Published: November 2012
Sleep is a normal recurring state that manifests as loss of responsiveness to the external environment. Sleep had been seen as a passive state that ensues in the absence of wakefulness. However, it is now known to be an active physiologic state involving dynamic changes in neural, metabolic, and cardiorespiratory function. Sleep disorders encompass a wide range of conditions that have been most recently categorized in the International Classification of Sleep Disorders, Second Edition (ICSD-2).1 The ICSD-2 lists more than 80 distinct sleep disorders sorted into 8 categories, including the insomnias, sleep-related breathing disorders, hypersomnias of central origin, circadian rhythm sleep disorders, parasomnias, and sleep-related movement disorders.
Normal sleep and wake states are generated by a complex neuronal network in the brain and are regulated by homeostatic and circadian mechanisms. Sleep may be divided into 2 main stages: rapid eye movement (REM) and non-REM (NREM) sleep. REM sleep is also known as paradoxical sleep because it resembles wakefulness with desynchronized electroencephalography (EEG) activity, phasic events such as REM, and bursts of muscle activity. REM sleep also is characterized by dreaming. NREM sleep is characterized by synchronized EEG activity, muscle relaxation, and decreased heart rate, blood pressure, and tidal volume.
Sleep homeostasis refers to the regulatory mechanism that maintains an overall constancy of sleep intensity and duration. Sleep deprivation creates a sleep debt that must be repaid, resulting in compensatory heightened pressure to sleep and eventual increased sleep intensity and duration. Conversely, excessive sleep reduces sleep propensity and amount of sleep.
Sleep physiology changes with age as the brain matures and eventually degenerates. With advancing age, there is a decline in the percentage of sleep that is deep, more frequent awakenings, and sleep fragmentation. In the elderly, sleep disorders such as obstructive sleep apnea (OSA) occur more frequently. Sleep needs also vary with age, decreasing from 16 hours a day in infancy and stabilizing at 7½ to 8 hours for most normal adults.
A suggested practical approach when assessing patients with sleep-related disturbances is to elicit symptoms and signs according to the 3 cardinal clinical presentations of sleep disorders: insomnia, excessive daytime sleepiness, and abnormal movements or behavior in sleep.
Patients with insomnia most commonly describe difficulty with falling asleep and, less commonly, difficulty maintaining sleep or a perception of unrefreshing sleep. Regardless of the cause, insomnia often results in daytime fatigue, general malaise, and, in severe cases, cognitive and mood disturbances.
Chronic insomnia often affects social and occupational functioning and diminishes quality of life. In patients with insomnia related to medical and psychiatric conditions, associated manifestations include chronic pain or other physical discomfort, depression, anxiety, and, often psychosocial stressors. Neurodegenerative disorders, such as Parkinson disease and dementia, are commonly associated with sleep disturbance. Medications such as steroids, bronchodilators, and some antidepressants can cause insomnia, so taking a careful drug history from the patient is important. Chronic insomnia is often multifactorial, encompassing components related to psychophysiologic issues, drugs, and underlying disease, as well as maladaptive behaviors.
Inadequate sleep hygiene, a common problem of patients with chronic insomnia, is classified in the ICSD-2 as a distinct insomnia diagnosis. This term refers to a range of well-recognized sleep-incompatible behaviors, which include excessive use of substances that disrupt sleep (eg, caffeine, nicotine, and alcohol), mentally or physically arousing activities close to bedtime, excessive napping or time in bed, irregular sleep-wake times, and preoccupation with sleep difficulty.
Excessive daytime sleepiness refers to the inability to stay alert during the major awake period of the day, resulting in falling asleep at inappropriate times. Excessive daytime sleepiness is more likely to occur in monotonous situations when alerting stimuli are absent, and it is associated with increased risk of accidents, such as when operating motor vehicles or other machinery. The severity of sleepiness can be quantified subjectively using scales such as the Epworth Sleepiness Scale (Table 1) or can be measured objectively in the sleep laboratory using the multiple sleep latency test (MSLT) or maintenance of wakefulness test (MWT).2 The MSLT measures the physiologic tendency to fall asleep in quiet situations, and the MWT measures the ability to stay awake in quiet situations.
|How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just tired? (This refers to your usual way of life in recent times. Even if you have not done some of these things recently try to work out how they would have affected you.)|
Use the following scale to choose the most appropriate number for each situation:
0 = no chance of dozing
|Sitting and reading|
|Sitting inactive in a public place (e.g. a theater or a meeting)|
|As a passenger in a car for an hour without a break|
|Lying down to rest in the afternoon when circumstances permit|
|Sitting and talking to someone|
|Sitting quietly after a lunch without alcohol|
|In a car, while stopped for a few minutes in traffic|
*A score of ≥10 indicates sleepiness.
These conditions encompass the NREM and REM parasomnias, sleep-related movement disorders (mainly, restless leg syndrome [RLS] and periodic limb movement disorder [PLMD]), and sleep-related epilepsy. The NREM parasomnias are disorders of arousal seen usually in the pediatric population and include confusional arousals, sleepwalking, and sleep terrors. The REM parasomnias include nightmare disorder and REM sleep behavior disorder (RBD). Because the synchronized state of NREM sleep facilitates epileptic activity in general, some epileptic syndromes have a marked tendency to manifest predominantly during sleep and must be distinguished from the parasomnias, which usually requires EEG documentation of epileptiform discharges. Epileptic phenomena are characterized by repetitive stereotypic behavior, but they can be difficult to distinguish clinically from nonepileptic phenomena.
Most sleep disorders can be diagnosed by a comprehensive sleep history, which includes a detailed account of routine sleep-related habits (eg, bedtime, wake time, and number of awakenings), sleep duration, sleeping environment, daytime activities, psychosocial stressors, current drug use, and abnormal behavior in sleep. Important collateral information is often provided by a bed partner, other observer, or family member regarding behavior that the patient may be unaware of, such as snoring or acting out dreams. Sleep questionnaires detailing pertinent sleep-related information and sleep logs are often useful, especially in documenting sleep-wake patterns in the circadian-rhythm sleep disorders.
The Epworth Sleepiness Scale is often used to assess the level of daytime sleepiness and to monitor the response to therapeutic interventions.2 A score of 10 or more indicates that the patient is considered sleepy. Diagnosis of most sleep disorders can be made on the medical history alone, which is based on pattern recognition of clinical characteristics determined from the comprehensive sleep history and a physical examination.
Patients with sleep-onset difficulty might have one of the insomnias as classified in the ICSD-2. Restless leg syndrome should be considered, and a careful history should be taken to rule out drugs and underlying medical problems that cause insomnia. The circadian rhythm disorders are less common causes of sleep-onset insomnia. Also uncommon are sleep-maintenance problems alone causing unrefreshing sleep (without snoring or marked excessive daytime sleepiness) due to OSA or abnormal behavior in sleep. These strikingly abnormal sleep phenomena are usually evident from the history.
Psychophysiologic insomnia, also known as primary insomnia, occurs in about 12% to 15% of patients seen at sleep disorders clinics and affects 1% to 2% of the general population. It is characterized by a physiologic heightened-arousal state that predisposes patients to learned sleep-preventing associations, usually in the setting of social and environmental psychosocial stressors. Persons with psychophysiologic insomnia are typically light or poor sleepers, and can develop chronic insomnia after an initial episode of acute insomnia that failed to resolve following a precipitating stressful event. A counterproductive over-concern with sleep and the consequences of lack of sleep ensue, leading to a mental hyperarousal state (racing mind) and a form of conditioned insomnia associated with the person's habitual bedtime rituals and sleeping environment. Such patients typically report sleeping better while away from home and their usual routines, such as on vacation or during a business trip. This form of insomnia is often perpetuated because habits incompatible with healthy sleep develop, such as excessive time in bed tossing and turning, watching the clock, intense preoccupation with sleep, and abuse of prescription sleep aids. It is also associated with an increased risk of depression and dependence on hypnotics.
Insomnia due to underlying psychopathology (usually depression or anxiety) is one of the most frequently encountered problems at sleep disorders clinics, affecting about 3% of the general population. This condition is usually seen more in women and in middle-aged patients. Insomnia may be a presenting symptom in a variety of psychiatric conditions, including mood, anxiety, psychotic, and personality disorders.3
Insomnia is the most common sleep disturbance associated with major depression, which is seen in 80% to 85% of patients, usually manifesting as recurrent or early morning awakenings. In anxiety disorders, difficulty falling asleep is more typical and accompanies excessive worrying about a range of activities or events. In contrast to psychophysiologic insomnia, where anxiety is typically focused on sleep difficulty alone, patients with anxiety disorder manifest more pervasive anxiety symptoms attributable to a broader range of reasons. In this diagnostic category, which can closely resemble psychophysiologic insomnia, the underlying mental disorder plays a key role in the insomnia, with greater persistence and severity of the mood or anxiety disorder.
Adjustment insomnia or acute insomnia refers to sleep disturbance of relatively short duration (<3 months) caused by an identifiable stressor. The 1-year prevalence of adjustment insomnia is estimated to be about 15% to 20%, and is more common in women and older adults. The sleep disturbance can occur after positive or negative events, such as getting a new job, an unexpected windfall of money, work stress, bereavement, or relationship problems. Adjustment insomnia is expected to resolve once the acute stressor is removed or when the person has adapted to the triggering circumstances.
Jet lag disorder is a temporary condition that occurs after air travel across at least 2 time zones. Symptoms of insomnia (or excessive daytime sleepiness) occur because the endogenous circadian clock is initially asynchronous with the external environment. Besides insomnia, associated symptoms can include general malaise and gastrointestinal upset.
Shift workers who have to work during the body's usual sleep period as determined by the endogenous circadian clock often complain of sleep-onset insomnia in the morning after the night shift (and conversely, excessive sleepiness when working at night). Shift-work disorder is usually evident from a careful review of the work schedule and typically resolves when the sleep period is restored to a conventional time. Like most circadian rhythm disorders, this diagnosis can be made from the patient history.
The most common nonpathologic cause of daytime sleepiness is probably volitional lack of adequate sleep. Habitual sleep duration should be part of the sleep history, and sleeping less than 4 to 5 hours per night is generally insufficient to maintain normal daytime alertness. The most common cause of excessive daytime sleepiness seen in sleep disorders clinics is OSA. Narcolepsy and the other hypersomnias of central origin are less common.
The condition known as OSA is characterized by recurrent episodes of complete (apnea) or partial (hypopnea) upper airway obstruction during sleep. OSA is often associated with oxygen desaturation and recurrent arousals, which are usually quantifiable and confirmed on polysomnography (PSG). The prevalence of OSA syndrome (OSAS; ie, PSG confirmation of OSA in the presence of excessive daytime sleepiness) is estimated to be about 4% in men and 2% in women. Risk factors are obesity and craniofacial abnormalities that narrow the upper airway, such as retrognathia or adenotonsillar enlargement. Other risk factors are a large neck circumference, menopause, smoking, and endocrine disorders, such as hypothyroidism and acromegaly. OSA has been associated with hypertension, ischemic heart disease, stroke, and diabetes. The classic history that often suggests the diagnosis of OSAS includes snoring, excessive daytime sleepiness, witnessed apneas and choking/gasping episodes, and unrefreshing sleep regardless of duration. OSAS typically, but not always, occurs in an obese or overweight person. Confirmation of diagnosis is by PSG showing at least 5 apneas or hypopneas per hour (an apnea-hypopnea index [AHI] ≥5).
Narcolepsy is a rare hypersomnia of central origin affecting 0.02% to 0.18% of Western populations, with onset usually in adolescence or young adulthood (in those aged 15 to 25 years). It is characterized by excessive daytime sleepiness, cataplexy, often irresistible sleep attacks, sleep paralysis (transient inability to move or speak), and hypnagogic or hypnopompic hallucinations (usually vivid audiovisual phenomena that occur upon falling to sleep or waking). Classically, patients with narcolepsy report short, refreshing naps that are usually followed by 2 to 3 hours of alertness. Not all narcoleptic patients report cataplexy—the hallmark of narcolepsy—which refers to a sudden loss of muscle tone provoked by strong emotions, such as laughter or anger, with preserved consciousness. These patients form a subgroup listed in ICSD-2 as "narcolepsy without cataplexy."
Although a diagnosis can be made by clinical history in typical cases with all the classic features, PSG with MSLT is usually performed to rule out other common causes of excessive daytime sleepiness, like OSA. The MSLT usually shows short sleep-onset latency (<8 min.) and sleep-onset REM periods (SOREMPs), which refers to the abnormal appearance of REM sleep (usually seen 90 to 120 minutes into sleep) in a 20-minute nap.
This form of hypersomnia is characterized by excessive daytime sleepiness that occurs at a young age, usually before the age of 25 years, and is distinguished from narcolepsy by the absence of cataplexy and other narcolepsy-associated phenomena (eg, sleep paralysis and hypnagogic hallucinations). Also unlike narcoleptics who take short, refreshing naps, idiopathic hypersomnia patients have long, unrefreshing daytime sleep episodes. On MSLT, such patients also do not have SOREMPs, which are seen in narcolepsy.
In addition to insomnia, this group of disorders, which includes shift work sleep disorder, jet lag disorders, and advanced sleep phase disorder can also manifest with excessive daytime sleepiness. Advanced sleep phase disorder is in seen in about 1% of middle-aged and older adults and is characterized by sleep-wake times that are several hours earlier than conventional or desired times. There is a stable advance of the habitual sleep period, such as sleeping at 6 PM and waking at 2 AM. Such patients complain of excessive daytime sleepiness in the late afternoon and early evening and spontaneous early-morning awakenings.
RLS is a clinical diagnosis based on fulfilling 4 essential criteria originally proposed in 1995 by the International RLS Study Group and modified in 2002.4 The 4 essential criteria for RLS are:
RLS affects 5% to 15% of Caucasians, and presents in women more often than men. Sensorimotor symptoms predominate at bedtime and give rise to sleep-onset insomnia. RLS is associated with periodic limb movements in sleep (PLMS) in 80% to 90% of cases, which can contribute to sleep maintenance problems if these are associated with arousals. RLS may be idiopathic or may be related to iron deficiency, peripheral neuropathy, uremia, or pregnancy. The diagnosis is usually straightforward in patients with prominent sensory symptoms (usually in the legs) during wakefulness before sleep onset, which fulfill the clinical diagnostic criteria listed above.
RLS is often confused with periodic limb movement disorder (PLMD). In that disorder, abnormal limb movements manifest only in sleep rather than wakefulness before sleep onset, causing sleep-maintenance insomnia rather than sleep-onset insomnia as a result of repetitive, stereotyped (triple flexion) leg movements that cause repeated arousals. Whereas RLS is a clinical bedside diagnosis, PLMD requires documentation of frequent PLMS with associated arousals and sleep fragmentation on PSG.
Sleepwalking, or somnambulism, consists of abnormal behaviors during NREM sleep, such as walking around in an impaired state of consciousness, with or without other complex actions, such as violent behavior, driving a car, or climbing out a window. The prevalence of sleepwalking is higher in children (up to 17%) than in adults (up to 4%). Precipitating factors include sleep deprivation, sleep disorders that precipitate arousals, febrile illness in children, and physical or emotional stress in adults. The main concern of sleepwalking is the risk of self-injury. Any underlying triggers should be identified and treated appropriately.
Sleep terrors, or night terrors, occur in 2% to 3% of children and adults. They consist of arousals from deep NREM sleep and are characterized by intense behavioral manifestations of fear and autonomic hyperactivity (eg, tachycardia, tachypnea, pupillary dilation, and diaphoresis). The episodes are associated with frightening dreams, confusion, disorientation, and amnesia following each episode. They may be difficult to distinguish from other parasomnias or sleep-related epilepsy, which usually require PSG (with EEG) for diagnosis.
Nightmare disorder affects 2% to 8% of the general population, and up to 50% of young children. Recurrent frightening dreams occur in REM sleep, which often result in awakenings and sleep disruption. Patients usually can recall details of their disturbing dream on awakening. In adults, frequent nightmares have been associated with physical or emotional trauma, stress, and psychopathology. Nightmares are characterized by detailed recollection of bad dreams (unlike sleep terrors in which there is usually amnesia of the event), and should be differentiated from other parasomnias and nocturnal panic attacks. Underlying psychological disturbances should be identified.
RBD affects mainly older men (with a prevalence of 0.3% to 0.5% of the general population). It consists of dream-enactment behavior that causes injury (to self or bed partner) and sleep disruption. Typically, such episodes consist of acting out unpleasant or violent dreams with behavior such as shouting, punching, kicking, and running, and they are reported because of sleep-related injury, usually occurring in the last one third of the sleep period. RBD is associated with neurodegenerative disorders, such as Parkinson disease, and can also be acutely triggered by psychotropic medications or withdrawal from alcohol and sedative-hypnotic agents. As with the other parasomnias, PSG may be required to rule out seizures. Specific treatment is needed to prevent injury.
The estimated prevalence of sleep-related epilepsy ranges from 10% to 45% with no gender predominance. Epilepsy is a brain disorder characterized by a recurring tendency to unprovoked seizures, which are paroxysmal events resulting from abnormal, excessive discharge of cortical neurons. Sleep facilitates epileptic discharges, especially the synchronized state of NREM sleep. Several epileptic syndromes have a tendency to manifest mainly during sleep, such as juvenile myoclonic epilepsy and nocturnal frontal lobe epilepsy. Nocturnal seizures can mimic the NREM and REM parasomnias, the latter of which are usually not stereotyped in manifestation. Typically, in clinical practice it may be difficult to distinguish epileptic seizures from other abnormal behaviors or movements in sleep from history alone. PSG with video and full EEG recording is often required for comprehensive evaluation and definitive diagnosis.
Sleep studies are indicated mainly to confirm the nature and severity of sleep-related breathing disorders, help diagnose narcolepsy, and to document parasomnias and seizures.
Polysomnography (PSG) is the monitoring of physiologic parameters (with EEG, electromyography [EMG], electro-oculography [EOG], electrocardiography [ECG], airflow, respiratory effort, and pulse oximetry) and physiologic or pathologic events in the sleeping patient. Different NREM and REM sleep stages can be identified based on specific EEG, EMG, and EOG characteristics. Monitoring respiratory parameters and ECG allows simultaneous documentation of sleep-related cardiorespiratory disturbances in conditions such as OSA.
The multiple sleep latency test (MSLT) provides an objective measure of sleepiness. The MSLT is considered the gold standard in the objective evaluation of excessive daytime sleepiness. Mean sleep latency (MSL) less than 5 minutes is considered pathologic and correlates with severe sleepiness. The primary indication for the MSLT is to evaluate patients for a diagnosis of narcolepsy. In narcolepsy there is a very short MSL and at least 2 SOREMPs.
The maintenance of wakefulness test (MWT) is a variation of the MSLT and measures the ability of a person to stay awake in the setting of sleep disorders associated with excessive daytime sleepiness, such as narcolepsy and OSA. During nap trials of 20 minutes, a normal MSL is 18 minutes (representing 1 standard deviation below normal). An MSL of less than 11 minutes is considered impaired wakefulness. Values between 11 and 18 minutes are of questionable significance.
Good sleep hygiene instruction is helpful for most patients with insomnia because they usually have some component of inadequate sleep hygiene, regardless of the primary cause of the insomnia (Table 2). Especially important are having a fixed wake time and avoiding excessive time in bed engaged in activities other than sleeping. Patients are encouraged to limit time in bed in order to achieve a high percentage of actual sleep while in bed (sleep efficiency), principles encompassed in "stimulus control" and "sleep restriction" (Tables 3 and 4).5
|Get up at about the same time every morning, including weekends.|
|Maintain a regular schedule of going to bed and waking up.|
|Go to bed only when you are feeling sleepy.|
|Only use your bed for sleep and sexual activity.|
|Avoid watching television, working, or reading in bed.|
|If you are not asleep after 20 minutes, get out of the bed. Go back to bed only when you feel sleepy again.|
|Food and Drink|
|Avoid heavy meals within 2 hours of bedtime, but try not to go to bed hungry.|
|Try not to drink too much fluid close to bedtime to prevent needing to urinate during the night.|
|Avoid using alcohol as a sleep aid.|
|Limit caffeine use to 1 or 2 beverages a day, no later than 4 hours before bedtime.|
|Establish a relaxing pre-sleep routine while getting ready to go to bed (eg, reading watching TV, listening to music).|
|Set aside time to relax and practice natural relaxation techniques (eg, deep breathing, progressive muscle relaxation).|
|Create an atmosphere conducive to sleep.|
|Maintain a room temperature comfortable for sleeping.|
|Avoid loud noises and bright lights in the bedroom.|
|Avoid taking long daytime naps unless you are sleep deprived.|
|Afternoon naps should not exceed 1 hour.|
|Regular physical exercise is encouraged to promote sleep and overall well-being.|
|Vigorous physical activity should be avoided too close to bedtime.|
|Worry and Anxiety|
|Avoid things that can trigger worry or anxiety before bed, such as anxiety provoking, work-related, or other unpleasant tasks, or disturbing television programs.|
|Reduce the anxiety of anticipation of the following day by making simple preparations such as a to-do list or laying out the next day's clothes and shoes.|
|Keeping a written list of worries is beneficial for some people.|
|Determine the average estimated total sleep time (TST). This information can be obtained from a sleep diary (sleep log), which should be filled out for at least 2 weeks.|
|Restrict the time in bed (TIB) to the average estimated total sleep time.|
|Determine the patient's weekly sleep efficiency (TST/TIB x 100%) from the sleep log.|
|Increase time in bed by 15 to 20 minutes when sleep efficiency exceeds 90%. Decrease it by 15 to 20 minutes when sleep efficiency is below 80%. Keep time in bed the same when sleep efficiency is between 80% and 90%. Adjust time in bed until the ideal sleep duration is obtained.|
|Do not decrease time in bed to less than 5 hours.|
|Brief afternoon naps may be allowed in the early phase of treatment.|
Behavioral changes may be sufficient to improve insomnia in many cases. Cognitive behavioral therapy for insomnia (CBT-I) is a safe and effective means of treating insomnia through the correction of maladaptive attitudes and beliefs regarding sleep. CBT-I uses natural relaxation (eg, deep breathing and progressive muscle relaxation) and other techniques (eg, stimulus control and sleep restriction) as well as instruction in good sleep hygiene. CBT-I and drug therapy may be used in combination for patients with various forms of insomnia, such as psychophysiologic insomnia, idiopathic insomnia, or insomnia due to depression. CBT-I has been shown to provide significantly greater benefit compared to pharmacotherapy alone in terms of normalization of sleep (improved sleep onset latency and sleep efficiency); this is an effect that is also better sustained at long term follow-up.6 Recently, updated and published clinical practice guidelines recommend psychologic and behavioral interventions as effective in the treatment of chronic primary and comorbid (secondary) insomnia. These treatments (which include stimulus control therapy and relaxation therapy) should be utilized as initial intervention when appropriate and when conditions permit.7 Various meta-analyses and one major review by the Standards of Practice Committee of the American Academy of Sleep Medicine have concluded that CBT is effective in the treatment of primary insomnia.
Sedative-hypnotics are the mainstay of pharmacotherapy for acute and chronic insomnia. Other categories of drugs (eg, antidepressants, anxiolytic agents, antiepileptic drugs, antihistamines, and melatonin-related drugs) are often used (some off-label) for different types of chronic insomnia with comorbid conditions Table 4.
|Drug||Half-Life||Dose Range in Adults||Comments|
|Zaleplon||~1 hr||5-20 mg|
|Zolpidem||1.4-4.5 hr||5-10 mg||Adverse effects: Sleepwalking, sleep-eating|
|Zolpidem CR||1.4-4.5 hr||6.25-12.5 mg|
|Zopiclone||3.5-6.5 hr||3.75-7.5 mg||Not approved for use in the United States|
|Eszopiclone||5-7 hr||1-3 mg||Only FDA-approved agent for long-term use|
|Melatonin and Melatonin-Receptor Agonist|
|Melatonin||0.5-2 hr||0.3-40 mg|
|Ramelteon||1-2.6 hr||4-8 mg||Should not be used with fluvoxamine|
|Benzodiazepines FDA-approved for use in insomnia|
|Estazolam||10-24 hr||1-2 mg|
|Flurazepam||40-250 hr||15-30 mg|
|Quazepam||39-73 hr||7.5-30 mg|
|Temazepam||8-20 hr||7.5-30 mg|
|Triazolam||1.5-5.5 hr||0.125-0.5 mg|
|Alprazolam||6-20 hr||0.25-4 mg in divided doses|
|Clonazepam||18-40 hr||0.25-4 mg in divided doses|
|Lorazepam||10-20 hr||0.5-6 mg in divided doses|
|Amitriptyline||12-24 hr||10-150 mg (max 300 mg daily)|
|Doxepin||6-8 hr||10-150 mg (max300 mg daily; divided or once daily)|
|Fluvoxamine||15-22 hr||50-300 mg||Also treatment for obsessions and compulsions|
|Mirtazapine||20-40 hr||7.5-45 mg|
|Nefazodone||2-4 hr||50-600 mg (in divided doses)|
|Trazodone||3-6 hr||25-400 mg (in divided doses)|
|Diphenhydramine||2-8 hr||25-100 mg|
|Promethazine||9-16 hr||12.5-50 mg|
|Hydroxyzine||20-25 hr||12.5-100 mg||Also anxiolytic and anti-pruritic|
(Insomnia Related to Chronic Pain‡ and Epilepsy)
|Gabapentin||5-7 hr||100-1200 mg||Off-label use|
|Pregabalin||5-6.5 hr||75-300 mg||Off-label use; also anxiolytic|
*Off-label use, not FDA-approved for insomnia.
†Indicated for use in insomnia related to depression. Not FDA-approved for insomnia alone.
╪Examples: neuropathic pain, restless legs syndrome, fibromyalgia.
Newer drugs for insomnia include the nonbenzodiazepine sedative-hypnotics and the melatonin receptor agonist, ramelteon. Generally, shorter-acting drugs are used for insomnias manifesting with sleep-onset difficulty, and longer-acting medications are used for sleep-maintenance insomnia. The choice of drug also is determined by the presence of comorbid conditions (eg, depression, antidepressants; anxiety, anxiolytics; or neuropathic pain, antiepileptic drugs). For insomnia specifically caused by depression, antidepressants are the initial drugs of choice. For circadian rhythm disorders (eg, delayed sleep phase disorder), melatonin and melatonin receptor agonists have chronobiotic properties, in addition to their hypnotic effect, which may be helpful in shifting of the sleep phase. For sleep disturbances related to medical conditions causing pain, respiratory difficulty, or related to neurodegenerative disorders, the treatment is that of the underlying condition.
The short-term efficacy of benzodiazepines and nonbenzodiazepine sedative-hypnotics such as zolpidem is established, but long-term use of these agents is controversial because of issues of tolerance and dependence.8 Studies have supported longer term use with sustained efficacy of the nonbenzodiazepine sedative-hypnotics eszopiclone and extended release zolpidem.9,10 Longer term use of sedative-hypnotics should be closely monitored and avoided in patients who already have a history of substance abuse. The lowest effective dose should be used, and intermittent rather than daily use should be encouraged whenever possible to reduce the risk of tolerance. Tapering should be done very slowly over weeks. Patients should be advised of adverse reactions of sedative-hypnotics, including dependence, tolerance, and abnormal sleep-related behavior (eg, sleepwalking and sleep eating with zolpidem).
The FDA-approved medications for insomnia include the newer nonbenzodiazepine sedative-hypnotics such as zaleplon, zolpidem, eszopiclone, and ramelteon. With shorter half-lives than the older benzodiazepines, these newer agents are less likely to produce daytime sedation and cognitive disturbance (Table 4).
Patients should be advised of potential adverse reactions to sedative-hypnotics, including dependence, tolerance, and abnormal sleep-related behavior (e.g., sleepwalking and sleep eating with zolpidem).
In January 2013, the U.S. FDA lowered the current recommended dose of drugs containing zolpidem. The action was due to new data showing that the blood levels of the drug can be high enough the morning after use to impair activities that require alertness, including driving. Because women eliminate zolpidem more slowly than men do, the recommended dosage for women was lowered to 5 mg from 10 mg for immediate-release products and to 6.25 mg from 12.5 mg for extended-release products. For men, providers should also consider prescribing lower doses.
The treatment of insomnia related to RLS warrants separate mention and is summarized in Table 5. The management of RLS is divided into behavioral and pharmacologic interventions. In general, counter stimulation (rubbing legs, hot or cold baths, and ice packs), good sleep hygiene, reduced caffeine and alcohol intake, and avoidance, if possible, of drugs that exacerbate RLS (most antidepressants, neuroleptic agents, and antihistamines) are recommended. Other methods include distracting mental activity (games and hobbies), regular exercise (though not too late in the evening or at night), and avoiding provocative situations (long periods of sitting still). Delaying one's habitual sleep period to the time when symptoms are least troublesome (usually in the late morning) can facilitate sleep, although this is not practical for people with regular office hours. Patients with mild, infrequent RLS might benefit from these behavioral techniques alone, with RLS drugs taken infrequently as needed.
|Drug||Dose Range||Half Life||Side Effects|
(max 1200 mg/dose)
|5-7 hr||Sedation, dizziness, ataxia|
|L-dopa||50-200 mg||1.5-2 hr||Nausea, vomiting, orthostatic hypotension,
insomnia, hallucinations, augmentation
|Pramipexole*||0.125-1.5 mg||8-10 hr|
|Ropinirole*||0.25-3.0 mg||6-8 hr|
|Sedative Hypnotic Agents|
|Zaleplon||5-20 mg||~1 hr||Sedation, respiratory depression,
|Zolpidem||5-10 mg||1.4-4.5 hr|
|Clonazepam||0.25-4 mg||18-40 hr|
|Codeine||15-120 mg||2-3 hr||Sedation, constipation,
pruritus, dry mouth, dependence
|Oxycodone||5-30 mg||3 hr|
|Hydrocodone||5-30 mg||3 hr|
|Tramadol||50-300 mg||5-8 hr|
|Propoxyphene||100-600 mg||6-12 hr|
|Methadone||2.5-20 mg||16-22 hr|
*Instructions for patients: pramipexole 0.125 mg or ropinirole 0.25 mg: Take tablet 2 hours before bedtime. Increase to 1 tablet after 3 days if no side effects or benefit. Continue to increase by tablet every 3 days until there is benefit or side effects develop.
Patients with iron deficiency should be investigated for the underlying cause, and oral iron replacement should be initiated. Iron studies should be performed on RLS patients with anemia or a history to suggest acute or chronic blood loss. Iron supplementation with ferrous sulfate has been reported to be effective in relieving RLS symptoms in elderly patients with low ferritin levels (below 45 mcg/L).11 Oral iron therapy is safe, inexpensive, and effective in restoring iron balance. Generally, iron supplements are recommended for RLS patients with a serum ferritin level below 50 mcg/L. The cheapest preparation is iron sulfate, containing 300 mg of iron salts, of which 60 mg is elemental iron. Iron is best absorbed in a mildly acidic medium, so vitamin C (250 mg ascorbic acid) is given at the same time to enhance iron absorption. Iron should be given on an empty stomach, and 2 hours before or 4 hours after ingestion of antacids. Improvement may take weeks to months. Ferritin levels should be rechecked periodically.
The main categories of drugs used for the symptomatic treatment of RLS are the dopaminergic agents, antiepileptic drugs (mainly gabapentin), the sedative hypnotics, and the opioid drugs, which are listed in Table 5. Ideally, drug therapy should address the distressing limb sensations as well as associated problems, such as insomnia and depression. Most patients with RLS respond to dopaminergic agents.12,13 However, because of the significant problem of augmentation (about 80% with L-dopa and 30% with dopamine agonists), L-dopa is no longer considered first-line therapy. Its use is confined to intermittent dosing to provide rapid relief for infrequent symptoms. Augmentation refers to the worsening of RLS symptoms caused by a specific drug, usually the dopaminergic agents, within 6 months of initiating therapy. Typically, there is progressively earlier onset of symptoms with increasing symptom intensity. For patients with severe and frequent symptoms, a dopamine agonist is generally the initial drug of choice.
The mainstays of treatment of these disorders involve planned sleep schedules, timed light exposure, timed melatonin doses, sedative hypnotics, and alerting agents—details of which have been outlined in the 2007 American Academy of Sleep Medicine (AASM) Practice Parameters.14 Sedative-hypnotic medications and melatonin improve the quality and duration of daytime sleep of shift workers and sleep in jet lag–induced insomnia. Melatonin reduces sleep-onset latency and shifts circadian rhythms to an earlier time in delayed sleep phase disorder. Melatonin has also been recommended for advanced sleep phase disorder, although there is no reported evidence in support of this.
Behavioral modifications in sleep disorders that cause excessive daytime sleepiness include diet and exercise to promote weight loss, and positional therapy (not sleeping on the back) for OSA. Positional therapy has modest benefits in sleep quality, excessive daytime sleepiness, and AHI in positional OSA (defined as a supine AHI at least twice that of the lateral AHI). In narcolepsy, scheduled naps, which are typically refreshing, can help to sustain alertness and reduce the need for stimulant drugs. Planned sleep schedules are also an important part of treating circadian rhythm sleep disorders.
Wake-promoting agents that have been used in sleep disorders causing excessive daytime sleepiness include modafinil, methylphenidate, amphetamines, and caffeine. Modafinil and armodafinil can be used to enhance alertness in OSA, narcolepsy, and shift-work disorder. Modafinil promotes wakefulness by an unknown mechanism and is usually given in doses of 100 mg to 200 mg (maximum 400 mg) daily. Methylphenidate is a central nervous system (CNS) stimulant. The effective dose ranges from 10 mg to 60 mg daily in divided doses. Sustained-release formulations are available (eg, Ritalin-LA 10mg to 100 mg once daily and Concerta 18 mg to 54 mg once daily). Amphetamines are noncatecholamine sympathomimetic amines with CNS stimulant activity; they have a high potential for abuse. Examples are combined dextroamphetamine and amphetamine (Adderall, 10mg to 60 mg daily in divided doses) and dextroamphetamine alone (5 mg to 60 mg daily in divided doses). CNS stimulants cause elevations in blood pressure and heart rate, and have been associated with arrhythmias and sudden death.
Positive airway pressure (PAP) is the mainstay of treatment for OSA. This can take the form of continuous positive airway pressure (CPAP), autotitrating positive airway pressure (autoPAP), or bilevel positive airway pressure (BiPAP). Each has a different method of pressure delivery, and all are widely used. Although an effective treatment of choice, CPAP therapy has a high noncompliance rate, ranging from 5% to 50%.15 Modafinil is effective in reducing excessive daytime sleepiness and is approved for use in OSA patients with residual excessive daytime sleepiness despite adequate CPAP therapy. Oral appliances are recommended by the AASM as first-line treatment (as an alternative to CPAP) for mild to moderate OSA and in patients with severe OSA who refuse CPAP or in whom CPAP is not effective.16 Surgical options for OSA include bariatric surgery for morbid obesity, which is effective in reducing BMI and AHI, and upper airway surgery.
Modafinil and CNS stimulants are used as alerting agents in patients with narcolepsy. Symptoms of cataplexy are treated with REM suppressants such as tricyclic antidepressants (eg, protriptyline 15 mg to 40 mg per day or imipramine 50 mg to 150 mg per day) and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine 20 mg to 60 mg per day and sertraline 25 mg to 50 mg per day. Sodium oxybate (Xyrem) is a newer drug that may be a first-line agent for treating cataplexy. This medication also improves sleep quality and reduces excessive daytime sleepiness. The use of sodium oxybate is tightly regulated because of its abuse potential. It is available by prescription only through a restricted distribution program called the “Xyrem Success Program.” The effective dose range of sodium oxybate is 6-9 g/d taken at night. The recommended initial dose is 4.5 g/d taken at night in 2 equal divided doses. The starting dosage can be increased in increments of 1.5 g/d (0.75 g/dose) every 1 to 2 weeks to minimize adverse effects. The drugs for narcolepsy are listed in Table 6.
|Drug||Dose Range||Half Life||Side Effects|
|Drugs for excessive daytime sleepiness|
|Dextroamphetamine||305-60 mg||10-12 hr||Hypertension, arrhythmias, nervousness, irritability, headache, decreased appetite, and insomnia|
|Methylphenidate||10-60 mg||2-4 hrs|
|Modafinil||100-400 mg||15 hrs|
|Armodafinil||150-250 mg||12-15 hrs|
|Drugs for Cataplexy|
|Proptriptyline||15-40 mg||54-92 hrs||Anticholinergic side effects (tricyclic antidepressants)|
|Imipramine||50-150 mg||9-20 hrs|
|Fluoxetine||20-60 mg||48-72 hrs|
|Sertraline||25-50 mg||26 hr|
|Venlafaxine||75-225 mg||5-7 hr|
|Sodium oxybate||6-9 g||0.5-1 hr||Headache, nausea, dizziness, somnolence, vomiting, urinary incontinence, sleepwalking|
Parents should be reassured that parasomnias are common and generally benign. Often no specific therapy is required, but sensible safety precautions should be instituted, such as padding the bedroom environment, securing doors and windows, and installing alarm or monitoring systems that track the patient's movements. Parasomnias that pose a risk of injury to the patient or bed partner and those that are triggered by treatable conditions (eg, OSA and PLMD) require specific therapies. For frequent or potentially injurious parasomnias, benzodiazepines and tricyclic antidepressants may be helpful. Clonazepam has been used successfully, starting at low doses (eg, 0.25 mg at bedtime) and titrating according to effect and tolerability. It is especially helpful in RBD, which also may be treated with melatonin (dose range 3-12 mg at night) as an alternative immunotherapy or as an add-on for patients who do not tolerate long-acting benzodiazepines. Sleep-related epilepsy is treated with anticonvulsants.