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Pharmacotherapy for insomnia in children and adolescents: A rational approach

Pharmacotherapy for insomnia in children and adolescents: A rational approach
Author:
Judith A Owens, MD, MPH
Section Editor:
Ronald D Chervin, MD, MS
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: Dec 19, 2022.

INTRODUCTION — A variety of behavioral and medical problems can present with childhood insomnia, typically manifested as bedtime resistance, difficulty initiating sleep, night wakings, or combinations of these symptoms. As a result, it is imperative that the choice of therapy be diagnostically driven as well as developmentally appropriate.

The vast majority of sleep disturbances in children and adolescents are appropriately managed with behavioral therapy alone, and behavioral interventions should be considered first-line therapy, as has been recommended for adults [1]. However, in a limited number of clinical situations, pharmacologic intervention may be appropriate for management of the child or adolescent with significant difficulties in initiating or maintaining sleep, as long as a number of important caveats are taken into consideration.

A general approach to making decisions about pharmacotherapy for sleep in children is outlined below, followed by a brief summary of the main considerations for individual medications. Related information is included in other UpToDate topics:

(See "Assessment of sleep disorders in children".)

(See "Behavioral sleep problems in children".)

(See "Sleep in children and adolescents with attention deficit hyperactivity disorder".)

(See "Overview of the treatment of insomnia in adults".)

GENERAL APPROACH — Decisions about the use of pharmacotherapy for insomnia in children are informed by several considerations:

Efficacy – Little empirical evidence exists on effectiveness of these drugs in children. Only a few randomized controlled trials have been performed in children; most have demonstrated no or little efficacy and were conducted in highly selected patients, such as children with attention deficit hyperactivity disorder (ADHD) or autism. Most of the information available regarding use of these medications in children is from case reports or small case series, extrapolated from adult data, or reflects clinical experience.

Side effects – Potential short- and long-term side effects should be considered, including effects on sleep architecture and daytime drowsiness, as well as recurrence or even exacerbation (ie, rebound) of pretreatment insomnia symptoms following discontinuation of medication.

Safety – Unfortunately, the safety profile of sleep medications remain one of the most poorly researched areas in pediatric psychopharmacology. A specific concern is the risk of accidental overdose.

Ethical considerations – When the risk/benefit profile of a medication is unclear, ethical concerns are particularly important. These include the possibility that medication will replace or detract from a safer or more effective behavioral intervention. This concern is sometimes characterized as "medicating a parenting problem" and giving the "wrong message" (ie, "take a pill if you can't sleep") to families and caregivers about management of sleep issues.

Despite these considerations, there is clearly a perceived need for safe and effective ways to improve sleep in children, as prescribing or recommending sedatives and hypnotics for sleep complaints is quite common among child health professionals, including pediatricians, family practitioners, and child psychiatrists in the United States, Canada, and Europe [2-4].

In particular, use of the exogenous synthetic hormone melatonin has risen dramatically in the United States during the past decade, likely because it is a nonprescription drug and is often perceived as "safe" and "natural" (see 'Melatonin' below). However, even the use of relatively "benign" medications such as melatonin may be counterproductive if this practice supplants the use of more effective and long-lasting behavioral treatments. Moreover, the long-term efficacy and side effects of melatonin administered in childhood remain poorly understood due to the limited number and variable quality of pediatric randomized controlled trials [5].

Thus, decisions to initiate pharmacotherapy, including melatonin, should be undertaken thoughtfully, as outlined below. Consideration of pharmacotherapy for sleep should include each of the following steps:

Pretreatment evaluation — The first step is rigorous diagnostic assessment of the child's sleep problem. The diagnostic evaluation is discussed in detail elsewhere (see "Assessment of sleep disorders in children"). Important elements include:

Assessment of behavioral contributors – This is important because behavioral contributors are common and are amenable to behavioral interventions. They may be the primary problem or may exacerbate and perpetuate other sleep disorders. (See "Behavioral sleep problems in children".)

Screening for primary sleep disorders – Primary sleep disorders include obstructive sleep apnea (OSA) and restless legs syndrome (RLS). Identifying these disorders is critical because they would each warrant specific treatment; screening should include at minimum a focused history and examination. In addition, pharmacologic treatment of insomnia could potentially exacerbate coexisting sleep problems. For example, children with OSA are at risk for adverse effects from sedative medications that cause respiratory depression or from other medications that may cause significant weight gain. (See "Restless legs syndrome and periodic limb movement disorder in children" and "Evaluation of suspected obstructive sleep apnea in children".)

Evaluation of the impact of the sleep disturbance on the child's health and daily functioning – This includes careful assessment for possible neurobehavioral signs of daytime sleepiness (eg, mood changes, attention problems, impulsivity, poor school performance). Children experiencing significant problems with daytime function may be more likely to benefit from targeted intervention such as behavioral therapy or pharmacotherapy.

Psychosocial evaluation of the family – This includes the impact of the sleep disturbance on other family members and consideration of other variables that might impact medication choice and adherence. Such variables may include educational level, parenting skills and style, household composition, parental stress level and caregiver exhaustion, access to medications and other safety considerations, and previous experience with and acceptability of pharmacologic treatment. For example, situations arise, albeit relatively rarely, in which families are so exhausted and overwhelmed by a child's sleep problems that concerns about both safety and parental mental health are warranted.

Psychoeducation of the family — Important elements include:

A simple explanation of the basics of sleep regulation – Points should include the role of the sleep drive and predictable 24-hour circadian patterns of relative alertness and sleepiness, including the so-called "forbidden zone" or "second wind" phenomenon involving a surge in circadian alertness in the hour or so before the natural fall asleep time.

Multiple internal factors (such as hunger and boredom) and external factors (such as noise and light levels) can facilitate or inhibit sleep. Understanding these factors can often help caregivers and patients to appreciate the complexity of the sleep-wake system and recognize the importance of behavioral strategies as a complement to medication.

Education about appropriate and healthy sleep practices – Topics should include environmental measures, such as avoiding stimulation from electronics, ensuring low light levels, and providing a comfortable room temperature; sleep-wake scheduling; sleep practices such as establishment of a bedtime routine; and awareness of relevant physiology (for example, about caffeine use).

Treat behavioral contributors — The next step is to design and implement behavioral intervention to treat or optimize any behavioral contributors to the sleep problem. This means that medication should not be the first or sole treatment strategy. The plan should be tailored to the individual characteristics of the patient and family.

In most cases, behavioral interventions, including parenting strategies and attention to sleep hygiene, should be trialed before considering pharmacotherapy. In selected cases in which the sleep problem is causing significant child or family dysfunction, it may be appropriate to initiate pharmacotherapy at the same time as behavioral therapy.

Behavioral efforts should continue during and after pharmacotherapy, as they are important for long-term success. Data from adult treatment trials demonstrate that behavioral interventions produce durable, long-term improvement, whereas the efficacy of medications typically wanes following discontinuation of treatment. It is likely that a similar pattern applies in the pediatric population.

Individualize the decision about pharmacotherapy — The decision about whether to initiate pharmacotherapy should be individualized, based on the above evaluation. Other key considerations include:

Child's age – Pharmacotherapy is rarely appropriate for young children (<5 years), except for unusual circumstances such as significant caregiver physical or mental health issues or risk of child abuse. This is because behavioral causes and interventions are particularly common in this age group and also because of the lack of safety and efficacy data in this age group.

Acute versus chronic sleep problem – Children with underlying medical, psychiatric, or neurodevelopmental conditions, in comparison with otherwise healthy, typically developing children, are more likely to need longer-term pharmacotherapy to address sleep issues. For children with these comorbid conditions, it is particularly important to address behavioral issues and to select medications that are less likely to have long-term side effects.

Set treatment goals — If pharmacotherapy is initiated, it is important to set clear and realistic treatment goals, in collaboration with the family and patient. The goals should be clearly defined, realistic, and measurable. As examples, goals might include sleep onset consistently less than 30 minutes, improvement in mood and attentiveness, or decrease in subjective distress for the caregiver or child about the insomnia.

The most realistic immediate goal of treatment may be to improve rather than eliminate sleep problems. Defining goals helps to set realistic expectations and avoid frustration. In addition, the goals can serve as milestones at which termination of medication should be considered.

Choice of medication and dosing — Once the clinician and family have decided to initiate a trial of pharmacotherapy, the following should be considered:

Selection of the medication – This choice should be based on the clinician's judgment of the best match between the clinical circumstances (eg, type of sleep problem, patient characteristics, expected duration of therapy), the individual properties of currently available drugs (eg, onset of action, safety, and tolerability), and any comorbid disorders (eg, ADHD, anxiety, or depression). Specific considerations relating to the drugs used for management of ADHD are addressed separately. (See "Sleep in children and adolescents with attention deficit hyperactivity disorder", section on 'Subsequent management'.)

The half-life and duration of action of the medication is particularly important and should be appropriate for the presenting complaint. For children with sleep onset problems, a shorter-acting medication is generally desirable, whereas for sleep maintenance problems, longer-acting medications may be considered, while at the same time minimizing morning residual sleepiness or persistent grogginess. The properties of the sedative and hypnotic drugs are outlined in the following sections and accompanying tables. (See 'Nonprescription medications' below and 'Prescription insomnia drugs' below and 'Drugs used off-label for insomnia' below.)

Safety considerations:

Consider potential drug interactions when selecting and dosing the sleep medication. Concurrent medications may have pharmacodynamic interactions, as for sedative/hypnotics and opiates, or may have pharmacokinetic interactions, as for diphenhydramine and fluoxetine, a CYP2D6 and 2C19 inhibitor. Potential interactions can be investigated with the Lexicomp drug interactions tool included with UpToDate.

Specifically inquire about concurrent use of nonprescription sleep medications such as Tylenol PM, melatonin, or herbal preparations, which are often initiated by parents or caregivers or by adolescent patients without consulting the clinician. While these medications are generally viewed by parents and caregivers as "safe," the potential drug–drug interactions between most herbal preparations and sedatives and hypnotics, as well as other medications, are largely unknown and thus pose a potential safety threat. Maintaining an open and nonjudgmental approach is key to optimal communication and allows for the development of more effective and appropriate treatment strategies in cooperation with the family.

Assess for risk factors for drug misuse or special adverse effects. Adolescents should be screened for alcohol and drug use (including prescription opioids), as well as pregnancy, prior to initiation of therapy as many recreational substances may have synergistic clinical effects when combined with sedatives and hypnotics.

All sedative medications and supplements should be stored safely in locked containers out of the reach of children. (See "Prevention of poisoning in children".)

Dosing – The medication should be initiated at the lowest level likely to be effective and titrated up as necessary. This strategy is important because of the limited data on the pharmacokinetic and pharmacodynamic properties for hypnotic drugs in the pediatric population. For some medications (eg, zolpidem [6]), evidence suggests that younger children may require higher dosing (per kg) compared with adults due to differences in metabolism. For some medications, this difference in metabolism results in a paradoxical reaction, in which a dose that is not adequate to induce sleep causes initial grogginess and, subsequently, agitation and disinhibition.

Timing – Drug administration should be tailored to the drug's onset of action and the target time of sleep onset. Because most hypnotic medications have their onset of action within 30 minutes of administration and peak within one to two hours, they should be administered shortly before bedtime for sleep-onset insomnia, eg, within 30 minutes of lights out. Giving the medication too early, eg, more than two hours before desired sleep onset, is less likely to be effective. The "forbidden zone" or "second wind" phenomenon mentioned above may also impact timing of sedating medication.

Anticipatory guidance — Anticipatory guidance of the family includes:

Make a plan for potential modifications in dosing and timing of administration, depending on the child's response.

Clarify whether medication is to be used on a nightly or "as needed" basis. If the latter, clear parameters should be established regarding if and when medication should be administered (eg, if the child is not asleep within 60 minutes of lights out).

Specifically discuss the issue of dose escalation to avoid inadvertent overdose. Some caregivers may assume that if "one pill doesn't work, then two (or three) might." This is particularly critical with drugs that have a narrow therapeutic index, such as clonidine. In general, dose increases are best accomplished only after direct communication and consultation with the health care provider.

Duration of pharmacotherapy — The duration of pharmacotherapy depends on the type of sleep problem and the child's response to medical and behavioral treatment.

In general, medications should also be used for the shortest possible duration. However, the goal of limiting drug exposure should be balanced by ensuring adequate duration of therapy to allow behavioral interventions to be successfully implemented.

Avoid abrupt discontinuation of sleep medication, especially for drugs with short and intermediate half-lives. Failure to wean sleep medications gradually may result in "rebound insomnia" and may also increase the likelihood of other sleep disorders. For example, abrupt discontinuation of sleep medications that are potent rapid eye movement (REM) sleep suppressants (eg, selective serotonin reuptake inhibitors [SSRIs]) may result in a compensatory increase (rebound) in REM sleep and a subsequent increase in REM sleep-related phenomena, such as nightmares.

DRUGS FOR INSOMNIA — In practice, a variety of nonprescription (over-the-counter) and prescription medications are used to treat pediatric insomnia by pediatric health care practitioners or are initiated by a child's parents or caregivers, often without medical guidance. However, little empirical evidence exists regarding the efficacy, safety, and tolerability of these medications in the pediatric population. Furthermore, no hypnotics or other medications are approved by the US Food and Drug Administration (FDA) for treatment of insomnia in children under the age of 16 years. Therefore, pharmacotherapy for insomnia in children is always an off-label use and should be approached with careful evaluation of the potential benefits, risks, and treatment options for the individual patient. An overview of the options is presented in the table (table 1).

Nonprescription medications — Nonprescription medications that are commonly used for insomnia in children are antihistamines and melatonin. Both have potential pitfalls and different uses. They are listed in alphabetical order below.

Antihistamines — These medications can be considered for short-term situational or occasional use in younger children, especially those with comorbid atopic disease. Both prescription (eg, hydroxyzine) and nonprescription (eg, diphenhydramine) antihistamines are the most commonly prescribed and recommended sedatives in pediatric practice. Parents and providers often choose antihistamines because of familiarity, and widespread clinical experience indicates that these medications are largely well tolerated in children. However, tolerance to antihistamines tends to develop, necessitating increasing doses and precluding their chronic use. The pros and cons of this class of medication are summarized in the table (table 2).

First-generation drugs (diphenhydramine, hydroxyzine, chlorpheniramine, doxylamine) cross the blood–brain barrier and bind to histamine type 1 receptors in the brain. Second- and third-generation antihistamines, such as fexofenadine and loratadine, are significantly less sedating. They are generally rapidly absorbed and have rapid onset of action. Effects on sleep architecture are minimal.

The antihistamines diphenhydramine or doxylamine are in several nonprescription sleep aids. These drugs have modest efficacy in reducing sleep onset latency (SOL), as demonstrated in a few clinical trials, including in adults with psychiatric disorders. In children, there is mixed evidence for the efficacy of antihistamines for insomnia: A double-blind placebo-controlled pediatric study of diphenhydramine hydrochloride (1 mg/kg) showed significant subjective improvement in sleep latency and night wakings [7], although a subsequent study in 6- to 15-month-old infants found that diphenhydramine was no better than a placebo in reducing night wakings [8]. The American Academy of Sleep Medicine (AASM) practice guideline suggests against the use of diphenhydramine for insomnia in adults, primarily because of small effect size and low-quality data [9,10]. (See "Pharmacotherapy for insomnia in adults", section on 'Over-the-counter sleep aids'.)

Potential side effects of antihistamines include daytime drowsiness, anticholinergic effects (eg, dry mouth, blurred vision, urinary retention), and paradoxical excitation; fatal overdoses with diphenhydramine have been reported in infants.

Melatonin — The best established use of melatonin is for patients with a documented circadian phase delay. Melatonin is also a reasonable choice for children with sleep-onset insomnia who may need long-term pharmacotherapy, including those with autism spectrum disorder (ASD) or attention deficit hyperactivity disorder (ADHD) [11]. Melatonin has demonstrable efficacy in typically developing children with insomnia. However, it should not be used in healthy children without sleep problems to "promote restful sleep" or in adolescents with biologically based later sleep onset times in an attempt to "force" sleep onset to accommodate early school start times, for example. The pros and cons of melatonin are summarized in the table (table 3).

Clinical effects – Melatonin is generally considered effective for management of chronic or acute circadian rhythm disturbances (eg, delayed sleep-wake phase disorder [DSWPD], jet lag) in both typically developing, healthy children and adolescents and in children with neurologic or neurodevelopmental disorders such as blindness and ASD. However, the AASM clinical practice guideline recommending the use of strategically timed melatonin in DSWPD in otherwise healthy children and adolescents [12] was based on relatively weak evidence, and additional research in this population is clearly needed [13]. (See "Delayed sleep-wake phase disorder".)

Melatonin also may be helpful in management of sleep-onset insomnia in children, based primarily on data from patients with ADHD and autism. The rationale is based on the premise that at least some of these children have a circadian-mediated phase delay (ie, delayed sleep onset and offset compared with developmental norms). A meta-analysis of pediatric randomized controlled trials concluded that melatonin increased total sleep duration by approximately 30 minutes and was generally well tolerated but acknowledged that the 13 studies included were of limited scope and had high risk of bias [5]. Due to paucity of data and low quality of evidence, the clinical practice guidelines for adults recommend against the use of melatonin for sleep-onset or sleep-maintenance insomnia. However, the applicability of these data to pediatric populations is uncertain, and clinical experience suggests that melatonin may be efficacious for some children and adolescents, particularly in those with comorbid ADHD or autism [11].

Pharmacology – Melatonin is a hormone secreted by the pineal gland in response to decreased light, mediated through the suprachiasmatic nucleus. The mechanism of action of commercially available, immediate-release melatonin is to supplement the endogenous pineal hormone. The plasma level of exogenous melatonin peaks within approximately one hour of administration. Thus, it should be taken close to bedtime when given for sleep-onset insomnia. When treating circadian phase delay, it is most effective when given several hours prior to bedtime. This is because exogenous melatonin given earlier than the time of its usual endogenous secretion helps to shift the circadian rhythm forward (earlier).

Dosing and administration – Recommended dosing of melatonin depends on the type of sleep problem:

Circadian phase delay – Timing of administration should ideally be based on dim light melatonin onset (DLMO), which involves sequential evening measurement of salivary melatonin levels under low light conditions. However, this determination is impractical in most clinical settings. Thus, in the absence of these data, "chronobiotic" doses of melatonin (eg, 0.2 to 0.5 mg) are typically given three to five hours prior to actual sleep onset time (or one to two hours before the desired bedtime). These relatively small doses and advance administration are more effective for circadian phase delay than larger doses or those given closer to sleep onset [14] and appear to be safe [15].

Sleep-onset insomnia – Typical doses are 1 to 2 mg in preschool children, 2 to 3 mg in school-aged children, and 5 mg in adolescents, given 30 minutes before bedtime. Dosing should always begin at the lower range and be titrated up on a weekly basis as needed. Melatonin has mild hypnotic properties in these larger doses. Studies in children with autism have reported using doses of up to 10 mg (maximum dose recommended in guidelines for this population [11]).

Some evidence supports the short-term [16] and longer-term [17] efficacy and safety of sustained-release (controlled-release, prolonged-release) preparations in insomnia that is characterized by difficulty with sleep maintenance. In such patients, sustained-release preparations may achieve longer total sleep time, decreased SOL, and fewer night awakenings.

Melatonin is not regulated as a drug by the FDA. Therefore, the commercially available formulations can vary in strength and accuracy in regard to concentration. A Canadian study analyzing 31 commercially available melatonin supplements with liquid chromatography found that actual melatonin content varied from -83 to +478 percent of the labelled content, and lot-to-lot variability was as much as 465 percent [18]. An additional 26 percent of the samples contained serotonin (a precursor of melatonin) as a contaminant. "Pharmaceutical grade" melatonin, available on a number of internet sites, may provide a more reliable preparation.

Adverse effects – Studies of melatonin use for durations of up to four years have failed to demonstrate significant adverse effects in a variety of pediatric populations. However, potential side effects include suppression of the hypothalamic-gonadal axis (triggering precocious puberty on discontinuation), although at least one study found no effects on pubertal development [19]. Increased reactivity of the immune system in children with immune disorders or on immunosuppressants (ie, corticosteroids) has also been postulated. At least one small study in adults suggested no suppression of endogenous melatonin with exogenous administration [16]. However, without additional randomized clinical trials and systematic longitudinal follow-up, neither claims of safety concerns nor those of negligible risk of melatonin use in children can presently be fully substantiated.

Inhibitors of CYP1A2 (eg, tricyclic antidepressants [TCAs], fluvoxamine, cimetidine, or ciprofloxacin) may increase melatonin concentration; oral contraceptives may also decrease metabolism. Inducers of CYP1A2 such as carbamazepine, omeprazole, and smoking increase melatonin metabolism and may decrease its concentration.

As with all medications and supplements, melatonin should be stored safely in locked containers out of the reach of children. Of note, data from the National Poison Data System indicate that pediatric melatonin ingestions are rising in the United States, accounting for 5 percent of all pediatric ingestions reported to poison centers in the year 2021 [20,21].

Prescription insomnia drugs — Drugs that are used for insomnia in adults are listed below by pharmacologic category. Those that are approved by the FDA for treatment of insomnia in adults are indicated by an asterisk (*) and are listed first within each category. Unless specifically indicated, all clinical trial data are from adult populations. However, note that even in the adult population, confidence in the overall estimation of risk-to-benefit ratio is low [9] (see "Pharmacotherapy for insomnia in adults"). Pediatric-specific information regarding safety and efficacy from pediatric clinical trials is included when available, but this does not imply a preference for these specific medications.

Benzodiazepines* — Benzodiazepine receptor agonists (BZDs) include triazolam, estazolam, temazepam, lorazepam, flurazepam, and other agents. They have limited utility as hypnotics in children, although their other properties (for example, as anxiolytics), some with long duration of action, may be useful in some patients. The pros and cons of BZDs are summarized in the table (table 4).

The hypnotic effect of the BZDs is mediated by binding to several subtypes of the gamma-aminobutyric acid (GABA) type A receptor. GABA is the major inhibitory neurotransmitter in the brain. BZDs reduce sleep latency and may increase total sleep time; those BZDs with a longer half-life and duration of action have been more commonly used to address sleep maintenance. BZDs have effects on sleep architecture, most notably, reduction in slow-wave sleep (SWS). These drugs also have muscle relaxant, anxiolytic, and anticonvulsant properties. Clinical experience in adults with insomnia is described separately. (See "Pharmacotherapy for insomnia in adults", section on 'Benzodiazepine hypnotics'.)

Side effects of BZDs include morning residual sleepiness, daytime sleepiness, and compromised daytime functioning with the use of longer-acting BZDs; anterograde amnesia and disinhibition may also occur. All are schedule IV controlled substances, and the risk of habituation or addiction with these medications, as well as withdrawal phenomena, greatly limit their utility in children and adolescents. Among other risks, prescription of a benzodiazepine in adolescents and young adults with a sleep disorder has been associated with increased risk of drug overdose when compared with other insomnia medications, especially among individuals prescribed opioids in the preceding three months [22].

In general, BZDs should be reserved for clinical situations in which their other properties (eg, anxiolytic) are advantageous. Because of their SWS-suppressant effects, BZDs are occasionally used to treat intractable partial arousal parasomnias such as sleep terrors in children but only in severe cases that require pharmacotherapy because of safety concerns.

Nonbenzodiazepine receptor agonists — Nonbenzodiazepine BZD receptor agonists ("nonbenzodiazepines") act selectively on one of the GABA type A receptor subtypes; because of this selectivity, they have an improved safety profile and lower risk of dependence compared with BZDs. Effects on sleep architecture appear minimal, although they may increase SWS. (See "Pharmacotherapy for insomnia in adults", section on 'Nonbenzodiazepine BZRAs'.)

While these drugs are generally considered safe in adults, the FDA added a black box warning to the label due to reports of serious injury and, in some cases, fatalities related to complex sleep-related behaviors such as sleepwalking and sleep driving. While these have not been reported in children, the few pediatric trials reported an increase in sleep-related behavior side effects, as well as lack of efficacy. These concerns limit their utility in pediatric populations, except possibly in older adolescents. The pros and cons of nonbenzodiazepines are summarized in the table (table 5).

Selection of one of these drugs depends on the type of sleep complaint (sleep-onset and/or sleep-maintenance insomnia) and depends on the drug's duration of action:

Eszopiclone (Lunesta)*Eszopiclone has a longer half-life than the other nonbenzodiazepines listed below, has a clinical effect of approximately six hours, and has been used in adults for both sleep-onset and sleep-maintenance insomnia. Peak drug concentration occurs at 60 minutes. Fatty foods tend to delay the absorption. Side effects include unpleasant taste, dizziness, headache, and disinhibition. Abrupt withdrawal after prolonged use (>2 weeks) may be associated with rebound insomnia.

A randomized trial of eszopiclone for insomnia in children and adolescents with ADHD failed to demonstrate any beneficial effect [23].

Zaleplon (Sonata)*Zaleplon has a very short half-life and as such is primarily used for sleep-onset insomnia. It may also be useful for middle-of-the night administration (if at least four hours remain before desired morning wake time), although it is not FDA-approved for this indication. Potential side effects include dizziness, anterograde amnesia, confusion, disinhibition, and hallucinations. The most common adverse event reported in adults is headaches. Rebound insomnia may occur on discontinuation of this drug.

Zolpidem tartrate (Ambien)*Zolpidem has a half-life of two to three hours, so its primary use is for sleep-onset insomnia, although meta-analysis indicates significant improvement in sleep maintenance and total sleep time in adult populations. Clinical trials in adults also suggest continued hypnotic benefit at six months, without the development of tolerance. Disinhibition and hallucinations have been reported. Reports of sleep-related behavior such as sleep eating and sleep driving in adults taking zolpidem have raised additional concerns about its use in children. Rebound insomnia may occur on discontinuation.

An alternative delivery system (zolpidem tartrate sublingual tablet [Intermezzo])* is the first FDA-approved medication for middle-of the-night waking followed by difficulty returning to sleep in adults. The labeling requires that at least four hours remain before the planned time of waking. Extended-release zolpidem tartrate (Ambien-CR)* has a longer half-life, which may make it more useful in sleep maintenance. There is no label limitation on duration of use.

The limited clinical data on zolpidem in children raise concerns about lack of efficacy and side effects. One randomized trial in children 6 to 17 years old with ADHD-related insomnia reported no significant change in mean objective sleep latency compared with placebo, as measured by polysomnogram at week 4 [6]. Subjective improvement in insomnia was reported by parents and children in the older (12 to 17 years old) age group. Adverse events included an increased rate of hallucinations (zolpidem: 7.4 percent; placebo: 0 percent), dizziness (zolpidem: 23.5 percent; placebo: 1.5 percent), and headache (zolpidem: 12.5 percent; placebo: 9.2 percent).

Drugs with limited pediatric experience — While the following three drug categories have insufficient pediatric clinical use or experience to warrant specific recommendations for use, there may be specific clinical situations in which they may be useful, such as avoidance of scheduled drugs in an adolescent or failure to respond to previous trials of drugs within a more well-established class. Drug properties in adults are summarized below.

Ramelteon (Rozerem)*Ramelteon is a selectively acting synthetic melatonin receptor agonist. Its sleep-promoting effect may be related to reduction of the alerting output of the suprachiasmatic nucleus, and it is thought to reduce the circadian-mediated arousal that precedes sleep onset (the so-called "forbidden zone"). (See "Pharmacotherapy for insomnia in adults", section on 'Melatonin receptor agonist (ramelteon)'.)

Ramelteon shows moderate efficacy in reducing sleep latency and is approved for sleep-onset insomnia in adults. It is absorbed rapidly (0.5 to 1.5 hours) and has a short half-life (1.0 to 2.6 hours). In clinical trials in adults, the effect size is small and may not be clinically significant [9]; subjective improvements are less consistently reported than are objective polysomnographic improvements in sleep latency.

Side effects may include dizziness and fatigue as well as mood changes. Next-day effects on functioning, including psychomotor performance, memory, and attention, appear minimal. However, ramelteon has been reported to be associated with mild transient increases in prolactin in women with long-term (six months) administration and decreases in testosterone in older men. It has no abuse potential or limitations on duration of use.

The pros and cons of ramelteon are summarized in the table (table 6).

Suvorexant (Belsomra)*Suvorexant is the first FDA-approved orexin receptor antagonist. Meta-analysis of clinical data in adults suggests that it is effective for sleep-maintenance insomnia, but probably not for sleep-onset insomnia, at recommended doses [9]. It should be taken no more than once per night, within 30 minutes of lights out, with at least seven hours remaining before the planned time of waking. Side effects include next-day driving performance impairment at higher doses. (See "Pharmacotherapy for insomnia in adults", section on 'Dual orexin receptor antagonists'.)

Doxepin (Silenor)*Doxepin is a TCA with sedating effects because it is a selective histamine receptor antagonist. It is FDA-approved for use at low doses (3 or 6 mg) for the treatment of transient or chronic sleep-maintenance insomnia, for which it is effective because of its long half-life (15.3 hours). In clinical trials, low-dose doxepin demonstrated maintenance of sleep into the 7th and 8th hours of the night, with no meaningful residual effects on the following day.

Doxepin appears to have a favorable safety and tolerability profile, a low discontinuation rate, and no evidence of tolerance, amnesia, or complex sleep behaviors such as somnambulism or sleep eating. As this drug appears to not to have abuse potential, it is not designated as a controlled substance and thus could be useful in patients with a history of substance abuse. Limited retrospective data in children suggest that it can be effective for sleep maintenance at average doses of 6 to 10 mg nightly with a low rate of behavioral side effects (2 of 28 children in one study) [24]. (See "Pharmacotherapy for insomnia in adults", section on 'Antidepressants'.)

Drugs used off-label for insomnia — Prescription medications commonly used off-label for insomnia are listed below. They are presented in alphabetical order within each pharmacologic category to avoid any implication of relative preference. The available empirical evidence regarding safety and efficacy in children is insufficient to rank recommendations for the use of these medications.

Alpha-adrenergic agonists — Alpha-adrenergic agonists (especially clonidine) are commonly prescribed to treat childhood insomnia. Anecdotal clinical experience suggests that these drugs are generally effective and well tolerated in children with ADHD and sleep-onset insomnia, although little empirical evidence exists to justify the high level of clinician preference for these medications. The pros and cons of using this class of drugs for sleep are summarized in the table (table 7).

Clonidine — Clonidine is a central alpha-2-adrenergic agonist that decreases adrenergic tone. Due to its sedating effect, it has become one of the most widely used medications for insomnia by both pediatric and mental health practitioners, particularly in children with sleep-onset delay and ADHD. Despite its widespread use, data regarding safety and efficacy in children with ADHD and sleep problems are limited to several descriptive or retrospective studies, which report adequate clinical response and a relatively low side effect profile [25].

The immediate release form of the drug is rapidly absorbed with an onset of action within one hour and peak effects at two to four hours. Extended-release clonidine given at bedtime is also sedating, but clinical experience is mixed as to its effectiveness in treating sleep onset or sleep maintenance insomnia in children, and no comparative clinical data are available. Tolerance to clonidine often develops, which may necessitate dose escalation. Mid-sleep awakening may also occur as blood levels drop during the night. Effects on sleep architecture are fairly minimal but may include increased SWS and decreased rapid eye movement (REM) sleep. Thus, direct effects may include an increase in SWS partial-arousal parasomnias (eg, sleep terrors) and REM sleep rebound later in the night with a related increase in nightmares.

Clonidine has a narrow therapeutic index. As a result, concerns have been raised about the potential for accidental or intentional overdose and associated toxicity, which may include respiratory depression, hypotension, and bradycardia. Other potentially significant side effects include lethargy, irritability, and dysphoria. Rebound hypertension may occur on abrupt discontinuation. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Extended release clonidine'.)

Guanfacine — Guanfacine is a selective alpha-2A adrenergic receptor agonist used primarily to treat ADHD. Similar to clonidine, off-label use in children with insomnia takes advantage of one of the drug's common side effects: mild drowsiness.

Guanfacine is generally less sedating than clonidine. Its long half-life (17 hours) suggests that it may be more appropriate than clonidine for sleep-maintenance insomnia. However, a single randomized trial of the effect of extended-release guanfacine on sleep in children with ADHD found that total sleep time was actually decreased compared with placebo (-57 minutes versus +31 minutes); the decreased total sleep time was largely related to delayed sleep onset [26].

In addition to sedation, other common side effects include dry mouth, dizziness, abdominal pain, and constipation. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Extended release guanfacine'.)

Antidepressants — Antidepressants are frequently used for management of insomnia in clinical practice, but there is little rigorous research supporting this practice in adults or children. A systematic review in adults identified relatively few, mostly small studies with short-term follow-up and design limitations and suggested the effects of selective serotonin reuptake inhibitors (SSRIs) compared with placebo are uncertain, that there may be a small improvement in sleep quality with short-term use of low-dose doxepin and trazodone, and that tolerability and safety of antidepressants for insomnia is uncertain due to limited reporting of adverse events [27]. Thus, we suggest that antidepressants should be used for insomnia only in the presence of comorbid mood issues. Treating the underlying mood disorder will often result in improved sleep, and successful sleep interventions often result in improvements in mood. The antidepressant dose for insomnia is typically less than the dose used to treat mood disorders. The pros and cons of antidepressants for sleep are summarized in the table (table 8). Properties of specific classes of antidepressants are discussed in the following sections.

Antidepressants are believed to mediate sleep promotion by influencing activity of non-GABA neurotransmitters such as serotonin, histamine, and acetylcholine, which are involved in the regulation of sleep and wakefulness. Most antidepressants, especially those with anticholinergic effects, suppress REM sleep and increase latency to REM sleep; thus, abrupt withdrawal may lead to increased nightmares as a result of REM sleep rebound.

Tricyclic antidepressants — Most TCAs are sedating; the most sedating drugs are amitriptyline, doxepin, and trimipramine. TCAs decrease SOL and arousals and have been used to treat insomnia in adults who have underlying depression. Most of these medications have not been studied for insomnia in patients without underlying depression.

The most commonly reported side effects of TCAs are anxiety and agitation, as well as anticholinergic effects such as blurred vision, dry mouth, urinary retention, and orthostatic hypotension. There is a risk of cardiotoxicity, especially in prepubertal children, and TCAs should be used with extreme caution in clinical situations in which a risk exists for accidental or intentional overdose. Most TCAs are potent REM sleep suppressants; thus, rapid withdrawal may lead to REM sleep rebound and nightmares. TCAs also tend to suppress SWS, and withdrawal may lead to SWS rebound and an increase in partial-arousal parasomnias such as sleepwalking and sleep terrors. TCAs have been used clinically to treat severe partial-arousal parasomnias because of these direct effects on SWS. TCAs may also exacerbate restless legs syndrome (RLS) symptoms.

Atypical antidepressants

Mirtazapine (Remeron) is an atypical antidepressant with noradrenergic and specific serotonergic actions, with strong sedative properties at a low dose (7.5 mg). It has been shown to decrease SOL, increase sleep duration, and reduce wake after sleep onset in adults, including those with major depression, with relatively little effect on REM sleep. However, it may result in daytime somnolence. (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Mirtazapine'.)

Trazodone is a serotonin modulator commonly used for insomnia in adults and children with comorbid depression. It is one of the most sedating antidepressants because it both inhibits binding of serotonin and blocks histamine receptors. Despite increasing use of this drug for insomnia and subjective reports of improved sleep quality, minimal empirical evidence exists to suggest that trazadone is effective for sleep problems, particularly in individuals without a comorbid mood disorder [9,28]; there are very few published studies in children [29]. Although trazodone is commonly selected for sleep complaints in patients with comorbid depression, little empirical support exists for this preference compared with other sedating antidepressants. The AASM practice guideline suggests against the use of trazodone for sleep-onset or sleep-maintenance insomnia in adults without comorbid depression (only data from patients with primary insomnia were reviewed), based on paucity of data and the small effect sizes observed in the single randomized trial [9,10]. (See "Pharmacotherapy for insomnia in adults", section on 'Trazodone' and "Serotonin modulators: Pharmacology, administration, and side effects", section on 'Trazodone'.)

Trazodone suppresses REM sleep and may increase SWS. It is associated with a number of other significant side effects, including morning residual sleepiness and reports of priapism (prolonged penile erections) in adults and adolescents who are taking doses in the 50- to 150-mg range [30]. In addition, one study in adolescents with treatment-resistant depression found that those who had been treated with trazodone were substantially less likely to respond to an alternative antidepressant trial and more likely to express self-harm statements than those on no sleep medication [31]. Such issues were not observed with other sleep medications.

Selective serotonin reuptake inhibitors — Selective serotonin reuptake inhibitors (SSRIs) vary widely in their effects on sleep. Fluvoxamine, paroxetine, and citalopram tend to be sedating and may be useful for management of insomnia in patients with underlying depression. By contrast, fluoxetine and sertraline are more likely to cause activation with sleep onset delay and sleep disruption. Despite these distinctions, a systematic review did not find significant differences among SSRIs regarding treatment efficacy for insomnia in adults. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".)

SSRIs suppress REM sleep and often delay REM onset; SSRIs also tend to suppress SWS. SSRIs frequently are associated with motor restlessness and may exacerbate preexisting RLS and periodic limb movements.

Other medications — Other classes of medications that reportedly have been used in clinical practice for pediatric insomnia, especially in patients with a comorbid neurodevelopmental or mood disorder, include mood stabilizers and anticonvulsants (eg, carbamazepine, valproic acid, topiramate, gabapentin), atypical antipsychotics (risperidone, olanzapine, quetiapine), and chloral hydrate. In most instances, these medications are prescribed for other indications such as bipolar disorder, aggression, or pain but may simultaneously be prescribed for their sleep-promoting properties. Clinical data for all of these agents in the pediatric population are largely limited to case reports and case studies, and evidence is also very limited in adults [32].

Gabapentin has gained some clinical traction in the treatment of insomnia in children [33], based on clinical experience with insomnia and neurologic comorbidities in adults, and specifically those with comorbid pain conditions. While this approach has promise, evidence in pediatric patients with or without neurologic comorbidities is lacking.

All of these medications should be used with caution, if at all, for insomnia in children as no or limited data exist on safety and tolerability for this indication in either adults or children. Furthermore, the sedating effects may interfere with daytime functioning and learning, and tolerance frequently develops, necessitating dose escalation. In addition, effects may appear on other sleep parameters; for example, many of the newer atypical antipsychotics have weight gain as a significant side effect and thus can worsen sleep-disordered breathing. These agents also tend to suppress REM sleep and increase motor restlessness during sleep.

For risperidone, there have been a handful of case reports or case series reporting effective treatment of insomnia in special populations that have included children. However, a National Institutes of Health State-of-the-Science Panel on insomnia treatment in 2005 concluded that antipsychotic "use in the treatment of chronic insomnia cannot be recommended," due to the high risk:benefit ratio [34].

Similarly, chloral hydrate and barbiturates should not be used to treat insomnia in children, because of significant side effects.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Insomnia in children".)

SUMMARY

Appropriate use – There are limited clinical scenarios in which pharmacotherapy is warranted for treatment of sleep problems in children. This is because the vast majority of sleep disturbances in children and adolescents are appropriately managed with behavioral therapy alone. Moreover, very little empirical data exist on the safety or effectiveness of pharmacotherapy for sleep problems in children. (See 'General approach' above.)

In our clinical experience, pharmacotherapy is rarely necessary or appropriate for healthy children with sleep problems. Pharmacotherapy is more likely to be beneficial for children with complex medical, psychiatric, and/or neurodevelopmental comorbidities.

Pretreatment evaluation – The decision to initiate pharmacotherapy should be made on a case-by-case basis after a careful assessment of the sleep problem, including behavioral, medical, and psychosocial contributors. In most cases, behavioral interventions, including parenting strategies and attention to sleep hygiene, should be trialed before considering pharmacotherapy and should continue during and after pharmacotherapy. (See 'Pretreatment evaluation' above.)

Medication selection – Selection of a medication depends on the best match between the clinical situation (type of sleep problem, patient characteristics, and expected duration of therapy), the individual properties of the drugs (onset of action, safety, and tolerability), and any comorbid disorders (eg, attention deficit hyperactivity disorder [ADHD], anxiety, or depression) (table 1).

Antihistamines can be considered for short-term situational or occasional use in younger children, especially those with comorbid atopic disease (table 2). (See 'Antihistamines' above.)

Melatonin is most appropriately used in patients with circadian phase delay. It may be effective for children with sleep-onset insomnia who may need long-term pharmacotherapy, including those with autism spectrum disorder (ASD) or ADHD. Melatonin should not be used in healthy children without sleep problems to "promote restful sleep" (table 3). (See 'Melatonin' above.)

Benzodiazepines (BZDs) have limited utility for sleep in pediatric populations, although their other properties (for example, as long-acting anxiolytics) may be useful in some patients (table 4). (See 'Benzodiazepines*' above.)

Nonbenzodiazepine receptor agonists ("nonbenzodiazepines") also have limited utility in children, except possibly in older adolescents (table 5). Although they have a more selective profile than BZDs and are generally considered safe in adults, the few trials in children reported sleep-related behavior side effects, as well as lack of efficacy. (See 'Nonbenzodiazepine receptor agonists' above.)

Alpha-adrenergic agonists (clonidine or guanfacine) are commonly used off-label for treatment of insomnia in children, particularly those with sleep onset delay and ADHD, but data regarding safety and efficacy are limited (table 7). (See 'Alpha-adrenergic agonists' above.)

Antidepressants should be used for insomnia only in the presence of comorbid mood issues due to their potential side effects and lack of data on efficacy for sleep (table 8). (See 'Antidepressants' above.)

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References