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Treatment Considerations in
Pharmacologic Therapy ofInsomnia
33rd Annual Pacific NW RegionalRCSW 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
Universit of Washin ton
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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 acutemanagement 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.
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Control Animals: Temperatureand Sleep Stages
Edgar DM, Dement WC, Fuller CA. J Neurosci. 1993;13(3):1065-1079.
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Experimental Animals:Temperature and Sleep Stages
Edgar DM, Dement WC, Fuller CA. J Neurosci. 1993;13(3):1065-1079.
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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.
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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.
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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.
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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 andphysical activity, nighttime dark and inactivity
Maximize treatment of medical/psychiatric
illnesses Minimize external sleep-disruptive factors andmaximize external sleep-inducing factors
Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia,
Pa: Elsevier Saunders; 2005.
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Nonpharmacologic Treatmentof 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.
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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.
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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 sleeppattern
Mechanism other than
general CNS depression Sleep maintenance
Improved DaytimeFunction
No residual sedation
No respiratorydepression
No ethanol interaction
No tolerance No physical
dependence
No rebound insomnia
No effect on memory
Ideal Hypnotic
Pharmacokinetic
Properties
Pharmacokinetic
Effect
Side
Effect
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Pharmacologic Therapy
Benzodiazepine receptor agonists
Antidepressants
Antihistamines
Melatonin
Melatonin agonist (ramelteon)
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Benzodiazepine ReceptorAgonists: General Statements
Efficacious in insomnia
Side effects are usually an extensionof 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.
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Zolpidem: Effect on Sleep Latencyin People With Chronic Insomnia
*Significantly different from placebo (p
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Roth T, Roehrs T, Vogel G. Sleep. 1995;18(4):246-251.
Hypnotic Efficacy: Dose Effects
A placebo-controlled, double-blind, parallel-groupstudy evaluated the efficacy and safety of variousdoses of zolpidem
Recommended doses of zolpidem (up to 10 mg)decreased sleep latency and increased sleep durationand maintenance while showing no significant effect onnext day psychomotor performance
Doses at higher than recommended levels did not
improve sleep efficiency
May result in increased incidence of side effects
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Rebound Insomnia:Time to Sleep Onset
*Recommended dose for most nonelderly patients.
Data on file, Wyeth-Ayerst Laboratories.
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Rebound Insomnia
NS=No significant difference from placebo (p>0.05).
Data on file, Searle.
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*Significantly different from placebo (p
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Long-term Efficacy of Eszopiclone3 mg in Chronic Insomnia
Median Sleep Latency
*P
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Long-term Efficacy of Eszopiclone3 mg in Chronic Insomnia (contd)
Median Sleep Maintenance (WASO)
*P
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Long-term Efficacy of Eszopiclone3 mg in Chronic Insomnia (contd) Throughout the 6 months, eszopiclone improved
all of the symptoms of insomnia as definedby DSM-IV Significant and sustained improvements in sleep
latency, wake time after sleep onset, number ofawakenings, number of nights awakened per week,total sleep time and quality of sleep (P0.003)
Including patient ratings of daytime function (P0.002)
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.
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Benzodiazepine ReceptorAgonist Controversy
Tolerance infrequent1
Rebound insomnia may occur with any butappears less likely with zolpidem and zaleplon1,2
Addiction unlikely when recommended dosesare used3
Dysfunction present for duration of drug activity3
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.
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Benzodiazepine ReceptorAgonist Controversy (contd)
Dose escalation: Do not do it. Higher dose notlikely to be helpful
Dose schedule: Daily vs intermittent
Duration of therapy: Very little data Zolpidem: 35 days,1 3months,2 6 months3
Eszopiclone: 6 months4,5
Indiplon: 12 months6
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: http://abstractsonline.com/viewer/SearchResults.asp. Accessed on March 29, 2006.
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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 withdrawalsyndrome occurred
Tinnitus, involuntary movement, and perceptualchanges, confusion, paresthesia
Resolved over 4 weeks
Busto U, Sellers EM, Naranjo CA, Cappell H, Sanchez-Craig M, Sykora K. NEJM. 1986;315:854-859.
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Contraindications toBenzodiazepine Receptor Agonists
Sensitivity to drug
On call or other responsibilities during theduration 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.
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Risk of Falls in the Elderly
GABA receptors in cerebellum1
Benzodiazepine receptor agonists: Somestudies suggest increased sway increased risk
of falls1-3 Insomnia associated with increased risk
of falls1-3
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.
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Antidepressants
Paroxetine efficacious in insomnia1
Trazadone possibly efficacious in insomnia2
Doxepin possibly efficacious in insomnia3
In depression, choice of antidepressant maynot be important treating depression is whatis important4
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.
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Antihistamines
Typically long half-life
Residual sedation common
Minimal efficacy data
Murray L, Kelly G, eds. Physicians Desk Reference. Montvale, NJ: Thomson PDR; 2005.
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Melatonin
Probably not a good hypnotic when usedat night
Some elderly may benefit
Although PM melatonin may worsen advanced sleepphase syndrome
Blind people
May be useful when trying to sleep duringperiods of high biological clock activity(shift work, jet lag, etc)
Some side effects (vasoconstriction)
Brzezinsk A. NEJM1997;336(3):186-195.
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Ramelteon
Reduces latency to persistent sleep in transientinsomnia model1
First night effect among normal sleepers
May have promise in circadianre-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.
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Ramelteon-transient Insomnia
Roth T, Stubbs C, Walsh JK. Sleep. 2005;28:303-307.
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Treatment Generalizations
Hypnotics generally helpful as long as useis 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
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.
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My Insomnia Treatment Paradigm
Transient Recurring Chronic
Good
Sleeper
Hypnotic therapy Anticipatory hypnotic
Anticipatory
CBT
CBT
May consider
hypnotic
Poor
Sleeper
CBT
Considerhypnotic
CBT especially anticipatory
Consider anticipatoryhypnotic
CBT
May considerhypnotic
CBT, cognitive behavioral therapy
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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
Eszopiclone 1-3 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.
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Principles of Benzodiazepine ReceptorAgonist (BZA) Hypnotic Therapy
Use lowest dose of shortest acting BZA that is effective(lower doses in the elderly)
Document efficacy discontinue if not efficacious
Dont escalate beyond recommended highest
hypnotic dose
Start on weekend to assess effect
Warn about effects (drowsiness, amnesia)
Mention possibility of rebound insomnia upon suddendiscontinuation (usually lasts only 1 or 2 nights)
Benzodiazepine receptor agonists. Up-to-date Web site available at: www.uptodate.com. Accessed March 29, 2006.
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InsomniaComplaint
Acute
Short-acting
Benzodiazepine Receptor AgonistReview Sleep Hygiene
Chronicity
Chronic
Chronic
Intermittent
Insomnia
Sleep Hygiene
Anticipatory Behavioral Rx
Anticipatory Short-acting
BenzodiazepineReceptor Agonist
Chronic/Persistent
AssociatedMedical/PsychologicalSleep Disorder
Treat Medical/PsychologicalSleep Disorder
Insomnia
No Yes
No AssociatedMedical/Psychological
Conditions
Need to Provide
Prompt Relief
No
Sleep Hygiene Behavioral
Sleep restriction Stimulus control
Relaxation Cognitive
Considerbenzodiazepinereceptor agonistorSSRI or otherantidepressant
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
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Conclusions
Cognitive behavioral therapy (CBT) andbenzodiazepine receptor agonists are effectivein 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 donot appear to be durable after discontinuation
Act quickly to improve insomnia
Dose escalation adds little