Melatonin in sleepless children : everything has a rhythm?

Abstract

Every living organism has an biological clock regulating endogenous melatonin production, synchronized by exogenous impulses like daylight, temperature and feeding. Inappropriately applied bright light disturbs this melatonin rhythm. Some large swine producers apply artificial light three times a day for three hours; we compared the 24 hour melatonin rhythm of pigs in a large swine production unit with pigs in a farm with natural light schemes (chapter two). No significant differences were found comparing mean melatonin levels of both farms of different light and feeding phases. We measured salivary melatonin concentrations after a single dose melatonin at 11 a.m. in three patients with worsening sleep quality after initial good response to melatonin treatment (chapter three). These levels remained above 50 pg/mL, in contrast to levels found in three controls with sustained response to melatonin. After resuming melatonin treatment with a considerably lower dose sleep problems disappeared, suggestive of slow melatonin hepatic CYP1A2 metabolisation. In patients with loss of response to melatonin, a melatonin clearance test and a considerably dose reduction is advised. In chapter four the meta-analysis of the efficacy and safety of exogenous melatonin in advancing sleep-wake rhythm in patients with delayed sleep phase disorder is described. Five trials including 91 adults and four trials including 226 children showed that melatonin treatment advanced mean DLMO by 1.18 hours and clock hour of sleep onset (SOT) by 0.67 hours. Melatonin decreased sleep-onset latency (SOL) by 23.27 minutes. In conclusion, melatonin is effective in advancing sleep-wake rhythm and DLMO in delayed sleep phase disorder. In chapter five a post-hoc analysis of two previously published trials in children with CSOI assessing onset and stability of the therapeutic effect of 4-weeks melatonin treatment is described. One week and four weeks of melatonin treatment showed a phase-advance of SOT from 22:05 to 20:45 hrs. respectively 21:09 hrs. and SOL decreased from 53 min to 18 respectively 25 min. The onset of melatonin treatment effect can be expected within a few days after commencement and remains stable after that. The Meldos study (chapter six) aimed to establish a dose–response relationship for melatonin 0.05, 0.1, 0.15 mg/kg or placebo in advancing DLMO, SOT, and reducing SOL in 72 children aged 6-12 yrs with CSOI in a 1-week randomized, double-blind trial. Treatment with melatonin significantly advanced SOT and DLMO by 1 hour and decreased SOL by 35 min. This effect of melatonin was not dose related but increased with an earlier circadian time of administration. Melatonin 0.05 mg/kg given at least 1-2 hrs before DLMO and before desired bedtime is effective for treatment of CSOI in children. After mean 3.1 yrs, we evaluated pubertal development, sleep quality and mental health development of 51 former Meldos participants with questionnaires (chapter seven). Mean questionnaire scores did not differ significantly from published scores of the general Dutch population of the same age and sex, indicating that melatonin treatment (mean dose 2.69 mg) in children may be sustained over a long period of time without deviation of sleep, puberty and mental health.