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
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Considerazioni sulla terapia farmacologica per l'insonnia
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Treatment Considerations in Pharmacologic Therapy of
Insomnia33rd Annual Pacific NW Regional
RCSW 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
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.
Control Animals: Temperature and Sleep Stages
Edgar DM, Dement WC, Fuller CA. J Neurosci. 1993;13(3):1065-1079.
Experimental Animals: Temperature and Sleep Stages
Edgar DM, Dement WC, Fuller CA. J Neurosci. 1993;13(3):1065-1079.
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.
• 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.
Nonpharmacologic Treatment of Insomnia• Sleep Hygiene1
• Sleep Restriction1
• Stimulus Control1
• Cognitive Behavioral Therapy2
• Relaxation2
• Paradoxical Intention2
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.
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.
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
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.
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.
Roth T, Roehrs T, Vogel G. Sleep. 1995;18(4):246-251.
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
Rebound Insomnia: Time to Sleep Onset
*Recommended dose for most nonelderly patients. Data on file, Wyeth-Ayerst Laboratories.
Rebound Insomnia
NS=No significant difference from placebo (p>0.05).Data on file, Searle.
• CBT especially anticipatory• Consider anticipatory
hypnotic
• CBT• May consider
hypnotic
CBT, cognitive behavioral therapy
Benzodiazepine Receptor Agonists1,2
Dose T1/2 Residual SedationFlurazepam 15-30 mg 47-100 h HighQuazepam 7.5-15.0 mg 39-73 h High
Estazolam 0.1-2.0 mg 10-24 h Medium/HighTemazepam 7.5-20.0 mg 3.5-18.4 h Medium/High
Eszopiclone1-3 mg 6 h Low/MediumTriazolam 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: www.uptodate.com. Accessed March 29, 2006.
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: www.uptodate.com. Accessed March 29, 2006.
benzodiazepine receptor agonist orSSRI 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
Insomnia Treatment Algorithm
Adapted from Simon RD. Postgraduate Medicine. 2003
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