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
a

Department of Psychology, Saint Josephs University and Sleep Center, Childrens 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 speakers bureau of King and Sepracor and a consultant for Pzer, Johnsons Baby, and Wyeth. Dr Emslie is a member of the speakers bureau of McNeil and a
consultant for Eli Lilly, GlaxoSmithKline, Forest, Pzer, and Wyeth-Ayerst. Drs Blumer, Glaze, and Steinberg are consultants for Sano-Aventis. Dr Johnson is a member of the speakers bureau of Sano-Aventis.
Dr Rosen is a consultant for Sano-Aventis and Cephalon. Dr Roth is a member of the speakers bureau of Sano-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, Pzer, Roche, Sano, Sepracor, Somaxon, Syrex, Takeda, Transoral, Vanda, Vivometrics, and
Wyeth. Dr Genel is a consultant for Pzer 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.

www.pediatrics.org/cgi/doi/10.1542/
peds.2005-1693

METHOD. The National Sleep Foundation, in collaboration with Best Practice Project

doi:10.1542/peds.2005-1693

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.

This work was presented in part at the

Pharmacological Management of Insomnia
in Children and Adolescents conference;
November 12, 2004; Baltimore, MD

RESULTS. Conference participants unanimously agreed that there is a need for phar-

PEDIATRICS (ISSN Numbers: Print, 0031-4005;

Online, 1098-4275). Copyright 2006 by the
American Academy of Pediatrics

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

Key Words
insomnia, clinical trials, pediatric,
pharmacotherapy, sleep disorders
Abbreviations
ADHDattention-decit/hyperactivity
disorder
PDDpervasive developmental disorder
MDDmajor depressive disorder
DSPS delayed sleep phase syndrome
PSGpolysomnography
Accepted for publication Jan 23, 2006
Address correspondence to Jodi A. Mindell,
PhD, Department of Psychology, Saint
Josephs University, Philadelphia, PA 19131.
E-mail: jmindell@sju.edu

PEDIATRICS Volume 117, Number 6, June 2006

e1223

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-thecounter agents for the management of pediatric insomnia.

BACKGROUND

HERE 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.15 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.68 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.911
Compounding the situation is the absence of pharmaceuticals currently indicated for hypnotic use in the pediatric population, leading parents to administer overthe-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.1218 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

e1224

MINDELL et al

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, thera-

peutic 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.
Denition 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.2021 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.2224 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, Retts
disorder, childhood disintegrative disorder, Aspergers
disorder, and PDD not otherwise specified); ADHD; genetic disorders, such as Angelman syndrome; and
chronic neurologic disorders, such as epilepsy and
Tourettes 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.2529 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 patients 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
PEDIATRICS Volume 117, Number 6, June 2006

e1225

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 highpriority group of children with neuropsychiatric disorders for study.3036 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
e1226

MINDELL et al

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.4045
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,5052 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 childs sleep characteristics.
Actigraphy, activity-based sleep monitoring, uses a
wristwatch-like device that is attached to a patients
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 childs 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).
PEDIATRICS Volume 117, Number 6, June 2006

e1227

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 multipledose 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 come1228

MINDELL et al

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 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 subjects 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
Secretarys 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 caregivers 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 childs 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 Aspergers 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
childs 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 effiPEDIATRICS Volume 117, Number 6, June 2006

e1229

cacy profiles of sedative/hypnotics, providing these patients a better nights 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.
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,
e1230

MINDELL et al

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; SanofiAventis; Sepracor, Inc; and Takeda Pharmaceuticals
North America, Inc.
Conference Organizers
National Sleep Foundation and Best Practice Project
Management.
Author and Contributor Afliations
Altos Pediatric Associates (Dr Babcock), Baylor College
of Medicine (Dr Glaze), Best Practice Project Management (Dr Meyer), The Childrens HospitalBoston (Dr
Ferber), Childrens 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 DAndrea), Miami Childrens 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 TexasSouthwestern (Dr Emslie),
Yale University (Dr Genel), and independent consultant
(Dr Steinberg).

ACKNOWLEDGMENTS
This work was supported by the National Sleep Foundation and Best Practice Project Management, Inc.
REFERENCES
1. Adair GH, Bauchner H. Sleep problems in childhood. Curr Probl
Pediatr. 1993;23:147170
2. Owens JA, Spirito A, McGuinn M, Nobile C. Sleep habits and
sleep disturbance in elementary school-aged children. J Dev
Behav Pediatr. 2000;21:2736
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 children with intellectual disability. J Intellect Disabil Res. 2002;46:
537547
6. Sadeh A. Raviv A. Gruber R. Sleep patterns and sleep disruptions in school-age children. Dev Psychol. 2000;36:291301
7. Lindblom N, Heiskala H, Kaski M, et al. Neurological impairments and sleep-wake behaviour among the mentally retarded. J Sleep Res. 2001;10:309 318
8. Quine L. Sleep problems in primary school children: comparison between mainstream and special school children. Child
Care Health Dev. 2001;27:201221
9. Stores G. Sleep-wake function in children with neurodevelopmental 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;28:15611567
11. Wiggs L, Stores G. Behavioural treatment for sleep problems in
children with severe intellectual disabilities and daytime challenging behaviour: effect on mothers and fathers. Br J Health
Psychol. 2001;6:257269
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, double-blind comparison of the effects of nefazodone and fluoxetine on sleep architecture and quality of sleep in depressed
outpatients. J Clin Psychopharmacol. 1997;17:161168
14. Ledoux S, Choquet M, Manfredi R. Self-reported use of drugs
for sleep or distress among French adolescents. J Adol Health.
1994;15:495502
15. McNicholas F. Psychotropic prescribing practices of paediatricians in the UK. Child Care Health Dev. 2001;27:497508
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 pharmacotherapy 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 treatment of pediatric insomnia: results of a survey of communitybased 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 attention-deficit hyperactivity disorder (ADHD): a review of naturalistic and stimulant intervention studies. Sleep Med Rev. 2004;
8:379 402
23. Manni R, Ratti MF, Marchioni E, et al. Poor sleep in adolescents: 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. Pediatrics. 2001;107(4). Available at: www.pediatrics.org/cgi/
content/full/107/4/e60
25. Bruni O, Ferri R, DAgostino G, Miano S, Roccella M, Elia M.
Sleep disturbances in Angelman syndrome: a questionnaire
study. Brain Dev. 2004;26:233240
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 SmithMagenis 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 children with attention-deficit/hyperactivity disorder (ADHD).
Sleep. 2001;24:303312
32. OBrien L, Ivanenko A, Crabtree VM, et al. Sleep disturbances
in children with attention deficit hyperactivity disorder. Pediatr
Res. 2003;54:237243
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 monitoring during sleep of children with ADHD on methylphenidate 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 label study. Eur J Pediatr. 2003;162:554 555
36. OBrien 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;94:93102
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 Adolesc Psychopharmacol. 1997;7:97107
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 Program. J Allergy Clin Immunol. 2002;110:395 403
41. Reuveni H, Chapnick G, Tal A, Tarasiuk A. Sleep fragmentation
in children with atopic dermatitis. Arch Pediatr Adolesc Med.
1999;153:249 253

PEDIATRICS Volume 117, Number 6, June 2006

e1231

42. Parker KP. Sleep disturbances in dialysis patients. Sleep Med Rev.
2003;7:131143
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:
143148
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

e1232

MINDELL et al

48. Kuhn BR, Eliott AJ. Treatment efficacy in behavioral pediatric

sleep medicine. J Psychosomatic Res. 2003;54:587597
49. Mindell JA. Empirically supported treatments in pediatric
psychology: Bedtime refusal and night wakings in young children. J Pediatr Psychol. 1999;24:465 481
50. Harding SM. Sleep in fibromyalgia patients: subjective and
objective findings. Am J Med Sci. 1998;315:367376
51. Labyak SE, Bourguignon C, Docherty S. Sleep quality in children with juvenile rheumatoid arthritis. Holist Nurs Pract. 2003;
17:193200
52. Moldofsky H. Management of sleep disorders in fibromyalgia.
Rheum Dis Clin North Am. 2002;28:353365
53. Davidson JR, MacLean AW, Brundage MD, Schulze K. Sleep
disturbance in cancer patients. Soc Sci Med. 2002;54:1309 1321
54. Wendler D, Belsky L, Thompson KM, Emanuel EJ. Quantifying
the federal minimal risk standard implications for pediatr res
without a prospect of direct benefit. JAMA. 2005;294:826 832