Sleep-Wake Disorders PDF

Sleep-Wake Disorders Sulaiman Almohaish PharmD, BCPS Clinical Assistant Professor of Pharmacotherapy Objectives Define sleep disorder Understand the differences between different sleep disorders Understand the diagnosis and treatment assessment Review different therapy plans and choose the...

Sleep-Wake Disorders Sulaiman Almohaish PharmD, BCPS Clinical Assistant Professor of Pharmacotherapy Objectives Define sleep disorder Understand the differences between different sleep disorders Understand the diagnosis and treatment assessment Review different therapy plans and choose the right therapy for each patient Stages of Sleep Nonrapid eye movement (Non-REM) sleep – 75% of total sleep Rapid eye movement (REM) sleep – 25% of total sleep Non-REM Sleep N1: Transition from wakefulness to deeper sleep Usually lasts between 15-30 minutes N2: Intermediate sleep (lighter alpha-wave sleep) Sleep spindles and k-complexes seen on EEG N3 (+/- N4): Deep sleep (delta sleep) Most likely has a restorative function (e.g. protein synthesis, wound healing, and restoration of immune function) REM Sleep Characterized by Two states Inactivity of all voluntary muscles Phasic with the exception of the Sudden bursts of sympathetic extraocular muscles nervous system (SNS) activity associated with rapid eye movement Rapid eye movements Sudden increases in arterial blood Associated with dreaming pressure, cardiac arrhythmias and sudden changes in heart and respiratory rates Tonic Parasympathetically driven state with no eye movements, decreased EEG amplitude, and atonia Physiological Changes During Sleep Autonomic activity Neuroendocrine activity Non-REM: Slow, regular HR and RR Cortisol concentrations are lowest REM: Irregular HR, RR, and BP at sleep onset with rapid fluctuations Growth hormone released during delta sleep Body temperature Melatonin secretion increases Poikilothermic in REM sleep during sleep and suppressed by Lowest in early morning bright light Nocturnal erections during REM sleep in males Sleep Changes with Age Both quantity and quality of sleep change N3 declines with age N1 increased with age Number of arousals and amount of wakefulness also increase with older age Why Do We Need to Sleep Anyway? Theories of Sleep Restorative Theory of Sleep (sleep restores tissues and prepares for the body for the next day) Adaptive Theory of Sleep (sleep increases survival) Energy Conservation Theory (low metabolism for energy conservation) The average person requires 8 hours of sleep each night Recent studies have shown 7 hours may be more optimal in terms of health Risks of Poor Sleep Increased mortality Increased heart attacks Similar to alcohol impairment in terms of increased automobile accidents Obesity (increased cortisol, insulin resistance, etc) Pain condition worsened ADHD symptomatology Sleep Studies Measurement of Sleep and Sleepiness Polysomnography Multiple sleep latency test (MSLT) Maintenance of wakefulness test (MWT) Sleep Parameters Sleep onset latency (LSO) Time that it takes to transition from wakefulness to sleep. Normal is ~15 minutes Latency to persistent sleep (LPS) Time from lights out until the first 10 minutes of consistent sleep Total sleep time (TST) Total sleep period (time in bed) minus the time spent awake Wake time after sleep onset (WASO) Time spent awake after initial sleep onset until final awakening Sleep efficiency (SE) The ratio of TST divided by the time spent in bed. Greater than or equal to 85% is considered normal Polysomnography Simultaneous recording of several physiologic variables by attaching electrodes to the scalp, face, eyes and chin Other physiological parameters may be measured Airflow and breathing effort Oxyhemoglobin saturation Leg movements Electrocardiogram Body position Multiple Sleep Latency Test (MSLT) Objective measure of daytime Mean sleep latency computed sleepiness ≤ 5 minutes: Severe daytime sleepiness Patient given 4-5 opportunities to nap ≥ 15 minutes: Normal alertness on a bed in a darkened room for up to Abnormal REM sleep during 2 or more 15 minutes of sleep naps may be indicative of narcolepsy EEG, eye movements, muscle tone measured Latency from wakefulness to sleep onset also measured Maintenance of Wakefulness Test Patients are asked to stay awake as long as possible while reclining in a dark quiet room May be a more practical method to determine whether a person’s sleepiness is likely to impair his/her ability to drive or work Standardized Rating Scales Pittsburgh Sleep Quality Index (PSQI) Epworth Sleepiness Scale (ESS) Stanford Sleepiness Scale (SSS) Insomnia Severity Index (ISI) Dysfunctional Beliefs and Attitudes about Sleep Questionnaire (DBAS) Insomnia Severity Index (ISI) Pittsburgh Sleep Quality Index (PSQI) Epworth Sleepiness Scale Self-rated Cut-off scores vary among institutions 8-9: Usually considered the average amount of daytime sleepiness 10-15: Very or excessively sleepy >16: Dangerously sleepy Treatment Goals Improvement in sleep quality and/or time Improvement of insomnia-related daytime impairments Improvement of energy Attention or memory difficulties Cognitive dysfunction Fatigue Symptomatic symptoms Reduce sleep latency and wakefulness after sleep onset Increase total sleep time Sleep Disorders Insomnia Disorder Rapid Eye Movement Sleep Narcolepsy Behavior Disorder Circadian Rhythm Sleep-Wake Restless Legs Syndrome Disorder Nightmare Disorder Hypersomnia Sleep Terror Disorder Breathing-Related Sleep Sleepwalking Disorder Disorder Insomnia Disorder Insomnia Disorder A subjective report of difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity for sleep, and that result in some form of daytime impairment  Transient lasts a few days and usually associated with a stressful event Short-term lasts up to 4 weeks and is usually associated with an acute or situational stressors Long-term lasts more than 4 weeks Risk Factors Situational Pharmacologically induced Jet lag or shift work Diuretics, steroids, stimulants, antiseizure medications Work or financial stress, major life events Medical CV, Endocrine disorders, GI, respiratory, chronic pain, pregnancy Psychiatric Mood disorders, substance use disorders Smoking or caffeine dependence Neurotransmitter Pathophysiology Sleep Promoting Substances Wake Promoting Substances Gamma aminobutryic acid Norepinephrine (GABA) Acetylcholine Adenosine Histamine Melatonin Dopamine Orexin Signs and Symptoms Difficulty falling asleep Difficulty maintaining sleep Difficulty returning to sleep Frequent awakenings Waking too early Excessive daytime sleepiness Difficulty concentrating Memory impairment Nonpharmacological Treatment Stimulus control procedures 1. Establish regular time to wake up and to go to sleep 2. Sleep only as much as necessary to feel rested 3. Go to bed only when sleepy 4. Avoid trying to force sleep; if you do not fall asleep within 20 - 30 minutes, leave the bed and perform a relaxing activity (eg, read, listen to music) until drowsy 5. Avoid blue spectrum light from television, smart phones, tablets, and other mobile devices. 6. Avoid daytime naps 7. Schedule worry time during the day. Do not take your troubles to bed Nonpharmacological Treatment Sleep hygiene recommendations 1.Exercise routinely (eg, three to four times weekly) but not close to bedtime because this can increase wakefulness 2. Create a comfortable sleep environment by avoiding temperature extremes, loud noises, and illuminated clocks in the bedroom 3. Discontinue or reduce the use of alcohol, caffeine, and nicotine 4. Avoid drinking large quantities of liquids in the evening. 5. Do something relaxing and enjoyable before bedtime Pharmacological vs Nonpharmacological Treatment Pharmacotherapy Cognitive Behavioral Therapy Effective during the course of (CBT) treatment for chronic insomnia Significant improvement of chronic insomnia in the short-term Does not provide sustained improvement following Improvement appears to be discontinuation sustained for up to two years Pharmacological Treatment Stages Short-to-intermediate acting benzodiazepine receptor agonists (BzRAs) or melatonin receptor agonist Alternate BzRA or melatonin receptor agonist Sedating antidepressants (e.g. trazodone, mirtazapine, amitriptyline) BzRA or melatonin receptor agonist plus sedating antidepressant Other sedating agents (antipsychotics such as quetiapine and olanzapine)  Benzodiazepines Medication Approved FDA Uses* Duration Dosing Triazolam A, F Short Adult: 0.25-0.5 mg Elderly: 0.125 mg Estazolam A, C, D, E Short-to intermediate Adult: 1-2 mg Elderly: 0.5-1 mg Temazepam A, C Short-to-intermediate Adult: 15-30 mg Elderly: 7.5-15 mg Quazepam A, C, D, E Long Adult: 7.5-30 mg Elderly: ----- Flurazepam B, C, D, E Long Adult: 15-30 mg Elderly: ----- A=Short term treatment of insomnia; B=Insomnia; C=Difficulty falling asleep; D=Frequent nocturnal awakenings; E=Early morning awakening; F=Sleep onset  Benzodiazepine receptor agonists (BzRAs) Medication Approved Duratio Dosing FDA Uses* n Zaleplon A < 4 hrs Adults: 5-20 mg Elderly: 5-10 mg Eszopiclone A, B > 6 hrs Sleep onset: 2 mg Sleep maintenance: 3 mg Elderly: 1-2 mg Zolpidem A ~ 6 hrs Adult males: 10 mg Adult females/elderly: 5 mg Zolpidem SL A ,C < 4 hrs Adult males: 10 mg/3 mg Adult females/elderly: 5 mg/1.75 mg Zolpidem CR A, B > 6 hrs Adult males: 12.5 mg Adult females/elderly: 6.25 mg A=Sleep onset; B=Sleep maintenance; C=Middle-of-the-night wakening followed by difficulty returning to sleep Adverse Events Benzodiazepines Non-Benzodiazepines CNS depression Headache Development of tolerance Next day somnolence Next day “residual” or “hangover” CNS depression effects Sleep-related behavior Rebound insomnia Hallucinations in pediatrics Psychomotor impairment (zolpidem) Respiratory depression Unpleasant taste (eszopiclone) Paradoxical reactions Sleep-related behavior Pregnancy/Lactation Benzodiazepines Non-Benzodiazepines Associated with a slight risk of cleft Use only if benefit outweighs risk palate Breast feeding not recommended Use in late pregnancy can cause with zaleplon (use caution with respiratory issues and CNS others especially during peak blood depression in the neonate levels which typically occur ~1 hour Withdrawal and “floppy baby after ingestion) syndrome” have been reported Generally, not recommended during breast feeding (if used, monitor infant for increased sedation and reduced feeding) Melatonin Receptor Agonist Ramelteon M1 and M2 receptor agonist Concerns Sleep-onset insomnia Sleep-related activities Abnormal thinking/behavioral Dose: 8 mg changes Short-acting Worsening depression and suicidal ideation Maximal effect may take up to 3 Hypersensitivity reactions weeks of nightly use (angioedema) Reproductive hormonal regulation disturbances Only use in pregnancy if risk outweighs benefit. Not recommended for use during lactation. Doxepin Low dose TCA, selective H1 Contraindications antagonist activity Severe urinary retention Sleep maintenance Untreated narrow angle glaucoma Severe sleep apnea Taken with a high fat meal will delay Tmax by ~3 hrs Concerns Next day somnolence CYP2C19 interactions Worsening of depression/suicidal Dosing thinking Adults: 6 mg GI symptoms Elderly: 3 mg Hypertension Pregnancy Category C. Peak levels approximately 4-5 hours post-ingestion. Suvorexant Orexin receptor antagonist Dosing: 10 mg nightly (usual), 20 mg nightly (max), need to administer at least 7 hours before planned awakening and without food CYP3A4 interactions Similar sleep behaviors as other agents Use with caution in patients with depression Increased exposure in females and obese patients Antidepressants Certain antidepressants (amitriptyline, doxepin, mirtazapine, paroxetine, trazodone) are employed in lower than antidepressant therapeutic dosages for the treatment of insomnia. These medications are not FDA approved for insomnia and their efficacy for this indication is not well established. OTC Products Antihistamines: Valerian (300-600 mg) 1/ Diphenhydramine & Doxylamine Thought to act upon GABA 2/ Mild insomnia, sleep induction only Small but consistent effects on sleep latency 3/ Tachyphylaxis, Anticholinergic Inconsistent effects on sleep 4/ Tolerance may develop if used > continuity, sleep duration and sleep 10 days architecture Melatonin Small effects on sleep latency Little effect on wake after sleep onset and total sleep time Best for circadian rhythm disorders not insomnia Considered safe for short term use Duration of Treatment Initial treatment period of 2-4 weeks Ongoing therapy if severe, chronic insomnia Regular follow-up visits at least every 6 months to monitor efficacy, side effects, tolerance and abuse/misuse of medications Attempt periodically to reduce frequency/dose in order to minimize side effects and determine lowest effective dose Discontinuation If hypnotic is used for more than a few days  gradually taper both the dose and frequency of administration Rebound insomnia and withdrawal lasts 1-3 days Worsening of symptoms Potential physical/psychological withdrawal effects Recurrence of insomnia Narcolepsy Narcolepsy Irresistible attacks of refreshing sleep occurring almost daily (Excessive Daytime Sleepiness “EDS”) for at least 3 months plus one or both of the following: Cataplexy (60-70%) Sudden loss of muscle tone, triggered by emotions Lasts < 2 minutes and patient remains conscious Abnormal manifestations of REM sleep Hallucinations that occur on falling asleep (hypnagogic) and/or awakening (hypnopompic) Sleep paralysis occurs at onset or termination of sleep Treatment of EDS Schedule naps Modafinil  Fewer peripheral and cardiovascular side effects SE: headache, nausea, nervousness, anxiety, insomnia Methylphenidate, amphetamines  More side effects than Modafinil SE: insomnia, hypertension, palpitations, irritability CNS stimulants Suppress REM sleep which may help control cataplexy and REM- sleep abnormalities Use caution in cardiovascular, cerebrovascular disease or seizures Selegiline is another possible option Treatment of Cataplexy and REM-Associated Effects Sodium oxybate  FDA approved  Take one dose at bedtime and another dose 2.5-4 hours later Treatment of Cataplexy and REM-Associated Effects Unapproved options TCAs: Clomipramine, protriptyline, and imipramine SSRI: Fluoxetine SNRI: Venlafaxine Low dose selegiline Circadian Rhythm Sleep-Wake Disorder Circadian Rhythm Sleep-Wake Disorder Sleep-wake patterns are misaligned with the societal clock on a persistent or recurrent basis Patients nap throughout the 24-hour period, but total sleep time is normal Can be induced by shift work, jet lag, and substance abuse May be seen in patients with dementia, mental retardation, and blindness Melatonin Receptor Agonist Tasimelteon (Hetlioz) M1 and M2 receptor agonist Concerns Dose: 20 mg/day PO Risk of adverse reactions may be increased in geriatric Therapeutic effect may not occur patients for weeks or months Headache Has not shown potential for abuse Nightmares/abnormal dreams Extensively metabolized, caution is advised in patients with mild to moderate hepatic impairment Pregnancy category C Obstructive Sleep Apnea Hypopnea  Obstructive Sleep Apnea Hypopnea Repetitive upper airway collapse during sleep Witnessed apneas, gasping or both Snoring, choking, nocturnal reflux symptoms and morning headache Risk factors: Obesity (BMI > 30 kg/m2) Large neck sizes Co-morbid hypertension Depression Hypothyroidism Obstructive Sleep Apnea Hypopnea Complications: All the health risks of poor sleep Association with hypertension (often resistant to treatment), heart failure and stroke Higher incidence of cardiovascular events Treatment Continuous positive airway pressure (CPAP) therapy (bi-level positive airway pressure or BiPAP is an alternative) Weight management Oral devices Surgical therapy Tracheostomy No drug treatment but modafinil may be used to treat symptoms Rapid Eye Movement Sleep Behavior Disorder Rapid Eye Movement Sleep Behavior Disorder Acting out dreams during sleep, often in a violent manner Treatment Clonazepam 0.5-2 mg at bedtime Can also use melatonin 3-12 mg at bedtime Remove dangerous objects from the bed Cushions on floor Restless Legs Syndrome (RLS) Restless Legs Syndrome (RLS) Creepy-crawly, burning, tingly achy feelings that create a desire to move limbs Worse in the evening and at rest but can also occur during sleep Goal: Suppress abnormal sensations and leg movements Low iron levels can make symptoms worse so iron supplementation should be used in patients who are iron-deficient RLS Medication Options Class Medications Disadvantage Dopamine Levodopa/carbidopa Nausea/vomiting, high incidence of agonists (Sinemet®) symptom augmentation Pramipexole (Mirapex®), Nausea/vomiting, risk of compulsive ropinirole (Requip®), behavior rigotine (Neupro®) Cabergoline (Dostinex®) Fibrosis, valvulopathy, use reserved for refractory cases only, benefit must outweigh risk Anticonvulsants Gabapentin (Neurontin®) Dizziness, ataxia Hypnotic agents Clonazepam (Klonopin®), Tolerance, carryover sedation temazepam (Restoril ) Zolpidem (Ambien®) Tolerance Zaleplon (Sonata®) Tolerance, may not last the entire night Opioids Hydrocodone, codeine, Constipation, nausea, sedation oxycodone, tramadol Questions?