SPECIAL ARTICLE
Pharmacologic Management of Insomnia in Children
and Adolescents: Consensus Statement
Jodi A. Mindell, PhDa, Graham Emslie, MDb, Jeffrey Blumer, MD, PhDc, Myron Genel, MDd, Daniel Glaze, MDe, Anna Ivanenko, MD, PhDf,
Kyle Johnson, MDg, Carol Rosen, MDc, Frank Steinberg, DOh, Thomas Roth, PhDi, Bridget Banasj
aDepartment of Psychology, Saint Joseph’s University and Sleep Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania;bDepartment of Psychiatry,
University of Texas Southwestern Medical Center at Dallas, Dallas, Texas;cDepartment of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland,
Ohio;dChild Health Research Center, Department of Pediatrics, School of Medicine, Yale University, New Haven, Connecticut;eDepartments of Pediatrics and Neurology,
Baylor College of Medicine, Houston, Texas;fDepartments of Psychiatry and Neurosciences, Loyola University Medical Center, Chicago, Illinois;gDepartments of
Psychiatry and Pediatrics, Oregon Health and Science University, Portland, Oregon;hMedical Consultant, Evanston, Illinois;iSleep Disorders and Research Center, Henry
Ford Hospital, Detroit, Michigan;jMedical Writer, Boston, Massachusetts
Financial Disclosure: Dr Mindell is a member of the speaker’s bureau of King and Sepracor and a consultant for Pfizer, Johnson’s Baby, and Wyeth. Dr Emslie is a member of the speaker’s bureau of McNeil and a consultant for Eli Lilly, GlaxoSmithKline, Forest, Pfizer, and Wyeth-Ayerst. Drs Blumer, Glaze, and Steinberg are consultants for Sanofi-Aventis. Dr Johnson is a member of the speaker’s bureau of Sanofi-Aventis. Dr Rosen is a consultant for Sanofi-Aventis and Cephalon. Dr Roth is a member of the speaker’s bureau of Sanofi-Aventis and is a consultant for Acadia, Actelion, AstraZeneca, Aventis, Cephalon, Cypress, Eli Lilly, GlaxoSmithKline, Hypnion, King, Lundbeck, McNeil, Merck, Neurocrine, Neurogen, NovaDel, Organon, Orginer, Pfizer, Roche, Sanofi, Sepracor, Somaxon, Syrex, Takeda, Transoral, Vanda, Vivometrics, and Wyeth. Dr Genel is a consultant for Pfizer and Off the Record Research.
ABSTRACT
OBJECTIVE.The purpose of this work was to develop a consensus statement on the current status and future role for pharmacologic management of insomnia in children and adolescents.
METHOD.The National Sleep Foundation, in collaboration with Best Practice Project Management, Inc, convened expert representatives involved in the study and treatment of pediatric insomnia and conducted a 2-day conference to examine the role of pharmacologic management of pediatric insomnia and to make recommen-dations regarding the development of clinical trials in this area. After a series of presentations providing background on the current knowledge of pediatric insom-nia and its treatment alternatives, workgroups provided recommendations for the evaluation of pharmacologic treatment of insomnia in specific populations of children and adolescents and developed guidelines for the core methodologic issues relevant to the design of clinical trials. The group developed consensus recommendations for clinical trials in this area encompassing: (1) high-priority patient populations for research, (2) inclusion/exclusion criteria, (3) outcome measures, (4) ethical considerations unique to clinical trials involving children and adolescents, and (5) priorities for future research that will enhance the under-standing of pediatric insomnia.
RESULTS.Conference participants unanimously agreed that there is a need for phar-macologic management of pediatric insomnia. Furthermore, the widespread use of “hypnotic” and psychotropic medications for children in the absence of safety and efficacy data indicates a knowledge gap about the best pharmacologic practices for
www.pediatrics.org/cgi/doi/10.1542/ peds.2005-1693
doi:10.1542/peds.2005-1693
This work was presented in part at the Pharmacological Management of Insomnia in Children and Adolescents conference; November 1–2, 2004; Baltimore, MD
Key Words
insomnia, clinical trials, pediatric, pharmacotherapy, sleep disorders
Abbreviations
ADHD—attention-deficit/hyperactivity disorder
PDD—pervasive developmental disorder MDD—major depressive disorder DSPS— delayed sleep phase syndrome PSG—polysomnography
Accepted for publication Jan 23, 2006
Address correspondence to Jodi A. Mindell, PhD, Department of Psychology, Saint Joseph’s University, Philadelphia, PA 19131. E-mail: [email protected]
management of pediatric insomnia. Attendees reached consensus on methodologic issues in the study of phar-macologic treatment of pediatric insomnia including agreeing on a definition of pediatric insomnia as “re-peated difficulty with sleep initiation, duration, consol-idation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in daytime functional impairment for the child and/or family.” It was agreed that priority should be given to insomnia studies in children with attention-deficit/hyperactivity disorder and those with pervasive developmental disor-ders/autism spectrum disorder. There was also agree-ment on the need for pharmacokinetic and pharmaco-dynamic studies to determine appropriate dose levels and to evaluate safety with a wide range of doses.
CONCLUSIONS.The treatment of pediatric insomnia is an unmet medical need. Before appropriate pharmacologic management guidelines can be developed, rigorous, large-scale clinical trials of pediatric insomnia treatment are vitally needed to provide information to the clinician on the safety and efficacy of prescription and over-the-counter agents for the management of pediatric insomnia.
BACKGROUND
T
HERE IS A great need to understand and effectively treat pediatric insomnia. Although extensive popu-lation-based studies have yet to be conducted, pediatric insomnia in children and adolescents is a widespread problem.1–5 Although case definitions (in terms of age, frequency, severity, and duration of symptoms) and sample populations (healthy versus children with neu-rologic or psychiatric comorbidities) have varied, the prevalence of pediatric insomnia in children that goes beyond bedtime refusal and night wakings ranges from 1% to 6% in the general population and is as high as 50 –75% in children with neurodevelopmental or psy-chiatric comorbidities.6–8 New studies continue to dem-onstrate the negative consequences of sleeplessness in children and adolescents, including hyperactivity, irrita-bility, restlessness, poor concentration, impulsiveness, suicide risk, and poor memory. Families of children with sleep disturbances also suffer, exhibiting negative effects on daytime function and well-being, as well as elevated levels of family stress.9–11Compounding the situation is the absence of pharma-ceuticals currently indicated for hypnotic use in the pe-diatric population, leading parents to administer over-the-counter treatments and physicians to prescribe drugs without a proven record of safety and effectiveness in children or a determination of pediatric dosing. The lack of appropriately labeled drugs is counter, however, to
current use.12–18 A recent survey of community-based
pediatricians indicated that a majority of responders had recommended either OTC sleep aids (75%) and/or prescription medication (50%) for the management of
pediatric insomnia.19 In addition, children with atten-tion-deficit/hyperactivity disorder (ADHD) or depression were commonly prescribed treatments for insomnia, in-cluding clonidine, antidepressants, mood stabilizers, and antihistamines. In addition, many medications that are commonly used as hypnotics in children are being used for their sedative adverse effects rather than for primary effects on sleep/wake mechanisms or hyperarousal. De-spite the widespread use of prescription therapies and other products, including antihistamines, little data exist on their efficacy for the treatment of insomnia in chil-dren and adolescents. Chilchil-dren often demonstrate safety profiles that differ significantly from adults. As a result, simply prescribing a reduced dosage of a drug approved for adult usage or using drugs indicated for other condi-tions is not a satisfactory solution. Thus, further research is needed regarding the most appropriate treatment re-gimes for both the general pediatric population and sub-populations in terms of commonly prescribed medica-tions to treat both their primary disorder and comorbid insomnia.
Conference
Responding to the above concerns, the National Sleep Foundation, in collaboration with Best Practice Project Management, Inc, convened a 2-day conference on the “Pharmacological Management of Insomnia in Children and Adolescents” in November 2004. The goals of this meeting were to (1) determine whether there was a medical need for the treatment of insomnia in children and, if so, to determine in what subpopulations that need was the greatest; (2) to develop recommendations for clinical trials that would pave the way for pediatric use of insomnia medications; and (3) to suggest areas of further research that could enhance the understanding of pediatric insomnia. Participants included clinical re-searchers with experience in childhood and adult insom-nia, pharmaceutical industry representatives, staff of the Food and Drug Administration and National Institutes of Health, and members of the National Sleep Foundation. The specific objectives of the conference were to (1) develop a consensus definition of pediatric insomnia, (2) understand the current status and need for nonpharma-cologic and pharmanonpharma-cologic management of pediatric in-somnia, and (3) develop recommendations for clinical trials in the pharmacologic management of pediatric in-somnia.
thera-peutic end points, and regulatory and ethical issues. The remainder of the conference consisted of working ses-sions for the development of consensus recommenda-tions.
Two primary pediatric populations at high risk for insomnia were identified: (1) children with neuropsy-chiatric disorders, and (2) children with a variety of other medical conditions and sleep disorders associated with insomnia symptoms. Participants were assigned to workgroups, and each workgroup was charged with de-veloping consensus recommendations for the develop-ment of guidelines for clinical trials for the pharmacologic management of pediatric insomnia. The workgroups pre-sented their work-in-process to the entire group twice, providing the opportunity for all conference participants to hear and comment on the efforts of other groups. All of the participants agreed to the proposed recommenda-tions as described below; thus, this article presents a summary of the consensus recommendations reached by the group.
Definition of Pediatric Insomnia
Insomnia in adults is a generally well-understood con-dition that is highly prevalent, with⬃10% of the general adult population experiencing chronic insomnia.20–21 In-somnia in children, however, is a less understood con-dition. Unlike insomnia in the adult population, pediat-ric insomnia is often reported by a caregiver and is usually described as difficulty in falling asleep and/or staying asleep. Prevalence estimates are 1– 6% (10 –30% if including bedtime refusal and night wakings), with higher prevalence in children with other neurodevelop-mental or psychiatric comorbidities.22–24 This insomnia can be the end result of multiple etiologies, including behavioral, environmental, psychiatric, medical, and psychosocial. Pediatric insomnia also differs from the adult manifestation in that children, as a result of sleep loss, often exhibit paradoxical behaviors, including hy-peractivity and restlessness, and that the reporter of the symptoms is often a parent or other caregiver.
In light of these nuances, a suitable definition of pediatric insomnia was an important focus of this con-sensus meeting. The definition endorsed by the group is a version of the International Classification of Sleep Disorders-2 definition for adult insomnia that has been modified to take into account the uniqueness of insom-nia in the pediatric population.
Pediatric Insomnia
Repeated difficulty with sleep initiation, duration, con-solidation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in daytime functional impairment for the child and/or family. The phrases “age-appropriate,” “functional,” and “for the child and/or family” were added to the International
Classification of Sleep Disorders-2 definition of insomnia for the pediatric population.
This definition intentionally includes both children with behavioral insomnia and those with insomnia that persists despite proper sleep hygiene. Good sleep prac-tices (avoiding caffeinated beverages, age appropriate sleep/wake schedules, and limit setting regarding such practices as late night television viewing) and proven behavioral strategies (such as extinction programs or bedtime fading) should be the first lines of treatment. Participants in the conference were primarily concerned with children who do not respond to behavioral inter-ventions and who would be candidates for pharmaco-logic management of their insomnia and, thus, an im-portant group to target for clinical trials.
Study Design for Clinical Trials in Pediatric Insomnia
Participants
Neuropsychiatric Disorders With Comorbid Insomnia Children with neuropsychiatric disorders commonly ex-hibit chronic sleep disturbances. This group of children is composed of many subpopulations with varying degrees of impairment and symptomatology, including pervasive developmental disorders ([PDDs] autistic disorder, Rett’s disorder, childhood disintegrative disorder, Asperger’s disorder, and PDD not otherwise specified); ADHD; ge-netic disorders, such as Angelman syndrome; and chronic neurologic disorders, such as epilepsy and Tourette’s disorder. The clinical experience of the par-ticipants and results of studies conducted in recent years indicate that these patients have low response rates to behavioral therapy in the management of their sleep disturbances.
Children with PDD (incorporates autism spectrum disorder) were identified as one of the highest priority populations of children with neuropsychiatric disorders for future trials of pharmacologic sleep agents.25–29PDD patients were recommended because of (1) the signifi-cant number of children with PDD; (2) the well-estab-lished diagnostic criterion for the various disorders in-cluded in the PDD category, making this population relatively easy to define and recruit for study; (3) the PDD patient’s general lack of responsiveness to behavior therapy; and (4) the chronic nature of their insomnia. This patient population commonly has disruptive night-time behaviors and difficulties with sleep onset and maintenance that interfere with adequate sleep time, which negatively impact daytime functioning.
on them and, as a result, drug interactions may compli-cate the assessment of a hypnotic agent. Finally, there is moderate concern that some patients in this population may be unwilling or unable to tolerate the procedures necessary for sleep monitoring. It is believed, however, that, overall, the PDD group of children deserved study and that as long as an individual had been stable on a treatment regimen for a reasonable period of time, they should be eligible for study participation.
Children with ADHD were identified as another high-priority group of children with neuropsychiatric disor-ders for study.30–36Studies have indicated that as many as 50 – 60% of children with ADHD experience sleep prob-lems. Furthermore, there is evidence from several small studies that improved sleep in children with ADHD can lead to a reduction of ADHD symptoms. Thus, this group was chosen for study because of (1) the prevalence of the condition, (2) the existence of standard diagnostic criteria for identification and evaluation of ADHD, and (3) considerable evidence from multiple studies suggest-ing that ADHD patients experience higher rates of sleep disturbances than the general pediatric population. Fur-thermore, children with ADHD as a group are the most likely to be receiving off-label hypnotic therapy.
As with children with PDD, issues involved in study-ing this population were also discussed. Children with ADHD frequently have comorbid disorders and are often taking medication that may confound data interpreta-tion. It was recommended, however, that children with stable ADHD who also had a stable medication dosage and/or behavioral treatments are an important thera-peutic target.
In both adults and children, insomnia is a frequent symptom of mood and anxiety disorders, including ma-jor depressive disorder (MDD), bipolar disorder, gener-alized anxiety disorder, separation anxiety disorder, and posttraumatic stress disorder. Studies have indicated that as many as 75% of children with MDD have sleep prob-lems.37 Thus, another potential area of future study is MDD, because insomnia is frequently associated with depression. Although there are few pediatric studies on the impact of antidepressants on sleep in children, a few reports have suggested that sleep improves with some antidepressant treatments. Whether this improvement is directly related to the effect of the medication or is a result of overall improvement in the depression remains unclear. However, there is at least initial evidence that hypnotics may play an important role in improving sleep in children with depression, and, hence, research into this area is needed.
The final area of potential study suggested within the neuropsychiatric disorders was that of insomnia associ-ated with anxiety disorders in children.38,39To date, there have been no polysomnographic studies of anxiety dis-order-associated insomnia other than in children with posttraumatic stress disorder, a disorder in which there
seems to be fairly consistent reports of sleep disturbance. No treatment studies have been reported, however. The role of hypnotics in anxiety disorders is less clear than for ADHD and depression.
Medical Disorders With Comorbid Insomnia and/or Primary Sleep Disorders
Several medical and primary sleep disorders for which pharmacologic management for sleep disturbances may be appropriate were identified, including delayed sleep phase syndrome (DSPS), psychophysiological (primary) insomnia, behavioral insomnia of childhood, short-term insomnia (commonly because of acute pain, hospitaliza-tion, or travel), and insomnia associated with medical conditions, such as asthma, cystic fibrosis, rheumatic disorders, chronic pain, and cancer and its treat-ments.40–45
Insomnia associated with DSPS has a significant
im-pact on daytime functioning.46,47 Pharmacologic
ment may be an important adjunct to circadian treat-ments for this sleep disorder. Unlike children with ADHD and PDD, those with DSPS may have lower oc-currences of comorbidities and may be less likely to be on medication, potentially making them an interesting population for studies of insomnia pharmacotherapy. In addition, studies could potentially provide generalizable insights into other pediatric insomnias. There is signifi-cant concern, however, that these patients may not be the best choice for early clinical trials, because there is often confusion between DSPS and biological- and life-style-related sleep phase delays that are especially com-mon during adolescence.
The other noted medical disorders associated with insomnia may also not be ideal populations for early clinical trials. Behavioral insomnia of childhood (sleep onset association type, limit setting type, and combined type) was rejected because of the established efficacy of
behavioral therapy.48,49Two common forms of primary
because of the high likelihood of drug-drug interactions that would confound the results, the ever-changing clin-ical status of the patients, and the heterogeneity of the conditions.
Inclusion and Exclusion Criteria
A 2-tiered set of inclusion criteria for trial participation eligibility was endorsed by conference participants. Dur-ing the first screen, patients should be evaluated for their primary disorder, using disease-specific validation crite-ria to ensure that the study population is adequately homogeneous. Individuals passing the first screen should then be evaluated for insomnia using age-appro-priate criteria for bedtimes, duration of sleep, and sleep continuity (awakenings).
Appropriate exclusion criteria recommended by all of these workgroups were similar to standards used in most adult sleep studies. These include exclusion of other sleep disorders that may be associated with insomnia symptoms (eg, sleep-related breathing disorders, restless legs syndrome, and periodic limb movement disorder) and other conditions (eg, alcohol and substance abuse). All were endorsed as relevant exclusions for pediatric trials. Furthermore, comorbid psychiatric disorders, in-cluding conduct disorder, clinically significant MDD and anxiety disorder, and oppositional defiant disorder, were also recommended exclusions unless they are the pri-mary study group.
The conference participants noted that requiring pa-tients to discontinue ongoing treatment, such as for ADHD, had the potential to be harmful. In addition, discontinuation of these medications would create study conditions that do not adequately mirror the actual sit-uation in which insomnia therapies would be prescribed. As a result, conference participants agreed that children should not be excluded from clinical studies if they are on additional pharmacologic therapies for their primary disorder, as long as their condition is stable and the drug dose is stable for a reasonable period of time. Three months was suggested as an appropriate length of time to demonstrate “stability.” In addition, children should only be included if there is no temporal relationship between the onset of the insomnia and the use of the specific medication.
Outcome Measures
Polysomnography and Actigraphy
Polysomnography (PSG) is considered the “gold stan-dard” for studying sleep. It involves recordings of elec-troencephalogram, electro-oculogram, electromyogram, oxygen saturation, airflow, respiratory movements, and limb muscle activity. PSG will be an important diagnostic step in clinical trials for insomnia treatment to screen for other sleep disorders, such as obstructive sleep apnea, that can cause sleep disruption. Although home-PSG
equipment is beginning to be used by some research centers, most PSG studies continue to be performed in sleep laboratories. There is concern, however, that some children, especially those with PDD, may not tolerate the multiple physiologic sensors placed during the PSG pro-cedure, thus limiting the sleep study as valid measure of the child’s sleep characteristics.
Actigraphy, activity-based sleep monitoring, uses a wristwatch-like device that is attached to a patient’s wrist or ankle during a recording period to measure activity as a surrogate for sleep-wake. Actigraphy pro-vides a significant advantage in that it can easily be conducted at home and, thus, may provide a more nat-ural view of patient sleep. Actigraphy also provides a measure of night-to-night variability and can potentially detect unreported circadian sleep disturbances. Actigra-phy, however, cannot be used to screen for an underly-ing sleep disorder, such as sleep apnea. Although actig-raphy is a reliable measure of total sleep time, it may not be an accurate measure of sleep latency, because it may be difficult to distinguish quiet wakefulness versus actual sleep.
Thus, both PSG and actigraphy will be appropriate and complementary assessment tools to be used at dif-ferent points during pediatric drug development. PSG remains an important screening tool and can also pro-vide a more complete picture of sleep architecture at important clinical end points. For some children, the PSG procedure itself, conducted in an unfamiliar envi-ronment with multiple physiologic sensors, either may not be tolerated or may interfere with the child’s usual sleep. Actigraphy can provide assessment of sleep pat-terns throughout the study and is less prone to negative laboratory effects. The option of in-home PSG recordings as a more acceptable, less burdensome estimate of usual sleep warrants further investigation, but excessive sen-sor loss in an unattended setting may limit this ap-proach, especially in the PDD or ADHD clinical popula-tions.
Subjective Assessment
Primary Disease Outcomes
Small studies have shown both improvements in day-time functioning and reductions in symptomatology when children with insomnia and ADHD or PDD were treated for sleep disturbances. Unfortunately, these find-ings are mostly supported by anecdotal clinical evidence. The consensus recommended against the inclusion of primary disease outcome measures. Requiring an insom-nia therapy to demonstrate a positive impact on a con-dition other than insomnia would be an unreasonably difficult hurdle to pass and would set a new precedent beyond the current accepted scope of the drug develop-ment process.
Methodologic Issues
Dose Definition
All of the participants agreed on the need for clinical trials to determine safe and efficacious doses of hypnot-ics in children and adolescents. The pediatric population covers a broad range of ages and body weights with a corresponding range in ability to metabolize pharmaceu-ticals. This diversity necessitates single- and multiple-dose pharmacokinetic studies covering appropriate age ranges to ensure that the compounds under evaluation have well-understood absorption, distribution, metabo-lism, and elimination profiles specific for pediatric pop-ulations and that appropriate dosing is selected for clin-ical trials.
An additional concern is the formulation in which medications would be studied. Many children have dif-ficulty swallowing pills, the most common formulation of adult medication. Ideally, pediatric medication should be available in acceptable or multiple formulations (eg, syrup, suspension, and sprinkle) that are easy to swallow and that have an agreeable taste.
Behavioral Therapy
Behavioral therapy can be extremely effective in some forms of pediatric insomnia, and in some conditions it is preferable to pharmacologic treatment. Studies have shown that extinction (putting the child to bed and ignoring inappropriate behavior, including crying, until morning), graduated extinction (combining extinction with parental checks of the child), and parent education about pediatric sleep are empirically supported treat-ments, having significant impact on resolving behavioral insomnia. For children with ADHD, because of their underlying neurobehavioral abnormalities, behavioral interventions have been more difficult to implement, and children have been less responsive. Thus, it is rec-ommended that a child should not be required to com-plete and fail a course of behavioral therapy before be-coming eligible to participate in a clinical trial. Instead, when appropriate, clinical trials should include both be-havioral and pharmacologic therapy (singly and in
com-bination) to understand the most effective treatment combinations for each group of patients. However, it should be noted that basic sleep-promoting practices should be in place to ensure that the insomnia is not related to such factors as caffeine use, late-night televi-sion viewing, or age-inappropriate sleep-wake sched-ules. All of the families participating in clinical trials should receive basic information of positive sleep prac-tices in children and adolescents.
Study Duration and Discontinuation Effects
Studies should be conducted using a duration that is appropriate for the target population of each study. Be-cause the disorders suggested for study are chronic dis-orders, longer-term studies should be considered (3– 6 months). In addition, study designs should include a mechanism for measuring drug discontinuation effects either through a placebo run-out phase or other appro-priate follow-up mechanism.
Statistical Issues
A consideration of statistical issues is instrumental in the development of pediatric hypnotic clinical trials. There are a multitude of issues that will need to be considered, including the likelihood of significant individual varia-tion in response to medicavaria-tion and difficulties estimating sample sizes given our limited knowledge of effect sizes for medications for pediatric insomnia. Another issue of concern will be the potential for heterogenous partici-pant populations resulting in significant variability in pretreatment baseline data.
Ethical Considerations
Clinical trials involving children and adolescents require a high degree of sensitivity to ethical issues involved in research. Since 1977, recommendations for research in-volving children from the National Commission for the Protection of Human Subjects of Biomedical and Behav-ioral Research, codified as “The Common Rule,” 45 CFR 46, Subpart D, require that children participating in clin-ical research be subject to only minimal risk unless there is prospect of direct benefit. Children may be exposed to a “minor increment over minimal risk” in research that offers no direct benefit but is “likely to yield generaliz-able knowledge about the subject’s disorder or condi-tion.” Minimal risk is defined as “the probability and magnitude of harm or discomfort anticipated in the re-search are not greater in and of themselves than those ordinarily encountered in daily life or during the perfor-mance of routine physical or psychological tests.” The definitions of “minimal risk” and “minor increment over minimal risk” are imprecise, and there has been signifi-cant discussion recently regarding this issue and what
defines more than minimal risk.54 A federal panel, the
drafted more explicit guidelines for stratifying risk, al-though the basic categories of research permitted in children will likely remain unchanged.
Two related topics in the pharmacologic management of pediatric insomnia include: (1) ensuring that drug research focuses on the well-being of the child and the family, and (2) data safety monitoring boards in pediatric clinical investigations be used routinely. Insomnia is somewhat unique among childhood ailments in that reports of the condition reflect the caregiver’s perception of normal childhood sleep patterns. There was concern on the part of both the Food and Drug Administration and clinician participants that research for drug devel-opment should be concentrated on treating the child. Distress experienced by the child’s parent or the family may be significant but is not an appropriate motive for exposing a child to pharmacologic therapy. To this end, there was agreement that studies should be confined to children with clinically measurable evidence of insom-nia. Recent concerns about the difference between safety profiles of the selective serotonin reuptake inhib-itors in children relative to adults has highlighted the potential dangers of low-frequency adverse effects unique to children. Conference participants endorsed the use of data safety monitoring boards responsible for ensuring the safe conduct of any study.
A final ethical issue is the high likelihood of dimin-ished capacity for consent in some of these populations. Clearly, obtaining assent from children is something that always needs to be managed with pediatric populations, but this will be a more sensitive issue with some of the recommended study populations, especially children with PDDs, such as autistic disorder and Asperger’s dis-order. A significant number of children with PDDs are nonverbal, and many are unable to provide informed consent. Although caregivers are legally responsible for informed consent for all children, the necessary cautions and safeguards become even more important with this group of children because of their diminished capacity to provide consent, as well as feedback, either to their parents or investigators.
Research Needs and Recommendations
The consensus recommendations discussed in this article are intended to provide guidance to sponsors, regulators, and investigators on the opportunities and challenges involved in developing clinical trials for pediatric insom-nia. It is important to restate the point that few studies have been conducted on pharmacologic management of pediatric insomnia, resulting in important knowledge gaps. These gaps in the current understanding of child-hood insomnia can help define a research agenda to better characterize the disorder, identify valid assess-ment tools, and improve treatassess-ment options.
Characterizing the Population
Few, relatively small-scale studies of the prevalence of childhood insomnia in population-based samples have been conducted. Most research has focused on individ-uals whose families have actively sought treatment for pediatric insomnia or another primary disorder with comorbid insomnia. As a result, little knowledge of the true frequency of occurrence, causes, comorbidities, and consequences of pediatric insomnia exists. Many ques-tions also remain about potential linkages between cul-tural, ethnic, socioeconomic, and developmental factors and pediatric insomnia. Population-based studies could provide valuable insights into these questions and estab-lish the basis for future recommendations for standard guidelines for pediatrician interaction with all children, not only those actively presenting with pediatric insom-nia.
Evidence exists that treating sleep disturbances may have a positive impact on aspects of a comorbid disorder, including ADHD and depression. More extensive, rigor-ous studies are needed to characterize the type and degree of improvement for each patient population, ul-timately providing guidance to clinicians on the relative importance of treating sleep problems in patients under-going treatment for another disorder.
Improving Diagnostic and Assessment Tools
Additional research focusing on diagnostic and assess-ment tools for sleep disorders in children are needed, as well as appropriate ways to assess daytime functioning in children. Daytime consequences of insomnia vary across age groups, for example, young children tend to dem-onstrate hyperactivity, whereas teenagers are more likely to be sleepy during the day. This complicates the development of assessment tools. As a first step, how-ever, validated adult insomnia subjective measurement tools could potentially be modified to reflect the differ-ent symptoms presdiffer-ent in younger patidiffer-ents. Investiga-tions of these modified scales could enhance the value of information resulting from pediatric clinical trials. When developing tools for pediatric research, it is important to remember the need for 2 sets of tools: one measuring the child’s sleep disturbance and a second tool measuring the impact on family functioning.
Summary
effi-cacy profiles of sedative/hypnotics, providing these pa-tients a better night’s sleep.
Consensus was achieved on the major methodologic questions addressed during 2 days of deliberation. The first key point of agreement was the endorsement of a definition of pediatric insomnia as “repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age appropriate time and opportunity for sleep and results in some form of daytime functional impairment for the child and/or family.” Entry criteria for the duration or chronicity of the problem of insomnia may differ from study to study but should be specified a priori. Second, patients with either comorbid PDD or ADHD were endorsed as appropriate groups for initial research, especially because these groups commonly re-ceive pharmacotherapy for insomnia.
Agreement on study design included consensus on the need for pharmacokinetic and pharmacodynamic studies to determine appropriate doses and safety pro-files before larger-scale clinical trials. Offering education about age-appropriate good sleep practices and, possibly, evaluation of behavior in general, as well as behavioral interventions, was recommended as a desirable addition to clinical trials of any pharmaceutical compound. Fur-thermore, the use of concomitant medications should not be an exclusion criterion, because this would pro-vide a distorted view of actual usage conditions in the conditions most likely to benefit from this therapy. PSG and actigraphy were both endorsed as useful tools to examine clinically relevant outcomes for insomnia, which are improving total sleep time, shortening sleep onset delay, decreasing wake time after sleep onset and number of night wakings, and eliminating early morn-ing wakmorn-ings that result in insufficient sleep. Finally, improvement in PDD and ADHD disease outcomes should not be considered as primary study outcomes for insomnia but should be used with care in clinical re-search and used only as secondary drug development outcome measures.
APPENDIX
Writing Group Members
Jodi A. Mindell, PhD, and Graham Emslie, MD (chairs); Jeffrey Blumer, MD, PhD, Myron Genel, MD, Daniel Glaze, MD, Anna Ivanenko, MD, PhD, Kyle Johnson, MD, Carol L. Rosen, MD, Frank Steinberg, DO, Thomas Roth, PhD, Bridget Banas.
Conference Cochairs
Jodi Mindell, PhD, and Graham Emslie, MD.
Speakers
Jeffrey Blumer, MD, PhD, Graham Emslie, MD, Myron Genel, MD, Daniel G. Glaze, MD, Anna Ivanenko, MD,
PhD, Kyle Johnson, MD, Lisa Mathis, MD, Jodi Mindell, PhD, Carol L. Rosen, MD, and Thomas Roth, PhD.
Workgroups
Workgroup I: Medical/Behavioral/Primary Sleep Disorders Carol L. Rosen, MD, and Manisha B. Witmans, MD (cochairs).
Workgroup II: Psychiatric
Anna Ivanenko, MD, PhD, and Kyle Johnson, MD (co-chairs).
Workgroup III: Neurologic
Jeffrey Blumer, MD, PhD, and Daniel G. Glaze, MD (co-chairs).
Conference Sponsors
King Pharmaceuticals, Inc; Organon; Pfizer, Inc; Sanofi-Aventis; Sepracor, Inc; and Takeda Pharmaceuticals North America, Inc.
Conference Organizers
National Sleep Foundation and Best Practice Project Management.
Author and Contributor Affiliations
ACKNOWLEDGMENTS
This work was supported by the National Sleep Founda-tion and Best Practice Project Management, Inc.
REFERENCES
1. Adair GH, Bauchner H. Sleep problems in childhood.Curr Probl Pediatr.1993;23:147–170
2. Owens JA, Spirito A, McGuinn M, Nobile C. Sleep habits and sleep disturbance in elementary school-aged children. J Dev Behav Pediatr.2000;21:27–36
3. Blader JC, Koplewicz HS, Abikoff H, Foley C. Sleep problems of elementary school children. A community survey.Arch Pediatr Adolesc Med.1997;151:473– 480
4. Kataria S, Swanson MS. Trevathan GE. Persistence of sleep disturbances in pre-school children. J Pediatr. 1987;110: 642– 646
5. Didden R, Korzilius H, van Aperlo B, van Overloop C, de Vries M. Sleep problems and daytime problem behaviours in chil-dren with intellectual disability.J Intellect Disabil Res.2002;46: 537–547
6. Sadeh A. Raviv A. Gruber R. Sleep patterns and sleep disrup-tions in school-age children.Dev Psychol.2000;36:291–301 7. Lindblom N, Heiskala H, Kaski M, et al. Neurological
impair-ments and sleep-wake behaviour among the mentally re-tarded.J Sleep Res.2001;10:309 –318
8. Quine L. Sleep problems in primary school children: compar-ison between mainstream and special school children. Child Care Health Dev.2001;27:201–221
9. Stores G. Sleep-wake function in children with neurodevelop-mental and psychiatric disorders.Semin Pediatr Neurol.2001;8: 188 –197
10. Fallone G, Acebo C, Seifer R, Carskadon MA. Experimental restriction of sleep opportunity in children: effects on teacher ratings.Sleep.2005;28:1561–1567
11. Wiggs L, Stores G. Behavioural treatment for sleep problems in children with severe intellectual disabilities and daytime chal-lenging behaviour: effect on mothers and fathers.Br J Health Psychol.2001;6:257–269
12. Stores G. Medication for sleep-wake disorders.Arch Dis Child. 2003;88:899 –903
13. Armitage R, Yonkers K, Cole D, Rush AJ. A multicenter, dou-ble-blind comparison of the effects of nefazodone and fluox-etine on sleep architecture and quality of sleep in depressed outpatients.J Clin Psychopharmacol.1997;17:161–168 14. Ledoux S, Choquet M, Manfredi R. Self-reported use of drugs
for sleep or distress among French adolescents.J Adol Health. 1994;15:495–502
15. McNicholas F. Psychotropic prescribing practices of paediatri-cians in the UK.Child Care Health Dev.2001;27:497–508 16. Kopferschmitt J, Meyer P, Jaeger A, Mantz JM, Roos M. Sleep
disorders and use of psychotropic drugs in 6-year-old children [in French].Rev Epidemiol Sant Publ.1992;40:467– 471 17. Owens JA, Babcock D, Blumer J, et al. The use of
pharmaco-therapy in the treatment of pediatric insomnia in primary care: Rational approaches. A consensus meeting summary. J Clin Sleep Med.2005;1:49 –59
18. Gyllenhaal C, Merritt S, Peterson S, Block K, Gochenour T. Efficacy and safety of herbal stimulants and sedatives in sleep disorders.Sleep Med Rev.2000;4:229 –251
19. Owens JA, Rosen CL, Mindell JA. Medication use in the treat-ment of pediatric insomnia: results of a survey of community-based pediatricians. Pediatrics. 2003;111(5). Available at: www.pediatrics.org/cgi/content/full/111/5/e628
20. Silber MH. Clinical practice. Chronic insomnia.N Engl J Med. 2005;353:803– 810
21. Sateia MJ, Nowell PD. Insomnia.Lancet.2004;364:1959 –1973
22. Cohen-Zion M, Ancoli-Israel S. Sleep in children with atten-tion-deficit hyperactivity disorder (ADHD): a review of natu-ralistic and stimulant intervention studies.Sleep Med Rev.2004; 8:379 – 402
23. Manni R, Ratti MF, Marchioni E, et al. Poor sleep in adoles-cents: a study of 869 17-year-old Italian secondary school students.J Sleep Res.1997;6:44 – 49
24. Stein MA, Mendelsohn J, Obermeyer WH, Amromin J, Benca R. Sleep and behavior problems in school-aged children. Pedi-atrics. 2001;107(4). Available at: www.pediatrics.org/cgi/ content/full/107/4/e60
25. Bruni O, Ferri R, D’Agostino G, Miano S, Roccella M, Elia M. Sleep disturbances in Angelman syndrome: a questionnaire study.Brain Dev.2004;26:233–240
26. McArthur AJ, Budden SS. Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment.Dev Med Child Neurol. 1998;40:186 –192
27. Robinson AM, Richdale AL. Sleep problems in children with an intellectual disability: parental perceptions of sleep problems, and views of treatment effectiveness.Child Care Health Dev. 2004;30:139 –150
28. Smith AC, Dykens E, Greenberg F. Sleep disturbance in Smith-Magenis syndrome.Am J Med Genet.1998;81:186 –191 29. Elia M, Ferri R, Musumeci SA, et al. Sleep in subjects with
autistic disorder: a neurophysiological and psychological study. Brain Dev.2000;22:88 –92
30. Corkum P, Tannock R, Moldofsky H. Sleep disturbances in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry.1998;37:637– 646
31. Corkum P, Tannock R, Moldofsky H, Hogg-Johnson S, Humphries T. Actigraphy and parental ratings of sleep in chil-dren with attention-deficit/hyperactivity disorder (ADHD). Sleep.2001;24:303–312
32. O’Brien L, Ivanenko A, Crabtree VM, et al. Sleep disturbances in children with attention deficit hyperactivity disorder.Pediatr Res.2003;54:237–243
33. Prince JB, Wilens TE, Biederman J, et al. Clonidine for sleep disturbances associated with attention-deficit hyperactivity disorder: a systematic chart review of 62 cases.J Am Acad Child Adolesc Psychiatry.1996;35:599 – 605
34. Schwartz G, Ben Amor L, Grizenko N, et al. Actigraphic mon-itoring during sleep of children with ADHD on methylpheni-date and placebo.J Am Acad Child Adolesc Psychiatry.2004;43: 1276 –1282
35. Tjon Pian Gi CV, Broeren JP, Starreveld JS, Versteegh FG. Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open la-bel study.Eur J Pediatr.2003;162:554 –555
36. O’Brien LM, Gozal D. Sleep in children with attention deficit/ hyperactivity disorder.Minerva Pediatr.2004;56:585– 601. 37. Ivanenko A, Crabtree VM, Gozal D. Sleep in children with
psychiatric disorders.Pediatr Clin N Am.2004;51:51– 68 38. Johnson EO, Chilcoat HD, Breslau N. Trouble sleeping and
anxiety/depression in childhood.Psychiatr Res.2000;94:93–102 39. Kallepalli BR, Bhatara VS, Fogas BS, Tervo RC, Misra LK. Trazodone is only slightly faster than fluoxetine in relieving insomnia in adolescents with depressive disorders.J Child Ado-lesc Psychopharmacol.1997;7:97–107
40. Strunk RC, Sternberg AL, Bacharier LB, Szefler SJ, for the Childhood Asthma Management Program Research Group. Nocturnal awakening due to asthma in children with mild to moderate asthma in the Childhood Asthma Management Pro-gram.J Allergy Clin Immunol.2002;110:395– 403
42. Parker KP. Sleep disturbances in dialysis patients.Sleep Med Rev. 2003;7:131–143
43. Holley JL, Nespor S, Rault R. Characterizing sleep disorders in chronic hemodialysis patients.ASAIO Trans.1991;37:M456 – M457
44. Engstrom CA, Strohl RA, Rose L, Lewandowski L, Stefanek ME. Sleep alterations in cancer patients.Cancer Nurs.1999;22: 143–148
45. Craig TJ, Teets S, Lehman EB, Chinchilli VM, Zwillich C. Nasal congestion secondary to allergic rhinitis as a cause of sleep disturbance and daytime fatigue and the response to topical nasal corticosteroids.J Allergy Clin Immunol.1998;101:633– 637 46. Ando K, Kripke DF, Ancoli-Israel S. Estimated prevalence of delayed and advanced sleep phase syndromes.Sleep Res.1995; 24:509
47. Regestein QR, Monk TH. Delayed sleep phase syndrome: a review of its clinical aspects.Am J Psychiatry.1995;152:602– 608
48. Kuhn BR, Eliott AJ. Treatment efficacy in behavioral pediatric sleep medicine.J Psychosomatic Res.2003;54:587–597 49. Mindell JA. Empirically supported treatments in pediatric
psychology: Bedtime refusal and night wakings in young chil-dren.J Pediatr Psychol.1999;24:465– 481
50. Harding SM. Sleep in fibromyalgia patients: subjective and objective findings.Am J Med Sci.1998;315:367–376
51. Labyak SE, Bourguignon C, Docherty S. Sleep quality in chil-dren with juvenile rheumatoid arthritis.Holist Nurs Pract.2003; 17:193–200
52. Moldofsky H. Management of sleep disorders in fibromyalgia. Rheum Dis Clin North Am.2002;28:353–365
DOI: 10.1542/peds.2005-1693
2006;117;e1223
Pediatrics
Banas
Ivanenko, Kyle Johnson, Carol Rosen, Frank Steinberg, Thomas Roth and Bridget
Jodi A. Mindell, Graham Emslie, Jeffrey Blumer, Myron Genel, Daniel Glaze, Anna
Consensus Statement
Pharmacologic Management of Insomnia in Children and Adolescents:
Services
Updated Information &
http://pediatrics.aappublications.org/content/117/6/e1223 including high resolution figures, can be found at:
References
http://pediatrics.aappublications.org/content/117/6/e1223#BIBL This article cites 52 articles, 1 of which you can access for free at:
Subspecialty Collections
http://www.aappublications.org/cgi/collection/pharmacology_sub
Pharmacology
icine_sub
http://www.aappublications.org/cgi/collection/adolescent_health:med
Adolescent Health/Medicine
following collection(s):
This article, along with others on similar topics, appears in the
Permissions & Licensing
http://www.aappublications.org/site/misc/Permissions.xhtml in its entirety can be found online at:
Information about reproducing this article in parts (figures, tables) or
Reprints
DOI: 10.1542/peds.2005-1693
2006;117;e1223
Pediatrics
Banas
Ivanenko, Kyle Johnson, Carol Rosen, Frank Steinberg, Thomas Roth and Bridget
Jodi A. Mindell, Graham Emslie, Jeffrey Blumer, Myron Genel, Daniel Glaze, Anna
Consensus Statement
Pharmacologic Management of Insomnia in Children and Adolescents:
http://pediatrics.aappublications.org/content/117/6/e1223
located on the World Wide Web at:
The online version of this article, along with updated information and services, is
by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
