Melatonin treatment has consistent but transient beneficial effects on sleep measures and pain in patients with severe chronic pain: the DREAM–CP randomised controlled trial
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SUBMITTER: Onyeakazi U
PROVIDER: S-EPMC10925889 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Project description:IntroductionChronic pain is prevalent, and approximately half of patients with chronic pain experience sleep disturbance. Exogenous melatonin is licensed to treat primary insomnia and there is some evidence for analgesic effects of melatonin.The aim of this study is to investigate the effects of oral melatonin (as Circadin) 2 mg at night in adults with severe non-malignant pain of at least 3 months' duration.Methods and analysisWe will conduct a randomised double-blind placebo-controlled cross-over study. The primary outcome is sleep disturbance. Secondary outcomes are pain intensity, actigraphy, fatigue, reaction time testing, serum melatonin and endogenous opioid peptide levels along with patient views about study participation.We aim to recruit 60 patients with severe chronic pain (average pain intensity ≥7 on the Brief Pain Inventory (BPI)) from a tertiary referral pain clinic in Northeast Scotland. Participants will be randomised to receive melatonin (as modified release Circadin) 2 mg daily for 6 weeks or placebo, followed by a 4-week washout period, then 6 weeks treatment with the treatment they did not receive. Participants will complete the Verran Snyder-Halpern Sleep Scale, Pittsburgh Sleep Quality Index, Pain and Sleep Questionnaire 3-item index, BPI and psychomotor vigilance reaction time testing at 6 points over 20 weeks. Actigraphy watches will be used to provide objective measures of sleep duration and latency and other sleep measures and will prompt patients to report contemporaneous pain and fatigue scores daily.Cross-over analyses will include tests for effects of treatment, period, treatment-period interaction (carryover effect) and sequence. Within-patient effects and longitudinal data will be analysed using mixed linear models, accounting for potential confounders.Ethics and disseminationApproved by Office for Research Ethics Committees Northern Ireland, reference 19/NI/0007. Results will be published in peer-reviewed journals and will be presented at national and international conferences.Trial registration numberISRCTN12861060.
| S-EPMC7076250 | biostudies-literature
Project description:Collecting dream reports typically requires waking subjects up from their sleep-a method that has been used to study the relationship between dreams and memory consolidation. However, it is unclear whether these awakenings influence sleep-associated memory consolidation processes. Furthermore, it is unclear how the incorporation of the learning task into dreams is related to memory consolidation. In this study we compared memory performance in a word-picture association learning task after a night with and without awakenings in 22 young and healthy participants. We then examined if the stimuli from the learning task are successfully incorporated into dreams, and if this incorporation is related to the task performance the next morning. We show that while the awakenings impaired both subjective and objective sleep quality, they did not affect sleep-associated memory consolidation. When dreams were collected during the night by awakenings, memories of the learning task were successfully incorporated into dreams. When dreams were collected in the morning, no incorporations were detected. Task incorporation into non-rapid eye movement sleep dreams, but not rapid eye movement sleep dreams positively predicted memory performance the next morning. We conclude that the method of awakenings to collect dream reports is suitable and necessary for dream and memory studies. Furthermore, our study suggests that dreams in non-rapid eye movement rather than rapid eye movement sleep might be related to processes of memory consolidation during sleep.
| S-EPMC6378621 | biostudies-literature
Project description:Surrogates which allow one to predict the effect of the treatment on the outcome of interest from the effect of the treatment on the surrogate are of importance when it is difficult or expensive to measure the primary outcome. Unfortunately, the use of such surrogates can give rise to paradoxical situations in which the effect of the treatment on the surrogate is positive, the surrogate and outcome are strongly positively correlated, but the effect of the treatment on the outcome is negative, a phenomenon sometimes referred to as the "surrogate paradox." New results are given for consistent surrogates that extend the existing literature on sufficient conditions that ensure the surrogate paradox is not manifest. Specifically, it is shown that for the surrogate paradox to be manifest it must be the case that either there is (i) a direct effect of treatment on the outcome not through the surrogate and in the opposite direction as that through the surrogate or (ii) confounding for the effect of the surrogate on the outcome, or (iii) a lack of transitivity so that treatment does not positively affect the surrogate for all the same individuals for whom the surrogate positively affects the outcome. The conditions for consistent surrogates and the results of the article are important because they allow investigators to predict the direction of the effect of the treatment on the outcome simply from the direction of the effect of the treatment on the surrogate. These results on consistent surrogates are then related to the four approaches to surrogate outcomes described by Joffe and Greene (2009, Biometrics 65, 530-538) to assess whether the standard criteria used by these approaches to assess whether a surrogate is "good" suffice to avoid the surrogate paradox.
| S-EPMC4221255 | biostudies-literature
Project description:The link between dreams and creativity has been a topic of intense speculation. Recent scientific findings suggest that sleep onset (known as N1) may be an ideal brain state for creative ideation. However, the specific link between N1 dream content and creativity has remained unclear. To investigate the contribution of N1 dream content to creative performance, we administered targeted dream incubation (a protocol that presents auditory cues at sleep onset to introduce specific themes into dreams) and collected dream reports to measure incorporation of the selected theme into dream content. We then assessed creative performance using a set of three theme-related creativity tasks. Our findings show enhanced creative performance and greater semantic distance in task responses following a period of N1 sleep as compared to wake, corroborating recent work identifying N1 as a creative sweet spot and offering novel evidence for N1 enabling a cognitive state with greater associative divergence. We further demonstrate that successful N1 dream incubation enhances creative performance more than N1 sleep alone. To our knowledge, this is the first controlled experiment investigating a direct role of incubating dream content in the enhancement of creative performance.
| S-EPMC10185495 | biostudies-literature
Project description:SummaryLarge-scale transcriptome studies with multiple samples per individual are widely used to study disease biology. Yet, current methods for differential expression are inadequate for cross-individual testing for these repeated measures designs. Most problematic, we observe across multiple datasets that current methods can give reproducible false-positive findings that are driven by genetic regulation of gene expression, yet are unrelated to the trait of interest. Here, we introduce a statistical software package, dream, that increases power, controls the false positive rate, enables multiple types of hypothesis tests, and integrates with standard workflows. In 12 analyses in 6 independent datasets, dream yields biological insight not found with existing software while addressing the issue of reproducible false-positive findings.Availability and implementationDream is available within the variancePartition Bioconductor package at http://bioconductor.org/packages/variancePartition.Contactgabriel.hoffman@mssm.edu.Supplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC8055218 | biostudies-literature
Project description:BackgroundMelatonin may reduce REM-sleep behavior disorder (RBD) symptoms in Parkinson's disease (PD), though robust clinical trials are lacking.ObjectiveTo assess the efficacy of prolonged-release (PR) melatonin for RBD in PD.MethodsRandomized, double-blind, placebo-controlled, parallel-group trial with an 8-week intervention and 4-week observation pre- and postintervention (ACTRN12613000648729). Thirty PD patients with rapid eye movement sleep behavior disorder were randomized to 4 mg of prolonged-release melatonin (Circadin) or matched placebo, ingested orally once-daily before bedtime. Primary outcome was the aggregate of rapid eye movement sleep behavior disorder incidents averaged over weeks 5 to 8 of treatment captured by a weekly diary. Data were included in a mixed-model analysis of variance (n = 15 per group).ResultsNo differences between groups at the primary endpoint (3.4 events/week melatonin vs. 3.6 placebo; difference, 0.2; 95% confidence interval = -3.2 to 3.6; P = 0.92). Adverse events included mild headaches, fatigue, and morning sleepiness (n = 4 melatonin; n = 5 placebo).ConclusionProlonged-release melatonin 4 mg did not reduce rapid eye movement sleep behavior disorder in PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC7027846 | biostudies-literature
Project description:ObjectiveTo assess the effectiveness and safety of melatonin in treating severe sleep problems in children with neurodevelopmental disorders.Design12 week double masked randomised placebo controlled phase III trial.Setting19 hospitals across England and Wales.Participants146 children aged 3 years to 15 years 8 months were randomised. They had a range of neurological and developmental disorders and a severe sleep problem that had not responded to a standardised sleep behaviour advice booklet provided to parents four to six weeks before randomisation. A sleep problem was defined as the child not falling asleep within one hour of lights out or having less than six hours' continuous sleep.InterventionsImmediate release melatonin or matching placebo capsules administered 45 minutes before the child's bedtime for a period of 12 weeks. All children started with a 0.5 mg capsule, which was increased through 2 mg, 6 mg, and 12 mg depending on their response to treatment.Main outcome measuresTotal sleep time at night after 12 weeks adjusted for baseline recorded in sleep diaries completed by the parent. Secondary outcomes included sleep onset latency, assessments of child behaviour, family functioning, and adverse events. Sleep was measured with diaries and actigraphy.ResultsMelatonin increased total sleep time by 22.4 minutes (95% confidence interval 0.5 to 44.3 minutes) measured by sleep diaries (n=110) and 13.3 (-15.5 to 42.2) measured by actigraphy (n=59). Melatonin reduced sleep onset latency measured by sleep diaries (-37.5 minutes, -55.3 to -19.7 minutes) and actigraphy (-45.3 minutes, -68.8 to -21.9 minutes) and was most effective for children with the longest sleep latency (P=0.009). Melatonin was associated with earlier waking times than placebo (29.9 minutes, 13.6 to 46.3 minutes). Child behaviour and family functioning outcomes showed some improvement and favoured use of melatonin. Adverse events were mild and similar between the two groups.ConclusionsChildren gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required.Trial registrationISRCT No 05534585.
| S-EPMC3489506 | biostudies-literature
Project description:BackgroundDelayed Sleep-Wake Phase Disorder (DSWPD) is characterised by sleep initiation insomnia when attempting sleep at conventional times and difficulty waking at the required time for daytime commitments. Although there are published therapeutic guidelines for the administration of melatonin for DSWPD, to our knowledge, randomised controlled trials are lacking. This trial tested the efficacy of 0.5 mg melatonin, combined with behavioural sleep-wake scheduling, for improving sleep initiation in clinically diagnosed DSWPD patients with a delayed endogenous melatonin rhythm relative to patient-desired (or -required) bedtime (DBT).MethodsThis randomised, placebo-controlled, double-blind clinical trial was conducted in an Australian outpatient DSWPD population. Following 1-wk baseline, clinically diagnosed DSWPD patients with delayed melatonin rhythm relative to DBT (salivary dim light melatonin onset [DLMO] after or within 30 min before DBT) were randomised to 4-wk treatment with 0.5 mg fast-release melatonin or placebo 1 h before DBT for at least 5 consecutive nights per week. All patients received behavioural sleep-wake scheduling, consisting of bedtime scheduled at DBT. The primary outcome was actigraphic sleep onset time. Secondary outcomes were sleep efficiency in the first third of time in bed (SE T1) on treatment nights, subjective sleep-related daytime impairment (Patient Reported Outcomes Measurement Information System [PROMIS]), PROMIS sleep disturbance, measures of daytime sleepiness, clinician-rated change in illness severity, and DLMO time.FindingsBetween September 13, 2012 and September 1, 2014, 307 participants were registered; 116 were randomised to treatment (intention-to-treat n = 116; n = 62 males; mean age, 29.0 y). Relative to baseline and compared to placebo, sleep onset occurred 34 min earlier (95% confidence interval [CI] -60 to -8) in the melatonin group. SE T1 increased; PROMIS sleep-related impairment, PROMIS sleep disturbance, insomnia severity, and functional disability decreased; and a greater proportion of patients showed more than minimal clinician-rated improvement following melatonin treatment (52.8%) compared to placebo (24.0%) (P < 0.05). The groups did not differ in the number of nights treatment was taken per protocol. Post-treatment DLMO assessed in a subset of patients (n = 43) was not significantly different between groups. Adverse events included light-headedness, daytime sleepiness, and decreased libido, although rates were similar between treatment groups. The clinical benefits or safety of melatonin with long-term treatment were not assessed, and it remains unknown whether the same treatment regime would benefit patients experiencing DSWPD sleep symptomology without a delay in the endogenous melatonin rhythm.ConclusionsIn this study, melatonin treatment 1 h prior to DBT combined with behavioural sleep-wake scheduling was efficacious for improving objective and subjective measures of sleep disturbances and sleep-related impairments in DSWPD patients with delayed circadian phase relative to DBT. Improvements were achieved largely through the sleep-promoting effects of melatonin, combined with behavioural sleep-wake scheduling.Trial registrationThis trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000425897.
| S-EPMC6005466 | biostudies-literature
Project description:Expression of DREAM in dorsal root ganglia and spinal cord is related to endogenous control mechanisms of acute and chronic pain. In primary sensory trigeminal neurons high levels of endogenous DREAM protein are preferentially localized in the nucleus, suggesting a major transcriptional role. Here, we show that DREAM participates in the control of trigeminal pain perception through the regulation of prodynorphin and BDNF. Furthermore, genome-wide analysis of trigeminal neurons in daDREAM transgenic mice revealed that cathepsin L (CTSL) and the monoglyceride lipase (MGLL) are new DREAM downstream targets and have a role in the regulation of trigeminal nociception.
2016-04-22 | GSE69619 | GEO
Project description:Cardiovascular disease is the cause of physical infirmity and thousands of deaths annually. Typically, during heart failure, cardiomyocyte mitochondria falter in terms of energy production and metabolic processing. Additionally, inflammation and the accumulation of non-contractile fibrous tissue contribute to cardiac malfunction. Melatonin, an endogenously produced molecule, experimentally reduces the initiation and progression of atherosclerotic lesions, which are often the basis of coronary artery disease. The current review critically analyzes published data related to the experimental use of melatonin to forestall coronary artery pathologies. Collectively, these studies document melatonin's anti-atherosclerotic actions in reducing LDL oxidation and triglyceride levels, lowering endothelial malfunction, limiting adhesion molecule formation, preventing macrophage polarization to the M1 pro-inflammatory phenotype, changing cellular metabolism, scavenging destructive reactive oxygen species, preventing the proliferation and invasion of arterial smooth muscle cells into the lesioned area, restricting the ingrowth of blood vessels from the vasa vasorum, and solidifying the plaque cap to reduce the chance of its rupture. Diabetic hyperglycemia, which aggravates atherosclerotic plaque formation, is also inhibited by melatonin supplementation in experimental animals. The potential value of non-toxic melatonin as a possible inhibitor of cardiac pathology in humans should be seriously considered by performing clinical trials using this multifunctional molecule.
| S-EPMC10820220 | biostudies-literature