LEARNING OBJECTIVES List key differences between insomnia and obstructive sleep apnea Identify at least two appropriate pharmacologic treatment options for insomnia INSOMNIA VS. SLEEP APNEA Morganne Smyth, Pharm.D. Pharmacy Practice Resident St. Luke s Medical Center, Boise, ID ISHP 2013 Spring Meeting Assess how current FDA warnings have affected options for the treatment of insomnia 2 INTRODUCTION OBSTRUCTIVE SLEEP APNEA Obstructive Sleep Apnea (OSA) Affects up to 4% of middle-aged adults Common complaints Loud snoring Disrupted sleep Daytime sleepiness Up to 80% of patients with OSA are undiagnosed 50% of patients who present with a stroke have sleep apnea 35% of patients with high blood pressure have sleep apnea 3 SLEEP APNEA Apnea is Greek for without breath Breathing pauses during sleep At least ten-second intervals of absence of breathing Multiple seconds to minutes (up to 30 times/hr) Snorting/choking/gasping sound may occur when breathe again Usually not associated with breathing problems during the day Difficult to diagnose Symptoms usually recognized by spouse (loud snoring) Polysomnogram (sleep study) for diagnosis 4 Victor LD, Am Fam Physician, 1999, Nov 15;60(8):2279-86. National Stroke Foundation, 2005, www.stroke.org U.S. Food and Drug Administration, Consumer Updates, 2013. 1
OBSTRUCTIVE SLEEP APNEA SLEEP APNEA QUESTIONNAIRE Normal airway Obstruction Abnormal airway during sleep 5 6 Victor LD, Am Fam Physician, 1999, Nov 15;60(8):2279-86. Victor LD, Am Fam Physician, 1999, Nov 15;60(8):2279-86. SLEEP APNEA RISK FACTORS Age 40-60 years highest risk Ethnicity African American, Pacific Islander, and Hispanic groups at higher risk Family history Obesity Physical characteristics Large neck (>17 in men; >16 in women) Facial/Shull characteristics (narrow upper jaw, receding chin, overbite, large tongue, soft palate changes) Smoking and alcohol use Other medical conditions Diabetes, GERD 7 CONSEQUENCES OF SLEEP APNEA Increased risk of the following: Heart conditions Chest pain Cardiac arrhythmias (irregular heartbeat) Heart attack Stroke Motor vehicle accidents Work-related accidents Depression 8 Victor LD, Am Fam Physician, 1999, Nov 15;60(8):2279-86. U.S. Food and Drug Administration, Consumer Updates, 2013. 2
TREATING SLEEP APNEA CPAP THERAPY First line Behavioral measures Lose weight Decrease alcohol intake Decrease/stop taking medications that make you drowsy Second line CPAP CPAP (continuous positive airway pressure) machine Other options Dental appliances/devices Surgery There are currently NO medication therapies available to treat obstructive sleep apnea 9 Mask over nose/mouth Connects to machine kept at the bedside Mild air pressure used to keep airway open Decreases sleep disruptions from decreased oxygen intake Decreases snoring Leads to decreased daytime sleepiness 10 U.S. Food and Drug Administration, Consumer Updates, 2013, www.fda.gov National Heart, Lung, and Blood Institute [Internet], Department of Health and Human Services, 2012, www.nhlbi.nih.gov DENTAL APPLIANCES/DEVICES DENTAL APPLIANCES/DEVICES Used for OSA in patients unable to tolerate or have not have improvement with CPAP therapy Mandibular advancement device (MAD) Most widely used Forces lower jaw forward and down Tongue retaining device (TRD) Splint that hold the tongue in place Disadvantages Mandibular advancement device Not as effective as CPAP Pain, dry lips, tooth discomfort May cause long term changes in dental structure 11 Tongue retaining device 12 University of Maryland Medical Center, obstructive sleep apnea - dental devices, 2009, www.umn.edu 3
INTRODUCTION - INSOMNIA One of the most common medical complaints 35% of the population reports insomnia within the last year Increasing prevalence with increasing age More common in: Females Unemployed Divorced, widowed, separated Lower socioeconomic status Only 30% of patients with insomnia report the problem to their physician 13 CLASSIFICATION OF SLEEP DISORDERS Primary Sleep Disorders Dyssomnias abnormality in amount, quality, or timing of sleep Primary insomnia Primary hypersomnia Narcolepsy Breathing-related sleep disorder Circadian rhythm sleep disorder Jet lag Shift work Parasomnias abnormal behavioral or psychological events associated with sleep Nightmare/Sleep terror disorder Sleepwalking Sleep disorders related to another mental disorder 14 Wells BG, Pharmacotherapy Handbook, 2009, pg. 814. DURATION Transient (2-3 days) or short term (up to 3 weeks) Jet lag Shift work changes Acute illness Major life events Chronic insomnia (greater than 1 month) Medical disorder Psychiatric disorder Medication-related cause INSOMNIA DIAGNOSIS One or more of the following: Difficulty initiating sleep Difficulty maintaining sleep Waking up too early or nonrestorative/poor sleep quality Problems with sleep despite adequate opportunity for sleep Different from sleep deprivation Must also have daytime impairment from sleep difficulty 15 16 Wells BG, Pharmacotherapy Handbook, 2009, pg. 814. Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504. 4
DAYTIME IMPAIRMENT HOW MUCH SLEEP IS ENOUGH? One of the following to qualify for daytime impairment Fatigue or lethargy Problems with attention, concentration, or memory Poor school/work performance Irritability Low motivation or energy Increased errors/accidents at work or while driving Headaches GI symptoms Concerns or worries about sleep loss 17 Hours of Sleep 18 16 14 12 10 8 6 4 2 0 Average Amount of Required Sleep 18 Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504. U.S. Food and Drug Administration, Consumer Updates, 2013, www.fda.gov INSOMNIA OR NOT? Some people require only a few hours of sleep with no residual daytime sleepiness As people age, they require less sleep NOT considered insomnia due to absence of daytime symptoms Does not appear to be associated with adverse health outcomes Called short sleep requirement or short sleepers Spending less time sleeping due to busy lifestyle NOT considered insomnia if sleep comes easily when given the opportunity Known as sleep deprivation 19 HOW IS OSA DIFFERENT THAN INSOMNIA? Obstructive sleep apnea is caused by a physical obstruction of the airway Awakening due to decreased oxygen intake Given the opportunity to sleep (without the obstruction), individuals are able to sleep Similar to sleep deprivation problem Would sleep if had adequate opportunity CANNOT be treated with medication Many medications used to treat insomnia need to be avoided in patients with obstructive sleep apnea Avoid central nervous system depressants (i.e. benzodiazepines) 20 Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504. 5
CONSEQUENCES OF INADEQUATE SLEEP MEDICATION-RELATED CAUSES Decreased quality of life Tired, sleepiness, confusion, anxiety, depression Less likely to receive job promotions, more sick time Comorbidities May have increased risk of high blood pressure, heart attacks, and other heart conditions Strongly associated with development of psychiatric disorders Depression, anxiety, drug abuse 21 Beta blockers Metoprolol Asthma medications Albuterol, theophylline Antidepressants Fluoxetine, nortriptyline Decongestants Pseudoephedrine Stimulants ADHD medications Steroids Prednisone, methylprednisolone *List not inclusive of all medicationrelated causes 22 Chawla J, Insomnia, 2013, emedicine.medscape.com INSOMNIA AND OTHER MEDICAL CONDITIONS MENOPAUSE AND INSOMNIA 80 70 60 50 40 30 20 10 0 Prevalence of Chronic Insomnia in other Medical Conditions Insomnia No Insomnia More sleep complaints during perimenopausal period Insomnia common complaint in women with early menopause May be secondary to vasomotor symptoms (hot flashes, night sweats) during menopause Sleep quality has shown to be better after menopause More deep sleep and longer sleep times More self-reported dissatisfaction with sleep (even though getting better sleep) 23 24 Taylor DJ, Sleep, 2007 Feb;30(2):213-8. Young T, Sleep, 2003, Sep;26(6):667-72. 6
MANAGEMENT Identifying cause of insomnia (if identifiable) Treat comorbid conditions Education Sleep hygiene Stress management Monitoring of mood symptoms Eliminating unnecessary pharmacotherapy BEHAVIORAL THERAPY Sleep hygiene Stimulus control Relaxation Sleep restriction Cognitive therapy Cognitive behavioral therapy Pharmacologic therapies 25 26 Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504. Schutte-Rodin S, J Clin Sleep Med, 2008 Oct 15;4(5):487-504. SLEEP HYGIENE Sleep only as long as you need to feel rested Get out of bed Maintain a regular sleep schedule Do NOT force sleep Avoid caffeine after lunch Avoid alcohol near bedtime Avoid smoking/nicotine intake Decrease stimuli in bedroom Take care of worries before bed Exercise 20 mins. during the day 4 5 hours prior to bedtime STIMULUS CONTROL People who suffer from insomnia associated the bed/bedroom with fear of not sleeping Do not go to bed unless sleepy Only used the bed for sleep or sex Do not spend > 20 mins in bed without falling asleep Get up and do something relaxing Alarm set to wake a same time everyday No naps allowed Avoid daytime naps 27 28 7
RELAXATION THERAPY Used each evening prior to sleep Progressive muscle relaxation Head-to-toe progression of contraction followed by relaxation Relaxation response Lie or sit comfortably Close eyes and focus on deep breathing Focus on one neutral image Peaceful word or place SLEEP RESTRICTION THERAPY Stay in bed longer to make up for lost sleep Shift in circadian rhythm Decrease time spent in bed to time actually sleeping (not < 5 hours) No naps during the day Sleep efficiency calculated Time sleeping/time in bed (%) time by 15-30 mins when > 85% 29 30 COGNITIVE THERAPY Patients awake at night Concern of poor functioning next day Worry exacerbates difficulty sleeping Work with therapist Deal with anxiety Establish realistic expectations COGNITIVE BEHAVIORAL THERAPY Combines many strategies over several weeks Education Stimulus Control Sleep Hygiene Sleep Restriction 31 Cognitive Therapy 32 8
PHARMACOLOGICAL THERAPY PHARMACOLOGICAL TREATMENT Benzodiazepines Non-benzodiazepine sedatives Melatonin agonist Antihistamines 33 Caution in the following patient groups Pregnancy Fetal malformations in first trimester Alcohol consumption Excessive sedation Renal/hepatic disease Accumulation of drug Pulmonary disease/sleep apnea Worsen disease/hypoventilation Nighttime decision-makers On-call, taking care of children Older adults Increased risk of side effects 34 UpToDate, Treatment of Insomnia, 2013, www.uptodate.com BENZODIAZEPINES Benzodiazepines have sedative, anxiolytic, muscle relaxant, and anticonvulsant properties Reduce time to onset of sleep Increase total sleep time All schedule IV controlled substances Medications commonly used Triazolam (Halcion ) Quick-acting, but also short-acting Lorazepam (Ativan ) Short-intermediate acting Estazolam (Prosom ) and temazepam (Restoril ) Intermediate-acting Flurazepam (Dalmane ) and quazepam (Doral ) Long-acting due to active metabolites 35 BENZODIAZEPINES Adverse Effects Drowsiness, incoordination, decreased concentration, and cognitive deficits Daytime tolerance to these effects may occur Anterograde amnesia Abuse risk Tolerance May develop after 2 12 weeks of continuous use Rebound insomnia Decrease risk by taking lowest dose and tapering medication Increased falls and hip fractures Longer-acting flurazepam and quazepam increase falls/fractures especially in the elderly 36 Wells BG, Pharmacotherapy Handbook, 2009, pg. 814. Wells BG, Pharmacotherapy Handbook, 2009, pg. 814. 9
NON-BENZODIAZEPINES NON-BENZODIAZEPINES Zolpidem (Ambien ) Minimal anxiolytic activity No muscle relaxant properties Not an anticonvulsant Comparable efficacy to benzodiazepines Zaleplon (Sonata ) Rapid onset, half-life of 1 hour Does NOT reduce nighttime awakenings or help increase total sleep time Eszopiclone (Lunesta ) Rapid onset Approved to help with sleep onset and maintenance 37 Drug Indication Half-life Notes Zolpidem (Ambien) Zolpidem CR (Ambien CR) Zolpidem sublingual (Intermezzo) Zaleplon (Sonata) Eszopiclone (Lunesta) Sleep onset insomnia Sleep onset or maintenance insomnia Sleep maintenance insomnia Sleep onset insomnia Sleep onset or maintenance insomnia ~2.5 hrs New warnings released in January 2013 1.4 4.5 hrs 1.4 6.7 hrs Controlled-release formula To be given in the middle of the night 1 hour Not indicated for long-term use 6 9 hrs For sleep onset and maintenance 38 Wells BG, Pharmacotherapy Handbook, 2009, pg. 814. UpToDate, Treatment of Insomnia, 2013, www.uptodate.com NON-BENZODIAZEPINES COMPLEX SLEEP-RELATED BEHAVIORS Adverse effects Similar to benzodiazepines Less severe Dizziness Headache Somnolence Daytime sedation Complex-sleep related behaviors Unpleasant taste (Eszopiclone) Hallucinations (Zolpidem) Less risk of abuse versus benzodiazepines Non-benzodiazepines Sleep eating Sleep driving Phone calls while sleeping Engaging in sexual behaviors while not fully awake Higher doses of medications have been attributed to these complex sleep behaviors 39 40 Wells BG, Pharmacotherapy Handbook, 2009, pg. 814 UpToDate, Treatment of Insomnia, 2013, www.uptodate.com U.S. Food and Drug Administration, Consumer Updates, 2013. Hwang TJ, J Clin Psychiatry, 2010 Oct;71(10):1331-5 10
MELATONIN AGONIST Ramelteon (Rozerem ) Involved with circadian rhythm Fewer and less severe side effects than benzodiazepines and non-benzodiazepines Less daytime residual effects No withdrawal or rebound insomnia Not known to be habit-forming Only sedative-hypnotic that is not a controlled substance Common side effects Somnolence Nausea Fatigue Headache 41 ANTIHISTAMINES First-generation (sedating) antihistamines Most common Diphenhydramine (Benadryl ) Doxylamine (Unisom ) Less effective than other options Anticholinergic side effects Dry mouth Blurred vision Urinary retention Constipation Side effects usually more severe in elderly patients 42 UpToDate, Treatment of Insomnia, 2013, www.uptodate.com UpToDate, Treatment of Insomnia, 2013, www.uptodate.com Wells BG, Pharmacotherapy Handbook, 2009, pg. 814 INSOMNIA TREATMENT ZOLPIDEM WARNING General recommendations Do not take medications for insomnia unless you have a full 7-8 hours to dedicate to sleep Lowest doses needed Decrease daytime sleepiness/side effects Easier to taper off medication Use for the shortest time necessary Decrease risk of tolerance Try other non-medication therapies Caution during next day when starting new insomnia medications Recognize how the medication will affect you UpToDate, Treatment of Insomnia, 2013, www.uptodate.com 43 January 2013 FDA Safety Communication Blood levels of zolpidem in certain patients may be high enough in the morning to impair activities requiring alertness (i.e. driving) Highest risk in extended-release product (Ambien CR ) New recommendations to consider lower doses in all patients Decrease dose especially in women due to slower elimination of the drug from the body Slower elimination has not been demonstrated in men, but lower doses should be recommended in general U.S. Food and Drug Administration [Internet], Zolpidem Containing Products: Drug Safety Communication - FDA Requires Lower Recommended Doses, 2013, www.fda.gov 44 11
INSOMNIA IN THE ELDERLY Up to 60% of adults > 65 years of age suffer from insomnia Age-related changes in sleep patterns Underlying illness Medication side effects Less sleep necessary Risk of using traditional sleep aids is higher in elderly patients 5-33% of elderly patients receive a benzodiazepine or other non-benzodiazepine sleep aids 45 NON-PHARMACOLOGIC OPTIONS IN THE ELDERLY Identify and manage exacerbating factors Pain Shortness of breath (heart failure) Chest pain COPD GI disease (acid reflux, ulcer) Neurologic or mood disorders Parkinson s, dementia, anxiety, depression 46 Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919. Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919. NON-PHARMACOLOGIC OPTIONS IN THE ELDERLY Target sleep hygiene Avoid nicotine, alcohol, and caffeine Increase exercise and light exposure in the day Limit napping Reduce light and noise in the sleep environment Keep temperature comfortable Avoid meals and liquids close to bedtime PHARMACOLOGIC OPTIONS Some evidence that newer non-benzodiazepine hypnotics are safer for the elderly sleep cycle changes, rebound insomnia, tolerance, and hangover Start with lower doses in older patients May try ramelteon (Rozerem) No dependence/abuse risk Helps in sleep initiation, but not maintenance 47 48 Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919. Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919. 12
PHARMACOLOGIC OPTIONS Other options Trazodone, an antidepressant, may increase deep sleep Not well studied, early on appears to be beneficial Non-habit forming AE: Dry mouth, nausea, arrhythmias, orthostatic hypotension Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919. 49 SELF-TREATMENT IN THE ELDERLY Alcohol Causes early awakening Antihistamines (i.e. diphenhydramine) Anticholinergic effects, cognitive impairment, urinary retention Residual daytime sleepiness Melatonin Helps with difficulty falling asleep Valerian May takes several night/weeks to see benefit Kava AVOID, may cause hepatotoxicity Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919. 50 META-ANALYSIS - ELDERLY INSOMNIA META-ANALYSIS TREATMENT BENEFIT 24 Randomized Controlled Trials 2417 subjects with insomnia > 60 years of age No other psychiatric/psychological disorders Treated with benzodiazepines, zopiclone, zolpidem, zapelon, diphenhydramine, and placebo Results Sleep time increased by ~25 min/night Benzodiazepines increased sleep by ~34 min/night Adverse effects Cognitive events ~5 times as common Daytime fatigue ~4 times more common Adverse events similar between benzodiazepine and nonbenzodiazepines 51 52 Glass J, BMJ, 2005 Nov 19;331(7526):1169. Glass J, BMJ, 2005 Nov 19;331(7526):1169. 13
META-ANALYSIS ADVERSE EFFECTS 53 META-ANALYSIS Limitations Medications grouped together Subjective measures Excluded patients with other psychiatric/psychological disorders Did not assess dependence risk Conclusions Clinical benefits of sleep aids in the elderly may be modest Greater risk of adverse events occurring in the older population 54 Glass J, BMJ, 2005 Nov 19;331(7526):1169. Glass J, BMJ, 2005 Nov 19;331(7526):1169. SUMMARY Insomnia diagnosis Difficultly initiating, maintaining, or poor quality/nonrestorative sleep Daytime impairment Difficulty despite adequate time for sleep Obstructive sleep apnea treatments Lifestyle changes CPAP therapy No medication therapies available Insomnia treatments Behavioral therapies are first line New zolpidem recommendations Lower doses in women due to slower elimination Risks of pharmacologic treatment in the elderly may outweigh the benefit 55 REFERENCES Chawla J, Park Y, Passaro EA. Insomnia. Medscape Reference. c2013 WebMD LLC [updated 18 Jan 2013, cited 15 Mar 2013]. Available from: http://emedicine.medscape.com/article/1187829-overview Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: metaanalysis of risks and benefits. BMJ. 2005 Nov 19;331(7526):1169. Hwang TJ, Ni HC, Chen HC, Lin YT, Liao SC. Risk predictors for hypnosedativerelated complex sleep behaviors: a retrospective, cross-sectional pilot study. J Clin Psychiatry. 2010 Oct;71(10):1331-5 Insomnia in the elderly. Pharmacist's Letter/Prescriber's Letter 2009;25(9):250919. National Heart, Lung, and Blood Institute [Internet]. What is CPAP? Department of Health and Human Services [updated 13 Dec 2011, cited 15 Mar 2013]. Available from: http://www.nhlbi.nih.gov/health/health-topics/topics/cpap/ National Stroke Foundation [Internet]. Stroke Related Sleep Disorders. National Stroke Foundation c2005 [cited 13 Mar 2013]. Available from: http://www.stroke.org/site/docserver/sleepq.pdf?docid=862 Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008 Oct 15;4(5):487-504. Taylor DJ, Mallory LJ, Lichstein KL, Durrence HH, Riedel BW, Bush AJ. Comorbidity of chronic insomnia with medical problems. Sleep. 2007 Feb;30(2):213-8. 56 14
REFERENCES (CONT.) U.S. Food and Drug Administration [Internet]. Consumer Updates. U.S. Department of Health and Human Services Available from: www.fda.gov/consumer/features/sleepdrugs073107.html U.S. Food and Drug Administration [Internet]. Zolpidem Containing Products: Drug Safety Communication - FDA Requires Lower Recommended Doses. U.S. Department of Health and Human Services [updated 1 Jan 2013, cited 14 Mar 2013]. Available from: http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalpr oducts/ucm334738.htm University of Maryland Medical Center [Internet]. Obstructive sleep apnea - Dental Devices. c2011 University of Maryland Medical Center [updated 23 Jun 2009, cited 15 Mar 2013]. Available from: http://www.umm.edu/patiented/articles/what_dental_devices_used_treat_sleep_apnea_000 065_9.htm UpToDate [database on the Internet]. Overview of insomnia. Waltham, MA: UpToDate, Inc.; c2013. Available from: www.uptodate.com Victor LD. Obstructive sleep apnea. Am Fam Physician. 1999 Nov 15;60(8):2279-86. Wells BG, DiPiro JT, Schwinghammer TL, DiPiro CV. Sleep Disorders. In: Pharmacotherapy Handbook. 7th ed. New York, NY: McGraw-Hill;2009:814. Young T, Rabago D, Zgierska A, Austin D, Laurel F. Objective and subjective sleep quality in premenopausal, perimenopausal, and postmenopausal women in the Wisconsin Sleep Cohort Study. Sleep. 2003 Sep;26(6):667-72. QUESTIONS? 57 58 15