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Pediatric Sleep
Disorders: Evidence
BasedUse
ofMedications
ForThe
PrimaryCare
Physician
Daniel Castellanos, MDAssistant Dean for Graduate Medical Education
Founding Chair, Department of Psychiatry & Behavioral Health; Professor of Psychiatry & Behavioral Health and Pediatrics
Herbert Wertheim College of Medicine, Florida International University
Disclosures
Consultant, Florida Medicaid Drug Therapy Management Program for Behavioral HealthUniversity of South Florida/AHCA
No other relevant financial disclosures
Castellanos 2016
Castellanos 2016
I. Identify of pediatric sleep disorders
II. Recognize non-pharmacologic management of pediatric sleep issues
III. Identify medication treatment of these disorders, with emphasis on evidence based use of medications.
Learning Objectives
Castellanos 2016
I. Overview
of pediatric
sleep disorders
Castellanos 2016
Castellanos 2016
Overview of
pediatric sleep
disorders
Pediatric sleep disorders represent highly common phenomena that often interfere with daily patient and family functioning
Dysomnias
Parasomnias
Castellanos 2016
Overview of
pediatric sleep
disorders
Dyssomnias
Patients with dyssomnias present with difficulty initiating or maintaining sleep or with excessive daytime somnolence.
Insomnia disorder (DSM-5) - primary insomnia (DSM-IV)
Includes changes with normal sleep efficiency, sleep-wake cycles, and sleep architecture.
This may be a lifelong pattern.
Defined as primary disturbances in the quantity, quality, or timing of sleep.
Castellanos 2016
Insomnia Disorder Criteria
The problems with sleep are often associated with the following:
Difficulty initiating sleep:
In children, this includes difficult initiating sleep without a caregiver.
Difficulty initiating sleep means that the subjective sleep latency is greater than 20-30 minutes.
Castellanos 2016
Insomnia Disorder Criteria
Difficulty maintaining sleep:
In children, this includes difficulty returning to sleep without caregiver
Difficulty maintaining sleep is the subjective time awake after sleep onset is longer than 20-30 minutes.
Castellanos 2016
Insomnia Disorder Criteria
Early morning awakening with difficulty returning to sleep.
There is no standard definition of early morning awakening, but it usually requires awakening 30 minutes before the scheduled time or before total sleep time reaches 6.5 hours.
Significant distress or impairment, occurring 3 nights per week, present for at least 3 months, and occurring despite sufficient time for sleep.
Castellanos 2016
Dyssomniavs
Parasomnia Parasomnias
Result in disruption of an existing state of sleep.
Include:
NREM sleep arousal disorders (Sleep terror disorder/Night terrors)
Nightmare disorder
REM sleep behavior disorder
Restless legs syndrome (RLS)
Castellanos 2016
Medications Used to Treat
Pediatric Sleep Disturbances
Meds Used to
Treat Insomnia
Castellanos 2016
Levels of Scientific Evidence
Randomized controlled trials
Non-randomized controlled trials; large meta-analysis
Observational studies with controls
Observational studies without controls; case series
Case reports; anecdotal reports; clinical consensus
Source: Adapted from US Dept of Health and Human Services; http://www.ahrq.gov/
Highest
Lowest
Castellanos 2016
Medications for
Sleep Disturbance
Melatonin
Diphenhydramine
Clonidine
Trazodone
Mirtazapine
Benzodiazepines
Amitriptyline
Castellanos 2016
Melatonin
Castellanos 2016
Melatonin
Melatonin is a hormone synthesized in the pineal gland from the amino acid, tryptophan.
Secretion of melatonin from the pineal gland is controlled by the hypothalamus, the site of the biological clock.
It appears in blood during the early evening, with peak concentrations occurring around 2.00–3.00 AM and then decreases to be undetectable by the time people are breakfasting.
Castellanos 2016
RCTs Melatonin Use in Children
Study NDuration
(days)Dosages Results
Type of Study
Smits et al (2001) 40 28 5 mg POS RCT
Smits et al (2003) 62 28 5 mg POS RCT
van Geijlswijk et al (2010)
70 70.05 mg/kg, 0.1 mg/kg, 0.15 mg/kg
POS RCT
Wilhelmsen-Langeland et al
(2013)
40(16-25 yo;
16/40 in HS)14 3 mg NS RCT
Saxvig et al (2014)40
(16-25 yo; 16/40 in HS)
14 3 mg NS RCT
Castellanos 2016
Other Studies Melatonin Use in Children & Adolescents
Study NDuration
(days)Dosages Results Type of Study
Ivanenko et al (2003) 32 60 2 mg POS Open label
Szeinberg et al (2003)
62 (adolescents)
180 3-5 mg POS Retrospective
Wilhelmsen-Langeland et al
(2013)
40(16-25 yo;
16/40 in HS)90 3mg POS
Open labelcontinuation
Saxvig et al (2014)40
(16-25 yo; 16/40 in HS)
90 3 mg POSOpen label
continuation
Castellanos 2016
Melatonin
13 controlled studies of melatonin for sleep disturbance in children with neurodevelopmental disorders (n = 424)
Dose 1-10 mg
Melatonin > placebo in all 13 studies
Multiple studies report increased speed of falling asleep & better sleep efficiency.
Adverse events = mild and similar to placebo
Source: Hollway and Aman Res Dev Disabil 32: 939-962, 2011.
Castellanos 2016
MelatoninSide
Effects
The most common melatonin side effects include:
Daytime sleepiness
Headaches
Dizziness
Less common side effects: abdominal discomfort, mild anxiety, irritability, confusion and short-lasting feelings of depression.
Castellanos 2016
MelatoninInteractions
Consider interactions with various medications, including:
Anticoagulants
Immunosuppressants
Diabetes medications
Birth control pills
Castellanos 2016
MelatoninSafety
There have been no appropriate studies to show that melatonin is safe in the long term for children.
Possibly safe vs unsafe. Because of its effects on other hormones, melatonin might interfere with development during adolescence.
Despite this, melatonin use has generally been regarded as safe by study authors and reviewers, despite the lack of rigorous clinical trials assessing its safety.
Castellanos 2016
MelatoninTypical hypnotic doses of melatonin are:
2.5 mg to 3 mg in children
5 mg to 10 mg in adolescents
No data for children under 2 yo
Melatonin is administered from 30 min to 60 min prior to the desired bedtime.
May find differences in response due to OTC proprietary brands.
.
Castellanos 2016
Melatonin
Chronobiological use:
Since melatonin is also associated with a hypnotic effect and a greater propensity to sleep, it has been suggested that exogenous melatonin could act as a chronobiological substance with hypnotic properties.
Its action will be more chronobiological or more hypnotic depending on the time when it is administered rather than on the administered dose, because it does not alter the total sleep time.
Castellanos 2016
Melatonin
Typical chronobiological doses of melatonin are:
0.3-6 mg in children & adolescents
No data for children under 2 yo
Administered up to 6 hours before the usual bedtime.
.
Castellanos 2016
Clonidine
Castellanos 2016
Clonidine
No controlled studies in children with sleep disturbance
Ming et al 2008: Open label trial of clonidine in ASD:
-decreased sleep latency by 2.2 hrs
-reduced night awakenings by 1.5
Clinical/anecdotal reports
No trials with guanfecine though might expect more sustained effect
Source: Ming et al. Use of clonidine in children with autism spectrum disorders. Brain Dev. 2008 Aug;30(7):454-60.
Castellanos 2016
May develop tolerance and develop mid-nocturnal awakening
Monitor BP and pulse
Avoid abrupt discontinuation
Guanfecine; clonidine ER
Clonidine
Castellanos 2016
ClonidineSide
EffectsThe most common clonidine side effects include:
Drowsiness
Dizziness
Dry mouth
Constipation
Less common: Fainting, irritability, depression, tachycardia, arrhythmia, rebound hypertension
Castellanos 2016
Clonidine 0.025 - 0.3mg qHS
Begin (0.1 mg) ½ to 1 tab at bedtime; increase by that amount weekly to 0.2 to 0.3 mg at bedtime
If no significant improvement in sleep after one week, begin increasing by ½ tab each week at hs until there has been a satisfactory improvement in the sleep disturbance, treatment-limiting side effects have emerged or a total daily dose of 0.3 mg has been reached.
Clonidine
Castellanos 2016
Diphenhydramine
Castellanos 2016
Diphenhydramine
5 controlled studies of diphenhydramine in persons (children & adults) with sleep disturbance
Results were mixed
Only ONE RCT (N=50) involving children
No RCTs since 1990
Can cause paradoxical worsening of sleep and behavior.
Castellanos 2016
DiphenhydramineChildren
Russo et al, 1976 randomized double-blind placebo-controlled trial (n=50)
Age 2-12 yo
Dose 1.0 mg/kg
Diphenhydramine was significantly better than placebo in:
reducing sleep latency
time and the number of awakenings per night
while sleep duration was marginally increased (NS)
Castellanos 2016
Other RCTs Diphenhydramine Use
Study Ages N Dosages ResultsType of Study
Sunshine et al (1978)Post partum
women557 12.5; 25; 50 mg POS RCT
Rickels et al (1983) 18-70 yo 111 1.0 mg/kg POS RCT
Borbély & Youmbi-Baldener (1988)
22-30 yo 10 50 or 75 mg NS RCT
Kudo & Kurihara(1990)
15-82yo 144 12.5; 25; 50 mg MIXED RCT
Castellanos 2016
DiphenhydramineSide
EffectsThe most common diphenhydramine side effects include:
Drowsiness
Dizziness
Constipation
Stomach upset
Blurry vision
Dry mouth/nose/throat
Less common: Restlessness or paradoxical excitement, confusion, difficulty urinating, tachycardia, arrhythmia
Castellanos 2016
Diphenhydramine
Starting dose: 12.5-25 mg
Titrate if necessary, based on response and body weight
Monitor for paradoxical worsening or excitement
Discontinuation: As clinical appropriate. No clear discontinuation parameters available
Diphenhydramine
Castellanos 2016
Mirtazapine
Limited evidence exists for the use of mirtazapine
No controlled studies in children with sleep disturbance
Open label trial in 26 ~1/3 responded with improved sleep, few side effects
Castellanos 2016
Mirtazapine:
Begin (15 mg) ¼ tab at bedtime; increase by this amount weekly to 3.75 to 45 mg at bedtime
Prominent adverse events are increased appetite, weight gain and sedation
Available in a soluble tablet
Mirtazapine
Castellanos 2016
Benzodiazepines
No controlled studies of benzodiazepines in children
Can cause paradoxical worsening of sleep and behavior.
Benzos can contribute to cognitive impairment and cause physical dependence
Castellanos 2016
Trazodone
No controlled studies in children with sleep disturbance
Begin (50 mg) ½ to 1 tab at bedtime; increase by this amount weekly to 25 to 300 mg at bedtime
Discuss potential adverse event of priapism
Castellanos 2016
Amitriptyline
No controlled studies in children with sleep disturbance
Begin (50 mg) ½ to 1 tab at bedtime; increase by this amount weekly to 25 to 300 mg at bedtime
Can lower the seizure threshold
Consider baseline electrocardiogram
Blood level available
Castellanos 2016
Herbal supplements
Chamomile, lavender, tryptophan, kava kava
Possible side effects: necrotizing hepatitis (kava kava); eosinophilia myalgia syndrome (tryptophan)
Use of herbal supplements have limited-to-no evidence of efficacy
Castellanos 2016
NOTE:
Use of antipsychotic meds, such as quetiapine (Seroquel®), is not recommended for the management of insomnia due to the potential metabolic side effects.
Insomnia
Castellanos 2016
To Summarize….
Castellanos 2016
Don’t prescribe medication to treat childhood insomnia, which usually arises from parent-child interactions and responds to behavioral intervention.
No medications are approved by the FDA for the treatment of pediatric insomnia.
TakeAway
Pointsfor the
Prescriber
Castellanos 2016
There is insufficient evidence on dosage, safety profiles and efficacy about the use of hypnotics for handling pediatric insomnia.
The few studies published about the efficacy of using pharmacological treatment versus placebo show some results with statistically significant effects, but the clinical effectiveness is not clear.
TakeAway
Pointsfor the
Prescriber
Castellanos 2016
Pharmacotherapy should only be considered for short-term use if:
Insomnia results in significant impairments in child and/or caregiver daytime functioning.
Behavioral interventions alone are ineffective OR caregivers unable to implement.
TakeAway
Pointsfor the
Prescriber
Castellanos 2016
Pharmacotherapy with behavioral treatment may be appropriate for:
Short-term crisis intervention.
Insomnia with comorbid high risk psychiatric (ADHD, MDD) or neurodevelopmental conditions (ASD).
Insomnia exacerbates psychiatric, medical conditions.
TakeAway
Pointsfor the
Prescriber
Castellanos 2016
TakeAway
Pointsfor the
Prescriber
Begin with…
Comprehensive Assessment
Initial Treatment Plan- behavioral
Castellanos 2016
TakeAway
Pointsfor the
Prescriber
If medications are still indicated…
Melatonin
Clonidine (off label); Diphenhydramine
Limited evidence. May be used with caution (all off label)-Mirtazapine; Trazodone; Benzodiazepines; Amitriptyline
NOTE: Use of antipsychotic medications for insomnia is NOT recommended.
Castellanos 2016
Medications for Pediatric Sleep Disturbances
Medication Starting Dose Titration Discontinuation
Melatonin 1-3 mg q hs Up to 9/10 mg daily
As clinically appropriate
Clonidine 0.05 mg q hs/1 week
0.05 mg/ week 0.05 mg/3 days
Diphenhydramine 12.5-25 mg q hs If necessary, based on
response and body weight
As clinicallyappropriate
Mirtazapine 3.75 mg q hs/1 week
3.75 mg/ week 7.5 mg/ 3 days
Trazodone* 25 mg q hs/1 week
25 mg/ week 25-50 mg/3 days
*Note. Continue titration until symptoms are adequately controlled, treatment-limiting side effects emerge or max daily dose is reached.
Parting Thoughts
Children are our future
We all share a responsibility for their welfare
Castellanos 2016
Castellanos 2016
Appendix.
Normal Sleep
PhasesComprehensive
Assessment &
Non-pharmacologic management
Castellanos 2016
I. Normal
Sleep Phases
Castellanos 2016
Normal Sleep
PhasesNewborns (0-3 months)
Sleep during the early months occurs around the clock and the sleep-wake cycle interacts with the need to be fed, changed and nurtured.
Newborns sleep a total of 10.5 to 18 hours a day on an irregular schedule with periods of one to three hours spent awake.
The sleep period may last a few minutes to several hours.
Castellanos 2016
Normal Sleep
PhasesInfants (4-11 months)
6 months of age, nighttime feedings are usually not necessary and many infants sleep through the night
70-80 % will do so by 9 months of age.
Typically sleep 9-12 hours during the night and take 30” to 2-hour naps, one to four times a day – fewer as they reach age one.
When infants are put to bed drowsy but not asleep, they are more likely to become "self- soothers" which enables them to fall asleep independently at bedtime and put themselves back to sleep during the night.
Those who have become accustomed to parental assistance at bedtime often become "signalers" and cry for their parents to help them return to sleep during the night.
Castellanos 2016
Normal Sleep
PhasesToddlers (1-2 years)
Need about 11-14 hours of sleep in a 24-hour period.
When they reach about 18 months of age their naptimes will decrease to once a day lasting about 1 – 3 hours.
Naps should not occur too close to bedtime as they may delay sleep at night.
Many toddlers experience sleep problems including resisting going to bed and nighttime awakenings.
Nighttime fears and nightmares are also common
Castellanos 2016
Normal Sleep
PhasesPreschoolers (3-5 years)
Typically sleep 11-13 hours each night and most do not nap after five years of age.
As with toddlers, difficulty falling asleep and waking up during the night are common.
With further development of imagination, preschoolers commonly experience nighttime fears and nightmares.
In addition, sleepwalking and sleep terrors peak during preschool years.
Castellanos 2016
Normal Sleep
PhasesSchool-aged Children (6-12 years)
Children aged six to 13 need 9-11 hours of sleep.
Usually increasing demand on their time from school (eg, HW), sports and other extracurricular/social activities.
Become more interested in TV, computers, the media and internet as well as caffeine products – all of which can lead to difficulty falling asleep, nightmares and disruptions to their sleep.
In particular, watching TV close to bedtime has been associated with bedtime resistance, difficulty falling asleep, anxiety around sleep and sleeping fewer hours.
Sleep problems and disorders are prevalent at this age
Castellanos 2016
Normal Sleep
PhasesAdolescents (13 + years)
Circadian rhythm changes means it’s normal for teenagers to want to go to bed later at night – often around 11 pm or later – then get up later in the morning.
Biological sleep patterns shift toward later times for both sleeping and waking during adolescence -- meaning it is natural to not be able to fall asleep before 11:00 pm.
Teens need about 8 to 10 hours of sleep each night to function best.
Teens tend to have irregular sleep patterns across the week — they typically stay up late and sleep in late on the weekends, which can affect their biological clocks and hurt the quality of their sleep.
Most teens do not get enough sleep…. About 85-90% of adolescents don’t get the recommended amount of sleep on school nights.
Castellanos 2016
II. Comprehensive
Assessment
Castellanos 2016
Comprehensive assessment
Primary sleep disorders (OSA, RLS, circadian rhythm disorders)
Medical, psychiatric and neurodevelopmental co-morbidities (particularly ADHD, depression & ASD
Concomitant medications, especially psychotherapeutic medications (eg, stimulants)
Comprehensive Assessment
Castellanos 2016
Comprehensive assessment…
Exacerbation primary sleep disorders
Assessment of proper sleep hygiene (e.g., electronic use, caffeine, napping)
Caregiver role
Presentation: sleep onset/maintenance
Insomnia
Castellanos 2016
III. Non-pharmacologic
management of
pediatric sleep
issues
Castellanos 2016
Behavioral interventions
Caregiver-based for younger children
Sleep training, bedtime fading, bedtime pass
CBT-I for older children and adolescents
Stimulus control, sleep restriction
Healthy sleep practices for all
Regular sleep schedule, avoidance nighttime screens, limit caffeine, age-appropriate napping.
Insomnia
Castellanos 2016
Toddlers (1-2 yo)
Maintain a daily sleep schedule and consistent bedtime routine.
Make the bedroom environment the same every night and throughout the night.
Set limits that are consistent, communicated and enforced.
Encourage use of a security object such as a blanket or stuffed animal.
Castellanos 2016
Infants (< 1 yo)
Develop regular daytime and bedtime schedules.
Create a consistent and enjoyable bedtime routine .
Establish a regular "sleep friendly" environment.
Encourage baby to fall asleep independently.
Castellanos 2016
Pre-School Children
(3-5 yo)
Maintain a regular and consistent sleep schedule.
Relaxing bedtime routine that ends in the room where the child sleeps.
Child should sleep in the same sleeping environment every night, in a room that is cool, quiet and dark – and without a TV.
Castellanos 2016
School Aged
Children (6-12 yo)
Teach parents & school-aged children about healthy sleep habits.
Continue to emphasize need for regular and consistent sleep schedule and bedtime routine.
Make child's bedroom conducive to sleep – dark, cool and quiet.
Keep TV and computers out of the bedroom.
Avoid caffeine.
Castellanos 2016
Adolescents
Make sleep a priority. Keep a sleep diary to help see patterns.
Naps can help and make teens work more efficiently, if planned right. Naps that are too long or too close to bedtime can interfere regular sleep.
Bedroom - keep it cool, quiet and dark. Let in bright light in the morning to signal the body to wake up.
Avoid coffee, tea, soda/pop, chocolate, nicotine and alcohol late in the day.
Castellanos 2016
Adolescents
Establish a bed and wake-time and stick to it, coming as close as you can on the weekends. A consistent sleep schedule helps the body to get in sync with its natural patterns.
Don’t eat, drink, or exercise within a few hours of your bedtime. Don’t leave your homework for the last minute. Try to avoid the TV, computer and telephone in the hour before you go to bed. Stick to quiet, calm