Melatonin is known to assist sleep-disturbance rhythms in children and it has been used empirically in sleep disorders clinics at the Mater Children’s Hospital, Brisbane, Australia, and elsewhere in the world. Presently, there is no conclusive data on melatonin usage with regard to standard evidence (systematic reviews), dose-response relationships and its impact on health-related quality of life. Despite its qualitative efficacy in assisting sleep disorders, melatonin is presently a complementary medicine and has not been subject to the stringent pre-marketing research and development required for registered pharmaceuticals for therapeutic usage in paediatric patient population. Therefore, the available data on evidence (efficacy/safety), dosing and health related quality of life is largely anecdotal. Inconclusive and variable published data in children adds to misconceptions about melatonin usage in sleep disorders. There is an urgent need to evaluate clinical, pharmacokinetic and evidence based approaches for studying melatonin in paediatric sleep disorders, with the overall goal of improving clinical outcomes in these patients.
This thesis aimed to explore the evidence-based, analytical, clinical and behavioural studies on melatonin in children with sleep disorders with the hypothesis to evaluate if melatonin administration restores normal circadian rhythms and sleep propensity in children with mismatched circadian sleep patterns. Four areas were investigated:
(a) To develop systematic reviews for melatonin usage in sleep disorders in children with visual impairment, typically developing children and a protocol for future systematic reviews in children with neurodevelopmental disorders
(b) To develop a sensitive, accurate and precise method for the determination of melatonin in saliva
(c) To apply this assay in a clinical study to determine if sublingual melatonin treatment restores normal circadian rhythms and sleep propensity in children with mismatched circadian sleep patterns
(d) To assess melatonin intervention with respect to quality of life and sleep habit from family/care-givers as a survey
A mixed method study design was used that comprised:
The evidence based approach was designed and developed in collaboration with the Cochrane Developmental Psychosocial and Learning Problems Group (CDPLG). Systematic reviews for melatonin in non-respiratory sleep disorders in children with visual impairment and typically developing children and a protocol for future systematic review were prepared for children with neurodevelopmental disorders. The next stage involved the development and validation of a HPLC-MS/MS method for measuring melatonin in human saliva. An Applied Biosystems API 3200 tandem mass spectrometer coupled to Shimadzu LC20 prominence HPLC system was utilised. Validation of the assay method, saliva sample collection device and clinical application was demonstrated. The developed and validated assay was utilised for measurement of melatonin concentration in a single-blinded pilot-scale dose-ranging study of melatonin in children with circadian rhythm sleep disorders, which formed the next phase of this thesis. A dose-escalation study design of 9 weeks (August 2010-October 2011), with baseline and placebo phase were followed by administration of sublingual melatonin dose of 0.5, 2 and 4 mg. Primary and secondary outcomes of total sleep time, sleep onset latency and number of night-time wakings were evaluated through subjective means of sleep diary filled by the carers of study participants and through objective means of actigraphy and measuring melatonin concentration. A survey on health related quality of life (HRQOL) and sleep parameters from the carers of the study participants formed the last stage of this thesis (as a part of the dose-ranging study). A quantitative (3 validated questionnaires on sleep parameters and HRQOL) and a qualitative (thematic analysis) approach were followed.
The thesis makes a number of important contributions to our understanding of different domain in the area of paediatric sleep medicine research for melatonin in circadian rhythm sleep disorders.
Evaluation of evidence-based data on melatonin in children with sleep disorders highlighted the lack of high quality evidence in this domain, and provided the knowledge gaps and recommendation for research and practice. The lack of included studies was attributed to the strict inclusion criteria followed by the Cochrane Group; only high-quality randomised controlled trials (RCTs) were evaluated. Including evidence from non-randomised studies involves a trade-off between availability and bias, and may adversely affect the therapeutic recommendation. A trend of ever increasing numbers of non-RCTs in this specialised niche was observed. For specialised therapeutic areas, a null-evidence report, based on inclusion criteria, runs the ethical risk of excluding potentially relevant practice-guiding evidence by determining that current practice lacks sufficient evidence. The need for tools to include non-RCTs in evidence based domain of Cochrane and the challenges involved were presented at the Annual Cochrane Symposium in Melbourne in July 2011. These findings and the knowledge gaps were published with Cochrane Database of Systematic reviews (see Chapter 2). Closing such gaps formed the basis for the subsequent phase of this thesis.
A tandem mass-spectrometry method for development and validation of melatonin in saliva formed the next stage. The linear working range the method established at 3.9 pg/mL – 1000 pg/mL. The method reproducibility was 23.0%, 1.6% and 1.1% at concentrations of 7.03 pg/mL, 450 pg/mL and 900 pg/mL, respectively. Accuracy exceeded 97.5%, 99.0% and 99.0% at concentrations of 7.03 pg/mL, 450 pg/mL and 900 pg/mL, respectively. Evaluation of Salivettes® for saliva sample collection showed interference when using citric acid impregnated swabs, but not with plain cotton swabs. The utility of the method was demonstrated in several applications. Clinical application of the method demonstrated normal circadian rhythms in healthy adult volunteers and disturbed sleep-phase in children with mismatched circadian rhythms.
Applying objective means for measuring sleep characteristics were included for a pilot-scale dose ranging study of melatonin. Clinically, there was an observable increase in total sleep time, reduction in sleep onset latency and less number of night-time waking with low dose melatonin (0.5-2 mg) as compared with baseline or placebo, however, the values did not reach a statistical significance. A delayed sleep-phase syndrome was commonly observed in the study participants. Sublingual melatonin helped in advancing the delayed sleep-phase syndrome. A majority of the children responded well to a 0.5 or 2 mg dose given 30 minutes before bedtime. This pilot scale dose-escalation study was designed to evaluate the appropriate dose one might consider for further RCTs. No adverse events or treatment-related comorbidities were observed or reported by the carers.
Evaluation of health-related quality of life and sleep characteristics through questionnaire and thematic analysis showed beneficial effect of melatonin. The extent of daytime sleepiness was evaluated from pediatric daytime sleepiness scale (PDSS). High scores were obtained before melatonin intervention demonstrating daytime sleepiness among the study participants. A significant improvement in HRQOL with regard to psychological health summary score (p=0.012), physical health summary score (p=0.018), and total health summary score (p=0.012) was observed (Wilcoxon Signed Ranked Test) through pediatric quality of life (Peds QL™) questionnaire. The qualitative analyses (thematic approach) provided a favourable outcome with melatonin intervention on sleep habit, school and/or social functioning and quality of life with good compliance. The result showed a positive and encouraging trend in favour of using melatonin intervention in these children, and paves the way for much larger, placebo-controlled randomised study designs.
There are ever increasing numbers of non-RCTs in studies on melatonin in children with circadian rhythm sleep disorders. The lack of an objective means of outcome like actigraphy and measuring melatonin concentration in such studies is common. A sensitive and accurate assay for melatonin in saliva samples demonstrated potential clinical applicability. Low-dose melatonin (0.5-2mg) was beneficial in the management of circadian rhythm sleep disorders with improvement in HRQOL and sleep characteristics.