Treatment Considerations in Pharmacologic Therapy of Insomnia

33rd 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

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.

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.

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.

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.

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

Ideal Hypnotic

Pharmacokinetic Properties

Pharmacokinetic Effect

Side Effect

Rapid absorption No active metabolites Optimal half-life

Rapid sleep induction Physiological sleep pattern Mechanism other than general CNS depression Sleep maintenance Improved Daytime Function

Adapted from Bartholini G. In: Sauvanet JP, Langer SZ, Morselli PL, eds. Imidazopyridines in Sleep Disorders. 1988:1-9.

No residual sedation No respiratory depression No ethanol interaction No tolerance No physical dependence No rebound insomnia No effect on memory

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

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.

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.

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.

Tolerance

*Significantly different from placebo (p<0.05). Scharf MB, Roth T, Vogel GW, Walsh JK. J Clin Psychiatry. 1994;55(5):192-199.

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.

Long-term Efficacy of Eszopiclone 3 mg in Chronic Insomnia (contd)

Median Sleep Maintenance (WASO)

*P<0.05 *^P=0.07 Krystal AD, Walsh JK, Laska E, et al. Sleep. 2003;26:793-799.

Long-term Efficacy of Eszopiclone 3 mg in Chronic Insomnia (contd)

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 (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.

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

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.

Benzodiazepine Receptor Agonist Controversy (contd)

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?

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.

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.

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.

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

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.

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

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.

Antihistamines
Typically long half-life Residual sedation common Minimal efficacy data

Murray L, Kelly G, eds. Physicians Desk Reference. Montvale, NJ: Thomson PDR; 2005.

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.

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

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.

Ramelteon-transient Insomnia

Roth T, Stubbs C, Walsh JK. Sleep. 2005;28:303-307.

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
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.

My Insomnia Treatment Paradigm

Transient Recurring
Anticipatory hypnotic Anticipatory CBT

Chronic
CBT May consider hypnotic

Good Sleeper

Hypnotic therapy

Poor Sleeper

CBT Consider hypnotic

CBT especially anticipatory Consider anticipatory hypnotic

CBT May consider hypnotic

CBT, cognitive behavioral therapy

Benzodiazepine Receptor Agonists1,2

Dose
Flurazepam Quazepam Estazolam Temazepam 15-30 mg 7.5-15.0 mg 0.1-2.0 mg 7.5-20.0 mg

T1/2
47-100 h 39-73 h 10-24 h 3.5-18.4 h

Residual Sedation
High High Medium/High Medium/High

Eszopiclone Triazolam
Zolpidem

1-3 mg 0.125-0.25 mg
5-10 mg

6h 1.5-5.5 h
1.4-4.4 h

Low/Medium Low/Medium
Low

Zaleplon

5-10 mg

1h

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 Dont 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.

Insomnia Treatment Algorithm

Insomnia Complaint Chronicity Acute Short-acting Benzodiazepine Receptor Agonist Review Sleep Hygiene Chronic Intermittent Insomnia Associated Medical/Psychological Sleep Disorder Treat Medical/ Psychological Sleep Disorder Insomnia Chronic

Chronic/Persistent

Sleep Hygiene Anticipatory Behavioral Rx Anticipatory Short-acting Benzodiazepine Receptor Agonist

No Associated Medical/Psychological Conditions

Need to Provide Prompt Relief

No

Yes No

Yes

Adapted from Simon RD. Postgraduate Medicine. 2003

Sleep Hygiene Behavioral Sleep restriction Stimulus control Relaxation Cognitive Consider benzodiazepine receptor agonist or SSRI or other antidepressant

Short-acting Benzodiazepine Agonist Sleep Hygiene Behavioral Sleep restriction Stimulus control Relaxation Cognitive Taper benzodiazepines after several weeks of good sleep

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