Hypnotics OPA March 3, 2007

922 views
795 views

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
922
On SlideShare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
17
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Hypnotics OPA March 3, 2007

  1. 1. Hypnotics OPA March 3, 2007 <ul><li>Jonathan Emens, M.D. </li></ul><ul><li>Sleep Medicine Clinic </li></ul><ul><li>Sleep and Mood Disorders Laboratory </li></ul><ul><li>Oregon Health & Science University Portland, OR </li></ul>
  2. 2. Disclosure <ul><li>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. </li></ul>
  3. 3. Outline <ul><li>Review of Sleep Physiology </li></ul><ul><li>Epidemiology of Insomnia </li></ul><ul><li>Morbidity in Insomnia </li></ul><ul><li>Diagnoses in Insomnia </li></ul><ul><li>Hypnotics </li></ul>
  4. 4. Brief review of Sleep <ul><li>Reversible, unresponsive state </li></ul>
  5. 5. Brief review of Sleep <ul><li>Reversible, unresponsive state </li></ul><ul><li>Divided into two states: NREM and REM </li></ul>
  6. 6. Brief review of Sleep <ul><li>Reversible, unresponsive state </li></ul><ul><li>Divided into two states: NREM and REM </li></ul><ul><li>NREM: Divided into 4 stages based on EEG patterns </li></ul>
  7. 7. EEG in NREM Sleep From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
  8. 8. EEG in NREM Sleep From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
  9. 9. EEG in NREM Sleep From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
  10. 10. EEG in NREM Sleep From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
  11. 11. Brief review of Sleep <ul><li>Reversible, unresponsive state </li></ul><ul><li>Divided into two states: NREM and REM </li></ul><ul><li>NREM: Divided into 4 stages based on EEG patterns </li></ul><ul><li>REM: distinct EEG, muscle atonia, rapid eye movements, dreams, PGO waves (measured in animals) </li></ul>
  12. 12. EEG, EOG, and EMG in REM Sleep
  13. 13. Sleep Staging <ul><li>Stage 1: 2-5% </li></ul>From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
  14. 14. Sleep Staging <ul><li>Stage 1: 2-5% </li></ul><ul><li>Stage 2: 45-55% </li></ul>From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
  15. 15. Sleep Staging <ul><li>Stage 1: 2-5% </li></ul><ul><li>Stage 2: 45-55% </li></ul><ul><li>Stage 3: 3-8% </li></ul>From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
  16. 16. Sleep Staging <ul><li>Stage 1: 2-5% </li></ul><ul><li>Stage 2: 45-55% </li></ul><ul><li>Stage 3: 3-8% </li></ul><ul><li>Stage 4: 10-15% </li></ul>From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
  17. 17. Sleep Staging <ul><li>Stage 1: 2-5% </li></ul><ul><li>Stage 2: 45-55% </li></ul><ul><li>Stage 3: 3-8% </li></ul><ul><li>Stage 4: 10-15% </li></ul><ul><li>REM: 20-25% </li></ul>From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
  18. 18. REM and NREM patterns <ul><li>First third of the night mostly NREM, especially stage 3 and 4 (slow wave) sleep </li></ul>
  19. 19. REM and NREM patterns <ul><li>First third of the night mostly NREM, especially stage 3 and 4 (slow wave sleep) </li></ul><ul><li>Last third of the night mostly REM sleep </li></ul>
  20. 20. REM and NREM patterns <ul><li>First third of the night mostly NREM, especially stage 3 and 4 (slow wave sleep </li></ul><ul><li>Last third of the night mostly REM sleep </li></ul><ul><li>Cycles of NREM and REM sleep occur every 90-110 minutes </li></ul>
  21. 21. REM and NREM patterns <ul><li>First third of the night mostly NREM, especially stage 3 and 4 (slow wave sleep) </li></ul><ul><li>Last third of the night mostly REM sleep </li></ul><ul><li>Cycles of NREM and REM sleep occur every 90-110 minutes </li></ul><ul><li>Amount of slow wave sleep (SWS) decreases with age (greater decreases in men) </li></ul>
  22. 22. Changes in Sleep with Age Ohayon M, et al. Sleep. 2004;27:1255-1273.
  23. 23. Memory impairment surrounding sleep onset From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
  24. 24. Insomnia Definitions <ul><li>“ difficulty in initiating and/or maintaining sleep.” – International Classification of Sleep Disorders (ICSD) </li></ul><ul><li>Difficulty Falling Asleep </li></ul><ul><li>Difficulty maintaining sleep </li></ul><ul><li>Early morning awakening </li></ul><ul><li>Daytime fatigue, poor concentration, and irritability </li></ul>
  25. 25. Epidemiology of Insomnia <ul><li>Depends on Definition: 4.4-48% prevalence in general population </li></ul>Ohayon M, Sleep Med Rev. 2002;6: 97-111.
  26. 26. Epidemiology of Insomnia <ul><li>Depends on Definition: 4.4-48% prevalence in general population </li></ul><ul><li>Insomnia Symptoms: 30-48% </li></ul>Ohayon M, Sleep Med Rev. 2002;6: 97-111.
  27. 27. Epidemiology of Insomnia <ul><li>Depends on Definition: 4.4-48% prevalence in general population </li></ul><ul><li>Insomnia Symptoms: 30-48% </li></ul><ul><li>Insomnia Symptoms > 3 times/week or “often” or “always”: 16-21% </li></ul>Ohayon M, Sleep Med Rev. 2002;6: 97-111.
  28. 28. Epidemiology of Insomnia <ul><li>Depends on Definition: 4.4-48% prevalence in general population </li></ul><ul><li>Insomnia Symptoms: 30-48% </li></ul><ul><li>Insomnia Symptoms > 3 times/week or “often” or “always”: 16-21% </li></ul><ul><li>Insomnia Symptoms that are “moderate” or “severe”: 10-28% </li></ul>Ohayon M, Sleep Med Rev. 2002;6: 97-111.
  29. 29. Epidemiology of Insomnia <ul><li>Depends on Definition: 4.4-48% prevalence in general population </li></ul><ul><li>Insomnia Symptoms: 30-48% </li></ul><ul><li>Insomnia Symptoms > 3 times/week or “often” or “always”: 16-21% </li></ul><ul><li>Insomnia Symptoms that are “moderate” or “severe”: 10-28% </li></ul><ul><li>Insomnia Symptoms with Daytime sequelae: 9-15% </li></ul>Ohayon M, Sleep Med Rev. 2002;6: 97-111.
  30. 30. Epidemiology of Insomnia <ul><li>Depends on Definition: 4.4-48% prevalence in general population </li></ul><ul><li>Insomnia Symptoms: 30-48% </li></ul><ul><li>Insomnia Symptoms > 3 times/week or “often” or “always”: 16-21% </li></ul><ul><li>Insomnia Symptoms that are “moderate” or “severe”: 10-28% </li></ul><ul><li>Insomnia Symptoms with Daytime sequelae: 9-15% </li></ul><ul><li>Dissatisfaction with amount or quality of sleep: 8-18% </li></ul>Ohayon M, Sleep Med Rev. 2002;6: 97-111.
  31. 31. Epidemiology of Insomnia <ul><li>Depends on Definition: 4.4- 48% prevalence in general population </li></ul><ul><li>Insomnia Symptoms: 30-48% </li></ul><ul><li>Insomnia Symptoms > 3 times/week or “often” or “always”: 16-21% </li></ul><ul><li>Insomnia Symptoms that are “moderate” or “severe”: 10-28% </li></ul><ul><li>Insomnia Symptoms with Daytime sequelae: 9-15% </li></ul><ul><li>Dissatisfaction with amount or quality of sleep: 8-18% </li></ul><ul><li>Insomnia Diagnosis (DSM-IV): 4.4-11.7% (many with symptoms don’t meet DSM criteria) </li></ul>Ohayon M, Sleep Med Rev. 2002;6: 97-111.
  32. 32. Epidemiology of Insomnia <ul><li>5,622 subjects </li></ul>Ohayon M, J Psychiatr Res. 1997;31:333-346.
  33. 33. Epidemiology of Insomnia <ul><li>5,622 subjects </li></ul><ul><li>18.7% had complaints of difficulty initiating or maintaining sleep or of non-restorative sleep </li></ul>Ohayon M, J Psychiatr Res. 1997;31:333-346.
  34. 34. Epidemiology of Insomnia <ul><li>5,622 subjects </li></ul><ul><li>18.7% had complaints of difficulty initiating or maintaining sleep or of non-restorative sleep </li></ul><ul><li>12.7% had sleep complaints for > 1 month that caused “clinically significant distress or impairment” </li></ul>Ohayon M, J Psychiatr Res. 1997;31:333-346.
  35. 35. Epidemiology of Insomnia <ul><li>5,622 subjects </li></ul><ul><li>18.7% had complaints of difficulty initiating or maintaining sleep or of non-restorative sleep </li></ul><ul><li>12.7% had sleep complaints for > 1 month that caused “clinically significant distress or impairment” </li></ul><ul><li>10.3% with Axis I or II disorder </li></ul>Ohayon M, J Psychiatr Res. 1997;31:333-346.
  36. 36. Epidemiology of Insomnia <ul><li>5,622 subjects </li></ul><ul><li>18.7% had complaints of difficulty initiating or maintaining sleep or of non-restorative sleep </li></ul><ul><li>12.7% had sleep complaints for > 1 month that caused “clinically significant distress or impairment” </li></ul><ul><li>10.3% with Axis I or II disorder </li></ul><ul><li>1.3% primary insomnia </li></ul>Ohayon M, J Psychiatr Res. 1997;31:333-346.
  37. 37. Epidemiology of Insomnia <ul><li>5,622 subjects </li></ul><ul><li>18.7% had complaints of difficulty initiating or maintaining sleep or of non-restorative sleep </li></ul><ul><li>12.7% had sleep complaints for > 1 month that caused “clinically significant distress or impairment” </li></ul><ul><li>10.3% with Axis I or II disorder </li></ul><ul><li>1.3% primary insomnia </li></ul><ul><li>0.5% general medical condition </li></ul>Ohayon M, J Psychiatr Res. 1997;31:333-346.
  38. 38. Epidemiology of Insomnia <ul><li>5,622 subjects </li></ul><ul><li>18.7% had complaints of difficulty initiating or maintaining sleep or of non-restorative sleep </li></ul><ul><li>12.7% had sleep complaints for > 1 month that caused “clinically significant distress or impairment” </li></ul><ul><li>10.3% with Axis I or II disorder </li></ul><ul><li>1.3% primary insomnia </li></ul><ul><li>0.5% general medical condition </li></ul><ul><li>0.3% circadian disorder </li></ul>Ohayon M, J Psychiatr Res. 1997;31:333-346.
  39. 39. Morbidity/Co-Morbidity <ul><li>Objective cognitive/performance deficits? </li></ul>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. 40. Morbidity/Co-Morbidity <ul><li>Objective cognitive/performance deficits? </li></ul><ul><li>Quality of life: subjective deficits in memory, concentration, & work performance </li></ul>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. 41. Morbidity/Co-Morbidity <ul><li>Objective cognitive/performance deficits? </li></ul><ul><li>Quality of life: subjective deficits in memory, concentration, & work performance </li></ul><ul><li>Psychiatric: prevalence of any psychiatric disorder is 2-3x greater in insomniacs, depression prevalence is 4x greater </li></ul>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. 42. Morbidity/Co-Morbidity <ul><li>Objective cognitive/performance deficits? </li></ul><ul><li>Quality of life: subjective deficits in memory, concentration, & work performance </li></ul><ul><li>Psychiatric: prevalence of any psychiatric disorder is 2-3x greater in insomniacs, depression prevalence is 4x greater </li></ul><ul><li>Medical: insomnia associated with multiple medical conditions; increased HD risk & impaired immune function? Increased mortality rates? –confounding factors. </li></ul>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. 43. Morbidity/Co-Morbidity Chang PP, Am J Epidemiol. 1997;146:105-114.
  44. 44. Morbidity/Co-Morbidity Weissman MM, Gen Hosp Psych. 1997;19:245-250.
  45. 45. Differential Diagnosis <ul><li>Psychiatric </li></ul><ul><li>Medical </li></ul><ul><li>Neurological </li></ul><ul><li>Environmental </li></ul><ul><li>Circadian Rhythm Disorder </li></ul><ul><li>Primary Sleep Disorder: sleep apnea, PLMs & restless legs syndrome, & parasomnias </li></ul><ul><li>“ Behavioral”: inadequate sleep hygiene </li></ul><ul><li>Stress related transient Insomnia </li></ul><ul><li>“ Primary Insomnias”: psychophysiological insomnia, sleep state misperception, & idiopathic insomnia (no primary insomnia in ICSD vs. DSM) </li></ul>From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2000
  46. 46. Treatment <ul><li>Treat underlying Medical Condition </li></ul><ul><li>Treat underlying Psychiatric Condition </li></ul><ul><li>Improve sleep Hygiene </li></ul><ul><li>Change environment </li></ul><ul><li>CBT: “primary insomnias”, transient insomnia </li></ul><ul><li>Pharmacological </li></ul><ul><li>Light, melatonin, or “chronotherapy” for Circadian disorders </li></ul>
  47. 47. Treatment <ul><li>Treat underlying Medical Condition </li></ul><ul><li>Treat underlying Psychiatric Condition </li></ul><ul><li>Improve sleep Hygiene </li></ul><ul><li>Change environment </li></ul><ul><li>CBT: “primary insomnias”, transient insomnia </li></ul><ul><li>Pharmacological </li></ul><ul><li>Light, melatonin, or “chronotherapy” for Circadian disorders </li></ul>
  48. 48. “ Hypnotics” <ul><li>Benzodiazepine Receptor Agonists (BzRAs) </li></ul><ul><ul><li>Benzodiazepines </li></ul></ul><ul><ul><li>Non-Benzodiazepines GABA A agonists </li></ul></ul><ul><li>Sedating Antidepressants </li></ul><ul><li>Sedating Antipsychotics </li></ul><ul><li>Antihistamines </li></ul><ul><li>Gamma-Hydroxybutyrate (GHB) </li></ul><ul><li>Melatonin and Melatonin agonists, Gabapentin, Valerian </li></ul>
  49. 49. BzRAs <ul><li>Benzodiazepines, zaleplon, zolpidem, zopiclone, & eszopiclone </li></ul><ul><li>All act on gamma-aminobutyric acid A (GABA A ) benzodiazepine receptor complex </li></ul><ul><li>Preoptic area of anterior hypothalamus? </li></ul>
  50. 50. From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005 GABA A benzodiazepine receptor complex <ul><li>5 glycoprotein subunits </li></ul><ul><li>Each subunit may have multiple forms </li></ul><ul><li>Benzodiazepine binding is inhibitory by increasing frequency of Cl - channel opening </li></ul>
  51. 51. From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005 GABA A benzodiazepine receptor complex <ul><li>Two common types of GABA A receptors: </li></ul><ul><li>- Type I (  1 ,  2 ,  2 ), 40% </li></ul><ul><li>- Type II (  3 ,  2 ,  2 ), 20% </li></ul><ul><li>Newer non-benzo. hypnotics preferentially bind to Type I receptors </li></ul>
  52. 52. 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*
  53. 53. BzRAs: Effects <ul><li>Anterograde amnesia. </li></ul>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. 54. BzRAs: Effects <ul><li>Anterograde amnesia. </li></ul><ul><li>PSG studies show decreased sleep latency and wake after sleep onset (WASO) and increased total sleep time (not zaleplon) </li></ul>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. 55. BzRAs: Effects <ul><li>Anterograde amnesia. </li></ul><ul><li>PSG studies show decreased sleep latency and wake after sleep onset (WASO) and increased total sleep time (not zaleplon) </li></ul><ul><li>Slight decrease in REM sleep </li></ul>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. 56. BzRAs: Effects <ul><li>Anterograde amnesia. </li></ul><ul><li>PSG studies show decreased sleep latency and wake after sleep onset (WASO) and increased total sleep time (not zaleplon) </li></ul><ul><li>Slight decrease in REM sleep </li></ul><ul><li>Suppress slow wave sleep (not zolpidem) </li></ul>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. 57. BzRAs: Effects <ul><li>Anterograde amnesia. </li></ul><ul><li>PSG studies show decreased sleep latency and wake after sleep onset (WASO) and increased total sleep time (not zaleplon) </li></ul><ul><li>Slight decrease in REM sleep </li></ul><ul><li>Suppress slow wave sleep (not zolpidem) </li></ul><ul><li>Tolerance? Studies: </li></ul><ul><ul><li>zolpidem and zaleplon nightly for 5 weeks </li></ul></ul><ul><ul><li>eszopiclone nightly for 6 months </li></ul></ul><ul><ul><li>Zolpidem (3-5x/week) for 12 weeks </li></ul></ul>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. 58. BzRAs: Effects <ul><li>Zolpidem, 10mg vs. Placebo </li></ul><ul><li>3-5x/week for 8 weeks </li></ul>Walsh JK et al., Sleep. 2000;23:1087-1096.
  59. 59. BzRAs: Effects Krystal AD et al., Sleep. 2003;26:793-799. <ul><li>Eszopiclone, 3mg vs. Placebo </li></ul><ul><li>Nightly for 6 months </li></ul><ul><li>Sleep Latency </li></ul>
  60. 60. BzRAs: Effects Krystal AD et al., Sleep. 2003;26:793-799. <ul><li>Eszopiclone, 3mg vs. Placebo </li></ul><ul><li>Nightly for 6 months </li></ul><ul><li>Time awake after sleep onset </li></ul>
  61. 61. BzRAs: Side effects & Safety <ul><li>Anterograde amnesia </li></ul><ul><li>Residual sedation – longer acting BzRAs </li></ul><ul><li>Rebound Insomnia? </li></ul><ul><li>Abuse and Dependence? </li></ul><ul><ul><li>Mostly used short term (2 weeks) </li></ul></ul><ul><ul><li>When used as a sleeping aid dose escalation rare </li></ul></ul><ul><ul><li>No studies of physical dependence with nighttime use </li></ul></ul><ul><ul><li>Low psychological dependence with nighttime use </li></ul></ul><ul><li>Increased fall risk in the elderly </li></ul><ul><li>Cognitive effects in the elderly </li></ul><ul><li>Increased mortality with sleep aids? </li></ul>From: Kryger, Roth, Dement, eds., Principles and Practice of Sleep Medicine, 2005
  62. 62. Smith MT et al., Am J Psych. 2002;159:5-11. Treatment: Comparisons
  63. 63. Smith MT et al., Am J Psych. 2002;159:5-11. Treatment: Comparisons
  64. 64. The End

×