Insomnia

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.[8] 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.[9]

Approximately one third of adults report some difficulty falling asleep and/or staying asleep during the previous 12 months, with 17% reporting this problem as a significant one.[10] From 9-12% experience daytime symptoms, 15% are dissatisfied with their sleep, and 6-10% meet the diagnostic criteria of insomnia syndrome.

Insomnia is more prevalent in women; middle-aged or older adults; shift workers; and patients with medical and psychiatric diseases. In young adults, difficulties of sleep initiation are more common; in middle-aged and older adults, problems of maintaining sleep are more common.

As many as 95% of Americans have reported an episode of insomnia at some point during their lives.[11] The 2008 update to the American Academy of Sleep Medicine (AASM) guideline for the evaluation and management of chronic insomnia calls insomnia an important public health issue.[1]

Classification (DSM-5 and ICSD-3)

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 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 International Classification of Sleep Disorders, Third Edition (ICSD-3) criteria are consistent with the changes to the DSM-5.

The DSM-5 defines insomnia as dissatisfaction with sleep quantity or quality, associated with one (or more) of the following symptoms:[12]

• Difficulty initiating sleep

• Difficulty maintaining sleep, characterized by frequent awakenings or problems returning to sleep after awakenings

• Early-morning awakening with inability to return to sleep

Other criteria include the following:

• The sleep disturbance causes clinically significant distress or impairments in social, occupational, educational, academic, behavioral, or other important areas of functioning

• The sleep difficulty occurs at least 3 nights per week

• The sleep difficulty is present for at least 3 months

• The sleep difficulty occurs despite adequate opportunity for sleep

• The insomnia cannot be explained by and does not occur exclusively during the course of another sleep-wake disorder

• The insomnia is not attributable to the physiological effects of a drug of abuse or medication.

• Coexisting mental disorders and medical conditions do not adequately explain the predominant complaint of insomnia

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.[8] 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.[13] 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.[14]

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.

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.[15]

In 2005, the National Institutes of Health held a State of the Science Conference on the Manifestations of Chronic Insomnia in Adults.[16] This conference focused on the definition, classification, etiology, prevalence, risk factors, consequences, comorbidities, public health consequences, and available treatments and evidence of efficacy. A summary of this conference can be obtained at the NIH Consensus Development Program Web site.

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.

The conference report concluded, based on review of the literature and the panel experts, that the limited understanding of the mechanistic pathways precludes drawing firm conclusions about the nature of the associations between other conditions and insomnia, or the directions of causality. Furthermore, the conference members expressed concern that the term secondary insomnia may promote undertreatment. Therefore, they proposed the term comorbid insomnia.

Evaluation

Evaluation of insomnia primarily comes from a detailed clinical history that includes a medical, psychiatric, and sleep history. The sleep history should elucidate the type of insomnia (eg, sleep initiation, sleep maintenance), its duration (transient, acute, or chronic), and its course (recurrent, persistent), as well as exacerbating and alleviating factors. In addition, the clinician should elicit a typical sleep schedule and a complete history of alcohol use, drug use, and intake of caffeinated beverages.

The sleep diary is essential for insomnia evaluation; its duration should be for 1-2 weeks. The diary is useful to document initial insomnia severity and to identify behavioral and scheduling factors. Also, a thorough psychological evaluation needs to include suspected psychiatric disorders.

The role of actigraphy in insomnia evaluation is not well established yet. In the current sleep research field, actigraphy is useful to evaluate circadian rhythm disorders. Polysomnography is not recommended for the evaluation of insomnia unless there is suspected underlying sleep apnea, paradoxical insomnia, or parasomnia.

A patient's report of insomnia is nonspecific and can encompass a variety of concerns, including difficulty falling asleep, awakening early or easily, problems with returning to sleep after awakening, or a general poor quality of sleep. Therefore, the clinician must determine what the patient means by “insomnia.”

For insomnia to be considered a disorder, it should be accompanied by daytime tiredness, loss of concentration, irritability, worries about sleep, loss of motivation, or other evidence of daytime impairment that is associated with the sleep difficulty (see Clinical Presentation).

The definition of primary (psychophysiologic) insomnia should meet the one of the following 2 conditions: (1) the patient has no current or past history of a mental or psychiatric disorder or (2) if the patient does have such a history, the temporal course of the insomnia shows some independence from the temporal course of the mental or psychiatric condition.

Management

Management of insomnia may involve further challenges. If sleep difficulties are not the presenting complaint, there is often too little time to address them at an office visit.

Physicians receive very little training in medical school on sleep disorders and their impact on patients’ overall health and quality of life. In fact, most providers rate their knowledge of sleep medicine as only fair. Finally, many providers are not aware of the safety issues; knowledgeable of the efficacy of cognitive-behavioral and pharmacologic therapies; or able to determine when a patient should be referred to a sleep medicine specialist.

The management of insomnia varies depending on the underlying etiology. If the patient has a medical, neurologic, psychiatric, or sleep disorder, treatment is directed at the disorder. Even when comorbid causes of insomnia (ie, medical, psychiatric) are treated, however, variable degrees of insomnia can persist that require additional interventions. In such cases, patients can benefit from cognitive-behavioral therapy (CBT)[17, 18] and a short course of a sedative-hypnotic or melatonin receptor agonist (see Treatment).

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

• Norepinephrine – norepinephrine-producing neurons in the locus coeruleus (LC)

• Serotonin – serotonergic neurons in the dorsal raphe nuclei (DRN)

• Dopamine – dopaminergic neurons in the ventral tegmental area (VTA)

• Acetylcholine – cholinergic neurons of the basal forebrain

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

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.

The homeostatic and circadian processes

Both animal and human studies support a model of 2 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.)

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.[19] Melatonin acts via 2 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 and colleagues proposed the flip-flop switch model of sleep-wake regulation.[20] This flip-flop circuit consists of 2 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.)

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 2 systems.[21]

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.[22]

Mechanisms of action of insomnia medication

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.[23, 24] (See the image below.)

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.)

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 US Food and Drug Administration (FDA) for the treatment of sleep-onset difficulty.[25]

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.[25]

Antihistamines

Diphenhydramine and doxylamine are commonly used in over-the-counter 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.

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.[26] The evidence supporting this theory is that compared with persons who have normal sleep, persons with insomnia have the following[27] :

• Higher rates of depression and anxiety

• Higher scores on scales of arousal

• Longer daytime sleep latency

• Increased 24-hour metabolic rates[28]

• Greater night-to-night variability in their sleep

• More electroencephalographic (EEG) beta activity (a pattern observed during memory processing/performing tasks) at sleep onset

• Increased global glucose consumption during the transition from waking to sleep onset, on positron emission tomography of the brain

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.[29]

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.[30, 31] 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 3 components: predisposing factors, precipitating factors, and perpetuating factors.[32] 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.

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.[33]

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.[34] 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.[35] 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.[36] 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.[37, 38, 39]

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.[40]

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.[41]

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.[42] 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.

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.[43] 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).

The International Classification of Sleep Disorders, 2nd Edition (ICSD-2)[44] classifies insomnia into 11 categories, as follows:

• Adjustment insomnia (acute insomnia)

• Psychophysiologic insomnia (primary insomnia)

• Paradoxical insomnia

• Insomnia due to medical condition

• Insomnia due to mental disorder

• Insomnia due to drug or substance abuse

• Insomnia not due to substance or known physiologic condition, unspecified

• Inadequate sleep hygiene

• Idiopathic insomnia

• Behavioral insomnia of childhood

• Primary sleep disorders causing insomnia

Adjustment insomnia (acute insomnia)

Adjustment insomnia is also known as transient, short-term, or acute insomnia. Causes can be divided into 2 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:

• Excessive focus on and heightened anxiety about sleep

• Difficulty falling asleep at the desired bedtime or during planned naps, but no difficulty falling asleep during other monotonous activities when not intending to sleep

• Ability to sleep better away from home than at home

• Mental arousal in bed characterized by either intrusive thoughts or a perceived inability to volitionally cease sleep-preventing mental activity

• Heightened somatic tension in bed reflected by a perceived inability to relax the body sufficiently to allow the onset of sleep

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:

• The patient reports a chronic pattern of little or no sleep most nights, with rare nights during which relatively normal amounts of sleep are obtained

• Sleep log data from one or more weeks of monitoring often show no sleep at all for several nights each week; typically, daytime naps are absent following such nights

• There is typically a mismatch between objective findings from polysomnography or actigraphy and subjective sleep estimates from a self-reported sleep diary

At least one of the following is observed:

• The patient reports constant or near-constant awareness of environmental stimuli throughout most nights

• The patient reports a pattern of conscious thoughts or rumination throughout most nights while maintaining a recumbent posture

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:

• Chronic pain syndromes from any cause (eg, arthritis, cancer)

• Advanced chronic obstructive lung disease

• Benign prostatic hypertrophy (because of nocturia)

• Chronic renal disease (especially if on hemodialysis)

• Chronic fatigue syndrome

• Fibromyalgia

• Neurologic disorders

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[45] :

• Heart disease (21.9% with chronic insomnia vs 9.5% without insomnia)

• High blood pressure (43.1% vs 18.7%)

• Neurologic disease (7.3% vs 1.2%)

• Breathing problems (24.8% vs 5.7%)

• Urinary problems (19.7% vs 9.5%)

• Chronic pain (50.4% vs 18.2%)

• Gastrointestinal problems (33.6% vs 9.2%)

In addition, people with the following medical problems more often reported chronic insomnia than did patients without such medical problems[45] :

• Heart disease (44.1% vs 22.8%)

• Cancer (41.4% vs 24.6%)

• High blood pressure (44% vs 19.3%)

• Neurologic disease (66.7% vs 24.3%)

• Breathing problems (59.6% vs 21.4%)

• Urinary problems (41.5% vs 23.3%)

• Chronic pain (48.6% vs 17.2%)

• Gastrointestinal problems (55.4% vs 20.0%)

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 (DSM-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 patient has current, ongoing dependence on or abuse of a drug or substance known to have sleep-disruptive properties either during periods of use or intoxication or during periods of withdrawal

• The patient has current ongoing use of or exposure to a medication, food, or toxin known to have sleep-disruptive properties in susceptible individuals

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 1 of the following:

• Improper sleep scheduling consisting of frequent daytime napping, selecting highly variable bed or rising times, or spending excessive amounts of time in bed

• Routine use of products containing alcohol, nicotine, or caffeine, especially in the period preceding bedtime

• Engagement in mentally stimulating, physically activating, or emotionally upsetting activities too close to bedtime

• Frequent use of the bed for activities other than sleep (eg, television watching, reading, studying, snacking, thinking, planning)

• Failure to maintain a comfortable sleeping environment

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.[46]

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:

• Falling asleep is an extended process that requires special conditions

• Sleep-onset associations are highly problematic or demanding

• In the absence of associated conditions, sleep onset is significantly delayed or sleep is otherwise disrupted

• Nighttime awakenings require caregiver intervention for the child to return to sleep

The limit-setting type is characterized by the following:

• The child has difficulty initiating or maintaining sleep

• The child stalls or refuses to go to bed at an appropriate time or refuses to return to bed following a nighttime awakening

• The caregiver demonstrates insufficient or inappropriate limit-setting to establish appropriate sleeping behavior in the child

Primary sleep disorders causing insomnia

Included in this category are the following:

• Restless legs syndrome(RLS)

• Obstructive sleep apnea/hypopnea syndrome

• Circadian rhythm disorders

Restless legs syndrome

RLS is a sleep disorder characterized by the following:

• An urge to move the legs, usually accompanied by uncomfortable and unpleasant physical sensations in the legs

• Symptoms begin or worsen during periods of rest or inactivity such as lying or sitting

• Symptoms are partially or totally relieved by moving, such as walking or stretching, at least as long as the activity continues

• Symptoms are worse or occur only in the evening or at night

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:

• Advanced sleep phase syndrome

• Delayed sleep phase syndrome

• Shift-work sleep disorder

• Irregular sleep-wake rhythm

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.

In a 1991 survey, 30-35% of adults in the United States reported difficulty sleeping in the past year, and 10% reported the insomnia to be chronic and/or severe. Despite the high prevalence, only 5% of persons with chronic insomnia visited their physicians to specifically discuss their insomnia. Only 26% discussed their insomnia during a visit made for another problem.[47]

A 2016 report from the CDC is the first to provide state-specific estimates of the prevalence of a ≥7 hour sleep duration in a 24-hour period. The report shows geographic clustering of lower prevalence estimates for this duration of sleep in the southeastern United States and in states along the Appalachian Mountains, which are regions with the highest burdens of obesity and other chronic conditions.[48]

In an epidemiologic study from Quebec, 29.9% of 2001 respondents reported insomnia symptoms, and 9.5% met criteria for insomnia syndrome.[49] A study of young adults in Switzerland indicated a 9% rate of chronic insomnia. A World Health Organization study of 15 sites found a prevalence of approximately 27% for patients reporting "difficulty sleeping."

National surveys in England showed a modest but steady increase in the prevalence of insomnia from 1993-2007. The percentage of respondents reporting any insomnia symptoms increased from 35.0% to 38.6% over that period, while insomnia diagnosis rose from 3.1% to 5.8%.[50] The following features were associated with insomnia:

• Female gender

• Increased age

• Lower educational attainment

• Depression

• Unemployment

• Economic inactivity

• Widowed, divorced, or separated status

Sex-, race-, and age-related demographics

Women are 1.4 times as likely as men to report insomnia symptoms.[51] Epidemiologic data indicate that 40% of women between the ages of 40 and 55 years report recent sleep difficulty resembling insomnia.[52]

A study by Strine and colleagues indicated that women who have menstrual-related problems are more likely to have insomnia than are women without such problems.[53] In fact, after adjustments were made for age, race and ethnicity, education, marital status, and employment status, women who had menstrual-related problems were 2.4 times as likely to report insomnia as women without such problems.

Ethnic groups appear to differ in the prevalence and severity of disordered sleep symptoms. A meta-analysis by Ruiter et al found that African Americans have a higher prevalence and greater severity of sleep-disordered breathing but that whites report more insomnia symptoms.[54]

Chronic insomnia increases in frequency with age and is more common in the elderly. This is presumed to be the result of greater psychosocial stressors, losses, and medical illnesses. Epidemiologic data indicate that the prevalence of chronic insomnia increases from 25% in the adult population to nearly 50% in the elderly population.[55]

Treatment of insomnia can improve these patients’ perceived health, function, and quality of life.[56] Consequences of untreated insomnia may include the following:

• Impaired ability to concentrate, poor memory, difficulty coping with minor irritations, and decreased ability to enjoy family and social relationships

• Reduced quality of life, often preceding or associated with depression and/or anxiety

• More than 2-fold increase in the risk of having a fatigue-related motor vehicle accident

• Apparent increase in mortality for individuals who sleep fewer than 5 hours each night

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.[57] 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.[58] Other studies, however, indicate an association between short sleep or sleep restriction and hypertension.[59, 60]

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.[61] 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.[62]

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.[63]

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.[43] 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.[43] 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.[64]

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.[65] 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.

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:

• Develop regular sleep habits; this means keeping a regular sleep and wake time, sleeping as much as needed to feel refreshed the following day, but not spending more time in bed than needed

• Avoid staying in bed in the morning to catch up on sleep

• Avoid daytime naps; if a nap is necessary, keep it short (less than 1 hour) and avoid napping after 3 pm

• Keep a regular daytime schedule; regular times for meals, medications, chores, and other activities helps keep the inner body clock running smoothly

• Do not read, write, eat, watch TV, talk on the phone, or play cards in bed

• Avoid caffeine after lunch; avoid alcohol within 6 hours of bedtime; avoid nicotine before bedtime

• Do not go to bed hungry, but do not eat a big meal near bedtime either

• Avoid sleeping pills, particularly over-the-counter remedies

• Slow down and unwind before bed (beginning at least 30 minutes before bedtime (a light snack may be helpful); create a bedtime ritual such as getting ready for bed, wearing night clothes, listening to relaxing music, or reading a magazine, newspaper, or book

• Avoid watching TV in the bedroom or sleeping on the sofa and then going to bed later in the night

• Avoid stimulating activities prior to bedtime (eg, vigorous exercise, discussing or reviewing finances, or discussing stressful issues with a spouse or partner or ruminating about them with oneself)

• Keep the bedroom dark, quiet, and at a comfortable temperature

• Exercise daily; this is best performed in the late afternoon or early evening (but not later than 6-7 pm)

• Do not force yourself to sleep; if you are unable to fall asleep within 15-30 minutes, get up and do something relaxing until sleepy (eg, read a book in a dimly lit room, watch a non-stimulating TV program); avoid watching the clock or worrying about the perceived consequences of not getting enough sleep

See the American Academy of Sleep Medicine Sleep Education site for valuable information.

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 2008 American Academy of Sleep Medicine (AASM) guideline consensus is that at a minimum, patients should complete the following evaluations[1] :

• A general medical and psychiatric questionnaire to detect comorbid disorders

• A sleepiness assessment, such as the Epworth Sleepiness Scale

• A 2-week sleep log to define sleep-wake patterns and their variability

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:

• Is the difficulty with falling asleep, frequent awakenings, or early morning awakening?

• If the problem is at sleep onset, are you sleepy when you get into bed?

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

• What time do you go to bed and get up in the morning?

• Do you go to bed and get up at the same times every day? How about during off days?

• Has this schedule changed recently?

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

• What are the temperature, bed comfort, and noise and light levels?

• Do you sleep better in a chair or when away from home (eg, hotel) than in your own bed?

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

• Before bedtime, do you relax or do you work?

• Do you read or watch television in bed?

• Is the television or a light kept on during the night?

• What do you do if you cannot fall asleep?

• If you wake up in the middle of the night, do you fall back to sleep easily? If not, what do you do?

• Do you take daytime naps?

• Do you exercise? If so, at what time?

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.[8]

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

• Fatigue

• Tiredness

• Lack of energy

• Irritability

• Reduced work performance

• Difficulty concentrating

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.)

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.

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

• During the past month, have you often been bothered by feeling “down,” depressed, or hopeless?

• During the past month, have you often been bothered by having little interest or pleasure in doing things?

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:

• Beta blockers

• Clonidine

• Theophylline (acutely)

• Certain antidepressants (eg, protriptyline, fluoxetine)

• Decongestants

• Stimulants

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

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.[1]

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:

• Large neck size (ie, >17 in. in men)

• Enlarged tonsils

• Mallampati airway score of 3 or 4 (see the image below)

• Low-lying soft palate, particularly in patients with hypertension or cardiac disease

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.

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.

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.

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 and daytime multiple sleep latency testing (MSLT) are not routinely indicated for the workup of insomnia.[1, 66] 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.[1]

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.[67] 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.

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.)

For diagnosis, the patient should maintain a sleep diary for 1-2 weeks. The 2008 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.[1] 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.

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.[2]

The American Academy of Sleep Medicine (AASM) guideline states that the 2 primary goals of treatment are to improve sleep quality and to improve related daytime impairments.[1] 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. In 2017, the AASM released an updated guideline for the pharmacologic treatment of chronic insomnia in adults.[7]

The AASM guideline recommends 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 guideline also encourages these interventions as initial therapy when appropriate.[1]  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.[68]

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 (see Sleep Diary). 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.[69, 70, 71] CBT is now considered the most appropriate treatment for patients with primary insomnia.[4, 5, 6] 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[17] and a short course of a sedative-hypnotic or melatonin receptor agonist. In the case of a psychiatric disorder (eg, depression[72] or anxiety), CBT and a short-term sedative-hypnotic in conjunction with an antidepressant can be beneficial.

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.[1]

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.

The American Academy of Sleep Medicine (AASM) evidence-based practice parameter found that CBT (all components), as well as individual components of stimulus-control, paradoxical intention, relaxation training, and biofeedback, were effective.[5] CBT has also been shown to be better in weaning patients from hypnotics than tapering medications alone.

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. A study by Edinger et al showed that a total of 4 biweekly individual treatments represents the optimal dosing of CBT.[73] 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.

A study by Buysse et al determined that brief behavioral treatment for insomnia (BBTI) was a simple, efficacious, and durable intervention for chronic insomnia in older adults.[74] BBTI consisted of behavioral instructions delivered in 2 intervention sessions and 2 telephone calls.

Some sleep centers have behavioral medicine specialists who can administer CBT. Preliminary evidence by Morin indicated that providing written information about CBT can be helpful.[75] An Internet-based CBT learning program for patients is also available for a nominal cost (see CBTforINSOMNIA.com).

The components of CBT include the following:

• Sleep hygiene education

• Cognitive therapy

• Relaxation therapy

• Stimulus-control therapy

• Sleep-restriction therapy

CBT for insomnia (CBT-I) is a term for the combination of cognitive therapy and behavioral therapy, such as stimulus-control therapy or sleep-restriction therapy (with or without relaxation therapy).[1]

The 2008 AASM guideline recommends 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.[1]

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 2008 AASM guideline recommends 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.[1]

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:

• Use the bed only for sleeping and sexual activity (no reading, TV, eating, or working in bed)

• Go to bed only when sleepy

• If unable to fall asleep in 15-20 minutes, get out of bed to do something relaxing until sleepy; this can be repeated as often as needed

• Do not spend more time in bed than is needed by establishing a standard wake-up time

• Refrain from daytime napping

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. Morin and colleagues 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 by Jacobs et al comparing zolpidem with CBT showed continued efficacy for the patients treated with CBT.[70]

A European study by Sivertsen and colleagues 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.[76] 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.[77]

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.[77]

The pharmacologic treatment of insomnia has made great advances in the last two decades. In the early 19th century, alcohol and opioids were used as sleeping medications. In the late 19th century, chloral hydrate was used (and misused, in combination with alcohol, as “knockout drops” or a “Mickey Finn”). Barbiturates were used from the early 20th century until the early 1960s, when benzodiazepines (ie, flurazepam and quazepam) were first approved by the US Food and Drug Administration (FDA) for the treatment of insomnia.

In 2017, the American Academy of Sleep Medicine (AASM) released an updated guideline for the pharmacologic treatment of chronic insomnia in adults.[7]

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.

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.[78, 79] Another study demonstrated continued efficacy at 12 months.[80]

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.[81] 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.[82, 83] 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.[84, 83]

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.[12]  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.[85]

Zaleplon has a very short half-life (1 hr) and is indicated for sleep-onset insomnia at doses ranging from 5-20 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:

• Therapy should be instituted with a low dose and maintained at the lowest effective dose

• Continued nightly use should be avoided; patients should be encouraged to use them only when truly necessary

• Use for more than 2-4 weeks should be avoided if possible

• Counsel patients to allow for at least 8 hours of sleep

• Impairment from sedative hypnotics can be present despite feeling fully awake

• Hypnotics with a rapid onset of action, such as zolpidem or zaleplon, are preferable when the problem is falling asleep

• If the problem is staying asleep, a hypnotic with a slower rate of elimination may be more appropriate (eg, temazepam, estazolam, flurazepam)

• If the patient is depressed, an antidepressant with sedative properties, such as trazodone, mirtazapine, or amitriptyline, may be preferable to a hypnotic

• Hypnotics should never be used with alcohol

• In general, pregnancy is a contraindication

• Benzodiazepines should be avoided in patients with known or possible sleep apnea

• Lower doses should be used in elderly patients

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.[1] Long-term administration of hypnotics may be intermittent, as needed, or nightly.[1] If possible, during long-term therapy, patients should receive an adequate trial of CBT.[1]

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[86, 87] )

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.[88] 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).[1, 7]

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.[7]

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.[89]

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.[85]

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.[90]

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.[91, 92, 93]

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).[7]

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.

Many clinicians believe that sedating antidepressants have fewer adverse effects than nonbenzodiazepine receptor agonists; however, this is not the case. 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.

The efficacy and safety of low-dose doxepin have been demonstrated in 2 randomized, double-blind, parallel-group, placebo-controlled trials. Low-dose doxepin is thought to be a hypnotic that primarily works through an antihistaminic effect.

Roth et al reported that low-dose doxepin (6 mg) provided significant improvements in sleep onset, maintenance, duration, and quality, as well as appearing to reduce early morning awakenings. These researchers used a first-night effect combined with a 3-hour phase advance to induce transient insomnia in healthy adults. The incidence of adverse events was comparable to placebo.[94] .

In a 12-week study of elderly patients with chronic primary insomnia, Krystal et al reported that a nightly 1-mg or 3-mg dose of doxepin resulted in significant and sustained improvements in most insomnia endpoints, including sleep maintenance and early morning awakenings. There was no evidence of next-day residual sedation or other significant adverse effects. Efficacy was assessed using polysomnography, patient reports, and clinician ratings.[95]

Antihistamines

Antihistamines are the major ingredient of over-the-counter (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.

Zhang et al reported that a nighttime dose of 50 mg diphenhydramine resulted in a next-day residual sedative effect. This double-blind, placebo-controlled, crossover study used positron emission tomography (PET) for an objective measurement of residual effect.[96]

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.[7]

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.[19] Most of the data, however, seem to suggest that melatonin taken before bedtime decreases sleep latency, may increase total sleep time,[97, 98] 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. The 2008 AASM guideline notes a relative lack of safety data and efficacy data and, therefore, states that melatonin is not recommended for the treatment of chronic insomnia.[1]

Some studies, however, suggest a possible role for melatonin in the elderly. In a 2010 study, Wade et al determined that prolonged-release melatonin (2 mg) improved sleep latency and additional sleep and daytime parameters in patients 65 years of age and older. These improvements were maintained or enhanced over a 6-month period, with no signs of tolerance.[99]

A double-blind, placebo-controlled clinical trial by Rondanelli et al in residents of a long-term care facility found that a nighttime dose of melatonin, combined with magnesium and zinc, appeared to improve residents’ quality of sleep and quality of life. The supplement, containing 5 mg melatonin, 225 mg magnesium, and 11.25 mg zinc, was administered 1 hour before bedtime.[100]

Melatonin is not recommended by the AASM for sleep onset or sleep maintenance insomnia.[7]

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.[101] 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.[102]

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.[103]

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.[104] For these reasons, the 2017 AASM guideline states that valerian and other alternative or herbal medications are not recommended for treatment of chronic insomnia.[7]

A longitudinal study by Sun et al 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.[105]

In June 2016, the FDA approved a prescription device for patients with insomnia, the Cerêve Sleep System, 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.[106]

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

• Avoid caffeinated beverages in the late afternoon or evening, since the stimulant activity of adenosine antagonism can promote hyperarousal

• Avoid alcohol in the evening, since this can worsen sleep-disordered breathing leading to frequent arousals; furthermore, while alcohol promotes sleep early in the night, it leads to more sleep disruption later in the evening

• Avoid large meals near bedtime, particularly with gastroesophageal reflux disease or delayed gastric emptying.

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.

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.[107]

However, aging should not be assumed to be the explanation for insomnia.[108] 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.[109]

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.[1] 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.[110]

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).

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:

• If the history suggests obstructive sleep apnea or restless legs syndrome/periodic leg movement disorder

• In cases of primary insomnia, particularly if it is psychophysiologic insomnia and of long duration

• The patient requires daily or near-daily sedative-hypnotics for insomnia for 30 days or more

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.

Low-value care

In 2014, as part of the Choosing Wisely® initiative from the American Board of Internal Medicine Foundation (ABIM), the AASM recommended that physicians avoid polysomnography (PSG) in patients with chronic insomnia unless symptoms suggest a comorbid sleep disorder. It further recommended that hypnotics be avoided as primary therapy for chronic insomnia in adults. Instead, clinicians should offer cognitive-behavioral therapy (CBT), reserving medication for adjunctive treatment when necessary.[111]

Evaluation

The American Academy of Sleep Medicine (AASM) guideline consensus is that insomnia is primarily diagnosed by clinical evaluation through a thorough sleep history and detailed medical, substance, and psychiatric history. At a minimum, patients should complete the following evaluations:[1]

• A general medical and psychiatric questionnaire to detect comorbid disorders

• A sleepiness assessment, such as the Epworth Sleepiness Scale

• A 2-week sleep log to define sleep-wake patterns and their variability

Sleep diary data should be collected before and during the course of active treatment and in the case of relapse or reevaluation in the long term.

Other testing (eg, blood, imaging studies) is not indicated for the routine evaluation of chronic insomnia unless there is suspicion for comorbid disorders.

Achieving healthy sleep

In 2015, the American Thoracic Society (ATS) released a policy statement stressing the importance of achieving good-quality sleep and avoiding sleep deprivation. Key recommendations include the following:[112]

• Good-quality sleep is critical for good health and overall quality of life
• Short sleep duration (6 hours or less per 24-hour period) is associated with adverse outcomes, including mortality
• Long sleep duration (>9 to 10 hours per 24-hour period) may also be associated with adverse health outcomes
• At a population level, the optimal sleep duration in adults for good health is 7 to 9 hours, although individual variability exists
• Because drowsy driving is an important cause of fatal and nonfatal motor vehicle crashes, all drivers (occupational and nonoccupational) should receive education about how to recognize the symptoms and consequences of drowsiness
• Better education is needed for the general public and healthcare providers regarding the effect of working hours and shift work on sleep duration and quality and the association of sleepiness with workplace injuries
• Sleep disorders are common, cause significant morbidity, and have substantial economic impact, but they are treatable; however, many individuals with sleep disorders remain undiagnosed and untreated
• Age-based recommendations for sleep duration in children should be developed; these should enable the child to awaken spontaneously at the desired time through implementation of regular wake and sleep schedules
• For adolescents, school start times should be delayed to align with the physiologic circadian propensity of this age group
• Healthcare providers should receive more education on sleep hygiene and encourage patients to maximize their sleep time
• Public education programs should be developed to emphasize the importance of sleep for good health
• Better education/awareness is needed of the importance of early identification of groups at high risk for obstructive sleep apnea (in children and adults)
• Better education of physicians as to the effectiveness of cognitive-behavior therapy for insomnia rather than immediate implementation of hypnotics and sedatives, and structural changes to increase access to this therapy

Pharmacological treatment for chronic insomnia

The following recommendations from the American Academy of Sleep Medicine (AASM) are intended as a guideline for clinicians in choosing a specific pharmacological agent for treatment of chronic insomnia in adults, when such treatment is indicated.[3]

For patients with primary insomnia (psychophysiologic, idiopathic or paradoxical ICSD-2 subtypes), when pharmacologic treatment is utilized alone or in combination therapy, the recommended general sequence of medication trials is as follows:

• Short-intermediate acting benzodiazepine receptor agonists (BZD or newer BzRAs) or ramelteon—zolpidem, eszopiclone, zaleplon, and temazepam
• Alternate short-intermediate acting BzRAs or ramelteon if the initial agent has been unsuccessful
• Sedating antidepressants, especially when used in conjunction with treating comorbid depression/anxiety—trazodone, amitriptyline, doxepin, and mirtazapine
• Combined BzRA or ramelteon and sedating antidepressant
• Other sedating agents—anti-epilepsy medications (gabapentin, tiagabine) and atypical antipsychotics (quetiapine and olanzapine)

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.[1] Pharmacologic therapy is used in concert with behavioral and psychological interventions.

Class Summary

Sedative-hypnotics include nonbenzodiazepine receptor agonists (zaleplon, zolpidem, eszopiclone); short-acting benzodiazepine receptor agonists (triazolam); intermediate-acting benzodiazepine receptor agonists (estazolam, temazepam); and selective melatonin agonists (ramelteon).

Nonbenzodiazepine receptor agonists have a nonbenzodiazepine structure and bind more specifically to the alpha-1 subunit of the gamma-aminobutyric acid–A (GABAA) receptor, which is associated with sedation. They are excellent choices for treatment of sleep-onset insomnia.

Both eszopiclone and sustained-release zolpidem are effective for both sleep-onset and sleep-maintenance insomnia, with a reduced abuse potential and long-term efficacy of up to 6 months as compared with nonselective benzodiazepine receptor agonists.

Short-acting (eg, triazolam) and intermediate-acting (eg, estazolam, temazepam) benzodiazepine receptor agonists are useful for sleep-onset insomnia. These agents have been the hypnotics of choice for many years because of their relative safety compared with the barbiturates, as well as their low cost. By binding to specific subunits of GABAA receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission by increasing the frequency of chloride channel opening.

Benzodiazepines are on the Beer’s List of potentially inappropriate medications for older patients. They are not recommended in the elderly because of the risk of falls; if used, they should be given at the lowest effective dose for the shortest amount of time. The older sedative-hypnotics that have a prolonged half-life increase the risk for next-day sedation and daytime psychomotor impairment and pose an increased risk for abuse and dependence. Other complications of benzodiazepine use include tolerance, withdrawal, abuse, and rebound insomnia.

Orexin inhibitors (eg, lemborexant, suvorexant) are options for patients with difficulties of sleep onset and/or sleep maintenance.

Selective melatonin agonists are indicated for insomnia characterized by difficulty with sleep onset, particularly for individuals who lack dim-light melatonin-onset stimulation. Melatonin itself is not regulated by the US Food and Drug Administration (FDA) and is thus not approved for treatment of insomnia. Melatonin does not appear to have obvious side effects other than sedation. Currently, ramelteon is the only melatonin receptor agonist approved by the FDA for treatment of insomnia and is available by prescription.

Zaleplon (Sonata)

A sedative-hypnotic of the pyrazolopyrimidine class, zaleplon has a rapid onset of action and an ultra-short duration of action, making it a good choice for treatment of sleep-onset insomnia. A second dose can be used during the middle of the night without residual sedation in the morning (this is believed to be an advantage of this hypnotic over others).

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

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.

Eszopiclone (Lunesta)

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.

Triazolam (Halcion)

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.

Estazolam

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.

Temazepam (Restoril)

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.

Ramelteon (Rozerem)

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).

Class Summary

Except for low-dose doxepin (Silenor), drugs in this category are not approved for treatment of insomnia by the US Food and Drug Administration (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.

Amitriptyline

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)

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

Nortriptyline (Pamelor)

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.

Class Summary

The side effect of drowsiness seen with some antidepressants can be used to benefit patients in the treatment of sleep-maintenance insomnia or insomnia associated with depression.

Mirtazapine (Remeron, Remeron SolTab)

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.

Trazodone (Oleptro)

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.

Nefazodone

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.

Suvorexant (Belsomra)

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.

Lemborexant (Dayvigo)

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.

Daridorexant (Quviviq)

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.