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Lancet (London, England) Jul 2022Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder.
METHODS
In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ.
FINDINGS
We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36-0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27-0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52-0·99; moderate], 0·70 [0·51-0·95; moderate] and 0·71 [0·52-0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28-3·13; very low]; zolpidem: 1·79 [1·25-2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01-3·33; low]), daridorexant (3·45 [1·41-8·33; low), and suvorexant (3·13 [1·47-6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27-2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36-0·90; very low]; lemborexant: 0·41 [0·04-0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16-1·10; very low]) and zolpidem (0·60 [0·00-1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20-0·93; very low]; zolpidem: 0·43 [0·19-0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11-3·70; very low]).
INTERPRETATION
Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice.
FUNDING
UK National Institute for Health Research Oxford Health Biomedical Research Centre.
Topics: Adult; Benzodiazepines; Doxepin; Eszopiclone; Humans; Melatonin; Network Meta-Analysis; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Zolpidem
PubMed: 35843245
DOI: 10.1016/S0140-6736(22)00878-9 -
The Cochrane Database of Systematic... Sep 2015Nausea, retching and vomiting are very commonly experienced by women in early pregnancy. There are considerable physical, social and psychological effects on women who... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Nausea, retching and vomiting are very commonly experienced by women in early pregnancy. There are considerable physical, social and psychological effects on women who experience these symptoms. This is an update of a review of interventions for nausea and vomiting in early pregnancy last published in 2014.
OBJECTIVES
To assess the effectiveness and safety of all interventions for nausea, vomiting and retching in early pregnancy, up to 20 weeks' gestation.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, the Cochrane Complementary Medicine Field's Trials Register (19 January 2015) and reference lists of retrieved studies.
SELECTION CRITERIA
All randomised controlled trials of any intervention for nausea, vomiting and retching in early pregnancy. We excluded trials of interventions for hyperemesis gravidarum, which are covered by another Cochrane review. We also excluded quasi-randomised trials and trials using a cross-over design.
DATA COLLECTION AND ANALYSIS
Four review authors, in pairs, reviewed the eligibility of trials and independently evaluated the risk of bias and extracted the data for included trials.
MAIN RESULTS
Forty-one trials involving 5449 women, met the inclusion criteria. These trials covered many interventions, including acupressure, acustimulation, acupuncture, ginger, chamomile, lemon oil, mint oil, vitamin B6 and several antiemetic drugs. There were no included studies of dietary and other lifestyle interventions. Evidence regarding the effectiveness of P6 acupressure, auricular (ear) acupressure and acustimulation of the P6 point was limited. Acupuncture (P6 or traditional) showed no significant benefit to women in pregnancy. The use of ginger products may be helpful to women, but the evidence of effectiveness was limited and not consistent, though three recent studies support ginger over placebo. There was only limited evidence from trials to support the use of pharmacological agents including vitamin B6, Doxylamine-pyridoxoine and other anti-emetic drugs to relieve mild or moderate nausea and vomiting. There was little information on maternal and fetal adverse outcomes and on psychological, social or economic outcomes.We were unable to pool findings from studies for most outcomes due to heterogeneity in study participants, interventions, comparison groups, and outcomes measured or reported. The methodological quality of the included studies was mixed. Risk of bias was low related to performance bias, detection bias and attrition bias for most studies. Selection bias risk was unclear for many studies and almost half of the studies did not fully or clearly report all pre-specified outcomes.
AUTHORS' CONCLUSIONS
Given the high prevalence of nausea and vomiting in early pregnancy, women and health professionals need clear guidance about effective and safe interventions, based on systematically reviewed evidence. There is a lack of high-quality evidence to support any particular intervention. This is not the same as saying that the interventions studied are ineffective, but that there is insufficient strong evidence for any one intervention. The difficulties in interpreting and pooling the results of the studies included in this review highlight the need for specific, consistent and clearly justified outcomes and approaches to measurement in research studies.
Topics: Acupuncture Therapy; Antiemetics; Female; Zingiber officinale; Humans; Morning Sickness; Nausea; Phytotherapy; Pregnancy; Pregnancy Complications; Randomized Controlled Trials as Topic; Treatment Outcome; Vitamin B 6; Vitamin B Complex; Vomiting
PubMed: 26348534
DOI: 10.1002/14651858.CD007575.pub4 -
Health Technology Assessment... Oct 2016Nausea and vomiting in pregnancy (NVP) affects up to 85% of all women during pregnancy, but for the majority self-management suffices. For the remainder, symptoms are... (Review)
Review
BACKGROUND
Nausea and vomiting in pregnancy (NVP) affects up to 85% of all women during pregnancy, but for the majority self-management suffices. For the remainder, symptoms are more severe and the most severe form of NVP - hyperemesis gravidarum (HG) - affects 0.3-1.0% of pregnant women. There is no widely accepted point at which NVP becomes HG.
OBJECTIVES
This study aimed to determine the relative clinical effectiveness and cost-effectiveness of treatments for NVP and HG.
DATA SOURCES
MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, PsycINFO, Commonwealth Agricultural Bureaux (CAB) Abstracts, Latin American and Caribbean Health Sciences Literature, Allied and Complementary Medicine Database, British Nursing Index, Science Citation Index, Social Sciences Citation Index, Scopus, Conference Proceedings Index, NHS Economic Evaluation Database, Health Economic Evaluations Database, China National Knowledge Infrastructure, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects were searched from inception to September 2014. References from studies and literature reviews identified were also examined. was hand-searched, as were websites of relevant organisations. Costs came from NHS sources.
REVIEW METHODS
A systematic review of randomised and non-randomised controlled trials (RCTs) for effectiveness, and population-based case series for adverse events and fetal outcomes. Treatments: vitamins B6 and B12, ginger, acupressure/acupuncture, hypnotherapy, antiemetics, dopamine antagonists, 5-hydroxytryptamine receptor antagonists, intravenous (i.v.) fluids, corticosteroids, enteral and parenteral feeding or other novel treatment. Two reviewers extracted data and quality assessed studies. Results were narratively synthesised; planned meta-analysis was not possible due to heterogeneity and incomplete reporting. A simple economic evaluation considered the implied values of treatments.
RESULTS
Seventy-three studies (75 reports) met the inclusion criteria. For RCTs, 33 and 11 studies had a low and high risk of bias respectively. For the remainder ( = 20) it was unclear. The non-randomised studies ( = 9) were low quality. There were 33 separate comparators. The most common were acupressure versus placebo ( = 12); steroid versus usual treatment ( = 7); ginger versus placebo ( = 6); ginger versus vitamin B6 ( = 6); and vitamin B6 versus placebo ( = 4). There was evidence that ginger, antihistamines, metoclopramide (mild disease) and vitamin B6 (mild to severe disease) are better than placebo. Diclectin [Duchesnay Inc.; doxylamine succinate (10 mg) plus pyridoxine hydrochloride (10 mg) slow release tablet] is more effective than placebo and ondansetron is more effective at reducing nausea than pyridoxine plus doxylamine. Diclectin before symptoms of NVP begin for women at high risk of severe NVP recurrence reduces risk of moderate/severe NVP compared with taking Diclectin once symptoms begin. Promethazine is as, and ondansetron is more, effective than metoclopramide for severe NVP/HG. I.v. fluids help correct dehydration and improve symptoms. Dextrose saline may be more effective at reducing nausea than normal saline. Transdermal clonidine patches may be effective for severe HG. Enteral feeding is effective but extreme method treatment for very severe symptoms. Day case management for moderate/severe symptoms is feasible, acceptable and as effective as inpatient care. For all other interventions and comparisons, evidence is unclear. The economic analysis was limited by lack of effectiveness data, but comparison of costs between treatments highlights the implications of different choices.
LIMITATIONS
The main limitations were the quantity and quality of the data available.
CONCLUSION
There was evidence of some improvement in symptoms for some treatments, but these data may not be transferable across disease severities. Methodologically sound and larger trials of the main therapies considered within the UK NHS are needed.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42013006642.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Antiemetics; Clinical Trials as Topic; Complementary Therapies; Cost-Benefit Analysis; Female; Fluid Therapy; Humans; Hyperemesis Gravidarum; Nausea; Pregnancy
PubMed: 27731292
DOI: 10.3310/hta20740 -
Expert Opinion on Drug Safety Dec 2014Approximately 10 - 15% of women reportedly take an antihistamine during pregnancy for the relief of nausea and vomiting, allergy and asthma symptoms, or indigestion.... (Review)
Review
INTRODUCTION
Approximately 10 - 15% of women reportedly take an antihistamine during pregnancy for the relief of nausea and vomiting, allergy and asthma symptoms, or indigestion. Antihistamines include histamine H1-receptor and H2-receptor antagonists.
AREAS COVERED
This is a systematic evaluation of the peer-reviewed epidemiologic literature published through February 2014 on the association between prenatal exposure to antihistamines and birth defects. Papers addressing histamine H1- or H2-receptor antagonists are included. Papers addressing pyridoxine plus doxylamine (Bendectin in the United States, Debendox in the United Kingdom, Diclectin in Canada, Lenotan and Merbental in other countries) prior to the year 2001 were excluded post hoc because of several previously published meta-analyses and commentaries on this medication.
EXPERT OPINION
The literature on the safety of antihistamine use during pregnancy with respect to birth defects is generally reassuring though the positive findings from a few large studies warrant corroboration in other populations. The findings in the literature are considered in light of three critical methodological issues: i) selection of appropriate study population; ii) ascertainment of antihistamine exposures; and iii) ascertainment of birth defect outcomes. Selected antihistamines have been very well studied (e.g., loratadine); others, especially H2-receptor antagonists, require additional study before an assessment of safety with respect to birth defect risk could be made.
Topics: Congenital Abnormalities; Female; Histamine Antagonists; Humans; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 25307228
DOI: 10.1517/14740338.2014.970164 -
The Primary Care Companion For CNS... 2015To investigate the level of evidence supporting the use of common over-the-counter (OTC) agents (diphenhydramine, doxylamine, melatonin, and valerian) for occasional...
OBJECTIVE
To investigate the level of evidence supporting the use of common over-the-counter (OTC) agents (diphenhydramine, doxylamine, melatonin, and valerian) for occasional disturbed sleep or insomnia.
DATA SOURCES
A systematic review of the literature was conducted on July 31, 2014, using MEDLINE (PubMed) and the search terms (insomnia OR sleep) AND (over*the*counter OR OTC OR non*prescription OR antihistamine OR doxylamine OR diphenhydramine OR melatonin OR valerian) with the filters English, human, and clinical trials.
STUDY SELECTION
Identified publications (from 2003 to July 31, 2014, following previous published literature reviews) that met the inclusion criteria were selected. The criteria included randomized placebo-controlled clinical studies that utilized overnight objective (polysomnography) or next-day participant-reported sleep-related endpoints and that were conducted in healthy participants with or without occasional disturbed sleep or diagnosed insomnia.
RESULTS
Measures of efficacy and tolerability were summarized for each study individually and grouped according to OTC agent: H1 antagonists or antihistamines (3 studies, diphenhydramine), melatonin (8), and valerian or valerian/hops (7). Of the 3 sleep agents, studies conducted with melatonin, especially prolonged-release formulations in older individuals with diagnosed insomnia, demonstrated the most consistent beneficial effects (vs placebo) on sleep measures, specifically sleep onset and sleep quality, with favorable tolerability. In contrast, the clinical trial data for diphenhydramine, immediate-release melatonin, and valerian suggested limited beneficial effects.
CONCLUSIONS
A review of randomized controlled studies over the past 12 years suggests commonly used OTC sleep-aid agents, especially diphenhydamine and valerian, lack robust clinical evidence supporting efficacy and safety.
PubMed: 27057416
DOI: 10.4088/PCC.15r01798