PEDIATRICS Vol. 117 No. 6 June 2006, pp. e1223-e1232 (doi:10.1542/peds.2005-1693)
SPECIAL ARTICLE |
Pharmacologic Management of Insomnia in Children and Adolescents: Consensus Statement
a Department of Psychology, Saint Joseph's University and Sleep Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
b Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
c Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, Ohio
d Child Health Research Center, Department of Pediatrics, School of Medicine, Yale University, New Haven, Connecticut
e Departments of Pediatrics and Neurology, Baylor College of Medicine, Houston, Texas
f Departments of Psychiatry and Neurosciences, Loyola University Medical Center, Chicago, Illinois
g Departments of Psychiatry and Pediatrics, Oregon Health and Science University, Portland, Oregon
h Medical Consultant, Evanston, Illinois
i Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan
j Medical Writer, Boston, Massachusetts
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ABSTRACT |
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 TOP ABSTRACT BACKGROUNDAPPENDIXREFERENCES |
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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 recommendations regarding the development of clinical trials in this area. After a series of presentations providing background on the current knowledge of pediatric insomnia 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 understanding of pediatric insomnia.
RESULTS. Conference participants unanimously agreed that there is a need for pharmacologic 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 management of pediatric insomnia. Attendees reached consensus on methodologic issues in the study of pharmacologic treatment of pediatric insomnia including agreeing on 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 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 disorders/autism spectrum disorder. There was also agreement on the need for pharmacokinetic and pharmacodynamic 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.
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
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BACKGROUND |
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TOPABSTRACTBACKGROUNDAPPENDIXREFERENCES |
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There is a great need to understand and effectively treat pediatric insomnia. Although extensive population-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 neurologic 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 psychiatric comorbidities.6–8 New studies continue to demonstrate the negative consequences of sleeplessness in children and adolescents, including hyperactivity, irritability, 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.9–11
Compounding the situation is the absence of pharmaceuticals currently indicated for hypnotic use in the pediatric 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 attention-deficit/hyperactivity disorder (ADHD) or depression were commonly prescribed treatments for insomnia, including 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. Despite the widespread use of prescription therapies and other products, including antihistamines, little data exist on their efficacy for the treatment of insomnia in children and adolescents. Children 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 conditions is not a satisfactory solution. Thus, further research is needed regarding the most appropriate treatment regimes for both the general pediatric population and subpopulations in terms of commonly prescribed medications 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 researchers with experience in childhood and adult insomnia, 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 nonpharmacologic and pharmacologic management of pediatric insomnia, and (3) develop recommendations for clinical trials in the pharmacologic management of pediatric insomnia.
The first part of the conference consisted of plenary presentations to establish a common background. These included discussions concerning an appropriate definition of pediatric insomnia, background on populations of children with increased rates of insomnia where the need for treatment is the greatest, current research on behavioral and pharmacologic therapy for treating pediatric insomnia, as well as pediatric-specific clinical research considerations, including dose definition, therapeutic end points, and regulatory and ethical issues. The remainder of the conference consisted of working sessions for the development of consensus recommendations.
Two primary pediatric populations at high risk for insomnia were identified: (1) children with neuropsychiatric 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 developing consensus recommendations for the development of guidelines for clinical trials for the pharmacologic management of pediatric insomnia. The workgroups presented 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 recommendations 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 condition that is highly prevalent, with 
10% of the general adult population experiencing chronic insomnia.20–21 Insomnia in children, however, is a less understood condition. Unlike insomnia in the adult population, pediatric 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 neurodevelopmental 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 hyperactivity 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 consensus 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 insomnia in the pediatric population.
Pediatric Insomnia
Repeated difficulty with sleep initiation, duration, consolidation, 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 practices (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 interventions and who would be candidates for pharmacologic management of their insomnia and, thus, an important 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 exhibit 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; genetic disorders, such as Angelman syndrome; and chronic neurologic disorders, such as epilepsy and Tourette's disorder. The clinical experience of the participants 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.25–29 PDD patients were recommended because of (1) the significant number of children with PDD; (2) the well-established diagnostic criterion for the various disorders included 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 nighttime behaviors and difficulties with sleep onset and maintenance that interfere with adequate sleep time, which negatively impact daytime functioning.
Although children with PDD would experience a real benefit from hypnotics, there are several difficulties inherent in working with this population. First, a diagnosis of PDD encompasses a wide range of impairment levels and comorbidities, necessitating the incorporation of a diverse population. Second, if PDD patients are treated with psychotropic medications, they will likely remain on them and, as a result, drug interactions may complicate 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 disorders for study.30–36 Studies have indicated that as many as 50–60% of children with ADHD experience sleep problems. 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 suggesting that ADHD patients experience higher rates of sleep disturbances than the general pediatric population. Furthermore, 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 studying this population were also discussed. Children with ADHD frequently have comorbid disorders and are often taking medication that may confound data interpretation. It was recommended, however, that children with stable ADHD who also had a stable medication dosage and/or behavioral treatments are an important therapeutic target.
In both adults and children, insomnia is a frequent symptom of mood and anxiety disorders, including major depressive disorder (MDD), bipolar disorder, generalized anxiety disorder, separation anxiety disorder, and posttraumatic stress disorder. Studies have indicated that as many as 75% of children with MDD have sleep problems.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 associated with anxiety disorders in children.38,39 To date, there have been no polysomnographic studies of anxiety disorder-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, hospitalization, or travel), and insomnia associated with medical conditions, such as asthma, cystic fibrosis, rheumatic disorders, chronic pain, and cancer and its treatments.40–45
Insomnia associated with DSPS has a significant impact on daytime functioning.46,47 Pharmacologic treatment may be an important adjunct to circadian treatments for this sleep disorder. Unlike children with ADHD and PDD, those with DSPS may have lower occurrences 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 significant 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 lifestyle-related sleep phase delays that are especially common 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.48,49 Two common forms of primary insomnia in adults, psychophysiologic and idiopathic insomnia, may lead to recruiting challenges because of its purported low prevalence rate and lack of descriptive clinical detail and definition in pediatric populations. Although insomnia is common in children with chronic medical conditions, such as cystic fibrosis and chronic pain related to rheumatological disorders,50–52 the lack of data about the prevalence of insomnia symptoms and the heterogenous sources of insomnia would make these clinical populations less desirable for initial study. Acute insomnia that might be associated with a hospitalization, a fracture, or the loss of someone close to the child was also eliminated, because the condition is too transient, with the insomnia often resolving without treatment. In addition, children in this group are very likely to be prescribed other short-term medications (eg, opiates) for the management of the acute problem. Finally, cancer, an area of medical need,53 was rejected for initial studies because of the high likelihood of drug-drug interactions that would confound the results, the ever-changing clinical 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. During the first screen, patients should be evaluated for their primary disorder, using disease-specific validation criteria to ensure that the study population is adequately homogeneous. Individuals passing the first screen should then be evaluated for insomnia using age-appropriate 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, including conduct disorder, clinically significant MDD and anxiety disorder, and oppositional defiant disorder, were also recommended exclusions unless they are the primary study group.
The conference participants noted that requiring patients 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 situation 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 standard" for studying sleep. It involves recordings of electroencephalogram, 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 procedure, 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 provides a significant advantage in that it can easily be conducted at home and, thus, may provide a more natural view of patient sleep. Actigraphy also provides a measure of night-to-night variability and can potentially detect unreported circadian sleep disturbances. Actigraphy, however, cannot be used to screen for an underlying sleep disorder, such as sleep apnea. Although actigraphy 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 different points during pediatric drug development. PSG remains an important screening tool and can also provide a more complete picture of sleep architecture at important clinical end points. For some children, the PSG procedure itself, conducted in an unfamiliar environment with multiple physiologic sensors, either may not be tolerated or may interfere with the child's usual sleep. Actigraphy can provide assessment of sleep patterns 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 sensor loss in an unattended setting may limit this approach, especially in the PDD or ADHD clinical populations.
Subjective Assessment
Pediatric sleep studies have used a variety of subjective reporting tools. The most common tools are questionnaires and sleep diaries. Few questionnaires have been validated as measures for pretreatment and posttreatment. Sleep diaries, the most common measure, have been shown to be reliable in comparison to actigraphy. Given the populations under consideration, parental completion of sleep diaries is also appropriate. Incentives and creative strategies to enhance daily compliance with reporting may be important, such as hand-held computer-based diaries and interactive voice reporting services. Self-report measures may be appropriate in some studies, (eg, adolescents with DSPS).
Primary Disease Outcomes
Small studies have shown both improvements in daytime functioning and reductions in symptomatology when children with insomnia and ADHD or PDD were treated for sleep disturbances. Unfortunately, these findings are mostly supported by anecdotal clinical evidence. The consensus recommended against the inclusion of primary disease outcome measures. Requiring an insomnia therapy to demonstrate a positive impact on a condition 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 development process.
Methodologic Issues
Dose Definition
All of the participants agreed on the need for clinical trials to determine safe and efficacious doses of hypnotics in children and adolescents. The pediatric population covers a broad range of ages and body weights with a corresponding range in ability to metabolize pharmaceuticals. 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, metabolism, and elimination profiles specific for pediatric populations and that appropriate dosing is selected for clinical trials.
An additional concern is the formulation in which medications would be studied. Many children have difficulty 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 treatments, 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 recommended that a child should not be required to complete and fail a course of behavioral therapy before becoming eligible to participate in a clinical trial. Instead, when appropriate, clinical trials should include both behavioral and pharmacologic therapy (singly and in combination) 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 television viewing, or age-inappropriate sleep-wake schedules. All of the families participating in clinical trials should receive basic information of positive sleep practices 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. Because the disorders suggested for study are chronic disorders, 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 appropriate 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 variation in response to medication 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 participant 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 involving children from the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, codified as "The Common Rule," 45 CFR 46, Subpart D, require that children participating in clinical 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 generalizable knowledge about the subject's disorder or condition." Minimal risk is defined as "the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological tests." The definitions of "minimal risk" and "minor increment over minimal risk" are imprecise, and there has been significant discussion recently regarding this issue and what defines more than minimal risk.54 A federal panel, the Secretary's Advisory Committee on Human Research Protections, has been reviewing Subpart D and has drafted more explicit guidelines for stratifying risk, although 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 development 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 insomnia. Recent concerns about the difference between safety profiles of the selective serotonin reuptake inhibitors 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 diminished 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 disorder. 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 insomnia. 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 childhood insomnia can help define a research agenda to better characterize the disorder, identify valid assessment tools, and improve treatment 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 individuals 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 questions also remain about potential linkages between cultural, ethnic, socioeconomic, and developmental factors and pediatric insomnia. Population-based studies could provide valuable insights into these questions and establish the basis for future recommendations for standard guidelines for pediatrician interaction with all children, not only those actively presenting with pediatric insomnia.
Evidence exists that treating sleep disturbances may have a positive impact on aspects of a comorbid disorder, including ADHD and depression. More extensive, rigorous studies are needed to characterize the type and degree of improvement for each patient population, ultimately providing guidance to clinicians on the relative importance of treating sleep problems in patients undergoing treatment for another disorder.
Improving Diagnostic and Assessment Tools
Additional research focusing on diagnostic and assessment 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 demonstrate hyperactivity, whereas teenagers are more likely to be sleepy during the day. This complicates the development of assessment tools. As a first step, however, validated adult insomnia subjective measurement tools could potentially be modified to reflect the different symptoms present in younger patients. Investigations 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
A 2-day conference was convened to achieve consensus recommendations on the pharmacologic management of insomnia in children and adolescents. Unanimously, participants agreed that studies of the safety and efficacy of pharmacologic treatment of insomnia in children and adolescents are needed. This population is frequently prescribed pharmacotherapy lacking evidence for efficacy or safety. Rigorous large-scale clinical trials will offer greatly needed information on the safety and efficacy profiles of sedative/hypnotics, providing these patients 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 receive pharmacotherapy for insomnia.
Agreement on study design included consensus on the need for pharmacokinetic and pharmacodynamic studies to determine appropriate doses and safety profiles 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. Furthermore, the use of concomitant medications should not be an exclusion criterion, because this would provide 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 morning wakings 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 research and used only as secondary drug development outcome measures.
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APPENDIX |
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TOPABSTRACTBACKGROUNDAPPENDIXREFERENCES |
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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 (cochairs).
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
Altos Pediatric Associates (Dr Babcock), Baylor College of Medicine (Dr Glaze), Best Practice Project Management (Dr Meyer), The Children's Hospital–Boston (Dr Ferber), Children's Hospital of Philadelphia (Drs Meltzer and Mindell), Food and Drug Administration (Drs Grylack, Mathis, McNiel, and Rappaport), Henry Ford Hospital (Dr Roth), Johns Hopkins University (Dr Riddle), King Pharmaceuticals (Ms Jacksland and Dr James), Loyola University Medical Center (Dr Ivanenko), Medical College of Wisconsin (Dr D'Andrea), Miami Children's Hospital (Dr Padilla), National Centers on Sleep Disorders Research (Dr Hunt), National Institutes of Mental Health (Dr del Carmen-Wiggins and Dr Lederhandler), National Institute of Nursing Research (Dr Koepke), National Sleep Foundation (Mr Pritz, Mr Drobnich, Mr Gelula, Ms McKenna Luz, Mr Sears, and Mr Steinitz), Oregon Health and Science University (Dr Johnson), Organon (Drs Igvy May and van Den Berg), Pfizer (Ms Tufts and Dr Wang), Sanofi-Aventis (Drs Gayda and Thacker), Sepracor (Ms Kirk and Dr Wessel), State University of New York Stonybrook (Dr Carlson), Takeda Pharmaceuticals (Dr Weigand), University of Alberta (Dr Witmans), University of Chicago (Dr Kohrman), University Hospital of Cleveland (Drs Blumer and Rosen), University of Texas–Southwestern (Dr Emslie), Yale University (Dr Genel), and independent consultant (Dr Steinberg).
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ACKNOWLEDGMENTS |
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This work was supported by the National Sleep Foundation and Best Practice Project Management, Inc.
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FOOTNOTES |
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Accepted Jan 23, 2006.
Address correspondence to Jodi A. Mindell, PhD, Department of Psychology, Saint Joseph's University, Philadelphia, PA 19131. E-mail: jmindell{at}sju.edu
This work was presented in part at the Pharmacological Management of Insomnia in Children and Adolescents conference; November 1–2, 2004; Baltimore, MD
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.
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TOPABSTRACTBACKGROUNDAPPENDIXREFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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