Transcript Document

Hypnotics
OPA
March 3, 2007
Jonathan Emens, M.D.
Sleep Medicine Clinic
Sleep and Mood Disorders Laboratory
Oregon Health & Science University Portland, OR
Disclosure
None of my slides, abstracts and/or
handouts contain any advertising, trade
names or product–group messages.
Any treatment recommendations I make
will be based on best clinical evidence
or guidelines.
Outline
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Review of Sleep Physiology
Epidemiology of Insomnia
Morbidity in Insomnia
Diagnoses in Insomnia
Hypnotics
Brief review of Sleep
• Reversible, unresponsive state
Brief review of Sleep
• Reversible, unresponsive state
• Divided into two states: NREM and REM
Brief review of Sleep
• Reversible, unresponsive state
• Divided into two states: NREM and REM
• NREM: Divided into 4 stages based on
EEG patterns
EEG in NREM Sleep
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
EEG in NREM Sleep
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
EEG in NREM Sleep
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
EEG in NREM Sleep
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
Brief review of Sleep
• Reversible, unresponsive state
• Divided into two states: NREM and REM
• NREM: Divided into 4 stages based on EEG
patterns
• REM: distinct EEG, muscle atonia, rapid
eye movements, dreams, PGO waves
(measured in animals)
EEG, EOG, and EMG in REM
Sleep
Sleep Staging
• Stage 1: 2-5%
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
Sleep Staging
• Stage 1: 2-5%
• Stage 2: 45-55%
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
Sleep Staging
• Stage 1: 2-5%
• Stage 2: 45-55%
• Stage 3: 3-8%
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
Sleep Staging
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Stage 1: 2-5%
Stage 2: 45-55%
Stage 3: 3-8%
Stage 4: 10-15%
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
Sleep Staging
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Stage 1: 2-5%
Stage 2: 45-55%
Stage 3: 3-8%
Stage 4: 10-15%
REM: 20-25%
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
REM and NREM patterns
• First third of the night mostly NREM,
especially stage 3 and 4 (slow wave)
sleep
REM and NREM patterns
• First third of the night mostly NREM,
especially stage 3 and 4 (slow wave
sleep)
• Last third of the night mostly REM sleep
REM and NREM patterns
• First third of the night mostly NREM,
especially stage 3 and 4 (slow wave
sleep
• Last third of the night mostly REM sleep
• Cycles of NREM and REM sleep occur
every 90-110 minutes
REM and NREM patterns
• First third of the night mostly NREM,
especially stage 3 and 4 (slow wave
sleep)
• Last third of the night mostly REM sleep
• Cycles of NREM and REM sleep occur
every 90-110 minutes
• Amount of slow wave sleep (SWS)
decreases with age (greater decreases
in men)
Changes in Sleep with Age
Ohayon M, et al. Sleep. 2004;27:1255-1273.
Memory impairment
surrounding sleep onset
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
Insomnia Definitions
• “difficulty in initiating and/or maintaining
sleep.” – International Classification of Sleep
Disorders (ICSD)
• Difficulty Falling Asleep
• Difficulty maintaining sleep
• Early morning awakening
• Daytime fatigue, poor concentration, and
irritability
Epidemiology of Insomnia
• Depends on Definition: 4.4-48% prevalence in
general population
Ohayon M, Sleep Med Rev. 2002;6: 97-111.
Epidemiology of Insomnia
• Depends on Definition: 4.4-48% prevalence in
general population
• Insomnia Symptoms: 30-48%
Ohayon M, Sleep Med Rev. 2002;6: 97-111.
Epidemiology of Insomnia
• Depends on Definition: 4.4-48% prevalence in
general population
• Insomnia Symptoms: 30-48%
• Insomnia Symptoms > 3 times/week or “often” or
“always”: 16-21%
Ohayon M, Sleep Med Rev. 2002;6: 97-111.
Epidemiology of Insomnia
• Depends on Definition: 4.4-48% prevalence in
general population
• Insomnia Symptoms: 30-48%
• Insomnia Symptoms > 3 times/week or “often” or
“always”: 16-21%
• Insomnia Symptoms that are “moderate” or “severe”:
10-28%
Ohayon M, Sleep Med Rev. 2002;6: 97-111.
Epidemiology of Insomnia
• Depends on Definition: 4.4-48% prevalence in
general population
• Insomnia Symptoms: 30-48%
• Insomnia Symptoms > 3 times/week or “often” or
“always”: 16-21%
• Insomnia Symptoms that are “moderate” or “severe”:
10-28%
• Insomnia Symptoms with Daytime sequelae: 9-15%
Ohayon M, Sleep Med Rev. 2002;6: 97-111.
Epidemiology of Insomnia
• Depends on Definition: 4.4-48% prevalence in
general population
• Insomnia Symptoms: 30-48%
• Insomnia Symptoms > 3 times/week or “often” or
“always”: 16-21%
• Insomnia Symptoms that are “moderate” or “severe”:
10-28%
• Insomnia Symptoms with Daytime sequelae: 9-15%
• Dissatisfaction with amount or quality of sleep: 8-18%
Ohayon M, Sleep Med Rev. 2002;6: 97-111.
Epidemiology of Insomnia
• Depends on Definition: 4.4- 48% prevalence in
general population
• Insomnia Symptoms: 30-48%
• Insomnia Symptoms > 3 times/week or “often” or
“always”: 16-21%
• Insomnia Symptoms that are “moderate” or “severe”:
10-28%
• Insomnia Symptoms with Daytime sequelae: 9-15%
• Dissatisfaction with amount or quality of sleep: 8-18%
• Insomnia Diagnosis (DSM-IV): 4.4-11.7% (many with
symptoms don’t meet DSM criteria)
Ohayon M, Sleep Med Rev. 2002;6: 97-111.
Epidemiology of Insomnia
• 5,622 subjects
Ohayon M, J Psychiatr Res. 1997;31:333-346.
Epidemiology of Insomnia
• 5,622 subjects
• 18.7% had complaints of difficulty initiating or
maintaining sleep or of non-restorative sleep
Ohayon M, J Psychiatr Res. 1997;31:333-346.
Epidemiology of Insomnia
• 5,622 subjects
• 18.7% had complaints of difficulty initiating or
maintaining sleep or of non-restorative sleep
• 12.7% had sleep complaints for > 1 month that
caused “clinically significant distress or impairment”
Ohayon M, J Psychiatr Res. 1997;31:333-346.
Epidemiology of Insomnia
• 5,622 subjects
• 18.7% had complaints of difficulty initiating or
maintaining sleep or of non-restorative sleep
• 12.7% had sleep complaints for > 1 month that
caused “clinically significant distress or impairment”
• 10.3% with Axis I or II disorder
Ohayon M, J Psychiatr Res. 1997;31:333-346.
Epidemiology of Insomnia
• 5,622 subjects
• 18.7% had complaints of difficulty initiating or
maintaining sleep or of non-restorative sleep
• 12.7% had sleep complaints for > 1 month that
caused “clinically significant distress or impairment”
• 10.3% with Axis I or II disorder
• 1.3% primary insomnia
Ohayon M, J Psychiatr Res. 1997;31:333-346.
Epidemiology of Insomnia
• 5,622 subjects
• 18.7% had complaints of difficulty initiating or
maintaining sleep or of non-restorative sleep
• 12.7% had sleep complaints for > 1 month that
caused “clinically significant distress or impairment”
• 10.3% with Axis I or II disorder
• 1.3% primary insomnia
• 0.5% general medical condition
Ohayon M, J Psychiatr Res. 1997;31:333-346.
Epidemiology of Insomnia
• 5,622 subjects
• 18.7% had complaints of difficulty initiating or
maintaining sleep or of non-restorative sleep
• 12.7% had sleep complaints for > 1 month that
caused “clinically significant distress or impairment”
• 10.3% with Axis I or II disorder
• 1.3% primary insomnia
• 0.5% general medical condition
• 0.3% circadian disorder
Ohayon M, J Psychiatr Res. 1997;31:333-346.
Morbidity/Co-Morbidity
• Objective cognitive/performance deficits?
Ford DE and Kamerow DB, JAMA. 1989;262:1479-1484.
Mellinger GD et al., Arch Gen Psych. 1985;42:225-232.
Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
Morbidity/Co-Morbidity
• Objective cognitive/performance deficits?
• Quality of life: subjective deficits in memory,
concentration, & work performance
Ford DE and Kamerow DB, JAMA. 1989;262:1479-1484.
Mellinger GD et al., Arch Gen Psych. 1985;42:225-232.
Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
Morbidity/Co-Morbidity
• Objective cognitive/performance deficits?
• Quality of life: subjective deficits in memory,
concentration, & work performance
• Psychiatric: prevalence of any psychiatric
disorder is 2-3x greater in insomniacs,
depression prevalence is 4x greater
Ford DE and Kamerow DB, JAMA. 1989;262:1479-1484.
Mellinger GD et al., Arch Gen Psych. 1985;42:225-232.
Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
Morbidity/Co-Morbidity
• Objective cognitive/performance deficits?
• Quality of life: subjective deficits in memory,
concentration, & work performance
• Psychiatric: prevalence of any psychiatric
disorder is 2-3x greater in insomniacs,
depression prevalence is 4x greater
• Medical: insomnia associated with multiple
medical conditions; increased HD risk &
impaired immune function? Increased
mortality rates? –confounding factors.
Ford DE and Kamerow DB, JAMA. 1989;262:1479-1484.
Mellinger GD et al., Arch Gen Psych. 1985;42:225-232.
Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
Morbidity/Co-Morbidity
Chang PP, Am J Epidemiol. 1997;146:105-114.
Morbidity/Co-Morbidity
Weissman MM, Gen Hosp Psych. 1997;19:245-250.
Differential Diagnosis
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Psychiatric
Medical
Neurological
Environmental
Circadian Rhythm Disorder
Primary Sleep Disorder: sleep apnea, PLMs & restless legs
syndrome, & parasomnias
• “Behavioral”: inadequate sleep hygiene
• Stress related transient Insomnia
• “Primary Insomnias”: psychophysiological insomnia, sleep state
misperception, & idiopathic insomnia (no primary insomnia in
ICSD vs. DSM)
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
Treatment
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Treat underlying Medical Condition
Treat underlying Psychiatric Condition
Improve sleep Hygiene
Change environment
CBT: “primary insomnias”, transient insomnia
Pharmacological
Light, melatonin, or “chronotherapy” for
Circadian disorders
Treatment
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Treat underlying Medical Condition
Treat underlying Psychiatric Condition
Improve sleep Hygiene
Change environment
CBT: “primary insomnias”, transient insomnia
Pharmacological
Light, melatonin, or “chronotherapy” for
Circadian disorders
“Hypnotics”
• Benzodiazepine Receptor Agonists (BzRAs)
– Benzodiazepines
– Non-Benzodiazepines GABAA agonists
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Sedating Antidepressants
Sedating Antipsychotics
Antihistamines
Gamma-Hydroxybutyrate (GHB)
Melatonin and Melatonin agonists,
Gabapentin, Valerian
BzRAs
• Benzodiazepines, zaleplon, zolpidem,
zopiclone, & eszopiclone
• All act on gamma-aminobutyric acidA
(GABAA) benzodiazepine receptor
complex
• Preoptic area of anterior hypothalamus?
GABAA benzodiazepine
receptor complex
•5 glycoprotein
subunits
•Each subunit may have
multiple forms
•Benzodiazepine
binding is inhibitory by
increasing frequency of
Cl- channel opening
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
GABAA benzodiazepine
receptor complex
•Two common types of
GABAA receptors:
- Type I (a1, b2, g2), 40%
- Type II (a3, b2,g2), 20%
•Newer non-benzo.
hypnotics preferentially
bind to Type I receptors
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
BzRAs: Pharmacokinetics
Half-life
(hr)
Onset of Action (min)†
Pharmacologically Active Metabolites
Dose (mg)
Quazepam
48-120
30
N-desalkyl (flurazepam)
7.5-15
Flurazepam
48-120
15-45
N-desalkyl (flurazepam)
15-30
Triazolam
2-6
2-30
None
0.125-0.25
Estazolam
8-24
Intermediate
None
1-2
Temazepam
8-20
45-50
None
15-30
Loprazolam
4.6-11.4
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None
1-2
Flunitrazepam
10.7-20.3
Short
N-desmethyl (flunitrazepam)
0.5-1
Lormetazepam
7.9-11.4
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None
1-2
Nitrazepam
25-35
Intermediate
None
5-10
Hypnotic Drugs*
Benzodiazepine hypnotics
Nonbenzodiazepine hypnotics
Eszopiclone
5-7
Intermediate
None
2-3 adult, 1
elderly
Zolpidem
1.5-2.4
Rapid
None
5-10 (age >65 yr)
10-20 (age <65
yr)
Zopiclone
5-6
Intermediate
None
3.75 (age >65 yr)
7.5 (age <65 yr)
Zaleplon
1
Rapid
None
5-10
Nonhypnotics sometimes used to aid sleep
Clonazepam
30-40
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4-Amino derivative
0.5-3¶
Diazepam
30-100
Rapid
N-desmethyl
2-10¶
Chlordiazepoxide
24-28
Intermediate
N-desmethyl (chlordiazepoxide, demoxepam, oxazepam )
10-25¶
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
BzRAs: Effects
• Anterograde amnesia.
Scharf MB et al., J Clin Psych. 1994;55:182-199.
Walsh JK et al., Sleep Med. 2000;1:41-49.
Krystal AD et al., Sleep. 2003;26:793-799.
Perlis M et al., J Clin Psych. 2004;65:1128-1137.
Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
BzRAs: Effects
• Anterograde amnesia.
• PSG studies show decreased sleep latency and
wake after sleep onset (WASO) and increased total
sleep time (not zaleplon)
Scharf MB et al., J Clin Psych. 1994;55:182-199.
Walsh JK et al., Sleep Med. 2000;1:41-49.
Krystal AD et al., Sleep. 2003;26:793-799.
Perlis M et al., J Clin Psych. 2004;65:1128-1137.
Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
BzRAs: Effects
• Anterograde amnesia.
• PSG studies show decreased sleep latency and
wake after sleep onset (WASO) and increased total
sleep time (not zaleplon)
• Slight decrease in REM sleep
Scharf MB et al., J Clin Psych. 1994;55:182-199.
Walsh JK et al., Sleep Med. 2000;1:41-49.
Krystal AD et al., Sleep. 2003;26:793-799.
Perlis M et al., J Clin Psych. 2004;65:1128-1137.
Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
BzRAs: Effects
• Anterograde amnesia.
• PSG studies show decreased sleep latency and
wake after sleep onset (WASO) and increased total
sleep time (not zaleplon)
• Slight decrease in REM sleep
• Suppress slow wave sleep (not zolpidem)
Scharf MB et al., J Clin Psych. 1994;55:182-199.
Walsh JK et al., Sleep Med. 2000;1:41-49.
Krystal AD et al., Sleep. 2003;26:793-799.
Perlis M et al., J Clin Psych. 2004;65:1128-1137.
Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
BzRAs: Effects
• Anterograde amnesia.
• PSG studies show decreased sleep latency and
wake after sleep onset (WASO) and increased total
sleep time (not zaleplon)
• Slight decrease in REM sleep
• Suppress slow wave sleep (not zolpidem)
• Tolerance? Studies:
– zolpidem and zaleplon nightly for 5 weeks
– eszopiclone nightly for 6 months
– Zolpidem (3-5x/week) for 12 weeks
Scharf MB et al., J Clin Psych. 1994;55:182-199.
Walsh JK et al., Sleep Med. 2000;1:41-49.
Krystal AD et al., Sleep. 2003;26:793-799.
Perlis M et al., J Clin Psych. 2004;65:1128-1137.
Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
BzRAs: Effects
• Zolpidem, 10mg
vs. Placebo
• 3-5x/week for 8
weeks
Walsh JK et al., Sleep. 2000;23:1087-1096.
BzRAs: Effects
• Eszopiclone, 3mg
vs. Placebo
• Nightly for 6
months
• Sleep Latency
Krystal AD et al., Sleep. 2003;26:793-799.
BzRAs: Effects
• Eszopiclone, 3mg
vs. Placebo
• Nightly for 6
months
• Time awake after
sleep onset
Krystal AD et al., Sleep. 2003;26:793-799.
BzRAs: Side effects & Safety
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Anterograde amnesia
Residual sedation – longer acting BzRAs
Rebound Insomnia?
Abuse and Dependence?
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Mostly used short term (2 weeks)
When used as a sleeping aid dose escalation rare
No studies of physical dependence with nighttime use
Low psychological dependence with nighttime use
• Increased fall risk in the elderly
• Cognitive effects in the elderly
• Increased mortality with sleep aids?
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
Treatment: Comparisons
Smith MT et al., Am J Psych. 2002;159:5-11.
Treatment: Comparisons
Smith MT et al., Am J Psych. 2002;159:5-11.
The End