1. Modern Management of Sleep Disorders Douglas C. Bauer, MD University of California, San Francisco No Disclosures

2. Introduction 40 million Americans suffer from sleep disorders 95% are undiagnosed and untreated Prevalence of sleep disorders increases with age

3. Percent Reporting Symptoms of Insomnia 2002 Sleep in America poll, National Sleep Foundation

4. Trends in Sleep Duration YearAvg Hours of Sleep 1910 1 9 1975 1 7.5 2000 2 6.9 1 Webb WB et al. Bull Psychom Soc 1975; 6: 47-48 2 National Sleep Foundation. 2000 Sleep in America poll

5. Consequences of Sleep Disorders Research has focused on daytime sleepiness, resulting in: Performance & productivity in the workplace Accidents and injuries Mood disorders & cognitive performance Quality of life Until very recently, sleep loss was not believed to have any impact on human health

6. Van Cauter Laboratories: Sleep Debt Study* 11 healthy college-aged men Sleep restriction (4 hours per night) for 6 consecutive 24-hour periods Measured endocrine function before and after sleep restriction * Spiegel et al, Lancet, 1999

7. Sleep Debt Study Results & Conclusions Sleep restriction results in: – Glucose tolerance, thyrotropin – Evening cortisol levels – Activity of sympathetic nervous system Conclusions: –Sleep debt has a harmful impact on endocrine function and carbohydrate metabolism. –These effects are similar to those seen in normal aging. –Sleep debt may increase the severity of age-related chronic diseases including obesity, diabetes, CVD… and osteoporosis?

8. Definitions Insomnia (insufficient or poor quality sleep) Hypersomnia (excessive daytime sleepiness) - Sleep disordered breathing/sleep apnea - Narcolepsy Parasomnia (coordinated motor activity) -Restless leg syndrome

9. Normal Sleep REM (Rapid Eye Movement) - Characteristic eye movement - EEG resembles wakefulness Non REM - 75% of sleep - Four stages: correlate with depth of sleep - Progressive cortical inactivity Sleep architecture changes with aging

10. Normal Age-Related Changes in Sleep Decreased total sleep time Alterations in sleep architecture – slow wave (stages 3 & 4) sleep – sleep latency – sleep efficiency Alterations in circadian rhythms –phase advance – amplitude of rhythm Increased fatigue and daytime napping

11. Insomnia in the Elderly High prevalence (> 50%) More common in women than men Often secondary to a primary sleep disorder Commonly associated with psychiatric disorders or depression

12. Symptoms of Insomnia Difficulty initiating or maintaining sleep Wake after sleep onset Early morning awakening Awakening not rested

13. Medical Conditions That Cause Insomnia Primary sleep disorder Hyperthyroidism Arthritis Chronic renal failure Chronic lung disease Heart failure Neurological disorders Dementia/AD Parkinsons disease Note: sleep disordered breathing is not a common cause of insomnia

14. Drugs That Cause Insomnia Alcohol CNS stimulants Beta-blockers Bronchodilators Calcium channel blockers Corticosteroids Decongestants Stimulating antidepressants Thyroid hormones Nicotine

15. Sleep-Disordered Breathing (Sleep Apnea) Symptoms include loud snoring, choking, gasping during sleep Usually associated with daytime sleepiness Risk factors include: Older age Male sex CVD risk factors such as obesity Craniofacial structure

16. Definition of Sleep Apnea/SDB Apnea = cessation of respiration Hypopnea = partial decrease (>50%) of respiration Duration 10 seconds Respiratory Disturbance Index (RDI): –# apneas + hypopneas / hour slept –typical cutpoint is RDI 15

17. Prevalence of Sleep Disordered Breathing Heavily dependent on definition used 2-4% in younger adults (20-60 yrs) > 10% in elderly

18. Consequences of Sleep Disordered Breathing Excessive daytime sleepiness Increased risk of accidents & injuries Cognitive impairments Increased risk of hypertension and cardiovascular events? –Via hypoxemia, sympathetic activation, acute hypertension and decreased stroke volume

19. Sleep Heart Health Study 6000+ participants from existing cohort studies: CHS, Framingham, ARIC Men & women, mean age 63y (min 40y) In-home polysomnography & ongoing ascertainment of CVD events Aim: to test whether SDB/apnea increases risk for incident CVD events Shahar, Am J Respir Crit Care Med. 2001 163(1):19-25

20. Prevalent HTN by Quartiles of RDI, Age < 65 Shahar, Am J Respir Crit Care Med. 2001 163(1):19-25 P(trend)<.001 in both men and women

21. Prevalent HTN by Quartiles of RDI, Age 65 p(trend)=.004 in women, NS in men Shahar, Am J Respir Crit Care Med. 2001 163(1):19-25

22. Odds for Prevalent CVD by Quartiles of RDI* P<.0003 *Both sexes, all ages

23. Other Causes of Hypersomnia: Narcolepsy - Extreme daytime sleepiness, frequent brief naps, cataplexy - Rare, familial, presents in 20s and 30s - Requires sleep study and daytime Multiple Sleep Latency Test (MSLT) - Treatment: stimulants, anticholinergics

24. Parasomnias: Restless Leg Syndrome Intense dysesthesias, repetitive jerking - Worse at bedtime - Often awakens patient - Often familial, progresses with age Etiology unknown Treatment - Sinemet 25/100 qhs (70% respond) - Clonazepam 0.5-2 mg qhs

25. Evaluation of Sleep Disorders: History Sleep pattern (patient and bedroom partner) - Insufficient sleep time - Delayed onset - Frequent or early awakening Daytime correlates Medications and habits Associated nocturnal symptoms

26. Evaluation of Sleep Disorders: Physical Exam and Routine Lab Less helpful than historical features Thorough exam of head and neck, and cardiorespiratory system Signs of coexisting disease or complications Consider thyroid function, Hct, UA, and glucose

27. Evaluation of Sleep Disorders: Sleep Studies Polysomnography (oximetry, EEG, EKG, EMG, observation) Indications - Unexplained hypersomnia (esp. with snoring) - Unexplained sleep-related CV findings (e.g. pulmonary hypertension) - Abnormal complex sleep behavior - Unremitting chronic insomnia that does not respond to therapy

28. Insomnia Therapies Which of following is superior to benzodiazepine receptor agonists for primary insomnia? 1) sleep hygiene 2) cognitive behavioral therapy 3) anti-histamines 4) anti-depressants (TCA, SSRI, and trazadone)

29. Treatment of Insomnia: Non-Pharmacologic Treat underlying disorders Begin with non-pharmacologic treatment - Sleep education (changes with aging) - Sleep hygiene (diet, exercise, habits, environment) - Establish optimal sleep pattern

30. Non-Pharmacologic Therapy: Cognitive Behavioral Therapy Cognitive therapy –Change maladaptive thought processes Behavioral therapy (stimulus control, sleep restriction, relaxation, good sleep hygiene) RCT of 46 adults with chronic insomnia –Superior short and long-term (6 mo) outcomes with CBT compared to zopiclone or placebo Sivertsen et al, Jama 2006, 295(25): 2851

31. Treatment of Insomnia: Pharmacologic Depression - TCA, trazadone, SSRI, combinations (suppress REM) - Not recommended if not depressed Anxiety, panic - Benzodiazepines (suppress REM and non REM stage 3 and 4) - Not recommended if not anxious Idiopathic?

32. Treatment of Insomnia: Pharmacologic Problems with anti-histamines: anti- cholinergic, sedation, cognitive dysfunction Problems with benzodiazepines: habit forming, tachyphylaxis, suppression of REM sleep, cognitive dysfunction, falls Short-term benzodiazepine use (<2 wk) may be helpful in some patients Alternatives to benzodiazepines?

34. Benzodiazepine Receptor Agonists Zolpidem (Ambien), Zaleplon (Sonata), Eszopiclone (Lunesta) - Activate 1 of 3 benzodiazepine receptors - No anxiolytic or muscle relaxing effects - No tolerance (studies up to one year) - Preserves REM sleep, less withdrawal, little abuse potential - Rapid onset, half life 2-3 hours

35. An unexpected side effect…

36. Other Drugs Melatonin (OTC) - Secreted by pineal gland, receptors in hypothalamus - Low serum levels associated with poor sleep - Not FDA approved; safety? Ramelteon (Rozerem) –Melatonin receptor agonist. FDA approved but no long-term safety data

37. Conclusions Sleep disorders are common Associated with significant morbidity Drugs treatment over utilized, non- pharmacologic treatment often successful Primary care providers can diagnose and treat most patients with insomnia Speciality referral (sleep study) for selected patients with unexplained hypersomnia or severe insomnia