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Hypnotics
OPAMarch 3, 2007
Jonathan Emens, M.D.Sleep Medicine Clinic
Sleep and Mood Disorders LaboratoryOregon 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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?
From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
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 (1, 2, 2), 40%
- Type II (3, 2,2), 20%
•Newer non-benzo. hypnotics preferentially bind to Type I receptors
Hypnotic Drugs*Half-life (hr) Onset of Action (min)† Pharmacologically Active Metabolites Dose (mg)
Benzodiazepine hypnotics
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 - None 1-2
Flunitrazepam 10.7-20.3 Short N-desmethyl (flunitrazepam) 0.5-1
Lormetazepam 7.9-11.4 - None 1-2
Nitrazepam 25-35 Intermediate None 5-10
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 - 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: Pharmacokinetics
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
Walsh JK et al., Sleep. 2000;23:1087-1096.
• Zolpidem, 10mg vs. Placebo
• 3-5x/week for 8 weeks
BzRAs: Effects
Krystal AD et al., Sleep. 2003;26:793-799.
• Eszopiclone, 3mg vs. Placebo
• Nightly for 6 months
• Sleep Latency
BzRAs: Effects
Krystal AD et al., Sleep. 2003;26:793-799.
• Eszopiclone, 3mg vs. Placebo
• Nightly for 6 months
• Time awake after sleep onset
BzRAs: Side effects & Safety
• Anterograde amnesia• Residual sedation – longer acting BzRAs • Rebound Insomnia? • Abuse and Dependence?
– 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
Smith MT et al., Am J Psych. 2002;159:5-11.
Treatment: Comparisons
Smith MT et al., Am J Psych. 2002;159:5-11.
Treatment: Comparisons
The End