Download Sleep Pharmacology

Sleep Pharmacology
Sanjeev V. Kothare, MD, FAASM
Conflicts of Interest
Sleep Pharmacology
Sanjeev V. Kothare,
Kothare, MD, FAASM
Interim Medical Director
Center for Pediatric Sleep Disorders
Boston Children’
Children’s Hospital
• National Institute of Health
– 1 RC1 HL099749-01 (R21) (2009-12)
– RFA-HL-09-001 (2010-14)
– 1R21 NS076859-01 (2011-13)
• Harvard Catalyst (2010-11)
Objectives
• Discuss therapeutic options for treatment
of sleep disorders in children
• Outline general guidelines for use of
sleep medications in children
• Review nonprescription drugs as well as
•
pharmacological profiles of prescription
drugs for treatment of insomnia of
childhood
Review side effects of these drugs
Contents
• Treatment of Insomnia
• Medical treatment of OSAS
• Treatment of hypersomnia including
narcolepsy
• Treatment of PLMS & RLS
Pediatric Insomnia
• initiation,
Definition:
Definition: “repeated difficulty with sleep
maintenance, duration, or
Pharmacologic Treatment of
Insomnia of Childhood
quality that occurs despite age
appropriate time & opportunity for sleep,
with resultant daytime functional
impairment”
impairment”
• adolescents,
Prevalence:
Prevalence: 6% in childhood, 11% in
& 5050-75% in children with
psychiatric or neuroneuro-developmental
disorders
Johnson EO et al. Pediatrics 2006
Copyright (c) 2012 Boston Children's Hospital
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Sleep Pharmacology
Sanjeev V. Kothare, MD, FAASM
PharmcoPharmco-Therapy of Pediatric Insomnia
• No evidence based information & lack of FDA
approved medications
Mindell JA et al. Pediatrics 2006
Owens JA et al. JCSM 2005
• Indications:
Indications: failure of behavioral interventions,
medical illness, neuroneuro-psychiatric & genetic
disorders, selfself-limited situations (death in the
family, travel)
• Contraindications:
Contraindications: substance abuse, drugdrug-drug
interactions, associated OSA, RLS/PLMS
Owens JA et al. Chi Adolesc Cli N Am 2009
PharmcoPharmco-Therapy of Pediatric Insomnia
PharmcoPharmco-Therapy of Pediatric Insomnia
• Always combined with behavioral
interventions, after discussing risk--
• Select appropriate medications:
•
•
•
•
•
• Timing
interventions, after discussing risk
benefit analysis with the family
Under close supervision for side effects,
tolerance, drug interactions
Refills only with close follow up
Aimed for short term use as far as
possible
Use of the smallest possible dose
Watch for lingering daytime sedation
PharmcoPharmco-Therapy of Pediatric Insomnia
• Screen adolescents for alcohol, drug
use, pregnancy
• Screen for undocumented OTC
medications
• Assess drug-drug interactions: (PK/PD)
• Paradoxical effects
(stimulation/dysinhibition)
• Exaggeration of co-existing OSA, RLS,
PLMS, RBD
Copyright (c) 2012 Boston Children's Hospital
– Short acting for sleep-onset
– Long acting for sleep maintenance
– Hypnotic versus chronobiotic (melatonin)
– Forbidden zone of circadian alertness
• Review side effect profile with family
• Frequent monitoring of efficacy & side effects
• Avoid abrupt discontinuation (to prevent
rebound)
PharmcoPharmco-Therapy of Pediatric Insomnia
• AlphaAlpha-2 agonists: clonidine, guanfacine
• Melatonin
• OTC medications: diphenhydramine,
diphenhydramine, hydroxyzine
• Chloral hydrate
• Barbiturates
• Benzodiazepines
• NonNon-benzodiazepine hypnotics
• SSRIs and Tricyclic antidepressants
• Neuroleptics
• AntiAnti-epileptic medications: gabapentin, pregabelin,
pregabelin,
tiagabin
• Herbal Medicines
Pelayo R et al. Sem Pediatr Neurol 2008
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Sleep Pharmacology
Sanjeev V. Kothare, MD, FAASM
AlphaAlpha-2 Agonists
• Clonidine (Catapres
(Catapres)): onset within 1 hr, peak
Alpha-2 Agonists
effect by 20.1-0.2
2-3 hrs, λ2 6 hrs, dosage 0.1mg, causes hypotension, bradycardia at
onset, and REM rebound with nightmares
and elevated BP when effect wears off, proproconvulsant, narrow therapeutic index
• Guanfacine (Tenex
(Tenex,, Intuniv)
Intuniv): less sedating,
longer λ2 of 8 hrs, 11-2 mg dosage, less
fluctuation of BP, not a propro-convulsant
Schnoes CJ et al. Clin Pediatr 2006
Melatonin
Melatonin
• Secreted by the pineal gland, acting on the
SCN
• Secretion is inhibited by light
• Promotes sleep initiation
• Half life of 40 minutes
• Hypnotic (MT1): when given one hour prior to
sleep onset (3(3-10 mg dose)
• Phase advancing (MT2): when given 5.55.5-6
hours prior to sleep onset (0.5(0.5-1 mg dose)
Mundey K et al. Sleep 2005
Melatonin
• Used extensively in DSPD, shift workers & jet
lag, ADHD, autism, Rett syndrome, blindness
• Has been used in children with neuroneurodevelopmental, psychiatric, and genetic
developmental, psychiatric, and genetic
disorders including autism, blindness, & brain
tumors
Malow et al 2008
Wright B et al J Autism Dev Disord 2010
Ramelteon (Rozerem)
• Selective MT / MT agonist
• No data regarding use in children
1
2
• Side effects are rare, but with longlong-term use,
hypothalamic gonadal axis suppression &
hypothalamic gonadal axis suppression &
delayed puberty may be seen, lowered seizure
threshold with higher doses, propro-inflammatory
properties (caution with asthma & steroid use)
Copyright (c) 2012 Boston Children's Hospital
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Sleep Pharmacology
Sanjeev V. Kothare, MD, FAASM
OTC Medications
OTC Medications
• Diphenhydramine (Benadryl) (0.5 mg/kg)
• Hydroxyzine (Atarax)
Atarax) (1 mg/kg)
• Significant side effects, tolerance, lingering
•
•
sedating effects in the morning, paradoxical
agitation
No more than a placebo effect !!
Data safety monitoring board halted study
due to lack of efficacy
Merenstein et al. Arch Pediatr Adolesc Med 2006
Russo et al 1976
Chloral Hydrate
• Sedating hypnotic acting on the GABA
receptor
• Dosage: 2525-50 mg/kg/day
• Development of tolerance, lingering
A
Chloral Hydrate
•
sedation in the morning, risk for hepatohepatotoxicity
ShortShort-term use only
Pershad J et al. Pediatr Emerg Care 1999
Benzodiazepines: GABAGABA-A agonists
• They lead to reduced sleep latency,
improved sleep initiation and sleep
Benzodiazepines: GABAGABA-A agonists
•
•
•
Copyright (c) 2012 Boston Children's Hospital
improved sleep initiation and sleep
maintenance, & suppression of SWS
They are also anxiolytics, muscle
relaxants, and have antianti-seizure
properties, useful in nonnon-REM
parasomnias
Tolerance, withdrawal, dependence,
respiratory compromise, and lingering
early morning sedation may develop
Paradoxical agitation, worsening of OSA
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Sleep Pharmacology
Sanjeev V. Kothare, MD, FAASM
NonNon-Benzodiazepine GABAGABA-A-α1 Agonists
NonNon-Benzodiazepine GABAGABA-A-α1 Agonists
• Zaleplon (Sonata), Zolpidem (Ambien), Eszopiclone
(Lunesta)
• Have been used in adults (Eszopiclone
(Eszopiclone)) for up to
one year without tolerance or dependence
• Little pediatric data is available, and they are not
FDA approved for use below age 16 yrs
• Case reports with use in teenagers have shown
•
parasomnias like sleep walking, drowsiness,
confusion, ataxia, dizziness
Can cause bizarre sleep parasomnias in adults like
sleepsleep-related eating and driving disorders
Walsh JK, et al. Sleep 2007
Kurta DL et al. J Toxicol Clin Toxicol 1997
Zolpidem Trial
• N=201, children with ADHD and
insomnia, ages 12-17 y
• Dosage 0.25 mg/kg, maximum 10 mg
• Minimum change in SOL, improved CGI
• No residual sedation or rebound
• SE: headaches, dizziness, hallucinations
• PK/PD: may need more dose than in
adults
Blumer 2009
Owens JA et al. Child Adolesc Psychiatr Clin N Am 2009
Benzodiazepines
SSRIs & TCIs
Copyright (c) 2012 Boston Children's Hospital
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Sleep Pharmacology
Sanjeev V. Kothare, MD, FAASM
Anti-Depressants: SSRI & TCIs
• Have been useful to treat insomnia associated
with anxiety and/or depression, suppressing
with anxiety and/or depression, suppressing
REM sleep
They are known to worsen PLMS, RLS, & RBD
•
Kothare et al Pediatr Neurol 2011
• Trazadone is a 5HT2 antagonist widely used in
doses of 25--100 mg for its sedating properties,
•
•
doses of 25 100 mg for its sedating properties,
with priapism as a rare side effect
Fluoxetin causes “Prozac eyes in nonnon-REM
sleep
Mirtazepine is a H1 receptor antagonist with
sedating properties
Owens JA et al.
Child Adolesc
Psychiatr Clin N
Am 2009
SSRIs
Owens JA et al.
Child Adolesc
Psychiatr Clin N
Am 2009
SSRIs
Half-Life
Mechanism of Effect on
Action
sleep
architecture
Fluoxetine
(Prozac)
5 days
5HT1
↓TST
↓SE
↑SOL
↑WASO
↓REM
↑REM Lat
Paroxetine
(Paxil)
21 hours
5HT1
anticholinergic
↓TST
↓SE
↑SOL
↑WASO
↓REM
↑REM Lat
Sertraline
(Zoloft)
26 hours
5HT1
↓TST
↑SOL
↓REM
↑ REM Lat
Citalopram/
Escitalopram
(Celexa)
(Lexapro)
24-48 hours
5HT1 (Most specific)
↓TST
↓REM
↑REM Lat
SNRIs
T 1/2
Mechanism
of Action
Sleep
Architecture
Venlafaxine
(Effexor)
+/- 5 hours
5HT>NE>DA
reuptake
↓TST
↓SE
↑SOL
↑ WASO
↓REM
↑ REM Lat
Duloxetine
(Cymbalta)
12 hours
NE and 5HT reuptake
↑SWS
↓REM
↓REM Lat
Mirtazipine
(Remeron)
20 hours
(time to
peak 2
hours)
NE =5HT reuptake
5HT2 and 5HT3
antagonist
H1 blocker
↓SOL
↑TST
↓WASO
Bupropion
(Welbutrin)
21 hours
NE and DA reuptake
inhib
↓ REM lat
↑REM
Copyright (c) 2012 Boston Children's Hospital
Neuroleptics
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Sleep Pharmacology
Sanjeev V. Kothare, MD, FAASM
Neuroleptics
• Olanzepine (Xyprexa)
Xyprexa) and risperidone
•
(Risperdal) increase N2 and SWS and
suppress REM sleep, while quetiapine
(Seroquel) leads to sleep stabilization
Risperidone has been shown to improve
sleep quality in 88% of children with
special needs and disruptive behavior
Keshavan MS et al. J Cli Psychopharmacol 2007
Capone GT et al. J Dev Behavior Pediatr 2008
Owens JA et al. Child Adolesc Psychiatr Clin N Am 2009
AntiAnti-Epileptic Medications
Anti-Epileptic Medications
• Gabapentin, pregabalin & tiagabine are
known to increase SWS
• Felbamate causes insomnia in 9% of the
epileptic population
• Lamotrigine can increase REM sleep, but
can also cause insomnia
• Ethosuximide can cause insomnia
• Valproic acid, phenobarbital cause
sedation and drowsiness
Kothare et al. Sleep Med 2010
Herbal Medicines
Herbal Medications
• Valerian
• Chamomile
• Lemon balm
• Passion flower
• KavaKava-kava (necrotizing hepatitis)
• Tryptophan (eosinophilic myalgia)
• Lavender
Gardiner P et al. Contemp Pediatr 2002
Copyright (c) 2012 Boston Children's Hospital
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Sleep Pharmacology
Sanjeev V. Kothare, MD, FAASM
Pharmacology of OSA
Owens JA et al. Child Adolesc Psychiatr Clin N Am 2009
Pharmacology of OSA
• Nasal Steroids (budesonide, fluticasone)
Gozal D et al. Pediatrics 2008
Brouillette RT et al. J Pediatr 2001
• Montelukast (Singulair) leukotriene
modifier
Treatment of Hypersomnia
Including Narcolepsy
Gozal D et al. Pediatrics 2006
• Antibiotics
• REM suppressing agents
Hudgel DW et al. AM J Resp Crit Care Med 1998
Thornton WK et al. J Oral Maxillofac Surg 1996
Treatment of Hypersomnia Including Narcolepsy
• Treatment of Hypersomnia
– Stimulants
– Modafinil & Armodafinil
• Treatment of REM intrusion in sleep &
wakefulness
(Cataplexy, Sleep Paralysis & HH Hallucinations)
Treatment of RLS & PLMS
– TCIs
– SSRIs
• Sodium Oxybate
Kothare SV et al. Minerva Pneumologica 2009
Copyright (c) 2012 Boston Children's Hospital
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Sleep Pharmacology
Sanjeev V. Kothare, MD, FAASM
Treatment of RLS & PLMS
• Oral Iron
• Pramipexole (Mirapex)
Mirapex)
• Rotigotine patch (Nupro
(Nupro))
• Ropinirole (Requip)
Requip)
• Pergolide (Permax)
Permax)
• L-Dopa (Sinemet)
Sinemet)
• Clonazepam
• Gabapentin/gabapentin
enacarbil (Horizant
TM)
• Opioids
Walters AS et al. Pediatr Neurol 2000
Cortese S et al. Sleep Medicine 2009
Caffeine Content in Various Drinks
Product
Serving size
Caffeine content (mg)
Coca-cola
Diet coke
Diet Pepsi
8 oz
8 oz
8 oz
23
31
24
Dr. Pepper/ Diet Dr. Pepper
8 oz
25
Mountain Dew / Diet Mountain Dew
Sunkist Orange Soda
Tab
8 oz
8 oz
8 oz
37
28
47
Red Bull
Cappucino
Coffee, decaf
Starbucks coffee, grande
330 ml
6 oz
8 oz
16 oz
80
35
5
550
Starbucks coffee, short
Starbucks coffee, tall
8 oz
12 oz
250
375
Iced tea
Chocolate milk
Anacin
Dexatrim
Excedrin, max strength
Midol
No Doz, max strength, Vivarin
Mystic teas
Dark chocolate, semi sweet
8 oz
8 oz
2 tabs
1 tab
2 tabs
1 tab
1 tab
8 oz
1 oz
25
5
65
200
130
32
200
17
20
Source: A Clinical Guide to Pediatric Sleep. Mindell JA and Owens JA (eds), Lippincott
Williams & Wilkins, Philadelphia, 2003; pp 181.
“To sleep: perchance to dream”
dream”
Shakespeare
Copyright (c) 2012 Boston Children's Hospital
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