7:45 8:45 am Management of Insomnia and Other Disorders SPEAKER Alon Y. Avidan, MD, MPH, FAAN, FAASM 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. 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. Disorders and Insomnia What is Insomnia? Difficulties Falling Asleep Difficulties Maintaining Early Morning Awakenings Alon Y. Avidan, M.D., M.P.H, Professor, UCLA Department of Neurology Director, UCLA Disorders Center 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 ICSD III Despite adequate opportunity for sleep. Prevalence of Insomnia by Age Group DSM-5 INSOMNIA 25. 3 nights/wk 3 months 20. 14. 15. Initiation Maintaining Waking early Percent Trouble falling asleep Frequent awakening or trouble returning to sleep after awakening Waking earlier than desired 18-34 35-49 50-64 65-79 Age Group Mellinger GD et al. Arch Gen Psychiatry. 1985;42:225-232. 6 APA Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: DSM-5
Causes of Insomnia Primary / psychophysiologic 20% Periodic limb movement 10% Circadian rhythm ( DSPS / shift ) 10% Breathing related 5% Psychiatric 40% Other 10% Substances 5% Ohayon MM. Med Rev. 2002;6:97-111. 8 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 Cognitive & Behavioral Therapy This technique Targets these symptoms Diagnosis 1,2 restriction Excessive time spent in bed; fragmented sleep Education, including good sleep practices 1,2 Stimulus control Relaxation Techniques Associating bed with wakefulness High physiologic, cognitive, or emotional arousal Nonpharmacologic and/or pharmacologic therapy 1,2 Cognitive Misconceptions about sleep and insomnia hygiene education Behaviors that undermine good quality sleep Referral to sleep specialist (in cases of treatment failure) 1 1. Kupfer DJ, Reynolds CF III. N Engl J Med. 1997;336:341 346 [Evidence Level C]; 2. Consensus Conference. Drugs and insomnia. JAMA. 12 1984;251:2410 2414. [Evidence Level C] 1. Spielman AJ et al. Psychiatr Clin North Am. 1987;10:541-553; 10:541-553. 2. Walsh JK et al. NIH Publication No. 98-4088. 3. Morin CM. Principles and Practice of Medicine. 2005:726-737. 4. Ringdahl EN et al. J Am Board Fam Pract. 2004;17:212-219.
14 What Do People Take to Try to Improve Their? 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;5:16-27. 2. Ancoli-Israel S, Roth T.. 1999;22(suppl 2):S347-S353. 3. Wagner J et al. Neuro 4. Larzelere MM, Wiseman P.Prim Care Clin Office Pract. 2002;29:339-360. 5. Mitler MM.. 2000;23(suppl 1):S39-S47. What Do People Take to Try to Improve Their? 28% use alcohol Characteristics of the Ideal Hypnotic No memory deficits No respiratory depression No interaction with ethanol No tolerance Rapid absorption Ideal Hypnotic Address underlying pathophysiology Rapid sleep induction Minimal adverse effect on sleep physiology Optimal duration of action No physical dependence No rebound insomnia No residual effects No formation of active metabolites Adapted from Mendelson et al. Med Rev 2004;8:7-17. 18 Drug classes Hypnotics: Mechanism of Action & Labeling Class 1 Drugs 1,2 Acts on:1 Controlled Substance Schedule 2 Barbiturates Phenobarbital, mephobarbital, amobarbital, secobarbital Non-selective CNS depressants II, III, IV Antipsychotics Quetiapine, risperidone, aripiprazole Dopamine, serotonin Not scheduled Histamine Receptor Antagonist BZA Receptor Agonists Melatonin Receptor Agonist Hypocretin Receptor Antagonist Antidepressants Tradozone, amitriptyline Serotonin/histamine Not scheduled Benzodiazepines Temazepam, estazolam, GABA IV flurazepam, quazepam, triazolam Antihistamines Diphenhydramine 5 Histamine Not scheduled Doxepin Zolpidem Eszopiclone Zaleplon Triazolam Ramelteon Suvorexant 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 1. Roth T, Culpepper L. Clinical Symposia. 2008;58:1-32; 2. Controlled Substances Act. http://www.deadiversion.usdoj.gov/21cfr/21usc/812.htm. 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;22:511-515.
DRUGS INDICATED FOR INSOMNIA Generic Brand T 1/2 (Hours) Dose (mg) Drug Class Flurazepam Dalmane 48-120 15-30 BZD Temazepam Restoril 8-20 15-30 BZD Triazolam Halcion 2-6 0.125-0.25 BZD Estazolam Prosom 8-24 1-2 BZD Quazepam Doral 48-120 7.5-15 BZD Zolpidem Ambien 1.5-2.4 5-10 non-bzd Zaleplon Sonata 1 5-20 non-bzd Eszopiclone Lunesta 5-7 1-3 non-bzd Zolpidem Ex Rel Ambien CR 1.5-2.4* 6.25-12.5 non-bzd Ramelteon Rozerem 1.5-5 8 MT agonist Silenor Doxepin 15.3 3, 6 H 1 Antagnonist Suvorexant Belsomra 12 5, 10, 15, 20 Hcrt Antagonist 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 7-8 6.25, 12.5 Intermezzo (Sublingual) (4 hrs) 4 1.75, 3.5 4 5, 10 Zolpimist (oral spray) Elduar (Sublingual) 4 5, 10 Silenor 7-8 3, 6 Ramelteon - 8 Suvorexant 7 5, 10, 15, 20 * Modified formulation. No short-term use limitation. BZRA Hypnotics: Possible Adverse Effects OREXIN MELATONIN HISTAMIN 25 26
27 OBSTRUCTIVE SLEEP APNEA SYNDROME THE ANATOMY OF SLEEP APNEA Obesity Trends in the US: CDC Dataset Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2014 Prevalence estimates reflect BRFSS methodological changes started in 2011. These estimates should not be compared to prevalence estimates before 2011. https://www.cdc.gov/obesity/data/databases.html *Sample size <50 or the relative standard error (dividing the standard error by the prevalence) 30%.
THE ANATOMY OF SLEEP APNEA Phenotypic Features Consistent with OSA 39 EKG Airflow Exhale Airway obstructs Airway opens Thorac ic effort Abd. effort Inhale Effort gradually increases Paradoxin g Paradoxing Ends SAO2 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. 2006 Jul;29(7):903-8. Treatment of OSA Weight loss CPAP/BiPAP Positional Tx Oral Appliances UPPP LAUP Bimax Advancement Trach Drugs Avoidance of Rx/Etoh
CPAP SLEEP HYPNOGRAM Splint the airway open Gold Standard Tx for OSA Courtesy Richard Schwab, M.D. UPENN OXYGEN SATURATION CONTINUOUS POSITIVE AIRWAY PRESSURE (CPAP) Restless Legs Syndrome Nasal Pillows Nasal Aire Willis Ekbom Disease Willis-Ekbom Disease Differential Diagnosis of RLS 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 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;4:101-119.
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):977-986 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 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: RBD Rates of Phenoconversion Parkinson s disease Dementia with Lewy Bodies Multiple System Atrophy Barcelona GroupIranzo A, Fernandez-Arcos A, Tolosa E et al, PLOS ONE 2014;9:e89741 Drug (*) Dose Level of Special considerations Recommendation Clonazepa m Melatonin Pharmacologic treatment of RBD Environmental Safety 0.25-2.0 mg QHS 3 mg to 12 mg before bedtime. Suggested ( ) Suggested ( ) (*) Not FDA approved for the treatment of RBD. ( ) Supported by sparse high grade evidence data, or a substantial amount of low-grade data and/or clinical consensus. ( ) Supported by low grade data. Use with caution in patient s with dementia, gait disorders, or concomitant OSA. Side effect include sedation, impotence, motor incoordination, confusion and memory dysfunction. 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