What is the evidence for pharmacotherapy?
Antihistamines. Histamine antagonists—which promote sleep by blocking the wakefulness-promoting and circadian-related effects of histamine—are the most commonly used medications to treat pediatric insomnia, despite a dearth of data from prospective trials.5,6 In 1 small study, Russo et al7 found diphenhydramine, 1 mg/kg at bedtime, reduced sleep latency and nighttime awakenings, and increased sleep duration in patients ages 2 to 12; similar effects have been observed in pediatric burn patients.8 There are some limited data for other H1 antagonists (eg, hydroxyzine) in pediatric insomnia.9-11
Alpha-2 agonists increase rapid eye movement sleep via dose-dependent downregulation of noradrenergic signaling12 and thus have been commonly prescribed for insomnia in children and adolescents. In fact, the nonselective alpha-2 agonist clonidine is among the most prescribed medications for youth with insomnia, and may be efficacious in youth with neurodevelopmental disorders and ADHD.13 In small retrospective studies, clonidine decreased sleep latency and nighttime awakenings in addition to increasing sleep duration.14 Also, clonidine was well tolerated but associated with daytime somnolence. Guanfacine—a selective alpha-2 agonist—is also commonly prescribed for insomnia in youth, although results of trials have been equivocal.15 Given the more rapid absorption and shorter Tmax of clonidine relative to guanfacine, the former may be preferred as a soporific.
Melatonin and melatonin agonists. The primary regulator of the sleep-wake cycle is melatonin, an endogenous hormone produced by the pineal gland in response to changes in retinal light perception. Exogenous melatonin supplementation may be the preferred initial pharmacotherapy for sleep-onset insomnia due to its chronobiotic properties.16 In clinical studies, both immediate-release17,18 and extended-release19 melatonin reduced sleep-onset latency and increased total sleep duration in pediatric patients, although the increase in total duration of sleep was greater with extended-release preparations. Additionally, tolerability data for melatonin in pediatric patients are encouraging. A 2-year randomized trial of prolonged-release melatonin for insomnia in pediatric patients found no adverse effects with regard to growth, body mass index, or pubertal development.20 Additionally, significant improvements in sleep quality, sleep patterns, and caregiver satisfaction were maintained throughout the trial, and no withdrawal symptoms were observed upon discontinuation.
Melatonin may have a particularly important role in circadian rhythm sleep disorders. In this regard, low-dose melatonin (0.5 mg), when timed relative to the endogenous dim light melatonin onset (DLMO), is more effective in shifting sleep phase than higher doses, which suggests that timing may have greater impact than dosage.21 Data regarding melatonin administration with respect to DLMO suggest that the optimal administration time is 4 to 6 hours before a child’s preferred bedtime, and doses of 0.5 to 1 mg have been effective when given in this window.22 Variation across studies has contributed to a lack of consensus regarding pediatric melatonin dosing. For example, .05 mg/kg may be a minimal effective dose when given 1 to 2 hours before bedtime18; however, in surveys doses vary considerably, with typical doses of 2.5 to 3 mg for prepubertal children and 5 mg for adolescents.5 Of note, in patients with decreased cytochrome P450 (CYP) 1A2 activity, lack of diurnal variation in melatonin serum concentration may decrease the effectiveness of melatonin.16Ramelteon is a potent agonist of the melatonin MT1 and MT2 receptors, with a significantly higher binding affinity than melatonin in vitro. In case reports, ramelteon was well-tolerated, improved delayed sleep onset, and decreased nighttime awakenings.23
Zolpidem, eszopiclone and zaleplon. Studies of selective GABAergic modulators and benzodiazepines have not produced positive results in prospective trials of youth with insomnia. Zolpidem was studied in children and adolescents (N = 201) with ADHD; although sleep latency did not differ between zolpidem and placebo, some significant improvements were observed in adolescents.24 Zolpidem was generally well tolerated, with approximately 10% of youth discontinuing due to adverse effects. Additionally, eszopiclone—which has a longer duration of action compared with zolpidem—has been studied in children and adolescents with ADHD (N = 486) who were also evaluated with a sleep study. No differences were observed between placebo and eszopiclone in terms of sleep latency and approximately 10% of patients discontinued treatment as a result of adverse events.25 We were unable to locate any prospective trials of zaleplon or benzodiazepine receptor agonists for insomnia in youth, although some reports suggest that clonazepam may have a possible role for specific parasomnias.26,27Dual orexin receptor antagonists. Suvorexant, an antagonist of the wakefulness-promoting neuropeptide orexin, improved subjective sleep quality in a prospective trial of adolescents with insomnia (N = 30), although dropout was high (44%).28 Of those patients, reasons for discontinuation included loss to follow-up, lack of effectiveness, and abnormal dreams. We were unable to locate any trials of lemborexant in pediatric patients.
Atypical antidepressants. Trazodone is commonly prescribed for insomnia in pediatric patients with comorbid mood or anxiety disorders. In open-label studies of children and toddlers, trazodone may be well-tolerated and improve sleep.29 Additionally, development of a physiologically based pharmacokinetic model to inform trazodone dosing for youth with insomnia is underway.30 Some studies in adolescents with depression suggest that caution should be used when combining trazodone with medications that inhibit CYP2D6. In the Treatment of SSRI-Resistant Depression in Adolescents study, none of the patients who were treated with trazodone (vs other soporifics) improved.31 This may relate to CYP2D6 interactions and accumulation of methyl-chloro-piperazine (mCPP), a trazodone metabolite that is associated with dysphoria, irritability, and depression.31 This finding has been replicated in a separate cohort of depressed adolescents.32
Because of its antihistaminergic effects, mirtazapine has been used to treat insomnia in adults. One open-label study of mirtazapine in children and young adults ages 3 to 23 with neurodevelopmental disorders suggested that mirtazapine improved behavioral symptoms and insomnia, and was associated with few treatment-limiting adverse effects.33
Tricyclic antidepressants. In a retrospective study of youth with insomnia who failed behavioral interventions and melatonin (N = 29), doxepin, a potent H1 antagonist, improved subjective sleep in one-half of patients.34
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