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The Cochrane Database of Systematic... Oct 2020Postoperative nausea and vomiting (PONV) is a common adverse effect of anaesthesia and surgery. Up to 80% of patients may be affected. These outcomes are a major cause... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Postoperative nausea and vomiting (PONV) is a common adverse effect of anaesthesia and surgery. Up to 80% of patients may be affected. These outcomes are a major cause of patient dissatisfaction and may lead to prolonged hospital stay and higher costs of care along with more severe complications. Many antiemetic drugs are available for prophylaxis. They have various mechanisms of action and side effects, but there is still uncertainty about which drugs are most effective with the fewest side effects.
OBJECTIVES
• To compare the efficacy and safety of different prophylactic pharmacologic interventions (antiemetic drugs) against no treatment, against placebo, or against each other (as monotherapy or combination prophylaxis) for prevention of postoperative nausea and vomiting in adults undergoing any type of surgery under general anaesthesia • To generate a clinically useful ranking of antiemetic drugs (monotherapy and combination prophylaxis) based on efficacy and safety • To identify the best dose or dose range of antiemetic drugs in terms of efficacy and safety SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and reference lists of relevant systematic reviews. The first search was performed in November 2017 and was updated in April 2020. In the update of the search, 39 eligible studies were found that were not included in the analysis (listed as awaiting classification).
SELECTION CRITERIA
Randomized controlled trials (RCTs) comparing effectiveness or side effects of single antiemetic drugs in any dose or combination against each other or against an inactive control in adults undergoing any type of surgery under general anaesthesia. All antiemetic drugs belonged to one of the following substance classes: 5-HT₃ receptor antagonists, D₂ receptor antagonists, NK₁ receptor antagonists, corticosteroids, antihistamines, and anticholinergics. No language restrictions were applied. Abstract publications were excluded.
DATA COLLECTION AND ANALYSIS
A review team of 11 authors independently assessed trials for inclusion and risk of bias and subsequently extracted data. We performed pair-wise meta-analyses for drugs of direct interest (amisulpride, aprepitant, casopitant, dexamethasone, dimenhydrinate, dolasetron, droperidol, fosaprepitant, granisetron, haloperidol, meclizine, methylprednisolone, metoclopramide, ondansetron, palonosetron, perphenazine, promethazine, ramosetron, rolapitant, scopolamine, and tropisetron) compared to placebo (inactive control). We performed network meta-analyses (NMAs) to estimate the relative effects and ranking (with placebo as reference) of all available single drugs and combinations. Primary outcomes were vomiting within 24 hours postoperatively, serious adverse events (SAEs), and any adverse event (AE). Secondary outcomes were drug class-specific side effects (e.g. headache), mortality, early and late vomiting, nausea, and complete response. We performed subgroup network meta-analysis with dose of drugs as a moderator variable using dose ranges based on previous consensus recommendations. We assessed certainty of evidence of NMA treatment effects for all primary outcomes and drug class-specific side effects according to GRADE (CINeMA, Confidence in Network Meta-Analysis). We restricted GRADE assessment to single drugs of direct interest compared to placebo.
MAIN RESULTS
We included 585 studies (97,516 randomized participants). Most of these studies were small (median sample size of 100); they were published between 1965 and 2017 and were primarily conducted in Asia (51%), Europe (25%), and North America (16%). Mean age of the overall population was 42 years. Most participants were women (83%), had American Society of Anesthesiologists (ASA) physical status I and II (70%), received perioperative opioids (88%), and underwent gynaecologic (32%) or gastrointestinal surgery (19%) under general anaesthesia using volatile anaesthetics (88%). In this review, 44 single drugs and 51 drug combinations were compared. Most studies investigated only single drugs (72%) and included an inactive control arm (66%). The three most investigated single drugs in this review were ondansetron (246 studies), dexamethasone (120 studies), and droperidol (97 studies). Almost all studies (89%) reported at least one efficacy outcome relevant for this review. However, only 56% reported at least one relevant safety outcome. Altogether, 157 studies (27%) were assessed as having overall low risk of bias, 101 studies (17%) overall high risk of bias, and 327 studies (56%) overall unclear risk of bias. Vomiting within 24 hours postoperatively Relative effects from NMA for vomiting within 24 hours (282 RCTs, 50,812 participants, 28 single drugs, and 36 drug combinations) suggest that 29 out of 36 drug combinations and 10 out of 28 single drugs showed a clinically important benefit (defined as the upper end of the 95% confidence interval (CI) below a risk ratio (RR) of 0.8) compared to placebo. Combinations of drugs were generally more effective than single drugs in preventing vomiting. However, single NK₁ receptor antagonists showed treatment effects similar to most of the drug combinations. High-certainty evidence suggests that the following single drugs reduce vomiting (ordered by decreasing efficacy): aprepitant (RR 0.26, 95% CI 0.18 to 0.38, high certainty, rank 3/28 of single drugs); ramosetron (RR 0.44, 95% CI 0.32 to 0.59, high certainty, rank 5/28); granisetron (RR 0.45, 95% CI 0.38 to 0.54, high certainty, rank 6/28); dexamethasone (RR 0.51, 95% CI 0.44 to 0.57, high certainty, rank 8/28); and ondansetron (RR 0.55, 95% CI 0.51 to 0.60, high certainty, rank 13/28). Moderate-certainty evidence suggests that the following single drugs probably reduce vomiting: fosaprepitant (RR 0.06, 95% CI 0.02 to 0.21, moderate certainty, rank 1/28) and droperidol (RR 0.61, 95% CI 0.54 to 0.69, moderate certainty, rank 20/28). Recommended and high doses of granisetron, dexamethasone, ondansetron, and droperidol showed clinically important benefit, but low doses showed no clinically important benefit. Aprepitant was used mainly at high doses, ramosetron at recommended doses, and fosaprepitant at doses of 150 mg (with no dose recommendation available). Frequency of SAEs Twenty-eight RCTs were included in the NMA for SAEs (10,766 participants, 13 single drugs, and eight drug combinations). The certainty of evidence for SAEs when using one of the best and most reliable anti-vomiting drugs (aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, and droperidol compared to placebo) ranged from very low to low. Droperidol (RR 0.88, 95% CI 0.08 to 9.71, low certainty, rank 6/13) may reduce SAEs. We are uncertain about the effects of aprepitant (RR 1.39, 95% CI 0.26 to 7.36, very low certainty, rank 11/13), ramosetron (RR 0.89, 95% CI 0.05 to 15.74, very low certainty, rank 7/13), granisetron (RR 1.21, 95% CI 0.11 to 13.15, very low certainty, rank 10/13), dexamethasone (RR 1.16, 95% CI 0.28 to 4.85, very low certainty, rank 9/13), and ondansetron (RR 1.62, 95% CI 0.32 to 8.10, very low certainty, rank 12/13). No studies reporting SAEs were available for fosaprepitant. Frequency of any AE Sixty-one RCTs were included in the NMA for any AE (19,423 participants, 15 single drugs, and 11 drug combinations). The certainty of evidence for any AE when using one of the best and most reliable anti-vomiting drugs (aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, and droperidol compared to placebo) ranged from very low to moderate. Granisetron (RR 0.92, 95% CI 0.80 to 1.05, moderate certainty, rank 7/15) probably has no or little effect on any AE. Dexamethasone (RR 0.77, 95% CI 0.55 to 1.08, low certainty, rank 2/15) and droperidol (RR 0.89, 95% CI 0.81 to 0.98, low certainty, rank 6/15) may reduce any AE. Ondansetron (RR 0.95, 95% CI 0.88 to 1.01, low certainty, rank 9/15) may have little or no effect on any AE. We are uncertain about the effects of aprepitant (RR 0.87, 95% CI 0.78 to 0.97, very low certainty, rank 3/15) and ramosetron (RR 1.00, 95% CI 0.65 to 1.54, very low certainty, rank 11/15) on any AE. No studies reporting any AE were available for fosaprepitant. Class-specific side effects For class-specific side effects (headache, constipation, wound infection, extrapyramidal symptoms, sedation, arrhythmia, and QT prolongation) of relevant substances, the certainty of evidence for the best and most reliable anti-vomiting drugs mostly ranged from very low to low. Exceptions were that ondansetron probably increases headache (RR 1.16, 95% CI 1.06 to 1.28, moderate certainty, rank 18/23) and probably reduces sedation (RR 0.87, 95% CI 0.79 to 0.96, moderate certainty, rank 5/24) compared to placebo. The latter effect is limited to recommended and high doses of ondansetron. Droperidol probably reduces headache (RR 0.76, 95% CI 0.67 to 0.86, moderate certainty, rank 5/23) compared to placebo. We have high-certainty evidence that dexamethasone (RR 1.00, 95% CI 0.91 to 1.09, high certainty, rank 16/24) has no effect on sedation compared to placebo. No studies assessed substance class-specific side effects for fosaprepitant. Direction and magnitude of network effect estimates together with level of evidence certainty are graphically summarized for all pre-defined GRADE-relevant outcomes and all drugs of direct interest compared to placebo in http://doi.org/10.5281/zenodo.4066353.
AUTHORS' CONCLUSIONS
We found high-certainty evidence that five single drugs (aprepitant, ramosetron, granisetron, dexamethasone, and ondansetron) reduce vomiting, and moderate-certainty evidence that two other single drugs (fosaprepitant and droperidol) probably reduce vomiting, compared to placebo. Four of the six substance classes (5-HT₃ receptor antagonists, D₂ receptor antagonists, NK₁ receptor antagonists, and corticosteroids) were thus represented by at least one drug with important benefit for prevention of vomiting. Combinations of drugs were generally more effective than the corresponding single drugs in preventing vomiting. NK₁ receptor antagonists were the most effective drug class and had comparable efficacy to most of the drug combinations. 5-HT₃ receptor antagonists were the best studied substance class. For most of the single drugs of direct interest, we found only very low to low certainty evidence for safety outcomes such as occurrence of SAEs, any AE, and substance class-specific side effects. Recommended and high doses of granisetron, dexamethasone, ondansetron, and droperidol were more effective than low doses for prevention of vomiting. Dose dependency of side effects was rarely found due to the limited number of studies, except for the less sedating effect of recommended and high doses of ondansetron. The results of the review are transferable mainly to patients at higher risk of nausea and vomiting (i.e. healthy women undergoing inhalational anaesthesia and receiving perioperative opioids). Overall study quality was limited, but certainty assessments of effect estimates consider this limitation. No further efficacy studies are needed as there is evidence of moderate to high certainty for seven single drugs with relevant benefit for prevention of vomiting. However, additional studies are needed to investigate potential side effects of these drugs and to examine higher-risk patient populations (e.g. individuals with diabetes and heart disease).
Topics: Adult; Anesthesia, General; Antiemetics; Drug Therapy, Combination; Female; Humans; Male; Network Meta-Analysis; Placebos; Postoperative Nausea and Vomiting; Randomized Controlled Trials as Topic
PubMed: 33075160
DOI: 10.1002/14651858.CD012859.pub2 -
European Journal of Pain (London,... Aug 2021Together, neck pain and back pain are the first cause of disability worldwide, accounting for more than 10% of the total years lived with disability. In this context,... (Review)
Review
Together, neck pain and back pain are the first cause of disability worldwide, accounting for more than 10% of the total years lived with disability. In this context, chiropractic care provides a safe and effective option for the management of a large proportion of these patients. Chiropractic is a healthcare profession mainly focused on the spine and the treatment of spinal disorders, including spine pain. Basic studies have examined the influence of chiropractic spinal manipulation (SM) on a variety of peripheral, spinal and supraspinal mechanisms involved in spine pain. While spinal cord mechanisms of pain inhibition contribute at least partly to the pain-relieving effects of chiropractic treatments, the evidence is weaker regarding peripheral and supraspinal mechanisms, which are important components of acute and chronic pain. This narrative review highlights the most relevant mechanisms of pain relief by SM and provides a perspective for future research on SM and spine pain, including the validation of placebo interventions that control for placebo effects and other non-specific effects that may be induced by SM. SIGNIFICANCE: Spinal manipulation inhibits back and neck pain partly through spinal segmental mechanisms and potentially through peripheral mechanisms regulating inflammatory responses. Other mechanisms remain to be clarified. Controls and placebo interventions need to be improved in order to clarify the contribution of specific and non-specific effects to pain relief by spinal manipulative therapy.
Topics: Back Pain; Chiropractic; Humans; Manipulation, Chiropractic; Manipulation, Spinal; Neck Pain; Placebos
PubMed: 33786932
DOI: 10.1002/ejp.1773 -
Annals of the Rheumatic Diseases Jan 2022Randomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Randomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a humanised type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, with placebo for the treatment of LN in combination with standard therapies.
METHODS
Patients with LN receiving mycophenolate and corticosteroids were randomised to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint was complete renal response (CRR) at week 52. Exploratory analyses through week 104 were conducted. The prespecified alpha level was 0.2.
RESULTS
A total of 125 patients were randomised and received blinded infusions. Achievement of CRR was greater with obinutuzumab at week 52 (primary endpoint, 22 (35%) vs 14 (23%) with placebo; percentage difference, 12% (95% CI -3.4% to 28%), p=0.115) and at week 104 (26 (41%) vs 14 (23%); percentage difference, 19% (95% CI 2.7% to 35%), p=0.026). Improvements in other renal response measures, serologies, estimated glomerular filtration rate and proteinuria were greater with obinutuzumab. Obinutuzumab was not associated with increases in serious adverse events, serious infections or deaths. Non-serious infusion-related reactions occurred more frequently with obinutuzumab.
CONCLUSIONS
Improved renal responses through week 104 were observed in patients with LN who received obinutuzumab plus standard therapies compared with standard therapies alone. Obinutuzumab was well tolerated and no new safety signals were identified.
TRIAL REGISTRATION NUMBER
NCT02550652.
Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; B-Lymphocytes; Double-Blind Method; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Humans; Lupus Nephritis; Male; Mycophenolic Acid; Placebos; Treatment Outcome; Young Adult
PubMed: 34615636
DOI: 10.1136/annrheumdis-2021-220920 -
The New England Journal of Medicine Dec 2021Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares.
METHODS
In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (range, 0 [no visible pustules] to 4 [severe pustulation]) at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1; scores range from 0 to 4, with higher scores indicating greater disease severity.
RESULTS
A total of 53 patients were enrolled: 35 were assigned to receive spesolimab and 18 to receive placebo. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab.
CONCLUSIONS
In a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis. (Funded by Boehringer Ingelheim; Effisayil 1 ClinicalTrials.gov number, NCT03782792.).
Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Double-Blind Method; Female; Humans; Injections, Intravenous; Male; Middle Aged; Placebos; Psoriasis; Receptors, Interleukin; Severity of Illness Index; Symptom Flare Up
PubMed: 34936739
DOI: 10.1056/NEJMoa2111563 -
The Cochrane Database of Systematic... Feb 2021Belimumab, the first biologic approved for the treatment of systemic lupus erythematosus (SLE), has been shown to reduce autoantibody levels in people with SLE and help... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Belimumab, the first biologic approved for the treatment of systemic lupus erythematosus (SLE), has been shown to reduce autoantibody levels in people with SLE and help control disease activity.
OBJECTIVES
To assess the benefits and harms of belimumab (alone or in combination) in systematic lupus erythematosus.
SEARCH METHODS
An Information Specialist carried out the searches of CENTRAL, MEDLINE, Embase, CINAHL, Web of Science, the World Health Organization (WHO) International Clinical Trials Registry Platform, and clinicaltrials.gov from inception to 25 September 2019. There were no language or date restrictions.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) or controlled clinical trials (CCTs) of belimumab (alone or in combination) compared to placebo/control treatment (immunosuppressive drugs, such as azathioprine, cyclosporine, mycophenolate mofetil or another biologic), in adults with SLE.
DATA COLLECTION AND ANALYSIS
We used standard methodologic procedures expected by Cochrane.
MAIN RESULTS
Six RCTs (2917 participants) qualified for quantitative analyses. All included studies were multicenter, international or US-based. The age range of the included participants was 22 to 80 years; most were women; and study duration ranged from 84 days to 76 weeks. The risk of bias was generally low except for attrition bias, which was high in 67% of studies. Compared to placebo, more participants on belimumab 10 mg/kg (Food and Drug Administration (FDA)-approved dose) showed at least a 4-point improvement (reduction) in Safety of Estrogen in Lupus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, a validated SLE disease activity index: (risk ratio (RR) 1.33, 95% confidence interval (CI) 1.22 to 1.45; 829/1589 in belimumab group and 424/1077 in placebo; I= 0%; 4 RCTs; high-certainty evidence). Change in health-related quality of life (HRQOL), assessed by Short Form-36 Physical Component Summary score improvement (range 0 to 100), showed there was probably little or no difference between groups (mean difference 1.6 points, 95% CI 0.30 to 2.90; 401 in belimumab group and 400 in placebo; I= 0%; 2 RCTs; moderate-certainty evidence). The belimumab 10 mg/kg group showed greater improvement in glucocorticoid dose, with a higher proportion of participants reducing their dose by at least 50% compared to placebo (RR 1.59, 95% CI 1.17 to 2.15; 81/269 in belimumab group and 52/268 in placebo; I= 0%; 2 RCTs; high-certainty evidence). The proportion of participants experiencing harm may not differ meaningfully between the belimumab 10 mg/kg and placebo groups: one or more serious adverse event (RR 0.87, 95% CI: 0.68 to 1.11; 238/1700 in belimumab group and 199/1190 in placebo; I= 48%; 5 RCTs; low-certainty evidence; ); one or more serious infection (RR 1.01, 95% CI: 0.66 to 1.54; 44/1230 in belimumab group and 40/955 in placebo; I= 0%; 4 RCTs; moderate-certainty evidence); and withdrawals due to adverse events (RR 0.82, 95% CI: 0.63 to 1.07; 113/1700 in belimumab group and 94/1190 in placebo; I= 0%; 5 RCTs; moderate-certainty evidence). Mortality was rare, and may not differ between belimumab 10 mg/kg and placebo (Peto odds ratio 1.15, 95% CI 0.41 to 3.25; 9/1714 in belimumab group and 6/1203 in placebo; I= 4%; 6 RCTs; low-certainty evidence).
AUTHORS' CONCLUSIONS
The six studies that provided evidence for benefits and harms of belimumab were well-designed, high-quality RCTs. At the FDA-approved dose of 10 mg/kg, based on moderate to high-certainty data, belimumab was probably associated with a clinically meaningful efficacy benefit compared to placebo in participants with SLE at 52 weeks. Evidence related to harms is inconclusive and mostly of moderate to low-certainty evidence. More data are needed for the longer-term efficacy of belimumab.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Bias; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Placebos; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome; Young Adult
PubMed: 33631841
DOI: 10.1002/14651858.CD010668.pub2 -
BMC Palliative Care Dec 2019Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal... (Randomized Controlled Trial)
Randomized Controlled Trial
Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo controlled, randomised clinical trial of efficacy and safety of cannabidiol (CBD).
BACKGROUND
Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal cannabinoids, but there is little high quality evidence to guide clinicians. This study aims to define the role of cannabidiol (CBD) in the management of symptom burden in patients with advanced cancer undergoing standard palliative care.
METHODS AND DESIGN
This study is a multicentre, randomised, placebo controlled, two arm, parallel trial of escalating doses of oral CBD. It will compare efficacy and safety outcomes of a titrated dose of CBD (100 mg/mL formulation, dose range 50 mg to 600 mg per day) against placebo. There is a 2-week patient determined titration phase, using escalating doses of CBD or placebo to reach a dose that achieves symptom relief with tolerable side effects. This is then followed by a further 2-week assessment period on the stable dose determined in collaboration with clinicians.
DISCUSSION
A major strength of this study is that it will target symptom burden as a whole, rather than just individual symptoms, in an attempt to describe the general improvement in wellbeing previously reported by some patients in open label, non controlled trials of medicinal cannabis. Randomisation with placebo is essential because of the well-documented over reporting of benefit in uncontrolled trials and high placebo response rates in cancer pain trials. This will be the first placebo controlled clinical trial to evaluate rigorously the efficacy, safety and acceptability of CBD for symptom relief in advanced cancer patients. This study will provide the medical community with evidence to present to patients wishing to access medicinal cannabis for their cancer related symptoms.
TRIAL REGISTRATION NUMBER
ALCTRN12618001220257 Registered 20/07/2018.
Topics: Administration, Oral; Adult; Cannabidiol; Double-Blind Method; Female; Humans; Medical Marijuana; Middle Aged; Neoplasms; Palliative Care; Placebos; Syndrome
PubMed: 31810437
DOI: 10.1186/s12904-019-0494-6 -
The Cochrane Database of Systematic... Jun 2021Febrile seizures occurring in a child older than one month during an episode of fever affect 2-4% of children in Great Britain and the United States and recur in 30%.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Febrile seizures occurring in a child older than one month during an episode of fever affect 2-4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. This is an updated version of a Cochrane Review previously published in 2017.
OBJECTIVES
To evaluate primarily the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures; and also to evaluate any other drug intervention where there is a sound biological rationale for its use.
SEARCH METHODS
For the latest update we searched the following databases on 3 February 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 31 January 2020). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including the Cochrane Epilepsy Group. We imposed no language restrictions and contacted researchers to identify continuing or unpublished studies.
SELECTION CRITERIA
Trials using randomised or quasi-randomised participant allocation that compared the use of antiepileptics, antipyretics or recognised Central Nervous System active agents with each other, placebo, or no treatment.
DATA COLLECTION AND ANALYSIS
For the original review, two review authors independently applied predefined criteria to select trials for inclusion and extracted the predefined relevant data, recording methods for randomisation, blinding, and exclusions. For the 2016 update, a third review author checked all original inclusions, data analyses, and updated the search. For the 2020 update, one review author updated the search and performed the data analysis following a peer-review process with the original review authors. We assessed seizure recurrence at 6, 12, 18, 24, 36, 48 months, and where data were available at age 5 to 6 years along with recorded adverse effects. We evaluated the presence of publication bias using funnel plots.
MAIN RESULTS
We included 42 articles describing 32 randomised trials, with 4431 randomised participants used in the analysis of this review. We analysed 15 interventions of continuous or intermittent prophylaxis and their control treatments. Methodological quality was moderate to poor in most studies. We found no significant benefit for intermittent phenobarbital, phenytoin, valproate, pyridoxine, ibuprofen, or zinc sulfate versus placebo or no treatment; nor for diclofenac versus placebo followed by ibuprofen, paracetamol, or placebo; nor for continuous phenobarbital versus diazepam, intermittent rectal diazepam versus intermittent valproate, or oral diazepam versus clobazam. There was a significant reduction of recurrent febrile seizures with intermittent diazepam versus placebo or no treatment at six months (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.48 to 0.85; 6 studies, 1151 participants; moderate-certainty evidence), 12 months (RR 0.69, 95% CI 0.56 to 0.84; 8 studies, 1416 participants; moderate-certainty evidence), 18 months (RR 0.37, 95% CI 0.23 to 0.60; 1 study, 289 participants; low-certainty evidence), 24 months (RR 0.73, 95% CI 0.56 to 0.95; 4 studies, 739 participants; high-certainty evidence), 36 months (RR 0.58, 95% CI 0.40 to 0.85; 1 study, 139 participants; low-certainty evidence), 48 months (RR 0.36, 95% CI 0.15 to 0.89; 1 study, 110 participants; moderate-certainty evidence), with no benefit at 60 to 72 months (RR 0.08, 95% CI 0.00 to 1.31; 1 study, 60 participants; very low-certainty evidence). Phenobarbital versus placebo or no treatment reduced seizures at six months (RR 0.59, 95% CI 0.42 to 0.83; 6 studies, 833 participants; moderate-certainty evidence), 12 months (RR 0.54, 95% CI 0.42 to 0.70; 7 studies, 807 participants; low-certainty evidence), and 24 months (RR 0.69, 95% CI 0.53 to 0.89; 3 studies, 533 participants; moderate-certainty evidence), but not at 18 months (RR 0.77, 95% CI 0.56 to 1.05; 2 studies, 264 participants) or 60 to 72 months follow-up (RR 1.50, 95% CI 0.61 to 3.69; 1 study, 60 participants; very low-certainty evidence). Intermittent clobazam compared to placebo at six months resulted in a RR of 0.36 (95% CI 0.20 to 0.64; 1 study, 60 participants; low-certainty evidence), an effect found against an extremely high (83.3%) recurrence rate in the controls, a result that needs replication. When compared to intermittent diazepam, intermittent oral melatonin did not significantly reduce seizures at six months (RR 0.45, 95% CI 0.18 to 1.15; 1 study, 60 participants; very-low certainty evidence). When compared to placebo, intermittent oral levetiracetam significantly reduced recurrent seizures at 12 months (RR 0.27, 95% CI 0.15 to 0.52; 1 study, 115 participants; very low-certainty evidence). The recording of adverse effects was variable. Two studies reported lower comprehension scores in phenobarbital-treated children. Adverse effects were recorded in up to 30% of children in the phenobarbital-treated groups and 36% in benzodiazepine-treated groups. We found evidence of publication bias in the meta-analyses of comparisons for phenobarbital versus placebo (seven studies) at 12 months but not at six months (six studies); and valproate versus placebo (four studies) at 12 months. There were too few studies to identify publication bias for the other comparisons. The methodological quality of most of the included studies was low or very low. Methods of randomisation and allocation concealment often did not meet current standards, and 'treatment versus no treatment' was more commonly seen than 'treatment versus placebo', leading to obvious risks of bias. AUTHORS' CONCLUSIONS: We found reduced recurrence rates for intermittent diazepam and continuous phenobarbital, with adverse effects in up to 30% of children. The apparent benefit for clobazam treatment in one trial needs to be replicated. Levetiracetam also shows benefit with a good safety profile; however, further study is required. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management, and, most importantly, the benign nature of the phenomenon.
Topics: Anticonvulsants; Antipyretics; Child; Child, Preschool; Confidence Intervals; Humans; Infant; Placebos; Publication Bias; Randomized Controlled Trials as Topic; Recurrence; Seizures, Febrile
PubMed: 34131913
DOI: 10.1002/14651858.CD003031.pub4 -
The Cochrane Database of Systematic... Sep 2020Skeletal muscle cramps are common and often occur in association with pregnancy, advanced age, exercise or motor neuron disorders (such as amyotrophic lateral... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Skeletal muscle cramps are common and often occur in association with pregnancy, advanced age, exercise or motor neuron disorders (such as amyotrophic lateral sclerosis). Typically, such cramps have no obvious underlying pathology, and so are termed idiopathic. Magnesium supplements are marketed for the prophylaxis of cramps but the efficacy of magnesium for this purpose remains unclear. This is an update of a Cochrane Review first published in 2012, and performed to identify and incorporate more recent studies.
OBJECTIVES
To assess the effects of magnesium supplementation compared to no treatment, placebo control or other cramp therapies in people with skeletal muscle cramps. SEARCH METHODS: On 9 September 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, CINAHL Plus, AMED, and SPORTDiscus. We also searched WHO-ICTRP and ClinicalTrials.gov for registered trials that might be ongoing or unpublished, and ISI Web of Science for studies citing the studies included in this review.
SELECTION CRITERIA
Randomized controlled trials (RCTs) of magnesium supplementation (in any form) to prevent skeletal muscle cramps in any patient group (i.e. all clinical presentations of cramp). We considered comparisons of magnesium with no treatment, placebo control, or other therapy.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials for inclusion and extracted data. Two review authors assessed risk of bias. We attempted to contact all study authors when questions arose and obtained participant-level data for four of the included trials, one of which was unpublished. We collected all data on adverse effects from the included RCTs.
MAIN RESULTS
We identified 11 trials (nine parallel-group, two cross-over) enrolling a total of 735 individuals, amongst whom 118 cross-over participants additionally served as their own controls. Five trials enrolled women with pregnancy-associated leg cramps (408 participants) and five trials enrolled people with idiopathic cramps (271 participants, with 118 additionally crossed over to control). Another study enrolled 29 people with liver cirrhosis, only some of whom suffered muscle cramps. All trials provided magnesium as an oral supplement, except for one trial which provided magnesium as a series of slow intravenous infusions. Nine trials compared magnesium to placebo, one trial compared magnesium to no treatment, calcium carbonate or vitamin B, and another trial compared magnesium to vitamin E or calcium. We judged the single trial in people with liver cirrhosis and all five trials in participants with pregnancy-associated leg cramps to be at high risk of bias. In contrast, we rated the risk of bias high in only one of five trials in participants with idiopathic rest cramps. For idiopathic cramps, largely in older adults (mean age 61.6 to 69.3 years) presumed to have nocturnal leg cramps (the commonest presentation), differences in measures of cramp frequency when comparing magnesium to placebo were small, not statistically significant, and showed minimal heterogeneity (I² = 0% to 12%). This includes the primary endpoint, percentage change from baseline in the number of cramps per week at four weeks (mean difference (MD) -9.59%, 95% confidence interval (CI) -23.14% to 3.97%; 3 studies, 177 participants; moderate-certainty evidence); and the difference in the number of cramps per week at four weeks (MD -0.18 cramps/week, 95% CI -0.84 to 0.49; 5 studies, 307 participants; moderate-certainty evidence). The percentage of individuals experiencing a 25% or better reduction in cramp rate from baseline was also no different (RR 1.04, 95% CI 0.84 to 1.29; 3 studies, 177 participants; high-certainty evidence). Similarly, no statistically significant difference was found at four weeks in measures of cramp intensity or cramp duration. This includes the number of participants rating their cramps as moderate or severe at four weeks (RR 1.33, 95% CI 0.81 to 2.21; 2 studies, 91 participants; moderate-certainty evidence); and the percentage of participants with the majority of cramp durations of one minute or more at four weeks (RR 1.83, 95% CI 0.74 to 4.53, 1 study, 46 participants; low-certainty evidence). We were unable to perform meta-analysis for trials of pregnancy-associated leg cramps. The single study comparing magnesium to no treatment failed to find statistically significant benefit on a three-point ordinal scale of overall treatment efficacy. Of the three trials comparing magnesium to placebo, one found no benefit on frequency or intensity measures, another found benefit for both, and a third reported inconsistent results for frequency that could not be reconciled. The single study in people with liver cirrhosis was small and had limited reporting of cramps, but found no difference in terms of cramp frequency or cramp intensity. Our analysis of adverse events pooled all studies, regardless of the setting in which cramps occurred. Major adverse events (occurring in 2 out of 72 magnesium recipients and 3 out of 68 placebo recipients), and withdrawals due to adverse events, were not significantly different from placebo. However, in the four studies for which it could be determined, more participants experienced minor adverse events in the magnesium group than in the placebo group (RR 1.51, 95% CI 0.98 to 2.33; 4 studies, 254 participants; low-certainty evidence). Overall, oral magnesium was associated with mostly gastrointestinal adverse events (e.g. diarrhoea), experienced by 11% (10% in control) to 37% (14% in control) of participants.
AUTHORS' CONCLUSIONS
It is unlikely that magnesium supplementation provides clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps. In contrast, for those experiencing pregnancy-associated rest cramps the literature is conflicting and further research in this population is needed. We found no RCTs evaluating magnesium for exercise-associated muscle cramps or disease-state-associated muscle cramps (for example amyotrophic lateral sclerosis/motor neuron disease) other than a single small (inconclusive) study in people with liver cirrhosis, only some of whom suffered cramps.
Topics: Adult; Age Factors; Aged; Cross-Over Studies; Female; Humans; Magnesium; Male; Middle Aged; Muscle Cramp; Muscle, Skeletal; Placebos; Pregnancy; Pregnancy Complications; Randomized Controlled Trials as Topic
PubMed: 32956536
DOI: 10.1002/14651858.CD009402.pub3 -
The Cochrane Database of Systematic... Feb 2021Depression is one of the most common morbidities of the postnatal period. It has been associated with adverse outcomes for women, children, the wider family and society... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Depression is one of the most common morbidities of the postnatal period. It has been associated with adverse outcomes for women, children, the wider family and society as a whole. Treatment is with psychosocial interventions or antidepressant medication, or both. The aim of this review is to evaluate the effectiveness of different antidepressants and to compare their effectiveness with placebo, treatment as usual or other forms of treatment. This is an update of a review last published in 2014.
OBJECTIVES
To assess the effectiveness and safety of antidepressant drugs in comparison with any other treatment (psychological, psychosocial, or pharmacological), placebo, or treatment as usual for postnatal depression.
SEARCH METHODS
We searched Cochrane Common Mental Disorders's Specialized Register, CENTRAL, MEDLINE, Embase and PsycINFO in May 2020. We also searched international trials registries and contacted experts in the field.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of women with depression during the first 12 months postpartum that compared antidepressant treatment (alone or in combination with another treatment) with any other treatment, placebo or treatment as usual.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data from the study reports. We requested missing information from study authors wherever possible. We sought data to allow an intention-to-treat analysis. Where we identified sufficient comparable studies we pooled data and conducted random-effects meta-analyses.
MAIN RESULTS
We identified 11 RCTs (1016 women), the majority of which were from English-speaking, high-income countries; two were from middle-income countries. Women were recruited from a mix of community-based, primary care, maternity and outpatient settings. Most studies used selective serotonin reuptake inhibitors (SSRIs), with treatment duration ranging from 4 to 12 weeks. Meta-analysis showed that there may be a benefit of SSRIs over placebo in response (55% versus 43%; pooled risk ratio (RR) 1.27, 95% confidence interval (CI) 0.97 to 1.66); remission (42% versus 27%; RR 1.54, 95% CI 0.99 to 2.41); and reduced depressive symptoms (standardised mean difference (SMD) -0.30, 95% CI -0.55 to -0.05; 4 studies, 251 women), at 5 to 12 weeks' follow-up. We were unable to conduct meta-analysis for adverse events due to variation in the reporting of this between studies. There was no evidence of a difference between acceptability of SSRI and placebo (27% versus 27%; RR 1.10, 95% CI 0.74 to 1.64; 4 studies; 233 women). The certainty of all the evidence for SSRIs was low or very low due to the small number of included studies and a number of potential sources of bias, including high rates of attrition. There was insufficient evidence to assess the efficacy of SSRIs compared with other classes of antidepressants and of antidepressants compared with other pharmacological interventions, complementary medicines, psychological and psychosocial interventions or treatment as usual. A substantial proportion of women experienced adverse effects but there was no evidence of differences in the number of adverse effects between treatment groups in any of the studies. Data on effects on children, including breastfed infants, parenting, and the wider family were limited, although no adverse effects were noted.
AUTHORS' CONCLUSIONS
There remains limited evidence regarding the effectiveness and safety of antidepressants in the management of postnatal depression, particularly for those with more severe depression. We found low-certainty evidence that SSRI antidepressants may be more effective in treating postnatal depression than placebo as measured by response and remission rates. However, the low certainty of the evidence suggests that further research is very likely to have an important impact on our effect estimate. There is a continued imperative to better understand whether, and for whom, antidepressants or other treatments are more effective for postnatal depression, and whether some antidepressants are more effective or better tolerated than others. In clinical practice, the findings of this review need to be contextualised by the extensive broader literature on antidepressants in the general population and perinatal clinical guidance, to inform an individualised risk-benefit clinical decision. Future RCTs should focus on larger samples, longer follow-up, comparisons with alternative treatment modalities and inclusion of child and parenting outcomes.
Topics: Adolescent; Adult; Antidepressive Agents; Bias; Depression, Postpartum; Female; Humans; Patient Dropouts; Placebos; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Young Adult
PubMed: 33580709
DOI: 10.1002/14651858.CD013560.pub2 -
The Cochrane Database of Systematic... Jul 2020Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, in which the pathogenesis is believed to be partly influenced by the gut... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, in which the pathogenesis is believed to be partly influenced by the gut microbiome. Probiotics can be used to manipulate the microbiome and have therefore been considered as a potential therapy for CD. There is some evidence that probiotics benefit other gastrointestinal conditions, such as irritable bowel syndrome and ulcerative colitis, but their efficacy in CD is unclear. This is the first update of a Cochrane Review previously published in 2008.
OBJECTIVES
To assess the efficacy and safety of probiotics for the induction of remission in CD.
SEARCH METHODS
The following electronic databases were searched: MEDLINE (from inception to 6 July 2020), Embase (from inception to 6 July 2020), the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane IBD Review Group Specialised Trials Register, World Health Organization (WHO) International Clinical Trials Registry, and ClinicalTrials.gov.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that compared probiotics with placebo or any other non-probiotic intervention for the induction of remission in CD were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed the methodological quality of included studies. The primary outcome was clinical remission. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for dichotomous outcomes.
MAIN RESULTS
There were two studies that met criteria for inclusion. One study from Germany had 11 adult participants with mild-to-moderate CD, who were treated with a one-week course of corticosteroids and antibiotics (ciprofloxacin 500 mg twice daily and metronidazole 250 mg three times a day), followed by randomised assignment to Lactobacillus rhamnosus strain GG (two billion colony-forming units per day) or corn starch placebo. The other study from the United Kingdom (UK) had 35 adult participants with active CD (CDAI score of 150 to 450) randomised to receive a synbiotic treatment (comprised of freeze-dried Bifidobacterium longum and a commercial product) or placebo. The overall risk of bias was low in one study, whereas the other study had unclear risk of bias in relation to random sequence generation, allocation concealment, and blinding. There was no evidence of a difference between the use of probiotics and placebo for the induction of remission in CD (RR 1.06; 95% CI 0.65 to 1.71; 2 studies, 46 participants) after six months. There was no difference in adverse events between probiotics and placebo (RR 2.55; 95% CI 0.11 to 58.60; 2 studies, 46 participants). The evidence for both outcomes was of very low certainty due to risk of bias and imprecision.
AUTHORS' CONCLUSIONS
The available evidence is very uncertain about the efficacy or safety of probiotics, when compared with placebo, for induction of remission in Crohn's disease. There is a lack of well-designed RCTs in this area and further research is needed.
Topics: Adult; Anti-Bacterial Agents; Bifidobacterium longum; Ciprofloxacin; Crohn Disease; Gastrointestinal Microbiome; Humans; Lacticaseibacillus rhamnosus; Metronidazole; Placebos; Probiotics; Randomized Controlled Trials as Topic; Remission Induction
PubMed: 32678465
DOI: 10.1002/14651858.CD006634.pub3