Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

55. Sleep Disorders

John M. Dopp and Bradley G. Phillips


KEY CONCEPTS

 Images Common causes of insomnia include concomitant psychiatric disorders, significant psychosocial stressors, excessive alcohol use, caffeine intake, and nicotine use.

 Images Good sleep hygiene, including relaxing before bedtime, exercising regularly, establishing a regular bedtime and wake-up time, and discontinuing alcohol, caffeine, and nicotine, alone and in combination with drug therapy, should be part of patient education and treatments for insomnia.

 Images Long-acting benzodiazepines should be avoided in the elderly.

 Images Benzodiazepine tolerance and dependence are avoided by using low-dose therapy for the shortest possible duration.

 Images Obstructive sleep apnea may be an independent risk factor for the development of hypertension. When hypertension is present, it is often refractory to drug therapy until sleep-disordered breathing is alleviated.

 Images Nasal continuous positive airway pressure is the first-line therapy for obstructive sleep apnea, and weight loss should be encouraged in all obese patients.

 Images Pharmacologic management of narcolepsy is focused on two primary areas: treatment of excessive daytime sleepiness and rapid eye movement (REM) sleep abnormalities.

 Images Short-acting benzodiazepine receptor agonists, ramelteon, or melatonin taken at appropriate target bedtimes for east or west travel reduce jet lag and shorten sleep latency.

 Images Dopamine agonists are effective for restless legs syndrome and have replaced levodopa as first-line therapy.


Approximately 70 million Americans suffer with a sleep-related problem, and as many as 60% of those experience a chronic disorder.1 In a study by the National Institute on Aging, of 9,000 patients aged 65 years and older, more than 80% report a sleep-related disturbance.1

INTRODUCTION TO SLEEP

Sleep Cycles

Sleep is divided into two phases: nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. Each night humans typically experience four to six cycles of NREM and REM sleep, with each cycle lasting between 70 and 120 minutes.2 There are four stages of NREM sleep. Healthy sleep will typically progress through the four stages of NREM sleep prior to the first REM period. From wakefulness, sleep typically progresses quickly through stages 1 and 2. Stage 1 of NREM sleep is the stage between wakefulness and sleep, and individuals describe this experience as being awake, being drowsy, or being asleep. During stages 3 and 4 NREM, both metabolic activity and brain waves slow. This slow-wave sleep occurs most frequently early in the sleep period. Stages 3 and 4 sleep are called delta sleep, as the sleep is characterized by high-amplitude slow activity known as delta waves (0.5 to 3 Hz) with no eye movements and low tonic muscle activity.

REM sleep involves a dramatic physiologic change from NREM sleep, to a state in which the brain becomes electrically and metabolically activated.2 REM occurs in bursts and is accompanied by a 62% to 173% increase in cerebral blood flow, generalized muscle atonia, bursts of bilateral REMs, poikilothermia, dreaming, and fluctuations in respiratory and cardiac rate.2 REM cycles tend to lengthen in the later stages of the sleep cycle.2

Circadian Rhythm

At birth human infants spend up to 20 hours a day sleeping. At 3 to 6 months of age there is a differentiation between REM and NREM sleep. By age 3 years the ultradian sleep–wake rhythm changes to a circadian pattern. The suprachiasmatic nucleus of the brain serves as the biologic clock and paces the circadian rhythm. Although the length of a day is 24 hours, in environments devoid of light cues, the sleep–wake cycle lasts about 25 hours.3 In midlife, there is a gradual decline in sleep efficiency and sleep time.2 The elderly have lighter and more fragmented sleep, with intermittent arousals, shifts in the sleep stages, and a gradual reduction of slow-wave sleep.

Neurochemistry

The neurochemistry of sleep is complex, as sleep cannot be localized to either a specific area of the brain or a neurotransmitter. NREM sleep appears to be controlled by the basal forebrain, the lower brain stem to the thalamus, and hypothalamus.3 Numerous neurotransmitters mediate NREM sleep, including γ-aminobutyric acid (GABA) and adenosine.3 REM sleep appears to be turned on by cholinergic cells in the mesencephalic, medullary, and pontine gigantocellular regions. REM sleep appears to be turned off by the dorsal raphe nucleus, the locus coeruleus, and the nucleus para-brachialis lateralis, the latter two of which are primarily noradrenergic. The ascending reticular activating system and the posterior hypothalamus facilitate arousal and wakefulness.4 Dopamine has an alerting effect; decreases in dopamine promote sleepiness.5 Neurochemicals involved in wakefulness include norepinephrine and acetylcholine in the cortex and histamine and neuropeptides such as substance P and corticotropin-releasing factor in the hypothalamus.5,6

Polysomnography

Sleep is typically measured and observed in sleep laboratories using an electroencephalogram (EEG), electrooculograms of each eye, electrocardiogram, electromyogram, air thermistors, abdominal and thoracic strain belts, and oxygen saturation monitor. This study is named polysomnography (PSG) and is used to assess and record variables that characterize sleep and aid in diagnosis of sleep disorders. Variables obtained during PSG include sleep onset, arousals, sleep stages, eye movements, leg and jaw movements, arrhythmias, airflow during sleep, respiratory effort, and oxygen desaturations. Home sleep monitoring that measures variables such as electrocardiogram, oxygen saturation, airflow, and respiratory effort is also increasingly used to diagnose sleep apnea.

CLASSIFICATION OF SLEEP DISORDERS

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) classifies sleep disorders into four categories based on etiology and requires a symptom duration of at least 1 month before a sleep disorder can be diagnosed.7,8 Primary sleep disorders are those disorders in which there is no other etiology (mental disorder, substance-related disorder, or medical condition) responsible for the disorder. They appear to be based on an endogenous abnormality of the sleep–wake cycle or circadian rhythm, and they are divided into dyssomnias (abnormality in the amount, quality, or timing of sleep) and parasomnias (abnormal behavioral or physiologic events associated with sleep, e.g., sleepwalking and REM behavior disorder). Dyssomnias include sleep disorders such as insomnia, narcolepsy, obstructive sleep apnea (OSA), and circadian rhythm disorders.

Insomnia

Insomnia is the most common complaint in general medical practice.9 It causes distress, frequently because of a fear or a feeling of not being able to fall asleep at bedtime, and can impair work-related productivity because of daytime fatigue or drowsiness. Insomnia is subjectively characterized as a complaint of difficulty falling asleep, difficulty maintaining sleep, or experiencing nonrestorative sleep.7,8Insomnia lasting two or three nights is considered to be transient insomnia, whereas short-term insomnia usually resolves in less than 3 weeks. Insomnia, according to the DSM-IV-TR, is considered to be chronic when it lasts longer than 1 month.8

Epidemiology

Primary insomnia usually begins in early or middle adulthood and is rare in childhood or adolescence. Symptoms of insomnia occur in 33% to 50% of the adult population.9 A 1-year prevalence study of insomnia in the United States reports that one third of the individuals surveyed complained of insomnia, and 17% reported that the symptoms were serious.1 Conservative estimates of chronic insomnia range from 9% to 12% in adulthood and up to 20% in the elderly.1,10 Although young adults are more likely to complain that they have difficulty falling asleep, middle-aged and elderly adults are more likely to complain that they have middle-of-the-night awakening or early morning awakening. Women complain of insomnia twice as frequently as men. Individuals who are elderly, unemployed, separated, or widowed, and those with a lower socioeconomic status report a significantly higher incidence of insomnia than the general population. Forty percent of individuals with insomnia also have a concurrent psychiatric disorder (anxiety, depression, or substance abuse).11

Approximately 10% to 20% of those with insomnia use nonprescription drugs or alcohol to self-treat.

Differential Diagnosis

Primary insomnia is considered to be an endogenous disorder caused by either a neurochemical or a structural disorder affecting the sleep–wake cycle. Individuals with primary insomnia can be light sleepers who are easily aroused by noise, temperature, or anxiety. Some studies suggest that primary insomnia is a “hyperarousal state,” in that insomnia patients have increased metabolic rates compared with controls and thus take longer to fall asleep.2 Comorbid or secondary insomnia is frequently a symptom or manifestation of another medical disorder. Evaluation of patients with a complaint of transient or short-term insomnia should focus on recent stressors, such as a separation, a death in the family, a job change, or college exams.

Images Chronic insomnia is frequently comorbid with psychiatric or medical conditions. A complete diagnostic examination should be completed in these individuals and should include routine laboratory tests, physical and mental status examinations, as well as ruling out any medication- or substance-related causes.12 Special consideration should also be given to other sleep disorders that can have a similar presentation, including restless legs syndrome (RLS), periodic limb movements of sleep (PLMS), and sleep apnea. Common causes of insomnia are listed in Table 55-1.

TABLE 55-1 Common Etiologies of Insomnia

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TREATMENT

Desired Outcomes

The goals of treatment of insomnia are to correct the underlying sleep complaint, consolidate sleep, improve daytime functioning and sleepiness, and avoid adverse effects from selected therapies. Drug therapy should be used in the lowest possible dose, for the shortest possible time period.

Treatment Principles

Therapeutic management of insomnia is initially based on whether the individual has experienced a transient, short-term, or chronic sleep disturbance. Clinical history should assess the onset, duration, and frequency of the symptoms; effect on daytime functioning; sleep hygiene habits; and history of previous symptoms or treatment.13 Management of all patients with insomnia should include identifying the cause of the insomnia, patient education on sleep hygiene, and stress management. Any unnecessary pharmacotherapy should be eliminated.10 Transient insomnia, which occurs as a result of an acute stressor, is expected to resolve quickly and should be treated with good sleep hygiene and careful use of sedative–hypnotics.11 Short-term insomnia, associated with situational, personal, or medical stress, can be treated similarly.13 Chronic insomnia requires careful assessment for possible underlying medical causes, nonpharmacologic approaches, and careful use of sedative–hypnotics.12

Nonpharmacologic Therapy

Images In many cases insomnia can be treated without sedative–hypnotics. Education about normal sleep and habits for good sleep hygiene are important for all patients with insomnia. Nonpharmacologic interventions for insomnia frequently consist of short-term cognitive behavioral therapies, most commonly stimulus control therapy, sleep restriction, relaxation therapy, cognitive therapy, paradoxical intention, biofeedback, and education on good sleep hygiene (Table 55-2).10,14 In patients aged 55 and older, research indicates that cognitive behavioral therapy may be more effective than pharmacologic therapy at improving certain measures of insomnia.15,16

TABLE 55-2 Nonpharmacologic Recommendations for Management of Insomnia

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Pharmacologic Therapy

Miscellaneous Agents

Antihistamines exhibit sedating properties and are included in many nonprescription sleep agents. They are effective in the treatment of mild insomnia and are generally safe.13 Diphenhydramine and doxylamine are more sedating than pyrilamine. Patients quickly experience tolerance to sedative effects, and increasing the dose of antihistamines will not produce a linear increase in response. Antihistamines are considered to be less effective than benzodiazepines, and they have the disadvantages of anticholinergic side effects, which are especially troublesome in the elderly.13,17

Antidepressants are alternatives for patients with nonrestorative sleep who should not receive benzodiazepines, especially those who have depression, pain, or a risk of substance abuse. Using antidepressants for insomnia without depression is common but not well studied, and the doses used for treating insomnia are not effective antidepressant doses.9,13,14 Sedating antidepressants such as amitriptyline, doxepin, and nortriptyline are effective for inducing sleep continuity, although daytime sedation and side effects can be significant.9,13 Anticholinergic activity, adrenergic blockade, and cardiac conduction prolongation can be problematic, especially in the elderly and in overdose situations.9 Low-dose doxepin (3 to 6 mg) was recently FDA-approved for the treatment of sleep maintenance insomnia. Mirtazapine is a sedating antidepressant that may help patients sleep, but it may also cause daytime sedation and weight gain.

Trazodone in doses of 25 to 100 mg at bedtime is sedating and can improve sleep continuity.11 Trazodone is popular for the treatment of insomnia in patients prone to substance abuse, as dependence is not a problem with trazodone, and in patients with selective serotonin reuptake inhibitor and bupropion-induced insomnia.11 Other side effects include carryover sedation and α-adrenergic blockade. Orthostasis can occur at any age, but it is more dangerous in the elderly. Priapism is a rare but serious side effect.18

Ramelteon is a melatonin receptor agonist approved for the treatment of sleep-onset insomnia. It is selective for the MT1 and MT2 melatonin receptors that are thought to regulate the circadian rhythm and sleep onset. The recommended dose is 8 mg taken at bedtime to induce sleep. Although generally well tolerated, the most common adverse events reported are headache, dizziness, and somnolence. Ramelteon is not a controlled substance and can be a viable option for patients with a history of substance abuse. It effectively treats sleep-onset difficulties in patients with chronic obstructive pulmonary disease and sleep apnea.19,20

Valerian is a herbal sleep remedy that has been studied for its sedative–hypnotic properties in patients with insomnia. The mechanism of action is not fully understood but may involve increasing concentrations of GABA. The recommended dose for insomnia ranges from 300 to 600 mg. An equivalent dose of dried herbal valerian root is 2 to 3 g soaked in one cup of hot water for 20 to 25 minutes.21

Benzodiazepine Receptor Agonists

The most commonly used treatments for insomnia have been the benzodiazepine receptor agonists (BZDRAs). BZDRAs are effective as sedative–hypnotics and are FDA-labeled for the treatment of insomnia (Table 55-3). The FDA requires BZDRA labeling to include a caution regarding anaphylaxis, facial angioedema, and complex sleep behaviors (e.g., sleep driving, phone calls, sleep eating, etc.). The BZDRAs consist of the newer nonbenzodiazepine GABAA agonists and the traditional benzodiazepines. All BZDRAs bind to GABAA receptors in the brain, resulting in agonist effects on GABAergic transmission and hyperpolarization of neuronal membranes. Traditional benzodiazepines have sedative, anxiolytic, muscle relaxant, and anticonvulsant properties; newer nonbenzodiazepine GABA agonists possess only sedative properties.

TABLE 55-3 Pharmacokinetics of Benzodiazepine Receptor Agonists

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Benzodiazepine Hypnotics

Benzodiazepines relieve insomnia by reducing sleep latency and increasing total sleep time. They increase stage 2 sleep while decreasing delta sleep.11 Benzodiazepine hypnotics should not be prescribed for individuals who are pregnant or who have untreated sleep apnea or a history of substance abuse. Patients should be instructed to avoid alcohol and other CNS depressants.

Adverse Effects Side effects are dose dependent and vary according to the pharmacokinetics of the individual benzodiazepine. High doses with long or intermediate elimination half-lives have a greater potential for producing daytime sedation, psychomotor incoordination, and cognitive deficits. Most traditional benzodiazepines maintain hypnotic efficacy for 1 month. However, tolerance can develop with time.

Anterograde amnesia, an impairment of memory and recall of events occurring after the dose is taken, has been reported with most BZDRAs (it is more likely to occur with short-acting agents).11 Rebound insomnia, characterized by increased wakefulness beyond baseline amounts that last for one to two nights after abrupt discontinuation, occurs with BZDRAs. The lowest effective dosage should be used to minimize rebound insomnia and avoid adverse effects on memory.

Images Benzodiazepine half-lives are prolonged in older patients, increasing the potential for drug accumulation and the incidence of CNS side effects, including prolonged sedation and cognitive and psychomotor impairment. BZDRAs with long elimination half-lives (e.g., flurazepam and quazepam) are generally not first-line agents in these patients. Benzodiazepine use is associated with increased risk of falls and hip fractures in the elderly, but since insomnia itself increases fall and fracture risk, it is unclear if benzodiazepines increase risk independent of sleep problems.22


Clinical Controversy…

Recent population studies suggest that use of sedative–hypnotics may be associated with increased mortality. Even though causality cannot be established based on the evidence to date, these studies raise important concerns. Although the evidence does not warrant discontinuation of hypnotics, it reemphasizes the importance of using sedative–hypnotics prudently at the lowest dose possible, for the shortest duration necessary.

Nonbenzodiazepine GABAA Agonists

Zolpidem, zaleplon, and eszopiclone are nonbenzodiazepine hypnotics that selectively bind to GABAA receptors and effectively induce sleepiness. Zolpidem has a duration of action of 6 to 8 hours.23 It is comparable in efficacy to benzodiazepine hypnotics and is effective for reducing sleep latency and nocturnal awakenings and increasing total sleep time. It does not appear to have significant effects on next-day psychomotor performance. Sustained-release, sublingual, and reduced-strength (1.75 and 3.5 mg) formulations of zolpidem are available and are used to increase total sleep time, to reduce sleep latency, and for middle-of-the night rescue dosing, respectively.

Zolpidem is less disruptive of sleep stages than benzodiazepines. Adverse effects are dose related and can include drowsiness, amnesia, dizziness, headache, and GI complaints.23 Sleep eating during zolpidem therapy can result in significant weight gain.23 The recommended daily dose of zolpidem is 10 or 5 mg in elderly patients and those with hepatic impairment. Because food decreases its absorption, zolpidem should be taken on an empty stomach.24

Zaleplon has a rapid onset of action and a half-life of 1 hour, and it is metabolized to inactive metabolites.25 It is effective for decreasing time to sleep onset but not for reducing nighttime awakening or for increasing total sleep time.26 Because of its short half-life, zaleplon has no effect on next-day psychomotor performance and can be used as a sleep aid for middle-of-the-night awakenings.27 The recommended dose is 10 mg in adults and 5 mg in the elderly.25 The most common adverse effects with zaleplon are dizziness, headache, and somnolence. There are two drug interactions of note: zaleplon plasma levels are increased when combined with cimetidine and decreased with rifampin.23

Eszopiclone is effective at reducing time to sleep onset, wake time after sleep onset, and number of awakenings, and increasing total sleep time and sleep quality. Eszopiclone’s duration of action is up to 6 hours,28 so it can be a good option for treatment of sleep maintenance insomnia or early morning awakenings. The most common adverse effects with eszopiclone are somnolence, unpleasant taste, headache, and dry mouth.28 Eszopiclone is labeled for long-term use and may be taken nightly for up to 6 months.28,29

Other Considerations

In general, the nonbenzodiazepine hypnotics seem to be associated with less withdrawal, tolerance, and rebound insomnia than the benzodiazepine hypnotics. None of the nonbenzodiazepine GABAA agonists have significant active metabolites.

Evaluation of Therapeutic Outcomes

An algorithm for the evaluation and treatment of dyssomnias is shown in Figure 55-1. Patients with short-term or chronic insomnia should be evaluated after 1 week of therapy to assess for drug efficacy, adverse effects, and adherence to nonpharmacologic recommendations.

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FIGURE 55-1 Algorithm for treatment of dyssomnias. (BZDRA, benzodiazepine receptor agonist; CPAP, continuous positive airway pressure.) (Adapted with permission from reference 30.)

Patients should be instructed to keep a sleep diary. The diary requires daily recording of bedtime, wake time, latency of sleep onset, number and duration of awakenings, medication ingestion, naps, and an index of sleep quality. For patients with chronic insomnia, possible medical, psychiatric, and pharmacologic causes should be identified and managed.11 Patients with insomnia should receive education about possible medication side effects and their management.

Images Clinicians should educate patients about the concepts of tolerance, withdrawal, and rebound insomnia. Tolerance and dependence can be avoided by using hypnotics at the lowest possible dose, intermittently, and for the shortest duration possible. Patients should receive instruction about frequency of drug use and the expected duration of therapy, to help prevent development of dependence. Withdrawal symptoms can be diminished by tapering the dosage gradually.

SLEEP APNEA

Sleep apnea is a common disease, affecting 20 to 25 million Americans. It has a higher prevalence in men, particularly in African American and Hispanic populations.31,32 Sleep apnea also occurs in children and adolescents. It is characterized by repetitive episodes of cessation of breathing during sleep followed by blood oxygen desaturation and brief arousal from sleep to restart breathing. As a result, individuals with sleep apnea experience fragmented sleep, poor sleep architecture, and periods of apnea and hypopnea. PSG is used to diagnose and quantify sleep apnea as central, obstructive, or mixed. Central sleep apnea (CSA) involves impairment of the respiratory drive, whereas OSA is caused by upper airway collapse and obstruction. Patients with mixed sleep apnea experience both CSA and OSA. Severity of sleep apnea is determined by the number of apnea (total cessation of airflow) and hypopnea (partial airway closure with blood oxygen desaturation) episodes documented by PSG, which is expressed as the respiratory disturbance index (RDI). Mild sleep apneics have an RDI of between 5 and 15 episodes/h, moderate 15 to 30 episodes/h, whereas individuals with severe OSA exhibit more than 30 episodes/h.

OSA is associated with motor vehicle accidents, depression, increased cancer risk, stroke, and cardiovascular disease.3336 Alleviation of sleep-disordered breathing may improve patient outcomes, particularly those related to cardiovascular disease.36

Obstructive Sleep Apnea

OSA is characterized by partial or complete closure of the upper airway, posterior from the nasal septum to the epiglottis, during inspiration. The reason for the loss of upper airway patency is not fully understood and is likely caused by several competing factors. Anatomical factors including neck obesity, narrow airway, and fixed upper airway lesions (e.g., polyps, enlarged tonsils) can narrow the upper airway. Intraluminal negative pressure generated during each inspiration also promotes collapse of the upper airway that competes with dilating forces, primarily the pharyngeal dilator muscle. Acromegaly, amyloidosis, and hypothyroidism as well as neurologic conditions that impair upper airway muscle tone may cause OSA. The hallmarks of OSA are witnessed apneas, gasping, or both. Other recognized signs, symptoms, and considerations of sleep apnea include obesity, snoring, daytime sleepiness, family history, and hypertension.

Images OSA is increasingly linked to cardiovascular and cerebrovascular morbidity and mortality, independent of other risk factors.36 Individuals with OSA are at risk for developing hypertension, and when hypertension is present, it is often resistant to drug therapy.37 Alleviation of sleep-disordered breathing (with nasal continuous positive airway pressure [CPAP]) can improve blood pressure and attenuate some of the potential hemodynamic and neurohumoral responses that may link OSA to systemic disease.38,39

TREATMENT

Obstructive Sleep Apnea

Desired Outcomes

In the absence of an underlying cause (e.g., hypothyroidism, acromegaly), alleviation of sleep-disordered breathing and prevention of associated complications are the primary goals of treatment. Nonpharmacologic measures are the treatments of choice. There is no drug therapy for OSA. However, medications that worsen sleep should be avoided. Practice parameters for the medical treatment of OSA have been published by the American Academy of Sleep Medicine.40

Nonpharmacologic Therapy

Positive Airway Pressure

Images Nasal positive airway pressure (PAP) during sleep is the standard treatment for most patients with OSA. PAP produces a positive pressure column in the upper airway using room air to maintain patency. A flexible tube connects the PAP machine to a mask that covers the nose.

PAP delivery may be continuous (CPAP) or bilevel, providing a reduced applied pressure during expiration. During PSG, the pressure setting is increased (up to 20 cm H2O) until sleep-disordered breathing is eliminated. Barriers to PAP adherence, such as ill-fitted mask and nasal dryness, can be managed. PAP nonadherence for one night results in a complete reversal of the gains made in daytime alertness.41 In the clinical setting, poor PAP adherence may impact blood pressure control and management in patients with OSA and hypertension.

Weight Reduction

Obesity can worsen sleep apnea, and weight management should be implemented for all overweight patients with OSA. OSA can predispose to weight gain, and in obese patients with mild OSA weight loss alone can be effective.42Individuals who are morbidly obese and have severe OSA can undergo gastric stapling for weight loss.

Surgery

Surgical therapy (uvulopalatopharyngoplasty) opens the upper airway by removing the tonsils, trimming and reorienting the posterior and anterior tonsillar pillars, and removing the uvula and posterior portion of the palate. This is not a first-line option because it is invasive. In very severe cases tracheostomy may be necessary. This procedure can be indicated for select individuals who are morbidly obese, have severe facial skeletal deformity, experience severe drops in oxygen saturation (e.g., less than 70%), or have significant cardiac arrhythmias associated with their OSA.

Other Therapies

For individuals who experience OSA only during certain sleep positions (e.g., when lying on their back), positional therapies can be effective alone but are usually used in conjunction with PAP therapy. Oral appliances can be used to advance the lower jawbone and to keep the tongue forward to enlarge the upper airway. These therapies should be considered when PAP therapy cannot be tolerated.43

Pharmacologic Therapy

The most important pharmacologic intervention is the avoidance of all CNS depressants (e.g., alcohol, hypnotics) and drugs that promote weight gain. Weight gain worsens OSA. CNS depressant use is potentially lethal, as it reduces the brain’s reflex ability to cause a mini-arousal and resume breathing. In addition, certain CNS depressants can relax airway muscles, promoting upper airway collapse. Medications that can cause rhinopharyngeal inflammation and cough as a side effect of therapy (i.e., angiotensin-converting enzyme [ACE] inhibitor) may also worsen sleep-disordered breathing.

There is no drug therapy for OSA. In clinical trials, serotonergic agents (e.g., fluoxetine, paroxetine), tricyclic antidepressants (TCAs) (i.e., imipramine, protriptyline), respiratory stimulants (theophylline), medroxyprogesterone, and clonidine do not clinically improve severity of OSA. The effects of antihypertensive agents on sleep apnea are inconsistent and are likely not clinically significant.

Wake-promoting medications (e.g., modafinil, armodafinil) are FDA-approved to improve wakefulness in patients who have residual excessive daytime sleepiness (EDS) while being treated with PAP. Initiation of therapy should be attempted in patients only after PAP therapy has been optimized to alleviate sleep-disordered breathing and EDS. Therapy should be avoided in those with concomitant cardiovascular disease. In patients with concurrent rhinitis, nasal steroids are recommended for use along with PAP therapy.

Evaluation of Therapeutic Outcomes

Individuals with sleep apnea should be evaluated after 1 to 3 months of treatment for improvement in alertness and daytime symptoms (e.g., sleepiness, memory, and irritability) and weight reduction. Individuals experiencing symptoms (e.g., daytime sleepiness, snoring, loss of blood pressure control) despite PAP therapy should have PSG repeated. Symptoms can recur if patients gain weight, requiring a higher pressure setting. Conversely, PAP pressure settings can be decreased if weight loss is achieved. Patient adherence to PAP therapy can be monitored by assessing the built-in compliance meter that measures the hours used at effective pressure.

Central Sleep Apnea

CSA causes fragmented sleep and consequent daytime somnolence. However, unlike OSA, arousals from sleep are not required to initiate airflow. During PSG, there is an absence of airflow out of the mouth and nose with no activation of the inspiratory muscles. The prevalence of CSA is not well established and is less than OSA. CSA can be idiopathic but more commonly is caused by underlying autonomic nervous system lesions (e.g., cervical cordotomy), neurologic diseases (e.g., poliomyelitis, encephalitis, and myasthenia gravis), high altitudes, opioid abuse, and congestive heart failure. For these reasons, potential underlying causes for CSA should be evaluated and treated. For example, worsening CSA in heart failure patients can signal the need to optimize heart failure therapies. Practice parameters for the treatment of CSA have been published by the American Academy of Sleep Medicine.44

Drug therapy for CSA is limited and is individualized for each patient, based on underlying etiology. Acetazolamide, which induces a metabolic acidosis that stimulates respiratory drive, and theophylline, which improves severity of CSA, have been studied but have minimal effects on clinical variables.45,46


CLINICAL PRESENTATION Narcolepsy

Symptoms

    • Patients may complain of EDS and disrupted nighttime sleep; often they have some accompanying REM sleep abnormality, sleep paralysis, cataplexy, and/or hallucinations.

Laboratory Tests

    • Although not routinely tested, there is a high incidence of human leukocyte antigen (HLA) haplotypes DR2 and HLA-DQ6/DQB1 in narcolepsy.

Other Diagnostic Tests

    • Narcolepsy is definitively diagnosed using the multiple sleep latency test (nap test). The patient takes four to five naps in a day, and narcolepsy is diagnosed if the patient falls asleep quickly (within less than 5 minutes) and goes into REM sleep in two of those nap periods.

NARCOLEPSY

Narcolepsy is a severely debilitating neurologic disease that affects between 0.03% and 0.06% of adult Americans.47 Despite the debilitating nature of the disease, it can be undiagnosed or misdiagnosed for years. It is equal or somewhat higher in men compared with women, and it develops during adolescence. It is commonly recognized in the second decade of life and increases in severity through the third and fourth decades.47 Individuals with narcolepsy complain of EDS, and in the sleep laboratory, individuals with narcolepsy exhibit impairment of both the onset and the offset of REM and NREM sleep and have arousals and disturbed sleep during the night.

Four characteristic symptoms differentiate narcolepsy from other sleep disorders and are known as the narcolepsy tetrad: EDS, cataplexy, hallucinations, and sleep paralysis. Cataplexy, a sudden bilateral loss of muscle tone of varying severity and duration without the loss of consciousness, occurs in 70% to 80% of people with narcolepsy.47 Patients can suffer subtle changes, such as jaw or head slumping, or severe weakness, such as knee buckling or collapsing to the ground. Cataplexy is often precipitated by situations characterized by high emotion (e.g., laughter, anger, excitement). Cataleptic episodes can be brief, lasting seconds, or can last for several minutes. Sleep paralysis is an episodic loss of voluntary muscle tone that occurs when the individual is falling asleep or waking. Individuals are conscious but not able to move or speak. Hallucinations while falling asleep (i.e., hypnagogic) and on awakening (i.e., hypnopompic) are brief, dream-like experiences that intrude into wakefulness and are experienced by nearly 70% of narcoleptics. Unfortunately, these symptoms sometimes lead to an incorrect diagnosis of mental illness.47Cataplexy, sleep paralysis, and hypnagogic hallucinations can be caused by REM sleep disturbances.48

Loss of normal function of the hypocretin-orexin neurotransmitter system appears to play a central role in the pathophysiology of narcolepsy. Neurons containing hypocretin-orexin are found in the lateral hypothalamus and project to various parts of the brain that are thought to regulate sleep. In 75% of narcoleptic patients, hypocretin-orexin is undetectable in cerebrospinal fluid.49 Because narcoleptic patients have deficiencies in hypocretin-orexin–producing neurons,50 an autoimmune process may be responsible for the destruction of hypocretin-producing cells.51,52 Onset of disease occurs in adolescence or adulthood, but not at birth, suggesting that environmental influences might also play a role. Molecular studies of HLA have found a high prevalence of the HLA-DR2 and HLA-DQ6/DQB1 haplotypes in narcoleptics.49 However, the HLA-DR2 haplotype is also common in the nonnarcoleptic population and is not diagnostic.48 There may also be a genetic component, as 3% of patients have a first-degree relative with the disorder.48

TREATMENT

Desired Outcomes

Nonpharmacologic management of narcolepsy includes counseling the patient and family concerning the illness to alleviate misconceptions around the individual’s behavior. Good sleep hygiene should be encouraged as well as two or more scheduled daytime naps. Daytime naps lasting 15 minutes each can help the individual with narcolepsy feel refreshed.

Images Pharmacologic management of narcolepsy is focused on two primary areas: treatment of EDS and REM sleep abnormalities. Drug therapy for narcolepsy is summarized in Table 55-4.

TABLE 55-4 Drugs Used to Treat Narcolepsy

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Pharmacologic Therapy

Modafinil, a racemic compound unrelated to psychostimulants, is a recognized standard treatment for EDS.53 Armodafinil is the active R-isomer of modafinil and is also FDA-approved for treatment of EDS in narcolepsy. The precise mechanism of action of modafinil and armodafinil is not fully understood. Common adverse effects are usually mild and include headache, nausea, nervousness, anxiety, and insomnia. The dose of modafinil is between 200 and 400 mg/day, and armodafinil doses are between 150 and 250 mg/day.54 Although both of these agents are effective in treating EDS, they lack efficacy for the treatment of cataplectic symptoms.55

EDS can also be treated with stimulants to improve alertness and to increase daytime performance. Dextroamphetamine and methylphenidate also have FDA approval for the treatment of narcolepsy. Methamphetamine and mixed amphetamine salts have also been used on an off-label basis. Methylphenidate and amphetamines have a fast onset of action and durations of 6 to 10 and 3 to 4 hours, respectively. The dose can range from 5 to 60 mg daily.

Stimulants improve alertness and daytime performance, and they can elevate mood and prevent sleep. Side effects can include insomnia, hypertension, palpitations, and irritability. Tolerance to long-term stimulant therapy can occur, necessitating dosage increases. Amphetamine use is associated with more likelihood of abuse and tolerance, especially when prescribed in high doses. Lisdexamfetamine is a new amphetamine prodrug rapidly absorbed and converted in the body to dextroamphetamine. It has a longer duration of action and less risk of abuse since it is active only when taken orally.

The most effective treatments for cataplexy are TCAs, venlafaxine, and fluoxetine. The mechanism of antidepressants in relieving cataplexy, hypnagogic hallucinations, and sleep paralysis can be mediated through blockade of serotonin and norepinephrine reuptake in the locus coeruleus and raphe and subsequent suppression of REM sleep.56 Imipramine, protriptyline, clomipramine, fluoxetine, and nortriptyline are effective in approximately 80% of patients. Selegiline improves hypersomnolence and cataplexy through REM suppression and an increase in REM latency. Methylphenidate and amphetamines alone are usually ineffective for complete relief of cataplexy.

Sodium oxybate (γ-hydroxybutyrate, Xyrem) improves symptoms of EDS and decreases episodes of sleep paralysis, cataplexy, and hypnagogic hallucinations. Nightly administration of sodium oxybate changes sleep architecture to resemble normal sleep. It increases slow-wave sleep, decreases nighttime awakenings, and increases REM efficiency.57 Sodium oxybate is available only as a liquid and is taken as two doses; one is taken at bedtime and the second dose is taken 2.5 to 4 hours later. Sodium oxybate is a potent sedative–hypnotic and should not be used concomitantly with any other sedating medications. The most common side effects include nausea, somnolence, confusion, dizziness, and incontinence.


Clinical Controversy…

In narcoleptic patients sodium oxybate effectively improves cataplexy and daytime sleepiness. Some practitioners advocate that sodium oxybate can be prescribed as monotherapy to control all narcolepsy symptoms. However, the majority of studies have evaluated the effects of sodium oxybate on daytime sleepiness with concomitant stimulant therapy, and additive benefits are obtained with dual therapy. Many subjects taking sodium oxybate will also require stimulant therapy to optimally control daytime sleepiness. Further study is needed.

Evaluation of Therapeutic Outcomes

The primary objective of pharmacologic treatment of narcolepsy is to reduce symptoms that adversely impact quality of life. The goal is to produce the fullest possible return of normal function for patients at work, school, home, and in social settings. Patients with narcolepsy should keep a diary of the frequency and severity of cataplexy, sleep paralysis, and sleep hallucinations. Patients should be evaluated regularly during medication titrations and then every 6 to 12 months to assess for adverse drug effects (e.g., sleep disturbances, hypertension, and cardiovascular abnormalities). The healthcare provider should consider the benefit-to-risk ratio for the individual patient, the cost of medication, the convenience of administration, and the cost of laboratory tests when selecting narcolepsy therapies.53 One wake-promoting agent may work better than another in an individual patient. Thus, if one agent is not effective at adequate doses, a trial with another agent should be undertaken.

CIRCADIAN RHYTHM DISORDERS

The sleep–wake cycle is under the circadian control of oscillators and can be disrupted by misalignment between an individual’s biologic clock and external demands on the sleep cycle. Circadian rhythm sleep disorders usually present with either insomnia or hypersomnia, depending on the individual’s performance requirements. Two commonly occurring circadian rhythm sleep disorders are jet lag and shift work sleep problems.

Jet Lag

Jet lag occurs when a person travels across time zones, and the external environmental time is mismatched with the internal circadian clock. Sleep disturbances typically last for 2 to 3 days but can last as long as 7 to 10 days if the time zone changes are greater than 8 hours. Compared with westward travel, eastward travel is associated with a longer duration of jet lag. Jet lag leads to increased incidence of GI disturbances and a decrease in alertness and performance.

Images Treatment of jet lag includes nonpharmacologic approaches alone or in combination with drug therapy. Jet lag can be minimized in coast-to-coast travel in the United States if the duration is less than 7 days and the normal sleep–wake cycle is observed. For travel lasting longer than 7 days, jet lag severity can be lessened by 1- to 2-hour adjustments in sleep and wake times prior to departure to the destination time zone. Short-acting BZDRAs, ramelteon, and 0.5 to 5 mg melatonin, taken at appropriate target bedtimes for east or west travel, reduce jet lag and shorten sleep latency.58

Shift Work Sleep Disorder

Shift workers comprise approximately 20% of the workforce.59 Night shift work causes a misalignment in the sleep–wake cycle and circadian rhythm that is associated with a decrease in alertness, performance, and quality of daytime sleep. More than 65% of workers on rotating shifts complain of insomnia, compared with only 20% who work one shift.60 Shift workers ultimately are at risk of developing shift work sleep disorder (SWSD). SWSD is a complaint of insomnia or excessive sleepiness that occurs because of circadian sleep disruption due to working shifts during normal sleep time.7,59Shift workers have a higher injury rate, divorce rate, occurrence of on-the-job sleepiness, and incidence of substance use. They may also be at increased risk of developing peptic ulcers, depression, breast cancer, and sleepiness-related accidents.5961 Night shift workers are usually in a state of permanent circadian misalignment because of the tendency to revert to conventional sleep schedules on their days off.60

Treatment for shift work sleep problems includes optimizing sleep hygiene, extending daytime sleep by sleeping in the afternoon, scheduling a 2- to 3-hour nap on days off from work, or switching to a day shift job. Short-acting BZDRAs, ramelteon, and melatonin can consolidate sleep during day sleep periods and reduce lost sleep time. Modafinil and armodafinil are FDA-approved to improve wakefulness in patients with EDS associated with SWSD. Scheduled exposure to bright lights at night and darkness in the daytime improves adaptation to night work and daytime sleep.60

Restless Legs Syndrome

RLS, or Ekbom’s syndrome, is characterized by paresthesias that are usually felt deep in the calf muscles but can also appear in the thighs and arms with the urge to keep limbs in motion. RLS occurs in both males and females, and it occurs more frequently in the elderly. It has been associated with chronic kidney disease, iron deficiency anemia, and pregnancy. Caffeine, stress, alcohol, and fatigue can worsen symptoms. Recent data suggest that RLS can be caused by iron deficiency in the substantia nigra in the CNS.62 The diagnosis of RLS is based on patient- or partner-reported symptoms and specific diagnostic criteria. Criteria required to diagnose RLS include (a) an urge to move the limbs that is usually associated with uncomfortable and unpleasant sensations, (b) symptoms that begin or worsen during rest or inactivity, (c) symptoms that are exclusively present or worse in the evening or night, and (d) symptoms that are temporarily relieved by movement.63 The discomfort returns when the person tries to sleep, resulting in insomnia. Practice parameter recommendations for treatment of RLS are shown in Table 55-5.

TABLE 55-5 Evidence-Based Guidelines for Drug Therapy of RLS

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Images Dopamine agonists ropinirole, pramipexole, and rotigotine are FDA-approved, are effective for RLS, and are standard treatments.64 Lower doses of dopamine agonists are used when treating RLS compared with Parkinson’s disease. Providers should caution patients that compulsive behaviors (e.g., gambling, shopping, eating, etc.) may emerge during therapy with dopamine agonists. Levodopa therapy is associated with a high incidence of symptom augmentation and, because of a short half-life, might not provide relief over the entire night. Augmentation is a worsening in symptom severity, increase in symptom distribution, or emergence of symptoms earlier in the evening. Sedative–hypnotic agents can be effective in patients who have frequent awakenings from their RLS symptoms. Clonazepam at doses ranging from 0.5 to 2 mg has been most frequently studied; however, patients may experience carryover sedation because of its long duration of action. Shorter half-life sedative–hypnotics (e.g., zolpidem, zaleplon) can improve sleep and reduce daytime sleepiness without carryover sedation. Opiates such as methadone 5 to 20 mg, codeine 30 to 120 mg, and oxycodone 2.5 mg are effective for patients with painful RLS. The potential for tolerance and dependence on opiate therapy should be considered. Gabapentin 300 to 900 mg near bedtime can also be considered for those with paresthetic or painful RLS symptoms.65 Gabapentin enacarbil (Horizant) is a gabapentin prodrug that is now FDA-approved for the treatment of RLS at a dose of 600 mg taken at 5 PM. Iron studies should be completed in patients with RLS and iron supplementation initiated in those who are iron deficient. In patients with ferritin concentrations less than 50 to 75 mcg/L (ng/mL), iron supplementation improves RLS symptoms.66 Patients with RLS or PLMS should be evaluated regularly to monitor for excessive daytime somnolence, tolerance, efficacy, and adverse effects of the medication. Therapy should be monitored for adverse effects found in Table 55-6.

TABLE 55-6 Monitoring Table for Medications Used to Treat RLS and PLMS

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Periodic Leg Movements of Sleep

RLS patients commonly have PLMS, while approximately one third of patients with PLMS have RLS.64 PLMS are stereotypic, repetitive, periodic movements of the legs that occur during sleep every 20 to 40 seconds and last 10 minutes to several hours.64 The movements usually involve the big toe, but the ankle, knee, and hip can also flex. They can be terminated by a violent kick or other body movement. Often patients will be unaware of these movements and only recognize consequent insufficient sleep and morning leg cramps. A bed partner can describe PLMS. PLMS is diagnosed in the sleep laboratory using electromyogram recordings.

PLMS can occur with RLS or alone because of systemic disease (e.g., renal failure) or drug therapy.67 TCAs, SSRIs, dopaminergic antagonists, xanthines, nicotine, alcohol, and caffeine can all worsen PLMS. The treatment approach for PLMS is similar to that of RLS. If PLMS do not cause disruptions for the patient or bed partner or daytime symptoms, they may not require treatment. Symptomatic or problematic PLMS should be treated with dopaminergic medications to suppress limb movements or sedative–hypnotics to reduce awakenings and consolidate sleep.

PARASOMNIAS

Parasomnias are abnormal behavior or physiologic events that either occur during sleep or are exaggerated by sleep. Many of these disorders are considered to be disorders of partial arousal from various sleep stages. Parasomnias can be categorized as disorders of arousal (sleepwalking, sleep terrors), sleep–wake transition disorders (sleep-talking), rhythmic movement disorder, REM parasomnias (REM behavior disorder, nightmares), and miscellaneous parasomnias (enuresis, bruxism). Sleepwalking, sleep terrors, and sleep-talking predominantly occur during NREM sleep, whereas others (REM behavior disorder) occur during REM sleep.

Sleepwalking and sleep terrors are found normally in children between the ages of 4 and 12 years and usually resolve in adolescence. These disorders are increasingly recognized to also occur in adulthood, and, contrary to previous beliefs, are not related to psychological or psychiatric pathology.68 Sleep terrors can begin in adults between the ages of 20 and 30 years. Onset of sleepwalking in adults without a childhood history of sleepwalking should prompt a search for a neurologic or substance use condition.69 Sleepwalking and sleep terror disorder involve intrusions of wakefulness into NREM sleep during the first third of the night. In sleepwalking, individuals become ambulatory, are difficult to awaken, and are amnestic for the event. Sleep terrors involve intense fear and autonomic arousal. Individuals are difficult to awaken, inconsolable, and amnestic for the event.69 Patients with REM behavior disorder act out their dreams, often in a violent manner, and are at risk for injury.

Treatment of sleepwalking involves protecting the individual from harm by putting safety latches on doors and windows, removing hazardous objects from bedrooms, and covering glass doors with heavy curtains. In adult patients, benzodiazepines, SSRIs, or TCAs can be beneficial therapies for sleepwalking or other NREM disorders of arousal.68 Benzodiazepines can also be helpful in curtailing sleep terrors in adults.69 Nightmares are anxiety-provoking dreams characterized by vivid recall. Treatment is directed at reducing stress, anxiety, and sleep deprivation. In extreme cases, low-dose benzodiazepines can be indicated. Clonazepam is the treatment of choice for REM behavior disorder. Melatonin (3 to 12 mg at bedtime) can also be an effective therapy for REM behavior disorder.70

PERSONALIZATION OF THERAPY

For the treatment of insomnia, the choice of a particular BZDRA can be based on its pharmacokinetic profile. When used as a single dose, extent of distribution and elimination half-life are important in predicting the duration of action. However, after multiple doses, the elimination half-life and formation of active metabolites determine the extent of drug accumulation and resultant clinical effects.11Advanced age, liver dysfunction, and drug interactions can prolong drug effects. The pharmacokinetic profiles of BZDRAs are summarized in Table 55-3. To individualize treatment of narcolepsy many clinicians prescribe both immediate-release and sustained-release stimulants to increase alertness throughout the day. Sustained-release stimulants are prescribed with scheduled administration times, and immediate-release stimulants can be taken as needed when the patient requires alertness (e.g., driving, etc.).

ABBREVIATIONS

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