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