1. Hypnotics OPA March 3, 2007 Jonathan Emens, M.D. Sleep Medicine Clinic Sleep and Mood Disorders Laboratory Oregon Health & Science University Portland, OR

2. 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.

3. Outline Review of Sleep Physiology Epidemiology of Insomnia Morbidity in Insomnia Diagnoses in Insomnia Hypnotics

4. Brief review of Sleep Reversible, unresponsive state

5. Brief review of Sleep Reversible, unresponsive state Divided into two states: NREM and REM

6. Brief review of Sleep Reversible, unresponsive state Divided into two states: NREM and REM NREM: Divided into 4 stages based on EEG patterns

7. EEG in NREM Sleep From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005

8. EEG in NREM Sleep From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000

9. EEG in NREM Sleep From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005

10. EEG in NREM Sleep From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005

11. 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)

12. EEG, EOG, and EMG in REM Sleep

13. Sleep Staging Stage 1: 2-5% From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000

14. Sleep Staging Stage 1: 2-5% Stage 2: 45-55% From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000

15. 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

16. 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

17. 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

18. REM and NREM patterns First third of the night mostly NREM, especially stage 3 and 4 (slow wave) sleep

19. 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

20. 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

21. 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)

22. Changes in Sleep with Age Ohayon M, et al. Sleep. 2004;27:1255-1273.

23. Memory impairment surrounding sleep onset From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000

24. 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

25. Epidemiology of Insomnia Depends on Definition: 4.4-48% prevalence in general population Ohayon M, Sleep Med Rev. 2002;6: 97-111.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. 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.

32. Epidemiology of Insomnia 5,622 subjects Ohayon M, J Psychiatr Res. 1997;31:333-346.

33. 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.

34. 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.

35. 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.

36. 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.

37. 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.

38. 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.

39. 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

40. 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

41. 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

42. 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

43. Morbidity/Co-Morbidity Chang PP, Am J Epidemiol. 1997;146:105-114.

44. Morbidity/Co-Morbidity Weissman MM, Gen Hosp Psych. 1997;19:245-250.

45. 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

46. 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

47. 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

48. “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

49. BzRAs Benzodiazepines, zaleplon, zolpidem, zopiclone, & eszopiclone All act on gamma-aminobutyric acid A (GABA A ) benzodiazepine receptor complex Preoptic area of anterior hypothalamus?

50. 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

51. 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

52. Hypnotic Drugs* Half-life (hr)Onset of Action (min) † Pharmacologically Active MetabolitesDose (mg) Benzodiazepine hypnotics Quazepam 48-12030N-desalkyl (flurazepam)7.5-15 Flurazepam48-12015-45N-desalkyl (flurazepam)15-30 Triazolam 2-62-30None0.125-0.25 Estazolam 8-24IntermediateNone1-2 Temazepam 8-2045-50None15-30 Loprazolam4.6-11.4-None1-2 Flunitrazepam10.7-20.3ShortN-desmethyl (flunitrazepam)0.5-1 Lormetazepam7.9-11.4-None1-2 Nitrazepam25-35IntermediateNone5-10 Nonbenzodiazepine hypnotics Eszopiclone5-7IntermediateNone2-3 adult, 1 elderly Zolpidem1.5-2.4RapidNone5-10 (age >65 yr) 10-20 (age <65 yr) Zopiclone5-6IntermediateNone3.75 (age >65 yr) 7.5 (age <65 yr) Zaleplon 1RapidNone5-10 Nonhypnotics sometimes used to aid sleep Clonazepam 30-40-4-Amino derivative0.5-3 ¶ Diazepam30-100RapidN-desmethyl2-10 ¶ Chlordiazepoxide24-28IntermediateN-desmethyl (chlordiazepoxide, demoxepam, oxazepam )oxazepam 10-25 ¶ From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005 BzRAs: Pharmacokinetics

53. 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

54. 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

55. 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

56. 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

57. 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

58. BzRAs: Effects Walsh JK et al., Sleep. 2000;23:1087-1096. Zolpidem, 10mg vs. Placebo 3-5x/week for 8 weeks

59. BzRAs: Effects Krystal AD et al., Sleep. 2003;26:793-799. Eszopiclone, 3mg vs. Placebo Nightly for 6 months Sleep Latency

60. BzRAs: Effects Krystal AD et al., Sleep. 2003;26:793-799. Eszopiclone, 3mg vs. Placebo Nightly for 6 months Time awake after sleep onset

61. 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

62. Smith MT et al., Am J Psych. 2002;159:5-11. Treatment: Comparisons

63. Smith MT et al., Am J Psych. 2002;159:5-11. Treatment: Comparisons

64. The End