Sleep disorders are among the most common clinical problems encountered in medicine and psychiatry. Inadequate or nonrestorative sleep can markedly impair a patient’s quality of life.[1] Sleep disorders may be primary or may result from a variety of psychiatric and medical conditions.
Primary sleep disorders result from an endogenous disturbance in sleep-wake generating or timing mechanisms, often complicated by behavioral conditioning. They may be divided into the following 2 broad categories:
It is important to distinguish these primary sleep disorders from secondary sleep disorders. At times, determining whether anxiety and depression are causing sleep problems or the anxiety and depression are secondary to a primary sleep problem is difficult. (See Anxiety Disorders and Depression.)
Primary insomnia is the general term for difficulty in initiating or maintaining sleep. Because sleep requirements vary from individual to individual, insomnia is considered clinically significant when a patient perceives the loss of sleep as a problem. Insomnia may be further characterized as either acute (transient) or chronic.
Sleep is divided into the following 2 categories, each of which is associated with distinct patterns of central nervous system (CNS) activity:
Disturbances in the pattern and periodicity of REM and NREM sleep are often found when people admit to experiencing sleep disorders.
Sleep-wake cycles are governed by a complex group of biologic processes that serve as internal clocks. The suprachiasmatic nucleus, located in the hypothalamus, is thought to be the body’s anatomic timekeeper, responsible for the release of melatonin on a 25-hour cycle. The pineal gland secretes less melatonin when exposed to bright light; therefore, the level of this chemical is lowest during the daytime hours of wakefulness.
Multiple neurotransmitters are thought to play a role in sleep. These include serotonin from the dorsal raphe nucleus, norepinephrine contained in neurons with cell bodies in the locus ceruleus, and acetylcholine from the pontine reticular formation. Dopamine, on the other hand, is associated with wakefulness.
Abnormalities in the delicate balance of all of these chemical messenger systems may disrupt various physiologic, biologic, behavioral, and EEG parameters responsible for REM (ie, active) sleep and NREM (slow-wave) sleep.
The major causes of insomnia may be divided into medical conditions, psychological conditions, and environmental problems.
Cardiac conditions that may give rise to disordered sleep include ischemia and congestive heart failure. Neurologic conditions include stroke, degenerative conditions, dementia, peripheral nerve damage, myoclonic jerks, restless leg syndrome, hypnic jerk, and central sleep apnea. Endocrine conditions affecting sleep are related to hyperthyroidism, menopause, the menstrual cycle, pregnancy, and hypogonadism in elderly men.
Pulmonary conditions include chronic obstructive pulmonary disease, asthma, central alveolar hypoventilation (the Ondine curse), and obstructive sleep apnea syndrome (associated with snoring). Gastrointestinal (GI) conditions include gastroesophageal reflux disease. Hematologic conditions include paroxysmal nocturnal hemoglobinuria, which is a rare, acquired, hemolytic anemia associated with brownish-red morning urine.
Substances that may result in insomnia include stimulants, opioids, caffeine, and alcohol, or, withdrawal from any of these also may cause insomnia. Medications implicated in insomnia include decongestants, corticosteroids, and bronchodilators.
Other conditions that may affect sleep include fever, pain, and infection.
It should be borne in mind in mind that the major psychiatric conditions now are known to have a biologic basis and thus constitute a subset of medical conditions.
Depression may cause alterations in REM sleep. As many as 40% of people with depression have insomnia. Posttraumatic stress disorder (PTSD) can produce vivid and terrifying nightmares. Anxiety disorders predispose to insomnia. The most common of these are generalized anxiety disorder, panic disorder, and anxiety disorders not otherwise specified. Thought disorders and misperception of sleep state are other potential states that cause insomnia.
Psychotropic medications, such as antidepressants, may interfere with normal REM sleep patterns. Rebound insomnia from benzodiazepines or other hypnotic agents is common.
Stressful or life-threatening events (eg, bereavement or PTSD) may cause insomnia. Shift work may disturb the sleep cycle, as may jet lag or changes in altitude. Sleep deprivation may occur as a result of an overly warm sleeping environment, environmental noise, or frequent intrusions (such as occur in an intensive care unit [ICU]).
Approximately one third of all Americans have sleep disorders at some point in their lives. Between 20% and 40% of adults report difficulty sleeping at some point each year, and about 17% of adults consider the problem to be serious. Sleep disorders are a common reason for patient visits throughout medicine. Approximately one third of adults have insufficient sleep syndrome. Twenty percent of adults report chronic insomnia.
Increasing age predisposes to sleep disorders (5% incidence in persons aged 30-50 years and 30% in those aged 50 years or older). People who are elderly experience a decrease in total sleep time, with more frequent awakenings during the night. Elderly persons also have a higher incidence of general medical conditions and are more likely to be taking medications that cause sleep disruption.
People who are elderly may have widespread or multisite pain that is associated with sleep difficulty, according to the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly study (MOBILIZE) study.[2]
Primary insomnia is more common in women, with a female-to-male ratio of 3:2. Hormonal variations during the menstrual cycle or during menopause may cause disruptions in sleep. Obstructive sleep apnea (OSA) is more common in men (4%) than in women (2.5%).
The prognosis varies widely, depending on the cause of the insomnia or other sleep disorder. For example, insomnia due to OSA resolves with successful treatment of the apnea, whereas insomnia due to refractory major depression is itself refractory until a successful treatment can be found for the depression.
Chronic insomnia is associated with an increased risk of depression and accompanying danger of suicide, anxiety, excess disability, reduced quality of life, and increased use of health care resources.
Insufficient sleep can result in industrial and motor vehicle crashes, somatic symptoms, cognitive dysfunction, depression, and decrements in daytime work performance owing to fatigue or sleepiness.
Yaffe et al suggest that older women with sleep-disordered breathing (characterized by recurrent arousals from sleep and intermittent hypoxemia) have an increased risk of developing cognitive impairment compared with those without sleep-disordered breathing.[3]
One study suggests that among police officers in the United States and Canada, sleep disorders are common and are significantly associated with an increased risk of self-reported adverse outcomes in terms of health, performance, and safety.[4]
All individuals should be taught and encouraged to practice good sleep hygiene (see Treatment). Educating patients’ families about proper sleep hygiene is imperative, especially because bed partners can be adversely affected by sleep disorders such as OSA. Patients should be instructed to use the bed for sleep and sex only (no television watching or reading in bed). They should also be warned to not drive or operate machinery while taking sedative-hypnotic medications. Document these admonitions clearly in the medical record.
For patient education resources, see the Mental Health and Behavior Center and the Sleep Disorders Center, as well as Disorders That Disrupt Sleep (Parasomnias), Insomnia, Primary Insomnia, REM Sleep Behavior Disorder, Understanding Insomnia Medications, Sleep Disorders in Women, Sleep Disorders and Aging, and Sleeplessness and Circadian Rhythm Disorder.
Insomnia may present as decreased sleep efficiency or decreased total hours of sleep, with some associated decrease in productivity or well-being. Because sleep requirements vary from person to person, the quality of sleep is more important than the total number of hours slept. The total number of hours slept should be compared with each individual’s lifelong normal night sleep time.
Initial insomnia (also referred to as early insomnia or sleep-onset insomnia) is characterized by difficulty in falling asleep, with an increase in sleep latency (ie, the time between going to bed and falling asleep). Initial insomnia is frequently related to anxiety disorders.
Middle insomnia (also referred to as sleep-maintenance insomnia) refers to difficulty in maintaining sleep. Decreased sleep efficiency is present, with fragmented unrestful sleep and frequent waking during the night. Middle insomnia may be associated with medical illness, pain syndromes, or depression.
In terminal insomnia (also referred to as late insomnia or early morning wakening insomnia), patients consistently wake up earlier than needed. This symptom is frequently associated with major depression.
Alterations of the sleep-wake cycle may be a sign of circadian rhythm disturbances, such as those caused by jet lag and shift work.
Hypersomnia, or excessive daytime sleepiness, is often attributable to ongoing sleep deprivation or poor-quality sleep arising from causes ranging from sleep apnea to substance abuse or medical problems.
In delayed sleep phase syndrome, the patient is unable to fall asleep until very early morning. As time progresses, the onset of sleep becomes progressively delayed.
Sleepwalking, also called somnambulism, refers to episodes of complex behaviors occurring during non–rapid eye movement (NREM) sleep (stages 3 and 4), of which the patient is amnestic afterward.
Nightmares are repeated awakenings from sleep caused by vivid and distressing recall of dreams. Nightmares usually occur during the second half of the sleep period. Upon wakening from the dream, the person rapidly reorients to time and place.
Night terrors are recurrent episodes of abrupt awakening from sleep characterized by a panicky scream, with intense fear and autonomic arousal. The individual usually has no recall of the details of the event and is unresponsive during the episode. Night terrors occur during the first third of the night, during stages 3 and 4 of NREM sleep.
Sleep paralysis occurs when an individual begins waking up while still in REM sleep and is therefore paralyzed. Individuals can have hallucinatory and paranoid experiences.[5]
Bed partners of patients who snore may provide a history of snoring. Such a history may help determine whether a patient experiences obstructive sleep apnea (OSA).
Signs of sleep disorders include the following:
Sleep apnea is potentially very serious. In addition to loss of sleep it can have adverse cognitive effects, can damage the brain, and can damage the cardiovascular system. Two thirds of people with sleep apnea are depressed.[6]
Mood and anxiety disorders may develop from untreated sleep disturbances, and current medical literature supports the theory that these brain-based mental status changes are risk factors for morbidity and mortality from a host of medical conditions (eg, cardiovascular disease).[7]
Caution is advised in the treatment of patients who are elderly and others who may be at increased risk for falls.
Laboratory studies appropriate for those with sleep disorders include the following:
Oximetry may be performed during sleep to examine blood oxygen levels for clinically important desaturations suggestive of sleep apnea or other forms of sleep-disordered breathing.
Although no imaging studies are directly indicated for the workup of insomnia, underlying medical conditions call for appropriate investigation using suitable studies.
A Beck Depression Index or similar clinical screening tool may be used to detect an underlying depressive illness as a contributing factor in insomnia.
An Epworth Sleepiness Score or another objective measure of daytime sleepiness may lead to clues to the presence of another underlying sleep disorder. For example, approximately 20% of patients with sleep apnea present with a history of nighttime insomnia; however, patients are excessively sleepy by day and have an abnormal score on the Epworth Sleepiness Scale.
Subjective measures of sleep are obtained by means of a sleep journal. A sleep journal kept for approximately 2 weeks may help determine the extent of the sleep disturbance. Patients should record the total hours slept per night, the frequency of nighttime awakenings, and the level of restfulness provided after sleep.
Additional, more objective measures of sleep may be available if a patient has a sleep partner who keeps a 2-week journal or provides a relevant history.
Objective measures of sleep may be obtained by means of electroencephalography (EEG) or polysomnography (PSG). These studies may be helpful in determining sleep and wakefulness in the intensive care unit (ICU) or in the sleep laboratory.
Monitored PSG is the standard for evaluating measures of sleep. This study includes measures of multiple channels of EEG, electrooculography (EOG), chin and leg electromyography (EMG), nasal and oral airflow, oximetry, abdominal and chest movements, and electrocardiography (ECG). Monitored PSG can help the physician discriminate between rapid eye movement (REM) sleep and non-REM (NREM) sleep, as well as determining causes of sleep disturbance.
Patients with chronic medical conditions, such as fibromyalgia or anxiety disorders, often have characteristic alpha brain-wave activity that intrudes into the deeper stages of sleep. This activity can readily be seen on the EEG during PSG. Patients with insomnia often have some degree of sleep-state misperception, wherein they perceive and believe that they achieve significantly less sleep than they actually do. This can be documented by correlating the EEG findings from the PSG with patient subjective reports of sleep duration and onset.
Evaluate patients for other primary sleep disorders (eg, sleep apnea); the impact of prescribed medication; and underlying medical, psychiatric, and substance abuse disorders. Teach good sleep hygiene. If necessary, consider medication.
Consultation can help evaluate patients for medical (including psychiatric) causes of insomnia. The evaluation team optimally should include a psychiatrist, neurologist, pulmonologist, sleep medicine specialist, and dietitian. Surgical referral may be indicated to correct some underlying medical conditions that cause insomnia, such as for palate surgery in some cases of sleep apnea.
Educating patients in good sleep hygiene is the keystone of treatment. The following advice should be given to patients:
Sleep apnea can be alleviated by losing weight, the use of continuous positive airway pressure (CPAP), and, sometimes, surgical treatment.
When patients who are sleepwalkers, it may be necessary to prevent them from accidentally hurting themselves at night by walking into things or out of the house.
Light-phase shift therapy is useful for sleep disturbances associated with circadian rhythm abnormalities. Patients may be exposed to bright light, from either a light box or natural sunlight, to help normalize the sleep schedule.
Cognitive behavioral therapy (CBT) are efficacious for short-term treatment of insomnia, as are hypnotic medications (see below), but few patients achieve complete remission with any single treatment.
Morin et al studied 160 adults with persistent insomnia and demonstrated that CBT, either alone or in combination with zolpidem, yielded significant improvements in sleep latency, time awake after sleep onset, and sleep efficiency during initial therapy.[8] Combined therapy produced a higher remission rate than CBT alone during the 6-month extended therapy phase and the 6-month follow-up period (56% vs 43%). Long-term outcome was optimized when medication was discontinued during maintenance CBT.
A variety of software programs are commercially available that use wrist bands or motion-detection technology embedded in smart phones to identify and record a patient’s sleep cycles and behavior. This information is then used to give feedback to the patient about the duration and quality of their sleep and to make suggestions on how they can get more consistent and refreshing sleep. Some of the devices incorporate an alarm that is programmed to avoid waking the patient from deep sleep.
Many agents are useful in treating insomnia.[9] Short-term drug therapy is preferred to restore a normal sleep pattern. Generally, hypnotic drugs are approved for 2 weeks or less of continuous use. In chronic insomnia, longer courses may be indicated, which require long-term monitoring to ensure ongoing appropriate use of the medication.
Barbiturates and chloral hydrate are seldom used now, because of safety concerns related to their undesirably low therapeutic indexes.
Drugs that block the histamine type 1 receptor are used primarily in over-the-counter preparations, which are inexpensive and help some patients. However, in view of the anticholinergic properties of these agents, they should be used cautiously in older patients and in patients who have conditions such as prostatic hypertrophy, cognitive disorders, and constipation. In addition, most of these drugs have a long duration of action, and their sedative effects may persist well into the following day.
Zolpidem and zaleplon[10] are the newest and, arguably, the safest agents that have been approved by the US Food and Drug Administration (FDA) for short-term hypnotic use. Zolpidem is available an extended-release version that lasts slightly longer than the original preparation. In addition, the FDA has approved eszopiclone as the first agent for long-term use in the management of chronic insomnia.
Tasimelteon (Hetlioz) was approved by the US Food and Drug Administration (FDA) in January 2014 for treatment of non–24-hour sleep-wake disorder in the totally blind. Approval was based on results of 2 trials: the Safety and Efficacy of Tasimelteon (SET) trial, a 26-week study that included 84 patients, and the Randomized Withdrawal study of the Safety and Efficacy of Tasimelteon (RESET), a 19-week trial that included 20 patients, all of whom had been previously screened during the SET trial and entrained during open-label tasimelteon treatment.
Entrainment of the circadian rhythm, as measured by urinary 6-hydroxymelatonin sulfate (aMT6s), a main metabolite of melatonin, was the primary efficacy endpoint for SET. Scores on the 24-hour clinical response scale were another defined endpoint for SET. Outcomes for RESET included maintenance of entrainment (aMT6s) and maintenance of clinical response. Study results demonstrated that tasimelteon entrains the master clock (both melatonin and cortisol) and has clinically meaningful effects on the sleep-wake cycle in terms of the timing and amount of sleep, and improved measure of global functioning.[11, 12]
Suvorexant (Belsomra) was approved by the FDA in August 2014 and is the first orexin receptor antagonist for insomnia. It is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R by suvorexant is thought to suppress wake drive. Approval was based on three clinical trials involving more than 500 participants. The recommended dose is 10 mg for most patients. After taking 20 mg, impairment of next-day driving was observed.[13]
Trazadone is frequently used and has a relative good safety profile.
No special diet is needed to treat insomnia, but large meals and spicy foods should be avoided in the 3 hours before bedtime. Patients should avoid sleep-disturbing substances such as alcohol, nicotine, and caffeine. Alcohol creates the illusion of good sleep, but it adversely affects sleep architecture. Nicotine and caffeine are stimulating and should be avoided in the second half of the day, from late afternoon on. Consumption of tryptophan-containing foods may help induce sleep; the classic example is warm milk.
Strenuous exercise during the day may promote better sleep, but this same exercise during the 3 hours before bedtime can cause initial insomnia. Stimulating activities should be avoided 3 hours before bedtime. Examples include tense movies, exciting novels, thrilling television shows, arguments, and vigorous physical exercise other than coitus.
Inpatient care is rarely, if ever, required for treatment of insomnia. Only a severe underlying medical, psychiatric, or substance abuse disorder would warrant inpatient care. The numerous possible medical causes of sleep disorders make them difficult to diagnose and necessitate regular appropriate follow-up care until the final diagnosis has been made and successful treatment has been implemented. Several medical specialists may be needed for care and consultations; these may be coordinated by the patient’s internist, personal physician, or medical sleep specialist. Regular follow-up care, even if infrequent, is necessary once appropriate medication is successfully in use. (However, medication may be unnecessary.)
Many agents are useful in treating insomnia. Short-term drug therapy is preferred to restore a normal sleep pattern. Generally, hypnotic drugs are approved for 2 weeks or less of continuous use. In chronic insomnia, longer courses may be indicated, which require long-term monitoring to ensure ongoing appropriate use of the medication.
Clinical Context: Temazepam's intermediate rate of absorption and duration of action make it useful for treating initial and middle insomnia. Because temazepam has no active metabolite, cognitive impairment and grogginess the following day are reduced. Temazepam enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Clinical Context: Triazolam is frequently chosen as a short-term adjunct to behavioral therapy. This short-acting agent is effective in helping patients fall asleep. It is not effective in persons with sleep maintenance problems. Triazolam enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Clinical Context: Estazolam is an intermediate-acting agent with a slow onset of action and a long duration. It is a good agent for sleep-maintenance insomnia. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Clinical Context: Quazepam is used for sleep-maintenance insomnia. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Clinical Context: Flurazepam is frequently chosen as a short-term treatment of insomnia. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Benzodiazepine receptor agonists are the mainstay in treatment of insomnia. Flurazepam, temazepam, quazepam, estazolam, and triazolam are the benzodiazepines that are approved by the US Food and Drug Administration (FDA) as hypnotics. These drugs bind to a special benzodiazepine site on the gamma-aminobutyric acid (GABA) receptor complex, enhancing the activity of this neurotransmitter. All have variable half-lives and different metabolites that affect their onset and duration of action.
This class of drugs suppresses rapid eye movement (REM) sleep and reduces stages 3 and 4 sleep while increasing stage 2 sleep. The drug described here, temazepam, is only 1 example of this class of medications.
Clinical Context: Zolpidem binds at a benzodiazepine receptor subtype (omega I). This receptor is found more in the central nervous system (CNS) than in the peripheral nervous system, which helps to account for the drug's hypnotic effect without significant muscle-relaxant properties. Unlike benzodiazepines, zolpidem does not suppress normal sleep architecture.
Zolpidem is rapidly absorbed, with a fast onset of action (20-30 min), and thus is a good drug for sleep induction. It decreases sleep latency and increases sleep duration.
Clinical Context: Zaleplon is not structurally related to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. It interacts with the GABA-benzodiazepine receptor complex, causing sedation. It should be taken immediately before bedtime.
Zaleplon decreases the time to sleep onset. Its shorter onset of action means that peak serum concentrations are achieved within 1 hour of administration. This may account for the lower incidence of daytime grogginess and the reduced withdrawal rebound insomnia.
Clinical Context: Eszopiclone is a nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. Its precise mechanism of action is unknown, but it is believed to interact with GABA receptors at binding domains close to or allosterically coupled to benzodiazepine receptors. It is indicated for treatment of insomnia by decreasing sleep latency and improving sleep maintenance. It has a short half-life (6 h).
The starting dose is 1 mg immediately before bedtime, with at least 7-8 h remaining before the planned time of awakening. The dose may be increased if clinically warranted to 2-3 mg HS in nonelderly adults, and 2 mg in elderly or debilitated patients.
Clinical Context: Tasimelteon is a melatonin receptor agonist with high affinity for MT1 and MT2 receptors in the suprachiasmatic nucleus of the brain. MT1 and MT2 are thought to synchronize the body's melatonin and cortisol circadian rhythms with the day-night cycle in patients with non–24-hour disorder. It is indicated for non–24-hour sleep-wake disorder in the totally blind.
Clinical Context: Ramelteon is a melatonin receptor agonist with high selectivity for human melatonin MT1 and MT2 receptors. MT1 and MT2 are thought to promote sleep and to be involved in maintenance of circadian rhythm and normal sleep-wake cycles. Ramelteon is indicated for insomnia characterized by difficulty with sleep onset.
Melatonin receptor agonists (tasimelteon, ramelteon) have been approved by the FDA. Tasimelteon is indicated for non–24-hour sleep-wake disorder. Ramelteon is indicated for insomnia characterized by difficulty with sleep onset.
Clinical Context: Trazodone's mechanism of action is not fully understood but is believed to involve selective inhibition of serotonin uptake by brain synaptosomes and potentiation of behavioral changes induced by the serotonin precursor 5-HT. The major adverse effect of trazodone is sedation.
Although no antidepressants have been specifically approved for use in the treatment of sleep disorders, the cyclic antidepressant trazodone is routinely used for this purpose.
Clinical Context: Suvorexant is an orexin receptor antagonist. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R by suvorexant is thought to suppress wake drive. It is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.
Orexin promotes wakefulness. Antagonism of the orexin receptor suppresses this action by orexin.