Review article
Pharmacological treatment of sleep disturbance in developmental disabilities: A review of the literature

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Abstract

Sleep disturbance is a common problem in children with developmental disabilities. Effective pharmacologic interventions are needed to ameliorate sleep problems that persist when behavior therapy alone is insufficient. The aim of the present study was to provide an overview of the quantity and quality of pharmacologic research targeting sleep in children with developmental disabilities. Efficacy studies of medications most likely to be prescribed to children are reviewed in detail. Medline and PsychInfo searches were performed to identify relevant clinical trials and case reports, published between 1975 and 2009. Key search terms included sleep, children, antihistamines, alpha adrenergic agonists, antidepressants, antipsychotics, melatonin, ramelteon, benzodiazepines, and nonbenzodiazepines. The literature search identified 58 articles that met the inclusion criteria. Well-controlled studies employing both objective polysomnography and subjective sleep measures are needed to determine the efficacy and safety of currently prescribed pediatric sleep medicines. Melatonin appears to be the most widely assessed agent and safest choice for children with developmental disabilities. Trazodone, mirtazapine, and ramelteon hold promise but require further study.

Research highlights

▶ Comprehensive literature search of pharmacological treatment of sleep disturbance in children and adults with developmental disabilities.▶ Key search terms included sleep, children, antihistamines, alpha adrenergic agonists, antidepressants, antipsychotics, melatonin, ramelteon, benzodiazepines, and nonbenzodiazepines (Z drugs).▶ Results Fifty eight articles met inclusion criteria. Twenty five controlled trials in typical children and children with developmental disabilities, 15 uncontrolled trials in children, and 18 controlled studies in adults.▶ Diphenhydramine use persists in pediatric populations with sleep problems, despite the lack of empirical evidence showing its effectiveness.▶ Clonidine's use as a hypnotic has not been adequately researched in pediatric populations, and it appears to decrease REM sleep.▶ Benzodiazepines carry a number of adverse effects, and the risks that undermine their use as hypnotics.▶ Zolpidem has not proven effective in the treatment of childhood insomnia. It may be useful in adolescents and adults.▶ Zaleplon has been studied in adults only, and it has been effective in reducing SOL but not fragmented sleep.▶ Imipramine is not recommended for use as a hypnotic as it may produce alerting effects.▶ Amitriptyline, improves sleep initiation and maintenance, but reduces REM sleep and may cause rebound insomnia following its discontinuation.▶ Melatonin appears to have the most empirical evidence for use and the best pharmacokinetic/dynamic profile treatment for sleep disorders.▶ Other promising hypnotics appear to be trazodone, mirtazapine, and ramelteon.

Introduction

According to a multidisciplinary task force developed under the auspices of the American Academy of Sleep Medicine, pediatric insomnia may be defined as difficulty of initiating or maintaining sleep that is viewed as a problem by the child or caregiver (Owens et al., 2005). In addition, clinical significance is characterized by the frequency, chronicity, severity, and the associated impairment in daytime functioning in either the child or the child's family. The sleep problem may be due to a primary sleep disorder or it may be secondary to some other condition (e.g., psychiatric, neurologic, medical, drug, or alcohol related) (Owens et al.; Bezchlibnyk-Butler and Jeffries, 2005, Palermo et al., 2002, American Academy of Sleep Medicine, 2001).

Recent studies suggest that the prevalence of sleep disorders in children with developmental disabilities ranges from 25% to 86% (Didden and Sigafoos, 2001, Richdale et al., 2000, Robinson and Richdale, 2004, Wiggs and Stores, 1996), and that children with neurologic injury, genetic, psychiatric, and behavioral syndromes, are especially susceptible to certain types of insomnia (Owens et al., 2005). Examples of these include children who are blind or have an autism spectrum disorder (ASD) and experience circadian rhythm disturbance, children with Williams syndrome and associated periodic limb movement disorder (PLMD), delayed sleep onset or fragmented sleep in young females with Rett's syndrome, severe insomnia often associated with Smith-Magenis syndrome, and the increased number of nighttime arousals found in children with Tourette's syndrome (Owens et al.).

Prior to recommending pharmacological intervention for the treatment of insomnia in a child with a developmental disability (DD), it is important to determine whether the sleep problem is behaviorally or medically based and whether it is a symptom of another primary medical problem (Owens, Palermo, & Rosen, 2002). Palermo et al. (2002), rationalized that three groups of children should be considered for treatment with pharmacotherapy: (a) children whose sleep disturbances demonstrate chronicity and severely impact their behavior and functioning; (b) children whose sleep disturbances require rapid, reliable amelioration; and (c) children whose sleep disorders are attributed to developmental or structural damage that interferes with sensory or social cues necessary for sleep organization. For these children, it is useful to employ pharmacotherapy in combination with environmental changes (i.e., sleep hygiene) and behavioral interventions for treatment.

Presently, there are no Food and Drug Administration (FDA)-approved medications for pediatric insomnia. Pediatricians, however, are prescribing a number of over-the-counter and prescription medications for children with sleep problems (Meltzer et al., 2007, Owens, 2009, Pelayo and Dubik, 2008, Stojanovski et al., 2007). One complicating issue is the general lack of specialized training available to parents and caregivers of children with sleep disturbances (Pelayo, Chen, Monzon, & Guilleminault, 2004). Without training in non-drug treatments as part of a multimodal management plan, pharmacological treatment alone may lead to unsatisfactory results for patients and their families (Pelayo et al.). In addition to following principles of good sleep hygiene (Owens et al., 2005), the most common behavioral interventions used for treating disturbances of sleep include stimulus control (i.e., bedroom/bed used only for sleep), extinction/graduated extinction (i.e., removal of parental attention/allowance parental scheduled checks) and bedtime fading (i.e., put the child to bed late, then gradually move bedtime up by 15 min intervals) (Owens et al., 2002).

When put into practice reliably and consistently, behavioral interventions alone may lead to improved sleep and functioning for the whole family. However, parents sometimes experience problems during the initial stages of a behavior plan's implementation. A parent may be reluctant to use extinction if it means ignoring the child's cries during the night (Palermo et al., 2002) and training parents can take a significant amount of time, which could cause even more distress for the family, especially if the child engages in an extinction burst during the training period. For children with chronic and severe sleep problems that are neurologically based or are due to structural damage, the addition of adjunct pharmacotherapy often proves necessary to enhance the quality of the child's sleep.

Results of three surveys and a retrospective chart review showed that pediatricians and psychiatrists are prescribing nine classes of drugs to children for sleep disturbances (Efron et al., 2003, Meltzer et al., 2007, Schnoes et al., 2006, Owens et al., 2003). The most commonly prescribed medications were antihistamines, alpha-adrenergic agonists, antidepressants, melatonin, anitpsychotics, benzodiazapines, and “Z-drugs” (zaleplon and zolpidem). In this paper, I systematicallyreview the current research on “sleep medicines” (and others) used to treat children with developmental disabilities and sleep disturbances.

Section snippets

Inclusion/exclusion criteria

A literature search for sleep studies was conducted in PsycInfo and Medline databases. In addition, reference sections of relevant articles were reviewed to identify any applicable sleep research that may have been overlooked. To be included in this review, studies had to (a) be written in English; (b) involve children, adolescents, or adults; (c) target sleep disorders, such as dysomnias, or parasomnias that interfere with sleep initiation and maintenance; and (d) include a pharmacological

Overall quality of reviewed research

The literature search identified 25 randomized, double-blind, PBO-controlled, trials in typical children and children with DDs, 15 uncontrolled trials in children, and 18 fully controlled studies in adults that met the inclusion criteria. I made one exception and included two quasi-controlled adult studies of trazodone, as they provided important additional information in regard to the use of this agent (Saletu-Zyhlarz et al., 2001, Saletu-Zyhlarz et al., 2002). Taken as a whole, this suggests

Discussion

Upon inspection of the tables in this manuscript it is evident that the quality of research differs noticeably among the 58 studies cited. The chasm appears widest between industry-driven adult clinical trials and investigator-driven studies focused on pediatric research. Keeping in mind Sprague and Werry's (1971) criteria for conducting valid scientific research, level of control, in addition to the quality of the outcome measures determines the degree of confidence we have in the study

Conclusion

Diphenhydramine use persists in pediatric populations with sleep problems, despite the lack of empirical evidence showing its effectiveness. Frequency of use may be a by-product of its over-the-counter access and its effectiveness in mediating allergic reactions. But, how much do we really know about this class of drug and its effectiveness in ameliorating sleep? It is time to either confirm or disconfirm its efficacy with well-controlled clinical trials employing both objective and subjective

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