Melatonin in the treatment of insomnia in children and adolescents

AIMS AND METHOD

To review the efficacy and safety of melatonin in the treatmentof insomnia in children and adolescents, through a Medlinesearch covering the years 1966 to November 2003.

RESULTS

Five placebo-controlled studies and several case series wereidentified. Melatonin reduces sleep latency, but does not consistentlyimprove other aspects of sleep disturbance. Safety, particularlyin the medium- and longterm, is poorly evaluated; short-termconcerns include exacerbation of epilepsy and asthma.

CLINICAL IMPLICATIONS

Melatonin might be effective in the short-term treatment ofsleep onset insomnia. The optimal dose is unknown. It cannotcurrently be recommended for the treatment of other forms ofsleep disturbance or for routine long-term use. Melatonin isnot a licensed medicine in the UK.

Introduction

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Introduction

From early childhood onwards, the cycle of wakefulness and sleepinessis regulated by a circadian ‘clock’ in the suprachiasmaticnucleus (SCN) of the hypothalamus. This clock is regulated(reset) by various cues, including that of the light-dark cycleof day and night.

In the neonate, there is little entrainment of the sleep-wakecycle to the light-dark cycle (Garcia et al, 2001). By theage of 6 months, circadian rhythms have become establishedand sleep patterns have taken on a roughly 24 hour cycle of nocturnal sleep plus daytime naps. By the age of 6 years, mostchildren sleep only at night. Total sleep time gradually decreaseswith age and by adolescence has stabilised to a daily averageof about 8 hours and the sleep-wake cycle to slightly morethan 24 hours. This cycle is reset daily by the SCN.

Insomnia is a common problem in children with sensory deficitsand some learning disability syndromes. It is also a symptomof childhood psychiatric disorders such as depression and attention-deficithyperactivity disorder. Persistent sleep disturbance in a youngchild can adversely affect family life. Mothers of learning-disabledchildren with severe sleep problems have been reported to bemore irritable and less affectionate towards their childrenthan mothers of such children without sleep problems (Quine, 1992).Successful treatment of the child’s sleep problemsgenerally leads to improvements in the mother’s mentalstate, confidence and relationship with the child, as wellas in the child’s behaviour (Minde et al, 1994).

In adolescence, delayed sleep phase syndrome, in which the sleep-wakecycle may be particularly prolonged, is common. About 10% ofotherwise normal children (Smits et al, 2001) and up to 80%of children with developmental disorders (Jan & O’Donnell, 1996)are affected.

The role of melatonin

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The role of melatonin

Melatonin is an endogenous hormone chemically related to serotonin.It is produced by the pineal gland in the midbrain. Body levelsfollow a circadian course, being stimulated by the eveningonset of dim light and suppressed by bright light. The eveningrise in melatonin precedes the rise in sleepiness by about1.5-2 hours (Tzischinsky & Lavie, 1994). The circadianrhythm of sleep consolidation (the ability to stay asleep)may also be related to melatonin levels, but this has yet tobe demonstrated. Melatonin acts by resetting any disruptionof SCN rhythms. Given its association with circadian rhythms,oral melatonin could be expected to treat sleep disturbances.Many case studies, case series, open and controlled studieshave been published. These are summarised below.

Case series
Jan & O’Donnell (1996) gave melatonin (2.5-25 mg)to 100 children with developmental disorders, half of whom werevisually impaired or blind. Benefits including fewer tantrums,better attention and improved socialisation were noted in 80%.In a further case series, Palm et al (1997) gave melatonin(0.5-4 mg) 30-60 min before the scheduled bedtime to eight children and young adults. All the children were learning-disabled andblind, and four also had hearing impairments. All improvedin terms of sleep-wake timings.

In a case series of two children with Rett syndrome, a dramatically beneficial effect on the regulation of the sleep-wake cyclewas seen in one child, with the other child showing marginalbenefit (Miyamoto et al, 1999). Jan (2000) gave melatonin(3 mg) to 10 children with developmental disorders and severe sleep disorders: 8 of the 10 improved with respect to delayof sleep onset, early morning waking, duration of unbrokensleep and total duration of sleep. In the most recent caseseries, Ivanenko et al (2003) gave melatonin (average dose2 mg) an hour before bedtime to 32 children with chronic sleepproblems. Partial or complete resolution of sleep problemswas achieved in 29. Some children (number unstated) were receivingother unspecified medical and behavioural interventions.

Controlled studies
Five placebo-controlled studies have been published. Camfieldet al (1996) gave melatonin (0.5 mg or 1mg) or placebo in2-week alternating phases at 18.00 to six children with fragmentedsleep and developmental disorders, none of whom showed anysignificant improvement in sleep patterns. McArthur & Budden (1998) gave nine children with Rett syndrome variable dosesof melatonin or placebo for a 4-week period with a 1-week drugwash-out period between the treatment and placebo phases. Sleep latency was reduced significantly in the treatment phase, althoughindividual response varied greatly. Dodge & Wilson (2001),in a 6-week double-masked, placebo-controlled study, comparedmelatonin with placebo in 20 children with developmental disorders.Significant reductions in sleep latency were observed, butsleep duration and number of awakenings did not change.

Smits et al (2001) gave 40 children with sleep onset insomniaeither 5 mg melatonin or placebo once daily at 18.00 for 4weeks. Children with developmental disorders were excluded.Melatonin was significantly better than placebo with respectto lights-off time, sleep onset and sleep duration, but notsleep latency or wake-up time. Two children had mild headacheduring the first 2 days of treatment with melatonin, and onechild developed mild generalised epilepsy while taking open-labelmelatonin 4 months after the start of the trial. On 18-monthfollow-up, 13 children were able to stop taking melatonin without further sleep disturbance.

In a further similar study (Smits et al, 2003), 62 childrenwith idiopathic chronic sleep-onset disorder were given melatonin5 mg or placebo for 4 weeks after a 1-week baseline period.The active group improved significantly in measures of generalhealth, sleep onset time and sleep offset time. There was nochange in lights-off time or total sleep time. Children withcomorbid psychiatric illness were excluded from this study,with the exception of those treated with methylphenidate. Theactive and placebo groups contained markedly different numbersof children prescribed methylphenidate (22% v. 54%). This couldhave biased the result, as methylphenidate is independentlyassociated with insomnia.

Melatonin is widely prescribed by child psychiatrists in theUK, although it is not a licensed medicine.

Side-effects

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Side-effects

Since melatonin is a natural substance, it is often assumedthat its side-effect profile is benign. However, most otherendogenous hormones produce considerable adverse effects inhigh or inappropriately phased doses and it should be anticipatedthat melatonin might behave similarly. Many of the publishedreports involved children with developmental abnormalities,which limited the scope for detection of subtle adverse effects.Most studies involved short-term use of melatonin and did notsystematically inquire about side-effects.

Sheldon (1998) reported that melatonin increased seizure frequencyin neurologically disabled children, an effect that disappearedwhen melatonin was discontinued and reappeared on further challenge.Also, Smits et al (2001) reported the development of mildepilepsy in one child. Whether seizure threshold is affectedin the general population is unknown.

Melatonin raises levels of inflammatory cytokines such as interleukins1 and 6 and tumour necrosis factor alpha (Maestroni, 1993),and this effect may have adverse consequences for people withinflammatory-mediated conditions such as asthma. Sutherlandet al (2003) and Sutherland et al (2002) reported that peakendogenous levels of melatonin were elevated in people withnocturnal asthma and were inversely correlated with measuresof respiratory function; they concluded that the ‘avoidanceof exogenous melatonin supplementation by persons with asthmamight be warranted’.

Melatonin has contraceptive properties and can affect the onsetof puberty (Weaver, 1997). It also has antioxidant (Pieri et al, 1994)and cytostatic (Brzezinski, 1997) properties. These effects are minimal at physiological levels, but maybecome more apparent when synthetic melatonin is taken in supraphysiologicaldoses: the cut-off point between physiological and pharmacologicallevels in adults is estimated to be produced by doses of 500µg, and this is likely to be less in children.

In clinical depression in adults, there is evidence that therisk-benefit ratio for melatonin may be adverse. Carman etal (1976) found that melatonin exacerbated symptoms of dysphoria,reduced sleep and led to weight loss in a small, double-blind,cross-over study in moderately to severely depressed adultpatients. It has been suggested that seasonal affective disordermight respond to propranolol through the suppression of endogenousmelatonin production (National Institute of Mental Health USA, 2003).

Overview

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Overview

Five placebo-controlled trials in children have been identified.Most of the published literature consists of case reports andcase series, which used a variety of doses and formulationsof melatonin. The nature of the populations treated is diverse,and most studies report shortterm use in which the placeboeffect would be highest. Oral melatonin may reduce sleep latency, but its effects on other aspects of sleep are inconsistentbetween studies. The optimal dosages and duration of treatmentare unknown. Side-effects have been poorly evaluated to date,although worsening of seizures and asthma have been reportedin the short term. Long-term side-effects are not established, although melatonin is known to have significant effects onmany body systems. Melatonin is not a licensed medicine inthe UK and the prescriber is fully accountable for any problemsthat might result from its use.

References

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