Insomnia

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Practice Essentials

Insomnia is characterized by persistent difficulty with sleep initiation, maintenance, or quality despite adequate opportunity for sleep. Symptoms may present as nighttime sleep disturbances and/or daytime impairments.

Signs and symptoms

Nighttime symptoms include:

Daytime symptoms include:

Acute insomnia (lasting < 1 month) is often triggered by situational stressors(eg, illness, work stress, bereavement).

Chronic insomnia (lasting ≥ 3 months and occurring ≥ 3 nights per week) is associated with underlying medical, psychiatric, or behavioral factors.

See Presentation for more detail.

Diagnosis

Insomnia is a clinical diagnosis. Diagnostic studies are indicated principally for the clarification of comorbid disorders. Measures that may be considered include the following:

See Workup for more detail.

Management

Cognitive-behavioral therapy for insomnia (CBT-I) is considered the most appropriate treatment for patients with primary insomnia, though it is also effective for comorbid insomnia as adjunctive therapy.[2]

Components of CBT-I include:

Pharmacologic treatment may be considered when CBT-I alone is insufficient.

See Treatment and Medication for more detail.

Background

Insomnia is defined as repeated difficulty with sleep initiation, maintenance, consolidation, or quality that occurs despite adequate time and opportunity for sleep and that results in some form of daytime impairment.[3] Specific criteria vary, but common ones include taking longer than 30 minutes to fall asleep, staying asleep for less than 6 hours, waking more than 3 times a night, or experiencing sleep that is chronically nonrestorative or poor in quality.[4]

Diagnostic criteria

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) makes no distinction between primary and comorbid insomnia. This previous distinction had been of questionable relevance in clinical practice and a diagnosis of insomnia is made if an individual meets the diagnostic criteria, despite any coexisting conditions.

The DSM-5-TR defines insomnia as dissatisfaction with sleep quantity or quality, associated with one (or more) of the following symptoms:[5]

Other criteria include the following:

The International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR)[3]  has streamlined the classification of insomnia disorders. Unlike earlier editions that delineated multiple subtypes, the ICSD-3-TR now primarily recognizes Chronic Insomnia Disorder and Short-Term Insomnia Disorder.

Acute and chronic insomnia

Insomnia is usually a transient or short-term condition. In some cases, however, insomnia can become chronic.

Acute insomnia lasts up to 1 month. It is often referred to as adjustment insomnia because it most often occurs in the context of an acute situational stress, such as a new job or an upcoming deadline or examination. This insomnia typically resolves when the stressor is no longer present or the individual adapts to the stressor.

However, transient insomnia often recurs when new or similar stresses arise in the patient’s life.[3] Transient insomnia lasts for less than 1 week and can be caused by another disorder, changes in the sleep environment, stress, or severe depression.

Chronic insomnia lasting more than 1 month can be associated with a wide variety of medical and psychiatric conditions and typically involves conditioned sleep difficulty. However, it is believed to occur primarily in patients with an underlying predisposition to insomnia (see Pathophysiology). The different subtypes of chronic insomnia are described in Etiology.

Chronic insomnia has numerous health consequences (see Prognosis). For example, patients with insomnia demonstrate slower responses to challenging reaction-time tasks.[6] Moreover, patients with chronic insomnia report reduced quality of life, comparable to that experienced by patients with such conditions as diabetes, arthritis, and heart disease. Quality of life improves with treatment but still does not reach the level seen in the general population.[7]

In addition, chronic insomnia is associated with impaired occupational and social performance and an absenteeism rate that is 10-fold greater than controls. Furthermore, insomnia is associated with higher health care use, including a 2-fold higher frequency of hospitalizations and office visits. In primary care medicine, approximately 30% of patients report significant sleep disturbances.

Epidemiology

Studies indicate that approximately 12% of Americans have been diagnosed with chronic insomnia. Globally, about 10% of adults suffer from insomnia disorders, with an additional 20% experiencing occasional insomnia symptoms. Women, older adults, and individuals facing socioeconomic challenges are more susceptible to developing insomnia.[8, 9]

Insomnia often follows a chronic course, with studies showing a 40% persistence rate over a five-year period. Each year, approximately 25% of Americans experience acute insomnia; however, about 75% of these cases resolve without progressing to chronic insomnia.

The prevalence of insomnia varies across regions. In Europe, data indicates that between 5.5% and 6.7% of adults experience chronic insomnia.[10] In the Americas (Northern America, Latin America, and the Caribbean) an estimated 16.8% (123 million) of adults are affected.[11]

Anatomy

Sleep and wakefulness is a tightly regulated process. Reciprocal connections in the brain produce consolidated periods of wakefulness and sleep that are entrained by environmental light to occur at specific times of the 24-hour cycle.

Promotion of wakefulness

Brain areas critical for wakefulness consist of several discrete neuronal groups centered around the pontine and medullary reticular formation and its extension into the hypothalamus (see the image below). Although diverse in terms of neurochemistry, these cell groups share the features of a diffuse “ascending” projection to the forebrain and a “descending” projection to brainstem areas involved in regulating sleep-wake states. The neurotransmitters involved, along with the main cell groups that produce them, are as follows:

Histamine – histaminergic cells in the tuberomammillary nucleus (TMN) in the posterior hypothalamus

Each region and neurotransmitter contributes to the promotion of wakefulness, but chronic lesions of any one system do not disrupt wakefulness. This suggests a redundant system, wherein the absence of one neurotransmitter may be compensated by the other systems.

Promotion of sleep

The anterior hypothalamus includes the ventrolateral preoptic nucleus (VLPO), containing gamma-aminobutyric acid (GABA) and the peptide galanin, which are inhibitory and promote sleep (see the image below). These project to the TMN and the brainstem arousal regions to inhibit wakefulness.



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Ventrolateral pre-optic nucleus inhibitory projections to main components of the arousal system to promote sleep.

The homeostatic and circadian processes

Both animal and human studies support a model of two processes that regulate sleep and wakefulness: homeostatic and circadian. The homeostatic process is the drive to sleep that is influenced by the duration of wakefulness. The circadian process transmits stimulatory signals to arousal networks to promote wakefulness in opposition to the homeostatic drive to sleep. (See the image below.)



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Sleep-wake cycle.

Melatonin and the circadian process

The suprachiasmatic nucleus (SCN) is entrained to the external environment by the cycle of light and darkness. The retinal ganglion cells transmit light signals via the retinohypothalamic tract to stimulate the SCN. A multisynaptic pathway from the SCN projects to the pineal gland, which produces melatonin.

Melatonin synthesis is inhibited by light and stimulated by darkness. The nocturnal rise in melatonin begins between 8 and 10 pm and peaks between 2 and 4 am, then declines gradually over the morning.[12] Melatonin acts via two specific melatonin receptors: MT1 attenuates the alerting signal, and MT2 phase shifts the SCN clock. The novel sleep-promoting drug ramelteon acts specifically at the MT1 and MT2 receptors to promote sleep but is structurally unrelated to melatonin. It has a relatively a short half-life (2.6 hours).

The flip-flop switch model

Saper et al proposed the flip-flop switch model of sleep-wake regulation.[13] This flip-flop circuit consists of two sets of mutually inhibitory components. The sleep side is the VLPO, and the arousal side includes TMN histaminergic neurons and brainstem arousal regions (the DRN serotonergic neurons, VTA dopaminergic neurons, and LC noradrenergic neurons).

Each side of the switch inhibits the other. For example, when activation of one side is slightly stronger, the weaker side has increased inhibition, thus further tipping the balance toward the stronger side. This flip-flop switch allows for rapid state transitions. (See the schematic flip-flop switch model in the image below.)



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Schematic flip-flop switch model. Adapted from Saper C et al. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257-1263.

Hypocretin neurons in the posterolateral hypothalamus are active during wakefulness and project to all of the wakefulness arousal systems described above. Hypocretin neurons interact with both the sleep-active and the sleep-promoting systems and act as stabilizers between wakefulness-maintaining and sleep-promoting systems to prevent sudden and inappropriate transitions between the two systems.[14]

Narcolepsy with cataplexy illustrates the disruption of this system. These patients have a greater than 90% loss of hypocretin neurons, and they have sleep-wake state instability with bouts of sleep intruding into wakefulness.[15]

Pathophysiology

Insomnia usually results from an interaction of biological, physical, psychological, and environmental factors. Although transient insomnia can occur in any person, chronic insomnia appears to develop only in a subset of persons who may have an underlying predisposition to insomnia.[19] The evidence supporting this theory is that compared with persons who have normal sleep, persons with insomnia have the following:[20]

Hyperarousal

In experimental models of insomnia, healthy subjects deprived of sleep do not demonstrate the same abnormalities in metabolism, daytime sleepiness, and personality as subjects with insomnia. However, in an experimental model in which healthy individuals were given caffeine, causing a state of hyperarousal, the healthy subjects had changes in metabolism, daytime sleepiness, and personality similar to the subjects with insomnia.[22]

Clinical research has also shown that patients with chronic insomnia show evidence of increased brain arousal. For example, studies have indicated that patients with chronic primary insomnia demonstrate increased fast-frequency activity during non–rapid eye movement (NREM) sleep, which is an EEG sign of hyperarousal, and evidence of reduced deactivation in key sleep/wake regions during NREM sleep compared with controls.

Furthermore, patients with insomnia have higher day and night body temperatures, urinary cortisol and adrenaline secretion, and adrenocorticotropic hormone (ACTH) levels than patients with normal sleep.[23, 24] These results support a theory that insomnia is a manifestation of hyperarousal. In other words, the poor sleep itself may not be the cause of the daytime dysfunction, but merely the nocturnal manifestation of a general disorder of hyperarousability.

Spielman model

The Spielman model (see the image below) of chronic insomnia posits three components: predisposing factors, precipitating factors, and perpetuating factors.[25] According to this model, predisposing factors may cause the occasional night of poor sleep, but in general, the person sleeps well until a precipitating event (eg, death of a loved one) occurs, which triggers acute insomnia. If bad sleep habits develop or other perpetuating factors set in, the insomnia becomes chronic and will persist even with removal of the precipitating factor.



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Theoretical model of the factors causing chronic insomnia. Chronic insomnia is believed to primarily occur in patients with predisposing or constituti....

Genetics

A number of individual genes that are involved in sleep and wakefulness have been isolated. However, current evidence suggests that a network of genes, rather than a single gene or a subset of genes, is responsible for sleep. The neurotransmitters and signaling pathways that serve wakefulness also serve other functions.[26]

Studies indicate differential genetic susceptibility to exogenous influences such as caffeine, light, and stress. For example, one study found that differences in the adenosine 2A receptor gene (ADORA2) determine differential sensitivity to caffeine’s effect on sleep.[27] The ADORA2A 1083T>C genotype determined how closely the caffeine-induced changes in brain electrical activity (ie, increased beta activity) during sleep resembled the alterations observed in patients with insomnia.

In addition, circadian clock genes have been identified that regulate the circadian rhythm.[28] Such genes include CLOCK and Per2. A mutation or functional polymorphism in Per2 can lead to circadian rhythm disorders, such as advanced sleep phase syndrome (sleep and morning awakening occur earlier than normal) and delayed sleep phase syndrome (sleep and morning awakening are delayed).

A missense mutation has been found in the gene encoding the GABAA beta 3 subunit in a patient with chronic insomnia.[29] Polymorphisms in the serotonin receptor transporter gene may modulate the ability of an individual to handle stress or may confer susceptibility to depression. In depression, serotonin is an important neurotransmitter for arousal mechanisms. Furthermore, antagonism of the serotonin 5-HT2 receptor promotes slow-wave sleep.

Fatal familial insomnia

A rare condition, fatal familial insomnia (FFI, previously known as thalamic dementia) is an autosomal dominant human prion disease caused by changes in the PRNP (prion protein) gene. FFI involves a severe disruption of the physiologic sleep pattern that progresses to hallucinations, a rise in catecholamine levels, autonomic disturbances (tachycardia, hypertension, hyperthermia, and diaphoresis), and significant cognitive and motor deficits. Mean age of onset is 50 years, and average survival is 18 months.[30, 31, 32]

FFI and a subtype of familial Creutzfeldt-Jakob disease (CJD) share the same mutation at codon 178 (Asn178) in the PRNP gene. They differ in that a methionine-valine polymorphism is present at codon 129 in PRNP in this subtype of familial CJD.[33]

Sporadic fatal insomnia (SFI) shares a similar clinic course with FFI but does not appear to be inherited. A mutation at codon 178 of the PRNP gene is not found in these patients, but patients have been found to be homozygous for methionine at codon 129 in PRNP.[34]

Precipitating factors

In retrospective studies, a large proportion of patients with insomnia (78%) can identify a precipitating trigger for their insomnia. Morin and colleagues showed that these patients demonstrate an increased response to stress as compared with controls. A number of factors can trigger insomnia in vulnerable individuals, including depression, anxiety, sleep-wake schedule changes, medications, other sleep disorders, and medical conditions.[35] In addition, positive or negative family events, work-related events, and health events are common insomnia precipitants.

Perpetuating factors

Regardless of how insomnia was triggered, cognitive and behavioral mechanisms are generally accepted to be the factors that perpetuate it. Cognitive mechanisms include misconceptions about normal sleep requirements and excessive worry about the ramifications of the daytime effects of inadequate sleep. Conditioned environmental cues causing insomnia develop from the continued association of sleeplessness with situations and behaviors that are typically related to sleep.

As a result, patients often become obsessive about their sleep or try too hard to fall asleep. These dysfunctional beliefs often produce sleep disruptive behaviors, such as trying to catch up on lost sleep with daytime naps or sleeping in, which in turn reduces the patients’ natural homeostatic drive to sleep at their habitual bedtime. Learned sleep-preventing associations are characterized by overconcern about inability to fall asleep.

Consequently, these patients develop conditioned arousal to stimuli that would normally be associated with sleep (ie, heightened anxiety and ruminations about going to sleep in their bedroom). A cycle then develops in which the more these patients strive to sleep, the more agitated they become, and the less they are able to fall asleep. They also have ruminative thoughts or clock watching as they are trying to fall asleep in their bedroom.

Etiology

Many clinicians assume that insomnia is often secondary to a psychiatric disorder, However, a large epidemiologic survey showed that half of insomnia diagnoses were not related to a primary psychiatric disorder.[36] A diagnosis of insomnia does, however, increase the future risk for depression or anxiety. Insomnia may also be secondary to other disorders or conditions, or it may be a primary condition (see the image below).



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Frequency of insomnia causes.

Adjustment insomnia (acute insomnia)

Adjustment insomnia is also known as transient, short-term, or acute insomnia. Causes can be divided into two broad categories: environmental and stress-related. Environmental etiologies include unfamiliarity, excessive noise or light, extremes of temperature, or an uncomfortable bed or mattress. Stress-related etiologies primarily involve life events, such as a new job or school, deadlines or examinations, or deaths of relatives and close friends.

Adjustment insomnia typically lasts 3 months or less. The insomnia resolves when the stressor is no longer present or the individual adapts to the stressor.

Psychophysiologic insomnia (primary insomnia)

Primary insomnia begins with a prolonged period of stress in a person with previously adequate sleep. The patient responds to stress with somatized tension and agitation.

In a person experiencing normal sleep, as the initial stress abates, the bad sleep habits are gradually extinguished because they are not reinforced nightly. However, in a patient with a tendency toward occasional poor nights of sleep, the bad habits are reinforced, the patient "learns" to worry about his or her sleep, and chronic insomnia follows.

The patient will have evidence of conditioned sleep difficulty and or/heightened arousal in bed, as indicated by one or more of the following:

The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance abuse disorder.

Paradoxical insomnia

In paradoxical insomnia, one or more of the following criteria apply:

At least one of the following is observed:

The daytime impairment reported is consistent with that reported by other insomnia subtypes but is much less severe than expected given the extreme level of sleep deprivation reported. The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance-abuse disorder.

Insomnia due to medical condition

In patients with insomnia associated with a medical condition, medical disorders may include the following:

Neurologic disorders may include Parkinson disease, other movement disorders, and headache syndromes, particularly cluster headaches, which may be triggered by sleep.

In a retrospective community-based study, more people with chronic insomnia reported having the following medical conditions than did people without insomnia:[37]

In addition, people with the following medical problems more often reported chronic insomnia than did patients without such medical problems:[37]

The sleep disturbance cannot be better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance abuse disorder.

Insomnia due to mental disorders

Most chronic psychiatric disorders are associated with sleep disturbances. Depression is most commonly associated with early morning awakenings and an inability to fall back asleep. Conversely, studies have also demonstrated that insomnia can lead to depression: insomnia of more than 1-year duration is associated with an increased risk of depression.

Schizophrenia and the manic phase of bipolar illness are frequently associated with sleep-onset insomnia. Anxiety disorders (including nocturnal panic disorder and posttraumatic stress disorder) are associated with both sleep-onset and sleep-maintenance complaints.

To meet the formal definition of this form of insomnia, a mental disorder must be diagnosed according to the criteria of the Diagnostic and Statistical Manual, Fifth Edition, Text Revision (DSM-5-TR).[5] The insomnia must be temporally associated with the mental disorder; however, in some cases, insomnia may appear a few days or weeks before the emergence of the underlying mental disorder.

The insomnia is more prominent than that typically associated with the mental disorders, as indicated by causing marked distress or constituting an independent focus of treatment. The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance-abuse disorder.

Insomnia due to drug/substance abuse

Sleep disruption is common with the excessive use of stimulants, alcohol, or sedative-hypnotics. One of the following applies:

The insomnia is temporally associated with the substance exposure, use, or abuse, or acute withdrawal. The sleep disturbance cannot be better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance abuse disorder.

Insomnia not due to substance or known physiologic condition, unspecified

This diagnosis is used for forms of insomnia that cannot be classified elsewhere in ICSD-2 but are suspected to be the result of an underlying mental disorder, psychological factors, or sleep disruptive processes. This diagnosis can be used on a temporary basis until further information is obtained to determine the specific mental condition or psychological or behavioral factors responsible for the sleep difficulty.

Inadequate sleep hygiene

Inadequate sleep hygiene practices are evident by the presence of at least one of the following:

The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance abuse disorder.

Idiopathic insomnia

This sleep disturbance is a long-standing complaint of insomnia, with insidious onset in infancy or childhood. No precipitant or cause is identifiable. The course is persistent, with no sustained periods of remission. This condition is present in 0.7% of adolescents and 1% of very young adults.[38]

Behavioral insomnia of childhood

A child's symptoms meet the criteria for insomnia based on parents’ or other adult caregivers’ observations. Two types of this sleep disturbance are recognized: sleep-onset association and limit-setting.

The sleep-onset association type is characterized by the following:

The limit-setting type is characterized by the following:

Primary sleep disorders causing insomnia

Included in this category are the following:

Restless legs syndrome

RLS is a sleep disorder characterized by the following:

RLS may be associated with periodic limb movement disorder (PLMD), which is characterized by repetitive periodic leg movements that occur during sleep. If RLS is predominant, sleep-onset insomnia is generally present; if PLMD is predominant, sleep-maintenance insomnia is more likely.

Obstructive sleep apnea/hypopnea syndrome

A minority of patients with obstructive sleep apnea/hypopnea syndrome complain of insomnia rather than hypersomnolence. Often, these patients complain of multiple awakenings or sleep-maintenance difficulties. They may also have frequent nocturnal awakenings because of nocturia.

Circadian rhythm disorders

Circadian rhythm disorders include the following:

In advanced sleep phase syndrome, patients feel sleepy earlier than their desired bedtime (eg, 8 pm) and they wake up earlier than they would like (eg, 4-5 am). This condition is more common in the elderly (see Geriatric Sleep Disorder). These patients typically complain of sleep-maintenance insomnia.

In delayed sleep phase syndrome, patients do not feel sleepy until much later than the desired bedtime, and they wake up later than desired or socially acceptable. On sleep diaries or actigraphy, these patients show a consistent sleep time with earlier wake times that correspond to school or work days and delayed wake times on weekends, time off, and vacations.

Delayed sleep phase syndrome often begins in adolescence and may be associated with a family history in up to 40% of patients. These patients report difficulty falling asleep at usually socially desired bedtimes and complain of excessive daytime sleepiness during school or work.

Shift-work sleep disorder is a complaint of insomnia or excessive sleepiness that typically is temporally related to a recurring work schedule that overlaps with the usual sleep time. This can occur with early morning shifts (eg, starting at 4-6 am), where patients are anxious about waking up in time for their early shift, particularly when they have a rotating-shift schedule. Evening shifts that end at 11 pm can result in insomnia because the patient may need some time to wind down from work before retiring to bed.

Night shift work can be associated with both sleep-onset and sleep-maintenance insomnia. Triggers may include exposure to sunlight on the drive home from work, daylight exposure in the bedroom, and social and environmental cues (eg, picking up children at school, paying bills, household chores).

Irregular sleep-wake rhythm is typically seen in persons with poor sleep hygiene, particularly those who live or work alone with minimal exposure to light, activity, and social cues. It may also be seen in persons with dementia or some other neurodegenerative disorder. These patients randomly nap throughout the day, making it difficult, if not impossible, to fall asleep at a habitual bedtime with a consolidated sleep period.

Prognosis

Treatment of insomnia can improve these patients’ perceived health, function, and quality of life.[39] Consequences of untreated insomnia may include the following:

A prospective cohort study in ethnic Chinese in Taiwan demonstrated that sleep duration and insomnia severity were associated with all-cause death and cardiovascular disease events.[40] Other studies have yielded conflicting results regarding the cardiovascular consequences of insomnia. A 6-year prospective cohort study did not find an association between the development of hypertension and insomnia.[41] Other studies, however, indicate an association between short sleep or sleep restriction and hypertension.[42, 43]

A study of persons with insomnia and short sleep duration demonstrated an increased risk of hypertension to a degree comparable to that seen with sleep-disordered breathing.[44] A case-control study in normotensive subjects with chronic insomnia showed a higher nighttime systolic blood pressure and blunted day-to-night blood pressure dipping.[45]

Knutson et al found that the quantity and quality of sleep correlate with future blood pressure. In an ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study, measurement of sleep for 3 consecutive days in 578 subjects showed that shorter sleep duration and lower sleep maintenance predicted both significantly higher blood pressure levels and adverse changes in blood pressure over the next 5 years.[46]

Patients with insomnia report decreased quality of life compared with normal controls in all dimensions of the 36-item Short Form Health Survey (SF-36). Patients with insomnia report excessive fatigue as measured by the Fatigue Severity Scale and the Profiles of Mood Status (POMS).

Associations of insomnia with depression and anxiety

Insomnia is known to be associated with depression and anxiety.[36] What remains unknown is the nature of the association. For example, insomnia may presage the development of an incipient mood disorder, or mood disorders may independently predispose to insomnia.

In an early study of the association between insomnia and depression and anxiety, Ford and Kamerow found that after adjusting for medical disorders, ethnicity, and sex, patients with insomnia were 9.8 times more likely to have clinically significant depression and 17.3 times more likely to have clinically significant anxiety than persons without insomnia.[36] A meta-analysis by Baglioni et al concluded that in nondepressed people with insomnia, the risk of developing depression is twice as high as in people without sleep difficulties.[47]

Ohayon and Roth found that symptoms of insomnia were reported to occur before the first episode of an anxiety disorder 18% of the time; simultaneously 39% of the time; and after the onset of an anxiety disorder 44% of the time.[48] In addition, insomnia symptoms were reported to occur before the first episode of a mood disorder 41% of the time; simultaneously 29% of the time; and after the onset of a mood disorder 29% of the time.

Patient Education

All patients with insomnia, whether transient or chronic, should be educated about sleep and the elements of good sleep hygiene. Sleep hygiene refers to daily activities and habits that are consistent with or promote the maintenance of good quality sleep and full daytime alertness.

Educate patients on the following elements of good sleep hygiene:

History

The patient history is the most important part of the evaluation for insomnia. It must include a complete sleep history, medical history, psychiatric history, social history, and medication review. The American Academy of Sleep Medicine (AASM) guideline consensus is that at a minimum, patients should complete the following evaluations:[49]

Sleep history

For the sleep history, the examiner must determine the timing of insomnia, the patient's sleep habits (commonly referred to as sleep hygiene), and whether the patient is experiencing the symptoms of the sleep disorders associated with insomnia.

To determine the timing of insomnia, ask the patient the following questions:

To determine the sleep schedule, ask the patient questions such as the following:

Inquire about the patient's sleep environment, as follows:

Sleep habits can also be determined with questioning. Individuals with insomnia often have poor sleep hygiene. Questions regarding sleep hygiene are as follows:

Ask patients about symptoms of other sleep disorders, such as obstructive sleep apnea (eg, snoring, witnessed apneas, gasping) and restless legs syndrome/periodic limb movement disorder (eg, restless feeling in legs on lying down, which improves with movement; rhythmic kicking during the night; sheets in disarray in the morning).

Ask about daytime effects, which should be present if the patient is truly not sleeping at night. In fact, a patient who has no daytime effects is probably getting adequate sleep and may have sleep-state misperception insomnia (sometimes called paradoxical insomnia). This rare condition, which appears to constitute less than 5% of insomnia cases, is defined by a marked discrepancy between the subjective complaint of insomnia and the objective polysomnographic findings.[3]

Common complaints of daytime effects in patients with insomnia are as follows:

These complaints should be distinguished from the complaint of excessive sleepiness, which is uncommon in insomnia. If a patient complains of excessive daytime sleepiness (ie, Epworth Sleepiness Scale Score >10), another sleep disorder should also be considered. (See the image below for the Epworth Sleepiness Scale.)



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Epworth Sleepiness Scale.

Medical and psychiatric history

Perform a thorough medical history and review of systems. Also perform a thorough psychological review to screen for psychiatric disorders. In particular, assess for signs and symptoms of anxiety or depression. Diagnostic criteria for generalized anxiety disorder are listed in the image below.



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Diagnostic criteria for generalized anxiety disorder.

A 2-question case-finding instrument can help screen for depression. The questions are as follows:

A patient who answers “No” to both questions is unlikely to have major depression. A patient who answers “Yes” to either should receive diagnostic testing for depression.

Family history

A family history should be obtained in all patients with insomnia. Though rare, fatal familial insomnia (FFI) should be considered if first-degree relatives are affected, because this disorder is inherited in an autosomal dominant pattern. A family history can also be helpful in identifying patients at risk for heritable conditions that may contribute to more common causes of insomnia, including psychiatric disorders.

Social history

For transient or short-term insomnia, inquire about recent situational stresses, such as a new job, new school, relationship change, or bereavement. For chronic insomnia, attempt to relate the onset of insomnia to past stresses or medical illnesses. Inquire about the use of tobacco, caffeinated products, alcohol, and illegal drugs.

Medication history

Medications that commonly cause insomnia include the following:

Also inquire about over-the-counter and herbal remedies that the patient may be taking.

Physical Examination

The physical examination may be helpful because findings may offer clues to underlying medical disorders that predispose the patient to insomnia. It may also facilitate the differential diagnosis or classification of insomnia.[49]

If the history suggests sleep apnea, perform a careful head and neck examination. Common anatomic features associated with obstructive sleep apnea/hypopnea syndrome include the following:

Other features include an enlarged tongue, retrognathia, micrognathia, or a steep mandibular angle. An elevated body mass index (BMI) of 30 kg/m2 or higher is also common.



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Mallampati airway scoring.

If the patient reports symptoms of restless legs syndrome or any other neurologic disorder, perform a careful neurologic examination. If the patient reports daytime symptoms consistent with any of the medical causes of insomnia, a careful examination of the affected organ system (eg, lungs in chronic obstructive pulmonary disease) may be helpful.

Associated Problems

Despite inadequate sleep, many patients with insomnia do not complain of excessive daytime sleepiness, such as involuntary episodes of drowsiness in boring, monotonous, nonstimulating situations. However, they do complain of feeling tired and fatigued, with poor concentration. This may be related to a physiologic state of hyperarousal (see Pathophysiology). In fact, despite not getting adequate sleep, patients with insomnia often have difficulty falling asleep even for daytime naps.

Insomnia can also be a risk factor for depression and a symptom of a number of medical, psychiatric, and sleep disorders. In fact, insomnia appears to be predictive of a number of disorders, including depression, anxiety, alcohol dependence, drug dependence, and suicide. The annual cost of insomnia is not inconsequential, with the estimated annual costs for insomnia being $12 billion for health care and $2 billion for sleep-promoting agents.[50]

It had been widely believed that most cases of chronic insomnia are secondary to another medical or psychiatric condition and can be addressed by effective treatment of that underlying condition. In fact, insomnia often persists despite treatment of the primary condition, and in certain cases, persistence of insomnia can increase the risk of relapse of the primary condition. Thus, clinicians need to understand that insomnia is a condition in its own right that requires prompt recognition and treatment to prevent morbidity and improve patients’ quality of life.

Approach Considerations

Insomnia is a clinical diagnosis. Diagnostic studies are indicated principally for the clarification of comorbid disorders.

Before therapy is instituted, most patients are asked to keep a sleep log for 2–4 weeks. This log, in which the patient records bed and wake times, sleep duration, and daytime naps and activities, gives a clearer picture of the degree of sleep disturbance and allows development of a tailored treatment.

Studies for Hypoxemia

Patients with a history suggestive of chronic obstructive pulmonary disease (COPD) and insomnia should have oximetry or an arterial blood gas (ABG) test performed to determine whether they are hypoxemic. Insomnia in COPD frequently begins with the development of nocturnal hypoxemia, although nocturnal hypoxemia is not required for insomnia to occur. Oxygen therapy may improve insomnia but rarely eliminates it.

Nocturnal hypoxemia is present if the patient has daytime hypoxemia or, frequently, exercise-related hypoxemia. If the oximetry or ABG result is negative for hypoxemia, an exercise desaturation study or overnight oximetry may be helpful to determine whether the patient needs oxygen.

Polysomnography

Polysomnography and daytime multiple sleep latency testing (MSLT) are not routinely indicated for the workup of insomnia.[49, 51] However, patients with a history suggestive of sleep apnea should be referred to a sleep center for polysomnography, as should patients who have precipitous arousals with violent or injurious behavior, as well as some patients with restless legs syndrome (RLS)/periodic limb movement disorder (PLMD). Treatment failure may also be an indication for polysomnography.[49]

Actigraphy

For actigraphy, a portable device is worn around the wrist to record gross motor activity and light/darkness over extended periods. This study provides an indirect objective measure of sleep and wake time. Actigraphy has shown concordance with polysomnography in the assessment of total sleep time.[52] The role of actigraphy in insomnia evaluation has not been well established, but actigraphy can help document sleep patterns and circadian rhythms.

Distinguishing primary insomnia from circadian-rhythm disorders and identifying paradoxical insomnia is useful, particularly with insomnia that is refractory to treatment.

Sleep Diary

A sleep diary is appropriate when a patient reports an irregular sleep schedule. Maintaining a sleep diary can be done in conjunction with wrist actigraphy. In the diary, patients should record estimates of the time at which they do the following:

  1. Go to bed
  2. Fall asleep
  3. Awaken during the night
  4. Lie in bed awake
  5. Get out of bed in the morning

Patients should also record when and how long they exercise, when they take medications, and when they consume caffeinated or alcoholic beverages. (Click on the image below to download a sample sleep diary form.)



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Sleep diary.

For diagnosis, the patient should maintain a sleep diary for 1-2 weeks. The American Academy of Sleep Medicine (AASM) guideline recommends collection of sleep diary data both before and during active treatment and afterward if a relapse occurs or if the patient’s status needs to be reevaluated.[49] Although the sleep diary provides detailed information about sleep patterns, it can be confounded by the patient's subjective assessment of when they fall asleep and awaken during the night.

Genetic Testing

If a patient with rapidly progressing insomnia has any first-degree relatives who died with insomnia, there may be concern for fatal familial insomnia (FFI). Genetic testing for this rare condition is available and consists of sequencing the PRNP gene. Brain imaging—specifically, positron-emission tomography (PET) to look for hypometabolism in the thalamus and cingulated cortex—may also assist in the diagnosis of FFI.[1]

Approach Considerations

The American Academy of Sleep Medicine (AASM) guidelines state that the two primary goals of treatment are to improve sleep quality and to improve related daytime impairments.[53, 54] Strategies for achieving these goals will vary depending on the underlying etiology. If the patient has a medical, neurologic, or sleep disorder, treat the disorder. In particular, adequate pain control can greatly relieve the insomnia associated with pain syndromes.

The AASM guidelines recommend psychological and behavioral interventions (including, but not limited to, cognitive-behavioral therapy [CBT]) as effective in the treatment of chronic comorbid insomnia as well as primary insomnia. The guidelines also encourage these interventions as initial therapy when appropriate.[53]  A study of 291 patients aged 60 years and older (mean age, 70 years; 58% women) with confirmed insomnia disorder and no major depression within the previous 12 months found CBT significantly reduced risk of depression in patients with insomnia.[55]

The treatment of primary (psychophysiologic) insomnia begins with education about the sleep problem and appropriate sleep hygiene measures (elements of good sleep hygiene are described in Patient Education). Before therapy is instituted, most patients are asked to maintain a sleep diary for 1–2 weeks. This provides a clearer picture of the degree of sleep disturbance and allows development of a tailored treatment.

Strong evidence supports the use of nonpharmacologic interventions (eg, CBT) for insomnia. Head-to-head comparison has shown that the long-term benefits of nonpharmacologic interventions are superior to those of medication.[56, 57, 58] CBT is now considered the most appropriate treatment for patients with primary insomnia.[59, 60, 61] Use of this therapy is based on the fact that primary insomnia is associated with physiologic, emotional, and cognitive arousal and conditioning to arousal in bed.

If the patient has a psychiatric disorder, the disorder should be treated. Management may involve medications, psychotherapy, and possible referral to a psychiatrist, psychologist, or therapist. If the insomnia is related to medication or drug abuse, the offending medication or drug must be slowly tapered and withdrawn.

Even when comorbid causes of insomnia (ie, medical, psychiatric) are treated, however, variable degrees of insomnia persist that require additional interventions. These patients can benefit from CBT[62] and a short course of a sedative-hypnotic or melatonin receptor agonist. In the case of a psychiatric disorder (eg, depression[63] or anxiety), CBT and a short-term sedative-hypnotic in conjunction with an antidepressant can be beneficial.

Cognitive-Behavioral Therapy

Cognitive-behavioral therapy (CBT) can be used to ameliorate factors that perpetuate or exacerbate chronic insomnia, such as poor sleep habits, hyperarousal, irregular sleep schedules, inadequate sleep hygiene, and misconceptions about sleep. CBT is most effective for primary insomnia, but it is also effective for comorbid insomnia as adjunctive therapy.[64]

Multiple randomized, controlled trials have demonstrated the efficacy of CBT. Sleep latency, total sleep time, duration of wakefulness, and sleep quality have been shown to improve with CBT. From 50–75% of patients attain clinically significant improvement. CBT also improves the absolute amount of slow-wave sleep by 30%. Six-month follow-up has shown sustained efficacy for this treatment modality.

According to the American Academy of Sleep Medicine (AASM) guidelines, cognitive-behavioral therapy for insomnia (CBT-I) should be the initial treatment approach, with pharmacologic options considered when CBT-I is not available, not effective, or not preferred by the patient.[53]  CBT-I is a combination of cognitive therapy and behavioral therapy, such as stimulus-control therapy or sleep-restriction therapy (with or without relaxation therapy).

The components of CBT-I include the following:

The AASM guidelines recommend including at least one behavioral intervention in initial treatment. Multicomponent therapy that includes behavioral therapy without cognitive therapy is also recommended in the treatment of chronic insomnia.[53]

Limitations of CBT are that providers must be trained in its use and that the technique is time consuming. Most studies of CBT used trained psychologists to work with patients for an average of 5.7 sessions over 6.5 weeks, with each session lasting at least 20–40 minutes. One study showed that a total of four biweekly individual treatments represents the optimal dosing of CBT.[65]  Obviously, this would not be practical for most primary care providers or neurologists. In addition, it is currently not known how effective CBT can be when administered by a nonpsychologist.

Some sleep centers have behavioral medicine specialists who can administer CBT. Preliminary evidence indicated that providing written information about CBT can be helpful.[66]  An Internet-based CBT learning program for patients is also available for a nominal cost (see CBTforINSOMNIA.com).

Another type of behavioral intervention called brief behavioral treatment for insomnia (BBTI) was found to be a simple, efficacious, and durable intervention for chronic insomnia in older adults.[67]

Sleep hygiene education

Sleep hygiene education addresses behaviors that are incompatible with sleep. These include caffeine or alcohol use, environmental noise, inappropriate room temperature, and watching TV in bed. The AASM guidelines recommend adherence to sleep hygiene rules for all patients with chronic insomnia but finds insufficient evidence of effectiveness when following these sleep hygiene rules as monotherapy and, thus, advises its use as adjunctive therapy.[53]

Cognitive therapy and relaxation therapy

In cognitive therapy, the patient is educated to correct inaccurate beliefs about sleep and to reduce catastrophic thinking and excessive worrying about the consequences of failing to obtain adequate sleep.

Relaxation therapy comprises several techniques. In progressive relaxation, the patient is taught to recognize and control tension through a series of exercises that consist of first tensing and then relaxing each muscle group in a systematic way. Guided imagery and meditation teach the patient how to focus on neutral or pleasant targets in place of racing thoughts. Biofeedback techniques can also be used. These techniques have the advantages of providing patients with immediate feedback regarding their level of tension and rapidly teaching them how to relax.

Stimulus-control therapy

Stimulus-control therapy works to reassociate the bed with sleepiness instead of arousal. Rules for its use include the following:

Sleep-restriction therapy

Sleep-restriction therapy is based on the fact that excessive time in bed often perpetuates the insomnia. Limiting the time spent in bed leads to more efficient sleep that is both consolidated and more regular and predictable. Time in bed is allowed to increase as the patient demonstrates a continuing ability to sleep in an efficient and consolidated manner.

This treatment plan consists of limiting time in bed to the patient's estimated total sleep time (not less than 5 hours) and increasing it by 15–30 minutes for a given week when the patient estimates that his or her sleep efficiency (SE; ratio of time asleep to time in bed) has reached greater than 85%. The amount of time in bed remains the same when the SE falls between 80 and 85% and is decreased by 15–30 minutes for a given week when the SE is less than 80%. Periodic (weekly) adjustments are made until the optimal sleep duration is achieved.

Use sleep-restriction therapy with caution in patients with occupations for which sleep deprivation can have devastating consequences. These include commercial truck drivers, operators of heavy machinery, and pilots.

Efficacy of CBT versus sedative-hypnotics for primary insomnia

Several randomized trials comparing CBT against hypnotics for primary insomnia have been published. One study compared temazepam with CBT in older patients and found similar short-term effects, but there was continued efficacy after discontinuation of therapy in the CBT group only. A study comparing zolpidem with CBT showed continued efficacy for the patients treated with CBT.[57]

A European study showed that CBT was superior to zopiclone (not available in the United States). In fact, zopiclone was found to be no different from placebo on 3 of 4 outcome measures.[68] CBT, on the other hand, reduced total awake time by 52%, improved sleep efficiency, and increased slow-wave sleep. At 6 months, sleep efficiency was still improved with CBT. The limitation of this study was that it consisted of 44 older individuals using zopiclone.

Efficacy of combined CBT and sedative-hypnotics

Several studies have demonstrated that after 10–24 months’ follow-up, patients in the CBT group demonstrated sustained benefit that was not seen in the combined CBT-hypnotic group. This could be because patients were less willing to practice CBT techniques during the initial phase if they obtained rapid, short-term improvement of sleep with a sedative-hypnotic. In this regard, many sleep experts feel that CBT should be considered as initial therapy for primary insomnia and adjunctive therapy for secondary insomnia.

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.[69]

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.[69]

Pharmacologic Treatment of Insomnia

The American Academy of Sleep Medicine (AASM) guideline[54] for the pharmacologic treatment of chronic insomnia in adults recommends the following medications:

It is important to note that these recommendations are classified as "weak," indicating a lower degree of certainty in the outcome and appropriateness for all patients. Clinicians should consider individual patient circumstances, preferences, and potential adverse effects when selecting a pharmacologic treatment for chronic insomnia.

Benzodiazepines include long-acting forms (eg, flurazepam, quazepam), intermediate-acting forms (eg, temazepam, estazolam), and short-acting forms (triazolam). The long-acting agents are rarely used today for insomnia because of daytime sedation, cognitive impairment, and increased risk of falls in elderly patients.

Benzodiazepines were commonly used until the 1980s, when tolerance, dependence, and daytime side effects were recognized as major limitations of these agents, particularly those with long elimination half-lives. Temazepam is still used for a short-term course (ie, from days to 1–2 weeks), at a dose of 15–30 mg at bedtime.

In the 1990s, antidepressants were widely used for primary insomnia, and they continue to be widely used, despite the fact that few randomized, controlled trials have demonstrated their efficacy in treating primary insomnia. At present, sedative-hypnotics remain the most commonly prescribed sleep medications.

Sedative-hypnotic drugs

Sedative-hypnotic medications do not usually cure insomnia, but they can provide symptomatic relief as sole therapy or as an adjunct with CBT. Furthermore, some patients cannot adhere to or do not respond to CBT and are candidates for these agents. The nonbenzodiazepine receptor agonists (eg, eszopiclone, zolpidem, zaleplon) are believed to be less habit-forming than benzodiazepines and, therefore, represent important advances in the long-term treatment of chronic insomnia.

The most appropriate use of nonbenzodiazepine receptor agonists is for transient and short-term insomnia in combination with nonpharmacologic treatment. Most authorities now agree that they should infrequently be the only therapy for chronic insomnia. 

Short-term use of a hypnotic may be considered for patients with acute insomnia that is severe, causes significant distress, or requires rapid symptom relief. It is also an option when behavioral treatments are unavailable, inaccessible, or have been ineffective, as well as for patients who are unable or unwilling to engage in behavioral therapy.[54]

In the past, most studies of the efficacy of sedative-hypnotics had been short-term trials, generally less than 4 weeks. Use for longer than 4 weeks was thought to result in tolerance and decreased efficacy, although supportive findings are scarce, and the epidemiologic literature suggests that patients report continued efficacy with continued use. Nevertheless, because of the addictive nature of benzodiazepines, most authorities believe that the duration of use of these drugs should be limited.

Studies have indicated, however, that nonbenzodiazepine receptor agonists can have long-term efficacy for 6–12 months without the development of tolerance. Eszopiclone, the first sedative-hypnotic to be tested over a 6-month period, showed continued efficacy with nightly use over that period, with improved quality of life, reduced work limitations, and reduced global insomnia severity.[70, 71] Another study demonstrated continued efficacy at 12 months.[72]

Krystal et al showed long-term efficacy and safety of sustained-release zolpidem (Ambien-CR) for 6 months in a double-blind, placebo-controlled trial.[73] Zolpidem can be used at a dose of 5 or 10 mg at bedtime for sleep-onset insomnia; zolpidem-controlled release can be used at doses of 6.25 or 12.5 mg for patients with sleep-maintenance insomnia or patients with both sleep-onset and sleep-maintenance insomnia.

Lower zolpidem doses were recommended by the FDA in January 2013, owing to the risk of next-morning mental impairment.[74, 75] Data show that zolpidem blood levels may remain high enough the morning after nighttime usage to impair activities that require alertness, including driving. This next-morning impairment is highest for the controlled-release dosage form and is more prevalent in women because of their slower elimination compared with men.

The revised labeling for zolpidem recommends that the initial dose for immediate-release zolpidem products (Ambien and Edluar) be 5 mg for women and either 5 mg or 10 mg for men. The recommended initial dose for extended-release zolpidem (Ambien CR) is 6.25 mg for women and either 6.25 or 12.5 mg for men. The FDA also added a warning against driving or other activities requiring mental alertness the day after taking extended-release zolpidem at the 6.25-mg or 12.5-mg dose, because drug levels can remain high enough to impair these activities.[76, 75]

Eszopiclone has a half-life of 5-7 hours and can be used for sleep-maintenance insomnia. The starting dose is 1 mg immediately before bedtime, with at least 7-8 hours 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. Next-day impairment can occur after taking after a starting dose of 2 mg. FDA findings from observing 91 healthy adults showed that individuals who took a 3 mg dose of eszopiclone displayed severe psychomotor and memory impairment 7.5 hours later and that driving skills, memory, and coordination could remain impaired up to 11 hours later.[5]  In a comprehensive comparative-effectiveness analysis, eszopiclone and lemborexant showed the best efficacy, acceptability, and tolerability for acute and long-term insomnia treatment. However, eszopiclone may cause substantial side effects.[77]

Zaleplon has a very short half-life (1 hr) and is indicated for sleep-onset insomnia at doses ranging from 5 to 20 mg. It can also be used for sleep-maintenance insomnia if taken at the time of awakening during the night. However, the patient should allow at least 4 hours for remaining sleep to avoid possible daytime sedation.

The following general precautions should be taken when using sedative-hypnotics:

Long-term hypnotic pharmacotherapy may be necessary in patients with severe or treatment-resistant insomnia or chronic comorbid disorders, but follow-up must include regular assessment of necessity, efficacy, and adverse effects.[49] Long-term administration of hypnotics may be intermittent, as needed, or nightly.[49] If possible, during long-term therapy, patients should receive an adequate trial of CBT.[49]

These agents should be used with caution in patients with a history of insufficient sleep syndrome, particularly in patients prone to alcohol use, since this group can be predisposed to the development of parasomnias (eg, sleep-walking or sleep-related eating disorder[78, 79] )

In most patients, the risk of dependency is low. Few patients escalate the dose or use the drug more frequently than prescribed. Roehrs et al found no dose escalation after 12 months of nightly use of zolpidem by patients with primary insomnia.[80] Nevertheless, sedative-hypnotics should be avoided in patients with a history of substance abuse.

Rebound insomnia may develop when a sedative-hypnotic is abruptly withdrawn. This is more likely to occur with larger doses and with the short-acting agents. Using smaller doses and tapering the drug can avoid rebound insomnia. The AASM guideline states that these measures are aided by concurrent CBT for insomnia (CBT-I).[49, 54]

Orexin inhibitors

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.

The American Academy of Sleep Medicine (AASM) recommends that suvorexant be used as a treatment for sleep maintenance insomnia as opposed to no treatment.[54]

A second orexin inhibitor, lemborexant (Dayvigo), was approved by the FDA in December 2019. A major metabolite of lemborexant, M10, binds with comparable affinity as the parent drug to orexin receptors OX1R and OX2R. It is indicated for insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

Approval of lemborexant was based on results from the phase 3 studies, SUNRISE 1 and SUNRISE 2, that included nearly 2000 patients. Sleep onset and maintenance was improved compared with placebo. Middle-of-the-night safety (including wakening to sound) and next-day postural stability and memory studies over 12 months were also conducted. There were no meaningful differences between lemborexant 5 mg, 10 mg, or placebo with ability to wake to sound in the middle of the night; however, balance impairment at 4 hours postdose was evident with lemborexant compared with placebo.[81]

A large-scale systematic review and network meta-analysis analyzed data from 154 double-blind, randomized controlled trials of medications (licensed or not) used for acute and long-term treatment of insomnia in 44,089 adults (mean age, 51.7 years; 63% women). Results showed that benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more effective than placebo for the acute treatment of insomnia.[77]

Daridorexant (Quviviq) is a dual orexin receptor antagonist that blocks the binding of neuropeptide orexins, OX1R and OX2R, and is believed to decrease overactive wakefulness. In January 2022, the FDA approved daridorexant for insomnia in adults.

Approval was based on the Phase 3 extensive clinical program that had 1854 adults with insomnia at more than160 clinical trial sites in multiple different countries. Two clinical trials studied the efficacy of daridorexant in adults with insomnia who were randomized to receive either daridorexant or placebo over 3 months. The primary endpoints for both studies were the changes from baseline to month 1 and month 3 in Latency to Persistent Sleep and Wake After Sleep Onset (WASO) objectively by polysomnography. The secondary endpoints included in the statistical testing hierarchy with type I error control were patient-reported Total Sleep Time (sTST), evaluated every morning at home using a validated sleep diary questionnaire.

In study 1, the daridorexant 25-mg and 50-mg doses showed a statistically significant improvement in all endpoints against placebo, at both months 1 and 3. In study 2, the daridorexant 25-mg dose showed statistically significant improvement on WASO and sTST at months 1 and 3 when compared to the placebo. The 10-mg dose did not show significant improvement on the 3 measurements.[82]

Ramelteon

Ramelteon (Rozerem), a melatonin receptor agonist, is approved by the FDA for use in persons with insomnia. It has been shown to have no potential for abuse and, as such, is the first nonscheduled prescription drug available in the United States for the treatment of insomnia.

Ramelteon is a specific melatonin receptor agonist that binds to the melatonin MT1 and MT2 receptors. It has a half-life of 1-3 hours. The MT1 receptor attenuates the alerting signal of the suprachiasmatic nucleus (SCN) clock, and the MT2 receptor phase shifts (advances) the SCN clock to promote sleep.

Controlled trials have shown a decrease in sleep latency but no change in wake time after sleep onset and no next-morning residual effects. Additionally, studies thus far on elderly patients have shown no impairment in night balance, mobility, or memory.[83, 84, 85]

This medication is suited for patients with sleep-onset insomnia, particularly for elderly patients with gait disorders who have an increased risk of falls and in patients with a history of substance abuse. The typical starting dose is 8 mg before bedtime. Ramelteon is not effective for sleep-maintenance insomnia. The AASM recommends ramelteon for the treatment of sleep onset insomnia (versus no treatment).[54]

Sedating antidepressants

Although there is a paucity of clinical data on the use of sedating antidepressants for the treatment of primary insomnia without mood disorders, these agents are still sometimes used. Sedating tricyclic antidepressants, such as amitriptyline, nortriptyline, and doxepin, and the tetracyclic drug mirtazapine have been used.

Tricyclic drugs and mirtazapine can cause daytime sedation, weight gain, dry mouth, postural hypotension, and cardiac arrhythmias. Trazodone can cause priapism in men, daytime sedation, and hypotension.

Except for low-dose doxepin (Silenor), drugs in this category are not approved for treatment of insomnia by the FDA, and there have been few randomized, placebo-controlled trials demonstrating efficacy for insomnia. Nevertheless, these agents can be useful, especially in patients with comorbid depression or anxiety.

Antihistamines

Antihistamines are the major ingredient of OTC sleep aids and are the ingredient in cold and sinus formulas sold as bedtime-use medications. Nevertheless, common antihistamines (ie, first-generation H1-receptor antagonists such as diphenhydramine, hydroxyzine, and doxylamine) are not indicated for the treatment of sleeplessness.

While H1 antihistamines have sedative effects in healthy individuals, no study has established an effective dose range for these agents’ hypnotic effect in patients with insomnia. These agents may have some subjective benefit, but long-term efficacy and safety have not been demonstrated. Thus, their regular use in individuals with insomnia is not advised.[54]

Melatonin

Melatonin has also become a popular OTC sleep aid. Melatonin is a naturally occurring hormone secreted by the pineal gland. The concentration of melatonin is highest in the blood during normal times of sleep and lowest during normal times of wakefulness. The general consensus is that melatonin given during normal waking hours has hypnotic properties.

However, the timing of evening administration is critical as to whether a hypnotic or chronobiologic effect occurs. Melatonin given early in the evening appears to increase sleep time; however, administration 30 minutes before a normal bedtime has not resulted in a decreased sleep latency or an increase in sleep time.

Most studies of melatonin have been small and of limited duration, and the results have conflicted somewhat, with several studies showing limited or no effect.[12] Most of the data, however, seem to suggest that melatonin taken before bedtime decreases sleep latency, may increase total sleep time,[86, 87] and may entrain irregular circadian rhythms.

Studies of melatonin in individuals with chronic insomnia have not demonstrated objective changes in patient sleep habits or changes in mood or alertness the day after treatment. In addition, a dose-response relationship has not been determined. OTC melatonin is also sold at doses much higher than those that naturally occur in the blood.

Melatonin is not recommended by the AASM for sleep onset or sleep maintenance insomnia.[54]

Alternative and herbal medications

Alternative and herbal medications have also been tried in the treatment of insomnia. Valerian root extract is the most widely used and studied of these agents. A 2006 meta-analysis of 16 randomized, controlled trials of valerian for the treatment of insomnia had conflicting results.[88] The pooled data did seem to show evidence of improved sleep; however, the authors noted a possible publication bias that may have contributed to this result.

A 2010 met-analysis of 18 randomized, controlled trials of valerian for the treatment of insomnia detected no publication bias. However, although the results suggested that valerian may be effective for subjective improvement of insomnia, its effectiveness has not been demonstrated with quantitative or objective measurements.[89]

A randomized, placebo-controlled trial by Taavoni et al found that valerian improves the quality of sleep in women with menopause who are experiencing insomnia. Patients in the treatment arm received 530 mg of concentrated valerian extract twice a day for 4 weeks.[90]

Other herbal remedies such as chamomile and St. Johns wort have not shown efficacy for insomnia. Furthermore, potential risks have been associated with the use of some OTC remedies, such as dogwood, kava kava, alcohol, and L-tryptophan.[91] For these reasons, the AASM guidelines state that valerian and other alternative or herbal medications are not recommended for treatment of chronic insomnia.[54]

Acupressure for Insomnia

A longitudinal study found that acupressure treatment can improve insomnia, with effects lasting after the end of intervention. In a randomized, controlled trial of 50 residents in long-term care facilities, 5 weeks of standard acupressure on the HT7 (Shenmen) points of both wrists significantly reduced insomnia, with the benefit persisting for up to 2 weeks afterward.[92]

Devices

In June 2016, the FDA approved a prescription device for patients with insomnia that helps reduce latency to stage 1 and stage 2 sleep by keeping the forehead cool. This device came about as a result of studies that showed that in patients with insomnia, the frontal cortex stays active, preventing them from getting deeper, more restorative sleep. The system consists of a bedside device controlled by software that cools and pumps fluid to a forehead pad that the patient wears throughout the night. Approval was based on three clinical studies that included more than 230 patients over 3800 research nights.[93]

Diet and Exercise

Dietary measures in patients with insomnia are matters of timing and avoidance. The following recommendations may be useful:

Exercise in the late afternoon or early evening (at least 6 hours before bedtime) can promote sleep. However, vigorous physical activity in the late evening (< 6 hours before bedtime) can worsen insomnia.

Treatment of Insomnia in Elderly Patients

The satisfaction of sleep declines with age. This probably is related to changes in sleep associated with age, such as a decrease in slow-wave sleep, increased time awake after sleep onset, and a tendency to go to bed early and rise early. Although napping is highly prevalent among elderly persons, it has not been consistently correlated with sleep disturbance.[94]

However, aging should not be assumed to be the explanation for insomnia.[95] Multiple factors affect sleep in the elderly, including nocturia, pain syndromes, and many medical disorders (eg, heart failure, chronic obstructive pulmonary disease, Parkinson disease). Other factors include restless legs syndrome, sleep apnea (all of which have increased frequency in the elderly), dementia, and, frequently, changing situational factors such as retirement, bereavement, or financial difficulties, which lead to anxiety and depression.[96]

As in younger patients, nonpharmacologic treatment should take precedence over pharmacologic treatment. Psychological and behavioral interventions are effective in older adults, according to the 2008 AASM guideline.[49] A 16-week randomized, controlled trial by Reid et al found that aerobic activity plus sleep hygiene improved sleep quality, mood, and quality of life in older adults with chronic insomnia.[97]

In elderly patients, hypnotics should be prescribed cautiously and in lower doses than for younger patients. Drugs tend to have a longer duration of effect in elderly patients as a result of changes in metabolism and elimination. This can lead to an increased incidence of falls and resulting bone fractures at night (if the patient gets up to use the bathroom when not fully awake or ataxic) and decrements in daytime alertness and performance (including increased incidence of motor vehicle accidents).

Consultations

Primary care physicians should be able to diagnose and treat transient or short-term insomnia. Chronic insomnia is often more difficult to treat, and referral to a specialist may be indicated. Patients with comorbid medical conditions may benefit from referral to the appropriate specialist.

Patients should be referred to a sleep specialist in the following cases:

Many sleep centers have a staff psychologist who specializes in treating insomnia. The advantages include experience in cognitive-behavioral techniques and providing sleep education, greater available time for the often-frequent follow-up that is needed, and the ability to ascertain whether other psychological factors are present that may need further evaluation by a psychiatrist.

Patients with a history of depression should be treated with an antidepressant or referred to a psychiatrist, based on the physician's comfort level in treating depression, the severity of depression, and the response to therapy. In addition, patients with a history of substance abuse or another major psychiatric disorder should also be referred to a psychiatrist.

Guidelines Summary

The following organizations have released guidelines for the management of insomnia. Key diagnostic and treatment recommendations have been reviewed and integrated throughout the article.  

Medication Summary

Medications used in the treatment of insomnia include nonbenzodiazepine receptor agonists, benzodiazepine receptor agonists, the selective melatonin receptor agonist ramelteon, and sedating antidepressants. All can be considered first-line agents for insomnia; agent choice is largely dictated by past trials, cost, side-effect profile, drug interactions, and patient preference.[49] Pharmacologic therapy is used in concert with behavioral and psychological interventions.

Benzodiazepines and benzodiazepine receptor agonists

Benzodiazepine receptor agonists (BZRAs) work through GABAA receptors to promote sleep by inhibiting brainstem monoaminergic arousal pathways, through facilitation of VLPO inhibitory GABAergic projections to arousal centers such as the anterior hypothalamus TMN, the posterolateral hypothalamic hypocretin neurons, and the brainstem arousal regions.

The GABAA receptor consists of 5 protein subunits arranged in a ring around a central pore. Most GABAA receptors consist of 2 alpha subunits, 2 beta subunits, and 1 gamma subunit. Upon GABAA receptor activation, chloride ions flow into the cell, resulting in neuronal hyperpolarization.[16, 17]  (See the image below.)



View Image

GABAA receptor complex subunits and schematic representation of agonist binding sites.

BZRAs enhance the effect of GABA by lowering the concentration of GABA required to open the GABA channel. BZRAs bind to a modulatory site on the GABAA receptor that is distinct from the GABA binding site and change the receptor complex allosterically to increase the affinity of the receptor to GABA, thus producing a larger postsynaptic current prolonging inhibition. Although BZRAs do not directly open the chloride channel, they modulate the ability of GABA to do so, thus enhancing its inhibitory effect.

Synaptic GABAA receptors typically contain a γ subunit in combination with an α1, α2, and α3 subunit. Most GABAA receptors expressed in the CNS are α1 β2 γ2, α2 β3 γ2, α3 β3 γ2, α5 β3 γ2.

While GABA binds at the junction between subunits α and β, BZRAs bind at the interface between α and γ. The α subunits of the GABAA receptor mediate sedative, amnestic, anxiolytic, myorelaxant, ataxic, and sedative effects. GABAA receptors containing the α1 subunit mediate the sedative-hypnotic and amnestic effects and, to some degree, the anticonvulsant effects of BZRAs.

For example, studies of knockout mice that express a benzodiazepine-insensitive α1 subunit fail to show the sedative, amnestic effects of diazepam. The nonbenzodiazepine receptor agonists (ie, zaleplon, zolpidem, eszopiclone) have relative selectivity for GABAA receptors containing the α1 subunit, thereby producing fewer adverse effects (ie, ataxia, anxiolytic, myorelaxation properties) than nonselective BZRAs. (See the image below outlining the GABAA receptor subunit functions.)



View Image

GABAA receptor subunit function(s).

Melatonin and melatonin receptor agonists

Melatonin is a hormone produced by the pineal gland during the period of sundown to sunrise. It exerts sleep-promoting effects through MT1/MT2 receptors via an unknown mechanism. Ramelteon is an agonist at MT1 and MT2 receptors that is approved by the FDA for the treatment of sleep-onset difficulty.[18]

Sedating antidepressants

These medications, which include amitriptyline, trimipramine, doxepin, trazodone, and mirtazapine, were identified as therapeutic agents for the treatment of insomnia when patients treated for depression reported sedating side effects. They exert their effects by blocking the receptors of wake-promoting neurotransmitters—namely, serotonin, norepinephrine, and histamine.[18]

Antihistamines

Diphenhydramine and doxylamine are commonly used in OTC insomnia medications. They exert their effect by disrupting wake-promoting histaminergic neurotransmission from the tuberomammillary nucleus by antagonism of the H1 receptor. Doxepin, mirtazapine, olanzapine, and quetiapine also exert sleep-promoting effects via this mechanism.

Estazolam

Clinical Context:  Estazolam is an intermediate-acting benzodiazepine with a slow onset of action and a long duration. Estazolam is a good agent for sleep-maintenance insomnia.

Eszopiclone (Lunesta)

Clinical Context:  Eszopiclone is a nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. The precise mechanism of action is unknown, but this agent is believed to interact with GABA receptors at binding domains close to or allosterically coupled to benzodiazepine receptors. It is indicated for insomnia to decrease sleep latency and improve 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.

Ramelteon (Rozerem)

Clinical Context:  Ramelteon is a melatonin receptor agonist that is indicated for insomnia characterized by difficulty with sleep onset. This agent has high selectivity for human melatonin MT1 and MT2 receptors. MT1 and MT2 are thought to promote sleep and to be involved in maintenance of the circadian rhythm and normal sleep-wake cycle. Stimulation of the MT1 receptor in the suprachiasmatic nucleus (SCN) inhibits neuronal firing (reduces alerting effect of the SCN), and stimulation of the MT2 receptor in the SCN affects the circadian rhythm, causing a phase advance (earlier sleep time).

Temazepam (Restoril)

Clinical Context:  Temazepam is a short- to intermediate-acting benzodiazepine with longer latency to onset and half-life. Temazepam may be more helpful in sleep-maintenance insomnia than in sleep-onset insomnia.

Triazolam (Halcion)

Clinical Context:  Triazolam depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. It is indicated for short-term insomnia. Triazolam was the first short-acting benzodiazepine for promoting sleep but fell out of favor after high-profile reports of amnesia with its use.

Zaleplon (Sonata)

Clinical Context: 

Zolpidem (Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist)

Clinical Context:  A sedative-hypnotic of the imidazopyridine class, zolpidem has a rapid onset and short duration of action. It is a good first choice for treatment of sleep-onset insomnia and produces no significant residual sedation in the morning.

The extended-release product (Ambien CR) consists of a coated 2-layer tablet and is useful for insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The first layer releases drug content immediately to induce sleep; the second layer gradually releases additional drug to provide continuous sleep. The higher-dose sublingual product (Edluar) is available as 5- and 10-mg tablets; an oral spray (Zolpimist) is also available for sleep-onset and/or sleep-maintenance insomnia. The low-dose sublingual product (Intermezzo) is indicated for middle-of-the-night awakening.

Amitriptyline

Clinical Context:  Amitriptyline is a tricyclic antidepressant (TCA) with sedative effects. It inhibits reuptake of serotonin and/or norepinephrine at the presynaptic neuronal membrane, which increases concentration in the central nervous system (CNS).

Doxepin (Silenor)

Clinical Context:  Low-dose doxepin is FDA approved for sleep-maintenance insomnia. It is available in 3- and 6-mg tablets.

Nortriptyline (Pamelor)

Clinical Context:  Nortriptyline has demonstrated effectiveness in the treatment of chronic pain.

By inhibiting the reuptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, this drug increases the synaptic concentration of these neurotransmitters in the CNS.

Mirtazapine (Remeron, Remeron SolTab)

Clinical Context:  Mirtazapine exhibits both noradrenergic and serotonergic activity. In cases of depression associated with severe insomnia and anxiety, it has been shown to be superior to other selective serotonin reuptake inhibitors (SSRIs). In patients with depression, the sedative properties of mirtazapine may help with sleep-onset insomnia. This drug is not an FDA-approved treatment for insomnia, and no randomized, placebo-controlled trials have demonstrated its efficacy for insomnia.

Nefazodone

Clinical Context:  Nefazodone inhibits serotonin reuptake and is a potent antagonist at the 5-HT2 receptor. It also has negligible affinity for cholinergic, histaminic, or alpha-adrenergic receptors. The FDA has added a Black Box warning regarding rare cases of liver failure with this drug.

Trazodone (Oleptro)

Clinical Context:  A nontricyclic antidepressant with short onset of action, trazodone consolidates sleep. It is an antagonist at the type 2 serotonin (5-HT2) receptor and inhibits reuptake of 5-HT; it also has negligible affinity for cholinergic and histaminergic receptors.

Daridorexant

Clinical Context:  Daridorexant is a dual orexin receptor antagonist that blocks the binding of neuropeptides orexins, OX1R and OX2R. It is indicated for insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

Lemborexant (Dayvigo)

Clinical Context:  Dual orexin antagonist (DORA). Orexins are neuropeptides that regulate the sleep-wake cycle; orexins promote wakefulness by binding G-protein-coupled receptors, OX1R and OX2R. It is indicated for insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

Suvorexant (Belsomra)

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.

How is insomnia defined?What are the AASM guidelines for evaluation of insomnia?What should be the focus of patient history in the evaluation of insomnia?Which medications commonly cause insomnia?What should be included in the physical exam for insomnia?How is insomnia diagnosed?What are the treatment goals for insomnia?What is the role of cognitive-behavioral therapy (CBT) in the treatment of insomnia?Which sedative-hypnotics are used in the treatment of insomnia?What are precautions for use of sedative-hypnotics to treat insomnia?Which sedating antidepressants are used in the treatment of insomnia?Which nonpharmacologic therapies may be helpful for the treatment of insomnia?What are concerns regarding a patient&#39;s report of insomnia?What is insomnia?How prevalent is insomnia?What are the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for insomnia?What is acute insomnia?What is chronic insomnia?Which disorders are associated insomnia?What is comorbid insomnia?What is included in the evaluation of insomnia?What is the role of a sleep diary in the evaluation of insomnia?What is the role of actigraphy in the evaluation of insomnia?What must be present for a diagnosis of insomnia?What is the definition of primary insomnia?What is the focus of treatment for insomnia?What is the prevalence of insomnia?What are risk factors for insomnia?How does the prevalence of insomnia vary by sex?What are the racial predilections of insomnia?How does the prevalence of insomnia vary by age?How does the brain regulate sleep?How does the brain promote wakefulness?How does the brain promote sleep?What are the homeostatic and circadian processes regulating sleep?How is melatonin synthesized during sleep?What is the flip-flop switch model of sleep regulation?What are the mechanisms of action of benzodiazepines and benzodiazepine receptor agonists for insomnia?What are the mechanisms of action of melatonin receptor agonists for insomnia?What are the mechanisms of action of sedating antidepressants for insomnia?What are the mechanisms of action of antihistamines for insomnia?What is the pathophysiology of insomnia?What is the role of hyperarousal in the pathophysiology of insomnia?What is the Spielman model of chronic insomnia?What is the role of genetics in the pathophysiology of insomnia?What is the pathophysiology of fatal familial insomnia (FFI)?What are the precipitating factors of insomnia?What are the perpetuating factors of insomnia?What causes insomnia?What is inadequate sleep hygiene in insomnia?What are the behavioral insomnias of childhood?How is insomnia classified in the International Classification of Sleep Disorders, 2nd Edition (ICSD-2)?What causes adjustment insomnia (acute insomnia)?What causes primary insomnia?What is paradoxical insomnia?What must be observed for a diagnosis of paradoxical insomnia?Which medical disorders have and etiologic role in insomnia?Which medical conditions are common in people with insomnia?Which mental disorders have an etiologic role in insomnia?What is the role of drug or substance abuse in the etiology of insomnia?How is insomnia not due to substance or known physiologic condition diagnosed?What is idiopathic insomnia?What primary sleep disorders cause insomnia?What is the role of restless legs syndrome (RLS) in the etiology of insomnia?What is the role of obstructive sleep apnea or hypopnea syndrome in the etiology of insomnia?What are Circadian rhythm disorders in insomnia?What are the consequences of untreated insomnia?What is the prognosis of insomnia?What is the association of insomnia with depression and anxiety?What is included in patient education about insomnia?What should be included in the patient history for insomnia?What must be determined in a sleep history for insomnia?What are questions to ask in the sleep history for insomnia?What are common daytime effects of insomnia?What should be the focus of the medical and psychiatric history in the evaluation of insomnia?How are patients with insomnia screened for depression?What is the role of family history in the evaluation of insomnia?What is the role of social history in the evaluation of insomnia?Which medications commonly cause insomnia?What is the role of a physical exam for insomnia?Which physical findings are significant in the evaluation of insomnia?Which disorders should be considered in the differential diagnoses of insomnia?Which medications are associated with insomnia?What are the differential diagnoses for Insomnia?What is the role of a sleep log in the diagnosis and management of insomnia?What studies are indicated for patients with chronic obstructive pulmonary disease (COPD) and insomnia?What is the role of polysomnography in the workup of insomnia?What is the role of actigraphy in the workup of insomnia?When is a sleep diary indicated in the workup of insomnia?What is the role of genetic testing in the workup of insomnia?What are the American Association of Sleep Medicine (AASM) treatment guidelines for insomnia?What is the role of cognitive-behavioral therapy (CBT) for insomnia?What is the efficacy of cognitive-behavioral therapy (CBT) for insomnia?What are the components of cognitive-behavioral therapy (CBT) for insomnia?What is cognitive-behavioral therapy for insomnia (CBT-I)?What are the AASM recommendations for initial treatment of insomnia?What is included in sleep hygiene education for the treatment of insomnia?What is the focus of cognitive therapy for insomnia?What is relaxation therapy for insomnia?What is stimulus-control therapy for insomnia?What is sleep-restriction therapy for insomnia?What is the efficacy of cognitive-behavioral therapy (CBT) compared to sedative hypnotics for treatment of insomnia?What is the efficacy of combined cognitive-behavioral therapy (CBT) and sedative hypnotics for insomnia?What is the role of medications in the treatment of insomnia?What is the role of sedative-hypnotic drugs in the treatment of insomnia?What is the efficacy of sedative-hypnotic drugs for the treatment of insomnia?What is the recommended dosage for sedative-hypnotic drugs in the treatment of insomnia?What are general precautions regarding the use of sedative-hypnotics for insomnia?What is the role of long-term hypnotic drug treatment for insomnia?What are risks associated with the use of sedative-hypnotics for insomnia?What is the role of suvorexant (Belsomra) in the treatment of insomnia?What is the role of ramelteon (Rozerem) in the treatment of insomnia?What is the role of sedating antidepressants in the treatment of insomnia?What is the role of antihistamines in the treatment of insomnia?What is the role of melatonin in the treatment of insomnia?What is the role of alternative and herbal medications in the treatment of insomnia?What is the role of acupressure for insomnia?What is the Cerêve Sleep System for the treatment of insomnia?Which dietary modifications are used in the treatment of insomnia?What are treatment options for insomnia in elderly patients?When is referral to a sleep specialist indicated for the treatment of insomnia?What are the AASM Choosing Wisely® recommendations regarding insomnia?What are the AASM guidelines for the evaluation of insomnia?What are the American Thoracic Society (ATS) guidelines for managing insomnia?Which medications are used in the treatment of insomnia?Which medications in the drug class Antidepressants, Other are used in the treatment of Insomnia?Which medications in the drug class Antidepressants, TCAs are used in the treatment of Insomnia?Which medications in the drug class Sedative/Hypnotics are used in the treatment of Insomnia?Which medications in the drug class Orexin Antagonists are used in the treatment of Insomnia?

Author

Jasvinder Chawla, MD, MBA, Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Erasmo A Passaro, MD, FAAN, FAES, FAASM, FACNS, Director, Comprehensive Epilepsy Program/Clinical Neurophysiology Lab, Bayfront Health System, Florida Center for Neurology; Director, Epilepsy Surgery Program, Johns Hopkins All Children's Hospital

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: UCB; Sunovion; Eisai, GWPharma.

Youngsook Park, MD, Co-Director in SLEEP Lab, Hines Veterans Affairs Medical Center; Assistant Professor of Neurology, Loyola University, Chicago Stritch School of Medicine

Disclosure: Received none from Hines VA Hospital for none.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Catalyst; Ceribell; Jazz; LivaNova; Neurelis; Neuropace; SK Life Science; Stratus; Synergy; UCB<br/>Serve(d) as a speaker or a member of a speakers bureau for: Catalyst; Jazz; LivaNova; Neurelis; SK Life Science; Stratus; Synergy; UCB<br/>Received research grant from: Cerevel Therapeutics; Ovid Therapeutics; Neuropace; Jazz; SK Life Science, Xenon Pharmaceuticals, UCB, Marinus, Longboard, Xenon<br/>Received income in an amount equal to or greater than $250 from: Catalyst; Ceribell; Jazz; LivaNova; Neurelis; Neuropace; SK Life Science; Stratus; Synergy; UCB.

Acknowledgements

Carmel Armon, MD, MSc, MHS Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center

Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Movement Disorders Society, and Sigma Xi

Disclosure: Avanir Pharmaceuticals Consulting fee Consulting

Kendra Becker, MD, MPH Sleep Medicine Department, Kaiser Permanente Fontana Medical Center

Kendra Becker, MD, MPH is a member of the following medical societies: American Academy of Sleep Medicine, American College of Physicians, and American Medical Association

Disclosure: Nothing to disclose.

Jose E Cavazos, MD, PhD, FAAN Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, Program Director of the Clinical Neurophysiology Fellowship, University of Texas School of Medicine at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center, University Hospital System; Director of the San Antonio Veterans Affairs Epilepsy Center of Excellence and Neurodiagnostic Centers, Audie L Murphy Veterans Affairs Medical Center

Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and American Neurological Association

Disclosure: GXC Global, Inc. Intellectual property rights Medical Director - company is to develop a seizure detecting device. No conflict with any of the Medscape Reference articles that I wrote or edited.

Zab Mosenifar, MD Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Professor and Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society

Disclosure: Nothing to disclose.

Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University School of Medicine; Consulting Staff, Pulmonary Disease and Critical Care Medicine Service, Henry Ford Health System

Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians and American Thoracic Society

Disclosure: Nothing to disclose.

James A Rowley, MD Professor, Fellowship Program Director, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine

James A Rowley, MD is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Silverio M Santiago, MD Clinical Professor of Medicine, University of California at Los Angeles School of Medicine; Chief, Department of Pulmonary and Critical Care Medicine, Medical Director, Sleep Disorders Center, Veterans Affairs Medical Center of West Los Angeles

Silverio M Santiago, MD is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Ron A Shatzmiller, MD, MSc Assistant Clinical Professor, Department of Neurology, Keck School of Medicine of the University of Southern California; Specialty Lead Physician, Healthcare Partners Medical Group, Arcadia, California

Ron A Shatzmiller, MD, MSc is a member of the following medical societies: American Academy of Neurology and American Academy of Sleep Medicine

Disclosure: Nothing to disclose.

Peter Smethurst, MD Attending Physician, Pulmonary, Critical Care and Sleep Medicine, St Joseph's Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Gregory Tino, MD Director of Pulmonary Outpatient Practices, Associate Professor, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Medical Center and Hospital

Gregory Tino, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

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The ascending arousal system. Adapted from Saper et al. Hypothalamic Regulation of Sleep and Circadian Rhythms. Nature 2005;437:1257-1263.

Ventrolateral pre-optic nucleus inhibitory projections to main components of the arousal system to promote sleep.

Sleep-wake cycle.

Schematic flip-flop switch model. Adapted from Saper C et al. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257-1263.

Theoretical model of the factors causing chronic insomnia. Chronic insomnia is believed to primarily occur in patients with predisposing or constitutional factors. These factors may cause the occasional night of poor sleep but not chronic insomnia. A precipitating factor, such as a major life event, causes the patient to have acute insomnia. If poor sleep habits or other perpetuating factors occur in the following weeks to months, chronic insomnia develops despite the removal of the precipitating factor. Adapted from Spielman AJ, Caruso LS, Glovinsky PB: A behavioral perspective on insomnia treatment. Psychiatr Clin North Am. 1987 Dec;10(4):541-53.

Frequency of insomnia causes.

Epworth Sleepiness Scale.

Diagnostic criteria for generalized anxiety disorder.

Mallampati airway scoring.

Sleep diary.

GABAA receptor complex subunits and schematic representation of agonist binding sites.

GABAA receptor subunit function(s).

Theoretical model of the factors causing chronic insomnia. Chronic insomnia is believed to primarily occur in patients with predisposing or constitutional factors. These factors may cause the occasional night of poor sleep but not chronic insomnia. A precipitating factor, such as a major life event, causes the patient to have acute insomnia. If poor sleep habits or other perpetuating factors occur in the following weeks to months, chronic insomnia develops despite the removal of the precipitating factor. Adapted from Spielman AJ, Caruso LS, Glovinsky PB: A behavioral perspective on insomnia treatment. Psychiatr Clin North Am. 1987 Dec;10(4):541-53.

Mallampati airway scoring.

Diagnostic algorithm for major depression.

Diagnostic criteria for generalized anxiety disorder.

Sleep diary.

GABAA receptor subunit function(s).

GABAA receptor complex subunits and schematic representation of agonist binding sites.

Sleep-wake cycle.

The ascending arousal system. Adapted from Saper et al. Hypothalamic Regulation of Sleep and Circadian Rhythms. Nature 2005;437:1257-1263.

Ventrolateral pre-optic nucleus inhibitory projections to main components of the arousal system to promote sleep.

Schematic flip-flop switch model. Adapted from Saper C et al. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257-1263.

Epworth Sleepiness Scale.

Frequency of insomnia causes.