John M. Dopp and Bradley G. Phillips
LEARNING OBJECTIVES
Upon completion of this chapter, the reader will be able to:
1. Articulate the incidence and prevalence of sleep disorders, list the sequelae of undiagnosed or untreated sleep disorders, and appreciate the importance of successful treatment of sleep disorders.
2. Describe the pathophysiology and characteristic features of the sleep disorders covered in this chapter including: insomnia, narcolepsy, restless legs syndrome (RLS), obstructive sleep apnea (OSA), and parasomnias.
3. Assess patient sleep complaints, conduct sleep histories, and evaluate sleep studies to recognize daytime and nighttime symptoms and characteristics of common sleep disorders.
4. Recommend and optimize appropriate sleep hygiene and nonpharmacologic therapies for the management and prevention of sleep disorders.
5. Recommend and optimize appropriate pharmacotherapy for sleep disorders.
6. Describe the components of a monitoring plan to assess safety and efficacy of pharmacotherapy for common sleep disorders.
7. Educate patients about preventive behavior, appropriate lifestyle modifications, and drug therapy required for effective treatment and control of sleep disorders.
KEY CONCEPTS
Insomnia is most frequently a symptom or manifestation of an underlying disorder (comorbid insomnia) but may occur in the absence of contributing factors (primary insomnia). Early treatment of insomnia may prevent the development of persistent psychophysiologic insomnia.
Patients with sleep complaints should have a careful sleep history performed to assess for possible sleep disorders and to guide diagnostic and therapeutic decisions.
Although clinical history guides diagnosis and therapy, only overnight polysomnography and multiple sleep latency tests (MSLTs) can definitively diagnose and/or guide therapy for obstructive sleep apnea (OSA), narcolepsy, and periodic limb movements of sleep.
Treatment goals vary between different sleep disorders but generally include restoration of normal sleep patterns, elimination of daytime sequelae, improvement in quality of life, and prevention of complications and adverse effects from therapy.
Benzodiazepine receptor agonists, including traditional benzodiazepines, zolpidem, zaleplon, and eszopiclone, are approved by the FDA for the treatment of insomnia and are first-line therapies.
Treatment of excessive daytime sleepiness in narcolepsy and other sleep disorders may require the use of sustained- and immediate-release stimulants to effectively promote wakefulness throughout the day and at key times that require alertness.
Restless-legs syndrome (RLS) treatment involves suppression of abnormal sensations and leg movements, and consolidation of sleep. Dopaminergic and sedative-hypnotic medications are commonly prescribed.
The primary therapy for OSA is nasal continuous positive airway pressure (CPAP) therapy because of its effectiveness.
It is important to review patient medication profiles for drugs that may aggravate sleep disorders. Patients should be monitored for adverse drug reactions, potential drug–drug interactions, and adherence to their therapeutic regimens.
Normal humans sleep up to one-third of their lives and spend more time sleeping compared with any other single activity. Despite this, our understanding of the full purpose of sleep and the mechanisms regulating sleep homeostasis remains incomplete. Sleep is necessary to maintain wakefulness, health, and welfare. Unfortunately, disruption of normal sleep is prevalent and represents a major cause of societal morbidity, lost productivity, and reduced quality of life.1 The link between adequate sleep and optimal health is becoming increasingly apparent, and sleep disturbances may contribute to the development and progression of comorbid medical conditions.
Sleep is governed and paced by the suprachiasmic nucleus in the brain that regulates circadian rhythm. Environmental cues and amount of previous sleep also influence sleep on a daily basis. There are two main types of sleep: rapid-eye-movement (REM) sleep, where eye movements and dreaming occur but the body is mostly paralyzed, and non-REM sleep, which consists of four substages (stages 1–4). Stage 1 serves as a transition between wake and sleep. Most of the time asleep is spent in stage 2 non-REM sleep. Stage 3 and stage 4 sleep often are grouped together and referred to as deep sleep, or delta sleep,because prominent delta waves are seen on the electroencephalogram (EEG) during these sleep stages.
EPIDEMIOLOGY AND ETIOLOGY
Sleep disorders are common. Approximately 50% of adults will report a sleep complaint over the course of their lives.2 In general, sleep disturbances increase with age, and each disorder may have gender differences. The full extent and impact of disordered sleep on our society are not known because many patients’ sleep disorders remain undiagnosed. Normal sleep, by definition, is “a reversible behavioral state of perceptual disengagement from and unresponsiveness to the environment.”3 As a result, individuals with sleep disorders will exhibit or complain about consequent symptoms (e.g., daytime sleepiness), or a bed partner will observe hallmark characteristics of the sleep disorder. Insomnia, restless legs syndrome (RLS), and sleep-related breathing disorders are the most common sleep disorders.
Insomnia
The prevalence of insomnia increases with age and is nearly 1.5 times greater in females than in males. Approximately one-third of patients older than age 65 have persistent insomnia.4,5 In the adult population, about 10% will experience chronic insomnia and slightly more will experience short-term insomnia. Insomnia is most frequently a symptom or manifestation of an underlying disorder (comorbid insomnia) but may occur in the absence of contributing factors (primary insomnia). Early treatment of insomnia may prevent the development of persistent psychophysiologic insomnia. Forty percent of patients with psychiatric conditions will have accompanying insomnia.6Comorbid insomnia may be triggered by acute stress and disappears when the stress resolves. Numerous coexisting medical conditions, such as pain, thyroid abnormalities, asthma, and reflux, and medications, including selective serotonin reuptake inhibitors (SSRIs), steroids, stimulants, and β-agonists, can interfere with sleep and cause comorbid insomnia. In cases of comorbid insomnia, the clinician should treat the underlying primary cause along with insomnia symptoms.
Narcolepsy
Although difficult to estimate, the prevalence of narcolepsy is between 0.03% and 0.06%.7 Significant differences have been reported for various ethnic groups. Narcolepsy has a higher prevalence in the Japanese and a lower prevalence in the Israeli populations.8,9 Cataplexy is not required for diagnosis, however, between 50% and 80% of patients with narcolepsy have accompanying cataplexy.10
Restless Legs Syndrome
RLS occurs in 6% to 12% of the population, making it a common sleep disorder.11,12 The prevalence of RLS increases with age and in various medical conditions such as end-stage renal disease (ESRD), pregnancy, and iron deficiency.13 RLS appears to be more common in women than in men and has a genetic link. The majority of patients (63–92%) report a positive family history for RLS.14
Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) is a common disorder that is often unrecognized, affecting 4% of middle-aged white men and 2% of middle-aged white women.15 In women, the frequency of OSA increases after menopause. OSA is as common or more common in African Americans and less common in Asian populations. The risk of OSA increases with age and obesity. Individuals with OSA experience repetitive upper airway collapse during sleep, which decreases or stops airflow, with subsequent arousal from sleep to resume breathing. The severity is determined by nocturnal polysomnography (NPSG) and is graded by the number of episodes of apnea (total cessation of airflow) and hypopnea (partial airway closure with blood oxygen desaturation) experienced during sleep. The severity is expressed as the respiratory disturbance index (RDI), quantified in events per hour. Mild sleep apneics have an RDI of between 5 and 15 episodes per hour; moderate, 15 and 30; and individuals with severe OSA can exhibit more than 30 episodes per hour.
Parasomnias
Non-REM parasomnias have variable prevalence rates depending on patient age and comorbid diagnoses. Sleep talking, bruxism, sleepwalking, sleep terrors, and enuresis occur more frequently in childhood than in adulthood. Nightmares appear to occur with similar frequency in adults and children. REM behavior disorder (RBD), an REM-sleep parasomnia, has a reported prevalence of 0.5% and frequently is associated with concomitant neurologic conditions.16 Chronic RBD is more common in elderly men and may have a familial disposition.
PATHOPHYSIOLOGY
Although the neurophysiology of sleep is complex, certain neurotransmitters promote sleep and wakefulness in different areas of the central nervous system (CNS). Serotonin is thought to control non-REM sleep, whereas cholinergic and adrenergic transmitters mediate REM sleep. Dopamine, norepinephrine, hypocretin, substance P, and histamine all play a role in wakefulness. Perturbations of various neurotransmitters are responsible for some sleep disorders and explain why various treatment modalities are beneficial.
Insomnia
Because insomnia is a complex and multifaceted disorder, there is no single pathophysiologic explanation for its various manifestations. Current hypotheses focus on a combination of possible models that incorporate physiologic, cognitive, and cortical arousal. Most insomnia models focus on hyperarousal and its interference with the initiation or maintenance of sleep.
Narcolepsy
The onset of narcolepsy–cataplexy is typically in adolescence and not at birth, suggesting that the disease may require environmental influence to develop. Currently, it is believed that narcolepsy results from autoimmune insult to the CNS because it is associated with HLA (major histocompatibility complex) DQB1*0602 and DQ1A1*0102.17,18 Concentrations of hypocretin (a wake-promoting neuropeptide) in the cerebrospinal fluid (CSF) of narcolepsy patients are reduced significantly, suggesting that the autoimmune attack is against hypocretin-producing cells in the hypothalamus.19 Intact hypocretin neurons normally stimulate arousal and wake-promoting neurons to stimulate cortical activation and behavioral arousal.
RLS and Periodic Limb Movements of Sleep
RLS is a neurologic medical condition characterized by an irresistible desire to move the limbs. It is thought that these abnormal sensations are a result of iron deficiency in the brain and iron-handling abnormalities in the CNS. Iron and H-ferritin concentrations, along with transferrin receptor and iron transporter numbers, are reduced in the substantia nigra of patients with RLS.20 These iron abnormalities lead to dysfunction of dopaminergic transmission in the substantia nigra.
Obstructive Sleep Apnea
At least 20 muscles and soft-tissue structures control patency of the upper airway. Patients with OSA may have differences in upper airway muscle activity during sleep and may have smaller airways, predisposing them to upper airway collapse and consequent apneic episodes during sleep. The inability of the upper airway to contend with factors that promote collapse, including fat deposition in the neck, negative pressure in the airway during inspiration, and a smaller lower jawbone, also may play a role in the pathogenesis of OSA. Hallmarks of OSA include witnessed apneas, gasping, or both.
Poor sleep architecture and fragmented sleep secondary to OSA can cause excessive daytime sleepiness (EDS) and neurocognitive deficits. These sequelae can affect quality of life and work performance, and may be linked to occupational and motor vehicle accidents. OSA is also associated with systemic disease such as hypertension, heart failure, and stroke.21,22 OSA is likely an independent risk factor for the development of hypertension.23 Further, when hypertension is present, it is often resistant to antihypertensive therapy. Fatal and nonfatal cardiovascular events are two- to threefold higher in male patients with severe OSA.24 OSA is associated with or aggravates biomarkers for cardiovascular disease, including C-reactive protein and leptin.25,26 Patients with sleep apnea often are obese and may be predisposed to weight gain. Hence, obesity may further contribute to cardiovascular disease in this patient population.
Several factors suggest an association between OSA and systemic disease. Breathing against a closed upper airway during sleep causes intermittent and repetitive episodes of hypoxemia and hypercapnia, dramatic changes in intratho-racic pressure, and activation of the sympathetic nervous system. These responses can produce acute hemodynamic and humoral responses. Blood pressure can increase to 220/120 mm Hg with each apneic episode.27Concentrations of circulating vasoconstrictors, such as endothelin-1 and norepinephrine, are increased during OSA.28 These acute responses to OSA may predispose to and enhance the progression of vascular disease in the longer term. This is supported by studies showing impaired endothelium-dependent vasodilation, an early marker for vascular disease, in patients with untreated moderate to severe OSA.29
Patient Encounter, Part 1
CH, a 53-year-old man with a history of hypertension, comes to your clinic complaining of sleepiness in the daytime, “crawly legs” at bedtime, and frequent awakenings at night. After further questioning, he explains that for the last hour or so before bedtime he cannot keep his legs still. He reports that he falls asleep relatively easily during the day. The symptoms have been gradually worsening over the past year and occur nightly. His wife reports that he kicks his legs the first part of the night, snores, and occasionally gasps for air after a breathing pause. His body mass index (BMI) is 30 kg/m2, and he has experienced recent weight gain and complains about morning headaches.
What sleep disorders do his symptoms suggest?
What sleep disorders could you diagnose subjectively? What is your initial recommendation?
What additional information do you need to know before creating a treatment plan for this patient?
Parasomnias
The pathogenesis of parasomnias (e.g., sleepwalking, enuresis, sleep talking) is variable and not well described and involves state dissociation, whereby two states of being overlap simultaneously. For example, abnormal activation of the central pattern generator of the spinal cord that produces motor movements is hypothesized to underlie sleepwalking behavior. In RBD, active inhibition of motor activity in the perilocus coeruleus region is lost, resulting in loss of paralysis and dream enactment.
Clinical Presentation and Diagnosis of Sleep Disorders
Patients with sleep disorders may complain about daytime symptoms. A bed partner may witness hallmark characteristics of the sleep disorder. Patients with sleep complaints should have a careful sleep history performed to assess their possible sleep disorder in order to guide diagnostic and therapeutic decisions.
Daytime Symptoms and Associated Characteristics—EDS is the primary symptom described by patients with sleep disorders. It is usually described as not waking up refreshed in the morning, or falling asleep or fighting the urge to sleep during the day despite a night of sleep. Other daytime characteristics of sleep disorders include:
• Irritability, fatigue, or depression
• Confusion, or impaired performance at work or school
• Cataplexy (associated with narcolepsy)
• Hypertension (associated with OSA)
Nighttime Sleep Complaints—Depending on the sleep disorder, patients may exhibit or experience various nocturnal complaints during sleep hours. Some of these complaints can be uncovered by clinical history alone (e.g., hallucinations, RLS, snoring), while others can be diagnosed during sleep studies (e.g., OSA, nighttime awakenings, somnambulism, PLMS, etc.). Frequent complaints include:
• Inability to fall asleep, nighttime awakenings
• Sleep walking (somnambulism), sleep talking (somniloquy)
• Cessation of breathing (apnea), snoring
• Sleep paralysis and/or hallucinations when waking or falling asleep
• Restlessness (PLMS or RLS)
CLINICAL PRESENTATION AND DIAGNOSIS
Although clinical history guides diagnosis and therapy, only overnight polysomnography and/or multiple sleep latency tests (MSLTs) can definitively diagnose and guide therapy for OSA, narcolepsy, and periodic limb movements of sleep.
Insomnia (Difficulty Initiating or Maintaining Sleep)
Insomnia is often characterized by difficulty falling asleep, frequent nocturnal awakenings, and early-morning awakenings, which may result in daytime impairments in concentration and school or work performance. In comorbid insomnia, social factors (e.g., family difficulties, bereavement), medications (e.g., antidepressants, β-agonists, corticosteroids, decongestants), and coexisting medical or psychiatric conditions (e.g., depression, bipolar disorder) may help to explain difficulties in initiating and maintaining sleep. Insomnia may be described as transient (a few days), short term (less than 3 weeks), or chronic (greater than 1 month) in duration.
Narcolepsy
The hallmark of narcolepsy is EDS and the need for unwanted episodes of sleep during the day. Patients with narcolepsy may experience repeated nighttime awakenings and terrifying dreams, along with difficulty falling asleep. Narcoleptics frequently experience abnormal manifestations of REM sleep, including hallucinations and sleep paralysis that occur on falling asleep and/or awakening. Cataplexy is a weakness or loss of skeletal muscle tone in the jaw, legs, or arms that is elicited by emotion (e.g., anger, surprise, laughter, or sadness).
Obstructive Sleep Apnea
Common characteristics of OSA include snoring, choking, gasping for air, nocturnal reflux symptoms, and morning headaches. A bed partner or roommate may observe these characteristics and witness episodes where the patient stops breathing during sleep. Obesity predisposes to and can worsen OSA. Patients with large neck sizes (greater than 45 cm [about 18 in.] neck circumference) and a body mass index (BMI) of 30 kg/m2 or greater are at higher risk for OSA. Hypertension, depression, and hypothyroidism are found frequently in patients with OSA.
PLMS and RLS
Although RLS symptoms can vary, patients commonly report creepy-crawly, burning, tingling, or achy feelings in the legs or arms. These sensations create a desire to move the limbs and may produce motor restlessness. Symptoms are worse in the evening and are worse or exclusively present at rest, with temporary relief with movement. Symptoms also can occur during sleep and often lead to semirhythmic (periodic) limb movements during sleep (PLMS). PLMS are objective findings during overnight polysomnography recorded by leg electrodes. PLMS are present in most patients with RLS but can occur independently. PLMS frequently are described by a bed partner as restlessness, or repeated kicking of legs or thrashing of arms during sleep.
Parasomnias
Parasomnias are characterized by undesirable physical or behavioral phenomena that occur during sleep (e.g., sleepwalking, sleep talking, bruxism [grinding of teeth], enuresis, night terrors, and RBD). RBD patients act out their dreams during sleep, often in a violent manner.
Circadian Rhythm Disorders
The most common circadian rhythm disorders (CRDs) include jet lag, shift-work sleep disruption, delayed sleep-phase disorder, and advanced sleep-phase disorder. Jet lag occurs when a person travels across time zones, and the external environmental time is mismatched with the internal circadian clock. Delayed and advanced sleep-phase disorders occur when bed and wake times are delayed or advanced (by 3 or more hours) compared with socially prescribed bed and wake times.
Sleep Diagnostics
Complete overnight polysomnography is the “gold standard” for diagnosing and identifying sleep-disordered breathing, PLMS, parasomnias, and nocturnal sleep irregularities rela ted to narcolepsy. Sleep is observed and monitored in a controlled setting using an EEG, electro-oculogram, electromyogram, ECG, air thermistors, abdominal and thoracic strain belts, and an oxygen saturation monitor. This setup assesses and records sleep onset, arousals, sleep stages, eye movements, leg and jaw movements, heart rhythm, arrhythmias, airflow during sleep, respiratory effort, and oxygen desaturations.
Evaluations of Daytime Sleepiness
The two most commonly performed objective evaluations to assess daytime sleepiness are the MSLT and the maintenance of wakefulness test (MWT). During the MSLT, the patient attempts to take a 20-minute nap every 2 hours during the day beginning 2 hours after morning awakening (following a normal night’s sleep) to evaluate physiologic sleepiness. The patient is instructed not to resist the urge to fall asleep. Sleep latency of less than 5 or 6 minutes is considered pathologically sleepy. The occurrence of an REM onset period during two naps is indicative of a diagnosis of narcolepsy. The MWT is performed to assess a patient’s ability to avoid succumbing to sleepiness (manifest sleepiness). Similar nap opportunities are set up for the MWT, with the exception that the patient is instructed to lie down in bed and attempt to stay awake. A subjective assessment of sleepiness can be completed using the Epworth Sleepiness Scale (ESS). The ESS is a validated questionnaire that is easy to use and reliably predicts subjective sleepiness. The maximum score is 24, and any patient with a score greater than 10 is considered sleepy.
Patient Encounter, Part 2: Medical History, Physical Exam, and Diagnostic Test
CH undergoes nocturnal polysomnography and returns to your clinic for follow-up.
PMH: Hypertension poorly controlled since 1999
FH: Father died at age 70 from stroke; mother is still alive with history of RLS and hypothyroidism.
SH: Married, works as an accountant, has never smoked, two drinks/night on the weekends
Meds: Hydrochlorothiazide 25 mg orally once daily; amlodipine 10 mg orally once daily
ROS: (+) daytime sleepiness (Epworth sleepiness score: 18/24)
PE:
VS: BP 154/84, P 78, RR 16, T 37°C (98.6°F)
Mouth: Airway crowded, large tonsils and uvula
Labs: Within normal limits
Overnight polysomnogram: Frequent obstructive apneas, hypopneas, and leg movements:
• RDI 12 events/h
• 310 leg movements, mostly occurring in first half of the night
• Successful alleviation of apneas and hypopneas with CPAP
Given this additional information, summarize the patient’s diagnosis.
Identify your treatment goals and recommendations for the patient.
What nonpharmacologic and pharmacologic alternatives are available for this patient if prescribed therapy is not successful or not tolerated?
TREATMENT
Treatment goals vary among different sleep disorders but generally include restoration of normal sleep patterns, elimination of daytime sequelae, improved quality of life, and prevention of complications and adverse effects from therapy. All patients presenting with sleep complaints should have a thorough inventory of their sleep habits and sleep hygiene investigated during the interview and history taking. Nonpharmacologic interventions for insomnia are outlined in Table 41–1. Sleep hygiene should be reinforced in all patients, and behavioral, cognitive, and stimulus-control interventions are used mainly for patients with insomnia-type complaints. Both pharmacologic and nonpharmacologic therapies are effective at improving sleep and reducing insomnia complaints. An algorithm for the initial assessment and first treatment step of EDS is provided in Figure 41–1.
Table 41–1 Nonpharmacologic Therapies for Insomnia
|
Sleep Hygiene |
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• Keep a regular sleep schedule |
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• Exercise frequently but not immediately before bedtime |
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• Avoid alcohol and stimulants (caffeine, nicotine) in the late afternoon and evening |
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• Maintain a comfortable sleeping environment that is dark, quiet, and free of intrusions |
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• Avoid consuming large quantities of food or liquids immediately before bedtime |
|
Stimulus Control |
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• Go to bed only when sleepy |
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• Avoid daytime naps |
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• If you cannot sleep, get out of bed and go to another room—only return to your bed when you feel the need to sleep |
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• Bed is for sleep and intimacy only (no eating or watching TV in bed) |
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• Always wake up at the same time each day |
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Relaxation Training |
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• Reduce somatic arousal (muscle relaxation) |
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• Reduce mental arousal (attention focusing procedures, imagery training, meditation, etc.) |
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• Biofeedback (use of visual or auditory feedback to reduce tension) |
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Cognitive Therapy |
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• Alter beliefs, attitudes, and expectations about sleep |
Insomnia
The ideal hypnotic drug would be effective at reducing sleep latency and increasing total sleep time and would be free of unwanted side effects. Benzodiazepine receptor agonists, including traditional benzodiazepines, zolpidem, zaleplon, and eszopiclone, are approved by the FDA for the treatment of insomnia and are first-line therapies.30,31 Not all products are available in all countries. Pharmacologic treatment of insomnia is recommended for transient and short-term insomnia. Long-term use of hypnotics is not contraindicated unless the patient has another contraindication to their use. Eszopiclone is the only sedative hypnotic approved by the FDA for chronic use up to 6 months.32Although not first-line agents for insomnia, sedating antidepressants are prescribed commonly, and the number of prescriptions for antidepressants for this purpose has increased dramatically over the last 20 years.33 These and other therapies, detailed below, are used to treat insomnia.
Benzodiazepine Receptor Agonists
There are currently eight benzodiazepine receptor agonists (BZDRAs) approved for insomnia, and the pharmacokinetic differences between these agents help to guide selection depending on patient considerations and specific sleep complaints (Table 41–2). These agents occupy the benzodiazepine receptors on the gamma-aminobutyric acid (GABA) type A receptor complex, resulting in opening of chloride channels that facil itate GABA inhibition a nd promote sleepiness.34 BZDRAs have become the first-line agents for treating insomnia and sleep-maintenance problems because they are all efficacious, have wide therapeutic indices, and in clinical use have a low incidence of abuse.30,34
Patients should be instructed to take BZDRAs at bedtime and to avoid engaging in activities requiring alertness after ingestion. The BZDRAs come closer to the “ideal hypnotic” compared with other agents because they increase total sleep time (except for zaleplon) and reduce sleep latency with fewer adverse effects. Although BZDRAs generally are well-tolerated and have good safety profiles, mild to moderate side effects can occur, and precautions are warranted, especially in high-risk populations.
Precautions and Safety The most common side effects associated with BZDRAs include residual sedation (a prolongation of the sedative effects into the waking hours after sleep), grogginess, and psychomotor impairment.35Careful selection of a hypnotic agent with a duration of action matching the patient’s budgeted sleep time can help minimize the risk of residual sedation. BZDRAs should be initiated at low doses, and agents with active metabolites (Table 41–2) should be avoided in elderly patients. BZDRAs may cause anterograde amnesia, defined as memory loss of activities and interactions after ingestion of the drug. All hypnotics can cause anterograde amnesia, and higher doses increase the extent of amnesia.36,37
On discontinuation of hypnotic BZDRAs, patients can experience rebound effects, specifically rebound insomnia that may last for one to two nights. Rebound insomnia occurs more frequently after discontinuation of shorter-duration BZDRAs (e.g., triazolam) compared with long-duration BZDRAs. Intermittent hypnotic therapy with the lowest dose possible reduces the likelihood of tolerance, dependence, and withdrawal when therapy is stopped. Patients should be counseled that rebound insomnia is not necessarily a return of their original symptoms, and it may take a few nights for rebound symptoms to subside.
Sedating Antidepressants
The increasing popularity of sedating antidepressants for the treatment of insomnia resulted in trazodone being the most prescribed drug in 2002.38 Other common antidepressants also prescribed for insomnia include amitriptyline, mirta-zapine, nefazadone, and doxepin. Antidepressants may be an appealing option for insomnia in patients with concomitant depression. However, at the doses frequently used for sleep, only mirtazapine exhibits significant antidepressant activity. Further, quality clinical studies demonstrating efficacy for treating insomnia are lacking. Side effects from antidepressants can be frequent and often are unpleasant, including carryover sedation, grogginess, anticholinergic effects, and weight gain. Tricyclic antidepressants (TCAs) should be used with caution in the elderly and patients with cardiovascular and hepatic impairment. Mirtazapine can cause daytime sedation, dizziness, and weight gain, a side effect that may worsen concomitant OSA.39 Trazodone can cause hypotension and dizziness, and should be used with caution in patients with heart disease or hypertension and those taking cardiovascular agents.40,41
FIGURE 41–1. Primary assessment and initial treatment for complaint of excessive daytime sleepiness. (BZDRA, benzodiazepine receptor agonist; CPAP, continuous positive airway pressure; DA, dopamine agonist; MSLT, multiple sleep latency test; OSA, obstructive sleep apnea; RLS, restless legs syndrome; SNRI, serotonin and norepinephrine reuptake inhibitor; NPSG, nocturnal polysomnography; TCA, tricyclic antidepressant.)
Over-the-Counter and Miscellaneous Agents
Over-the-counter antihistamines such as diphenhydramine are frequently used (usual doses 25 to 50 mg) for difficulty sleeping. Diphenhydramine is approved by the FDA for the treatment of insomnia and can be effective at reducing sleep latency and increasing sleep time.42 However, diphenhydramine produces undesirable anticholinergic effects and carryover sedation that limit its use. As with TCAs and BZDRAs, diphenhydramine should be used with caution in the elderly. Valerian root is a herbal sleep remedy that has inconsistent effects on sleep but may reduce sleep latency and efficiency at commonly used doses of 400 to 900 mg valerian extract. Ramelteon, a new melatonin receptor agonist, is indicated for insomnia characterized by difficulty with sleep onset. The recommended dose is 8 mg at bedtime. Ramelteon is not a controlled substance, and thus is a viable option for patients with a history of substance abuse.43
Narcolepsy
Therapy for narcolepsy involves two key principles: (a) treatment of EDS with scheduled naps and CNS stimulants, and (b) suppression of cataplexy and REM-sleep abnormalities with aminergic signaling drugs. Modafinil, methylphenidate, and amphetamines are effective FDA-approved drugs for the treatment of EDS with narcolepsy.44 Modafinil is potentially advantageous in part because it is a schedule IV medication in contrast to CNS stimulants, which are schedule II. Modafinil is renewable for 6 months at a time and may have fewer peripheral and cardiovascular effects than traditional stimulants. Selegiline, a selective monoamine oxidase B enzyme inhibitor, is metabolized to amphetamines and can be successful at reducing daytime sleepiness. In an individual patient, one wake-promoting agent may work better than another, and if the first drug selected is not successful at adequate doses, a trial with another agent should be attempted. Treatment of EDS in narcolepsy and other sleep disorders may require the use of sustained- and immediate-release stimulants to effectively promote wakefulness throughout the day and at key times that require alertness. One potential treatment regimen includes a sustained-release preparation first thing in the morning and again at noon, followed by an immediate-release preparation as needed in the late afternoon or prior to driving to maintain wakefulness. One advantage of traditional CNS stimulants over modafinil is their ability to suppress REM sleep, which also may help to control cataplexy and REM-sleep abnormalities.
Table 41–2 Pharmacokinetics and Dosing of Prescription Medicationsa Used to Treat Insomnia
Traditional CNS stimulants have the potential to increase blood pressure and heart rate when used long term. In addition, excessive CNS stimulation can cause tremors and tics and can carry over into evening hours, where initiation of normal nighttime sleep can be disrupted. Caution should be used in patients with underlying cardiovascular or cerebrovascular disease and in patients with a history of seizures because stimulants may lower the seizure threshold.
Cataplexy
Traditionally, aminergic signaling antidepressants have been used effectively to control symptoms of cataplexy, sleep paralysis, and other REM-sleep manifestations of narcolepsy. These include TCAs and certain selective serotonin and serotonin/norepinephrine reuptake inhibitors (SSRIs and SNRIs). Clomipramine, protriptyline, imipramine, venlafaxine, and fluoxetine are the agents that have been used most frequently. In addition, low-dose selegiline also has been effective at reducing cataplexy. Although these drugs are not approved by the FDA for treatment of cataplexy, they effectively suppress REM sleep and have been the mainstay of anticataplectic therapy for years. Sodium oxybate, a potent sedative with a very short duration of action, is FDA approved for the treatment of narcolepsy with cataplexy. The mechanism whereby it reduces cataplexy is unknown. Two doses per night are taken, one at bedtime and one follow-up dose taken 2½ to 4 hours later. Patients frequently need to set an alarm to wake up to take their second dose. Sodium oxybate is tightly regulated and is only available from one central pharmacy owing to the high abuse potential of its active ingredient (γ-hydroxybutyrate).
Restless Legs Syndrome
RLS treatment involves suppression of abnormal sensations and leg movements and consolidation of sleep. Dopaminergic and sedative-hypnotic medications are prescribed commonly. In the last few years, dopamine agonists (DAs) have become the therapy of choice for the treatment of RLS, replacing levodopa/carbidopa as first-line agents. The DAs offer many advantages over levodopa/carbidopa, including longer half-lives to cover overnight symptoms, flexible dosing, and a reduced incidence of symptom augmentation. Up to 80% of patients who take levodopa/carbidopa eventually will experience symptom augmentation: RLS symptoms appear earlier in the day, previously unaffected body parts become involved, and higher doses of medication are required to control symptoms.45 Ropinirole (Requip) and pramipexole (Mirapex) are FDA approved for the treatment of RLS, and ropinirole is available in a sustained-release product.46,47 Gabapentin is an effective treatment for RLS, particularly in patients with painful symptoms.48 BZDRAs such as temazepam, clonazepam, zolpidem, and zaleplon effectively reduce arousals associated with PLMS in patients with RLS.49 Their main benefit is derived from improving sleep continuity in patients with RLS, particularly as adjunct treatment with other pharmacologic therapies. Opioids are effective for some patients’ RLS symptoms, with oxycodone, propoxyphene, hydrocodone, and codeine being used most frequently. For both BZDRAs and opioids, caution should be used in the elderly, in patients who snore and are at risk for sleep apnea, and in patients with a history of substance abuse. Low iron levels frequently exacerbate RLS symptoms. Iron supplementation should be prescribed in patients who are iron-deficient. Iron supplementation in patients with serum ferritin concentrations of less than 50 mcg/L improves RLS symptoms. Medications frequently used for RLS are shown in Table 41–3.
Obstructive Sleep Apnea
The main therapy for OSA is nasal continuous positive airway pressure (CPAP) therapy. CPAP alleviates sleep-disordered breathing by producing a positive pressure column in the upper airway using room air. The CPAP machine is small enough to be transportable and sits at the bedside. A flexible tube connects the CPAP machine to a mask that covers the nose. During overnight polysomnography, the pressure setting is increased until sleep-disordered breathing is eliminated. CPAP therapy has been shown to have a favorable impact on blood pressure and to attenuate some of the potential hemodynamic and neurohumoral responses that may link OSA to systemic disease.
Table 41–3 Frequently Used Medications for RLS
Not all individuals tolerate CPAP therapy in part because it requires wearing a mask during sleep, and therapy can dry and irritate the upper airway. In some individuals, these barriers for adherence may be lessened or eliminated by properly fitting the mask, adding humidity or heat to therapy, or using bilevel positive airway pressure (BiPAP) therapy. BiPAP therapy applies a variable pressure into the airway during the inspiratory phase of respiration but, unlike CPAP, reduces the applied pressure during the expiratory phase of respiration.
There are other therapies for OSA. Obesity can worsen sleep apnea, and weight management should be implemented for all overweight patients with OSA. In obese patients with mild OSA, weight loss alone can be effective, and studies have reported improvement in severity of OSA with gastric stapling. For those patients who cannot tolerate CPAP, oral appliances can be used to advance the lower jawbone and to keep the tongue forward to enlarge the upper airway. For individuals who suffer OSA only during certain positions (e.g., when on their back) during sleep, positional therapies may be effective. 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 of its invasiveness. In very severe cases, tracheostomy may be necessary. This procedure may be indicated in selected individuals who are morbidly obese, have severe facial skeletal deformity, experience severe drops in oxygen saturation (e.g., SaO2 less than 70%), or have significant cardiac arrhythmias associated with their OSA.
There is no drug therapy for OSA. Drug therapy for symptoms of OSA may be considered in selected patients. For example, modafinil (Provigil) is a wake-promoting medication that is approved by the FDA to improve wakefulness in patients who have residual daytime sleepiness while treated with CPAP. Initiation of wake-promoting medications should be attempted only after patients are using optimal CPAP therapy to alleviate sleep-disordered breathing. Other therapies used in the past (e.g., medroxyprogesterone) are not effective and may worsen OSA. Untreated or inadequately treated sleep apnea may hinder achieving blood pressure control in hypertensive patients. OSA should be considered and evaluated in hypertensive patients who are resistant to therapy or have signs and symptoms of OSA.
Parasomnias
Non-REM parasomnias usually do not require treatment. If needed, low-dose benzodiazepines such as clonazepam can be prescribed for bothersome episodes. Clonazepam reduces the amount of sleep time spent in stages 3 and 4 of non-REM sleep, where most non-REM parasomnias occur. For treating RBD, clonazepam 0.5 to 2 mg at bedtime is the drug of choice, although melatonin 3 to 12 mg at bedtime also may be effective. Patients with RBD also should have dangerous objects removed from the bedroom and cushions placed on the floor to reduce the chance of injury from breakthrough episodes.
Circadian Rhythm Disorders
Melatonin at doses of 0.5 to 5 mg taken at appropriate target bedtimes for east or west travel is becoming the drug of choice for jet lag. Melatonin significantly reduces jet lag and shortens sleep latency in travelers.50 Hypnotic agents with relatively short durations of action (3 to 5 hours) also may be used to sustain sleep during the initial adaptation to the new time zone.
Drug–Disease and Drug–Drug Interactions
It is important to review patient medication profiles for drugs that may aggravate sleep disorders. Patients should be monitored for adverse drug reactions and potential drug–drug interactions. They should be assessed for adherence to their therapeutic regimens. Pharmacotherapy for sleep disorders should be individualized. Medications can be used commonly to treat several concomitant sleep disorders. Conversely, drug therapy may be effective for one sleep disorder and exacerbate another. For example, antidepressants may alleviate depressive symptoms but exacerbate symptoms of RLS. Medications that block dopaminergic transmission may worsen RLS symptoms. Smoking can worsen OSA, presumably by increasing upper airway edema. Alcohol and CNS depressants, including opiate analgesics, sedatives, and muscle relaxants, can worsen OSA, even in small doses, by reducing respiratory drive and relaxing the upper airway muscles responsible for maintaining patency. CNS depress ants should be avoided, and if they are necessary, they should not be administered before sleep. Drug therapy for sleep disorders should be patient specific, and careful consideration should be given to coexisting diseases, concomitant medications, and potential drug–drug and drug–disease interactions to optimize patient care and treatment.
Patient Encounter, Part 3: Modifying Treatment Plan
CH returns to the clinic 3 months later. The physician previously diagnosed him with OSA and RLS. He received a prescription for CPAPs for OSA and ropinirole 0.5 mg at bedtime for RLS at his last visit. Via phone calls, his ropinirole dose has been increased to 3 mg at bedtime. He has received moderate relief of his RLS symptoms, but on occasion, he still awakens and cannot fall back asleep. His sleepiness and RLS symptoms are improved: ESS 13/24.
Based on the information presented, recommend additional therapy for the patient.
What medications would you consider adding to reduce RLS symptoms and awakenings?
How would you assess the patient’s CPAP therapy and adherence?
What precautions would you want to counsel the patient on about his therapy?
Patient Care and Monitoring
Insomnia
1. Ideally limit hypnotic therapy to short-term use, and reevaluate after 2 to 3 weeks of therapy.
2. Evaluate improvement in the specific sleep complaint (e.g., how has therapy affected sleep latency or sleep maintenance?).
3. Inquire about carryover sedation and other side effects associated with the selected agent. Use a lower dose or select a drug with a shorter duration of action if the patient experiences carryover sedation.
4. Address other psychiatric and medical conditions that frequently coexist with insomnia and medications which can worsen symptoms.
Narcolepsy
1. Administer the ESS at each visit to monitor progress with modafinil or stimulant therapy. Unfortunately, EDS in narcolepsy patients rarely is fully reversed.
2. Evaluate how sleepiness changes throughout the day to best determine how to use sustained- and immediate-release stimulants to maintain wakefulness. If the patient complains of sleep disruption from stimulant therapy, move the dosing time a few hours earlier until sleep disruption is avoided.
3. Review patient’s sleep diaries to track the number of cataplexy, sleep paralysis, and hallucinatory events and when they occur.
RLS
1. Carefully assess both the patient’s and bed partner’s reports of the patient’s nighttime limb movements.
2. Measure sleepiness (via ESS) and RLS symptoms at each visit to track progress with therapy.
3. Evaluate potential side effects of therapy, including nausea, drowsiness, sleep attacks, compulsive behaviors, and headaches for the DA agents.
4. Review the sleep diaries and timing of RLS symptoms to screen for possible symptom augmentation.
5. If symptoms are not resolved, increase the dose of DA agent or add another agent such as gabapentin or a short-moderate duration sedative hypnotic.
OSA
1. Evaluate CPAP therapy annually or at any time individuals experience symptoms (e.g., daytime sleepiness) despite CPAP therapy. For example, change in pressure settings to alleviate OSA may be needed if weight gain occurs.
2. Monitor compliance with CPAP therapy. CPAP machines have a built-in compliance meter to measure the hours used at effective pressure. Patients should use CPAP therapy for at least 5 hours each night. In addition to alleviating sleep-disordered breathing, CPAP therapy may improve cardiovascular outcomes.
Parasomnias
1. Ask patients and family members about any bothersome or dangerous sleepwalking episodes since the last visit and if therapy has reduced the frequency of these events.
2. For RBD, review the sleep diaries and interview bed partners to determine the number and nature of episodes.
3. Inquire about carryover sedation and anterograde amnesia from therapy.
OUTCOME EVALUATION
To determine the success of treatment, evaluate whether the treatment plan restored normal sleep patterns, reduced daytime sequelae, and improved quality of life without causing adverse effects. Schedule patients for follow-up within 3 weeks for insomnia and within 3 months for other sleep disorders. Perform a detailed clinical history to determine the patient’s perception of treatment progress and symptoms along with medication effectiveness and side effects.
Instruct patients to keep sleep diaries of nightly sleep (number of hours, number of awakenings, and worsening or improved sleep) and daytime symptoms, along with documentation of episodes such as cataplexy or RBD. Increase medication to effective doses, and if necessary, start additional therapy to control symptoms. Patients with sleep disorders should experience relief of symptoms the first night of drug therapy but may not receive maximal benefit (effect on daytime symptoms) for a few weeks. Perform a detailed history of prescription, nonprescription, and complementary or alternative medications, and review the patient’s sleep diary, daytime symptoms, and nonpharmacologic therapies on a regular basis.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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