Pediatric Pharmacology Rafael Pelayo, MD, and Michael Dubik, MD

This article reviews the most common pharmacologic options in the treatment of sleep disorders in children. Despite the high prevalence of sleep disorders in children, there is a paucity of education and information available on the pharmacologic management of sleep disorders in children. The principles of sleep physiology and pathophysiology that help provide more rational pharmacologic management are discussed. Medications are typically not Food and Drug Administration (FDA) approved for the pediatric age range or for the specific . Medications have a role for , , , and sleep-related movement disorders. The available choices of are reviewed. Medications to increase alertness of narcoleptics and decrease are discussed. The use of dopaminergic agents for Restless Legs Syndrome is reviewed. The potential use of medication in is also reviewed. Pharmacologic guidelines need to be developed specifically for sleep disorders in children. Ideally, these guidelines should be FDA approved for the specific sleep disorder and for the pediatric age range. The devel- opment of easy to swallow, chewable or liquid forms of these medications are needed. Training programs should play the lead role in enhancing pediatricians’ knowledge of the pharmacologic treatment of sleep disorders in children. Semin Pediatr Neurol 15:79-90 © 2008 Elsevier Inc. All rights reserved.

his article reviews the most common pharmacologic op- Clonidine is not an indicated medication for insomnia in Ttions in the treatment of sleep disorders in children. adults. However, clonidine is one of the most commonly With regard to pharmacologic treatments options, the learn- prescribed medications for insomnia in children despite the ing process for all clinicians, whether they predominately absence of any randomized control trials supporting its use. treat adults or children, is very similar. First, we learn phys- Pediatricians prescribe clonidine for children of all ages, in- iology, then pathophysiology, and for the rest of our careers fants through teens1-3 How can this drug be such a popular we apply this knowledge to the pharmacologic management choice among pediatricians? Is the pathophysiology of in- of our patients. When we learn of new pharmacologic treat- somnia so different between adults and children that it is ment options, we try to place them within this framework of rational for an antihypertensive agent not be indicated for physiology and pathophysiology. Without knowledge of adult insomnia but somehow be routinely used in children? sleep physiology and pathophysiology, rational pharmaco- This article attempts to place the most common pharmaco- logic management is not possible. Despite their high preva- logic options within a framework of the pathophysiology of lence in children, sleep disorders are not emphasized during sleep disorders in children. the typical medical school or pediatric residency education. Stojanovski et al3 examined trends in physicians prescrib- This paucity of education may account for the relatively little ing medications for children with sleep difficulties in outpa- information available on the pharmacologic management of tient settings in the United States. The study used data from sleep disorders in children. the National Ambulatory Medical Care Survey collected from When medications are used to treat sleep disorders in chil- 1993 to 2004. The rate of medication prescriptions for chil- dren, they are typically neither Food and Drug Administra- dren with sleep disorders appears to be increasing. The study tion (FDA) approved for the pediatric age range or for the found that approximately 18.6 million visits occurred for specific sleep disorder. Clonidine is an example of the latter. sleep-related difficulty in children. In this 12-year study pe- riod, 81% of patients with pediatric insomnia were pre- scribed sleep medication; 33% received antihistamines, and From Stanford Sleep Disorders Clinic, Stanford University School of Medi- another 26% were prescribed alpha-2 agonists (presumably cine, Stanford, CA. clonidine). The finding that 81% of children were prescribed Address reprint requests to Rafael Pelayo, MD, Stanford Sleep Disorders Clinic, Stanford University School of Medicine, 401 Quarry Road, Stan- medication is particularly remarkable considering that only ford, CA 94305, Tel 650-723-6601, Fax 650-725-8910, E-mail: pelayo@48% of the adult patients suffering from insomnia were pre- stanford.edu scribed medication.3

1071-9091/08/$-see front matter © 2008 Elsevier Inc. All rights reserved. 79 doi:10.1016/j.spen.2008.03.004 80 R. Pelayo and M. Dubik

The paucity of information on the pharmacologic treat- the medication failed to achieve the desired result. In the ment of sleep disorders in children may not be surprising authors’ experience, the reason may not be because of the given the inherent problems of the clinical situation. Most choice of medication per se. A more likely reason for the pharmacologic guidelines were developed for sleep disorders absence of efficacy and/ or adverse reactions is the medication in adults and must be empirically extrapolated to children. dose or the time of administration. The physician is often forced to prescribe medications as an When prescribing a medication for a child, there is a nat- “off-label” indication. This may result in frustrating insurance ural inclination to give the lowest dose possible. However, reimbursement delays or denials for the family. These reim- children may have faster hepatic metabolism of the medica- bursement problems may affect the availability of a specific tion resulting in faster elimination. If the dose of the agent is medication and the family’s compliance with the medication too low, the medication may disinhibit a child but not make or force the physician to prescribe a less desirable alternative. the child actually fall asleep. The parents would report un- The medication may not be available commercially in an usual behavior. If a child typically fights their , be- easily administered form. Younger children may not be able cause for example, of a fear of being alone in the dark and the to swallow pills or ingest chewable tablets, requiring the local medication dose given to the child only makes that child pharmacist to compound the medication into a suspension. drowsy but without falling asleep, frightening hypnagogic In addition, because of the natural aversion among both par- hallucinations may occur. This might be particularly disturb- ents and physicians to use medications for pediatric sleep ing in children with an underlying psychiatric or neurologic disorders, medications are usually prescribed as a last resort condition for whom the outside world may already be con- or in the most refractory situations. At times, a decision to use fusing. With the resulting confusion or disorientation caused medication in a child may be made not necessarily to assist by too low a dose of a sedating medication, it is not surprising the child as much as to help the parents or other family that parents may report paradoxical reactions to the putative members sleep better. It is not unusual that parents may . finally seek help for a child’s longstanding sleep problem Not only is the specific medication and dosage key, but the when the parents feel they can no longer put up with inter- timing of administration is also very important. It is impor- ruptions to their own sleep. The clinician needs to be aware tant because of the circadian modulation of alertness. Hu- of this situation, which may cause guilty feelings to arise in mans will typically experience an enhanced alertness in the the family members. evening, which is often referred to as a “second wind.” During Further complicating the pharmacologic treatment of this circadian phase, it is harder to fall asleep. If the hypnotic sleep disorders in children is the general lack of specialized medication is given during this circadian time window, it training in sleep disorders available to all health care provid- may not work. If the medication is given too early while the ers, not just pediatricians, who are working with these chil- child is not ready to sleep but rather has heightened alertness, dren. Failure to consider or properly apply nondrug treat- dissociative phenomenon such as frightening hypnagogic ments as part of the comprehensive management of the child hallucinations may occur.4 In the situation of children with may also lead to unsatisfactory results for the patient and the neurologic or psychiatric disorders, they may not understand family. These factors result in children with sleep disorders that that the medication was meant to help them sleep. Typically, are not properly managed because of either underdosing or hypnotics only shorten the usual falling asleep time (sleep overdosing of medication or incorrect medication selection. latency) at most by only 20 or 30 minutes compared with A key principle in sleep pharmacology is not to equate placebo. Giving a medication 2 or 3 hours before the usual sedation with normal refreshing sleep. Perhaps the simplest falling asleep time could elicit this common scenario. This and best known example of this principle is alcohol. Con- same medication and dose given at a more appropriate circa- suming large amounts of alcohol can be very sedating, but we dian time could be effective. do not wake up feeling particularly refreshed after a night of This lack of proper management of the sleep problem may excessive drinking. There may be an overreliance on the ef- be particularly common among children with neurologic, fects of the medication by both the parents and health care psychiatric, behavioral, or emotional disorders. The use of provider without adequate understanding of the cause of the psychotropic medication in children has been increasing.5 If poor sleep or the appropriate application of behavioral tech- the child cannot communicate what they feel is causing the niques to help improve the child’s sleep. sleep difficulty, incorrect assumptions may be made by the A common scenario in clinical practice is a parent’s com- family and/or health care provider. In cases of insomnia, this plaint of a child’s paradoxical reaction to a hypnotic medica- can result in an escalating cycle of progressively more sedat- tion. “He did not sleep at all” or “he became hyper” may be ing agents with an increasing likelihood of adverse effects. the parent’s complaint. From a physiological point of view, Concomitant daytime sedation may occur, which may inter- how can we explain that a child did not get sleepy when given fere with the child’s daytime therapeutic program and exac- a hypnotic agent? Is the child’s brain missing the usual gamma- erbate the child’s disabilities. In some situations, the fear of aminobutyric acid (GABA) receptors? Of course not, but the putative addiction may limit the physician or the family from child’s poor reaction to the medication is not typically ques- using pharmacotherapy adequately to improve the child’s tioned, and the medication is simply removed from the lim- sleep. ited list of pharmacologic options available to the patient. A All discussions of pediatric sleep pharmacology need to more physiological approach would be to understand why take into account the cultural background of the family. The Pediatric sleep pharmacology 81 parents need to be in agreement about their expectations of Parents often seek medical attention for their sleepless in- the child’s sleep, especially if the parents have different cul- fant because of concerns that the infant may have a physical tural backgrounds. The parents’ own prior sleep experiences cause for the problem. In general, if the child’s growth, de- both in childhood and as adults should be explored. Also, the velopment, and examination are normal, a physical cause for influence of other family members, such as grandparents, in the poor sleep is less likely. Gastroesophageal reflux should shaping the family’s views should be considered. If the child be part of the differential diagnosis when evaluating these lives in 2 separate households, which typically occurs with children. One simple way to distinguish if the sleep problems divorce, is the sleep problem present in both homes or are in the infant are physical versus behavioral is for the parent to their differences? Will any prescribed medication be given in see if there is a difference in the way the child sleeps if he/she both homes? sleeps alone or with a parent. This should be observed over This article summarizes the authors’ opinion regarding the several nights before reaching a conclusion. If the child sleeps pharmacologic management of the most common sleep dis- much better when he/she is with the parent, the problem is orders in children. Given the paucity of evidence-based med- more likely behavioral. If the infant sleeps as poorly with or icine in pediatric sleep pharmacotherapy, the reader should without the parent, the problem may be physical. Gastro- be particularly cautious when applying this information to esophageal reflux and sleep-disordered breathing should be individual patients. The need for greater research, in partic- part of the differential diagnosis when evaluating these chil- ular double-blind placebo-controlled trials, cannot be over dren. In some situations, a combination of both physical and emphasized. behavioral factors may be playing a role. The health care provider must specifically ask the parents if they have given the child any substance to improve the Insomnia child’s poor sleep. The parents may not spontaneously men- tion that they have attempted to give the child a substance Insomnia is characterized in adults by difficulty falling asleep such as alcohol or over-the-counter acetaminophen or anti- and/or staying asleep associated with subjective daytime im- histamines. In addition, ambiguities and differences among pairment. In children, this same definition may be applied the parents about how the child should sleep may complicate but may need to be modified. Commonly, it is the parents’ the clinical situation. For example, 1 parent may prefer to subjective impairment that leads the family to seek medical cosleep with the child but the other parent may not. attention. The young child may awaken for a variety of rea- The medications that are most commonly used to help an sons but will often eventually fall back asleep. However, the infant sleep better are diphenhydramine and chloral hydrate. parents’ sleep schedule is disrupted. The medical history is The dosage guidelines and common side effects are discussed incomplete without a discussion of what the parents’ sleep later. was like before they were parents. If the parents’ had any prior sleep impairment, such as mild sleep apnea, they will Toddlers have greater difficulty handling the typical sleep disruptions Among toddlers, parental complaints of poor sleep are not of parenthood. The amount and schedule of sleep each of the common. The most common situations are behavioral in- 6 parents in the household preferred before they were parents somnia of childhood limit setting type and nocturnal fears. should be reviewed before making any pharmacologic deci- The child may appear to be physiological ready to sleep but sions. may either refuse to go to sleep or gets out of after he/she The sleepless child can be a challenging situation for both has been tucked into bed. Once the child falls asleep, the the family and the primary health care provider. The primary sleep should be of normal quality. Difficulty falling back to health care provider may have limited training in pediatric sleep may occur if the child’s sleep is disrupted. Medications 7,8 sleep disorders. The insomnia’s manifestation and manage- are not typically given in these situations. If the problem ment will depend on the child’s age. In general, behavior has reached such a magnitude that the child’s poor sleep is techniques should be the mainstay of treatment. Medications causing a disruption of the household or the parents’ sleep, may have a role as an adjunct in the insomnia management. then medications may be requested by the family. Within the context of behavior-modification program, a brief adjunctive Infants trial of medication might be attempted. For infants, the pharmacologic options for insomnia are lim- Adolescents ited. Insomnia in an otherwise healthy infant is typically The most common form of insomnia in adolescents is sleep- caused by behavioral problems such as behavioral insomnia onset insomnia typical of delayed sleep-phase syndrome. De- of childhood sleep-onset association type or nocturnal feed- layed sleep-phase syndrome is a condition in which the child ing.6 The child can sleep well if the associations the child falls asleep later than expected, has normal sleep during the establishes with are present throughout the sleep night, but has difficulty waking up at the expected time. period. If the associations, such as the presence of the par- Typically, the children are described as preferring to stay up ents, are absent during the sleep period, the child may have late at night. The children usually have a later sleep and difficulty returning to sleep after they have awoken. It is wakeup time on weekends and holidays. The treatment usu- important to keep in mind that what wakes up the infant may ally consists of behavioral changes when the child is moti- not be what is keeping the infant awake.7,8 vated to change the behavior. These behavioral changes may 82 R. Pelayo and M. Dubik also include exposure to bright light at the desired wakeup tamine is involved in a wide range of physiological functions time. The use of bright light to influence a circadian sleep such as regulation of the sleep-wake cycle, arousal, cognition, disorder is called phototherapy.9,10 and memory mainly through interactions with histamine H1 Children who are avoiding school may mimic this sleep receptors. Histaminergic neurons are located in the posterior disorder. To help the child fall asleep faster, different sub- hypothalamus and transmit histamine to almost all regions of stances have been tried. has been used with vari- the brain.21 able effect. Melatonin is further described later. Various studies have been performed to evaluate the use- Prescription hypnotics do not have an FDA indication for fulness of diphenhydramine in sleep disorders of both adults adolescents younger than 18 years old. An “off-label” use as and children. When given shortly before bedtime, a signifi- an adjunct to the behavioral modification of the circadian cant decrease in sleep latency time and number of awaken- problem may be considered in certain clinical situations. Be- ings was observed. The duration of activity after an average cause these patients typically only have sleep-onset insomnia dose of diphenhydramine is 4 to 6 hours.22 A plasma diphen- without significant nocturnal disruption, a short-acting hyp- hydramine level exceeding 30 ng/mL produces drowsi- notic agent may be considered for a short period of time. ness.22,23 The recommended dosage for adults is 25 to 50 mg, Zaleplon, a nonbenzodiazepine hypnotic, may theoretically whereas in children the lowest effective dose starts at 0.5 be used in adolescents with delayed sleep-phase syndrome mg/kg (maximum, 25 mg). because it has fast onset of action and its hypnotic effects Recently, a randomized controlled trial of infant response should wear off well before the desired wakeup time. Zale- to diphenhydramine was published called the “TIRED plon has a short elimination half-life of approximately 1 study.”24 This study recruited 44 infants aged 6 to 15 months hour. This short duration, unlike diphenhydramine, will with frequent parent-reported nighttime awakenings. The minimize any next day sedation. Because the duration of primary outcome was a parental report of improvement in medication treatment is expected to be of a relatively short the number of night awakenings requiring parental assis- time, zaleplon also had the additional benefit of minimal tance. The trial was stopped early because of the lack of rebound insomnia. Rebound insomnia refers to an exacerba- effectiveness of diphenhydramine over placebo. Only 1 of 22 tion of insomnia on abrupt cessation of a hypnotic. The de- children receiving diphenhydramine showed improvement gree of insomnia is more severe than the initial insomnia compared with 3 of 22 receiving placebo. The study con- before starting hypnotics. Rebound insomnia is more typical cluded that during 1 week of therapy and at follow-up 2 and of short-acting benzodiazepine hypnotics such as triazolam. 4 weeks later, diphenhydramine was no more effective than Gradual tapering is helpful to avoid a significant rebound placebo in reducing nighttime awakening or improving over- effect. all parental happiness with sleep for infants.24 A potential medication to consider in the treatment of The most common adverse reaction to diphenhydramine delayed sleep-phase syndrome in adolescents is ramelteon. at therapeutic doses is impaired consciousness. The predom- Ramelteon is a selective melatonin receptor agonist that has inant features in an overdose are anticholinergic effects, been approved for sleep-onset insomnia in patients 18 years which include fever, mydriasis, blurred vision, dry mouth, and older.11 It lacks the potential for abuse commonly asso- constipation, urinary retention, tachycardia, dystonia, and ciated with hypnotics. Systematic trials in younger patients confusion. Other common symptoms of diphenhydramine are not available. A case study did report efficacy in an 18- poisoning include catatonic stupor, anxiety, and visual hal- year old and a 7-year old with autism and insomnia.12 lucinations.13 Rare presentations include respiratory insuffi- ciency, rhabdomyolysis, cardiac rhythm disturbances, and Diphenhydramine seizures.13,25,26 Fatal intoxications with diphenhydramine in 5 infants Diphenhydramine hydrochloride, 2-(diphenylmethoxy)-N, were reported in a case series by Baker et al.17 The infants N-dimethylethylamine hydrochloride, is a competitive H1- were 6, 8, 9, 12, and 12 weeks old. Postmortem blood di- histamine receptor blocker that has multiple effects on the phenhydramine levels in the cases were 1.6, 1.5, 1.6, 1.1, and central and peripheral nervous systems. Diphenhydramine is 1.1 mg/L, respectively. In 1 case, the child’s father admitted rapidly absorbed from the gastrointestinal tract without any giving the infant diphenhydramine in an attempt to induce gastric irritation. Peak blood and tissue levels are achieved the infant to sleep; in another case, a daycare provider admit- within 2 hours of ingestion. It is an active ingredient in many ted putting diphenhydramine in the baby’s bottle.17 over-the-counter medications, including antiallergy, seda- tive, hypnotic, antitussive, and antiemetic preparations.13-19 Chloral Hydrate Diphenhydramine is characterized by ethylamine moieties, which make them highly lipophilic and hence easily able to Chloral hydrate (CH) is a commonly used sedative hypnotic penetrate the blood-brain barrier and occupy H1-receptor and is prescribed to both children and adults. The usual sites in the brain, a large number of which are located on the dosing ranges between 25 and 50 mg/kg/dose up to a maxi- frontal lobes and in the deep structures of the brain. Positron- mum of 1 g per dose orally or rectually. Even at higher doses, emission tomography studies conducted by Yanai et al20 80 to 100 mg/kg has been given to children younger than 5 showed that the first-generation agents occupy approxi- years with good effect and minimal toxicity.27 However, neo- mately 75% of the H1-receptor sites in the brain. Brain his- natal dosing may need adjustment, particularly when used in Pediatric sleep pharmacology 83 a multidose fashion.27 After it is absorbed from the gastroin- to the influence of peripherally active drugs.32 Melatonin is testinal tract, CH is converted by alcohol dehydrogenase, to synthesized from its precursor tryptophan, which is hydroxy- trichloroethanol (TCE), the active metabolite. TCE is slightly lated to 5-hydroxytryptophan and then decarboxylated to lipid soluble and therefore penetrates the blood-brain bar- serotonin. This is then N-acetylated and converted to mela- rier. A central nervous system depressant, TCE causes drows- tonin by hydroxyindole-O-methyltransferase. Production by iness and sedation and then sleep within 1 hour. The plasma the pineal gland shows a high-amplitude , t [1/2] of TCE is 8 to 12 hours in older children and adults, resulting in low plasma levels during the day and high levels but for neonates and infants it is 3 to 4 times longer.27 at night. This rhythmicity is comparable in humans and in Therapeutic doses normally reduce blood pressure mini- experimental animals (either diurnal or nocturnal), with mally and suppress respirations slightly, but protective air- daily dark-phase levels 3 to 10 times higher than during the way reflexes are not affected.27 However, children with ob- light phase.32 It is believed that the physiologic increase in structive sleep apnea (OSA), wheezing, Leigh’s disease, or blood melatonin concentration by 10- to 15-fold, which oc- other encephalic white-matter or brainstem disorders may be curs 1 to 2 hours before bedtime, may be the final trigger for at an increased risk for respiratory compromise. Respiratory inducing sleep.33 The circadian rhythm of melatonin usually suppression may also occur in overdose situations with deep develops between the second and third month of life; nighttime stupor and coma. Furthermore, cardiovascular instability, in melatonin is low or undetectable at to 2 to 3 months of age and the form of decreased myocardial contractility, shortened then increases steadily. Neonates and infants depend on their refractory period, and changes in myocardial sensitivity to mother’s melatonin circadian rhythm through her milk.32 endogenous catecholamines, accounts for most of the mor- Melatonin may possess a phase-setting effect instead of, or tality that occurs when CH is given in toxic levels. Similarly, in addition to, a direct hypnotic effect.32 Although its role in CH may be contraindicated in children who are also on stim- circadian rhythm-based sleep disorders like and de- ulants because of rare reports of malignant arrhythmias. Con- layed sleep-phase syndrome has been reported, the hypnotic comitant administration with diuretics such as furosemide effect of melatonin is less well shown. Improved subjective may lead to marked vasomotor instability. Although coad- sleep has been noted. Conflicting reports on the efficacy of ministration with other classes of sedatives always acts syn- melatonin have been attributed to possible differences in ergistically on the central nervous system, taking CH with melatonin dosages, the timing of administration, experimen- fluoxetine has also been reported to cause prolonged seda- tal approaches, and diversity of subjects. A recent meta-anal- tion but for unclear reasons. Tolerance to its sedating effects ysis published in the British Medical Journal concluded may occur. The chronic use of CH for insomnia should be “. . . no evidence that melatonin is effective in treating sec- discouraged given the potential for side effects and tolerance. ondary sleep disorders or sleep disorders accompanying A study comparing the use of CH to music therapy in chil- sleep restriction, such as jet lag and shiftwork disorder.”34 dren undergoing electroencephalographic testing found mu- In adults, small physiologic doses of 0.1 to 0.3 mg of sic therapy to be an effective alternative.28 melatonin in the evening can generate serum concentrations that are within the normal nocturnal range (50-200 pcg/mL). Melatonin is more effective when given 2 hours before bed- Other time than when given immediately before bedtime, and dose Over-the-Counter Hypnotics ranges between 0.3 mg and 10 mg are used for short-term insomnia. Although dosing guidelines have not yet been es- Besides diphenhydramine, other H1 antihistamines are also tablished, in adults doses starting between 0.3 and 1.0 mg often used for their sedative effects because they are lipid may be used and increased to effect. Unfortunately, dosing in 29 soluble and pass through the blood-brain barrier. Ethano- children is less clear, but in a case series of 15 neurologically lamines and phenothiazines have marked sedative effects, impaired children with chronic sleep disturbances, including whereas ethylenediamines cause moderate sedation and al- fragmented sleep and delayed sleep phase, 2 to 10 mg re- 30 kylamines mild sedation. However, centrally acting H1 an- sulted in subjective improvement in their sleep.32 tagonists have also been shown to have convulsant effects, However, the National Sleep Foundation has warned especially in young children, and overdosage has been asso- against using melatonin in patients with immune disorders, 17 ciated with seizure and death. Furthermore, these agents lymphoproliferative disorders, and in those taking cortico- may worsen OSA and also may suppress rapid eye movement steroids or other immunosuppressants, given its ability to (REM) sleep and produce a marked compensatory rebound enhance immune function.32 Finally, it must be kept in mind after withdrawal of these agents, resulting in worsened sleep that melatonin is still considered a “diet supplement,” and the 31 instability and fragmentation. FDA does not regulate its safety, purity, or efficacy.33 The use of melatonin for children may be most effective in Melatonin insomnia caused by circadian factors. This would include children with delayed sleep-phase syndrome and blind chil- Its name is derived from its effect on melanin pigmenta- dren. Children with midline brain defects such as agenesis of tion in frogs; melatonin (N-acetyl-5-methoxytryptamine) corpus callosum sometimes seem to respond to melatonin is the main hormone secreted by the pineal gland. Because treatment for insomnia. This may be caused presumably by the pineal gland lacks a blood-brain barrier, it is sensitive associated defects in the pineal region.35,36 Smits et al36 con- 84 R. Pelayo and M. Dubik ducted a double-blind placebo-controlled trial of 5 mg of activation of the GABA receptor.40 Benzodiazepines may have melatonin in children ages 6 to 12 years with sleep-onset muscle-relaxing properties and should be avoided in chil- insomnia. The melatonin-treated group reported falling dren with suspected syndrome. On a asleep 63 minutes earlier and had an increased total sleep polysomnogram, benzodiazepines may alter the normal sleep time of 41 minutes. stages referred to as sleep architecture. There can be drug- Recently, Weiss et al37 reported on the use of related artifacts such as atypical sleep spindles and suppres- and melatonin treatment for initial insomnia in children with sion of slow-wave sleep. Benzodiazepine hypnotics are not attention-deficit/hyperactivity disorder (ADHD). This is commonly used for children with sleep disorders. An impor- analogous to the use of combination of hypnotics and cogni- tant exception is clonazepam.41 Clonazepam is rapidly and tive behavioral therapy for adults with insomnia. In this completely absorbed after oral administration. The bioavail- study, 27 stimulant-treated children (6-14 years of age) with ability is about 90%. Maximum plasma concentrations are Ͼ ADHD and sleep onset of insomnia ( 60 minutes) received reached within 1 to 4 hours after oral administration. The sleep hygiene intervention. Nonresponders were randomized half-life of clonazepam is typically 30 to 40 hours. Clonaz- to a 30-day double-blind, placebo-controlled, crossover trial epam can be used to prevent parasomnias associated with of 5 mg pharmaceutical-grade melatonin. The results showed partial arousals such as sleep terrors or sleep walking. These a significant reduction in initial insomnia of 16 minutes with parasomnias may decrease as the child gets older. When melatonin relative to placebo. Of note, the improved sleep parasomnias are very frequent and disturbing to the patient 37 had no demonstrable effect on ADHD symptoms. A similar and family, a low dose of clonazepam at 0.25 to 0.5 mg may 38 report by Van der Heijden et al investigated the effect of be helpful. Clonazepam may increase the arousal threshold, melatonin treatment on sleep, behavior, cognition, and qual- allowing the child to sleep without interruption. Clonazepam ity of life in children with ADHD and chronic sleep-onset is available in thin wafers that dissolve on the tongue obviat- insomnia. A total of 105 medication-free children, ages 6 to ing the need for the child to swallow a pill. 12 years, with ADHD and sleep-onset insomnia participated in a randomized, double-blind, placebo-controlled trial us- ing 3 or 6 mg melatonin or placebo for 4 weeks. Melatonin Nonbenzodiazepine Hypnotics advanced circadian rhythms of sleep-wake and endogenous There are 3 nonbenzodiazepine hypnotics (perhaps a more melatonin and enhanced total time asleep in children with accurate term is selective benzodiazepine receptor agonists) ADHD and chronic sleep-onset insomnia. Similar to the currently available in the United States: zolpidem (both im- Weiss study, they found that improved sleep with melatonin mediate release and extended release), eszolpiclone, and had no effect on problem behavior, cognitive performance, or zaleplon.42,43 Their use in children is considered “off label,” quality of life.38 and therefore no official dosing guidelines are available. None of these medications are available in liquid form, which Clonidine makes them difficult to administer to small children. They Clonidine was originally marketed for the treatment of hy- arguably offer some advantages compared with older (non- pertension under the trade name Catapres (Boehringer In- selective) benzodiazepine hypnotics. These newer medica- gelheim Pharmaceuticals, Inc., Ridgefield, CT), but its sedat- tions preserve the overall sleep architecture. At the recom- ing properties have led to its use as a soporific. Clonidine is a mended doses, they do not typically have the insomnia central alpha2-adrenergic receptor agonist, with a half-life of rebound effects experienced with benzodiazepine hypnotics 6 to 24 hours. Onset of action is within 1 hour, with peak when they are abruptly stopped. effects at 2 to 4 hours. At least 50% is excreted unchanged in The standard adult dose of immediate-release zolpidem the urine. Although it is known to stimulate receptors on the and zaleplon is 10 mg. They both have a rapid onset of action presynaptic terminals of noradrenergic neurons with a result- and shorten sleep latency. Zolpidem has a half-life of 2.5 ant decrease in norepinephrine (NE) release, the actual hours, and zaleplon has a half-life of 1 hour. This difference mechanism of sedation is not clear. Side effects include hy- in duration is clinically important. Zolpidem may help im- potension, bradycardia, irritability, anticholinergic effects prove both sleep onset and, to some degree, sleep mainte- (eg, dry mouth), and REM suppression. With abrupt discon- nance insomnia symptoms. Zaleplon typically only improves tinuation, rebound hypertension and REM rebound can oc- the sleep-onset insomnia and is not expected to significantly cur. Although not used as a hypnotic in adults, clonidine is increase the total sleep time. Zaleplon’s shorter half-life may widely used for sedation in pediatrics for patients with sleep allow it to be administered after sleep disruption in some disturbances associated with neurodevelopmental disorders situations to help the patient to return to sleep, but this or ADHD. There is no manufacturer-recommended hypnotic practice has not been studied in children.44 dose, but, in practice, the starting dose is usually 50 ␮g, Zolpidem is widely prescribed for insomnia in adults both increased in 50-␮g increments.1,39 in the immediate-release and extended-release form. Al- though its use in children is off label, some limited data are Benzodiazepines available. Blummer and colleagues studied the pharmacoki- netic profile of zolpidem in children.45 In this study of phar- Benzodiazepine hypnotics have been used extensively in macokinetics of zolpidem was assessed in an open-label pro- adults with insomnia. The mechanism of action is based on tocol in children with insomnia. A total of 21 children, seven Pediatric sleep pharmacology 85 per age group (2-6, Ͼ6to12,Ͼ12 to 18 years) were studied. sis may not be established until years after the onset of symp- Overall, the authors concluded zolpidem was well tolerated toms. and a pediatric dose of 0.25 mg/kg was recommended for Successful treatment for narcolepsy needs include both future efficacy studies with a maximum dose of 20 mg. behavioral and pharmacological treatments. The situation is The standard adult dose of immediate release of zolpidem analogous to juvenile diabetes mellitus in which a combina- is 10 mg and the extended release dose is 12.5mg. The stan- tion of diet with medication can control the condition. With dard adult dose may be prescribed to older children that can the discovery of a gene responsible for narcolepsy, novel swallow the pill. It is not absolutely necessary to lower the potential therapeutic approaches may be discovered.50,51 The dose since these medications have short half-lives and mini- absence of hypocretin in the spinal fluid is diagnostic for mal side effects. Clearance of zolpidem in children is 3 times narcolepsy.52 higher than in young adults, and is lower in elderly adults.42 Drug therapy must take into account possible side effects, A 5 mg size of immediate release zolpidem and 6.25 mg of with the fact kept in mind that narcolepsy is a lifelong illness extended release is available and intended for use in the el- and patients will have to receive medication for years. Toler- derly or patients with decreased hepatic clearance. As de- ance or addiction may be seen with some compounds. The scribed above, in the authors’ experience, giving a lower dos- treatment of narcolepsy thus balances the avoidance of side age to children may be either ineffective or result in effects, including tolerance, with maintenance of an active frightening sleep epi-phenomenon such as hypnagogic hal- life. Physicians need to monitor for the development of hy- lucinations. The medication is most effective when taken on pertension, abnormal liver function, depression, irritability, an empty stomach. anorexia, insomnia, or psychosis associated with medica- Eszolpiclone is a nonbenzodiazepine hypnotic that was tions.49 46-48 more recently approved in the United States. This medi- There are no double-blind placebo-controlled trials of cation has a longer half life, 6 hours, than zolpidem and medication specifically for children with narcolepsy. The zaleplon. This may, theoretically, be helpful in children since drugs most widely used to treat excessive daytime sleepiness they typically sleep longer than adults. To date there are no are the central nervous system stimulants.53 Amphetamines published studies in children. were first proposed in 1935. The alerting effect of a single oral Prescription hypnotics do not have an FDA indication for dose of amphetamine is at its maximum 2 to 4 hours after adolescents younger than 18 years old. An “off label” use as administration, and many patients require a single daily or an adjunct to the behavioral modification of the circadian twice-daily dose. However, a number of side effects including problem may be considered in certain clinical situations. irritability, anxiety, nervousness, headache, psychosis, tachy- Since these patients typically only have sleep-onset insomnia cardia, hypertension, nocturnal sleep disturbances, toler- without significant nocturnal disruption a short acting hyp- ance, and drug dependence may arise. The use of methyl- notic agent may be considered for a short period of time. phenidate was later encouraged because of a shorter half-life Zaleplon, a nonbenzodiazepine hypnotic, may theoretically and a lower incidence of similar side effects. be used in adolescents with delayed sleep phase syndrome since it has fast onset of action and its hypnotic effects should There are 2 drugs with different modes of action that have 54,55 wear off well before the desired wake up time. Zaleplon has a changed our first-line treatment for narcolepsy. The first short elimination half-life of approximately 1 hour. This one, modafinil, is considered more as a “somnolytic” than a 56 short duration, unlike diphenhydramine, will minimize any nonspecific stimulant. Modafinil, which has been approved next-day sedation. Because the duration of medication treat- in the United States, has been reported to bring substantial 53 ment is expected to be of relatively a short time, zaleplon also improvement in adults. The mechanism of action of had the additional benefit of minimal rebound insomnia. modafinil is not entirely clear, but it is not dopamine medi- 57 Rebound insomnia refers to an exacerbation of insomnia on ated in the same way amphetamines are thought to work. abrupt cessation of a hypnotic. The degree of insomnia is The neuronal targets for modafinil in the brain include nuclei more severe than the initial insomnia before starting hypnot- of the hypothalamus and amygdala. The initial dose should ics. Rebound insomnia is more typical of short-acting benzo- be relatively low, 100 mg, to avoid headaches. The dosage diazepine hypnotics such as triazolam. Gradual tapering may can later be increased to 200 to 400 mg/d divided twice per be helpful to avoid a significant rebound effect. day. The second dose should be given ideally before 2 PM because of the medication’s long half-life. Modafinil does not have the typical side effects of amphetamine. The most com- Narcolepsy mon side effect is headache, and this negative effect may be Narcolepsy is a chronic neurologic condition disorder in eliminated if there is a progressive dose increase over time. which the boundaries between the awake, sleeping, and Modafinil should be considered the initial pharmacologic dreaming brain are blurred.49 The awake narcoleptic will feel agent used to treat the excessive daytime sleepiness of narco- sleepy. The sleeping narcoleptic will have disturbed sleep lepsy in children.53 because of arousals. A pathognomonic feature is the sudden Of note, there have been several studies on the use of loss of muscle tone elicited by emotions such as laughter modafinil in children with ADHD.58-61 A modified formula- called cataplexy. Narcolepsy often develops in childhood, tion modafinil under the trade name Sparlon had been de- particularly during the second decade. However, the diagno- veloped but at this time has not received approval by the 86 R. Pelayo and M. Dubik

FDA. A suspect case of Stevens Johnson reaction occurred Other compounds have been found to be effective in chil- during a clinical trial. dren with cataplexy, particularly imipramine and desipra- The second drug is gamma-hydroxybutyrate, GHB, which mine. Clomipramine and imipramine have anticholinergic after much difficulty was approved in the United States by the side effects, which may be problematic. Treatment with flu- FDA in July 2002.62-64 It is the first substance ever approved oxetine or viloxazine may decrease these side effects.49,53 specifically for cataplexy in addition to excessive sleepi- ness.65,66 The drug generic name is sodium oxybate and is OSA marketed under the brand name Xyrem (Jazz Pharmaceuti- cals, Palto CA). In the popular media, it has the infamous Pharmacologic interventions for OSA are very limited. Oxy- name of the “date rape drug”.67 Illegal use of this substance gen and protriptyline have been used with limited success. for recreational purposes has been of great concern. Impor- Although most children with OSA will respond clinically and tant central nervous system adverse events associated with polysomnographically to tonsillectomy and adenoidectomy, abuse of GHB include seizure, respiratory depression, and nasal positive airway pressure therapy remains a viable op- profound decreases in level of consciousness, with instances tion for those who are not completely cured after surgery or of coma and death. For events that occurred outside of clin- who have other associated medical conditions such as Down ical trials in people taking GHB for recreational purposes, the syndrome or obesity.71,72 In those with nocturnal desatura- circumstances surrounding the events are often unclear (eg, tion related to OSA, supplemental oxygen may also be used, dose of GHB taken and the nature and amount of alcohol or but generally only as a temporizing measure or in cases in any concomitant drugs). which usual treatments (children in whom tonsillectomy/ Sodium oxybate has powerful central nervous system–de- adenoidectomy is not curative and in those who cannot tol- pressant effects. GHB can increase slow-wave sleep.68 This erate positive airway pressure therapy and who refuse trache- medication when given at bedtime may be of value to reduce ostomy) prove unsuccessful because its use does not address cataplexy and enhance daytime alertness.62 Patients may pre- the pathophysiology associated with OSA, such as arousals fer this medication over other medications used for cata- from sleep and increased work of breathing Furthermore, plexy, particularly if insomnia is also present. supplemental oxygen has not been shown to result in objec- Sodium oxybate is rapidly but incompletely absorbed after tive changes in symptoms such as excessive daytime sleepi- oral administration; absorption is delayed and decreased by a ness, at least in adults with OSA.73 However, hypercapnia high fat meal. It is eliminated mainly by metabolism with a may occur with supplemental oxygen and thus should be half-life of 0.5 to 1 hour. Pharmacokinetics is nonlinear with assessed before starting this type of therapy.72,73 blood levels increasing 3.7-fold as dose is doubled from 4.5 Pharmacologic agents, such as protriptyline (PROT), have to 9 g (g). The pharmacokinetics is not altered with repeat been used in selected adults patients, but studies in children dosing. Sodium oxybate is required to be taken at bedtime are lacking. A nonsedating tricyclic antidepressant, PROT while in bed and again 2.5 to 4 hours later. The product’s was initially found to improve OSA by decreasing REM package insert does not recommend using the medication in time.74 Because respiratory events tend to be worse during patients younger than 16 years of age. The recommended this stage of sleep and apneas tend to last the longest, oxygen starting dose in adults is 4.5 g/d divided into 2 equal doses of saturation may improve with use of this medication and thus 2.25 g. The starting dosage can then be increased to a maxi- PROT may theoretically prove most useful in those with iso- mum of 9 g/d in increments of 1.5 g/d (0.75 g per dose). Two lated to or significantly worse in REM sleep.74,75 However, weeks are recommended between dosage increases to evalu- severe anticholinergic side effects like dry mouth, constipa- ate clinical response and minimize adverse effects. Sodium tion, urinary retention, and impotence occur in approxi- oxybate is effective at doses of 6 to 9 g/d. The efficacy and mately 50% of patients taking this medication, with the last 2 safety of sodium oxybate at doses higher than 9 g/d have not side effects often limiting its use. Furthermore, the lack of been investigated, and doses greater than 9 g/d ordinarily controlled studies in children precludes its general use in this should not be administered. Dosing guidelines for patients population. younger than 16 years old are not established.56,62-64,68 Iron- Nasal steroids have been proposed as a treatment for OSA ically, unlike most other medications discussed in this article, in children. Brouillette et al76 proposed a 6-week course of a sodium oxybate is sold as a liquid. This would allow this nasal glucocorticoid spray, fluticasone, would decrease the medication to be potentially given to younger children if severity of OSA in children with adenotonsillar hypertro- clinically indicated. phy.76 They conducted a randomized, triple-blind, placebo- Cataplexy seems to respond best to medications with nor- controlled, parallel-group trial of nasal fluticasone versus pla- adrenergic reuptake-blocking properties.69 There are no sys- cebo in children aged 1 to 10 years with OSA. Thirteen tematic trials of anticataplexy drugs on children. Postpuber- children received fluticasone, and 12 received placebo. The tal teenagers are usually treated as young adults. In this mixed/obstructive apnea/hypopnea index decreased from group, 2 medications have been more commonly used: clo- 10.7 Ϯ 2.6 (standard error) to 5.8 Ϯ 2.2 in the fluticasone mipramine and fluoxetine. Both of these drugs have active group but increased from 10.9 Ϯ 2.3 to 13.1 Ϯ 3.6 in the noradrenergic reuptake-blocking metabolites (desmethylclo- placebo group. The frequencies of hemoglobin desaturation mipramine and norfluoxetine). It is through these metabo- and respiratory movement/arousals also decreased more in lites that the therapeutic effect may be mediated.70 the fluticasone group. Changes from baseline in tonsillar size, Pediatric sleep pharmacology 87 adenoidal size, and symptom score were not significantly decarboxylation of levodopa to dopamine. In the brain, levo- different between groups. The authors concluded that nasal dopa is converted to dopamine by decarboxylation. The do- fluticasone decreased the frequency of mixed and obstructive pamine produced is responsible for its therapeutic effects.13 apneas and hypopneas, suggesting that topical corticoste- In modern practice, levodopa is almost always administered roids may be helpful in ameliorating pediatric OSA. How- in combination with a peripherally acting inhibitor of aro- ever, despite the decrease in overall mixed/obstructive apnea/ matic L-amino acid decarboxylase such as carbidopa. If levo- hypopnea index by almost 50%, the average index was still in dopa is administered alone, the drug is largely decarboxy- the pathological range and there was no improvement in the lated by enzymes in the intestinal mucosa and other children’s symptoms. The role of nasal steroids in the treat- peripheral sites so that relatively little unchanged drug ment of children with OSA is not entirely clear.77 Steroids reaches the cerebral circulation. In addition, dopamine re- may play a temporizing role until surgery or continuous pos- leased into the circulation by peripheral conversion of levo- itive airway pressure is available. dopa produces undesirable effects particularly nausea. The More recently, the role of nasal steroids in conjunction inhibition of peripheral decarboxylase markedly increases with receptor antagonist montelukast was studied in children the fraction of administered levodopa that remains unme- with residual OSA after adenotonsillectomy.78 Residual sleep tabolized and available to cross the blood-brain barrier and disordered breathing (SDB) may be present in many children reduces the incidence of gastrointestinal side effects like nau- 13 after surgery. In this study, children with residual SDB with sea. The main complication of levodopa therapy for RLS/ apnea hypopnea index Ͼ1 were enrolled. Treatment with PLM is the development of worsening symptoms during the montelukast and intranasal budesonide aqueous solution afternoon or early evening, despite adequate control later at was administered for a period of 12 weeks. Twenty-two chil- night. This phenomenon, which has been termed “restless dren received treatment and were compared with 14 chil- legs augmentation,” may occur frequently sometimes within dren with residual SDB who did not receive medication. months after therapy has been instituted. Once augmentation The mean AHI after surgery was 3.9 Ϯ 1.2/h, which im- has occurred, levodopa therapy should be discontinued, and proved to after treatment 0.3 Ϯ 0.3/h. The arterial oxygen a different agent should be used. Administering additional doses of levodopa earlier during the day usually results in saturation nadir improved from 87.3% to 92.5%. further exacerbation of the augmentation phenome- non.83,94,95 In addition to motor fluctuations and nausea, Restless Legs other adverse effects may be observed with levodopa therapy Syndrome/Periodic such as induction of hallucinations, confusion, and ortho- static hypotension. These other side effects are more typically Limb Movements of Sleep seen in adult patients with Parkinson’s disease using higher Restless Legs Syndrome (RLS) is an autosomal dominant dosages than used in the treatment of PLMS and RLS. In the chronic neurologic disorder.6 It is characterized by leg dis- clinical practice of treating children with PLMS and RLS, nausea is by far the most common side effect. Sensitivity to comfort that makes the patients want move their legs. The leg side effects makes it necessary to initiate therapy at very low discomfort may be hard to describe and in children may be doses (one half of a 25/100 levodopa/carbidopa tablet daily) characterized as “growing pains.”79-81 The discomfort is re- and increase as tolerated every few days. The therapeutic lieved with movement and is more common in the evening. dose for relief of PLMS and RLS symptoms will be lower than Periodic limb movement of sleep (PLMS) may occur alone that used in Parkinson’s disease. The maximal dose is deter- without RLS. RLS/PLMS can result in significant daytime dif- mined by side effects, but most adolescents require at least 75 ficulty as a result of sleep disruption. RLS and PLMS are both mg carbidopa and up to 1.5 g l-dopa.96 Levodopa is valuable associated with poor-quality sleep. This effect on sleep may 82-84 in the treatment of RLS/PLM disorder, but the mode of action lead to daytime behavior that mimics ADHD. of the drug is unknown. It seems likely that dopaminergic The pathophysiology of RLS has been associated with iron pathways are involved. Walters and Hening97 have suggested 84-90 metabolism. Iron is a cofactor for tyrosine hydroxylase in that the site of action is the postsynaptic dopamine receptor, dopamine synthesis. Iron deficiency exacerbates RLS symp- whereas Guilleminault et al98 suggested spinal dopaminergic toms. Iron supplementation may be helpful in children with mechanism as the site of action. There may be differences in 85 RLS. Improving this condition has been associated with the mechanism of action of these medications between pa- improved daytime behavior. Dopamine precursors and ago- tients with RLS and those with only PLMS. Allen et al90 have 91 nists have been effective in relieving both RLS and PLMS. developed a theory for the pathophysiology of idiopathic RLS.99-102 These patients have been found to improve with Carbidopa/Levodopa iron supplementation. Iron is a cofactor in the production of dopamine in the brain. Iron insufficiency in certain brain Levodopa (L-DOPA, LARODOPA, DOPAR, L-3,4-dihy- regions may occur in patients with RLS.90,101 droxyphenylalanine) the metabolic precursor of dopamine, is used for treating Parkinson’s disease. It is also used to treat Selective Dopamine Agonists RLS/periodic limb movements (PLMs) in sleep in both adults and pediatric population.92,93 Levodopa in itself is largely Selective dopamine agonists are potent treatments for PLMD inert. Its therapeutic as well as adverse effects result from the and RLS. They tend to have less side effects than carbidopa/ 88 R. Pelayo and M. Dubik levodopa. Pramipexole, ropinirole, and pergolide are the most 6. International Classification of Sleep Disorders (ed 2). Westchester, IL: commonly used medication in this category.91 Pramipexole American Academy of , 2005 and ropinirole were both FDA approved for the treatment of 7. Morgenthaler TI, Owens J, Alessi C, et al: Practice parameters for behavioral treatment of bedtime problems and night wakings in in- 103-105 RLS. Selective dopaminergic agonists have similar fants and young children. Sleep 29:1277-1281, 2006 side effects to carbidopa/levodopa but at a lower fre- 8. Morgenthaler T, Kramer M, Alessi C, et al: Practice parameters for the quency. These agents are more potent and allow for lower psychological and behavioral treatment of insomnia: An update. An dosages than with carbidopa/levodopa. Montplaisir et al106 American Academy of Sleep Medicine report. Sleep 29:1415-1419, have found pramipexole to be effective in a double-blind 2006 9. Wyatt JK: Delayed sleep phase syndrome: Pathophysiology and treat- placebo-controlled study in adults. The starting dose in ment options. Sleep 27:1195-1203, 2004 adults in this study was 0.375 mg. In children, the lowest 10. Chesson AL Jr, Littner M, Davila D, et al: Practice parameters for the dose available is an empiric starting dose. Pramipexole is use of light therapy in the treatment of sleep disorders. Standards of available in a 0.125-mg size tablet. This tablet is scored and Practice Committee, American Academy of Sleep Medicine. Sleep 22: can be halved if an even lower starting dosage is desired. It is 641-660, 1999 11. Johnson MW, Suess PE, Griffiths RR: Ramelteon: A novel hypnotic important to make medication changes slowly because the lacking abuse liability and sedative adverse effects. Arch Gen Psychi- symptoms of PLMS and RLS seem to fluctuate independently atry 63:1149-1157, 2006 of the medication. In addition, if the dosage is too high, 12. Stigler KA, Posey DJ, McDougle CJ: Ramelteon for insomnia in two significant side effects may occur. We advise parents to only youths with autistic disorder. 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