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.

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

• 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

PharmacokineticProperties

PharmacokineticEffect

SideEffect

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.

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.

*Significantly different from placebo (p<0.05).

Scharf MB, Roth T, Vogel GW, Walsh JK. J Clin Psychiatry. 1994;55(5):192-199.

Tolerance

Long-term Efficacy of Eszopiclone 3 mg in Chronic Insomnia

Median Sleep Latency

*P<0.005Krystal AD, Walsh JK, Laska E, et al. Sleep. 2003;26:793-799.

Long-term Efficacy of Eszopiclone 3 mg in Chronic Insomnia (cont’d)

Median Sleep Maintenance (WASO)

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

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.

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 (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 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 Chronic

Good

Sleeper

• Hypnotic therapy• Anticipatory hypnotic• Anticipatory

CBT

• CBT• May consider

hypnotic

Poor

Sleeper

• CBT• Consider

hypnotic

• 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.

Insomnia Complaint

Acute

Short-actingBenzodiazepine Receptor Agonist Review Sleep Hygiene

Chronicity

Chronic

ChronicIntermittentInsomnia

• Sleep Hygiene• Anticipatory Behavioral Rx• Anticipatory Short-acting

Benzodiazepine Receptor Agonist

Chronic/Persistent

AssociatedMedical/PsychologicalSleep Disorder

Treat Medical/PsychologicalSleep Disorder

Insomnia

No Yes

No AssociatedMedical/Psychological

Conditions

Need to ProvidePrompt Relief

No

• Sleep Hygiene• Behavioral – Sleep restriction – Stimulus control – Relaxation – Cognitive• Consider

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