Pharmacology of Sleep
Introduction
This chapter will cover general principles of medication use for sleep disorders in children with a focus on sedative/hypnotic medications for insomnia in children and adolescents.1,2 Specific pharmacologic interventions for other sleep disorders (such as narcolepsy or restless legs syndrome) are discussed in those respective chapters. General recommendations will be described first, followed by a discussion of specific features of those sleep medications that have been identified as commonly used in pediatric settings.
It should be noted that – other than for the treatment of enuresis – the only medication currently approved by the US Food and Drug Administration (FDA) for use in treating any sleep disorders in children under 18 years old is chloral hydrate (due to an old indication for its use in treating insomnia in children). In general, empirical data are limited regarding the efficacy, safety, and tolerability of pharmacologic interventions for sleep problems in the pediatric population. Most of the information available regarding use of these medications is taken from adult data or from case reports or small case series in pediatric populations. Only a few published studies have specifically examined the effectiveness of hypnotic/sedative use in children and adolescents in randomized placebo-controlled clinical trials. Despite this lack of evidence, a number of studies, in both the United States and Europe, suggest that prescribing, or recommending over-the-counter (OTC) use of, sedatives or hypnotics for sleep complaints is a relatively common practice among pediatricians, general practitioners, and child psychiatrists.3 Thus, while empirical data will be included whenever possible, recommendation for the rational use of these medications in clinical practice in this chapter will be largely based on recently developed consensus statements1,2 rather than on empirically based guidelines.
General Recommendations
Clinical Considerations
Treatment Strategies
Treatment strategies should always be diagnostically driven and based on systematic evaluation of possible etiologic factors.
Combination of Treatment Modalities
Medication should rarely be the first choice or sole treatment. In almost all cases, medication should be used in combination with non-pharmacologic behavioral management strategies. Although pharmacologic interventions are likely to have a more rapid and potent effect, non-pharmacologic treatments have been shown to result in more sustained improvement (persisting after medication has been discontinued).4 Combining therapies also helps to minimize side effects.
Sleep Hygiene
When working with children with sleep difficulties, existing unhealthy sleep practices should always be uncovered and addressed, and treatment recommendations must include institution of more appropriate sleep behaviors. Healthy sleep practices, commonly referred to as good sleep hygiene, include modifying daytime, bedtime, and within-sleep practices that positively impact wake-to-sleep transitions, for example by decreasing psychophysiological arousal and improving the sleep environment. Specific recommendations are usually made across a wide range of activities and typically include such suggestions as adoption of a nightly pleasant bedtime routine, maintenance of a consistent bedtime and wake time, use of a quiet, dark and cool bedroom, avoidance of caffeinated products, and assurance of appropriate levels of daily physical activity.
Sleep Education
Psycho-education regarding the basics of sleep and sleep regulation is a critical component of responsible medication management. For example, families should understand medication effects in relationship to homeostatic sleep regulation. Thus, they should know that a late-day nap might reduce the sleep drive such that even large doses of medication may be ineffective in facilitating sleep initiation at the desired bedtime. Clinicians can help parents to understand the appropriate role of pharmacotherapy by explaining that sleep is a biological function that is influenced by multiple internal and external facilitating and inhibiting factors and that medication acts to facilitate but does not ‘cause’ sleep.
Treatment Goals
Clear, well-defined treatment goals must be established with the patient and family. Treatment outcomes should be realistic, clearly defined, and measurable (with goals, for example, for sleep onset to be consistently less than 30 minutes, for improvement in mood and attentiveness, and for a decrease in subjective distress about the insomnia in caregiver and patient). Caregiver expectations regarding the potential impact of pharmacotherapy must be explicitly stated and appropriate; hence, the immediate goal of treatment will usually be to alleviate or improve, rather than to completely eliminate, sleep problems.
Exit Strategy
It is important at the outset of treatment to have a defined exit strategy regarding expectations of treatment and its duration (ideally less than 1 month). In fact, the duration of therapy should be discussed and clarified with the family at the outset; and, the clinician should begin planning for discontinuation of medication at the time of initiation. In most situations, medications should be used for the shortest possible duration.
Dosing
Dosing should be initiated at the lowest level likely to be effective and increased only as necessary. There should be clearly defined criteria for dose escalation with simultaneous monitoring for side effects. Close communication with the family, including during frequent follow-up visits, is a key component of successful and safe management.
Discontinuation
Abrupt discontinuation of medications – especially ones used on a nightly basis over an extended period of time – should generally be avoided. Drugs should be tapered gradually to reduce the possibility of rebound insomnia, an occurrence that is especially common when treatment is with high doses or with drugs having short or intermediate half-lives.
Dose Modification
Potential modifications in dosage and timing should be reviewed ahead of time with the family. For example, it should be clear if the medication is to be given on a nightly, or on an intermittent as needed basis. If the latter, then the criteria for administering the medication on any given night should be made completely clear (e.g., if still awake after 45 minutes of trying). If middle-of-the-night dosing for night wakings is to be employed, then the specific indications for such usage must be understood (e.g., only if there is at least 4 hours of remaining sleep opportunity).
Hazardous Activities
Patients, especially adolescents, should be cautioned to avoid hazardous activities – such as driving or using power tools – after taking a hypnotic medication.
Non-accidental Overdose
Any hypnotics, particularly those with high toxicity at overdose levels, should be used with extreme caution in patients with a history of depression due to the risk of non-accidental overdose.
Drug Screening
Adolescents should be screened for alcohol and drug use prior to initiation of sleep medication, as many recreational substances may have additive effects when combined with sedatives and hypnotics.
Use in Pregnancy
Because some sleep medications are contraindicated in pregnancy, pregnancy screening should be carefully considered in sexually active girls before initiating therapy, and the importance of contraception use during the course treatment should be discussed. This concern warrants checking for pregnancy in adolescent girls.
Pharmacologic Considerations
Patient and Drug Selection
Selection of patients to be treated should be based on the clinician’s judgment of the best possible match between the clinical circumstances (e.g., type of sleep problem and patient characteristics) and the properties of currently available drugs (including onset of action, safety, and tolerability). Medications selected should have pharmacologic characteristics (particularly onset and duration of action) appropriate for the presenting complaint. For children with sleep-onset problems, a shorter-acting medication is generally desirable, whereas longer-acting medications should be considered for sleep maintenance problems. Medications and time of administration should be chosen to minimize morning hangover or persistent grogginess. Usually, this means choosing an agent with the shortest possible half-life.
Timing
Consideration should be given to the timing of drug administration relative to the targeted time of sleep onset (e.g., ‘within 30 minutes of lights out’). There should be awareness of the wakeful period that precedes sleep readiness. This is the circadian-mediated period of alertness that occurs in adults and children, (usually) in the evening hours, just before sleep onset during a 1- or 2-hour window in which it becomes difficult or almost impossible to fall asleep. This is the so-called second-wind or wake maintenance zone (see Chapter 4). Most hypnotic medications have their onset of action within 30 minutes of administration and peak within 1–2 hours. Thus, giving the medication too early (e.g., 2 hours before sleep onset) is not only less likely to be effective than dosing closer to bedtime but – when administered during this window of increased circadian alertness – may induce dissociative phenomenon (i.e., disinhibition and hallucinations).5
Drug–drug Interaction
Medication should be used with caution when there is a potential for pharmacodynamic drug–drug interaction with concurrent medications (e.g., opiates) or pharmacokinetic drug–drug interaction (e.g., between fluoxetine, a CYP2D6 and -2C19 inhibitor, and diphenhydramine).6
Metabolic Considerations
Based on the meager pediatric pharmacokinetic/pharmacodynamic data that exist for hypnotic drugs, it appears that some medications (such as zolpidem (Ambien®)) are metabolized differently in younger children (see below). These data suggest that children may require higher doses than adults.7 Additionally, a dose that is not adequate to induce sleep could result in a paradoxical reaction in which the child becomes groggy, and subsequently agitated and disinhibited.7
Concurrent use of OTC Agents
Caregivers and patients should be questioned regarding concurrent use of parent- or self-initiated non-prescription sleep medications (Tylenol PM®, melatonin, herbals), as well as other OTC medications. In some cases, OTC sleep medications may interact with other prescription or OTC drugs, or they may exacerbate an underlying medical condition. Some of these medications have similar ingredients (e.g., diphenhydramine is the soporific ingredient in many OTC allergy/cold preparations and sleep aids). Although most complementary alternative therapies (e.g., herbal preparations such as chamomile or synthetic melatonin) are generally viewed by parents as safe, the potential drug–drug interactions between these agents and sedatives, hypnotics, and other medications are largely unknown. Such use should be approached with caution.
Tolerability
Adverse Effects
All medications prescribed for sleep problems should be closely monitored for the emergence of adverse effects. Some medications may even precipitate new, or exacerbate co-existing, sleep-related problems such as sleepwalking and daytime sleepiness. Discontinuation of these agents may also result in increased sleep problems. For example, when REM-suppressing medications are abruptly withdrawn, an increase in nightmares may be seen as a result of a subsequent rebound in REM sleep.8
Co-existing Sleep Problems
Insomnia in children commonly occurs in conjunction with other primary sleep disorders (e.g., obstructive sleep apnea, restless legs syndrome). Thus, the possibility of simultaneous occurrence of both medically based and behaviorally based sleep disorders warrants attention. In addition, pharmacologic treatment of insomnia could exacerbate the symptoms of co-existing sleep problems. For example, sedative/hypnotics with respiratory depressant properties (such as the benzodiazepines (BZDs)), and medications that may cause significant weight gain (e.g., mirtazapine), should be avoided if the insomnia occurs in the presence of obstructive sleep apnea, and sedating selective serotonin reuptake inhibitors (SSRIs) should be used with caution in the presence of insomnia as they may increase symptoms of restless legs syndrome (RLS).
Specific Medications Commonly Used for Pediatric Insomnia
Summaries of pharmacologic and clinical properties of sedatives/hypnotics frequently used in pediatric clinical settings are presented in Tables 7.1 and 7.2. The following discussion describes drug properties and specific cautions regarding use in the pediatric population. OTC drugs are discussed first; then there follows a description of prescription medications that are currently FDA-approved for treatment of insomnia in adults (BZD receptor agonists, melatonin receptor agonists, low-dose doxepin).9 Prescription medications commonly used off-label for childhood insomnia are discussed below, but the order of presentation should not be interpreted as implying any preference (given that the currently available empirical evidence regarding safety and efficacy of pharmacological insomnia treatment in children is inadequate to rank recommendations). Of the OTC medications discussed, most do not have pediatric dosing listed by the manufacturer, and dosing in clinical practice is often determined by choosing a proportion of the adult dose.
Table 7.1
Pharmacology of Selected Medications Used For Pediatric Insomnia
SWS, slow-wave sleep (stage 3–4); SOL, sleep-onset latency; NW, night wakings; BZD, benzodiazepine; NSAID, nonsteroidal anti-inflammatory drug; ETOH, alcohol.
*FDA-approved as hypnotic in adults.
Reprinted by permission of Oxford University Press, USA. From Owens, J. Insomnia in Children and Adolescents. Pediatric Psychopharmacology, 2003;2:660.
Table 7.2
Clinical Properties of Selected Medications Used for Pediatric Insomnia
*FDA-approved as hypnotic in adults.
Reprinted by permission of Oxford University Press, USA. From Owens, J. Insomnia in Children and Adolescents. Pediatric Psychopharmacology, 2003;2:660.
Nonprescription Medications
Antihistamines
Antihistamines – both OTC (e.g., diphenhydramine) and prescription (e.g., hydroxyzine) – are the most commonly prescribed or recommended sedatives in pediatric practice.3 Because of their widespread use and familiarity, many families and providers view antihistamines an acceptable choice for the treatment of childhood insomnia. Clinical experience suggests that these medications are generally well tolerated in children. First-generation drugs (diphenhydramine, hydroxyzine, chlorpheniramine) cross the blood–brain barrier and bind to H1 receptors in the central nervous system (CNS).10 By contrast, second- and third-generation antihistamines, such as terfenadine and loratadine, are significantly less sedating.10 Antihistamines are generally rapidly absorbed, and effects on sleep architecture appear to be minimal.10 Most OTC sleep aids (such as Tylenol PM®) contain diphenhydramine or doxylamine. A double-blind placebo-controlled study in 50 children with diphenhydramine HCL (1 mg/kg) showed significant subjective improvement in sleep latency and night waking.11 However, a more recent study in 6- to 15-month-old children found that diphenhydramine was no better than placebo in reducing night wakings.12

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