Elsevier

Brain and Development

Volume 22, Issue 4, 1 June 2000, Pages 213-217
Brain and Development

Original article
The therapeutics of melatonin: a paediatric perspective

https://doi.org/10.1016/S0387-7604(00)00120-0Get rights and content

Abstract

The production of melatonin by the pineal gland and its functions are considered, and then its possible uses in the treatment of children. Institutionalized children, and those with severe learning disorders, often have irregular sleep–wake patterns, and there is evidence that melatonin can result in improvement to the benefit of both the child and the carers. The affected children can become less irritable, calmer, happier, and content. Also they may socialize better and become more attentive, with an improvement in their cognitive abilities. Another group of children who are likely to suffer from disturbed sleep are those who are visually handicapped. Melatonin given in the evening can improve their sleep patterns, and often their performance. No important side-effects have been reported. It is generally accepted that if a child is liable to epileptic seizures sleep deprivation may well exacerbate them. There is some evidence from clinical trials that in that event melatonin can be helpful. There are many other problems in which it is claimed that treatment with melontin is justifiable. These are mentioned, but further confirmatory studies are needed in most of them. There is no doubt that melatonin can effect the circadian system, and shift the sleep–wake cycle; and that there are situations in which this can be desirable.

Introduction

The discovery of a neurohormone, melatonin, excreted mainly by the pineal gland has raised a number of therapeutic possibilities. It is produced during darkness and has been implicated in the regulation of the mammalian circadian system, especially in sleep and reproductive rhythms. It is also claimed that when the sleep pattern of children improved on treatment with melatonin they become less irritable, calmer, happier, more playful, content and affectionate, with fewer temper tantrums. Also, the children were able to socialize better and were gentler with their siblings and pets. They became more attentive, and their cognitive abilities and mobility improved [1]. In addition there is experimental evidence of a role in immunological reactions [2], and possibly reproductive functions [3]. Related to this may be an anti-cancer effect although this is more likely to be due to antimitotic activity [4]. The link between the pineal gland, and its influence on the thymus, does raise the possibility of using melatonin in the treatment of primary and secondary immunodeficiencies [5].

The pineal gland consists of two types of cells; pinealocytes which produce indolamines, mostly melotonin, and peptides; and neuroglial cells. In the production of melatonin tryptophan is converted to serotonin, and then to N-acetylserotonin, and finally to melatonin. Newborn infants produce little or no melatonin until about 3 months of age, and then the levels increase for the next 9 or 10 months and remain stable until the levels decline just before puberty. Circadian rhythms are an adaptation to the solar changes of light and dark, and it is the suprachiasmatic nucleus of the anterior hypothalamus which is responsible for this function. This nucleus, and the anterior hypothalamic area, the paraventricular nucleus, and the lateral hypothalamic area are influenced by light transmitted to the retina; and melatonin levels rise in darkness. There is also a correlation between this rise and the onset of sleep [6], and it is suggested that when melatonin is given in high doses it may promote sleep by causing relative hypothermia [4]. Nocturnal sleep onset correlates well with the onset of melatonin secretion, and the timed administration of medicinal melatonin can result in the earlier onset of endogenous night-time secretion, thus resetting the endogenous circadian pacemaker.

There are a number of conditions which are said to be improved by treatment with melatonin, but which need further study, such as tinnitus [7], facilitating the termination of benzodiazepine treatment while maintaining good sleep quality [8], and as already mentioned in the treatment of cancer [9]. It is also suggested that melatonin can help in the diagnosis of neoplastic disease, in the control of gastric ulcers and of colitis, and even in the treatment of migraine [10], and of tension headaches in patients who suffered from delayed sleep onset [11]. It is also possible that melatonin can be used in the prophylaxis of cluster headaches. The cause of these are unknown, but if melatonin plays a part in the regulation of core body temperature, and if concentrations of melatonin rise as body temperature falls, the link may be the finding of lower concentrations of this hormone among sufferers; as there is a suggestion that body heat can be a precipitating factor [12]. It is claimed that melatonin can improve the sleep disorders associated with severe depression, among adults anyhow [13]. Animal experiments may indicate that melatonin can have a protective effect when damage occurs in focal ischaemia [14], and in toxic damage to the dopaminergic system [15]; and this finding may warrant further study. Also chronic sleep disorders can adversely affect the child's development, as sleep plays a major role in the early maturational process in the brain [6]. There is still not universal agreement over the dose of melatonin, and this can vary from 0.3 to 25 mg of fast release synthetic melatonin. Infants are usually started on 2.5 mg and older children on 5 mg [1]. Plasma levels usually peak after about 1 h, and show a biphasic elimination pattern with half-lives of 3 and 45 min [16]. Also the content of melatonin products may vary.

Section snippets

Irregular sleep–wake patterns among institutionalized children, and those with severe learning disorders

Sleep disturbances are relatively common. Many elderly people complain of sleeping badly, although this may have to be confirmed by observation. However, there is evidence that during the night serum melatonin levels among the elderly who suffer from insomnia are low compared with age matched controls. They are even lower in such patients living in institutions rather than in the community, which may be linked to lack of exposure to bright light, insufficient physical exercise, or to some form

Irregular sleep–wake patterns among visually impaired children

Children who may be especially liable to suffer from disturbed sleep patterns are those with impaired vision. In a discussion of sleep disorders in visually impaired children, Stores and Ramchandani [22] stress the importance of early recognition and treatment of sleep disorders in visually impaired children, otherwise their development and behaviour may be adversely affected. Among a wide range of therapeutic possibilities they include the use of melatonin; but emphasise that its effectiveness

The benefits of melatonin in children with epilepsy

It is generally accepted that deprivation of sleep in a child suffering from epilepsy can result in an exacerbation of seizures, and melatonin can lead to an improved quality of sleep. A parental questionnaire was used to assess sleep problems by Cortesi et al. [28]. Eighty-nine children with idiopathic epilepsy were studied for comparison with 49 siblings and 321 healthy control children equally distributed for age and sex. The sleep problems included parasomnias, sleep fragmentation, daytime

Conclusions

Children with severe learning and behaviour disorders are particularly liable to sleep problems [32], and from these various studies there seems to be no doubt that for certain children treatment with melatonin, with its duel effect as a hypnotic and as a means of altering the circadian pacemaker which controls the time of sleeping and waking [33], will improve their sleep patterns; and as a result many aspects of their behaviour. This will not only be of benefit to the child but also be a

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