Hypnotics OPA March 3, 2007
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    Hypnotics OPA March 3, 2007 Hypnotics OPA March 3, 2007 Presentation Transcript

    • 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
      • 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 GABA A 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 acid A (GABA A ) benzodiazepine receptor complex
      • Preoptic area of anterior hypothalamus?
    • From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005 GABA A 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 GABA A benzodiazepine receptor complex
      • Two common types of GABA A receptors:
      • - Type I (  1 ,  2 ,  2 ), 40%
      • - Type II (  3 ,  2 ,  2 ), 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 10-25 ¶ N -desmethyl (chlordiazepoxide, demoxepam, oxazepam  ) Intermediate 24-28 Chlordiazepoxide 2-10 ¶ N -desmethyl Rapid 30-100 Diazepam 0.5-3 ¶ 4-Amino derivative - 30-40 Clonazepam   Nonhypnotics sometimes used to aid sleep 5-10 None Rapid 1 Zaleplon   7.5 (age <65 yr)         3.75 (age >65 yr) None Intermediate 5-6 Zopiclone 10-20 (age <65 yr)         5-10 (age >65 yr) None Rapid 1.5-2.4 Zolpidem 2-3 adult, 1 elderly None Intermediate 5-7 Eszopiclone Nonbenzodiazepine hypnotics 5-10 None Intermediate 25-35 Nitrazepam 1-2 None - 7.9-11.4 Lormetazepam 0.5-1 N -desmethyl (flunitrazepam) Short 10.7-20.3 Flunitrazepam 1-2 None - 4.6-11.4 Loprazolam 15-30 None 45-50 8-20 Temazepam   1-2 None Intermediate 8-24 Estazolam   0.125-0.25 None 2-30 2-6 Triazolam   15-30 N -desalkyl (flurazepam) 15-45 48-120 Flurazepam 7.5-15 N -desalkyl (flurazepam) 30 48-120 Quazepam   Benzodiazepine hypnotics Dose (mg) Pharmacologically Active Metabolites Onset of Action (min) † Half-life (hr) Hypnotic Drugs*
    • 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 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