Treatment Considerations in Pharmacologic Therapy of Insomnia 33rd Annual Pacific NW Regional RCSW Conference Spokane, W

1. Treatment Considerations in Pharmacologic Therapy ofInsomnia33rd Annual Pacific NW RegionalRCSW ConferenceSpokane, WA 4/24/2006 Richard D. Simon, Jr., MD Kathryn Severyns Dement Sleep Disorders Center Walla Walla, WA Clinical Assistant Professor of Medicine University of Washington

3. Control Animals: Temperature and Sleep Stages

4. Experimental Animals: Temperature and Sleep Stages

5. Biological Clock Increasing alerting influence throughout day Diminishing alerting influence throughout night Zeitgebers Light After temperature minimum: causes phase advance Before temperature minimum: causes phase delay Melatonin Evening dose: phase advance Morning dose: phase delay

6. Determinants of Sleep Biological Clock Homeostatic Sleep Drive Social/External Factors Intrinsic Illness

7. The ascending arousal system largely originates has two major branches. 1) An ascending pathway to the thalamus that activates the thalamic relay neurons that are crucial for transmission of information to the cerebral cortex. The major source of upper brainstem input to the thalamic-relay nuclei, as well as to the reticular nucleus of the thalamus, is a pair of acetylcholine-producing cell groups: the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT). The neurons of the PPT/LDT fire most rapidly during wakefulness and REM and are much less active in NREM. Their input to the reticular nucleus of the thalamus is crucial because it sits between the thalamic-relay nuclei and cerebral cortex, acting as a gating mechanism that can block transmission between the thalamus and cerebral cortex. 2) The second system bypasses the thalamus and instead activates neurons in the lateral hypothalamic area and basal forebrain, and throughout the cerebral cortex. This pathway originates from monoaminergic neurons in the upper brainstem and caudal hypothalamus, including the noradrenergic locus coeruleus, serotoninergic dorsal and median raphe nuclei, dopaminergic ventral periaqueductal grey matter and histaminergic tuberomammillary neurons. The input to the cerebral cortex is augmented by lateral hypothalamic peptidergic neurons (MCH or orexin/hypocretin) and BF neurons (Ach, GABA). Lesions here produce profound and long-lasting sleepiness, even coma. These neurons fire during wakefulness, slow down during NREM sleep, and stop during REM sleep. Orexin/hypocretin neurons in the LHA are most active during wakefulness whereas MCH neurons are active during REM sleep. The ascending arousal system largely originates has two major branches. 1) An ascending pathway to the thalamus that activates the thalamic relay neurons that are crucial for transmission of information to the cerebral cortex. The major source of upper brainstem input to the thalamic-relay nuclei, as well as to the reticular nucleus of the thalamus, is a pair of acetylcholine-producing cell groups: the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT). The neurons of the PPT/LDT fire most rapidly during wakefulness and REM and are much less active in NREM. Their input to the reticular nucleus of the thalamus is crucial because it sits between the thalamic-relay nuclei and cerebral cortex, acting as a gating mechanism that can block transmission between the thalamus and cerebral cortex. 2) The second system bypasses the thalamus and instead activates neurons in the lateral hypothalamic area and basal forebrain, and throughout the cerebral cortex. This pathway originates from monoaminergic neurons in the upper brainstem and caudal hypothalamus, including the noradrenergic locus coeruleus, serotoninergic dorsal and median raphe nuclei, dopaminergic ventral periaqueductal grey matter and histaminergic tuberomammillary neurons. The input to the cerebral cortex is augmented by lateral hypothalamic peptidergic neurons (MCH or orexin/hypocretin) and BF neurons (Ach, GABA). Lesions here produce profound and long-lasting sleepiness, even coma. These neurons fire during wakefulness, slow down during NREM sleep, and stop during REM sleep. Orexin/hypocretin neurons in the LHA are most active during wakefulness whereas MCH neurons are active during REM sleep.

8. VLPO promotes sleep. VLPO lesions produce insomnia. VLPO active primarily during sleep – GABA and galanin: these neurons form a dense cluster as well as a more diffuse extended area. Lesions of the VLPO cluster reduces NREM sleep, whereas lesions of the extended VLPO disrupts REM sleep. Extended VLPO projects primarily to LC and DR. VLPO cluster projects more heavily to histaminergic neurons which are closely linked to transitions between arousal and NREM sleep. The VLPO also receives afferents from each of the major monoaminergic systems – noradrenaline and serotonin inhibit VLPO neurons. GABA from tuberomammillary neurons inhibit VLPO. Therefore the VLPO is inhibited by the very systems that it inhibits.VLPO promotes sleep. VLPO lesions produce insomnia. VLPO active primarily during sleep – GABA and galanin: these neurons form a dense cluster as well as a more diffuse extended area. Lesions of the VLPO cluster reduces NREM sleep, whereas lesions of the extended VLPO disrupts REM sleep. Extended VLPO projects primarily to LC and DR. VLPO cluster projects more heavily to histaminergic neurons which are closely linked to transitions between arousal and NREM sleep. The VLPO also receives afferents from each of the major monoaminergic systems – noradrenaline and serotonin inhibit VLPO neurons. GABA from tuberomammillary neurons inhibit VLPO. Therefore the VLPO is inhibited by the very systems that it inhibits.

9. A circuit containing mutually inhibitory elements sets up a self-reinforcing loop, where activity in one of the competeing sides shuts down inhibitory inputs from the other side, and therefore disinhibits its own action. Mathematical models show that when either side of a flip-flop circuit is weakened, homeostatic forces cause the switch to ride closer to its transition point during both states. As a result, there is an increase in transitions, both during the wake and the sleep periods, regardless of which side is weakened. This is seen in animals with VLPO lesions which fall asleep about twice as often as normal animals, wake up much more often during their sleep cycle and, on the whole, only sleep for about ¼ as long per bout. Similar to elderly patients who experience age related loss of VLPO neurons. Orexin/hypocretin produced in the posterior half of the LHA. These neurons are active during wake especially during motor activity when animals actively explore their environment. These neurons reinforce the arousal system but don’t inhibit the VLPO. This may stabilize the “flip-flop” switch (like a finger). Homeostatic sleep drive may be related to accumulation of adenosine which may activate VLPO.A circuit containing mutually inhibitory elements sets up a self-reinforcing loop, where activity in one of the competeing sides shuts down inhibitory inputs from the other side, and therefore disinhibits its own action. Mathematical models show that when either side of a flip-flop circuit is weakened, homeostatic forces cause the switch to ride closer to its transition point during both states. As a result, there is an increase in transitions, both during the wake and the sleep periods, regardless of which side is weakened. This is seen in animals with VLPO lesions which fall asleep about twice as often as normal animals, wake up much more often during their sleep cycle and, on the whole, only sleep for about ¼ as long per bout. Similar to elderly patients who experience age related loss of VLPO neurons. Orexin/hypocretin produced in the posterior half of the LHA. These neurons are active during wake especially during motor activity when animals actively explore their environment. These neurons reinforce the arousal system but don’t inhibit the VLPO. This may stabilize the “flip-flop” switch (like a finger). Homeostatic sleep drive may be related to accumulation of adenosine which may activate VLPO.

10. SCN’s major projections are to adjacent subparaventricular zone (SPZ) and the dorsomedial nucleus of the mypothalamus (DMH). This has a SPZ ventral part (lesions of ventral SPZ disrupt the circadian rhythms of sleep and wakefulness as well as locomotor activity, but have minimal effects on body-temperature) and SPZ dorsal (lesions of dorsal SPZ severly impair circadian rhythms of body temperature but not wake-sleep or locomotor activity). Major target of SPZ isnthe DMH. The DMH receives many more input from SPZ than SCN thus the SPZ can amplify the output of the SCN. DMH lesions profoundly diminish circadian rhythms of sleep and wakefulness, as well as locomotor activity, corticosteroid secretion, and feeding. The DMH is one of the largest sources of input to the VLPO and orexin neruons and is crucial for conveying SCNH influences to the wake-sleep-regulatory system. DMH to VLPO comes largely from GABA (promotes wake by inhibiting sleep). DMH projects to LHA (glutamate and TRH). DMH more active during wake than sleep. Why so complicated? SCN is always active during light and the VLPO is always active during sleep. Nocturnal/dirunal animals must have circuitry allowing for circadian cycles to be set in opposite phases, despite an identical clock input and sleep-control system. Finland bats. SCN’s major projections are to adjacent subparaventricular zone (SPZ) and the dorsomedial nucleus of the mypothalamus (DMH). This has a SPZ ventral part (lesions of ventral SPZ disrupt the circadian rhythms of sleep and wakefulness as well as locomotor activity, but have minimal effects on body-temperature) and SPZ dorsal (lesions of dorsal SPZ severly impair circadian rhythms of body temperature but not wake-sleep or locomotor activity). Major target of SPZ isnthe DMH. The DMH receives many more input from SPZ than SCN thus the SPZ can amplify the output of the SCN. DMH lesions profoundly diminish circadian rhythms of sleep and wakefulness, as well as locomotor activity, corticosteroid secretion, and feeding. The DMH is one of the largest sources of input to the VLPO and orexin neruons and is crucial for conveying SCNH influences to the wake-sleep-regulatory system. DMH to VLPO comes largely from GABA (promotes wake by inhibiting sleep). DMH projects to LHA (glutamate and TRH). DMH more active during wake than sleep. Why so complicated? SCN is always active during light and the VLPO is always active during sleep. Nocturnal/dirunal animals must have circuitry allowing for circadian cycles to be set in opposite phases, despite an identical clock input and sleep-control system. Finland bats.

11. Diagnosis of Insomnia Primarily clinical – history Look for psychiatric illnesses and intrinsic sleep disorders Depression, anxiety Circadian rhythm, obstructive sleep apnea, restless legs syndrome Sleep Diary Co-investigator Actigraphy May be helpful Polysomnography Usually not needed

12. Principles of Improving Sleep Maximize homeostatic sleep drive Limit daytime napping Maximize synchrony between biological clock activity and desired sleep/wake schedule Regular sleep/wake schedule, daytime light and physical activity, nighttime dark and inactivity Maximize treatment of medical/psychiatric illnesses Minimize external sleep-disruptive factors and maximize external sleep-inducing factors

13. Nonpharmacologic Treatment of Insomnia Sleep Hygiene1 Sleep Restriction1 Stimulus Control1 Cognitive Behavioral Therapy2 Relaxation2 Paradoxical Intention2

14. Principles of Sleep Hygiene Awaken at approximately the same time each day (biological clock) Exposure to bright light during desired daytime hours (biological clock) Limit napping if insomnia is present (maximize homeostatic sleep drive) Limit or eliminate caffeine, nicotine, ethanol (external factors) Go to bed only when sleepy (maximize homeostatic sleep drive) Exercise daily Shut down your day at least 1 hour before bedtime (minimize cognitive arousals) Worry time (minimize cognitive arousals) Comfortable bedroom used only for sleeping (minimize cognitive arousals, stimulus control) There are many variations of this. Sleep hygiene refers to basic principles attempting to promote homeostatic sleep drive in synchrony with biologic clock alerting influences while minimizing sleep external factors and maximizing sleep promoting external factors. Occasionally this is all that is needed for mild insomnia. Emphasize caffeine – remember caffeine is a model for insomnia in humans.There are many variations of this. Sleep hygiene refers to basic principles attempting to promote homeostatic sleep drive in synchrony with biologic clock alerting influences while minimizing sleep external factors and maximizing sleep promoting external factors. Occasionally this is all that is needed for mild insomnia. Emphasize caffeine – remember caffeine is a model for insomnia in humans.

15. Characteristics of an “Ideal” Hypnotic Rapid absorption No active metabolites Optimal half-life

16. Pharmacologic Therapy Benzodiazepine receptor agonists Antidepressants Antihistamines Melatonin Melatonin agonist (ramelteon)

17. Benzodiazepine Receptor Agonists: General Statements Efficacious in insomnia Side effects are usually an extension of desired effects Sedation Amnesia Duration of action about 2 to 3 times T1/2 Rebound Addiction Newer “designer” drugs Efficacy: TST, Sleep efficiency, SOL, subjective too. Rebound: insomnia worse than before starting meds. Addiction: withdrawal of BZA is mild and last 2 weeks (NEJM article). Not a problem is one doesn’t exceed max dose recommendations. Designer drugs: quick onset action, BZA1 receptor activity, low receptor affinity, short T1/2.Efficacy: TST, Sleep efficiency, SOL, subjective too. Rebound: insomnia worse than before starting meds. Addiction: withdrawal of BZA is mild and last 2 weeks (NEJM article). Not a problem is one doesn’t exceed max dose recommendations. Designer drugs: quick onset action, BZA1 receptor activity, low receptor affinity, short T1/2.

18. Zolpidem: Effect on Sleep Latency in People With Chronic Insomnia

19. Hypnotic Efficacy: Dose Effects A placebo-controlled, double-blind, parallel-group study evaluated the efficacy and safety of various doses of zolpidem Recommended doses of zolpidem (up to 10 mg) decreased sleep latency and increased sleep duration and maintenance while showing no significant effect on next day psychomotor performance Doses at higher than recommended levels did not improve sleep efficiency May result in increased incidence of side effects

20. Rebound Insomnia: Time to Sleep Onset

21. Rebound Insomnia

22. Tolerance

23. Long-term Efficacy of Eszopiclone 3 mg in Chronic Insomnia

24. Long-term Efficacy of Eszopiclone 3 mg in Chronic Insomnia (cont’d)

25. Long-term Efficacy of Eszopiclone 3 mg in Chronic Insomnia (cont’d) Throughout the 6 months, eszopiclone improved all of the symptoms of insomnia as defined by DSM-IV Significant and sustained improvements in sleep latency, wake time after sleep onset, number of awakenings, number of nights awakened per week, total sleep time and quality of sleep (P=0.003) Including patient ratings of daytime function (P=0.002) No evidence of tolerance Most common adverse events were unpleasant taste and headache

26. Benzodiazepine Receptor Agonist Controversy Tolerance infrequent1 Rebound insomnia may occur with any but appears less likely with zolpidem and zaleplon1,2 Addiction unlikely when recommended doses are used3 Dysfunction present for duration of drug activity3 Long term open label studies support little tolerance.Long term open label studies support little tolerance.

27. Benzodiazepine Receptor Agonist Controversy (cont’d) Dose escalation: Do not do it. Higher dose not likely to be helpful Dose schedule: Daily vs intermittent Duration of therapy: Very little data Zolpidem: 35 days,1 3 months,2 6 months3 Eszopiclone: 6 months4,5 Indiplon: 12 months6 Discontinuation: Sudden or taper? Studies support both daily and intermittent dosing. I taper, although this is probably not necessary.Studies support both daily and intermittent dosing. I taper, although this is probably not necessary.

28. Benzodiazepine (BZD) Receptor Agonists Withdrawal 40 patients long-term BZD Switched to diazepam (15 mg/day) or placebo Tapered over 8 weeks Clinically important, mild, but distinct withdrawal syndrome occurred Tinnitus, involuntary movement, and perceptual changes, confusion, paresthesia Resolved over 4 weeks

29. Contraindications to Benzodiazepine Receptor Agonists Sensitivity to drug On call or other responsibilities during the duration of action of the hypnotic This is an absolute contraindication Drug/ETOH abuse (relative) Sleep-related breathing disorders (relative) The only absolute contraindication is, in my opinion, on call responsibilities. Zolpidem and Zaleplon have minimal effects on SBD.The only absolute contraindication is, in my opinion, on call responsibilities. Zolpidem and Zaleplon have minimal effects on SBD.

30. Risk of Falls in the Elderly GABA receptors in cerebellum1 Benzodiazepine receptor agonists: Some studies suggest increased sway = increased risk of falls1-3 Insomnia = associated with increased risk of falls1-3 Treated insomnia = data on falls not conclusive

31. Antidepressants Paroxetine efficacious in insomnia1 Trazadone possibly efficacious in insomnia2 Doxepin possibly efficacious in insomnia3 In depression, choice of antidepressant may not be important – treating depression is what is important4 Side effects may be significant

32. Antihistamines Typically long half-life Residual sedation common Minimal efficacy data A few studies suggest benefit.A few studies suggest benefit.

33. Melatonin Probably not a good hypnotic when used at night Some elderly may benefit Although PM melatonin may worsen advanced sleep phase syndrome Blind people May be useful when trying to sleep during periods of high biological clock activity (shift work, jet lag, etc) Some side effects (vasoconstriction) Most likely to be helpful in circadian abnormalities and blind people. May actually worsen ASPS if taken at night.Most likely to be helpful in circadian abnormalities and blind people. May actually worsen ASPS if taken at night.

34. Ramelteon Reduces latency to persistent sleep in transient insomnia model1 First night effect among normal sleepers May have promise in circadian re-entrainment (at least in rats)2

35. Ramelteon-transient Insomnia

36. Treatment Generalizations Hypnotics generally helpful as long as use is continued1 Act quickly to improve insomnia Dose escalation adds little Effects do not appear to be durable after discontinuation Cognitive-behavioral therapy (CBT)2 Takes longer for effect Effect is durable after CBT has been discontinued

37. My Insomnia Treatment Paradigm

38. Benzodiazepine Receptor Agonists1,2 Dose T1/2 Residual Sedation Flurazepam 15-30 mg 47-100 h High Quazepam 7.5-15.0 mg 39-73 h High Estazolam 0.1-2.0 mg 10-24 h Medium/High Temazepam 7.5-20.0 mg 3.5-18.4 h Medium/High Eszopiclone 1-3 mg 6 h Low/Medium Triazolam 0.125-0.25 mg 1.5-5.5 h Low/Medium Zolpidem 5-10 mg 1.4-4.4 h Low Zaleplon 5-10 mg 1 h Low/None I don’t use any with long to intermediate T1/2 for insomnia. Maybe if anxiety disorder, etc.I don’t use any with long to intermediate T1/2 for insomnia. Maybe if anxiety disorder, etc.

39. Principles of Benzodiazepine Receptor Agonist (BZA) Hypnotic Therapy Use lowest dose of shortest acting BZA that is effective (lower doses in the elderly) Document efficacy – discontinue if not efficacious Don’t escalate beyond recommended highest hypnotic dose Start on weekend to assess effect Warn about effects (drowsiness, amnesia) Mention possibility of rebound insomnia upon sudden discontinuation (usually lasts only 1 or 2 nights) When stopping, it is important to stop for at least 1 – 2 weeks. Patient may experience poor sleep. Co-investigator sleep diary at D/C of meds.When stopping, it is important to stop for at least 1 – 2 weeks. Patient may experience poor sleep. Co-investigator sleep diary at D/C of meds.

40. Insomnia Treatment Algorithm

41. Conclusions Cognitive behavioral therapy (CBT) and benzodiazepine receptor agonists are effective in the acute management of chronic insomnia There is little evidence to support other therapies CBT takes longer for effect and the effect is durable after therapy has been discontinued Hypnotics generally helpful although effects do not appear to be durable after discontinuation Act quickly to improve insomnia Dose escalation adds little