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					           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 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?
            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
Hypnotic Drugs*            (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: 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
•   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
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

				
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