Definitions. Prevalence. Chronic Insomnia DSM-5 INSOMNIA. Insomnia Is a Distinct Disorder That Should Be Treated ~10% 3 nights/wk 3 months

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2 Chronic Definitions Alon Y. Avidan, M.D., M.P.H UCLA Sleep Disorders Center Is a Distinct Disorder That Should Be Treated NIH (1983) 1 NIH (2005) 2 is a symptom, is a disorder not a disorder DSM-5 INSOMNIA Definition is secondary to a primary disorder is a disorder that typically is comorbid with other disorders 3 nights/wk 3 months Treatment Other Important to treat the primary disorder; insomnia may or may not receive attention Hypnotics should generally be used in the lowest doses and for the shortest period of time Chronic insomnia occurs in the context of medical and psychiatric disorders Treat insomnia as well as other disorders; improvements in insomnia may result in improvements in other disorders Chronic insomnia exists and merits treatment itself is associated with significant impairment in function and quality of life Initiation Trouble falling asleep Maintaining Frequent awakening or trouble returning to sleep after awakening Waking early Waking earlier than desired 1. National Institutes of Health. Drugs and : The Use of Medications to Promote Sleep. NIH Consensus Statement. 1983;4:1-19; 2. National Institutes of Health. State-of-the-Science Conference Statement. Manifestations and Management of Chronic in Adults. 2005:1-18. APA Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: DSM-5 Approximately 25 Million adults have chronic insomnia 1 Prevalence Approximately 75 Million adults have occasional insomnia 1 $109 Billion Total costs associated with insomnia 2 ~23.5 MM have symptoms consistent with the diagnosis of insomnia 1,3 ~10% of the US population 1,3

3 Prevalence of by Age Group Percent Evolution Age Group Mellinger GD et al. Arch Gen Psychiatry. 1985;42: Longitudinal Patterns of Transient Short Term Chronic Few Days Few days-month >1 month Exam Traumatic event Depression Clinical Symposia 56(1), 2006 Slide courtesy, Tom Roth Neuroimaging Evidence for Hyperarousal in is associated with greater brain metabolism. The inability to fall asleep may be related to failure of arousal mechanisms to decline in activity from waking to sleep states. Impact of Co-morbidity on Prevalence in Adults 50. CVD Arthritis Obesity OAD Other Disease 37.5 During sleep, there was a smaller decline observed in relative metabolism in brainstem, hypothalamic/basal forebrain, and limbic networks in insomnia patients vs. healthy subjects Percent With Without Klink, et al. Arch Intern Med. 1992;152:

4 Causes of Breathing Substances related 5% 5% Other 10% According to Timing at Night Circadian rhythm ( DSPS / shift ) 10% Periodic limb movement 10% Primary / psychophy siologic 20% Psychiatr ic 40% Sleep Initiation RLS Anxiety Drugs Circadian Rhythm Disorders Sleep Maintenance OSA Nocturia Poor sleep environment Terminal Early AM Awakening Depression Circadian Rhythm Disorders Ohayon MM. Sleep Med Rev. 2002;6: Persistence of in Older Adults at 2 Years DFA 36.7 SCD 28.7 EMA DaSom DFA SCD EMA 47.3 DaSom * Persistence of daytime somnolence was significantly associated with mortality (p=0.049); n=1050 DFA = difficulty falling asleep SCD = sleep continuity disturbance EMA = early morning awakening; DaSom = uncontrollable daytime somnolence. Ganguli M et al. J Am Geriatr Soc. 1996;44: Treatment Goals for Fears regarding Hypnotic side effects often contribute to under treatment of insomnia Restore and improve sleep quality and duration Prevent progression from transient, short-term insomnia to chronic insomnia Reduce contribution of, and impact on, comorbid conditions RISKS/ FEARS Fears of addiction, abuse Package label restrictions BENEFITS Efficacy of medications 1. Nadolski N. Plast Surg Nurs. 2005;25(4): Roth T, Culpepper L. Clin Symp. 2008;58(1):3-32.

5 Approach to the Management of Current Approaches for Treatment Diagnosis 1,2 Education, including good sleep practices 1,2 Nonpharmacologic and/or pharmacologic therapy 1,2 Referral to sleep specialist (in cases of treatment failure) 1 1. Kupfer DJ, Reynolds CF III. N Engl J Med. 1997;336: [Evidence Level C]; 2. Consensus Conference. Drugs and insomnia. JAMA. 1984;251: [Evidence Level C] 37 Cognitive & Behavioral Therapy This technique Sleep restriction Stimulus control Relaxation Techniques Targets these symptoms Excessive time spent in bed; fragmented sleep Associating bed with wakefulness High physiologic, cognitive, or emotional arousal Do s: Sleep Hygiene 101 Enhance sleep environment: dark, quiet, cool temper ature Increase exposure to bright light during the day Practice relaxing routine Reduce time in bed; regular sleep/wake cycle Incorporate regular exercise in the morning and/or afternoon Cognitive Misconceptions about sleep and insomnia Don ts: Sleep hygiene education Behaviors that undermine good quality sleep 1. Spielman AJ et al. Psychiatr Clin North Am. 1987;10: ; 10: Walsh JK et al. NIH Publication No Morin CM. Principles and Practice of Sleep Medicine. 2005: Ringdahl EN et al. J Am Board Fam Pract. 2004;17: watch the clock Use stimulants (e.g, caffeine, nicotine, particularly near bedtime) Consume a heavy meals or drink alcohol within 3 hours of bed Use bright light during the nigh, avoid TV/computers e-gadgets. AASM Practice Parameters: Standards Psychological and behavioral interventions are effective and recommended in the treatment of: Chronic primary insomnia Secondary insomnia in older adults among chronic hypnotic users AASM Practice Parameters: Standards AASM Guidelines 1. Other prescription drugs (e.g., gabapentin, tiagabine, quetiapine, olanzapine) should be avoided due to insufficient evidence for efficacy 2. Over the counter agents (e.g., antihistamines, valerian, melatonin) not recomme nded for long term use due to limited efficacy data. Agents NOT Recommended Alcohol Chloral hydrate Barbiturates Non barbiturate non benzodiazepines such as meprobamate Morgenthaler et al., Sleep 2006;29: Schutte Rodin et al. J Clin Sleep Med 2008; 4:

6 What Do People Take to Try to Improve Their Sleep? What Do People Take to Try to Improve Their Sleep? Alcohol 1,2,3 Herbals 3,4 Dietary supplements 1,4 Homeopathic preparations 4 Melatonin 1,3,4 OTC sleep aids 2 Sedating antidepressants 1 Sedative-hypnotics 1,5 Melatonin receptor agonist Hypocretin Receptor Antagonist 1. Neubauer DN. Clinical Cornerstone. 2003;5: Ancoli-Israel S, Roth T. Sleep. 1999;22(suppl 2):S347-S Wagner J et al. Neuro 4. Larzelere MM, Wiseman P.Prim Care Clin Office Pract. 2002;29: Mitler MM. Sleep. 2000;23(suppl 1):S39-S47. Drugs Most Commonly Used for 1 in Verispan PDDA; desired action of hypnotic, promote sleep or sedate night * Projected from 11 month s data 2007 Occurrences (millions) Rank Drug * 1 zolpidem trazodone eszopiclone quetiapine ramelteon mirtazepine temazepam amitriptyline lorazepam clonazepam alprazolam cyclobenzaprine clonidine tizanidine zaleplon carisoprodol Characteristics of the Ideal Hypnotic No memory deficits No respiratory depression No interaction with ethanol No tolerance No physical dependence Rapid absorption Ideal Hypnotic No rebound insomnia No residual effects Address underlying pathophysiology Rapid sleep induction Minimal adverse effect on sleep physiology Optimal duration of action No formation of active metabolites Adapted from Mendelson et al. Sleep Med Rev 2004;8: ASLEEP Ideal insomnia medicine ASLEEP Untreated insomnia AWAKE Take medicine AWAKE Time to wake up Hypnotic Use

7 Drug classes Histamine Receptor Antagonist BZA Receptor Agonists Melatonin Receptor Agonist Hypocretin Receptor Antagonist Agent Initiates Sleep Maintains Sleep Sleep with limited opportunity Required Inactivity (hr) Dose (mg) Eszopiclone 8+ 1,2,3 Zaleplon 4 5,10 Zolpidem 7-8 5,10 Extended release , 12.5 Doxepin Zolpidem Eszopiclone Zaleplon Triazolam Ramelteon Suvorexant Intermezzo (Sublingual) Zolpimist (oral spray) (4 hrs) , , 10 Elduar (Sublingual) 4 5, 10 Silenor 7-8 3, 6 Ramelteon - 8 Suvorexant 7 5, 10, 15, 20 BZRA Hypnotics: Possible Adverse Effects Guideline Consensus Recommendations 2008 AASM Chronic Clinical Guideline Consensus Recommendations Hypnotic treatment should be combined with CBTi when possible. OTC antihistamine as well as herbal and nutritional substances are not recommended in the Tx of chronic insomnia due to the relative lack of efficacy and safety data. Older approved drugs for insomnia including barbiturates, barbiturate-type drugs and chloral hydrate are not recommended for the Tx of insomnia AASM Chronic Clinical Guideline Consensus Recommendations The choice of a specific pharmacologic agent should be directed by: Patient preference & expectation Treatment goals Symptom pattern Cost Comorbid conditions Past treatment response Contraindications Concurrent medication interactions Side effects

8 2008 AASM Chronic Clinical Guideline Consensus Recommendations Effect size Efforts should be made to employ the lowest effective maintenance dosage of medication and to taper medication when conditions allow. Chronic hypnotic medication may be indicated for long-term use in those with severe or refractory insomnia or chronic comorbid illness Long-term use may be nightly, intermittent, or as needed in an on demand pattern. Cognitive therapy CBT-I Z-drugs 0.3 Hypnotics BMJ 2012;345:e8343 The Sleepless Patient: Summary is an extremely common problem Assessment requires careful inventory of potential confounders CBTi is an ideal ideal option Numerous medications are available: Risk analysis: evaluate cost benefit Rx has variable benefit profiles therapy needs to be tailored to meet patient s expectations. Comorbidity Hypnotic Outcome Rheumatoid Arthritis Menopausal Eszopiclone Eszopiclone Improved pain decreased awaking due to hot flashes Fibromyalgia Zolpidem sleep and energy Major Depression Eszopiclone, BZA Improve MDD along with sleep GAD Eszopiclone Improved Hamilton Anxiety Scale (HAMA) Post-Alcohol Discontinuation Trazodone Improves sleep time PTSD Eszopiclone (Prazosin) Improved Sleep & daytime PTSD Sx. References: 1Nolen et al. J Affect Disord Jul;28(3):179-88; 2Londborg PD et al. J Affect Disord Dec;61(1-2):73-9; 3Fava M et al. Biol Psychiatry Jun 1;59(11): ; 4Krystal AD. J Clin Sleep Med Feb 15;3(1):63-72; 5Pollack M et al. Arch Gen Psychiatry May;65(5):551-62; 6Le Bon O et al. J Clin Psychopharmacol Aug;23(4): Fava et al., J Clin Psychopharm.2009 Jun;29(3):222-30; 8Fava et al.j Clin Psych 2011.,9Germain et al, J Psychosom Res. 72(2):89-96:2012; 10Taylor et al., Biol Psych. 2008;63(6): Raskind et al., Biol Psych. 2008;61(8):928-34; 11Raskind et al., Am J Psych. 2003;160(2): Pollack et al., J Clin Psych. 2011;72(7): Limited evidence shows no benefit compared with placebo. The FDA does not regulate valerian, and thus different preparations vary in valerian content. Safety data are minimal, but there have been case reports of hepatotoxicity in persons taking herbal products containing valerian. Other herbal remedies have also been promoted, but efficacy evidence is lacking. Because melatonin is not regulated by the FDA, preparations containing it vary in strength, making comparisons across studies difficult. Although melatonin appears to be effective for the treatment of circadian rhythm disorders (e.g., jet-lag), little evidence exists for efficacy in the treatment of insomnia or its appropriate dosage. In short-term use, melatonin is thought to be safe, but there is no information about the safety of long-term use.

9 Diphenhydramine* Use As a Sedative- Hypnotic in Older Adults (H1 receptor antagonists i.e diphenhydramine) are the most commonly used OTC treatments for chronic insomnia, but there is no systematic evidence for efficacy and there are significant concerns about risks of these medications. Adverse effects include residual daytime sedation, diminished cognitive function, and delirium, the latter being of particular concern in the elderly. Other adverse effects include dry mouth, blurred vision, urinary retention, constipation, and risk of increased intraocular pressure in individuals with narrow angle glaucoma. % Use Over 10 Years OTC Diphenhydramine Prescription Sedative-Hypnotics (primarily benzodiazepines) *Diphenhydramine-containing products include: generic dyphenhydramine, Benadryl, Benylin, Nervine, Aid-To-Sleep, Nytol, Robitussin PM, Tylenol PM, Motrin PM, acetaminophen PM, Excedrin PM, Legatrin PM. 1. Basu R et al. Am J Geriatr Psychiatry. 2003;11: Rickels K et al. J Clin Pharmacol. 1983;23: Kudo Y and Kurihara M. J Clin Pharmacol. 1990;30: Winkelman J et al. Ann Clin Psychiatry. 2005;17: Richardson G et al. J Clin Pharmacol. 2002:22: ) 82 Adverse Events Associated with Trazodone All antidepressants have potentially significant adverse effects, raising concerns about the risk benefit ratio. There is a need to establish doseresponse relationships for all of these agents and communicate them to prescribers. Adverse events raise concerns, especially in older adults: 1 Dizziness 1 Oversedation 1,2 Priapism 3,4 Atrial and ventricular arrhythmias 3 Alpha-adrenergic blockade, including orthostatic hypotension 2 potential for falls 1. Mendelson WB. J Clin Psychiatry. 2005;66: Lippmann S et al. South Med J. 2001;94: Mendelson WB et al. Sleep Med Rev. 2004;8: Winkelman J and Pies R. Ann Clin Psychiatry. 2005;17: A number of other sedating medications have been used in the treatment of insomnia. These include barbiturates (e.g., phenobarbital) and antipsychotics (e.g., quetiapine and olanzepine). Studies demonstrating the usefulness of these medications for either short- or long-term management of insomnia are lacking. Furthermore, all of these agents have significant risks. Thus, their use in the treatment of chronic insomnia cannot be recommended.