Considerazioni sulla terapia farmacologica per l'insonnia
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Considerazioni sulla terapia farmacologica per l'insonnia






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  • 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.
  • 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.
  • 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.
  • 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.
  • 58 58 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.
  • 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.
  • Long term open label studies support little tolerance.
  • Studies support both daily and intermittent dosing. I taper, although this is probably not necessary.
  • The only absolute contraindication is, in my opinion, on call responsibilities. Zolpidem and Zaleplon have minimal effects on SBD.
  • A few studies suggest benefit.
  • Most likely to be helpful in circadian abnormalities and blind people. May actually worsen ASPS if taken at night.
  • I don’t use any with long to intermediate T1/2 for insomnia. Maybe if anxiety disorder, etc.
  • 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.

Considerazioni sulla terapia farmacologica per l'insonnia Presentation Transcript

  • 1. Treatment Considerations in Pharmacologic Therapy of Insomnia 33 rd Annual Pacific NW Regional RCSW Conference Spokane, 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
  • 2. NIH Conclusions
    • Insomnia is a major public health problem
    • Little is known about chronic insomnia
    • Efficacy of cognitive behavioral therapy and benzodiazepine receptor agonists in the acute management of chronic insomnia
      • Little evidence to support other therapies
    • Mismatch between potential life-long nature of insomnia and the longest clinical trials
    • Substantial private and public research effort is warranted
    • Educational programs are needed
    National Institutes of Health Statement Regarding the Treatment of Insomnia. Sleep . 2005;28:1049-1057.
  • 3. Control Animals: Temperature and Sleep Stages Edgar DM, Dement WC, Fuller CA. J Neurosci. 1993;13(3):1065-1079.
  • 4. Experimental Animals: Temperature and Sleep Stages Edgar DM, Dement WC, Fuller CA. J Neurosci. 1993;13(3):1065-1079.
  • 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
    Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine . Philadelphia, Pa: Elsevier Saunders; 2005.
  • 6. Determinants of Sleep
    • Biological Clock
    • Homeostatic Sleep Drive
    • Social/External Factors
    • Intrinsic Illness
    Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine . Philadelphia, Pa: Elsevier Saunders; 2005.
  • 7.  
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  • 10.  
  • 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
    Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine . Philadelphia, Pa: Elsevier Saunders; 2005.
  • 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
    Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine . Philadelphia, Pa: Elsevier Saunders; 2005.
  • 13. Nonpharmacologic Treatment of Insomnia
    • Sleep Hygiene 1
    • Sleep Restriction 1
    • Stimulus Control 1
    • Cognitive Behavioral Therapy 2
    • Relaxation 2
    • Paradoxical Intention 2
    1. Morin CM, Culbert JP, Schwartz SM . Am J Psychiatry. 1994;151(8):1172-1180. 2. Murtagh DR, Greenwood KM. J Consult Clin Psychol. 1995;63(1):79-89.
  • 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)
    Morin CM. J Clin Psy. 2004;65(suppl 16):33-40.
  • 15. Characteristics of an “Ideal” Hypnotic
    • Rapid absorption
    • No active metabolites
    • Optimal half-life
    Adapted from Bartholini G. In: Sauvanet JP, Langer SZ, Morselli PL, eds. Imidazopyridines in Sleep Disorders . 1988:1-9.
    • Rapid sleep induction
    • Physiological sleep pattern
    • Mechanism other than general CNS depression
    • Sleep maintenance
    • Improved Daytime Function
    • No residual sedation
    • No respiratory depression
    • No ethanol interaction
    • No tolerance
    • No physical dependence
    • No rebound insomnia
    • No effect on memory
    Ideal Hypnotic Pharmacokinetic Properties Pharmacokinetic Effect Side Effect
  • 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
    Nowell PD, Mazumdar S, Buysse DJ, et al. JAMA . 1997;278(24):2170-2177.
  • 18. Zolpidem: Effect on Sleep Latency in People With Chronic Insomnia *Significantly different from placebo ( p <0.05). Vogel G, et al. Sleep Res . 1989;18:30. Abstract.
  • 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
    Roth T, Roehrs T, Vogel G. Sleep. 1995;18(4):246-251.
  • 20. Rebound Insomnia: Time to Sleep Onset *Recommended dose for most nonelderly patients. Data on file, Wyeth-Ayerst Laboratories.
  • 21. Rebound Insomnia NS=No significant difference from placebo ( p >0.05). Data on file, Searle.
  • 22. Tolerance *Significantly different from placebo ( p <0.05). Scharf MB, Roth T, Vogel GW, Walsh JK. J Clin Psychiatry. 1994;55(5):192-199.
  • 23. Long-term Efficacy of Eszopiclone 3 mg in Chronic Insomnia Median Sleep Latency * P <0.005 Krystal AD, Walsh JK, Laska E, et al. Sleep. 2003;26:793-799.
  • 24. Long-term Efficacy of Eszopiclone 3 mg in Chronic Insomnia (cont’d) Median Sleep Maintenance (WASO) * P <0.05 * ^ P =0.07 Krystal AD, Walsh JK, Laska E, et al. Sleep. 2003;26:793-799.
  • 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
    Krystal AD, Walsh JK, Laska E, et al. Sleep. 2003;26:793-799.
  • 26. Benzodiazepine Receptor Agonist Controversy
    • Tolerance infrequent 1
    • Rebound insomnia may occur with any but appears less likely with zolpidem and zaleplon 1,2
    • Addiction unlikely when recommended doses are used 3
    • Dysfunction present for duration of drug activity 3
    1. Roth T, Roehrs TA, Stepanski EJ, Rosenthal LD. Am J Med. 1990;88(3A):43S-46S. Review. 2. Ancoli-Israel S, Walsh JK, Mangano RM, Fujimori M . J Clin Psychiatry . 1999;1(4):114-120. 3. Voderholzer U, Riemann D, Hornyak M, et al. Eur Arch Psychiatry Clin Neurosci. 2001;251(3):117-123.
  • 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 months 3
      • Eszopiclone: 6 months 4,5
      • Indiplon: 12 months 6
    • Discontinuation: Sudden or taper?
    1. Ambien [prescribing information]. New York, NY: Sanofi-Synthelabo Inc;2004. 2. Perlis ML, McCall WV, Krystal AD, Walsh JK. J Clin Psych . 2004;65:128-137. 3. Schenck CH, Mahowald MW, Sack RL. JAMA . 2003;289(19):2475-2479. 4. Krystal AD, Walsh JK, Laska E, et al. Sleep. 2003;26:793-799. 5. Roth T, Walsh J, Krystal A, et al. Sleep Med . 2005;6:487-495. 6. Indiplon APA data at: Accessed on March 29, 2006.
  • 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
    Busto U, Sellers EM, Naranjo CA, Cappell H, Sanchez-Craig M, Sykora K . NEJM . 1986;315:854-859.
  • 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)
    Murray L, Kelly G, eds. Physicians’ Desk Reference . Montvale, NJ: Thomson PDR; 2005.
  • 30. Risk of Falls in the Elderly
    • GABA receptors in cerebellum 1
    • Benzodiazepine receptor agonists: Some studies suggest increased sway ≥ increased risk of falls 1-3
    • Insomnia ≥ associated with increased risk of falls 1-3
    • Treated insomnia ≥ data on falls not conclusive
    1. Allain H, Bentue-Ferrer D, Polard E, Akwa Y, Patat A. Drugs Aging . 2005;22(9):749-765. 2. Avidan AY, Fries BE, James ML, Szafara KL, Wright GT, Chervin RD. JAGS. 2005;53(6):955-962. 3. Allain H, Bentue-Ferrer D, Tarral A, Gandon JM. Eur J Clin Pharmacol. 2004;59(3):170-198.
  • 31. Antidepressants
    • Paroxetine efficacious in insomnia 1
    • Trazadone possibly efficacious in insomnia 2
    • Doxepin possibly efficacious in insomnia 3
    • In depression, choice of antidepressant may not be important – treating depression is what is important 4
    • Side effects may be significant
    1. Nowell PD, Reynolds CF III, Buysse DJ, Dew MA, Kupfer DJ. J Clin Psychiatry . 1999;60(2):89-95. 2. Rosenberg RP. Ann Clin Psy. 2006;18(1):49-56. 3. Hajak G, Rodenbeck A, Voderholzer U, et al. J Clin Psychiatry. 2001;62(6):453-463. 4. Simon GE, Heiligenstein JH, Grothaus L, Katon W, Revicki D. J Clin Psychiatry. 1998;59(2):49-55.
  • 32. Antihistamines
    • Typically long half-life
    • Residual sedation common
    • Minimal efficacy data
    Murray L, Kelly G, eds. Physicians’ Desk Reference . Montvale, NJ: Thomson PDR; 2005.
  • 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)
    Brzezinsk A. NEJM 1997;336(3):186-195.
  • 34. Ramelteon
    • Reduces latency to persistent sleep in transient insomnia model 1
      • First night effect among normal sleepers
    • May have promise in circadian re-entrainment (at least in rats) 2
    1. Roth T, Stubbs C, Walsh JK. Sleep . 2005;28:303-307. 2. Hirai K, Kita M, Ohta H, et al. J Biol Rhythms . 2005;20:27-37.
  • 35. Ramelteon-transient Insomnia Roth T, Stubbs C, Walsh JK. Sleep . 2005;28:303-307.
  • 36. Treatment Generalizations
    • Hypnotics generally helpful as long as use is continued 1
      • 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
    1. Erman MK. J Clin Psy . 2005;66 (Suppl 9):18-23. 2. Edinger JD, Wohlgemuth WK, Radtke RA, Marsh GR, Quillian RE. JAMA. 2001;285:1856-1864.
  • 37. My Insomnia Treatment Paradigm CBT, cognitive behavioral therapy Poor Sleeper Good Sleeper Chronic Recurring Transient
    • CBT
    • May consider hypnotic
    • CBT especially anticipatory
    • Consider anticipatory hypnotic
    • CBT
    • Consider hypnotic
    • CBT
    • May consider hypnotic
    • Anticipatory hypnotic
    • Anticipatory CBT
    • Hypnotic therapy
  • 38. Benzodiazepine Receptor Agonists 1,2
    • 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
    1. Murray L, Kelly G, eds. Physicians’ Desk Reference . Montvale, NJ: Thomson PDR; 2005. 2. Benzodiazepine receptor agonists. Up-to-date Web site available at: Accessed March 29, 2006.
  • 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)
    Benzodiazepine receptor agonists. Up-to-date Web site available at: Accessed March 29, 2006.
  • 40. Insomnia Treatment Algorithm Insomnia Complaint Acute Short-acting Benzodiazepine Receptor Agonist Review Sleep Hygiene Chronicity Chronic Chronic Intermittent Insomnia • Sleep Hygiene • Anticipatory Behavioral Rx • Anticipatory Short-acting Benzodiazepine Receptor Agonist Chronic/Persistent Associated Medical/Psychological Sleep Disorder Treat Medical/ Psychological Sleep Disorder Insomnia No Yes No Associated Medical/Psychological Conditions Need to Provide Prompt Relief No • Sleep Hygiene • Behavioral – Sleep restriction – Stimulus control – Relaxation – Cognitive • Consider benzodiazepine receptor agonist or SSRI or other antidepressant Yes • Short-acting Benzodiazepine Agonist • Sleep Hygiene • Behavioral – Sleep restriction – Stimulus control – Relaxation – Cognitive • Taper benzodiazepines after several weeks of good sleep Adapted from Simon RD. Postgraduate Medicine . 2003
  • 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