• 
• 

Three Part Question

In [a pre-school child with visual impairment and mild to moderate learning difficulties in whom conventional treatments have failed] is [Melatonin] likely [to improve sleep outcome]?

Clinical Scenario

A girl aged 3 years and 6 months has neurofibromatosis with significant visual impairment and mild to moderate learning difficulties. She has always been difficult to settle to sleep and has frequent nocturnal wakenings. A sleep programme with specific behavioural management techniques has been used as have sedative medications such as Trimeprazine, which caused deterioration in concentration and daytime sleepiness. Should she be tried on Melatonin?

Search Strategy

Medline 1966 to present, EMBASE 1980- using OVID interface
{Melatonin.mp AND Sleep disorders.mp (and exploded) AND Learning disabilities (and exploded)} AND LIMIT to:Children <0 to 18 years> Human, English language. Secondary sources: DARE, Clinical Evidence Dec 2000, Medicines for Children RCPCH 1999- None. Embase - 0. Cochrane Library -Systematic Reviews- 0, Abstracts of Reviews of Effectiveness- 0, Controlled Trials Register –6 papers of which 2 relevant.(Same papers found through search detailed below)

Search Outcome

This gave 90 references –all titles checked – 15 considered – 6 included. 9 excluded as 3 non-systematic reviews, 2 other conditions, 1 non-delayed children, 1 slow-release melatonin, 2 abstracts only

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Jan JE et al 1994 Canada	15 children aged 6 months to 14 yrs, mean 6.8yr, most multiple disabled, 5 with epilepsy, 9 visually impaired. Melatonin 2.5mg to 5mg.	Double-blind placebo controlled trial. (Level 1b-).	Sleep charts	No adverse effects	6 (40%) not randomised Though type of sleep disturbance described
			Parental interview	No response in 2/15. 1 child-ceased effect even with 20mg after 6/12
Camfield et al 1996 Canada	6 children aged 3-13 yrs, blind with at least moderate learning disability, using 0.5 – 1mg melatonin	'n-of1' double blind placebo trial. (Level 2b-).	Number of nights without wakening between 10pm-7am.		Low dose used Timing in relation to desired sleep time may have been too long No adverse effects noted No information about blinding or randomisation
			Number of wakenings between 9pm-7am
			Sleep diary. Average number of hours sleep per 24 hours	Found MLT to be ineffective in 5/6
Palm et al 1997 Sweden	8 aged 3-23yrs (6 children aged 18 or less). All functionally blind M/S learning disabilities. 0.5-2mg melatonin age dependent	Open study (level 4-)	Sleep diaries for 6 week prior to treatment and several months during treatment		No side effects reported
			MLT levels in 7 children	MLT levels showed delayed peak
Sheldon 1998 USA	Consecutive recruitment. 6 children 9 months-18 yrs, multiple neurological deficits and chronic sleep disorders with 5mg at bedtime	Open study. (Level 4-) Research Letter.	Wrist Actigraph. Changes in sleep onset latency, Nocturnal wakenings, Total sleep time	Marked improvement in all 3 measures in 5/6	Study stopped due to increased or new seizure type activity on melatonin in 4/6 No info on types of AE meds used
O'Callaghan 1999 UK	7 Children age 2-28yrs with Tuberose Sclerosis with Epilepsy +SLD Randomised to placebo or 5mg Melatonin 20 min prior to bedtime	Crossover RCT double blind. (Level 1b-)	Sleep diary. Total sleep time, sleep onset latency. No awakenings	Mean improvement in total sleep time of 0.55hr (CI 0.088-1.01). No effect on fragmented sleep	Short treatment time for any adverse effects to become apparent. No effect noted on seizure frequency
Dodge et al 2001 USA	20 children with moderate to severe developmental disabilities (4/20 visual impairment). Age range 1-12 years. 36 recruited but only 20 completed study	RCT double blind, placebo control. (Level 2b-)	Sleep log and parental questionnaire. Sleep latency	Sleep latency improved in all but 2 children on MLT( p<0.05) more marked in those with greater sleep latency on baseline measure	No side effects reported Large drop out rate but no reported differences in diagnosis, age, epilepsy etc in those not completing No baseline data for type or severity of sleep problems in those dropping out
			Number of wakenings	No change
			Duration of sleep	Duration of sleep improved with MLT but no different from placebo.

Comment(s)

Most studies had small numbers of participants with significant drop out rates or non randomisation in larger studies. Very few of the studies give p values or confidence intervals – they appear far too small to give statistically meaningful effects. One of the trials (by Camfield) is very different in design, an 'N-of-1' study. These trials are designed for each individual patient, and allow for interpersonal variation in drug effect. Classically an N-of-1 trial has three blocks, during each block the patient receives sequentially therapy and placebo under double blind conditions with an appropriate washout period. Response in 2 or 3 blocks is considered positive, less than this due to chance alone. Even allowing for the difficulty of recruitment and objective assessment of outcomes in children with multiple difficulties, there is currently little good quality evidence for the effectiveness of Melatonin. The startling increase in seizures noted by the Sheldon paper is of great concern, especially in the UK where Melatonin is often given in an uncontrolled way with overseas imports of the drug. A large multicentre placebo controlled RCT is needed to try to clarify which children and what types of sleep disorder are most amenable to treatment, and to define the likely side effect profile.

Clinical Bottom Line

Melatonin may be effective in sleep onset difficulties, but not in fragmented sleep or early morning wakening, though evidence is poor quality. There is little evidence regarding Melatonin's longterm safety profile Melatonin should be used with caution in any child with epilepsy in view of increased seizure frequency in one study; 'N-of-1' methods may be considered.

References

1. Jan JE, Espezel H, Appleton RE. The treatment of sleep disorders with melatonin. Dev Med Child Neurol. 1994 Feb;36(2):97-107.
2. Camfield P, Gordon K, Dooley J, Camfield C. Melatonin appears ineffective in children with intellectual deficits and fragmented sleep: six J Child Neurol. 1996 Jul;11(4):341-3.
3. Palm L, Blennow G, Wetterberg L. Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances. Dev Med Child Neurol. 1997 May;39(5):319-25.
4. Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet. 1998 Apr 25;351(9111):1254.
5. O'Callaghan FJ, Clarke AA, Hancock E, Hunt. A, Osborne JP. Use of melatonin to treat sleep disorders in tuberous sclerosis. Dev Med Child Neurol. 1999 Feb;41(2):123-6.
6. Dodge NN, Wilson GA. Melatonin for treatment of sleep disorders in children with developmental disabilities. J Child Neurol. 2001 Aug;16(8):581-4.