presentation 2006 rcsw insomnia

8/2/2019 Presentation 2006 RCSW Insomnia

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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




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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




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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




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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

presentation 2006 rcsw insomnia

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