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1 4:30 5:45 pm Management of Insomnia and Other Disorders Presenter Disclosure Information The following relationships exist related to this presentation: Alon Y. Avidan, MD, MPH, FAAN, FAASM: Speakers Bureau for Merck & Co., Inc. and XenoPort, Inc. SPEAKER Alon Y. Avidan, MD, MPH, FAAN, FAASM Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. What is Insomnia? Prevalence of Insomnia by Age Group Difficulties Falling Asleep Difficulties Maintaining Early Morning Awakenings Next Day Consequences: Fatigue Attention, concentration, or memory impairment Social/vocational dysfunction Mood disturbance/irritability Proneness for errors/accident at work or while driving Tension headaches, and/or GI symptoms in response to sleep loss Concerns or worries about sleep Despite adequate opportunity for sleep. Percent Age Group ICSD III Mellinger GD et al. Arch Gen Psychiatry. 1985;42: DSM-5 INSOMNIA Causes of Insomnia 3 nights/wk 3 months Primary / psychophysiologic 20% Periodic limb movement 10% Initiation Maintaining Waking early Circadian rhythm ( DSPS / shift ) 10% Trouble falling asleep Frequent awakening or trouble returning to sleep after awakening Waking earlier than desired Breathing related 5% Substances 5% Psychiatric 40% Other 10% APA Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: DSM-5 Ohayon MM. Med Rev. 2002;6:

2 Insomnia According to Timing at Night Difficulties Initiating RLS Anxiety Drugs Difficulties Maintaining Primary Disorder: OSA, Nocturia Poor sleep environment Early morning awakening ASPS Depression Drugs Approach to the Management of Insomnia What Do People Take to Try to Improve Their? Diagnosis 1,2 Education, including good sleep practices 1,2 Nonpharmacologic and/or pharmacologic therapy 1,2 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 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 ;251: [Evidence Level C] 1. Neubauer DN. Clinical Cornerstone. 2003;5: Ancoli-Israel S, Roth T ;22(suppl 2):S347-S Wagner J et al. Neuropsychiatry. 1998;32: Larzelere MM, Wiseman P.Prim Care Clin Office Pract. 2002;29: Mitler MM ;23(suppl 1):S39-S47. What Do People Take to Try to Improve Their? Diary 28% use alcohol

3 Characteristics of the Ideal Hypnotic No memory deficits Rapid absorption Address underlying pathophysiology Drug classes No respiratory depression No interaction with ethanol Ideal Hypnotic Rapid sleep induction Minimal adverse effect on sleep physiology Histamine Receptor Antagonist BZA Receptor Agonists Melatonin Receptor Agonist Hypocretin Receptor Antagonist No tolerance No physical dependence No rebound insomnia No residual effects Optimal duration of action No formation of active metabolites Doxepin Zolpidem Eszopiclone Zaleplon Triazolam Ramelteon Suvorexant Adapted from Mendelson et al. Med Rev 2004;8: Hypnotics: Mechanism of Action & Labeling Class 1 Drugs 1,2 Acts on:1 Controlled Substance Schedule 2 Barbiturates Antipsychotics Phenobarbital, mephobarbital, amobarbital, secobarbital Quetiapine, risperidone, aripiprazole Non-selective CNS depressants Dopamine, serotonin II, III, IV Not scheduled Antidepressants Tradozone, amitriptyline Serotonin/histamine Not scheduled Benzodiazepines Temazepam, estazolam, flurazepam, quazepam, triazolam GABA Antihistamines Diphenhydramine 5 Histamine Not scheduled Nonbenzodiazepines Zolpidem, eszopiclone, zaleplon GABA IV Melatonin receptor agonist Ramelteon Melatonin Not scheduled Selective H 1 receptor antagonist 3 Doxepin Histamine H 1 Not scheduled Orexin receptor antagonist 4 Suvorexant Orexin IV IV DRUGS INDICATED FOR INSOMNIA Generic Brand T 1/2 (Hours) Dose (mg) Drug Class Flurazepam Dalmane BZD Temazepam Restoril BZD Triazolam Halcion BZD Estazolam Prosom BZD Quazepam Doral BZD Zolpidem Ambien non-bzd Zaleplon Sonata non-bzd Eszopiclone Lunesta non-bzd Zolpidem Ex Rel Ambien CR * non-bzd Ramelteon Rozerem MT agonist Silenor Doxepin , 6 H 1 Antagnonist Suvorexant Belsomra 12 5, 10, 15, 20 Hcrt Antagonist 1. Roth T, Culpepper L. Clinical Symposia. 2008;58:1-32; 2. Controlled Substances Act. Accessed June 9, 2015; 3. SILENOR (doxepin) [package insert]. Morristown, NJ: Pernix Therapeutics; 2014; 4. Belsomra (suvorexant) [package insert]. Whitehouse Station, NJ; Merck and Co. 2014; 5. Richardson GS et al. J Clin Psychopharmacol. 2002;22: * Modified formulation. No short-term use limitation. BZRA Hypnotics: Possible Adverse Effects Agent Initiates Maintains 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 Intermezzo (Sublingual) (4 hrs) , , 10 Zolpimist (oral spray) Elduar (Sublingual) 4 5, 10 Silenor 7-8 3, 6 Ramelteon - 8 Suvorexant 7 5, 10, 15, 20

4 MELATONIN OREXIN HISTAMIN OBSTRUCTIVE SLEEP APNEA SYNDROME

5 Obesity Trends in the US: CDC Dataset Phenotypic Features Consistent with OSA EKG Airflow Exhale Airway obstructs Airway opens Thoracic effort Inhale Effort gradually increases Abd. effort Paradoxing SAO2 Paradoxing Ends Blood oxygen levels reduce to < 3% of baseline value Obstructive Apnea A complete blockage of the airway despite efforts to breath. Notice the effort gradually increasing ending in airway opening. Kryger: Principles and Practice of Medicine, 5th ed. Nuchton, TJ et al Jul;29(7): Treatment of OSA SLEEP HYPNOGRAM Weight loss CPAP/BiPAP Positional Tx Oral Appliances UPPP LAUP Bimax Advancement Trach Drugs Avoidance of Rx/Etoh OXYGEN SATURATION

6 Willis-Ekbom Disease Essential Criteria* Supportive Features* disturbances Urge to move the legs usually accompanied or caused by uncomfortable leg Periodic leg movements sensations Positive family history for RLS Getting up: Temporary relief with movement partial or total relief from discomfort by walking or stretching Positive response to dopaminergic therapy Differential Diagnosis of RLS Rest: Onset or worsening of symptoms at rest or inactivity, such as when lying or sitting Evening: Worsening or onset of symptoms in the evening or at night * Diagnostic criteria developed by the International RLS (IRLS) Study Group in collaboration with the National Institutes of Health (NIH). Allen et al. Med. 2003;4: RLS RLS is a symptom based Dx PLMS PLMS are an EMG finding Management of RLS Conservative Tx Pharmacotehrapy RLS is Dx in the physician s office PLM s are Dx in the sleep lab Alerting activities Iron state Ferritin <45 ug/l 80% of people who have RLS will have PLM s 30% of individuals who have PLM s have RLS symptoms Avoid Etoh, Caffeine Nicotine Review Medications 1. Ropinirole, 2. Pramipexole, 3. Rotigotine 4. Gabapentin Enacarbil FDA-approved medication for the treatment of moderate-tosevere primary RLS. Hypnotics Levodopa, Opioids Silber, M, et al September 2013;88(9): Narcolepsy Disorder of unknown etiology Consists of: Excessive sleepiness REM sleep phenomena (i.e cataplexy) PARASOMNIAS Undesirable motor, or verbal phenomena that arise from sleep or sleep - wake transition

7 Case WAKE A 64 y/o man presented to the ER with a broken wrist experienced during a fighting dream. For the last 6m, he has been sleeping in a separate room than his wife after he had punched her during one of these dreams. What is the most likely diagnosis? REM NREM NREM REM Behavior Disorder RBD is most commonly associated with neurodegenerative disease, particularly ɑ-synucleinopathies: Parkinson s disease Dementia with Lewy Bodies Multiple System Atrophy Pharmacologic treatment of RBD Drug (*) Dose Level of Recommendation mg Clonazepam QHS Suggested ( ) Special considerations Environmental Safety Use with caution in patient s with dementia, gait disorders, or concomitant OSA. Side effect include sedation, impotence, motor incoordination, confusion and memory dysfunction. Melatonin 3 mg to 12 mg before bedtime. Suggested( ) Effective in patients with alphasynucleinopathies, memory problems, and sleep-disordered breathing. Side effects include headaches, sleepiness and delusions/hallucinations. Summary: Treatments of Disorders Condition Nonpharmacologic Pharmacologic Insufficient Syndrome Obstructive Apnea Increase total sleep time, e.g., naps Positive Pressure Therapy Airway surgery (CPAP) Not recommended Modafinil* (for residual sleepiness with CPAP compliance) Insomnia Behavioral Tx BZA *, non-bza agonists*, H1 antidepressants*, melatonin agonist, Hcrt antagonist* Narcolepsy Prophylactic power naps Modafinil,* dexamphetamine,* methylphenidate* RLS Hot bath, massage Dopaminergic agents, Dopamine agonist*, α2 delta ligand. Parasomnias Safety, Avoid exacerbating factors BZA