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BMJ Open Mar 2019To assess the methodological advantages and disadvantages of parallel and crossover designs in randomised clinical trials on methylphenidate for children and adolescents... (Meta-Analysis)
Meta-Analysis
Methodological advantages and disadvantages of parallel and crossover randomised clinical trials on methylphenidate for attention deficit hyperactivity disorder: a systematic review and meta-analyses.
OBJECTIVE
To assess the methodological advantages and disadvantages of parallel and crossover designs in randomised clinical trials on methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD).
DESIGN
Secondary analyses of a Cochrane systematic review.
SETTING AND PARTICIPANTS
We searched relevant databases up to March 2015 and included data from parallel and crossover randomised trials assessing children and adolescents up to 18 years with ADHD.
INTERVENTIONS
Methylphenidate compared with placebo or no-treatment interventions.
PRIMARY AND SECONDARY OUTCOMES
The primary outcomes were teacher-rated ADHD symptoms and serious adverse events. The secondary outcomes were non-serious adverse events.
RESULTS
We included 38 parallel trials (n=5111) and 147 crossover trials (n=7134). When comparing methylphenidate with placebo or no-treatment on ADHD symptoms, we found no differences between the end of parallel trials and the first-period from crossover trials (Χ²=1.06, df=1, p=0.30, I²=5.5%). We also found no differences when combining the end of first-period crossover trials with the end of parallel trials and comparing them to the end of last-period crossover trials (Χ²=3.25, df=1, p=0.07, I²=69.2%). We found no differences in serious and non-serious adverse events, and no risk of period and carryover effects. However, only two trials contributed data to the latter analyses.
CONCLUSIONS
Both parallel and crossover trials seem suitable for investigating methylphenidate in children and adolescents with ADHD, with comparable estimates on ADHD symptom severity and adverse events. However, parallel trials might still offer ethical and statistical advantages over crossover trials.
Topics: Adolescent; Child; Female; Humans; Male; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Cross-Over Studies; Methylphenidate; Randomized Controlled Trials as Topic
PubMed: 30928951
DOI: 10.1136/bmjopen-2018-026478 -
The Cochrane Database of Systematic... Jan 2019Laparoscopy is a common procedure used to diagnose and treat various gynaecological conditions. Shoulder-tip pain (STP) as a result of the laparoscopy occurs in up to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Laparoscopy is a common procedure used to diagnose and treat various gynaecological conditions. Shoulder-tip pain (STP) as a result of the laparoscopy occurs in up to 80% of women, with potential for significant morbidity, delayed discharge and readmission. Interventions at the time of gynaecological laparoscopy have been developed in an attempt to reduce the incidence and severity of STP.
OBJECTIVES
To determine the effectiveness and safety of methods for reducing the incidence and severity of shoulder-tip pain (STP) following gynaecological laparoscopy.
SEARCH METHODS
We searched the following databases: Cochrane Gynaecology and Fertility (CGF) Specialised Register, the Cochrane Central Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO and CINAHL from inception to 8 August 2018. We also searched the reference lists of relevant articles and registers of ongoing trials.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of interventions used during or immediately after gynaecological laparoscopy to reduce the incidence or severity of STP.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Primary outcomes: incidence or severity of STP and adverse events of the interventions; secondary outcomes: analgesia usage, delay in discharge, readmission rates, quality-of-life scores and healthcare costs.
MAIN RESULTS
We included 32 studies (3284 women). Laparoscopic procedures in these studies varied from diagnostic procedures to complex operations. The quality of the evidence ranged from very low to moderate. The main limitations were risk of bias, imprecision and inconsistency.Specific technique versus "standard" technique for releasing the pneumoperitoneumUse of a specific technique of releasing the pneumoperitoneum (pulmonary recruitment manoeuvre, extended assisted ventilation or actively aspirating intra-abdominal gas) reduced the severity of STP at 24 hours (standardised mean difference (SMD) -0.66, 95% confidence interval (CI) -0.82 to -0.50; 5 RCTs; 670 participants; I = 0%, low-quality evidence) and reduced analgesia usage (SMD -0.53, 95% CI -0.70 to -0.35; 4 RCTs; 570 participants; I = 91%, low-quality evidence). There appeared to be little or no difference in the incidence of STP at 24 hours (odds ratio (OR) 0.87, 95% CI 0.41 to 1.82; 1 RCT; 118 participants; low-quality evidence).No adverse events occurred in the only study assessing this outcome.Fluid instillation versus no fluid instillationFluid instillation is probably associated with a reduction in STP incidence (OR 0.38, 95% CI 0.22 to 0.66; 2 RCTs; 220 participants; I = 0%, moderate-quality evidence) and severity (mean difference (MD) (0 to 10 visual analogue scale (VAS) scale) -2.27, 95% CI -3.06 to -1.48; 2 RCTs; 220 participants; I = 29%, moderate-quality evidence) at 24 hours, and may reduce analgesia usage (MD -12.02, 95% CI -23.97 to -0.06; 2 RCTs; 205 participants, low-quality evidence).No study measured adverse events.Intraperitoneal drain versus no intraperitoneal drainUsing an intraperitoneal drain may reduce the incidence of STP at 24 hours (OR 0.30, 95% CI 0.20 to 0.46; 3 RCTs; 417 participants; I = 90%, low-quality evidence) and may reduce analgesia use within 48 hours post-operatively (SMD -1.84, 95% CI -2.14 to -1.54; 2 RCTs; 253 participants; I = 90%). We are uncertain whether it reduces the severity of STP at 24 hours, as the evidence was very low quality (MD (0 to 10 VAS scale) -1.85, 95% CI -2.15 to -1.55; 3 RCTs; 320 participants; I = 70%).No study measured adverse events.Subdiaphragmatic intraperitoneal local anaesthetic versus control (no fluid instillation, normal saline or Ringer's lactate)There is probably little or no difference between the groups in incidence of STP (OR 0.72, 95% CI 0.42 to 1.23; 4 RCTs; 336 participants; I = 0%; moderate-quality evidence) and there may be no difference in STP severity (MD -1.13, 95% CI -2.52 to 0.26; 1 RCT; 50 participants; low-quality evidence), both measured at 24 hours. However, the intervention may reduce post-operative analgesia use (SMD-0.57, 95% CI -0.94 to -0.21; 2 RCTs; 129 participants; I = 51%, low-quality evidence).No adverse events occurred in any study.Local anaesthetic into peritoneal cavity (not subdiaphragmatic) versus normal salineLocal anaesthetic into the peritoneal cavity may reduce the incidence of STP at 4 to 8 hours post-operatively (OR 0.23, 95% CI 0.06 to 0.93; 2 RCTs; 157 participants; I = 56%; low-quality evidence). Our other outcomes of interest were not assessed.Warmed, or warmed and humidified CO versus unwarmed and unhumidified COThere may be no difference between these interventions in incidence of STP at 24 to 48 hours (OR 0.81 95% CI 0.45 to 1.49; 2 RCTs; 194 participants; I = 12%; low-quality evidence) or in analgesia usage within 48 hours (MD -4.97 mg morphine, 95% CI -11.25 to 1.31; 1 RCT; 95 participants; low-quality evidence); there is probably little or no difference in STP severity at 24 hours (MD (0 to 10 VAS scale) 0.11, 95% CI -0.75 to 0.97; 2 RCTs; 157 participants; I = 50%; moderate-quality evidence).No study measured adverse events.Gasless laparoscopy versus CO insufflationGasless laparoscopy may be associated with increased severity of STP within 72 hours post-operatively when compared with standard treatment (MD 3.8 (0 to 30 VAS scale), 95% CI 0.76 to 6.84; 1 RCT; 54 participants, low-quality evidence), and there may be no difference in the risk of adverse events (OR 2.56, 95% CI 0.25 to 26.28; 1 RCT; 54 participants; low-quality evidence).No study measured the incidence of STP.
AUTHORS' CONCLUSIONS
There is low to moderate-quality evidence that the following interventions are associated with a reduction in the incidence or severity, or both, of STP, or a reduction in analgesia requirements for women undergoing gynaecological laparoscopy: a specific technique for releasing the pneumoperitoneum; intraperitoneal fluid instillation; an intraperitoneal drain; and local anaesthetic applied to the peritoneal cavity (not subdiaphragmatic).There is low to moderate-quality evidence that subdiaphragmatic intraperitoneal local anaesthetic and warmed and humidified insufflating gas may not make a difference to the incidence or severity of STP.There is low-quality evidence that gasless laparoscopy may increase the severity of STP, compared with standard treatment.Few studies reported data on adverse events. Some potentially useful interventions have not been studied by RCTs of gynaecological laparoscopy.
Topics: Acetaminophen; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Carbon Dioxide; Diclofenac; Drainage; Female; Gynecologic Surgical Procedures; Gynecological Examination; Humans; Incidence; Insufflation; Laparoscopy; Meperidine; Pain Measurement; Pain, Procedural; Pirinitramide; Pneumoperitoneum; Randomized Controlled Trials as Topic; Shoulder Pain
PubMed: 30699235
DOI: 10.1002/14651858.CD011101.pub2 -
The Cochrane Database of Systematic... Oct 2018Benign prostatic hyperplasia (BPH) is a common condition in ageing men that may cause lower urinary tract symptoms (LUTS). Treatment aims are to relieve symptoms and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Benign prostatic hyperplasia (BPH) is a common condition in ageing men that may cause lower urinary tract symptoms (LUTS). Treatment aims are to relieve symptoms and prevent disease-related complications. Naftopidil is an alpha-blocker (AB) that has a high affinity for the A1d receptor that may have advantages in treating LUTS in this setting. This is an update of a Cochrane Review first published in 2009. Since that time, several large randomised controlled trials (RCTs) have been reported, making this update relevant.
OBJECTIVES
To evaluate the effects of naftopidil for the treatment of LUTS associated with BPH.
SEARCH METHODS
We performed a comprehensive search using multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, LILAC, and Web of Science), trials registries, other sources of grey literature, and conference proceedings with no restrictions on the language of publication or publication status up to 31 May 2018 SELECTION CRITERIA: We included all parallel RCTs. We also included cross-over design trials.
DATA COLLECTION AND ANALYSIS
Two review authors independently classified and abstracted data from the included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. Primary outcomes were urological symptom scores, quality of life (QoL) and treatment withdrawals for any reason; secondary outcomes were treatment withdrawals due to adverse events, acute urinary retention, surgical intervention for BPH, and cardiovascular and sexual adverse events. We considered outcomes measured up to 12 months after randomisation as short term, and later than 12 months as long term. We rated the certainty of the evidence according to the GRADE approach.
MAIN RESULTS
We included 22 RCTs with 2223 randomised participants across four comparisons for short-term follow-up. This abstract focuses on only two of four comparisons for which we found data since two comparators (i.e. propiverine and Eviprostat (phytotherapy)) are rarely used. One study comparing naftopidil to placebo did not report any relevant outcomes and was therefore excluded. There were no trials that compared to combination therapy with naftopidil or any 5-alpha reductase inhibitors (5-ARIs) to combination therapy with other ABs and any 5-ARIs.All included studies were conducted in Asian countries. Study duration ranged from four to 12 weeks. Mean age was 67.8 years, prostate volume was 35.4 mL, and International Prostate Symptom Score was 18.3. We were unable to perform any of the preplanned subgroup analyses based on age and baseline symptom score.Naftopidil versus tamsulosinBased on 12 studies with 965 randomised participants, naftopidil may have resulted in little or no difference in urological symptom score (mean difference (MD) 0.47, 95% confidence interval (CI) -0.09 to 1.04 measured on a scale from 0 to 35 with higher score representing increased symptoms), QoL (MD 0.11, 95% CI -0.09 to 0.30; measured on a scale from 0 to 6 with higher scores representing worse QoL), and treatment withdrawals for any reason (risk ratio (RR) 0.92, 95% CI 0.64 to 1.34; corresponding to 7 fewer per 1000 participants, 95% CI 32 fewer to 31 more). Naftopidil may have resulted in little to no difference in sexual adverse events (RR 0.54, 95% CI 0.24 to 1.22); this would result in 26 fewer sexual adverse events per 1000 participants (95% CI 43 fewer to 13 more). We rated the certainty of evidence as moderate for urological symptom score and low for the other outcomes.Naftopidil versus silodosinBased on five studies with 652 randomised participants, naftopidil may have resulted in little or no difference in the urological symptom scores (MD 1.04, 95% CI -0.78 to 2.85), QoL (MD 0.21, 95% CI -0.23 to 0.66), and treatment withdrawals for any reason (RR 0.80, 95% CI 0.52 to 1.23; corresponding to 26 fewer per 1000 participants, 95% CI 62 fewer to 32 more). We rated the certainty of evidence as low for all these outcomes. Naftopidil likely reduced sexual adverse events (RR 0.15, 95% CI 0.06 to 0.42; corresponding to 126 fewer sexual adverse events per 1000 participants, 95% CI 139 fewer to 86 fewer). We rated the certainty of evidence as moderate for sexual adverse events.
AUTHORS' CONCLUSIONS
Naftopidil appears to have similar effects in the urological symptom scores and QoL compared to tamsulosin and silodosin. Naftopidil has similar sexual adverse events compared to tamsulosin but has fewer compared to silodosin.
Topics: Adrenergic alpha-Antagonists; Benzilates; Drug Combinations; Ethamsylate; Humans; Indoles; Lower Urinary Tract Symptoms; Male; Naphthalenes; Piperazines; Plant Extracts; Prostatic Hyperplasia; Prostatism; Quality of Life; Randomized Controlled Trials as Topic; Sulfonamides; Tamsulosin; Urological Agents
PubMed: 30306544
DOI: 10.1002/14651858.CD007360.pub3 -
The Cochrane Database of Systematic... Aug 2018Postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, reduces the incidence and severity of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, reduces the incidence and severity of opioid-induced adverse events (AEs).
OBJECTIVES
To assess the analgesic efficacy and adverse effects of single-dose intravenous diclofenac, compared with placebo or an active comparator, for moderate to severe postoperative pain in adults.
SEARCH METHODS
We searched the following databases without language restrictions: the Cochrane Central Register of Controlled Trials (Cochrane Register of Studies Online), MEDLINE, and Embase on 22 May 2018. We checked clinical trials registers and reference lists of retrieved articles for additional studies.
SELECTION CRITERIA
We included randomized trials that compared a single postoperative dose of intravenous diclofenac with placebo or another active treatment, for treating acute postoperative pain in adults following any surgery.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for review inclusion, assessed risk of bias, and extracted data.Our primary outcome was the number of participants in each arm achieving at least 50% pain relief over a four- and six-hour period.Our secondary outcomes were time to, and number of participants using rescue medication; withdrawals due to lack of efficacy, AEs, and for any cause; and number of participants experiencing any AE, serious AEs (SAEs), and NSAID-related AEs. We performed a post hoc analysis of opioid-related AEs, to enable indirect comparisons with other analyses of postoperative analgesics.For subgroup analysis, we planned to analyze different doses and formulations of parenteral diclofenac separately.We assessed the overall quality of the evidence for each outcome using GRADE and created two 'Summary of findings' tables.
MAIN RESULTS
We included eight studies, involving 1756 participants undergoing various surgeries (dental, mixed minor, abdominal, and orthopedic), with 20 to 175 participants receiving intravenous diclofenac in each study. Mean study population ages ranged from 24.5 years to 54.5 years. Intravenous diclofenac doses varied among and within studies, ranging from 3.75 mg to 75 mg. Five studies assessed newer formulations of parenteral diclofenac that could be administered as an undiluted intravenous bolus. Most studies had an unclear risk of bias for several domains and a high risk of bias due to small sample size. The overall quality of evidence for each outcome was generally low for reasons including unclear risk of bias in studies, imprecision, and low event numbers.Primary outcomeThree studies (277 participants) produced a number needed to treat for an additional beneficial outcome (NNTB) for at least 50% of maximum pain relief versus placebo of 2.4 (95% confidence interval (CI) 1.9 to 3.1) over four hours (low-quality evidence). Four studies (436 participants) produced an NNTB of 3.8 versus placebo (95% CI 2.9 to 5.9) over six hours (low-quality evidence). No studies provided data for the comparison of intravenous diclofenac with another NSAID over four hours. At six hours there was no difference between intravenous diclofenac and another NSAID (low-quality evidence).Secondary outcomesFor secondary efficacy outcomes, intravenous diclofenac was generally superior to placebo and similar to other NSAIDs.For time to rescue medication, comparison of intravenous diclofenac versus placebo demonstrated a median of 226 minutes for diclofenac versus 80 minutes for placebo (5 studies, 542 participants, low-quality evidence). There were insufficient data for pooled analysis for comparisons of diclofenac with another NSAID (very low-quality evidence).For the number of participants using rescue medication, two studies (235 participants) compared diclofenac with placebo. The number needed to treat to prevent one additional harmful event (NNTp) (here, the need for rescue medication) compared with placebo was 3.0 (2.2 to 4.5, low-quality evidence). The comparison of diclofenac with another NSAID included only one study (98 participants). The NNTp was 4.5 (2.5 to 33) for ketorolac versus diclofenac (very low-quality evidence).The numbers of participants withdrawing were generally low and inconsistently reported (very low-quality evidence). Participant withdrawals were: 6% (8/140) diclofenac versus 5% (7/128) placebo, and 9% (8/87) diclofenac versus 7% (6/82) another NSAID for lack of efficacy; 2% (4/211) diclofenac versus 0% (0/198) placebo, and 3% (4/138) diclofenac versus 2% (2/129) another NSAID due to AEs; and 11% (21/191) diclofenac versus 17% (30/179) placebo, and 18% (21/118) diclofenac versus 15% (17/111) another NSAID for any cause.Overall adverse event rates were similar between intravenous diclofenac and placebo (71% in both groups, 2 studies, 296 participants) and between intravenous diclofenac and another NSAID (55% and 58%, respectively, 2 studies, 265 participants) (low-quality evidence for both comparisons). Serious and specific AEs were rare, preventing meta-analysis.There were sufficient data for a dose-effect analysis for our primary outcome for only one alternative dose, 18.75 mg. Analysis of the highest dose employed in each study demonstrated a relative benefit compared with placebo of 1.9 (1.4 to 2.4), whereas for the group receiving 18.75 mg, the relative benefit versus placebo was 1.6 (1.2 to 2.1, 2 studies). Compared to another NSAID, the high-dose analysis demonstrated a relative benefit of 0.9 (0.8 to 1.1), for the group receiving 18.75 mg, the relative benefit was 0.78 (0.65 to 0.93). For direct comparison of high dose versus 18.75 mg, the proportion of participants with at least 50% pain relief was 66% (90/137) for the high-dose arm versus 57% (77/135) in the low-dose arm. There were insufficient data for subgroup meta-analysis of different diclofenac formulations.
AUTHORS' CONCLUSIONS
The amount and quality of evidence for the use of intravenous diclofenac as a treatment for postoperative pain is low. The available evidence indicates that postoperative intravenous diclofenac administration offers good pain relief for the majority of patients, but further research may impact this estimate. Adverse events appear to occur at a similar rate to other NSAIDs. Insufficient information is available to assess whether intravenous diclofenac has a different rate of bleeding, renal dysfunction, or cardiovascular events versus other NSAIDs. There was insufficient information to evaluate the efficacy and safety of newer versus traditional formulations of intravenous diclofenac. There was a lack of studies in major and cardiovascular surgeries and in elderly populations, which may be at increased risk for adverse events.
Topics: Acute Pain; Adult; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Humans; Injections, Intravenous; Pain, Postoperative; Placebos; Randomized Controlled Trials as Topic
PubMed: 30153336
DOI: 10.1002/14651858.CD012498.pub2 -
International Journal of Environmental... Aug 2018: This meta-analysis aims to study the effects of atomoxetine and methylphenidate on heart rate (HR), systolic blood pressure (SBP), and a number of adverse cardiac... (Meta-Analysis)
Meta-Analysis
The Effect of Methylphenidate and Atomoxetine on Heart Rate and Systolic Blood Pressure in Young People and Adults with Attention-Deficit Hyperactivity Disorder (ADHD): Systematic Review, Meta-Analysis, and Meta-Regression.
UNLABELLED
: This meta-analysis aims to study the effects of atomoxetine and methylphenidate on heart rate (HR), systolic blood pressure (SBP), and a number of adverse cardiac events on patients receiving treatment for attention-deficit hyperactive disorder (ADHD) in comparison to placebo and between atomoxetine and methylphenidate. : We searched the following databases: PubMed, EMBASE, and ScienceDirect. Meta-analysis was performed on studies that examined the relationships between methylphenidate or atomoxetine and HR, SBP, as well as a number of adverse cardiac events. These studies were either placebo-controlled or comparison studies between methylphenidate and atomoxetine. Meta-regression identified patient- and treatment-related factors that may contribute to heterogeneity. : Twenty-two studies were included and the total number of participants was 46,107. Children/adolescents and adults treated with methylphenidate had more significant increases in post- vs. pre-treatment HR (p < 0.001) and SBP (p < 0.001) than those treated by placebo. Children and adolescents treated with atomoxetine had more significant increases post- vs. pre-treatment HR (p = 0.025) and SBP (p < 0.001) than those treated with methylphenidate. Meta-regression revealed mean age of participants, mean dose, and duration of atomoxetine and methylphenidate as significant moderators that explained heterogeneity. There were no differences in the number of adverse cardiac events between participants with methylphenidate treatment and placebo or atomoxetine.
CONCLUSIONS
Children/adolescents and adults treated with methylphenidate resulted in significant increases in post- vs. pre-treatment HR and SBP as compared to placebo. Similarly, children and adolescents treated with atomoxetine had significant increases in post- vs. pre-treatment HR and SBP than those treated with methylphenidate. These findings have potential implications for continuous monitoring of HR and SBP throughout the course of treatment although the risk for adverse cardiac events were insignificant.
Topics: Adolescent; Adult; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Blood Pressure; Central Nervous System Stimulants; Child; Heart Rate; Humans; Methylphenidate
PubMed: 30127314
DOI: 10.3390/ijerph15081789 -
The Lancet. Psychiatry Sep 2018The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are... (Comparative Study)
Comparative Study Meta-Analysis
Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis.
BACKGROUND
The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults.
METHODS
We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976.
FINDINGS
133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD -1·02, 95% CI -1·19 to -0·85 for amphetamines, -0·78, -0·93 to -0·62 for methylphenidate, -0·56, -0·66 to -0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD -0·82, 95% CI -1·16 to -0·48) and modafinil (-0·76, -1·15 to -0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD -0·79, 95% CI -0·99 to -0·58), methylphenidate (-0·49, -0·64 to -0·35), bupropion (-0·46, -0·85 to -0·07), and atomoxetine (-0·45, -0·58 to -0·32), but not modafinil (0·16, -0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36-3·89) and adults (3·26, 1·54-6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20-5·81); and atomoxetine (2·33, 1·28-4·25), methylphenidate (2·39, 1·40-4·08), and modafinil (4·01, 1·42-11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs -0·46 to -0·24) and adults (-0·94 to -0·29). We did not find sufficient data for the 26-week and 52-week timepoints.
INTERPRETATION
Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs.
FUNDING
Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.
Topics: Adolescent; Adrenergic alpha-2 Receptor Agonists; Adult; Attention Deficit Disorder with Hyperactivity; Bupropion; Central Nervous System Stimulants; Child; Clonidine; Dose-Response Relationship, Drug; Humans; Methylphenidate; Network Meta-Analysis; Randomized Controlled Trials as Topic
PubMed: 30097390
DOI: 10.1016/S2215-0366(18)30269-4 -
The Cochrane Database of Systematic... Jun 2018This is an update of the original Cochrane Review published in Issue 4, 2011.Attention deficit hyperactivity disorder (ADHD) is the most prevalent of the comorbid... (Review)
Review
BACKGROUND
This is an update of the original Cochrane Review published in Issue 4, 2011.Attention deficit hyperactivity disorder (ADHD) is the most prevalent of the comorbid psychiatric disorders that complicate tic disorders. Medications commonly used to treat ADHD symptoms include stimulants such as methylphenidate and amphetamine; non-stimulants, such as atomoxetine; tricyclic antidepressants; and alpha agonists. Alpha agonists are also used as a treatment for tics. Due to the impact of ADHD symptoms on the child with tic disorder, treatment of ADHD is often of greater priority than the medical management of tics. However, for many decades, clinicians have been reluctant to use stimulants to treat children with ADHD and tics for fear of worsening their tics. OBJECTIVES: To assess the effects of pharmacological treatments for ADHD in children with comorbid tic disorders on symptoms of ADHD and tics.
SEARCH METHODS
In September 2017, we searched CENTRAL, MEDLINE, Embase, and 12 other databases. We also searched two trial registers and contacted experts in the field for any ongoing or unpublished studies.
SELECTION CRITERIA
We included randomized, double-blind, controlled trials of any pharmacological treatment for ADHD used specifically in children with comorbid tic disorders. We included both parallel-group and cross-over study designs.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures of Cochrane, in that two review authors independently selected studies, extracted data using standardized forms, assessed risk of bias, and graded the overall quality of the evidence by using the GRADE approach.
MAIN RESULTS
We included eight randomized controlled trials (four of which were cross-over trials) with 510 participants (443 boys, 67 girls) in this review. Participants in these studies were children with both ADHD and a chronic tic disorder. All studies took place in the USA and ranged from three to 22 weeks in duration. Five of the eight studies were funded by charitable organizations or government agencies, or both. One study was funded by the drug manufacturer. The other two studies did not specify the source of funding. Risk of bias of included studies was low for blinding; low or unclear for random sequence generation, allocation concealment, and attrition bias; and low or high for selective outcome reporting. We were unable to combine any of the studies in a meta-analysis due to important clinical heterogeneity and unit-of-analysis issues.Several of the trials assessed multiple agents. Medications assessed included methylphenidate, clonidine, desipramine, dextroamphetamine, guanfacine, atomoxetine, and deprenyl. There was low-quality evidence for methylphenidate, atomoxetine, and clonidine, and very low-quality evidence for desipramine, dextroamphetamine, guanfacine and deprenyl in the treatment of ADHD in children with tics. All studies, with the exception of a study using deprenyl, reported improvement in symptoms of ADHD. Tic symptoms also improved in children treated with guanfacine, desipramine, methylphenidate, clonidine, and a combination of methylphenidate and clonidine. In one study, tics limited further dosage increases of methylphenidate. High-dose dextroamphetamine appeared to worsen tics in one study, although the length of this study was limited to three weeks. There was appetite suppression or weight loss in association with methylphenidate, dextroamphetamine, atomoxetine, and desipramine. There was insomnia associated with methylphenidate and dextroamphetamine, and sedation associated with clonidine.
AUTHORS' CONCLUSIONS
Following an updated search of potentially relevant studies, we found no new studies that matched our inclusion criteria and thus our conclusions have not changed.Methylphenidate, clonidine, guanfacine, desipramine, and atomoxetine appear to reduce ADHD symptoms in children with tics though the quality of the available evidence was low to very low. Although stimulants have not been shown to worsen tics in most people with tic disorders, they may, nonetheless, exacerbate tics in individual cases. In these instances, treatment with alpha agonists or atomoxetine may be an alternative. Although there is evidence that desipramine may improve tics and ADHD in children, safety concerns will likely continue to limit its use in this population.
Topics: Adolescent; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Child, Preschool; Clonidine; Desipramine; Dextroamphetamine; Female; Guanfacine; Humans; Male; Methylphenidate; Randomized Controlled Trials as Topic; Selegiline; Tic Disorders
PubMed: 29944175
DOI: 10.1002/14651858.CD007990.pub3 -
The Cochrane Database of Systematic... May 2018Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. The psychostimulant methylphenidate is the most frequently used... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. The psychostimulant methylphenidate is the most frequently used medication to treat it. Several studies have investigated the benefits of methylphenidate, showing possible favourable effects on ADHD symptoms, but the true magnitude of the effect is unknown. Concerning adverse events associated with the treatment, our systematic review of randomised clinical trials (RCTs) demonstrated no increase in serious adverse events, but a high proportion of participants suffered a range of non-serious adverse events.
OBJECTIVES
To assess the adverse events associated with methylphenidate treatment for children and adolescents with ADHD in non-randomised studies.
SEARCH METHODS
In January 2016, we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 12 other databases and two trials registers. We also checked reference lists and contacted authors and pharmaceutical companies to identify additional studies.
SELECTION CRITERIA
We included non-randomised study designs. These comprised comparative and non-comparative cohort studies, patient-control studies, patient reports/series and cross-sectional studies of methylphenidate administered at any dosage or formulation. We also included methylphenidate groups from RCTs assessing methylphenidate versus other interventions for ADHD as well as data from follow-up periods in RCTs. Participants had to have an ADHD diagnosis (from the 3rd to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders or the 9th or 10th edition of theInternational Classification of Diseases, with or without comorbid diagnoses. We required that at least 75% of participants had a normal intellectual capacity (intelligence quotient of more than 70 points) and were aged below 20 years. We excluded studies that used another ADHD drug as a co-intervention.
DATA COLLECTION AND ANALYSIS
Fourteen review authors selected studies independently. Two review authors assessed risk of bias independently using the ROBINS-I tool for assessing risk of bias in non-randomised studies of interventions. All review authors extracted data. We defined serious adverse events according to the International Committee of Harmonization as any lethal, life-threatening or life-changing event. We considered all other adverse events to be non-serious adverse events and conducted meta-analyses of data from comparative studies. We calculated meta-analytic estimates of prevalence from non-comparative cohorts studies and synthesised data from patient reports/series qualitatively. We investigated heterogeneity by conducting subgroup analyses, and we also conducted sensitivity analyses.
MAIN RESULTS
We included a total of 260 studies: 7 comparative cohort studies, 6 of which compared 968 patients who were exposed to methylphenidate to 166 controls, and 1 which assessed 1224 patients that were exposed or not exposed to methylphenidate during different time periods; 4 patient-control studies (53,192 exposed to methylphenidate and 19,906 controls); 177 non-comparative cohort studies (2,207,751 participants); 2 cross-sectional studies (96 participants) and 70 patient reports/series (206 participants). Participants' ages ranged from 3 years to 20 years. Risk of bias in the included comparative studies ranged from moderate to critical, with most studies showing critical risk of bias. We evaluated all non-comparative studies at critical risk of bias. The GRADE quality rating of the evidence was very low.Primary outcomesIn the comparative studies, methylphenidate increased the risk ratio (RR) of serious adverse events (RR 1.36, 95% confidence interval (CI) 1.17 to 1.57; 2 studies, 72,005 participants); any psychotic disorder (RR 1.36, 95% CI 1.17 to 1.57; 1 study, 71,771 participants); and arrhythmia (RR 1.61, 95% CI 1.48 to 1.74; 1 study, 1224 participants) compared to no intervention.In the non-comparative cohort studies, the proportion of participants on methylphenidate experiencing any serious adverse event was 1.20% (95% CI 0.70% to 2.00%; 50 studies, 162,422 participants). Withdrawal from methylphenidate due to any serious adverse events occurred in 1.20% (95% CI 0.60% to 2.30%; 7 studies, 1173 participants) and adverse events of unknown severity led to withdrawal in 7.30% of participants (95% CI 5.30% to 10.0%; 22 studies, 3708 participants).Secondary outcomesIn the comparative studies, methylphenidate, compared to no intervention, increased the RR of insomnia and sleep problems (RR 2.58, 95% CI 1.24 to 5.34; 3 studies, 425 participants) and decreased appetite (RR 15.06, 95% CI 2.12 to 106.83; 1 study, 335 participants).With non-comparative cohort studies, the proportion of participants on methylphenidate with any non-serious adverse events was 51.2% (95% CI 41.2% to 61.1%; 49 studies, 13,978 participants). These included difficulty falling asleep, 17.9% (95% CI 14.7% to 21.6%; 82 studies, 11,507 participants); headache, 14.4% (95% CI 11.3% to 18.3%; 90 studies, 13,469 participants); abdominal pain, 10.7% (95% CI 8.60% to 13.3%; 79 studies, 11,750 participants); and decreased appetite, 31.1% (95% CI 26.5% to 36.2%; 84 studies, 11,594 participants). Withdrawal of methylphenidate due to non-serious adverse events occurred in 6.20% (95% CI 4.80% to 7.90%; 37 studies, 7142 participants), and 16.2% were withdrawn for unknown reasons (95% CI 13.0% to 19.9%; 57 studies, 8340 participants).
AUTHORS' CONCLUSIONS
Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate. Our certainty in the evidence is very low, and accordingly, it is not possible to accurately estimate the actual risk of adverse events. It might be higher than reported here.Given the possible association between methylphenidate and the adverse events identified, it may be important to identify people who are most susceptible to adverse events. To do this we must undertake large-scale, high-quality RCTs, along with studies aimed at identifying responders and non-responders.
Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Child, Preschool; Humans; Methylphenidate; Non-Randomized Controlled Trials as Topic; Patient Dropouts; Young Adult
PubMed: 29744873
DOI: 10.1002/14651858.CD012069.pub2 -
The Cochrane Database of Systematic... May 2018Despite the high prevalence of apathy in Alzheimer's disease (AD), and its harmful effects, there are currently no therapies proven to treat this symptom. Recently, a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Despite the high prevalence of apathy in Alzheimer's disease (AD), and its harmful effects, there are currently no therapies proven to treat this symptom. Recently, a number of pharmacological therapies have been investigated as potential treatments for apathy in AD.
OBJECTIVES
Objective 1: To assess the safety and efficacy of pharmacotherapies for the treatment of apathy in Alzheimer's disease (AD).Objective 2: To assess the effect on apathy of pharmacotherapies investigated for other primary outcomes in the treatment of AD.
SEARCH METHODS
We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), MEDLINE, Embase, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov and the World Health Organization (WHO) portal, ICTRP on 17 May 2017.
SELECTION CRITERIA
Eligible studies were double-blind, randomized, placebo-controlled trials (RCTs) investigating apathy as a primary or secondary outcome in people with AD.
DATA COLLECTION AND ANALYSIS
Three review authors extracted data. We assessed the risks of bias of included studies using Cochrane methods, and the overall quality of evidence for each outcome using GRADE methods. We calculated mean difference (MD), standardized mean difference (SMD) or risk ratio (RR) with 95% confidence intervals on an intention-to-treat basis for all relevant outcome measures.
MAIN RESULTS
We included 21 studies involving a total of 6384 participants in the quantitative analyses. Risk of bias is very low to moderate. All studies reported appropriate methods of randomization and blinding. Most studies reported appropriate methods of allocation concealment. Four studies, three with methylphenidate and one with modafinil, had a primary aim of improving apathy. In these studies, all participants had clinically significant apathy at baseline. Methylphenidate may improve apathy compared to placebo. This finding was present when apathy was assessed using the apathy evaluation scale (AES), which was used by all three studies investigating methylphenidate: MD -4.99, 95% CI -9.55 to -0.43, n = 145, 3 studies, low quality of evidence, but not when assessed with the neuropsychiatric inventory (NPI)-apathy subscale, which was used by two of the three studies investigating methylphenidate: MD -0.08, 95% CI -3.85 to 3.69, n = 85, 2 studies, low quality of evidence. As well as having potential benefits for apathy, methylphenidate probably also slightly improves cognition (MD 1.98, 95% CI 1.06 to 2.91, n = 145, 3 studies, moderate quality of evidence), and probably improves instrumental activities of daily living (MD 2.30, 95% CI 0.74 to 3.86, P = 0.004, n = 60, 1 study, moderate quality of evidence), compared to placebo. There may be no difference between methylphenidate and placebo in the risk of developing an adverse event: RR 1.28, 95% CI 0.67 to 2.42, n = 145, 3 studies, low quality of evidence. There was insufficient evidence from one very small study of modafinil to determine the effect of modafinil on apathy assessed with the FrSBe-apathy subscale: MD 0.27, 95% CI -3.51 to 4.05, n = 22, 1 study, low quality of evidence. In all other included studies, apathy was a secondary outcome and participants were not selected on the basis of clinically significant apathy at baseline. We considered the evidence on apathy from these studies to be indirect and associated with publication bias. There was low or very low quality of evidence on cholinesterase inhibitors (ChEIs) (six studies), ChEI discontinuation (one study), antipsychotics (two studies), antipsychotic discontinuation (one study), antidepressants (two studies), mibampator (one study), valproate (three studies) and semagacestat (one study).
AUTHORS' CONCLUSIONS
Methylphenidate may demonstrate a benefit for apathy and may have slight benefits for cognition and functional performance in people with AD, but this finding is associated with low-quality evidence. Our meta-analysis is limited by the small number of studies within each drug class, risk of bias, publication bias, imprecision and inconsistency between studies. Additional studies should be encouraged targeting people with AD with clinically significant apathy which investigate apathy as a primary outcome measure, and which have a longer duration and a larger sample size. This could increase the quality of evidence for methylphenidate, and may confirm whether or not it is an effective pharmacotherapy for apathy in AD.
Topics: Alanine; Alzheimer Disease; Antidepressive Agents; Apathy; Azepines; Benzhydryl Compounds; Biphenyl Compounds; Central Nervous System Stimulants; Cholinesterase Inhibitors; Humans; Methylphenidate; Modafinil; Randomized Controlled Trials as Topic; Sulfonamides; Valproic Acid
PubMed: 29727467
DOI: 10.1002/14651858.CD012197.pub2 -
Current Oncology (Toronto, Ont.) Apr 2018Our objective was to determine whether, compared with control interventions, pharmacologic interventions reduce the severity of fatigue in patients with cancer or... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Our objective was to determine whether, compared with control interventions, pharmacologic interventions reduce the severity of fatigue in patients with cancer or recipients of hematopoietic stem-cell transplantation (hsct).
METHODS
For a systematic review, we searched medline, embase, the Cochrane Central Register of Controlled Trials, cinahl, and Psychinfo for randomized trials of systemic pharmacologic interventions for the management of fatigue in patients with cancer or recipients of hsct. Two authors independently identified studies and abstracted data. Methodologic quality was assessed using the Cochrane Risk of Bias tool. The primary outcome was fatigue severity measured using various fatigue scales. Data were synthesized using random-effects models.
RESULTS
In the 117 included trials (19,819 patients), the pharmacologic agents used were erythropoietins ( = 31), stimulants ( = 19), l-carnitine ( = 6), corticosteroids ( = 5), antidepressants ( = 5), appetite stimulants ( = 3), and other agents ( = 48). Fatigue was significantly reduced with erythropoietin [standardized mean difference (smd): -0.52; 95% confidence interval (ci): -0.89 to -0.14] and with methylphenidate (smd: -0.36; 95% ci: -0.56 to -0.15); modafinil (or armodafinil) and corticosteroids were not effective.
CONCLUSIONS
Erythropoietin and methylphenidate significantly reduced fatigue severity in patients with cancer and in recipients of hsct. Concerns about the safety of those agents might limit their usefulness. Future research should identify effective interventions for fatigue that have minimal adverse effects.
Topics: Central Nervous System Stimulants; Erythropoietin; Fatigue; Hematopoietic Stem Cell Transplantation; Humans; Methylphenidate; Neoplasms; Severity of Illness Index
PubMed: 29719440
DOI: 10.3747/co.25.3883