved and AISRS score reduced ≥ 25%: 45% vs 6.9%, = .0020); those treated with solriamfetol also had greater improvement in total AISRS scores by week 3 through week 6 ( = .0012; week 6 effect size = 1.09). Significantly more solriamfetol-treated adults than placebo-treated adults had 0.5-standard deviation improvement in T-score on the BRIEF-A Global Executive Composite ( = .0173); those treated with solriamfetol also had greater mean change in GAF score (-4.8 vs -0.3, = .0006) and greater mean MASRS total score change ( = .0047; effect size = 1.23). Mean ESS score improved more with solriamfetol than with placebo ( = .0056), but this difference did not predict AISRS response ( = .3735). There was no significant association between solriamfetol and change in PSQI scores. Solriamfetol may be a novel and effective treatment for the management of ADHD in adults. Further replication in larger trials is indicated. ClinicalTrials.gov identifier: NCT04839562.
Topics: Adult; Humans; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Pilot Projects; Dose-Response Relationship, Drug; Treatment Outcome; Double-Blind Method
PubMed: 37819836
DOI: 10.4088/JCP.23m14934 -
The Cochrane Database of Systematic... Oct 2023Pharmacological interventions are frequently used for people with autism spectrum disorder (ASD) to manage behaviours of concern, including irritability, aggression, and... (Review)
Review
BACKGROUND
Pharmacological interventions are frequently used for people with autism spectrum disorder (ASD) to manage behaviours of concern, including irritability, aggression, and self-injury. Some pharmacological interventions might help treat some behaviours of concern, but can also have adverse effects (AEs).
OBJECTIVES
To assess the effectiveness and AEs of pharmacological interventions for managing the behaviours of irritability, aggression, and self-injury in ASD.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, 11 other databases and two trials registers up to June 2022. We also searched reference lists of relevant studies, and contacted study authors, experts and pharmaceutical companies.
SELECTION CRITERIA
We included randomised controlled trials of participants of any age with a clinical diagnosis of ASD, that compared any pharmacological intervention to an alternative drug, standard care, placebo, or wait-list control.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Primary outcomes were behaviours of concern in ASD, (irritability, aggression and self-injury); and AEs. Secondary outcomes were quality of life, and tolerability and acceptability. Two review authors independently assessed each study for risk of bias, and used GRADE to judge the certainty of the evidence for each outcome.
MAIN RESULTS
We included 131 studies involving 7014 participants in this review. We identified 26 studies as awaiting classification and 25 as ongoing. Most studies involved children (53 studies involved only children under 13 years), children and adolescents (37 studies), adolescents only (2 studies) children and adults (16 studies), or adults only (23 studies). All included studies compared a pharmacological intervention to a placebo or to another pharmacological intervention. Atypical antipsychotics versus placebo At short-term follow-up (up to 6 months), atypical antipsychotics probably reduce irritability compared to placebo (standardised mean difference (SMD) -0.90, 95% confidence interval (CI) -1.25 to -0.55, 12 studies, 973 participants; moderate-certainty evidence), which may indicate a large effect. However, there was no clear evidence of a difference in aggression between groups (SMD -0.44, 95% CI -0.89 to 0.01; 1 study, 77 participants; very low-certainty evidence). Atypical antipsychotics may also reduce self-injury (SMD -1.43, 95% CI -2.24 to -0.61; 1 study, 30 participants; low-certainty evidence), possibly indicating a large effect. There may be higher rates of neurological AEs (dizziness, fatigue, sedation, somnolence, and tremor) in the intervention group (low-certainty evidence), but there was no clear evidence of an effect on other neurological AEs. Increased appetite may be higher in the intervention group (low-certainty evidence), but we found no clear evidence of an effect on other metabolic AEs. There was no clear evidence of differences between groups in musculoskeletal or psychological AEs. Neurohormones versus placebo At short-term follow-up, neurohormones may have minimal to no clear effect on irritability when compared to placebo (SMD -0.18, 95% CI -0.37 to -0.00; 8 studies; 466 participants; very low-certainty evidence), although the evidence is very uncertain. No data were reported for aggression or self -injury. Neurohormones may reduce the risk of headaches slightly in the intervention group, although the evidence is very uncertain. There was no clear evidence of an effect of neurohormones on any other neurological AEs, nor on any psychological, metabolic, or musculoskeletal AEs (low- and very low-certainty evidence). Attention-deficit hyperactivity disorder (ADHD)-related medications versus placebo At short-term follow-up, ADHD-related medications may reduce irritability slightly (SMD -0.20, 95% CI -0.40 to -0.01; 10 studies, 400 participants; low-certainty evidence), which may indicate a small effect. However, there was no clear evidence that ADHD-related medications have an effect on self-injury (SMD -0.62, 95% CI -1.63 to 0.39; 1 study, 16 participants; very low-certainty evidence). No data were reported for aggression. Rates of neurological AEs (drowsiness, emotional AEs, fatigue, headache, insomnia, and irritability), metabolic AEs (decreased appetite) and psychological AEs (depression) may be higher in the intervention group, although the evidence is very uncertain (very low-certainty evidence). There was no evidence of a difference between groups for any other metabolic, neurological, or psychological AEs (very low-certainty evidence). No data were reported for musculoskeletal AEs. Antidepressants versus placebo At short-term follow-up, there was no clear evidence that antidepressants have an effect on irritability (SMD -0.06, 95% CI -0.30 to 0.18; 3 studies, 267 participants; low-certainty evidence). No data for aggression or self-injury were reported or could be included in the analysis. Rates of metabolic AEs (decreased energy) may be higher in participants receiving antidepressants (very low-certainty evidence), although no other metabolic AEs showed clear evidence of a difference. Rates of neurological AEs (decreased attention) and psychological AEs (impulsive behaviour and stereotypy) may also be higher in the intervention group (very low-certainty evidence) although the evidence is very uncertain. There was no clear evidence of any difference in the other metabolic, neurological, or psychological AEs (very low-certainty evidence), nor between groups in musculoskeletal AEs (very low-certainty evidence). Risk of bias We rated most of the studies across the four comparisons at unclear overall risk of bias due to having multiple domains rated as unclear, very few rated as low across all domains, and most having at least one domain rated as high risk of bias.
AUTHORS' CONCLUSIONS
Evidence suggests that atypical antipsychotics probably reduce irritability, ADHD-related medications may reduce irritability slightly, and neurohormones may have little to no effect on irritability in the short term in people with ASD. There was some evidence that atypical antipsychotics may reduce self-injury in the short term, although the evidence is uncertain. There was no clear evidence that antidepressants had an effect on irritability. There was also little to no difference in aggression between atypical antipsychotics and placebo, or self-injury between ADHD-related medications and placebo. However, there was some evidence that atypical antipsychotics may result in a large reduction in self-injury, although the evidence is uncertain. No data were reported (or could be used) for self-injury or aggression for neurohormones versus placebo. Studies reported a wide range of potential AEs. Atypical antipsychotics and ADHD-related medications in particular were associated with an increased risk of metabolic and neurological AEs, although the evidence is uncertain for atypical antipsychotics and very uncertain for ADHD-related medications. The other drug classes had minimal or no associated AEs.
Topics: Child; Adult; Adolescent; Humans; Autism Spectrum Disorder; Quality of Life; Antipsychotic Agents; Antidepressive Agents; Aggression; Self-Injurious Behavior; Fatigue; Neurotransmitter Agents
PubMed: 37811711
DOI: 10.1002/14651858.CD011769.pub2 -
Annual Review of Pharmacology and... Jan 2024Adverse nocebo responses can cause harm to patients and interfere with treatment adherence and effects in both clinic practice and clinical trials. Nocebo responses... (Review)
Review
Adverse nocebo responses can cause harm to patients and interfere with treatment adherence and effects in both clinic practice and clinical trials. Nocebo responses refer to negative outcomes to active medical treatments in clinical trials or practice that cannot be explained by the treatment's pharmacologic effects. Negative expectancies and nocebo effects are less known than placebo responses. Nocebo effects can be triggered by verbal suggestions, prior negative experiences, observation of others experiencing negative outcomes, and other contextual and environmental factors. As research advances over the years, mechanistic knowledge is accumulating on the neurobiological mechanisms of nocebo effects. This review summarizes studies on different facets of nocebo effects and responses and discusses clinical implications, ethical considerations, and future directions.
Topics: Humans; Nocebo Effect; Placebo Effect
PubMed: 37585661
DOI: 10.1146/annurev-pharmtox-022723-112425 -
Journal of the European Academy of... Dec 2023Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritic eczematous lesions. The effect of treatment withdrawal after response to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritic eczematous lesions. The effect of treatment withdrawal after response to upadacitinib oral treatment is not fully characterized.
OBJECTIVES
Assess the effect of upadacitinib withdrawal on skin clearance and itch improvement in adult patients with moderate-to-severe AD and evaluate the kinetics of recovery on rescue treatment.
METHODS
Data from a phase 2b randomized, placebo-controlled trial (NCT02925117) of upadacitinib in patients with moderate-to-severe AD were analysed. Patients were randomized 1:1:1:1 to receive upadacitinib 7.5 mg, 15 mg, 30 mg or placebo, and then at Week 16, patients were re-randomized 1:1 to receive the same dose of upadacitinib (upadacitinib 30 mg for patients initialized to placebo) or placebo. From Week 20, those who experienced loss of response defined as Eczema Area and Severity Index <50% improvement from baseline (EASI 50) received rescue treatment with upadacitinib 30 mg.
RESULTS
Patients who withdrew from upadacitinib experienced a rapid loss of skin clearance response, while those who switched from placebo to upadacitinib gained response. Loss of skin clearance response occurred within 4 weeks and worsening of itch occurred within 5 days. In patients who originally received placebo or a lower dose of upadacitinib leading to a loss of EASI response, rescue treatment with upadacitinib 30 mg resulted in rapid recovery or improvement of both skin and itch responses; most patients who were re-randomized to placebo achieved EASI 75 and IGA 0/1 by 8 weeks of rescue treatment. No new safety risks were observed.
CONCLUSIONS
Continuous treatment with upadacitinib is suggested to maintain skin clearance and antipruritic effects.
Topics: Adult; Humans; Dermatitis, Atopic; Treatment Outcome; Heterocyclic Compounds, 3-Ring; Pruritus; Retreatment; Double-Blind Method; Severity of Illness Index
PubMed: 37528500
DOI: 10.1111/jdv.19391 -
Veterinary Anaesthesia and Analgesia Sep 2023Bedinvetmab, a fully canine anti-nerve growth factor monoclonal antibody, was evaluated in dogs for control of osteoarthritis-related pain in a study conducted to...
A prospective, randomized, double-blind, placebo-controlled multisite, parallel-group field study in dogs with osteoarthritis conducted in the United States of America evaluating bedinvetmab, a canine anti-nerve growth factor monoclonal antibody.
OBJECTIVE
Bedinvetmab, a fully canine anti-nerve growth factor monoclonal antibody, was evaluated in dogs for control of osteoarthritis-related pain in a study conducted to support registration in the USA.
STUDY DESIGN
Randomized, double-blind, placebo-controlled, multicenter, parallel-group study.
ANIMALS
General practice client-owned dogs with osteoarthritis (n = 272).
METHODS
Dogs were block randomized 1:1 to placebo (saline, n = 137) or bedinvetmab (n = 135; 0.5-1.0 mg kg) administered subcutaneously, once monthly. The primary end point, day 28 Canine Brief Pain Inventory (CBPI) treatment success (TS), required pain severity score (PSS; 0-10) decrease ≥1 and pain interference score (PIS; 0-10) decrease ≥ 2. CBPI TS rates [and number needed to treat (NNT)], change in scores [and standardized effect size (ES)], change in quality of life (QoL) and bedinvetmab half-life were calculated.
RESULTS
Significant (p < 0.05) improvement with bedinvetmab over placebo occurred (days 28, 42, 56, 84) for CBPI TS. Of cases evaluable for day 28 CBPI TS (placebo, n = 131; bedinvetmab, n = 128), success rates were 36.6% and 47.4%, respectively (p = 0.0410) (NNT, 9.3; PSS and PIS ES, 0.3). CBPI TS increased after the second dose in both groups, plateaued for bedinvetmab at day 42 and decreased for placebo beginning day 84. Day 84 NNT (4.3), PSS (0.4) and PIS (0.5) showed continued improvement with monthly dosing. After the first dose, mean (± standard deviation) bedinvetmab half-life was 19.1 (8.3) days. Adverse events were similar between groups and not considered treatment-related. There was a significant effect of bedinvetmab versus placebo on all CBPI components (PIS, PSS, QoL).
CONCLUSIONS AND CLINICAL RELEVANCE
These results corroborated those previously reported and provide further support of safety and effectiveness of bedinvetmab (0.5-1.0 mg kg) administered subcutaneously at monthly intervals to dogs for control of osteoarthritis-related pain.
Topics: Dogs; Animals; Quality of Life; Prospective Studies; Dog Diseases; Osteoarthritis; Pain; Antibodies, Monoclonal; Double-Blind Method
PubMed: 37541934
DOI: 10.1016/j.vaa.2023.06.003