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

Research in Developmental Disabilities 32 (2011) 939–962

Contents lists available at ScienceDirect

Research in Developmental Disabilities

Review article

Pharmacological treatment of sleep disturbance in developmental disabilities: A review of the literature Jill A. Hollway *, Michael G. Aman The Nisonger Center UCEDD, The Ohio State University, I/DD Psychology, 1581 Dodd Drive, Columbus, OH 43210, United States

A R T I C L E I N F O

A B S T R A C T

Article history: Received 16 November 2010 Received in revised form 23 December 2010 Accepted 27 December 2010 Available online 5 February 2011

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. ß 2011 Elsevier Ltd. All rights reserved.

Keywords: Pharmocology Sleep disturbance Children Developmental disabilities

Contents 1.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Sleep disturbance in developmental disabilities . . . . . . . . . . . . . . . . 1.2. Current interventions for sleep disturbances . . . . . . . . . . . . . . . . . . Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Inclusion/exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Review criteria for study quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Overall quality of reviewed research. . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Drug classes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Antihistamines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Melatonin and melatonin agonists . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Alpha-adrenergic agonists/antiadrenergics . . . . . . . . . . . . . . . . . . . . 3.5. Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Pyrinidine derivatives [non-benzodiazepine, GABAergic (Z) drugs] . 3.7. Cyclic antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Corresponding author. Tel.: +1 624 247 6402; fax: +1 614 247 6402. E-mail address: [email protected] (J.A. Hollway). 0891-4222/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ridd.2010.12.035

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3.8. Atypical antipsychotics . . . . 3.9. Conventional antipsychotics Discussion . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .

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Abbreviations Key AI-arousal index

AMI-amitriptyline

DLMO-dim light melatonin onset

CDN-clonidine

EMA-early morning awakening

CZM-Clonazepam

EXT-extinction

DPH-diphenhydramine

ES- effect size

ESZ-eszopiclone

GH-growth hormone

FLX-fluoxetine

ITT-intent-to-treat

FZM-flurazepam

LM/HR-leg-movements per hour

HAL-haloperidol

LPS-latency to persistent sleep

IMI-imipramine

MI-movement index

MTN-melatonin

NAW-number of awakenings

MTZP-mirtazepine

NNW-number of nights awakened

NPZ-niaprazine

PLMD-periodic limb movement disorder

OZP-olanzapine

PSG-polysomnography

PAR-paroxetine

REM-rapid eye movement

PBO-placebo

REM-L-rapid eye movement latency

RISP-risperidone

RLS-restless leg syndrome

RTN-ramelteon

S1, S2, S3, S4-sleeps stages 1 through 4, respectively

TPZ-trimeprazine

SB-sleep bruxism

TZD-trazodone

SE-sleep efficiency

TZM-triazolam

SOI-sleep onset insomnia

ZAL-zaleplon

SOL-sleep onset latency

ZOL-zolpidem

SWS-slow wave sleep

> pharmacological effect significantly greater for

TAN-time awake at night

= pharmacological effects did not differ

TST-total sleep time WASO-wake after sleep onset Note to Readers: As the sleep literature contains a large and complex set of terminology, this listing is intended as an aid to the discussions and summaries that follow.

1. Introduction 1.1. Sleep disturbance in developmental disabilities 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 & Jeffries, 2005; Palermo, Koren, & Blumer, 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 & Sigafoos, 2001; Richdale, Francis, Gavidia-Payne, & Cotton, 2000; Robinson & Richdale, 2004; Wiggs & 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

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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. 1.2. Current interventions for sleep disturbances 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, Mindell, Owens, & Byars, 2007; Owens, 2009; Pelayo & Dubik, 2008; Stojanovski, Rasu, Balkrishan, & Nahata, 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 nondrug 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, Kuhn, Workman, & Ellis, 2006; Owens, Rosen, & Mindell, 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. 2. Method 2.1. 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 component. The content of the tables dispersed throughout this paper represent a hierarchy in the order of research studies starting with (a) randomized, double-blind, placebo-controlled studies of children with developmental disabilities and without, (b) partially controlled or uncontrolled studies of children, including case studies and retrospective chart reviews, and (c) given the paucity of evidence-based research conducted in children with sleep disturbances, fully controlled adult sleep studies were included when necessary to inform readers as to what may be expected when treating children with the agent. This, of course, assumes that findings with adults can be extrapolated to children, which may be a leap of faith. Chosen studies assessed the effectiveness and safety of pharmacological interventions for sleep initiation and maintenance problems. Studies that reported exclusively on core symptoms of other comorbid psychopathology were excluded. Studies of obstructive sleep apnea (OSA) and narcolepsy in children were also excluded, as treatment for these disorders was beyond the scope of this review. Throughout the text and within the tables, a standard set of abbreviations were used to define the sleep variables studied. These abbreviations often apply to both subjective (e.g., participant report) and objective measures [i.e., polysomnography

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(PSG), electroencephalography (EEG), etc.] and have been included in a table of key abbreviations, at the beginning of this review to facilitate reading. Mirroring this is a separate abbreviation key for the medications described in the tables. 2.2. Review criteria for study quality Studies that met the inclusion criteria were systematically reviewed to assess their scientific validity. All studies were evaluated for a multitude of design criteria, such as (a) random assignment, (b) placebo (PBO) controls, (c) balance for time, (d) appropriate statistical analysis and interpretation (Sprague & Werry, 1971; Wilkinson, 1999). Where the means and standard deviations were made available by the authors, effect sizes are presented. Effect sizes were calculated by subtracting the mean difference from baseline to endpoint of the control group from the mean difference of the treatment group and dividing by the pooled standard deviation of the baseline means from the two groups. 3. Results 3.1. 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, 2002). Taken as a whole, this suggests a serious lack of empirical evidence on which prescribing clinicians must base their decisions, when choosing hypnotics for their pediatric patients. 3.2. Drug classes 3.2.1. Antihistamines Antihistamines were not developed to ameliorate sleep problems but, in view of their sedative and hypnotic effects, physicians have prescribed them to children with sleep disturbances (Meltzer et al., 2007; Owens et al., 2003). Eight investigations were located, five of which were fully controlled (see Table 1). Throughout this review, all tabulated studies conducted with children and/or adolescents will appear in italics to distinguish them from studies with adults. 3.2.1.1. Diphenhyrdamine (Benadryl). Diphenhydramine is a first-generation antihistamine with hypnotic and sedative effects. It is a competitive H1 receptor blocker in the central and peripheral nervous systems (Pelayo et al., 2004). There have been relatively few pediatric studies assessing the effectiveness of diphenhydramine in childhood insomnia, which is surprising considering that it appears to be the most widely prescribed hypnotic by pediatricians and child psychiatrists for children with sleep problems (Meltzer et al., 2007; Owens et al., 2003). Sold over-the-counter, it is easily accessible which makes it difficult to determine its frequency of use. Three fully controlled studies of diphenhydramine in children with sleep problems were located, and the results were mixed. Merentstein, Diener-West, Halbower, Krist, and Rubin (2006) and Paul et al. (2004) found no significant differences between diphenhydramine and placebo on sleep quality and maintenance when studied in infants, children, and adolescents. In contrast to this, Russo, Vymutt, Gurura, and Allen (1976) conducted a study of diphenhydramine and placebo and found significant improvement in the areas of sleep initiation and maintenance in the diphenhydramine group. The primary outcome measures for all three studies were clinician-rated global assessments, and no objective measures were taken. 3.2.1.2. Trimeprazine tartrate (Temaril). Trimeprazine (TPZ) is a drug with powerful antihistaminic action. It is an H1 receptor antagonist and acts by blocking histamine effects while it competes with histamine for H1 receptor sites. Three fully controlled trimeprazine studies in children with night-waking problems were located. France, Blampied, and Wilkinson (1991) conducted a study of preschool children with chronic sleep disturbance. They found that trimeprazine and extinction were superior to placebo and extinction or extinction alone. Simonoff and Stores (1987) and Richman (1985), conducted two crossover studies of trimeprazine and placebo and found significant improvements in sleep maintenance variables. All three studies used subjective sleep measures only to assess sleep problems. 3.2.1.3. Niaprazine (Nopron). Niaprazine is a piperazine derivative drug which has sedative and hypnotic properties and acts as an antihistamine. Niaprazine is used in European countries to treat the disruptive behavior and insomnia that are often associated with autism (Ottaviano, Giannotti, & Cortesi, 1991; Rossi, Posar, & Parmeggiani, 1999). It has not been approved for use in the United States. One fully controlled study and one uncontrolled study of niaprazine were found. Rossi, Posar, and Parmeggiani conducted an open study of niaprazine in children with autism and sleep disturbance and found that niaprazine was more effective in treating sleep problems in children with mild-to-moderate intellectual disability (ID) rather than in those with severe ID. Ottaviano et al. conducted a study of niaprazine and placebo in children with mixed sleep disturbances. The results showed that niaprazine was effective in treating insomnia. Both studies utilized subjective measures to assess sleep disturbance.

Table 1 Studies of antihistamines in children and adolescents with sleep disorders. Participants

Level of control

Method

Outcome by variable

Merenstein et al. (2006)

Infants who woke 2 or more times a night; ages 6–15 months (mean 10.3); 25 males, 19 females; a bg = 44

Fully controlled

Randomized, double-blind, PBO-controlled, parallel groups design; PBO or diphenhydramine (DPH), prescribed at 1 mg per kilogram;10-weeks; sleep diary, parent report of number of night awakenings (sNAWs)a, parent happiness rating

Paul et al. (2004)

Children and adolescents with upper respiratory infections (URIs) and secondary sleep disturbance; ages 2–18 years (mean, 4.4); 42 males, 58 females; N = 100 children

Fully controlled

Rossi et al. (1999)

Children and adolescents with mood disorders, aggressiveness, and hyperkinesia sleep disturbances; ages 2–20 years (mean 9.9); 23 males, 2 females; N = 25 Children with sleep disturbances; ages 6 months to 6 years; gender not reported; N = 36

Uncontrolled

Randomized, double-blind, PBO-controlled, parallel groups, design; PBO or DPH 1.25 mg/kg/dose, dextromorphan (DM) 7.5–30 mg/dose depending on age; two nights, baseline and treatment; parent assessment of sleep quality secondary to URI and child’s sleep quality, 7-point Likert scale Open label trial; no randomization or control-group; niaprazine (NPZ) 1 mg/kg three times daily; 60 days; modified Behavioral Summarized Evaluation Scale (BSES) to include sleep disorders

Parent reported sNAWs showed that 3 participants (14%) in the PBO group improved compared to 1 (5%) in the DPH group (PBO > DPH)b. Intent-to-treat (ITT) analysis of secondary outcomes, revealed that placebo (PBO) was superior to DPH (PBO > DPH) as two additional parents in the placebo group reported improvement in sNAWs. Data safety and monitoring board (DSMB) terminated trial for lack of effectiveness of DPH over placebo. AEs mild and few reported. No significant findings, hence no ESs All three treatment groups showed significant improvement in study outcomes from one night to the next. No significant differences between groups (DPH = DM = PBO). Similar AEs reported between groups. No significant findings, hence no ESs

Ottaviano et al. (1991)

Fully controlled

France et al. (1991)

Infants with night waking; ages 7–27 mos (mean 14.26); 16 males, 19 females; N = 35

Fully controlled; two conditions

Simonoff and Stores (1987)

Children with night waking; ages 1–3 years; (mean 21.9 months); 8 males, 10 females; N = 18

Fully controlled

Randomized, double-blind, PBO-controlled trial parallel-groups design; PBO or NPZ 1 mg/kg; time-lapse videosystem for home-recorded sleep; ten sleep parameters, four scores 0–4; inter-rater reliability 0.82; BL video-recording, 7 days of treatment and EP video-recording Randomized, double-blind, PBO-controlled parallel groups design; two of three treatment groups randomized, 3rd group extinction (EXT) alone, no random assignment; PBO + EXT, trimeprazine tartrate (TPZ) 3 mg/mL + EXT, and EXT; daily sleep diary, Flint Infant Security Scale

Randomized, double-blind, placebo-controlled crossover design; PBO and TPZ 45-90 mg; 7-weeks, follow-up; symptom checklists, parent sleep diaries

NPZ was more effective in mild-to-moderate ID, showed a significant decrease in sleep disorders on the BSES (NPZ > PBO). AEs mild, a few participants experienced moderate diurnal drowsiness which was eliminated by reducing the dose. SDs not reported, hence no ESs Subjective sleep variables showed significant improvement in sNAWs, sSOL and sTST (NPZ > PBO). AEs not reported. SDs not reported, hence no ESs

Following 10 days of treatment sNAWs revealed significant differences between groups (TPZ/EXT > PBO/EXT) (ES .78) and (TPZ/EXT > EXT) (ES 1.5). Following 20 days of treatment sNAWS revealed significant differences between groups (TPZ/ EXT > PBO/EXT) (ES .54) and (TPZ/EXT > EXT) (ES .39). Following 30 days of treatment sNAWs revealed significant differences between groups (TPZ/EXT > PBO/EXT) (ES .14) and (TPZ/ EXT > EXT) (ES 1.29). Follow-up assessments revealed significant differences between groups (TPZ/EXT > PBO/EXT) (ES .28) and (TPZ/EXT > EXT) (ES1.1). All groups significantly increased their security scores over time (TPZ/EXT = PBO/EXT = EXT. Adverse events not reported Subjective sleep maintenance variables showed significant improvement in sTST, sNAWs, and time awake at night (TAN), (TPZ > PBO). AEs not reported. SDs not reported, hence no ESs

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Table 1 (Continued ) Participants

Level of control

Method

Outcome by variable

Richman (1985)

Children with severe waking problems; ages 21–24 months (mean 22.33); 25 males, 19 females; N = 44

Fully controlled

Randomized, double-blind, PBO-controlled crossover design; three treatment groups, ctwo of three groups randomly assigned, PBO and TPZ 30–60 mg (N = 22) or sleep diary alone; 10-weeks; parent sleep diaries

Russo et al. (1976)

Children with sleep disorder; ages 23.5 months– 12 years (mean 5.9); 25 males, 25 females; N = 50

Fully controlled

Randomized, double-blind, PBO-controlled, crossover study; PBO and DPH 10–50 mg; 2-weeks; CGI improvement, rated at Visits 1, 8, and 15

Results of crossover revealed significant improvement in sleep initiation and maintenances variables, sSOL and sNAWs in mean composite sleep scores (TPZ > PBO). No significant differences between groups at 6-month follow-up. No evidence of rebound effect at drug discontinuation. AEs not reported by parents, one child vomited after taking PBO. SDs not reported, hence no ESs CGI-I showed significant reductions in both sSOL and sNAW, during DPH dosing when compared to PBO (DPH > PBO); sTST showed no significant difference between groups. AEs reported in two of the 50 participants (PBO = mild rash; DPH = mild drowsiness). SDs not reported, hence no ESs

a Abbreviations. AE, Adverse event; BL, baseline; EP, end point; ES, effect size; EXT, extinction; ITT, intent-to-treat; NAWs, number of awakenings per night; NNW, number of nights awakened per week; NPZ, niaprazine; PBO, placebo; PSG, polysomnography; SD, standard deviation; SE, sleep efficiency; SO, sleep onset (time); SOI, sleep onset insomnia; SOL, sleep onset latency; sSOL, subjective sleep onset latency; TAN, time awake at night; TPZ, trimeprazine tartrate; TST, total sleep time. b > = superior to (i.e., DPH > PBO). c Fourteen parents would not accept drug treatment but agreed to participate in diary keeping for 10 weeks, therefore, 30 children randomized.

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In 1986, Zametkin, Reeves, Webster, and Werry (1986) found that the antihistamine promethazine (Phenergan) was ineffective as a treatment for symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) in children. Soon after the study began the researchers were forced to discontinue for lack of effect and possible worsening of ADHD behavior. Although, their study addressed behavior during the day, they expressed concern about the effects of this and similar agents when used for sleep induction. Their conclusion appears to be reasonable when we summarize the literature. Two out of three controlled studies of diphenhydramine showed no differences in effect between active treatment and placebo. The third showed significant improvement with diphenhydramine. Niaprazine appears to be an effective treatment for sleep disturbance and would warrant future study but it is not marketed in the United States. Three controlled studies of trimeprazine found that it was effective in treating sleep disturbance in children. However, the studies were conducted in the 1980s and early 1990s and since that time no other studies have assessed effects on sleep. Adverse events were not reported for all studies cited, outcome measures were subjectively rated measures of sleep, and sleep architecture was not evaluated. 3.3. Melatonin and melatonin agonists 3.3.1.1. Exogenous melatonin The mechanism of action for the hypnotic effects produced by exogenous melatonin in humans is not well understood. Three hypotheses are plausible; the mechanism may involve a phase shift of the endogenous circadian pacemaker, a reduction in core body temperature, and/or a direct action on somnogenic structures in the brain [U.S. Department of Health and Human Services: Agency for Healthcare Research and Quality (AHRQ), 2004]. There are a number of randomized controlled trials of exogenous melatonin in children with neurodevelopmental disabilities (see Table 2). In 13 pediatric efficacy evaluations of melatonin supplement, it was found that melatonin significantly improved sleep disturbance in a cross-study total of 424 children (Braam, Didden, Smits, & Curfs, 2008; Braam, Didden, Smits, Leopold, & Curfs, 2008b; Coppola et al., 2004; Garstang & Wallis, 2006; Hancock, O’Callaghan, & Osborne, 2005; McArthur & Budden, 1998; Niederhofer, Staffen, Mair, & Pittschieler, 2003; O’Callaghan, Clarke, Hancock, Hunt, & Osborne, 1999; Smits, Nagtegaal, van der Heijden, Coenen, & Kerkhof, 2001; Smits et al., 2003; van der Heijden, Smits, van Someren, Ridderinkhof, & Gunning, 2007; Wasdell et al., 2007; Weiss, Wasdell, Bomben, Rea, & Freeman, 2005). These studies were all properly controlled and used sample sizes that ranged from 7 to 107 participants. Both parallel groups and crossover designs were used. The results of all 13 were positive. The effect sizes for sleep onset latency (SOL) ranged from .25 to 1.63 and for total sleep time (TST) from .25 to 1.0. Exogenous melatonin was most effective in treating sleep initiation and maintenance problems (Braam, Didden, Smits, & Curfs, 2008; Braam, Didden, Smits, Leopold, & Curfs, 2008b; Garstang & Wallis, 2006). It has also proven useful in advancing dim light melatonin onset (DLMO) (i.e., increased endogenous salivary melatonin levels) in children with late DLMO, compared to typical children (Braam, Didden, Smits, & Curfs, 2008; Braam, Didden, Smits, Leopold, et al., 2008; van der Heijden et al., 2007). One study was located that did not show a positive response. Camfield, Gordon, Dooley, and Camfield (1996), found that the subjective sleep maintenance variables number of awakenings (sNAWs), number of nights awakened (sNNWs), and TST, did not improve with melatonin use when compared to placebo. Subjective SOL was not measured. The investigators concluded that melatonin did not improve sleep disturbance in children with developmental disabilities. At that time, there were few studies of melatonin, and its safety had not been established in pediatric populations. The prescribed dosing schedule was comparatively lower than those in later studies (see Table 2), and it may be that the range 0.5–1.0 mg was not high enough to elicit a signal. All studies cited in the table used subjective sleep measures, one used polysomnography (PSG) but did not report on changes in sleep architecture, and 5 others used actigraphy to measure sleep. Adverse events were found to be mild and similar between melatonin and placebo. Melatonin is appealing to pediatricians because of its favorable side effect profile, its rapid onset of action (Tmax 30–60 min) and its short elimination half-life (T1/2 30–50 min) (Braam, Didden, Smits, Leopold, et al., 2008; Coppola et al., 2004; Owens, 2009; Smits et al., 2003; van der Heijden et al., 2007; Wasdell et al., 2007; Weiss et al., 2005). 3.3.1.2. Ramelteon (Rozarem) Ramelteon is a potent MT1/MT2 melatonin receptor agonist. Its affinity for the human MT1 receptor is approximately 6fold greater than that of melatonin (Sateia, Kirby-Long, & Taylor, 2008). One study that included two case reviews of ramelteon in children with autism was located (Stigler, Posey, & McDougle, 2006). The investigators found that ramelteon improved sleep quality in both participants and that ramelteon was well tolerated. Four large controlled studies of ramelteon in adults showed significant improvements in primary insomnia and sleep maintenance variables. In two studies, the investigators used both subjective and objective measures and found that sleep quality improved in the ramelteon groups. The authors found that sleep architecture generally remained unaffected with the exception of a reduction in slow-wave sleep (SWS) (i.e., stages 3 and 4) (Erman, Seiden, Zammit, Sainati, & Zhang, 2006; Zammit et al., 2007). Two other studies also reported small but significant improvements in sleep initiation and sleep quality variables (Roth, Seiden, et al., 2005; Roth, Stubbs, & Walsh, 2005b; Roehrs & Roth, 2006). All four studies reported that adverse events were similar in both the active and the placebo conditions, while three out of four studies showed no residual or withdrawal effects in the ramelteon groups. Roth, Seiden, et al. (2005); Roth, Stubbs, et al. (2005) found a small but significant decline in alertness at the 64 mg dose. Ramelteon has a rapid onset of action (Tmax 0.78 h) and a short elimination half-life (T1/2 0.83 h) (Karim, Tolbert, & Cao, 2006).

946

Table 2 Studies of melatonin and melatonin analogs in children, adolescents (italicized) and adults with sleep disorders. Participants

Level of control

Method

Outcome by variable

Children, adolescents and young adults with Angelman’s Syndrome and chronic insomnia; ages 4.1020.11(mean 10.26); 3 males, 5 females;N = 8 Children, adolescents, and adults, with intellectual disabilities (ID) and sleep disturbances; ages 2–58 (mean 20.9); 19 males,10 females; N = 29 Children with sleep onset insomnia (SOI); ages 6–12y (mean 9.2); 78 male, 27 females; N = 105

Fully controlled

Randomized, double-blind placebo (PBO)controlled, parallel groups design; PBO or melatonin (MTN) 2.5-mg -5 .0-mg; 4 weeks of treatment; dim light melatonin onset (DLMO) measured between groups; parent sleep diaries Randomized, double-blind PBOcontrolled parallel groups design; PBO or MTN 2.5–5.0-mg; 4 weeks of treatment; parent sleep diaries; salivary DLMO measured at baseline (BL) and end point (EP) Randomized, double-blind PBOcontrolled, parallel groups design; PBO, MTN 3.0-mg, 6.0-mg; actigraphy at BL and Week 4; sleep logs; salivary DLMO at BL and Week 4 Randomized, double-blind, PBOcontrolled, crossover trial; PBO or MTN 1.0mg (fast) and 4.0-mg controlled-release tablets; run-in period of sleep hygiene,10days of treatment, washout period 1-week following treatment; actigraphy and parent sleep diaries (somnolog) Randomized double-blind, PBO-controlled crossover trial with open label (OL) extension; PBO or MTN 5.0-mg; 4 treatment weeks; parent sleep charts Phase I, sleep hygiene intervention (10 days); Phase II, double-blind PBO controlled crossover design (30 days), children with continued insomnia randomized to PBO or MTN 5.0-mg; OL extension; actigraphy, parent diaries (somnolog)

Significant improvement found in parent-defined sleep variables, subjective sleep onset latency (sSOL) (ES 1.63), subjective number of nights awakened (sNNW)a (ES .64), and subjective total sleep time (sTST) (ES .74) in the MTN group when compared to PBO (MTN > PBO).b Not enough salivary MTN samples available for evaluation of DLMO. Effect sizes may be unreliable due to small sample. No seizure activity reported Significant improvements found in parent-defined sleep variables, sSOL (ES .56), subjective number of night awakenings (sNAWs) (ES .28) sTST (ES .54), and DLMO (ES .96) in the MTN group when compared to PBO (MTN > PBO); minor and temporary side effects reported

Braam, Didden, Smits, Leopold, et al. (2008)

van der Heijden et al. (2007)

Fully controlled

Fully controlled

Wasdell et al. (2007)

Children with ‘‘neurodevelopmental disabilities’’ and insomnia; ages 2.05-17.81y (mean 7.38); 31 males, 20 females; N = 51

Fully controlled

Garstang and Wallis (2006)

Children with ASD and sleep problems; ages 4-16y (mean 8.64); 7 males, 4 females; N = 11

Fully controlled

Weiss et al. (2005)

Children with attention deficit hyperactivity disorder (ADHD) with stimulant treated insomnia; ages 6.5-14.7y (mean 10.29); 17 males, 2 females; N = 19

Fully controlled

Hancock et al. (2005)

Children, adolescents, and adults with tuberous sclerosis complex and sleep disorder; ages 4–31 years (mean 14.4; 4 males, 3 females; N = 7 Children, adolescents, and young adults with ID with or without epilepsy and sleep disorders; ages 3.6-26y (mean 10.5); 16 males, 9 females; N = 25

Partially controlled

Randomized, dose response, crossover trial; MTN 5.0-mg or 10.0-mg; 8 weeks; no PBO control; parent sleep and seizure diaries

Fully controlled

Randomized double-blind PBOcontrolled crossover trial; PBO and MTN 3.0-mg to 9.0-mg; 8 treatment weeks; parent questionnaire

Coppola et al. (2004)

Significant improvements found in actigraphic sleep variables, (SOL) (ES .91), TST (ES .69), sleep efficiency (SE) (ES .83) and in DLMO (ES 96) compared to PBO and in parent-defined difficulty falling asleep (ES 1.27) (MTN > PBO) Similar AEs between groups (MTN = PBO) Significant improvements found in actigraphic sleep variables, SOL (ES .46), TST (ES .25), parent diaries sSOLc (ES .83), sTST (ES .43), clinician-rated global impression of severity and improvement, CGI-S (ES 1.6) (MTN > PBO); validation of parent diaries with baseline actigraphy measures of TST (r = .70); AEs similar between MTN and PBO (MTN = PBO)

Significant improvements found in parent-defined sleep variables in MTN group sSOL, sNAWs, and sTST (MTN > PBO). Six males and 1 female completed trial; suspended early due to drug recall; no SDs or p values reported, hence no ESs Significant improvement in both actigraphic-defined and parent-defined sleep variables from baseline in the MTN group when compared to PBO (MTN > PBO); sleep hygiene decreased initial insomnia to <60 min in 5 children (ES .67); out of 27 participants 19 randomized to PBO or MTN 5.0 mg; significant reduction in insomnia by 16 minutes in the MTN group when compared to PBO (ES .60); combined sleep hygiene and MTN at study EP (ES 1.70); post-sleep hygiene somnolog and actigraph measures of SOL strongly correlated (r = 0.76); adverse events mild and similar between treatment groups (MTN = PBO) Subjective sleep measures from parent diaries (i.e., sSOL, sTST and sNAWs) showed no significant differences between groups (MTN 5.0-mg = MTN 10.0-mg); no significant differences in seizure activity was shown from BL (MTN = no MTN); no AEs reported by parents; no SDs reported, hence no ESs Twenty-eight percent of participants lost to follow-up (25 completed); significant improvement shown in parent-defined sleep variable, sSOL (ES .25) (MTN > PBO); no significant affects shown for sTST or sNAWs in MTN group (MTN = PBO); MTN was well tolerated and no side effects reported; 11 seizure-free participants at BL, remained seizure-free at EP, in 2 participants seizures reappeared after 1 month of treatment with MTN

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Source Braam, Didden, Smits, and Curfs (2008)

Adolescents with ID and nocturnal sleep deficits; ages 14–18 years; 10 males, 10 females; N = 20

Fully controlled

Smits et al. (2003)

Children with idiopathic sleeponset insomnia (SOI); ages 6–12 years (mean 9.65); 49 males, 13 females; N = 62

Fully controlled

Smits et al. (2001)

Children with idiopathic SOI; ages 6–12 years (mean 9.8); 28 males, 12 females; N = 40

Fully Controlled

O’Callaghan et al. (1999)

Children and adults with tuberous sclerosis and sleep disorders; ages 2–28 years (median 11); 3 males, 4 females; N=7

Fully controlled

McArthur and Budden (1998)

Children with Rett Syndrome and sleep disturbance; ages 4– 17 years (mean 10.1); 9 females; N=9 Children with ID and fragmented sleep; ages 3-13y (mean 7.25); 4 males 2 females; N=6 Children and adolescents with autism and treatmentrefractory severe insomnia; ages 7 and 18 years (mean 12.5); 2 males; N = 2

Fully controlled

Camfield et al. (1996)

Stigler et al. (2006)

Zammit et al. (2007)

Adults with chronic primary insomnia; ages 18–64 (mean 39.3); 133 males, 272 females; N = 405

Fully controlled

Uncontrolled

Fully controlled

Randomized double-blind PBO-controlled crossover trial; PBO and MTN 0.1-mg, 0.3mg, 3.0-mg; 9 weeks of treatment; matched for age and gender; polysomnography (PSG) recordings taken on Days 5-7; blood sample drawn every hr for 24 hrs to measure plasma MTN; self reports confirmed by continuous 1-week recordings of the motor activity Randomized double-blind PBO-controlled parallel groups design; PBO or MTN 5.0mg; 1 screening- week and 4 treatmentweeks; parent sleep logs; salivary MTN collection; parent-rated questionnaires Randomized, double-blind, PBO – controlled, parallel groups design; PBO or MTN 5.0-mg; 4 treatment weeks; actigraphy, parent sleep logs; salivary MTN collection; sustained attention task Randomized double-blind PBO-controlled crossover trial; PBO and MTN 5.0-mg; 2week treatment phase followed by a 1week washout and an alternative treatment phase; parent rated Quine Sleep Index and sleep diaries Randomized double-blind PBO-controlled crossover design; MTN 2.5–7.5 mg based on weight;10 weeks, one week BL assessment; actigraphy, parent diaries Randomized double-blind PBO-controlled crossover design; MTN 0.5–1.0 mg/day; parent diaries Case studies; participants followed for 1618 weeks; participant A, received ramelteon (RTN) 4.0-mg, 45 min before bedtime, later titrated to 8.0-mg; participant B, received RTN 4.0-mg nightly; parent report Randomized, double-blind, PBOcontrolled parallel groups design; PBO, RTN 8.0-mg, or 16.0 mg; 7-day singleblind screening period, 5-week doubleblind treatment period, and 2-day single-blind run-out period; PSGrecordings; post sleep questionnaires

PSG-defined SE (the ratio of TST and TSP) was significantly improved by all three MTN doses, the 0.3-mg dose causing the greatest effect when compared to PBO (MTN > PBO); significant increases in circulating-MTN levels found with the 0.3mg dose and MTN levels elevated to normal; AEs not reported; means and SDs not reported, hence no ESs

Significant differences found in parent-defined sleep variables, sSOL (ES .54), sSO (ES 1.1), and in DLMO (ES 1.3) when compared to PBO (MTN > PBO); mild AEs reported with recovery within 3 days of initial dosing

Actigraphic-defined SO (ES 1.9) showed significant improvement in the MTN group compared to PBO (MTN > PBO); parent defined sTST (ES 1.0) and sSO (ES .87) showed significant improvements in the MTN group when compared to PBO (MTN > PBO); significant DLMO (ES .12) sustained attention not affected (MTN = PBO); serious side effects did not occur Significant improvement shown in the parent-defined sleep variables sTST in MTN group when compared to PBO (MTN > PBO) sSOL and sNAWs not significant in the MTN group compared to PBO (MTN = PBO); AEs not reported; SDs not reported, hence no ESs

Actigraphic sleep initiation variables showed significant improvement in SOL (MTN > PBO), but no significant improvements in TST, NAWs or SE. AEs not reported, one parent of a child in the MTN group reported mood swings. SDs not reported, hence no ESs No parent reported improvement in sTST, sNAWs, and sNNW (MTN = PBO).AEs not reported; SDs not reported, hence no ESs

Clinician-rated global impression of improvement (CGI-I) for participants A and B at follow-up showed CGI-I ratings of 2 (much improved) and 1, (very much improved) respectively; RTN was well tolerated with no daytime residual effects

PSG-defined sleep initiation and maintenances variables showed significant decreases in latency to persistent sleep (LPS) at Weeks 1, 3, and 5, for both active treatment groups compared to PBO. TST and SE showed significant increases with both doses of RTN compared to PBO (RTN > PBO). Sleep architecture revealed a significant decrease in stages 3 and 4 or NREM slow wave sleep (SWS), with both doses of RTN compared to PBO (PBO > RTN). Subjective sleep measures showed decreases in sSOL with RTN 8.0-mg at Weeks 1, 3, and 5 and with RTN 16.0-mg at Weeks 1, and 3 (RTN > PBO); significant increases found in sTST at Weeks 1, 3, and 5 in the RTN 8.0-mg group and at Week 1 in the RTN 16.0-mg group (RTN > PBO); RTN showed no evidence of next day psychomotor impairment or rebound insomnia; AEs generally mild, severe AEs occurred in each group PBO = 7; RTN 8mg = 5; RTN 16-mg = 3); SDs not reported, hence no ES

J.A. Hollway, M.G. Aman / Research in Developmental Disabilities 32 (2011) 939–962

Niederhofer et al. (2003)

947

948

Table 2 (Continued ) Participants

Level of control

Method

Outcome by variable

Adults with chronic primary insomnia; ages 18–64 years (mean 37.7); 38 males, 69 females; N = 107

Fully controlled

Randomized, double-blind, PBOcontrolled crossover trial; RTN 4.0, 8.0, 16.0, 32.0-mg, and PBO, participants randomized to 1 of 10, five-period dosing sequences in a Latin square design; treatment consisted of five 2-day treatment periods with 5 to 12-day washout periods in between; PSGrecordings, sleep diaries

Roth et al. (2006)

Older adults with chronic primary insomnia; ages 64–93 years (mean 72.4); gender not reported; N = 582

Fully controlled

Roth, Seiden, et al. (2005); Roth, Stubbs, et al. (2005)

Healthy adults with transient insomnia; ages 35–60 years; 147 males, 228 females; N = 375

Fully controlled

Randomized, double-blind, PBOcontrolled parallel groups design; RTN 4.0-mg, 8.0-mg, or PBO; 5 evaluation periods (i.e., single-blind lead-in, double-blind treatment, single-blind run-out, final visit; 7 treatment weeks; sleep diaries, CGI-C, CGI-S; Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) Randomized, double-blind, PBOcontrolled parallel groups design; single dose of RTN 16.0-mg, 64.0-mg, or PBO; participants stratified into two groups according to reported sleep duration (6.5–7.5 h or 7.5–8.5 h) then randomly assigned; one treatment night (no adaptation night, novel environment) PSG-recordings, subjective measures, post-sleep questionnaire

PSG-defined sleep initiation and maintenance variables showed significant reductions in LPS and increase in TST (RTN > PBO), no significant differences found in WASO (RTN = PBO). Sleep architecture showed no significant differences between groups in percentage of time spent in stages 1, 2 and REM or in REM-L, a significant decrease in stage 3/4 (i.e., SWS) for each dose of RTN noted (PBO > RTN). Subjective sleep measures showed a significant reduction in sSOL in RTN 16.0-mg group, for all other doses of RTN no significant differences found in sSOL or sTST; subjective sleep quality did not differ between groups. Subgroup analysis grouped by median screening SOL and TST showed that participants with higher LPS (>66.5 min) at screening experienced dramatic reductions in time to persistent sleep; patients with shorter screening LPS ( 66.5) experienced only modest effects. No observable effects found in next-day performance and alertness measures. Safety of RTN at each dose found to be similar to PBO, ranging from 8.4-10.7%, PBO = 8.7%; SDs not reported, hence no ES Participant sleep diaries showed sSOL decreased significantly in both RTN groups, at Weeks 1 and 5, at Week 3 the RTN 8.0-mg group reported a significant reduction in sSOL (RTN > PBO). Significant increases in sTST observed at Weeks 1 and 3 (RTN > PBO), but not at Week 5 (RTN = PBO), CGI-I and CGI-S showed no significant differences between groups (RTN = PBO). Rebound insomnia and withdrawal effects not observed; no significant differences between groups in BWSQ scores from BL to EP (RTN = PBO); eight serious AEs reported, one transient ischemic attack in RTN 8.0-mg group, considered possibly related, others unrelated. SDs not reported, hence no ESs PSG-defined sleep initiation and maintenance variables revealed significant decrease in LPS in both the RTN 16.0-mg (ES .55) and 64.0-mg (ES .48) groups (RTN > PBO); TST was significantly increased with active treatment, RTN 16.0-mg (ES .35) and 64.0-mg (ES .28) (RTN > PBO); significant improvement observed in subjective sleep quality (ES .18); RTN 64.0-mg showed small but significant declines in alertness (ES .14) (PBO > RTN 64 mg), RTN 16.0-mg similar to PBO (RTN = PBO); no serious AEs reported

a Abbreviations. AE, Adverse event; BL, baseline; DLMO, dim light Melatonin onset; EP, end point; ES, effect size; ID, intellectual disabilities; LPS, latency to persistent sleep; MTN, Melatonin; NAWs, number of awakenings; NNW, number of nights awakened; PBO, placebo; PSG, polysomnography; RTN, ramelteon; SD, standard deviation; SE, sleep efficiency; SO, sleep onset (time); SOI, sleep onset insomnia; SOL, sleep onset latency; sSOL, subjective sleep onset latency; TST, total sleep time; WASO, wake after sleep onset. b > = superior to (i.e., MTN > PBO).

J.A. Hollway, M.G. Aman / Research in Developmental Disabilities 32 (2011) 939–962

Source Erman et al. (2006)

J.A. Hollway, M.G. Aman / Research in Developmental Disabilities 32 (2011) 939–962

949

Table 3 Studies of a2-adrenergic agonists in children, adolescents (italicized) and adults with sleep disorders. Source

Participants

Level of control

Method

Outcome by variable

Ming et al. (2008)

Children with autism and sleep and behavioral disorders; ages 4–16 years (median 12) 14 Males, 5 females; N = 19

Uncontrolled

Subjective sleep initiation and maintenance variables showed significant improvement in 16 of 17 children treated for sleep disturbance. AEsa rare and tolerable. SDs not reported, hence no ESs

Ingrassia and Turk (2005)

Children with neurodevelopmental disorders and sleep disturbance; ages 6–14 years (mean 11.0); 5 males, 1 females; N = 6 Children and adolescents with ADHD and sleep disturbance; ages 4-17 (mean 12.3); 51 males, 11 females; N = 62

Uncontrolled

Open-label; retrospective chart review; clonidine (CDN) .05 mg to 0.1 mg/day; treatment duration variable; parent ratings of sleep initiation and maintenance (1 = no improvement, 2 = some improvement, or 3 = complete resolution of symptoms) Open-label; retrospective chart review; CDN from 50 micrograms (mg) daily up to 225 mg/day, BID dosing; treatment duration variable; parent report of sSOL, sNAW and sEMA Open-label; retrospective, systematic search of computerized database in outpatient clinic psychopharmacology; CDN mean daily dose 245  24.1, mean bedtime dose 15 7  14.0); treatment variable mean treatment 35.5 mos; CGI-S and CGI-I

Gentili et al. (1996)

Adults, healthy volunteers; 23–46 years (mean 35); 8 males; N = 8

Fully controlled

Randomized, double-blind, PBOcontrolled crossover design; PBO, CDN 0.1 mg, and yohimbine 5.4 mg; 2 consecutive nights on three separate occasions for three weeks; PSG-recordings

Wagner et al. (1996)

Adults with sleep disturbance secondary to parensthias and restless leg syndrome (RLS); ages 29–61 years (mean 44.5); 8 male, 3 females; N = 11

Fully controlled

Randomized, double-blind, PBOcontrolled, 3-period, crossover design; PBO and CDN 0.1-1.0 mg /day; 3-weeks; PSG-recordings, actigraphy, patient diaries

Prince et al. (1996)

Uncontrolled

Subjective sleep initiation and maintenance variables showed that all 6 children had improved sleep using CDN. Few adverse events reported. SDs not reported, hence no ESs Clinician rated global assessments of sleep quality showed significant improvements in 53 of 62 participants. Prior to treatment, the overall mean severity score for sleep disturbance was 5.1 (markedly ill), following treatment with CDN, the mean dropped to 2.6 (mildly ill). Mild side effects were noted in 19 participants. SDs not reported, hence no ESs PSG –defined sleep initiation and maintenance variables showed no significant differences between groups. Sleep architecture showed significant differences between groups in REM % sleep. Compared to PBO, CDN significantly decreased time spent in REM sleep (ES 1.5) (PBO > CDN)b. No effects shown in the yohimbine condition. AEs not reported PSG-defined sleep initiation variables showed a significant decrease in SOL in CDN group compared to PBO (CDN > PBO). Subjective motor-restlessness variables showed significant decreases in leg sensations, motor restlessness, and daytime fatigue in the CDN group compared to PBO (CDN > PBO). Actigraphy variables showed no significant differences between groups. Sleep architecture and REM duration showed a significant decrease in the CDN group compared to PBO (PBO > CDN) and REM-L showed a significant increase in the CDN group compared to PBO (PBO > CDN). Large number of mild AEs decreased or subsided with dose reduction. SDs not reported, hence no ESs

a Abbreviations. AE, Adverse event; BL, baseline; EMA, early morning awakening; EP, end point; ES, effect size; NAW, number of awakenings; PBO, placebo; PLMD, periodic limb movement disorder; PSG, polysomnography; REM, rapid eye movement; REM-L, rapid eye movement latency; SD, standard deviation; SE, sleep efficiency; SOL, sleep onset latency; sSOL, subjective sleep onset latency; TST, total sleep time. b > = superior to (e.g., CDN > PBO).

It appears that medical professionals are making the right choice when prescribing exogenous melatonin for sleep disturbances in children with developmental disabilities. It is often the next step in a plan of treatment when behavioral interventions fail to improve sleep quality (Johnson & Malow, 2008; Owens et al., 2003). A possible limitation to the research outlined in Table 2, is the relative lack of objective outcome measures. Future studies of melatonin should include PSG-recordings to monitor change in sleep architecture. Ramelteon appears to be a promising treatment for sleep disturbances in children with developmental disabilities. It now carries an FDA indication for the treatment of insomnia in adults. Nevertheless, well controlled studies of ramelteon in children with sleep disturbances are needed to determine its safety and efficacy in this population, and PSG-recording is advisable to confirm or disconfirm the reported decrease in SWS.

950

J.A. Hollway, M.G. Aman / Research in Developmental Disabilities 32 (2011) 939–962

3.4. Alpha-adrenergic agonists/antiadrenergics 3.4.1.1. Clonidine (catepres, catapres-TTS) Clonidine is an antihypertensive. It is a central and peripheral a-adrenergic agonist that acts on presynaptic neurons and inhibits noradrenergic release and transmission at the synapse (Bezchlibnyk-Butler & Jeffries, 2005). Prescriptions of clonidine in children have been on the rise in the past two decades (Efron et al., 2003; Ingrassia & Turk, 2005; Schnoes et al., 2006; Zito et al., 2000). Currently, there are no well-controlled studies that address the effects of clonidine in children with sleep problems; a few uncontrolled investigations were located (see Table 3). Two retrospective chart reviews and a retrospective review of patient files as part of a computerized database were conducted in children with neurodevelopmental disorders and sleep disturbance (Ingrassia & Turk, 2005; Ming, Gordon, Kang, & Wagner, 2008; Prince, Wilens, Biederman, Spencer, & Wosniak, 1996). The investigators found clonidine to be an effective therapeutic intervention for alleviating sleep disturbances in 87 children, whose ages ranged from 4 to 17 years. Dose titration began at 0.05 mg and was gradually titrated up to 0.1 mg at bedtime. In all three studies, side effects were reportedly mild and tolerable. To date there have been two well-controlled studies of clonidine targeting sleep in adults (Gentili et al., 1996; Wagner et al., 1996) conducted two crossover studies of clonidine in 18 adult patients, whose ages ranged from 23 to 61 years. Polysomnographic recordings showed significant improvements in SOL in the clonidine groups. Sleep architecture variables for rapid-eye-movement (REM) sleep duration showed significant decreases with clonidine dosing in both studies. Wagner et al. reported a large number of side effects with clonidine, although they were considered mild and decreased or subsided with dose reduction. Clonidine appears to be effective in treating sleep disturbance in children. However, well controlled studies with adults found reduced REM sleep with clonidine use. Future trials of clonidine in children should be fully controlled with objective measures, including PSG-recordings, to determine its effectiveness and safety. 3.4.1.2. Guanfacine (Tenex) It appears that to date there are no studies that have evaluated the safety and effectiveness of guanfacine as a treatment for sleep disturbance in children (several search terms used in Psychinfo and Medline revealed no studies). 3.5. Benzodiazepines Benzodiazepines bind to the ‘‘benzodiazepine’’ subunit of the gamma aminobutyric acid (GABA) chloride receptor complex, facilitating the action of GABA on CNS excitability (Bezchlibnyk-Butler & Jeffries, 2005). These hypnotics have long been the drug class of choice for treating insomnia in adults (Gaillard & Blois, 1989). However, concerns in regard to psychomotor and cognitive impairment, rebound insomnia, and the potential risk for physical and behavioral dependence contribute to their limited use in children (Roehrs & Roth, 2006). Eight studies of benzodiazepines and their effects on sleep disorders were located (see Table 4). 3.5.1.1. Clonazepam (Klonopin) Clonazepam (CZM) is a benzodiazepine with strong anticonvulsant, muscle relaxant, and sedative properties (Bezchlibnyk-Butler & Jeffries, 2005). Five studies were located. Three uncontrolled studies of children with parasomnias and secondary sleep disturbance showed that clonazepam improved (a) nocturnal tongue biting, (b) REM sleep behavior disorder, and/or (c) periodic limb movement disorder (PLMD) (Arens et al., 1998; Goraya, Virdi, & Parmar, 2006; Thirumalai, Shubin, & Robinson, 2002). Of the 40 participants studied, one mild adverse event was reported (Thirumalai et al., 2002). In two fully controlled studies of adults without DDs, the investigators found that clonazepam significantly improved PLMD and decreased the number of night-time arousals (Edinger et al., 1996; Peled & Lavie, 1987). However, just one of the two studies found significant improvement in the number of limb movements per hour (LM/HR) while improving SOL, TST, and SE (Peled & Lavie, 1987). In both studies, the reported adverse events were mild and tolerable. 3.5.1.2. Flurazepam (Dalmane) One study of flurazepam (FZM) in children with movement arousal disorders was located. The investigators found that flurazepam decreased the number of nightly arousals associated with excessive limb movements (Reima˜o & Lefe˙vre, 1982). The investigators used subjective measures, and sleep architecture was not evaluated. Adverse events appeared mild and similar between conditions. 3.5.1.3. Triazolam (Halcion) One study in adults was located (Drake, Roehrs, Mangano, & Roth, 2000). The investigators found that triazolam (TZM) improved sleep initiation and maintenance variables but that it decreased SWS. Adverse events were not reported. Triazolam has been withdrawn in the UK because of its potential for psychiatric adverse drug reactions, but it continues to be available in the U.S. It appears that the muscle relaxant and sedative properties of benzodiazepines produce therapeutic effects by ameliorating the sleep disturbance associated with parasomnias (i.e., PLMD, tongue biting, and REM sleep behavior

Table 4 Studies of benzodiazepines in children, adolescents (italicized) and adults with sleep disorders. Participants

Level of control

Method

Outcome by variable

Goraya et al. (2006) Thirumalai et al. (2002)

Child with nocturnal tongue biting related to parasomnia; 14 months; male; N = 1

Uncontrolled

Case Study; clonazepam (CZM) 0.5 mg twice daily;16 months; parent report

Children with autism and disrupted sleep with nocturnal awakenings; ages 3–9 (mean 5.09); 9 males; 2 females; N = 11 Children with Williams Syndrome (WS) and periodic limb movement disorder (PLMD); ages 1.5–10 years (mean 4.7) gender not reported; N = 28

Uncontrolled

Case Studies; 5 out of 11 children diagnosed with REM sleep behavior disorder (RBD); CZM 0.25 mg – 0.5 mg /night; length of treatment not reported; parent report OL; 28 families surveyed for movement arousal disorders, 16 screened for PLMD, 7 PSG-recordings; 5 received CZM 0.250.75 (2 declined treatment); 36 months; 3 follow-up PSG-recordings at 3-6 months; parent- reported PLMD at 2-weeks and monthly thereafter Placebo-controlled, single-blind, all participants received both flurazepam (FZM) and PBO; 4-weeks total, 2-weeks PBO then 2-weeks FZM; global assessment was carried out for each sleep disorder by designations of N = no change, R = regular (decrease of 50%), G = good (reduction between 51 and 75%), VG = very good (reduction of 76–100%) Two randomized, double-blind, PBO-controlled, Latin square, crossover designs; Study 1 compared triazolam (TZM) 0.25 mg to zaleplon (ZAL) 10, 40 mg and PBO, study 2 compared TZM 0.25 mg to ZAL 20, 60 mg, and PBO; 4–7 weeks; PSG-recordings, sleep questionnaires

Decreased tongue biting over 16 months of treatment; following CZMa withdrawal, tongue biting occurred two times in a 12-month period. AEs not reported. No inferential statistics Of five children diagnosed with RBD, three participants had improved sleep with CZM, one child experienced paradoxical response and switched to carbamazapine, another child’s parents declined treatment. One AE was reported and CZM was well tolerated in the rest PSG-defined variables of PLMD in 3 CZM treated participants showed significant decreases in the PLMD-index 13.4 to 2.8 (ES = 2.2), PLMD-arousal index 3.4 to1.2 (ES = 2.4), PLMD-awake index 1.4 to 0.4 (ES = 1.25) from baseline to follow-up (FU CZM > BL NO CZM).b Four of five parents reported an immediate and sustained improvement with fewer awakenings and improved daytime irritability. AEs not reported Among 29 participants with excessive movement when sleeping, 27 showed significant improvement when changed from PBO to FZM. Among 15 patients with sleep bruxism, 9 showed significant improvement when changed from PBO to FZM. AEs reported included drowsiness (1-PBO, 1-FZM), nausea and vomiting (2-FZM), and irritability (2-PBO, 3-FZM). No SDs reported, hence no ESs

Arens et al. (1998)

Uncontrolled

Reima˜o et al. (1982)

Children with parasomnias including movement arousal disorder ages 1-15 y, insufficient data to calculate mean; 22 males, 18 females; N = 40

Partially controlled; treatment confounded with time

Drake et al. (2000)

Adults with primary insomnia; ages 21– 60 years (mean 42.85); 45 males, 38 females; study 1,N = 47; study 2,N = 36

Fully controlled

Edinger et al. (1996)

Adults with isomnia and PLMD; ages > 60 (mean 66.05); 7 males, 9 females; N = 16

Fully controlled

Randomized, double-blind, parallel-groups design (no PBO-control); CZM 0.5–1.5 mg or cognitive-behavioral therapy (CBT); 4-weeks; PSG-recordings; sleep logs

Peled and Lavie (1987)

Adults with PLMD, and insomnia or excessive daytime sleepiness; ages 3070 y; 12 males, 8 females; N = 20

Fully controlled

Randomized, double-blind PBO-controlled parallel-groups design; PBO or CZM 0.5-2.0 mg; 4-weeks; PSG-recordings, sleep questionnaire

PSG-defined sleep initiation and maintenance variables in Studies 1 and 2 showed that all active treatments significantly reduced LPS compared to PBO (TZM and ZAL > PBO). All ZAL doses significantly reduced LPS compared to TZM (ZAL > TZM). TZM was significantly more effective at increasing total sleep time compared to all ZAL doses and PBO (TZM > ZAL and PBO). Measures of sleep architecture showed that TZM significantly reduced percentage of stage 3 and 4 NREM sleep (SWS) compared to PBO in Study 2 (PBO > TZM), but not in Study 1 (TZM = PBO). TZM significantly reduced the percentage of REM sleep compared to PBO (PBO > TZM). ZAL 40 and 60 mg produced significant reductions in REM percentage compared to TZM (TZM > ZAL 40 and 60). Subjective sleep measures revealed that all active doses of medication except ZAL 20 mg increased sTST. Mild AEs reported by 64 participants in all groups, totaled 190 (PBO = 10%, ZAL = 19%, TZM = 12%). SDs not reported, hence no ESs Ambulatory PSG-recordings of sleep maintenance variables showed no significant improvement from BL in either group for TST, and WASO (CZM = CBT). Sleep log data showed significant improvements for both groups from BL to EP in sWASO, sTST, and sSE, no significant differences found between groups (CZM = CBT). CZM group showed significant improvement in the arousal index (AI) (ES .89) (CZM > CBT) but not the movement index (MI) when compared to CBT (CZM = CBT). AEs were mild in both treatment groups PSG-defined sleep movement and arousal variables showed significant decreases in the MI, AI, and number of leg movements per hour (LM/HR), in the CZM group compared to PBO (CZM > PBO). PSG-defined sleep initiation and maintenance variables showed significant improvements in SOL, TST, and SE in the CZM group compared to PBO (CZM > PBO). Increased somnolence and dizziness reported in the CZM group. SDs not reported, hence no ESs

951

a Abbreviations. AE, Adverse event; AI, arousal index; BL, baseline; CBT, cognitive-behavioral therapy; CZM, clonazepam; ES, effect size; FZM, flurazepam; LM/HR, leg movements per hour; MI, movement index; PBO, placebo; PLMD, periodic limb movement disorder; PSG, polysomnography; RBD, REM sleep behavior disorder; SD, standard deviation; SE, sleep efficiency; SOL, sleep onset latency; SWS, slow-wave-sleep; TST, total sleep time; TZM, triazolam; WASO, wake after sleep onset; ZAL, zaleplon. b > = superior to (e.g., CZM > PBO).

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Source

952

Table 5 Studies of nonbenzodiazepines in children, adolescents, (italicized) and adults (normal font) with sleep disorders. Participants

Level of control

Method

Outcome by variable

Children with ADHDa and sleep disturbance; ages 6 to 17y (no mean age); gender not reported; N = 201

Fully controlled

Double-blind, placebo (PBO)-controlled, parallel-groups design; randomization nonbalanced (2:1); participants stratified by age; PBO or zolpidem (ZOL)a 0.25mg/kg/ d (10 mg /d max); 8-weeks; PSGrecordings; clinician-led CGI-S and CGI-I (parent and child)

Armour et al. (2008)

Children with burn injuries and sleep deprivation; ages 3–18 years (mean 9.38); 28 males; 12 females; N = 40

Partially controlled

Blumer et al. (2008)

Children, ages 2–18 years (mean 9.47) 38 males, 27 females N = 65

Uncontrolled

Colle et al. (1991)

Children with short stature, ages 6.9–14.3 years (mean 10.8); 10 males, 2 females; N = 12; healthy adult males ages 24–36 years (mean 27.9); N = 12

Partially controlled, confounded by time

Erman et al. (2008)

Adults with primary insomnia; ages 21–64 years (no mean age); 16 males, 49 females; N = 65

Fully controlled

Walsh et al. (2000)

Healthy adults; ages 18–65 years (mean 42.1); 29 males, 84 females; N = 113

Fully controlled

Double-blind, crossover; ZOL 0.5 mg /kg to maximum of 20 mg /d and haloperidol (HAL) 0.05 mg /kg to maximum of 5 mg /d; no control group; 1 BL night prior to 1 night of treatment in each condition;PSGrecordings Dose escalation study of ZOL, to identify dosing for use in clinical efficacy trials; 3 age stratified-dose groups, (0.125mg/kg, 0.25 mg /kg, 0.50 mg /kg); No control group; pharmacokinetics assessed; PSGrecordings Double-blind crossover parallel-groups design; PBO and ZOL 10 mg effects on sleep disturbance associated with repeated blood sampling in children under investigation for growth hormone(GH) and healthy adults; PSGrecordings taken for 2 nights over a 7day interval; sleep variables recorded by trained nurse Randomized 6-way crossover dose response study of PBO and eszopiclone (ESZ) (1.0, 2.0, 2.5 and 3.0 mg), ZOL (10.0 mg); participants received 2 consecutive nights of treatment in each condition, with 3 to 7 nights washout between; PSG-recordings and self-report Randomized double-blind PBOcontrolled parallel groups design; PBO or ZAL 10 mg or 20 mg; 4 nights of PSGrecordings for screening, 2 nights of single-blind PBO and PSG-recordings (used as BL), 35 nights of treatment, 2 nights of single-blind PBO discontinuation, and follow-up medical assessment; PSG- recordings performed on the first 2 nights of each treatment week

PSG-defined sleep initiation and maintenance variables, LPS, TST, WASO, showed no significant differences between groups (ZOL = PBOb). Child CGI-I and CGI-S significant at Week 4 in favor of ZOL (ZOL > PBO) but not at Week 8, parent CGI-I did not differ from BL at Week 4, in contrast parent CGI-S showed significant improvement; both parent and child CGI-I and CGI-S showed a treatment-by-age interaction at Weeks 4 and 8 (mean CGI-I favored older age group compared to the younger). AEs occurred more frequently in ZOL group; majority mild to moderate; no daytime residual effects; SDs not reported, hence no ESs PSG-defined sleep maintenance variables TST, NAW, and latencies to stage sleep [1,2,3 4, rapid eye movement (REM) sleep] showed that neither ZOL nor HAL restored a normal quantity of sleep in burn patients and that both treatments had small effects on TST (ZOL = HAL); AEs not reported. SDs not reported, hence no ESs

PSG-defined sleep variables showed significant improvement in TST from BL to Day 3. ZOL well tolerated (14 participants experienced 22 mild AEs), one AE (abnormal eye movement) considered serious by the investigator, all resolved without intervention. BL means and SDs not reported, hence no ESs

sSOLc showed significant reductions in the ZOL group (children and adults) compared to PBO (ZOL > PBO); no significant differences found between the ZOL 10 mg and PBO groups on mean GH profiles; ZOL 10 mg effective in promoting sleep in young children undergoing overnight blood sampling and had no effect on nocturnal GH profiles; one adverse event reported in the ZOL group (floating sensation) SDs not reported, hence no ESs

PSG-defined sleep initiation and maintenance variables, LPS and SE showed significant improvement in the ESZ (1.0, 2.0, 2.5, 3.0 mg) and ZOL (10.0 mg) groups, WASO significantly improved in the ESZ 3.0 mg group (ESZ > PBO); sSOL, and sTST, showed significant improvement in the ESZ 2.0 and 3.0 mg groups and in the ZOL group (ESZ and ZOL > PBO), sWASO showed significant improvement in the ESZ (2.0 and 3.0 mg), ZOL (10.0 mg) and PBO groups; overall rate of CNS AEs 7.9% for PBO, 6.2%-12.5% for ESZ, 23.4% for ZOL; hallucinations occurred with ZOL. SDs not reported, hence no ESs PSG-defined sleep initiation and maintenance variables and subjective sleep ratings averaged each week. Median LPS significantly shorter in ZAL group for all treatments when compared to PBO (Week 1, ES .47; Week 3, ES .27; Week 5, ES .47) (ZAL 10 mg > PBO). No significant differences between groups in TST, NAWs, or in sleep stages (S1, S2, S3, S4) (ZAL = PBO).Week 2, REM percent significantly lower and Week 4 rapid eye movement latency (REM-L) significantly longer with ZAL 10 mg compared to PBO (PBO > ZAL). Data from 2 discontinuation nights showed no significant difference between groups (ZAL = PBO); Adverse event reporting appeared similar between groups (PBO 84% and ZAL 79%)

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Source Blumer et al. (2009)

Adults with insomnia; ages 59–95 years (mean 72.5); 137 males, 285 females; N = 422)

Fully controlled

Randomized, double-blind, PBOcontrolled, parallel-groups design; PBO run-in (nights -7 to -1 and PBO run-out (nights + 1 to + 7); 14 days of ZAL 5 mg, 10 mg/d or PBO; subjective sleep ratings

Elie et al. (1999)

Adults with primary insomnia or insomnia associated with mild nonpyschotic psychiatric disorders; ages 18–65 years (mean 43.2); 204 males, 373 females; N = 577

Fully controlled

Randomized double-blind PBOcontrolled parallel group design; PBO or ZOL 10 mg, ZAL 5, 10, 20 mg; 4 study phases, pre-study washout (1-3- weeks), single-blind PBO run–in period (7 nights and BL), double-blind treatment period (28 nights), single-blind, PBO run-out period (3 nights), and follow-up (after 4– 7 days of no treatment); participant rated pre-sleep and post-sleep questionnaires

Walsh et al. (1998)c

Adults with primary insomnia; ages 18–60 years (mean 40.2); 55 males, 77 females; N = 132

Fully controlled

Randomized, double-blind PBOcontrolled parallel groups design; PBO or ZAL 5 mg, 10 mg, or TZM 0.25 mg; 3 study phases, screening phase (3 nights) double-blind phase 1 (4 nights), discontinuation phase (2 nights), 4 treatment groups; PSG-recordings and participant rated post-sleep questionnaires

Median sSOL showed significant decreases in ZAL 5 mg and 10 mg groups at Weeks 1 and 2 when compared to PBO (ZAL > PBO); sTST showed a significant increase in ZAL 10 mg group at Week 1, but investigators attributed it to lower sTST scores at BL. No other significant changes noted and no meaningful differences in sNAWs reported. Small but significant improvements in median sleep quality scores noted in both ZAL groups during treatments (ZAL > PBO). No rebound insomnia in ZAL 5 mg group. However, ZAL 10 mg group showed significant decreases from BL in sTST, upon withdrawal. Both doses of ZAL appeared well tolerated when compared to PBO. Medians analyzed, no SDs reported, hence no ESs Median sSOL from daily post-sleep questionnaires significantly decreased during Week 1 with ZAL 5, 10, 20 mg, and ZOL 10 mg doses when compared to PBO (active treatment > PBO) and persisted through Week 4 with ZAL 10, 20 mg doses. A significant dose-dependent trend with increasing doses of ZAL found for all 4 weeks (ZAL > PBO). ZOL 10 mg significantly decreased sSOL during Weeks 1-3 (ZOL > PBO). ZAL 20 mg significantly increased sTST in all but Week 3 of double-blind treatment phase (ZAL > PBO). ZOL 10 mg increased sTST during all s of double-blind treatment (ZOL > PBO). No significant differences found between active treatment groups and PBO in sNAWs (active treatment = PBO). Significant rebound insomnia shown in sNAWs, for ZAL 10 and 20 mg and ZOL 10 mg groups, when compared with PBO (PBO > active treatment). Significant rebound effects shown in sSOL upon withdrawal of ZOL 10 mg (PBO > ZOL). No significant differences in AEs found between all active treatments and PBO. SDs not reported, h ence no ESs PSG-defined sleep initiation and maintenance variables showed LPS significantly decreased in both ZAL 5 and 10 mg groups on nights 4 to 5 (ZAL > PBO) with no significant differences between either dose and PBO on nights 16 to 17 (ZAL = PBO). TST not significantly different between either dose of ZAL (5, 10 mg) and PBO on either nights 4 to 5 or 16 to 17 (ZAL = PBO). NAWs not significantly different between either dose of ZAL (5, 10 mg) and PBO on either nights 4 to 5 or 16 to 17 (ZAL = PBO). Sleep architecture (sleep stages 1,2,3,4) showed no significant differences between all treatment conditions (active treatment = PBO). LPS and TST data for discontinuation (nights 18 and 19) showed no significant differences between both ZAL doses and PBO (ZAL = PBO) and showed no withdrawal effects when compared to BL. Data from post-sleep questionnaires showed that sSOL significantly decreased in ZAL 10 mg condition on nights 4 to 5 and home nights 6 to 14, compared to PBO (ZAL > PBO). sSOL for all active treatments did not differ from PBO on nights 15 to 16; sTST and sNAWs showed no significant differences between both ZAL conditions and PBO (ZAL = PBO). Subjective sleep maintenance variables showed no significant differences between treatment groups upon withdrawal of ZAL (5, 10 mg) (ZAL = PBO). Medians analyzed and no SDs reported, hence no ESs

a Abbreviations. ADHD, attention deficit hyperactivity disorder; AE, adverse event; BL, baseline; CGI, clinical global impression; CNS, centeral nervous system; ES, effect size; ESZ, eszopiclone; GH, growth hormone; HAL, haloperidol; LPS, latency to persistent sleep; NAWs, number of awakenings; PBO, placebo; PSG, polysomnography; REM, rapid eye movement; REM-L, rapid eye movement latency; SD, standard deviation; SE, sleep efficiency; SOL, sleep onset latency; S1, S2, S3, S4, sleep stages 1 through 4; sSOL, subjective sleep onset latency; TST, total sleep time; WASO, wake after sleep onset; ZAL, zaleplon; ZOL, zolpidem. b > = superior to (e.g., Zolpidem > PBO).

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Hedner et al. (2000)

953

954

J.A. Hollway, M.G. Aman / Research in Developmental Disabilities 32 (2011) 939–962

disorder). The question is whether the benefits of using a benzodiazepine outweighs the potential risks. The adverse events reported in the studies reviewed were mild and similar to those of placebo. In only one study was increased somnolence and dizziness reported. The adverse effects typically associated with benzodiazepine use include tolerance, dependence, daytime residual effects, rebound insomnia, and cognitive impairment (American Academy of Sleep Medicine, 2001; Holbrook, Crowther, Lotter, Cheng, & King, 2000). It seems that future studies targeting parasomnias in children should evaluate alternatives that are safer than benzodiazepines. 3.6. Pyrinidine derivatives [non-benzodiazepine, GABAergic (Z) drugs] The short-acting ‘‘Z-drug’’ hypnotics, zolpidem and zaleplon, appear similar to benzodiazepines in that they are active at the GABA receptor complex. However, these non-benzodiazepine agents are more selective for certain subunits of the GABA receptor (Drover, 2004) and are reported to have lower tolerance and dependency potential than barbiturates and benzodiazepines (Lancel, 1999). Table 5 shows the results of the current literature regarding zaleplon and zolpidem. 3.6.1.1. Zolpidem tartrate (Ambien) To date, four efficacy studies of zolpidem in children with disturbed sleep have revealed mixed results in initiation and maintenance variables. One fully controlled trial showed no differences between treatment groups in PSG-defined variables. However, analysis of child global ratings showed greater improvement favoring zolpidem at Week 4 with a treatment-byage interaction in child and parent global ratings at Weeks 4 and 8. Greater improvement for older participants may suggest that age is a moderator of therapeutic effect (Blumer, Findling, Shih, Soubrane, & Reed, 2009). Adult efficacy studies of zolpidem appear to bear this out, as greater therapeutic effect has been observed in adults with primary insomnia (Erman et al., 2006; Kryger, Steljes, Pouliot, Neufeld, & Odynski, 1991). Three other quasi-controlled or uncontrolled studies in children showed small but significant improvements in sleep initiation and maintenance variables or non-significant improvements in all sleep variables (Armour, Gottschlich, Khoury, Warden, & Kagan, 2008; Blumer et al., 2008; Colle et al., 1991). Zolpidem was well tolerated, and CNS adverse events were typically mild to moderate and generally resolved without intervention (Blumer et al., 2009; Blumer et al., 2008). There were no reports of daytime sleepiness or next day residual effects in the zolpidem group, but there were mixed results in regard to rebound insomnia after zolpidem withdrawal. In one study of adults, significant rebound effects and withdrawal symptoms were reported after 4 weeks of zolpidem use (Elie, Ru¨ther, Farr, Emilien, & Salinas, 1999). Another study monitored changes in sleep architecture, and zolpidem did not have a significant effect (Armour et al., 2008). With only four studies available thus far, more studies are needed to determine the efficacy of zolpidem in children. 3.6.1.2. Zaleplon (Sonata) Zaleplon has a rapid onset of action and a relatively short duration of sedative activity which makes it attractive for use in children with sleep initiation problems (Walsh et al., 2000). There are currently no studies of zaleplon in children, but there are several studies in adults with primary insomnia. Zaleplon has been found to be effective in treating sleep onset insomnia (SOI) and is especially useful for evening and mid-night dosing because it is essentially free of residual effects (Barbera & Shapiro, 2005). In the literature reviewed, treatment emergent adverse events remained minimal (Elie et al., 1999; Hedner, Yaeche, Emilien, Farr, & Salinas, 2000; Walsh et al., 1998; Walsh et al., 2000). However, in one study, zaleplon was found to have an adverse effect on sleep architecture, as it prolonged rapid-eye-movement latency (REM-L) and reduced REM sleep time (Walsh et al., 2000). Upon zaleplon withdrawal, no significant rebound phenomena occurred (Elie et al., 1999; Hedner et al., 2000; Walsh et al., 2000), and there was no evidence of tolerance to its hypnotic effects (Walsh et al., 1998). Zaleplon may be a good candidate for targeting SOI in children with DDs because it is short acting, quickly metabolized, and is not prone to induce rebound or residual effects. The fact that it may alter sleep architecture is cause for concern, and future studies would provide a service by using PSG to determine if this is an issue. Longer acting than zaleplon, zolpidem, may be an effective alternative for adolescents and adults with sleep initiation and maintenance problems, but it may not be the optimal choice for children. Its effectiveness has not been established in children, and it conveys with it the possibility of rebound effects upon withdrawal. Zaleplon, the shortest acting of the Zdrugs, appears to be useful in treating adults with sleep initiation issues, but it is unclear whether it is useful in children and may not be useful for maintenance issues such as number of night-time arousals. Fully controlled studies of zolpidem and zaleplon are needed to determine safety and effectiveness in this population. 3.7. Cyclic antidepressants Sedating antidepressants are often prescribed by physicians on an ‘‘off-label’’ basis to treat sleep disturbances (Mindel et al., 2006; Owens et al., 2003). Yet few studies have been conducted that focus specifically on improving sleep disturbance in children (see Table 6). 3.7.1.1. Trazodone (Desyrel) Trazodone is a serotonin antagonist reuptake inhibitor (SARI) and has antidepressant and sedative properties (Bezchlibnyk-Butler & Jeffries, 2005). It is commonly prescribed for children with DDs (Meltzer et al., 2007), but there are no

Table 6 Studies of antidepressants in children, adolescents (italicized), and adults with sleep disorders. Participants

Level of control

Method

Outcome by variable

Children, adolescents, with sleep bruxism (SB)a; ages 6–18 years (mean 13.07); 17 males, 11 females; N = 28 Children, adolescents, with Ipsoclonus-myoclonus syndrome and sleep disturbance; ages <1.5 years to > 5 years (mean 4.3 years); 22 males, 29 females; N = 51 Children with Pervasive Developmental Disorder (PDD) and intellectual disability (ID) and associated symptoms (insomnia); ages 3.8-23.5y (mean 10.1); 21 males, 5 females; N = 26 Adolescents with insomnia associated with a depressive disorder, ages 13-17 y; 15 males, 45 females; N = 60 Child with severe Sleep Terror disorder and insomnia; age 7y;1 female; N = 1 Children with depressive symptoms, ages 6–14 years (mean 10.3); 7 males, 5 females; N = 12

Uncontrolled

Open-label; trazodone (TZD) started at 0.5 mg /kg/d (range 0.5-2.0); no control group or standardized assessments; 4week acute trial; parent report

TZD significantly decreased SB and face/jaw pain from BL to EP (ES 2.0) (TZD > BL)b; Mild adverse events (AEs) in of participants

Uncontrolled

Open-label; TZD started at 25 mg (range 25-150); 17 of 51 participants (34%) received TZD; no control group, or standardized instruments; duration of treatment was variable; parent report

95% (n = 16) of TZD group showed significant improvement in sleep quality and behavior by parent interview (TZD > BL). AEs minimal and well tolerated, even in toddlers. SDs not reported; hence no ESs

Uncontrolled

Open-label; mirtazapine (MTZP) started at 7.5 mg and increased by increments of 7.5 mg up to 45 mg/d in divided doses; >4weeks; CGI-I and CGI-S

30.8% of participants responded to MTZP, showing significant improvement from BL to EP in sleep quality on modified CGI improvement item for sleep (ES .64) (MTZP > BL). AEs, transient or mild and included increased appetite, irritability and sedation

Uncontrolled

Open-label retrospective chart review; 3 treatments (mean daily dose), TZD (71 mg), fluoxetine (FLX) (20 mg), TZD/FLX (68/29 mg); no control group, or quantitative outcome variables; duration of treatment variable by self-report Case study; started at 25 mg TZD, titrated to 150 mg;7 months parent report

Days to insomnia resolution significantly faster in TZD group as compared to FLX group (ES .54); resolution to insomnia was slightly later in older children. AEs not reported.

Pranzatelli et al. (2005)

Posey et al. (2001)

Kallepalli et al. (1997)

Balon (1994)

Kupfer et al. (1979)

Uncontrolled

Uncontrolled

Open-label; imipramine (IMI) started at 25 mg h.s. and titrated to 5mg/kg or 200 mg daily (mean daily dose 156.2 mg) titration period 7-21 days; no control group; 3 nights of EEG-sleep recordings taken at baseline, 2 follow-up recordings done 3 weeks after IMI initiation

Selcuk et al. (2002)c

Young healthy adults; ages 18– 30 years (mean 24); 12 males, 8 females; N = 20

Fully controlled

Randomized, double-blind, PBO-controlled parallel groups design; PBO or MTZP 30 mg; PSG-recordings on 3 consecutive nights (adaptation, BL, treatment)

Saletu-Zyhlarz et al. (2002)

Adults with nonorganic insomnia related to a depressive episode; ages 35–75 years (mean 53.55); 12 males, 10 females; N = 22

Partially* controlled;drug confounded with time

Single-blind, PBO-controlled, crossover study; healthy control group; no random assignment; TZD 100 mg /d; PSGrecordings taken on 3 consecutive nights (i.e., adaptation, PBO, TZD), Self-Assessment of Sleep and Awakening Quality Scale (SSA), psychometric testing for daytime quality

Participant stopped experiencing night terrors at optimal dose and insomnia improved; AEs not reported; SDs not reported, hence no ESs EEG-defined sleep initiation and maintenance variables showed significant differences between baseline sleep variables and follow-up; IMI significantly increased wakefulness and decreased TST and SE; IMI increased stage 2 sleep and decreased stage 4 sleep (SWS); IMI increased REM-L and decreased REM (BL > IMI); AEs not reported. SDs not reported, hence no ESs PSG-defined sleep initiation and maintenance variables showed significant improvements in SE (ES 1.3), NAWs (ES .86) and WASO (ES 1.3) (MTZP > PBO); sleep architecture revealed significant increase in slow wave sleep (SWS) (ES .86) (MTZP > PBO) and no significant difference between groups in REM and REM-L (MTZP = PBO); significant group differences at BL for outcome variables may have been a confound PSG-defined sleep initiation and maintenance variables showed significant improvement in SE (77% to 92%), TST, and NAWs in TZD group (TZD > PBO). Effects on sleep architecture revealed increases in S3, S4, and REM sleep in TZD group (TZD > PBO) and no change in REM-L (TZD = PBO). Subjective sleep quality significantly improved in TZD group and total SSA score decreased significantly (TZD > PBO); TZD group showed no significant differences in psychometric testing compared to PBO (TZD = PBO). AEs not reported. SDs not reported, hence no ESs

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Source Shakibaei et al. (2008)

955

Participants

Level of control

Method

Outcome by variable

Adults with nonorganic insomnia related to dysthymia; aged 27–72 years (mean 50.4); 3 males, 8 females; N = 11

Partially* controlled;drug confounded with time

Single-blind, PBO-controlled, crossover study, no random assignment; TZD100 mg /d; PSG-recordings taken on 3 consecutive nights (i.e., adaptation, PBO, TZD); SelfAssessment of Sleep and Awakening Quality Scale (SSA)

Staner et al. (1995)

Adults with MDD; 18–65 years (mean 42.1y); 7 males, 33 females; N = 40

Fully controlled

Randomized, double-blind parallel-groups trial; 10-day PBO run-in; paroxetine (PAR) 30 mg /d, compared to amitriptyline (AMI)150 mg /d; 6-week acute (day-1 and day-2)and subchronic trial; Sleep EEG scored blind to membership

PSG-defined sleep initiation and maintenance variables revealed nonsignificant increases in SE in TZD group (79%-87%) (TZD = PBO). Slight, but significant differences found in sleep architecture in TZD group (prolongation of S3 & S4 and REM %) (TZD > PBO); REM-L prolonged in TZD group (PBO > TZD). SSA showed no significant improvement in sleep quality (TZD = PBO). SDs not reported, hence no ESs EEG-defined sleep variables showed significant differences between PAR and AMI groups following acute phase, SOL (ES .91), TST (ES .88), (AMI > PAR) no significant difference found between groups on NAWs. Subchronic phase showed significant differences in SOL (ES .27), TST, (ES .51) and NAWs (ES 1.2) with PAR significantly increasing SOL and NAWs and exerting alerting effect (AMI > PAR). Significant differences between groups observed from subchronic phase to withdrawal. Rebound effects observed in AMI group compared to PAR for SOL and TST, SOL (ES 2.1), TST (ES 2.0) and a significant decrease in NAWs (ES .58) occurred in the PAR group upon withdrawal; drug by time interactions occurred. Both groups reported similar numbers of AEs (AMI group reported anticholinergic AEs, PAR group headaches, nausea, anxiety)

a Abbreviations. AE, adverse event; AMI, amitriptyline; BL, baseline; EMA, early morning awakening; EP, end point; ES, effect size; IMI, imipramine; LPS, latency to persistent sleep; MTZP, mirtazepine; NAWs, number of awakenings; PAR, paroxetine; PBO, placebo; PSG, polysomnography; REM, rapid eye movement; REM-L, rapid eye movement latency; SB, sleep bruxism; SD, standard deviation; SE, sleep efficiency; SOL, sleep onset latency; S1, S2, S3, S4, sleep stages 1 though 4; SWS, slow wave sleep; TZD, trazodone; TST, total sleep time; WASO, wake after sleep onset. b > = superior to (e.g., TZD > PBO).

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Source Saletu-Zyhlarz et al. (2001)

956

Table 6 (Continued )

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randomized controlled trials of trazodone in children with sleep disorders and relatively few open-label studies. In four open-label studies of trazodone, children with insomnia secondary to either a parasomnia or a neurodevelopmental disorder showed improvement in sleep initiation and maintenance variables (Balon, 1994; Kallepalli, Bhatara, Fogas, Tervo, & Misra, 1997; Pranzatelli et al., 2005; Shakibaei, Gholamrezaei, & Heidari, 2008). Similarly, two studies of trazodone confined to adults with insomnia secondary to depressive disorder also showed significant improvement in several PSG-defined sleep initiation and maintenance variables (Saletu-Zyhlarz et al., 2001, 2002). Trazodone showed positive effects on sleep architecture, in that it increased both REM and SWS. Adverse events were mild and well tolerated for all studies. A special concern for males treated with trazodone is priapism, although reports remain rare (Mendelson, 2005). Priapism was not reported in the studies reviewed for this paper. The results of the above-mentioned studies are encouraging as trazodone was found to be effective, produced mild side effects, and improved sleep architecture. Controlled studies are needed to verify these findings. 3.7.1.2. Mirtazapine (Remeron) Mirtazapine is a noradrenergic/specific serotonergic antidepressant (NaSSA), and it increases noradrenergic and serotonergic transmission via blockade of alpha-adrenoreceptors. One open-label study of mirtazapine in children was located (Posey, Guenn, Kohn, Swiezy, & McDougle, 2001). Approximately 31% of the study participants showed improved sleep quality. PSG-recordings were not taken. A controlled study of mirtazapine in adults showed improvements in sleep maintenance variables, and no differences were found between groups in REM sleep and REM-L (Selcuk, Isik, & Cosar, 2002). SWS was prolonged in the mirtazapine group. Mirtazapine shows some promise as a hypnotic agent for children; however, not enough evidence exists to determine its risk/benefit ratio. Studies with stronger controls and objective measures are needed to replicate these findings. 3.7.1.3. Imipramine (Tofranil) An open-label study of imipramine (Tofranil) in children was located (Kupfer, Coble, Kane, Petti, & Conners, 1979). The investigators found that rather than improving sleep, imipramine had an alerting effect on study participants. EEGrecordings showed prolonged REM-L, decreased REM sleep, and decreased SWS. 3.7.1.4. Amitriptyline (Elavil) Two studies of amitriptyline in adults were located. In a controlled trial of amitriptyline and paroxetine (Paxil), the results showed that amitriptyline improved sleep initiation and maintenance variables but that paroxetine had the opposite effect and actually worsened insomnia (Staner et al., 1995). Rebound effects were observed after withdrawal of amitriptyline alone, but both groups experienced a similar number of adverse events. The results of another controlled study in adults showed that amitriptyline improved sleep maintenance. However, amitriptyline also reduced REM sleep (Kupfer, Spiker, Coble, & McPartland, 1978). Of the cyclic antidepressant hypnotics reviewed, trazodone appears to be the safest and most effective antidepressant for use in children. Nevertheless, studies of trazodone in children provide us with limited information, and there remains a definite need for fully controlled studies utilizing objective and subjective sleep measures. 3.8. Atypical antipsychotics Atypical antipsychotics are prescribed for use in typically developing children and those with developmental disabilities primarily to decrease disruptive behaviors (Akhondzadeh et al., 2008; Biederman et al., 2006; Leblanc et al., 2005; Research Units on Pediatric Psychopharmacology, 2002; Reyes, Buitelaar, Toren, Augustyns, & Eerdekens, 2006; Troost et al., 2005). In addition, the atypical antipsychotics, risperidone, and olanzapine, have been prescribed for sleep disturbances in children (Meltzer et al., 2007; Schnoes et al., 2006). 3.8.1.1. Risperidone (Risperdal) Risperidone is an atypical antipsychotic that blocks postsynaptic dopamine and serotonin receptors and is distinguished from conventional antipsychotics by greater 5-HT2 rather than D2 blockade (Bezchlibnyk-Butler & Jeffries, 2005; Research Units on Pediatric Psychopharmacology, 2002). Risperidone may be the most frequently used antipsychotic in the pediatric population (Aman, Lam, & Collier-Crespin, 2003; Langworthy-Lam, Aman, & Van Bourgondien, 2002). However, just one case study of risperidone in a child with Tourette’s Syndrome and sleep disturbance was located. Since blockade of dopamine systems can induce sleep disturbances, the investigators analyzed sleep patterns prior to and following treatment with risperidone (Arana-Lechuga, Sanchez-Escando´n, CastilloMontya, Tera´n-Pe´rez, & Vela´zquez-Moctezuma, 2008). After six months of treatment, the investigators found that risperidone improved sleep quality by increasing TST, and decreasing SOL and NAWs. A possible disadvantage was that restorative SWS also decreased. The investigators found that both the motor tics and the associated sleep problems had remitted. No statistical tests of significance were conducted. Aman et al. (2005) conducted a comprehensive evaluation of possible adverse events in 101 children with autism. A measure of total sleep time per night showed slightly increased sleep for the risperidone group, but the difference did not approach statistical significance.

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3.8.1.2. Olanzapine (Zyprexa) According to Meltzer et al. (2007), olanzapine (OZP) is prescribed to children for sleep problems. However, it appears that there are no studies available that have evaluated the safety and effectiveness of olanzapine as a treatment for sleep disturbance in children or adults. After using several search terms in Psychinfo and Medline, no studies were located. 3.9. Conventional antipsychotics 3.9.1.1. Haloperidol (Haldol) Haloperidol is a conventional antipsychotic, and its primary action has been attributed to D2 blockade. In a randomized, double-blind crossover design of haloperidol and zolpidem targeting sleep disturbances in children with a mean percent total body surface area burn of 50.1, investigators found that haloperidol was unable to restore normal quantity and quality of sleep and that it had a small effect on TST (Armour et al., 2008). The results of this comparison study are in Table 5 (with the ‘‘Z Drugs’’). A large amount of literature describes the effects of atypical antipsychotics in children with disruptive behavior, and there is a good deal of information on the safety of these agents (Aman et al., 2005), but there is not enough empirical evidence to determine whether atypical antipsychotics are effective hypnotics. Well controlled clinical trials focusing on childhood sleep disorders should be conducted while utilizing both subjective and objective measures in order to interpret the effect of atypical antipsychotics on sleep architecture. 4. 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 results. Out of 58 studies cited in this manuscript, 43 or approximately 75% were controlled trials and of these 58% focused on pediatric research while 42% studied adults. In addition, 79% were investigator-driven studies and 21% were industry-driven clinical trials. It appears that there may be some clear advantages to research funded by pharmaceutical companies. Industry-driven studies tend to enroll larger sample sizes, which increases power to detect treatment effects. For example, in two clinical trials of zolpidem, the average number of study participants was 321. Similarly, three studies of zaleplon enrolled an average of 222 participants per study, while four studies of ramelteon, reported an average of 367 participants. In contrast, the average sample size for 14 fully controlled investigator-driven studies of melatonin in children was 30 participants. Sample size appears to be one benefit to industry funded research. Another benefit is that these studies tend to use stateof-the-art technology to measure sleep variable outcomes. Standardized methodology including the gold standard PSG (Moser et al., 2009; Rechtchaffen & Kales, 1968) appears to be the norm. Within this review, 66% of industry-driven studies used PSG to measure sleep, while only 35% of investigator-driven studies used it. PSG provides objective information in regard to sleep initiation and maintenance variables and important safety information for detecting change in sleep architecture. In addition to PSG, industry clinical trials use subjective measures (e.g., rating scales, clinical global impressions, sleep diaries) to measure sleep. Subjective sleep measures have been criticized for their unreliability, as they often do not accurately describe the treatment effect (Carskadon, Seifer, & Acebo, 1991; Lewis, 1969; Kryger, Steljes, Pouliot, Neufeld, & Odynski, 1991). However, significant small-to-moderate correlations between objective and subjective sleep measures have been found (Kryger et al., 1991). This is encouraging, as many more sleep studies have relied exclusively on patient or parent report to detect improvement. Out of the 43 controlled studies cited here 50% used subjective sleep measures alone. The lack of objective measures in these studies may reflect the complexity (and expense) of using PSG in pediatric populations with developmental disabilities. PSG recordings are conducted overnight in sleep laboratories and an additional adaptation night is necessary, even for adult participants. Also, placing electrodes can be a quite daunting to the most resolute researcher when studying pediatric participants with heightened sensory sensitivities. Both objective and subjective measures provide information regarding the efficacy of a pharmacological treatment. However, the subjective measures provide clues as to the social validity of the intervention. This refers to the treatment’s effectiveness in improving sleep quality; its acceptability to patients and their parents; and its practicality for generalization (Cooper, Heron, & Heward, 1987). PSG-recordings provide not only efficacy data but also important safety information in regard to changes that occur in sleep architecture. In summary, some advantages that pharmaceutical investigations have over investigator driven studies include: (a) greater power to detect signal, (b) a reduction of error variance associated with subjective measures of sleep, and (c) enhanced external validity. PSG recording has shown that some hypnotic agents have elicited changes in sleep architecture and have reduced REM (e.g., clonidine, zolpidem, triazolam, and imipramine) and SWS (e.g., ramelteon, triazolam, imipramine). These results may have important implications for the treatment of sleep disturbance in children who are intellectually disabled. There exists a

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body of evidence indicating that a reduction in REM sleep may interfere with the consolidation of memory traces necessary for skill development (Laureys et al., 2001; Maquet et al., 2000; Stickhold, Hobson, Fosse, & Fosse, 2001), and there is an established inverse relationship between an individual’s level of intellectual functioning and time spent in REM sleep (Harvey & Kennedy, 2002; Espie et al., 1998; Espie & Tweedie, 1991). Therefore, in a population of children who struggle to learn and maintain adaptive skills, with an already diminished REM sleep sequence, the effect of one of these REM-reducing drugs could cause further deterioration in skill acquisition. Similar to REM sleep, SWS plays a role in the consolidation of procedural memory and the enhancement of synaptic plasticity (Aton et al., 2009; Gais, Plihal, Wagner, & Born, 2000; Hoffman & McNaughton, 2002; Stickhold, 2005; Walker & Stickhold, 2006); the suppression of this restorative restful stage of the sleep sequence could hinder learning. And, of course, children with developmental disabilities may be ill equipped to complain about such an effect. The studies cited in this paper were almost exclusively efficacy studies, and safety was often followed as a secondary outcome. Even so, it appears that there is a general lack of information in regard to adverse events, and it is possible that critical developmental events may be altered by certain classes of hypnotics. More research is needed to determine the effects of these agents on the developing brain (Seibt et al., 2008). Future researchers should focus on safety issues as well as efficacy to aide clinicians in determining the best medication for their pediatric patients with developmental disabilities. 5. 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 measures. Clonidine’s use as a hypnotic has not been adequately researched in pediatric populations, and it does appear to decrease REM sleep. Therefore, more studies monitoring sleep architecture and its effects are necessary to determine the medication’s safety and efficacy as a sleep aide. The benzodiazepines carry a number of adverse effects, and there are risks that undermine their use as hypnotics. The ‘‘Z’’ drug zolpidem has not proven effective in the treatment of childhood insomnia. It may be useful in adolescents and adults, but more studies are needed to rule out rebound effects. Zaleplon has been studied in adults only, and it has been effective in reducing SOL but not fragmented sleep. More studies in children are needed to determine efficacy. The antidepressant imipramine is not recommended for use as a hypnotic as it may produce alerting effects and amitriptyline, though improving sleep initiation and maintenance, reduces REM sleep and may cause rebound insomnia following its discontinuation. Medical professionals follow a specific set of guidelines when prescribing hypnotics to children and adults (Kupfer & Reynolds, 1997; Palermo et al., 2002). Choosing the optimal hypnotic may be a challenge for clinicians, as there are several considerations to take into account when deciding on a sleep medication. Properties carried by the most favorable hypnotics include (a) high oral bioavailability; (b) short elimination half-life; (c) rapid onset of action; (d) once-nightly dosing; (e) low risk for dependence, abuse, tolerance, withdrawal, and rebound, without daytime residual effects. These agents should also carry favorable side-effect profiles, and show no significant reductions in REM and NREM sleep stages (Palermo et al., 2002). Considering the quality level of the research studies cited in this manuscript and the guidelines for hypnotic prescribing discussed above, melatonin appears to have the most empirical evidence and the best pharmacokinetic/dynamic profile for its use in children with developmental disabilities and should be considered the first line of treatment for sleep disorders. 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