Your Family Physician

Introduction

Background

Sleep disorders are among the most common clinical problems encountered in medicine and psychiatry. Sleep problems can be primary or result from a variety of psychiatric and medical conditions. Inadequate or nonrestorative sleep can markedly impair a patient's quality of life.¹

Primary sleep disorders result from an endogenous disturbance in sleep-wake generating or timing mechanisms, often complicated by behavioral conditioning. Primary sleep disorders are subdivided into parasomnias and dyssomnias. Parasomnias are unusual experiences or behaviors during sleep and include sleep terror disorder and sleepwalking (which occur during Stage 4 sleep) and nightmare disorder (which occurs during REM sleep). Dyssomnias are characterized by abnormalities in the amount, quality, or timing of sleep. These include primary insomnia and hypersomnia, narcolepsy, breathing-related sleep disorder (ie, sleep apnea), and circadian rhythm sleep disorder.

Assessing if a sleep disorder is primary or secondary is important. At times, assessing if anxiety and depression are causing sleep problems or if the anxiety and depression are secondary to a primary sleep problem is difficult. See Medscape's Anxiety Disorders and Depression Resource Centers.

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 characterized further as acute (transient) or chronic.

Pathophysiology

Rapid eye movement and nonrapid eye movement

Sleep is divided into 2 categories, rapid eye movement (REM) and nonrapid eye movement (NREM). Each of these sleep states is associated with distinct central nervous system activity.

NREM sleep is further divided into 4 progressive categories, termed stages 1-4 sleep. The arousal threshold rises with each stage of sleep, with stage 4 (delta) being the sleep state from which a person is least able to be aroused, characterized by high-amplitude slow waves.

REM sleep is characterized by muscle atonia, episodic REMs, and low-amplitude fast waves on electroencephalogram (EEG) readings. Dreaming occurs mainly during REM sleep.

Disturbances in the pattern and periodicity of REM and NREM sleep are often found when people aver to experiencing sleep disorders.

Sleep-wake cycles

Sleep-wake cycles are governed by a complex group of biological 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.

Frequency

United States

Approximately one third of all Americans have sleep disorders at some point in their lives. Approximately 20-40% of adults report difficulty sleeping at some point each year. Approximately 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.

Mortality/Morbidity

• 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.

Sex

• 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 is more common in men (4%) than in women (2.5%).

Age

• Increasing age predisposes to sleep disorders (5% in persons aged 30-50 y and 30% in those aged 50 y or older).
• People who are elderly experience a decrease in total sleep time, with more frequent awakenings during the night.
• People who are elderly have a higher incidence of general medical conditions and are more likely to be taking medications that cause sleep disruption.

Clinical

History

Insomnia may present as decreased sleep efficiency or decreased total hours of sleep, with some associated decrease in productivity or well-being. Sleep quality is more important than the total number of hours slept because sleep requirements vary from person to person. Compare the total number of hours slept with each individual's lifelong normal night sleep time.

• Initial insomnia is characterized by difficulty falling asleep, with increased sleep latency (time between going to bed and falling asleep). Initial insomnia is frequently related to anxiety disorders.
• Middle insomnia refers to difficulty 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 early morning wakening, 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 for reasons 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 during 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.
• The bed partner of patients who snore may provide a history of snoring. Such a history may help identify whether a patient experiences obstructive sleep apnea.

Physical

• Hypertension (can be caused by sleep apnea)
• Disturbed coordination (caused by sleep deprivation)
• Drowsiness
• Poor concentration
• Slowed reaction time
• Weight gain

Causes

The major causes of insomnia may be divided into medical conditions, psychological conditions, and environmental problems.

• Medical conditions
  • Cardiac conditions 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 conditions include gastroesophageal reflux disease.
  • Hematological 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 include fever, pain, and infection.
• Psychiatric conditions: Bear in mind that the major psychiatric conditions now are known to have a biological basis and 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.
• Environmental problems
  • Stressful or life-threatening events (eg, bereavement, PTSD) may cause insomnia.
  • Shift work may disturb the sleep cycle, as might 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 in an intensive care unit setting).

Differential Diagnoses

Other Problems to Be Considered

Stimulant abuse (eg, amphetamine abuse)

Workup

Laboratory Studies

Lab studies appropriate for those with sleep disorders include the following:

• Hemoglobin and hematocrit
• Arterial blood gases
• Thyroid function tests
• Drug and alcohol toxicology screening

Imaging Studies

Although no imaging studies are indicated directly for the workup of insomnia, underlying medical conditions require appropriate investigation using suitable studies.

Other Tests

• Oximetry may be performed during sleep to examine blood oxygen levels for clinically important desaturations suggestive of sleep apnea or other sleep-disordered breathing.
• 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 other objective measure of daytime sleepiness may lead to clues 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.

Procedures

• 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, frequency of nighttime awakenings, and level of restfulness provided after sleep.
  • Further objective history might be available if patients have a sleep partner who keeps a 2-week journal or provides history.
• Objective measures of sleep may be obtained using EEG monitoring or polysomnography.
  • Monitored polysomnography is the criterion standard for evaluating measures of sleep. This study includes measures of multiple channels of electroencephalogram (EEG), electrooculogram (EOG), chin and leg electromyogram, nasal and oral airflow, oximetry, abdominal and chest movements, and ECG. Monitored polysomnography can help the physician discriminate between REM and NREM sleep, as well as causes of sleep arousal.
  • Polysomnogram may be useful in determining the etiology of the sleep disturbance.
  • These studies may be helpful in determining sleep and wakefulness in the intensive care unit or in the sleep laboratory.
  • 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 the polysomnogram (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.
  
  

Treatment

Medical Care

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.

• Educating the patient on good sleep hygiene is the center of treatment.
  • Use the bed for sleep and sex only (no television watching or reading in bed).
  • Avoid caffeine, especially late in the day. Avoid activities that will get you stimulated and upset late in the day. Practice relaxation techniques before bedtime.
  • Exercise each day.
  • Maintain a regular schedule for bedtime and wakening; avoid naps.
  • Do not watch the clock while in bed. Avoid struggling to fall asleep in bed. Instead, get up and spend quiet time out of bed until sleep comes.
• Sleep apnea can be helped by losing weight, the use of continuous positive airway pressure, and sometimes surgery.
• If someone sleep walks you may need to take steps 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) and hypnotic medications are efficacious for short-term treatment of insomnia, but few patients achieve complete remission with any single treatment. Morin et al studied 160 adults with persistent insomnia and demonstrated that CBT used singly or in combination with zolpidem produced significant improvements in sleep latency, time awake after sleep onset, and sleep efficiency during initial therapy (all P <0.001). p =" .05).">2

Surgical Care

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.

Consultations

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.

Diet

• 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 sleep architecture is affected adversely. 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.

Activity

• 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.

Medication

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.

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, are inexpensive, and are helpful to some patients. However, in view of the anticholinergic properties of these agents, caution should be exercised in their use with older patients and with those who have disorders 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 (Ambien) and zaleplon³ (Sonata) are the newest and, arguably, the safest agents that are US Food and Drug Administration (FDA) approved for short-term hypnotic use. Zolpidem (Ambien CR) has recently released an extended-release version that lasts slightly longer than the original preparation. In addition, the FDA recently approved the new agent eszopiclone (Lunesta) as the first agent for long-term use in the management of chronic insomnia.

Benzodiazepines

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 as hypnotics.

These drugs bind to a special benzodiazepine site on the GABA receptor complex, enhancing 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 REM sleep and reduces stages 3 and 4 sleep while increasing stage 2 sleep. The drug described here, temazepam, is only one example of this class of medications. A more detailed discussion of the other agents in this class can be found elsewhere in the text.

Temazepam (Restoril)

Intermediate rate of absorption and duration of action make this drug useful for treating initial and middle insomnia. Has no active metabolite, which reduces cognitive impairment and grogginess the following day.

Imidazopyridine

Zolpidem is the sole member of this class of medications. It binds at a benzodiazepine receptor subtype (omega I). Found more in CNS more than in peripheral nervous system, which helps to account for hypnotic effect with no significant muscle-relaxant properties. Unlike benzodiazepines, normal sleep architecture not suppressed.

Zolpidem (Ambien)

Rapidly absorbed, with fast onset (20-30 min) of action, which makes this a good drug for sleep induction. Decreases sleep latency and increases duration of sleep.

Pyrazolopyrimidine

Zaleplon is the sole agent in this class of nonbenzodiazepine hypnotics.

Zaleplon (Sonata)

Not structurally related to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. Interacts with GABA-benzodiazepine receptor complex, causing effects in sedation. Should be taken immediately before bedtime.
Decreases time to sleep onset. Shorter onset of action means peak serum concentrations achieved within 1 h of administration. This may account for lower incidence of daytime grogginess and less withdrawal rebound insomnia.

Pyrrolopyrazine

This is another nonbenzodiazepine sedative/hypnotic drug class indicated to improve sleep onset and maintenance.

Eszopiclone (Lunesta)

Nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. The precise mechanism of action is unknown but is believed to interact with GABA-receptor at binding domains close to or allosterically coupled to benzodiazepine receptors. Indicated for insomnia to decrease sleep latency and improve sleep maintenance. Short half-life of 6 h. Higher doses (ie, 2 mg for elderly adults and 3 mg for nonelderly adults) are more effective for sleep maintenance, whereas lower doses (ie, 1 mg for elderly adults and 2 mg for nonelderly adults) are suitable for difficulty in falling asleep.
Decreases sleep latency and improves sleep maintenance.

Melatonin receptor agonist

Ramelteon is the first and only nonscheduled insomnia medication with a novel mechanism of action.

Ramelteon (Rozerem)

Melatonin receptor agonist with high selectivity for human melatonin MT₁ and MT₂ receptors. MT₁ and MT₂ are thought to promote sleep and be involved in maintenance of circadian rhythm and normal sleep-wake cycle. Indicated for insomnia characterized by difficulty with sleep onset.

Antidepressants

Although no antidepressants are approved specifically for use in the treatment of sleep disorders, a cyclic antidepressant, trazodone (Desyrel), is used routinely for this purpose.

Trazodone (Desyrel)

Mechanism of action not fully understood. Thought to selectively inhibit serotonin uptake by brain synaptosomes and potentiate behavioral changes induced by serotonin precursor, 5-HT. Major adverse effect is sedation.

Follow-up

Further Inpatient Care

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.

Further Outpatient Care

Multiple possible medical etiologies of sleep disorders make them difficult to diagnose and necessitate regular appropriate follow-up care until final diagnosis has been made and successful treatment has been implemented. Several medical specialists may be needed for care and consultations and can be coordinated by the patient's internist, personal physician, or medical sleep specialist.

Inpatient & Outpatient Medications

Regular follow-up care, even if infrequent, is necessary once appropriate medication is successfully in use. (However, medication may be unnecessary.)

Deterrence/Prevention

• In addition to specific treatment for diagnosed sleep disorders, good sleep hygiene should be taught to every patient (and this information should be publicly available). Just as with dental hygiene, appropriate sleep habits should be cultivated by all individuals at all times.
• See Medical Care for more information.

Complications

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).

Prognosis

The prognosis varies widely depending on the etiology of the insomnia or other sleep disorder. For example, insomnia due to obstructive sleep apnea resolves with successful treatment of the apnea, while insomnia due to refractory major depression is itself refractory until a successful treatment can be found for the depression.

Patient Education

• All individuals should be taught and encouraged to practice good sleep hygiene, as outlined in Medical Care.
• Educating the patient's family about proper sleep hygiene is imperative, especially because the patient's spouse can be adversely affected by sleep disorders such as sleep apnea.
• Use the bed for sleep and sex only (no television watching or reading in bed).
• For excellent patient education resources, visit eMedicine's Mental Health and Behavior Center and Sleep Disorders Center. Also, see eMedicine's patient education articles 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.

Miscellaneous

Medicolegal Pitfalls

• Patients should be warned to not drive or operate machinery while taking sedative-hypnotic medications. Document these admonitions clearly in the medical record.
• Caution is advised in the treatment of patients who are elderly and others who may be at increased risk for falls.