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When to use drugs to help sleep
  1. P Gringras
  1. Paul Gringras, Evelina Children’s Hospital, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK; Paul.gringras{at}gstt.nhs.uk

Abstract

Paediatric sleep medicine is a relatively new but important and rapidly growing field. It is increasingly recognised that many “adult” sleep disorders begin in childhood where the consequences of missed diagnoses can be devastating. Adequate training of all health care professionals and careful eliciting of symptoms remains the first step in ensuring accurate and timely diagnoses. Although behavioural approaches play a huge role in paediatric sleep medicine, at times severe sleep disorders also require pharmacological treatments. However, the evidence base for these is weak, and currently treatments of conditions including insomnia, narcolepsy and restless legs syndrome in childhood still rely on hopeful extrapolation from adult data. A growth in randomised controlled trials over the last 5 years is encouraging; trial methodologies are also improving. International working groups and multicentre trials will increasingly be needed to evaluate the new technologies and pharmacological treatments that are emerging.

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The impact of paediatric sleep disorders on the child and their carers is usually plain to see. Families are physically and emotionally exhausted, and often need support themselves to follow any therapeutic intervention. Their children really do need a “good night’s sleep” for optimal daytime learning and behaviour. The impact of sleep loss on brain plasticity suggests the cognitive effects are likely to be even more important in early infancy than in any other period of life.1 Physical health is also compromised by inadequate sleep, and there are important links between short sleep and obesity in childhood.2

Paediatric sleep disorders are often missed; instead of simply being sleepy during the day, children who have slept poorly are more likely to present as irritable and hyperactive, with poor memory and creative skills.3 This problem is further compounded by the lack of training of their teachers and health professionals concerning children and their sleep.4

A thorough knowledge of normal sleep ranges and expected developmental changes is required before problems can be identified. Taking a detailed sleep history from a child and their carer need not take long but does need background awareness of all the possible diagnoses. Young children and those with developmental difficulties in particular, need to feel relaxed and able to talk about, write about, or draw pictures illustrating any symptoms they have experienced. Formal diagnoses should be possible in most cases and are detailed in the second International Classification of Sleep Disorders: Diagnostic and Coding Manual (ICSD).5

With the realisation that established adult sleep disorders may begin in childhood came an inevitable extrapolation to children of adult treatment approaches. However, effective surgical, psychological and pharmacological interventions differ across the age ranges. The use of most pharmacological interventions for paediatric sleep disorders lacks a robust evidence base and requires the use of unlicensed or off-label medication. Many studies have been small and poorly controlled, although the situation is now improving. However, this provides little solace to a desperate family having to cope with a child’s intolerable sleep problems, often without the resources to obtain respite or behavioural support. The balance between ethics, economics and evidence is difficult but hopefully may be made a little clearer with this review.

METHODOLOGY

This article is deliberately pragmatic and symptom based. Childhood sleep difficulties broadly separate into four problem categories: falling asleep at the right time, staying asleep, unusual behaviours that occur during the night, and finally being too sleepy during the day. Pharmacological management of sleep difficulties related to nocturnal seizure activity and psychiatric co-morbidities is outside the scope of this article.

The suggested management strategies are based on the available evidence as well as peer consensus and personal practice where the evidence is lacking. Literature searches were conducted for all paediatric sleep disorders (1950–2008 limited to “All child (age 0-18 years)”) in Medline, Psychinfo, Embase, the Cochrane database and Google Scholar. CINAHL yielded no extra information. Hand searching of existing personal references and of relevant original and review articles was also carried out.

Table 1 summarises the pharmacological strategies discussed in this article. Although the focus is on pharmacological options, treatment of co-morbidities and non-pharmacological interventions are briefly discussed where they are particularly important.

Table 1 Treatment options in paediatric sleep disorders*

CANNOT FALL ASLEEP AT THE RIGHT TIME

The definition of insomnia in children is much more challenging than in adults. The sleep behaviours are usually described by the caregivers and not by the children themselves. Whether particular sleep behaviours are a problem depends on a complex combination of parental perceptions, expectations, cultural standards and biological norms. Bedtime expectations, for example, differ widely within European countries, although there is no evidence that the sleep physiology of the children is different.6

Sleep onset insomnia

The infant that falls asleep perfectly when lying on their mother’s lap and having their hair stroked will require this same routine when they wake during the night. We find it helpful to show parents examples of sleep studies demonstrating how often typically developing toddlers wake during the night and point out that most can learn to settle on their own.

In a minority of young children there can be physical co-morbidities including gastro-oesophageal reflux, milk allergy or any physical cause of pain. Mood disorders become more important as causes of both insomnia and poor sleep maintenance in older children.7

This sleep problem is also more common in children with learning difficulties, autism, and attention deficit hyperactivity disorder (ADHD). Whether this relates to the general lack of awareness of zeitgebers (environmental cues that help set circadian rhythms), physiological disturbance of the circadian and homeostatic sleep mechanisms, or an exaggeration of daytime behavioural problems is still unclear, and every case is likely to be different.

Interventions for insomnia

Behavioural

Prescribing medication prior to behavioural intervention can seem an appealing option for a busy clinician and exhausted family who feel they have already tried the “bedtime hygiene stuff”. However, the evidence shows the immediate and sustained value of behavioural approaches, even in difficult groups of children who may have associated developmental or medical problems.8 This evidence and our clinical experience strongly suggest that a paediatric sleep disorder team should always include a clinical child psychologist. Our psychologist finds that even a few well timed phone calls can successfully support a family through the difficult stages of either extinction (leaving the child to cry) or graduated extinction (going in after a few minutes of crying and then increasing the intervals).

Melatonin

The administration of melatonin in sleep disorders has increased dramatically since its original use in helping the sleep of adults with visual impairments. It has acquired a major role in the treatment of paediatric sleep disorders, despite a relatively low level of supportive evidence and huge variation in dose range and indications amongst clinicians.9

It is known that melatonin activates brain melatonin 1 (M1) and melatonin 2 (M2) receptors, but the reason why exogenous melatonin may work in paediatric sleep disorders remains unclear; however, there are a number of possible explanations. These include the suggestions that melatonin acts to entrain a problematic circadian rhythm disorder, treats an endogenous melatonin deficiency state, acts as a soporific, or increases the duration of particularly important sleep stages. A number of melatonin analogues are being developed. Some have been trialled against placebo, but perhaps unsurprisingly, not against melatonin itself.

In randomised studies of typically developing children with sleep onset insomnia, melatonin significantly improves sleep latency (time to fall asleep) and quality of life, although it has not been shown to make a significant difference to total time asleep.10

Similar results have emerged from studies of children with ADHD and problems falling asleep. In one study, sleep hygiene was initiated first and was effective for many children.11 Those with persistently increased sleep latency entered the randomised controlled trial (RCT) phase which further reduced sleep latency. The combined sleep hygiene and melatonin intervention from baseline to 90 days’ post trial resulted in a mean decrease in sleep onset insomnia of 60 min.

A larger RCT with 105 children with ADHD and sleep onset insomnia also demonstrated a significant reduction in sleep latency and was the first study to also show an significant increase in mean total time asleep.12 Analysis of the timing of the dim light melatonin onset (a physiological marker of sleep phase) suggested that in this group melatonin was acting to advance sleep phase rather than merely behaving as a soporific. In both these studies there was no significant daytime effect on behaviour, cognition or quality of life.

Results from studies in children with learning difficulties, autism and epilepsy broadly show the same results and are summarised in recent systematic reviews.13 14 Since these reviews were published, a placebo controlled crossover trial using 5 mg of controlled release melatonin has demonstrated improvements of approximately 30 min in both sleep latency and total sleep time in children with neurodevelopmental difficulties and delayed sleep phase/impaired sleep maintenance.15 It is hoped that ongoing multicentre trials will start to clarify the appropriate dose ranges and the impact of genetic and developmental factors.16

The adverse effects of melatonin across studies are few and in controlled studies occur in equal frequencies in melatonin and placebo arms. However, controlled studies have all been short term (average 4 weeks) and data on long term effects are vague. A recently published open-label study provided some longer term data on the use of melatonin in children with sleep disorders.17 Forty four children with neurodevelopmental disabilities were recruited to continue with melatonin treatment. Adverse reaction to melatonin therapy and development of tolerance were not evident. There was no suggestion from the parents at any time that therapy activated an epileptic event in the 19 subjects who had a seizure disorder, and no new cases of seizures were noted. Because of the theoretical potential for melatonin to affect pubertal development this was carefully assessed. The median age of onset of puberty was 11.5 years. Interestingly, precocious puberty developed in five children who had severe neurodevelopmental disorders, but this was all prior to melatonin therapy.

Antihistamines

The sedative side effects of antihistamines have long been used for childhood insomnia, and may improve sleep and speed up behavioural programmes over short periods.18 However, tolerance can develop quickly and some children can experience dramatic and paradoxical over-arousal. The TIRED RCT specifically investigated the use of diphenhydramine in infants aged from 6 to 15 months and found it was no more effective than placebo in reducing night-time awakening.19

Clonidine

Clonidine is an antihypertensive agent with sedative side effects. The therapeutic window is narrow, both for adverse effects on sleep architecture and toxicity. Tolerance can develop over time leading to increased doses and increased risk of adverse effects. Despite these concerns, it is still widely used by as many as a third of clinicians surveyed in the USA.20

Benzodiazepines and non-benzodiazepine hypnotics

The use of benzodiazepines for adult insomnia remains controversial and there is still debate about the proposed superiority of the newer “z drugs”.21

Benzodiazepines can shorten sleep latency and decrease awakenings for adolescents, but also change sleep architecture. Children seem to be particularly sensitive to adverse effects including daytime behavioural disinhibition, ataxia and amnesia.

The newer non-benzodiazepine “z drugs” include zolpidem, zopiclone and zalepon. There are no paediatric data to support the use of zopiclone or zalepon. More is known about the pharmacokinetics of zolpidem in children22 and a recent RCT compared it to placebo for children with insomnia associated with ADHD.23 Reports from this study describe no superiority of zolpidem to placebo on sleep measures, and a high, 7% drop-out rate due to adverse effects of which dizziness, headaches and hallucinations were the most common.

Chloral hydrate and triclofos

Chloral hydrate and triclofos were formerly popular hypnotics for children but have a very long half-life and considerable potential for “hang-over” effects in children. The half-life of chloral hydrate itself is short (a few minutes), but the half-lives of its active metabolites are longer, being 8–12 h for trichloroethanol and 67 h for trichloroacetic acid. Chloral hydrate and triclofos are now mainly used for sedation during diagnostic procedures. Toxicity is also a concern due to a central nervous system depressant action and arrhythmogenic potential.

Herbal preparations

Lavender oil and other herbal options to improve sleep have been well described since the times of Hippocrates and Galen. In many cases the evidence base for these compounds is neither worse nor better than for many existing prescribed medications.24 Having first been described in the second century, there is equivocal evidence from basic science and clinical studies that Valeriana officinalis may have a role in the treatment of insomnia, but there are very few data on its use in children and only one small controlled study.25

Delayed sleep phase syndrome

In this disorder sleep onset is significantly delayed in relation to the desired bed time as a result of a delayed circadian rhythm. The quality of sleep is normal, but getting up early in the mornings is a huge problem. Young people describe feeling “permanently jet lagged”. A family history of “night owls” is common, reflecting a genetic tendency as well as developmental (there is a physiological delay in sleep phase around adolescence) and environmental pressures.26

Treatments

The challenge of treatment is to stop daytime naps and achieve a consistent and appropriate morning wake time. Practically this can be very difficult to do and gradual “resetting” of sleep wake times is necessary. Chronotherapy in this condition requires a seemingly paradoxical method of steadily delaying bed time by up to 3 h each night (a young person usually falling asleep at 4 am will be asked to stay awake until 7 am the following day and so on) until the desired time is reached.27

There is good evidence that melatonin given at night time will phase advance (so that they fall asleep earlier in the evening) young adults with delayed sleep phase syndrome over the short term,28 but there are no studies on younger children, and the relapse rate may be high on stopping treatment. The dose and timing appear to be important; the melatonin ideally needs to be administered about 4–6 h before the dim light melatonin onset time.

Combinations of exogenous melatonin and morning bright light phototherapy are helpful.29 In our clinical practice we find chronotherapy helpful in restoring normal sleep wake timing, and then a combination of early evening melatonin and morning bright light (light treatment with up to 2000 lx to suppress endogenous melatonin production) necessary to maintain an appropriate circadian rhythm.

UNUSUAL BEHAVIOURS THAT OCCUR DURING THE NIGHT

Parasomnias that arise out of non-REM sleep

A range of sleep disorders arise out of incomplete transitions between deep non-REM slow wave sleep and waking. These include confusional arousals, sleepwalking and night terrors. The timing of events is characteristic, usually occurring in the first third of the night. In the case of night terrors, it is often the parents and not the child who are “terrified” by the child’s fearful expression, screaming and inability to be consoled. As most children will outgrow these benign events, explanation and reassurance is usually all that is required. In more persistent or severe cases, it can be helpful to exclude precipitating factors such as sleep disordered breathing and periodic limb movement disorder.

We find a strategy of scheduled wakening30 shortly after the child has fallen asleep to be symptomatically useful in many cases. When the arousals are severe, persistent and interfere with quality of life (eg, the young person is not allowed to go on sleepovers or school trips), the short term use of benzodiazepines, usually low dose clonazepam, can be helpful.

Nightmares and parasomnias that arise from REM sleep

Nightmares arise from REM sleep and are vividly recalled by the child and young person, in contrast to night terrors. There is no evidence to support pharmacological interventions. However, nightmares can be precipitated by certain medications, including β blockers, and withdrawal of drugs that suppress REM sleep (REM rebound).

REM sleep behaviour disorder describes the return of muscle tone during REM sleep (when there is normally low or absent muscle tone). This results in children being able to physically enact their dreams with jumping, punching and running behaviours observed during dreams.31 REM behaviour disorder is very rare in childhood and narcolepsy and various neurological conditions, including brain stem tumours, need to be excluded before concluding there is an idiopathic origin.

Rhythmic movement disorders

Rhythmic movement disorders occur during transitions from wake to sleep but can also take place throughout the night. They include head banging, body rocking and moaning and are common in young children. Again, the parents are understandably distressed and concerned, yet the child will usually remember nothing. Scheduled waking can again be tried, but reassurance is the most important step with only one report of a combined behavioural and pharmacological approach.32

PROBLEMS STAYING ASLEEP

Restless legs and periodic limb movement disorder

Restless legs syndrome (RLS) describes unpleasant sensations in the legs that lead to a strong desire to get up and walk around, which temporarily relieves the symptoms. Symptoms worsen in the evening or night and are often better in the mornings. Having initially been recognised in adults, this disorder is increasing described in children, and interestingly some sleep physicians suggest that many cases of growing pains in childhood were in fact descriptions of RLS.33 Literature reviews also suggest associations with ADHD and untreated sleep disordered breathing.34 35

RLS is often accompanied by the rhythmic movement of the legs (or less commonly the arms) during the night, known as periodic limb movement disorder (PLMD). Both of these conditions are usually impossible to diagnose on the basis of history and require formal polysomnographic studies with anterior tibialis surface EMG recordings to monitor leg movements.

RLS and PLMD become clinically important when associated with daytime tiredness or inattention. In most children, specific pharmacological therapy is unnecessary unless the disorder is causing significant functional disturbance, such as insomnia or excessive daytime sleepiness.

The level of iron in cerebrospinal fluid (CSF) is thought to be important in the pathogenesis of PLMD in some cases. Ferritin levels are often measured for guidance, although CSF measurements and imaging studies may be more accurate. Many children with PLMD and low ferritin levels show a response to oral iron therapy.36

In current adult practice, dopamine agonists (ropinarole, pramipexole) are proposed treatments but there are very few data on their safety or efficacy in childhood.37 Gabapentin and clonazepam are less favoured in adults and again there are no robust paediatric studies.

Obstructive sleep apnoea syndrome

Sleep related breathing disorders are common in childhood, particularly at certain ages and in relation to certain clinical conditions and genetic syndromes.

Because most cases of obstructive sleep apnoea are due to adenotonsillar hypertrophy at around 3–5 years of age, surgical removal of tonsils and adenoids is the usual treatment.

In mild cases intranasal steroid sprays (usually fluticasone) can provide short term improvement38 as can leukotriene antagonists.39

EXCESSIVE SLEEPINESS DURING THE DAY

Narcolepsy

Narcolepsy in childhood usually begins with excessive daytime sleepiness. Vivid sounds and images before sleep onset (hypnagogic hallucinations), abrupt loss of muscle tone (cataplexy) often triggered by laughter or surprise, and later sleep paralysis can occur. The symptoms of narcolepsy are said to result predominantly from intrusive periods of REM sleep phenomena.

The discovery of absent or low levels of the hormone hypocretin (measured in CSF and normally produced by cells in the lateral hypothalamus) in most cases of narcolepsy with cataplexy can helps to support clinical diagnoses in difficult childhood cases.

Although most common in the second decade, around a third of people with narcolepsy have onset in childhood before the age of 15.40 Early diagnosis remains difficult with symptoms of daytime sleepiness usually preceding cataplexy. Children and their parents are still often blamed or accused of illicit drug use or too many late nights. The presentation of cataplexy also can be subtle and mistaken for clumsiness or misdiagnosed as epilepsy leading to inappropriate investigations and treatment.41

Excessive daytime sleepiness is the first and sometimes the only symptom that requires treatment. Thorough explanation to parents and schools can help with the provision of scheduled naps during the day.

There is good evidence in adult populations that both modafinil and methylphenidate can reduce the degree of daytime sleepiness.42 There are some data for adolescents but none for younger children. There is a disappointing lack of modafanil/methylphenidate comparative trials to help decide which to use first for children and young people.

In adults cataplexy has traditionally been treated using clomipramine or other antidepressants. More recently, sodium oxybate has been increasingly shown to reduce both cataplexy and night time sleep fragmentation with a reduction in daytime sleepiness.43 However, the potential for abuse is a cause for concern and as yet there are no controlled studies regarding the safety or efficacy of such treatments in children.

Trials of immunosuppressive treatments are based on the hypothesis that in genetically susceptible individuals, destruction of hypocretin neurons in the lateral hypothalamus occurs by a possibly reversible autoimmune process. Immunosuppression with prednisolone has not been successful, and there are still only case reports of transient improvements in children treated early in their disease course with intravenous immunoglobulin.44

Future avenues of interest include the possibility of specific CSF hypocretin-1 replacement therapies.

Kleine Levin syndrome

Recurrent hypersomnia or Kleine Levin syndrome is a rare disorder characterised by recurrent episodes of extreme sleepiness that typically occur weeks or months apart. Often the episodes are associated with hyperactive and irritable behaviours and increased appetite. Inappropriate sexualised behaviours can occur and young people describe a feeling of depersonalisation. A review of all the literature recently concluded that the prognosis was good (with or without treatment) with episodes often commencing in adolescence and ceasing when subjects were between 20 and 25 years old.45

There are no RCTs of treatment response in adults or children. The survey above identifies lithium as the most commonly used treatment; however, it requires administration during and between episodes with serum monitoring throughout. Stimulants are also suggested for sleepiness in this review, but in our limited experience time spent more awake (especially if accompanied by hyperactive and disinhibited behaviours) does not always improve the quality of life for sufferer or carers.

CONCLUSION

There are a number of diagnostic and therapeutic challenges that currently affect paediatric sleep medicine. In common with so much of paediatric practice, the majority of medications used are either unlicensed or off label.

Adult trial data include some adolescents, but there are rarely any data on children. Methodological problems affect many of the paediatric trials that do exist, and for many relatively rare conditions, multi-centre trials will be required to recruit enough subjects.

In conditions such as narcolepsy and RLS, the physiological and genetic bases are becoming clearer and are likely to influence diagnosis and management. For sleep disorders such as insomnia, the causes are more heterogeneous, with complex combinations of psychological as well as physiological factors affecting management.

Although there are many gaps in our current knowledge, this also makes paediatric sleep medicine an exciting and rapidly developing speciality with many clinical and research opportunities. Current clinical trials suggest that the role of melatonin for insomnia and medications for narcolepsy and RLS will be clearer in the near future, and there are fresh treatment options on the horizon. New technologies will allow more home based recording of physiological sleep parameters to aid diagnosis, and will capture changes in quality of life, daytime cognition and daytime behaviour to aid outcome measures.

REFERENCES

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Footnotes

  • Competing interests: The author is co-lead applicant on the ongoing MENDS Health Technologies Assessment funded trial of melatonin in developmental disabilities. Alliance Pharmaceuticals have supported this study through development of a CTA and supply of melatonin and placebo. The author has given independent educational lectures, received honoraria and attended events sponsored by Janssen-Cilag and UCB Pharma.

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