Medscape - Insomnia

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com/article/1187829-print
emedicine.medscape.com
Insomnia
Updated: Aug 31, 2022
Author: Jasvinder Chawla, MD, MBA; Chief Editor: Selim R Benbadis, MD
Overview
Practice Essentials
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. As many as 95% of Americans
have reported an episode of insomnia at some point during their lives.
Signs and symptoms
The American Academy of Sleep Medicine (AASM) guideline consensus is that, at a minimum, patients with insomnia 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
A careful sleep history should be obtained, addressing the following:
Timing of insomnia
Patient’s sleep habits (commonly referred to as sleep hygiene)
Presence or absence of symptoms of sleep disorders associated with insomnia
A thorough medical history should be obtained, including a review of systems.
A thorough psychological history should be obtained to screen for psychiatric disorders, focusing particularly on anxiety and
depression.
A family history should be obtained, with particular attention to the following:
Risk of fatal familial insomnia (FFI): Though rare, this condition should be considered if first-degree relatives are
affected
Risk of heritable conditions that may contribute to more common causes of insomnia (eg, psychiatric disorders)
A social history should be obtained, addressing the following:
Transient or short-term insomnia: Recent situational stresses
Chronic insomnia: Past stresses or medical illnesses
Use of tobacco, caffeinated products, alcohol, and illegal drugs
The medication history should be reviewed, focusing on agents that commonly cause insomnia, such as the following:
Beta blockers
Clonidine
Theophylline (acutely)
Certain antidepressants (eg, protriptyline, fluoxetine)
Decongestants
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Stimulants
Over-the-counter and herbal remedies
Physical examination may offer clues to underlying medical disorders predisposing to insomnia.[1] Specific
recommendations include the following:
History suggestive of sleep apnea: Careful head and neck examination
Symptoms of restless legs syndrome or periodic limb movement disorder or any other neurologic disorder: Careful
neurologic examination
Daytime symptoms consistent with a medical cause of insomnia: Careful examination of the affected organ system
(eg, lungs in chronic obstructive pulmonary disease)
See Clinical Presentation for more detail.
Diagnosis
Insomnia is a clinical diagnosis. Diagnostic studies are indicated principally for the clarification of comorbid disorders.
Measures that may be considered include the following:
Studies for hypoxemia
Polysomnography and daytime multiple sleep latency testing (MSLT)
Actigraphy
Sleep diary
Genetic testing (eg, for FFI)
Brain imaging (eg, to assist in the diagnosis of FFI[2] )
See Workup for more detail.
Management
The AASM guidelines list two primary treatment goals, as follows:[1, 3]
To improve sleep quality
To improve related daytime impairments
The AASM guidelines recommend including at least one behavioral intervention in initial treatment. Cognitive-behavioral
therapy (CBT) is considered the most appropriate treatment for patients with primary insomnia, though it is also effective for
comorbid insomnia as adjunctive therapy.[1, 4, 5, 6, 7]
The components of CBT include the following:
Sleep hygiene education
Cognitive therapy
Relaxation therapy
Stimulus-control therapy
Sleep-restriction therapy
Sedative-hypnotics are the most prescribed drugs for insomnia. Though not usually curative, they can provide symptomatic
relief when used alone or adjunctively. Such agents include the following:
Short- and intermediate-acting benzodiazepines (eg, triazolam, temazepam, estazolam)
Eszopiclone
Zolpidem
Zaleplon
Ramelteon
The following general precautions should be taken when sedative-hypnotics are used:
Start with a low dose, and maintain at the lowest effective dose
Avoid continued nightly use; encourage patients to use them only when truly necessary
Avoid using for more than 2-4 weeks if possible
Counsel patients to allow for at least 8 hours of sleep
Be aware that impairment can be present despite a feeling of being fully awake
When the problem is falling asleep, prefer hypnotics with a rapid onset of action (eg, zolpidem, zaleplon)
When the problem is staying asleep, consider a hypnotic with a slower rate of elimination (eg, temazepam,
estazolam, flurazepam)
If the patient is depressed, consider an antidepressant with sedative properties (eg, trazodone, mirtazapine,
amitriptyline) in preference to a hypnotic
Never use hypnotics with alcohol
Avoid using in pregnant patients
Avoid using benzodiazepines in patients with known or possible sleep apnea
Use lower doses in elderly patients
Other pharmacological therapies use for insomnia include the following:
Tricyclic antidepressants (ie, amitriptyline, nortriptyline)
Heterocyclics (ie, doxepin, trazodone)
Other antidepressants (ie, mirtazapine)
Melatonin agonist (ramelteon)
Orexin antagonists (eg, daridorexant, lemborexant, suvorexant)
Other measures that may be helpful include the following:
Acupressure
Dietary modification
Exercise (at least 6 hours before bedtime)
See Treatment and Medication for more detail.
Background
Insomnia is defined as repeated difficulty with sleep initiation, maintenance, consolidation, or quality that occurs despite
adequate time and opportunity for sleep and that results in some form of daytime impairment.[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).
Anatomy
Sleep and wakefulness is a tightly regulated process. Reciprocal connections in the brain produce consolidated periods of
wakefulness and sleep that are entrained by environmental light to occur at specific times of the 24-hour cycle.
Promotion of wakefulness
Brain areas critical for wakefulness consist of several discrete neuronal groups centered around the pontine and medullary
reticular formation and its extension into the hypothalamus (see the image below). Although diverse in terms of
neurochemistry, these cell groups share the features of a diffuse “ascending” projection to the forebrain and a “descending”
projection to brainstem areas involved in regulating sleep-wake states. The neurotransmitters involved, along with the main
cell groups that produce them, are as follows:
Histamine – histaminergic cells in the tuberomammillary nucleus (TMN) in the posterior hypothalamus
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.
Ventrolateral pre-optic nucleus inhibitory projections to main components of the arousal system to promote sleep.
The homeostatic and circadian processes
Both animal and human studies support a model of 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.)
Sleep-wake cycle.
Melatonin and the circadian process
The suprachiasmatic nucleus (SCN) is entrained to the external environment by the cycle of light and darkness. The retinal
ganglion cells transmit light signals via the retinohypothalamic tract to stimulate the SCN. A multisynaptic pathway from the
SCN projects to the pineal gland, which produces melatonin.
Melatonin synthesis is inhibited by light and stimulated by darkness. The nocturnal rise in melatonin begins between 8 and
10 pm and peaks between 2 and 4 am, then declines gradually over the morning.[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.)
Schematic flip-flop switch model. Adapted from Saper C et al. Hypothalamic regulation of sleep and circadian rhythms.
Nature 2005;437:1257-1263.
Hypocretin neurons in the posterolateral hypothalamus are active during wakefulness and project to all of the wakefulness
arousal systems described above. Hypocretin neurons interact with both the sleep-active and the sleep-promoting systems
and act as stabilizers between wakefulness-maintaining and sleep-promoting systems to prevent sudden and inappropriate
transitions between the 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.)
GABAA receptor complex subunits and schematic representation of agonist binding sites.
BZRAs enhance the effect of GABA by lowering the concentration of GABA required to open the GABA channel. BZRAs bind
to a modulatory site on the GABAA receptor that is distinct from the GABA binding site and change the receptor complex
allosterically to increase the affinity of the receptor to GABA, thus producing a larger postsynaptic current prolonging
inhibition. Although BZRAs do not directly open the chloride channel, they modulate the ability of GABA to do so, thus
enhancing its inhibitory effect.
Synaptic GABAA receptors typically contain a γ subunit in combination with an α1, α2, and α3 subunit. Most GABAA
receptors expressed in the CNS are α1 β2 γ2, α2 β3 γ2, α3 β3 γ2, α5 β3 γ2.
While GABA binds at the junction between subunits α and β, BZRAs bind at the interface between α and γ. The α subunits of
the GABAA receptor mediate sedative, amnestic, anxiolytic, myorelaxant, ataxic, and sedative effects. GABAA receptors
containing the α1 subunit mediate the sedative-hypnotic and amnestic effects and, to some degree, the anticonvulsant
effects of BZRAs.
For example, studies of knockout mice that express a benzodiazepine-insensitive α1 subunit fail to show the sedative,
amnestic effects of diazepam. The nonbenzodiazepine receptor agonists (ie, zaleplon, zolpidem, eszopiclone) have relative
selectivity for GABAA receptors containing the α1 subunit, thereby producing fewer adverse effects (ie, ataxia, anxiolytic,
myorelaxation properties) than nonselective BZRAs. (See the image below outlining the GABAA receptor subunit functions.)
GABAA receptor subunit function(s).
Melatonin and melatonin receptor agonists
Melatonin is a hormone produced by the pineal gland during the period of sundown to sunrise. It exerts sleep-promoting
effects through MT1/MT2 receptors via an unknown mechanism. Ramelteon is an agonist at MT1 and MT2 receptors that is
approved by the 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.
Pathophysiology
Insomnia usually results from an interaction of biological, physical, psychological, and environmental factors. Although
transient insomnia can occur in any person, chronic insomnia appears to develop only in a subset of persons who may have
an underlying predisposition to insomnia.[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.
Theoretical model of the factors causing chronic insomnia. Chronic insomnia is believed to primarily occur in patients with
predisposing or constitutional factors. These factors may cause the occasional night of poor sleep but not chronic
insomnia. A precipitating factor, such as a major life event, causes the patient to have acute insomnia. If poor sleep habits
or other perpetuating factors occur in the following weeks to months, chronic insomnia develops despite the removal of
the precipitating factor. Adapted from Spielman AJ, Caruso LS, Glovinsky PB: A behavioral perspective on insomnia
treatment. Psychiatr Clin North Am. 1987 Dec;10(4):541-53.
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.
Etiology
Many clinicians assume that insomnia is often secondary to a psychiatric disorder, However, a large epidemiologic survey
showed that half of insomnia diagnoses were not related to a primary psychiatric disorder.[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).
Frequency of insomnia causes.
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
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
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.
Epidemiology
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]
Prognosis
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.
Patient Education
All patients with insomnia, whether transient or chronic, should be educated about sleep and the elements of good sleep
hygiene. Sleep hygiene refers to daily activities and habits that are consistent with or promote the maintenance of good
quality sleep and full daytime alertness.
Educate patients on the following elements of good sleep hygiene:
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.
Presentation
History
The patient history is the most important part of the evaluation for insomnia. It must include a complete sleep history,
medical history, psychiatric history, social history, and medication review. The 2008 American Academy of Sleep Medicine
(AASM) guideline consensus is that at a minimum, patients should complete the following evaluations[1] :
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.)
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.
Diagnostic criteria for generalized anxiety disorder.
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.
Physical Examination
The physical examination may be helpful because findings may offer clues to underlying medical disorders that predispose
the patient to insomnia. It may also facilitate the differential diagnosis or classification of insomnia.[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.
Mallampati airway scoring.
If the patient reports symptoms of restless legs syndrome or any other neurologic disorder, perform a careful neurologic
examination. If the patient reports daytime symptoms consistent with any of the medical causes of insomnia, a careful
examination of the affected organ system (eg, lungs in chronic obstructive pulmonary disease) may be helpful.
DDx
Diagnostic Considerations
Disorders to consider in the differential diagnosis of insomnia include the following:
Central sleep apnea (primary or due to drug or substance)
Cheyne-Stokes breathing pattern (associated with heart failure)
High-altitude periodic breathing
Jet-lag disorder
Medication-related insomnia
Medications associated with insomnia are as follows:
Central nervous system stimulants (dextroamphetamine, methylphenidate)
Antihypertensives (alpha blockers, beta blockers)
Respiratory medications (albuterol, theophylline)
Decongestants (phenylephrine, pseudoephedrine)
Hormones (corticosteroids, thyroid medications)
Antiepileptic drugs (lamotrigine)
Other noncontrolled substances (caffeine, alcohol, nicotine)
Differential Diagnoses
Depression
Obstructive Sleep Apnea (OSA)
Periodic Limb Movement Disorder
Restless Legs Syndrome
Sleeplessness and Circadian Rhythm Disorder
Workup
Workup
Approach Considerations
Insomnia is a clinical diagnosis. Diagnostic studies are indicated principally for the clarification of comorbid disorders.
Before therapy is instituted, most patients are asked to keep a sleep log for 2-4 weeks. This log, in which the patient records
bed and wake times, sleep duration, and daytime naps and activities, gives a clearer picture of the degree of sleep
disturbance and allows development of a tailored treatment.
Studies for Hypoxemia

Patients with a history suggestive of chronic obstructive pulmonary disease (COPD) and insomnia should have oximetry or
an arterial blood gas (ABG) test performed to determine whether they are hypoxemic. Insomnia in COPD frequently begins
with the development of nocturnal hypoxemia, although nocturnal hypoxemia is not required for insomnia to occur. Oxygen
therapy may improve insomnia but rarely eliminates it.
Nocturnal hypoxemia is present if the patient has daytime hypoxemia or, frequently, exercise-related hypoxemia. If the
oximetry or ABG result is negative for hypoxemia, an exercise desaturation study or overnight oximetry may be helpful to
determine whether the patient needs oxygen.
Polysomnography
Polysomnography and daytime multiple sleep latency testing (MSLT) are not routinely indicated for the workup of insomnia.
[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]
Actigraphy
For actigraphy, a portable device is worn around the wrist to record gross motor activity and light/darkness over extended
periods. This study provides an indirect objective measure of sleep and wake time. Actigraphy has shown concordance with
polysomnography in the assessment of total sleep time.[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.
Sleep Diary
A sleep diary is appropriate when a patient reports an irregular sleep schedule. Maintaining a sleep diary can be done in
conjunction with wrist actigraphy. In the diary, patients should record estimates of the time at which they do the following:
1. Go to bed
2. Fall asleep
3. Awaken during the night
4. Lie in bed awake
5. Get out of bed in the morning
Patients should also record when and how long they exercise, when they take medications, and when they consume
caffeinated or alcoholic beverages. (Click on the image below to download a sample sleep diary form.)
Sleep diary.
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.
Genetic Testing
If a patient with rapidly progressing insomnia has any first-degree relatives who died with insomnia, there may be concern
for fatal familial insomnia (FFI). Genetic testing for this rare condition is available and consists of sequencing the PRNP
gene. Brain imaging—specifically, positron-emission tomography (PET) to look for hypometabolism in the thalamus and
cingulated cortex—may also assist in the diagnosis of FFI.[2]
Treatment
Approach Considerations
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
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:
Cognitive therapy
Relaxation 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 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 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 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]
Pharmacologic Treatment of Insomnia

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]
Acupressure for Insomnia

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]
Devices
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]
Diet and Exercise

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.
Treatment of Insomnia in Elderly Patients

The satisfaction of sleep declines with age. This probably is related to changes in sleep associated with age, such as a
decrease in slow-wave sleep, increased time awake after sleep onset, and a tendency to go to bed early and rise early.
Although napping is highly prevalent among elderly persons, it has not been consistently correlated with sleep disturbance.
[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).
Consultations
Primary care physicians should be able to diagnose and treat transient or short-term insomnia. Chronic insomnia is often
more difficult to treat, and referral to a specialist may be indicated. Patients with comorbid medical conditions may benefit
from referral to the appropriate specialist.
Patients should be referred to a sleep specialist in the following cases:
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.
Guidelines
Guidelines Summary
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]
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)
Medication
Medication Summary
Medications used in the treatment of insomnia include nonbenzodiazepine receptor agonists, benzodiazepine receptor
agonists, the selective melatonin receptor agonist ramelteon, and sedating antidepressants. All can be considered first-line
agents for insomnia; agent choice is largely dictated by past trials, cost, side-effect profile, drug interactions, and patient
preference.[1] Pharmacologic therapy is used in concert with behavioral and psychological interventions.
Sedative-Hypnotics
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).
Antidepressants, TCAs
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.
Antidepressants, Other
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.
Orexin Antagonists
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.
Questions & Answers

Overview
How is insomnia defined?
What are the AASM guidelines for evaluation of insomnia?
What should be the focus of patient history in the evaluation of insomnia?
Which medications commonly cause insomnia?
What should be included in the physical exam for insomnia?
How is insomnia diagnosed?
What are the treatment goals for insomnia?
What is the role of cognitive-behavioral therapy (CBT) in the treatment of insomnia?
Which sedative-hypnotics are used in the treatment of insomnia?
What are precautions for use of sedative-hypnotics to treat insomnia?
Which sedating antidepressants are used in the treatment of insomnia?
Which nonpharmacologic therapies may be helpful for the treatment of insomnia?
What are concerns regarding a patient's report of insomnia?
What is insomnia?
How prevalent is insomnia?
What are the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for insomnia?
What is acute insomnia?
What is chronic insomnia?
Which disorders are associated insomnia?
What is comorbid insomnia?
What is included in the evaluation of insomnia?
What is the role of a sleep diary in the evaluation of insomnia?
What is the role of actigraphy in the evaluation of insomnia?
What must be present for a diagnosis of insomnia?
What is the definition of primary insomnia?
What is the focus of treatment for insomnia?
How does the brain regulate sleep?
How does the brain promote wakefulness?
How does the brain promote sleep?
What are the homeostatic and circadian processes regulating sleep?
How is melatonin synthesized during sleep?
What is the flip-flop switch model of sleep regulation?
What are the mechanisms of action of benzodiazepines and benzodiazepine receptor agonists for insomnia?
What are the mechanisms of action of melatonin receptor agonists for insomnia?
What are the mechanisms of action of sedating antidepressants for insomnia?
What are the mechanisms of action of antihistamines for insomnia?
What is the pathophysiology of insomnia?
What is the role of hyperarousal in the pathophysiology of insomnia?
What is the Spielman model of chronic insomnia?
What is the role of genetics in the pathophysiology of insomnia?
What is the pathophysiology of fatal familial insomnia (FFI)?
What are the precipitating factors of insomnia?
What are the perpetuating factors of insomnia?
What causes insomnia?
What is inadequate sleep hygiene in insomnia?
What are the behavioral insomnias of childhood?
How is insomnia classified in the International Classification of Sleep Disorders, 2nd Edition (ICSD-2)?
What causes adjustment insomnia (acute insomnia)?
What causes primary insomnia?
What is paradoxical insomnia?
What must be observed for a diagnosis of paradoxical insomnia?
Which medical disorders have and etiologic role in insomnia?
Which medical conditions are common in people with insomnia?
Which mental disorders have an etiologic role in insomnia?
What is the role of drug or substance abuse in the etiology of insomnia?
How is insomnia not due to substance or known physiologic condition diagnosed?
What is idiopathic insomnia?
What primary sleep disorders cause insomnia?
What is the role of restless legs syndrome (RLS) in the etiology of insomnia?
What is the role of obstructive sleep apnea or hypopnea syndrome in the etiology of insomnia?
What are Circadian rhythm disorders in insomnia?
What is the prevalence of insomnia?
What are risk factors for insomnia?
How does the prevalence of insomnia vary by sex?
What are the racial predilections of insomnia?
How does the prevalence of insomnia vary by age?
What are the consequences of untreated insomnia?
What is the prognosis of insomnia?
What is the association of insomnia with depression and anxiety?
What is included in patient education about insomnia?
Presentation
What should be included in the patient history for insomnia?
What must be determined in a sleep history for insomnia?
What are questions to ask in the sleep history for insomnia?
What are common daytime effects of insomnia?
What should be the focus of the medical and psychiatric history in the evaluation of insomnia?
How are patients with insomnia screened for depression?
What is the role of family history in the evaluation of insomnia?
What is the role of social history in the evaluation of insomnia?
Which medications commonly cause insomnia?
What is the role of a physical exam for insomnia?
Which physical findings are significant in the evaluation of insomnia?
DDX
Which disorders should be considered in the differential diagnoses of insomnia?
Which medications are associated with insomnia?
What are the differential diagnoses for Insomnia?
Workup
What is the role of a sleep log in the diagnosis and management of insomnia?
What studies are indicated for patients with chronic obstructive pulmonary disease (COPD) and insomnia?
What is the role of polysomnography in the workup of insomnia?
What is the role of actigraphy in the workup of insomnia?
When is a sleep diary indicated in the workup of insomnia?
What is the role of genetic testing in the workup of insomnia?
Treatment
What are the American Association of Sleep Medicine (AASM) treatment guidelines for insomnia?
What is the role of cognitive-behavioral therapy (CBT) for insomnia?
What is the efficacy of cognitive-behavioral therapy (CBT) for insomnia?
What are the components of cognitive-behavioral therapy (CBT) for insomnia?
What is cognitive-behavioral therapy for insomnia (CBT-I)?
What are the AASM recommendations for initial treatment of insomnia?
What is included in sleep hygiene education for the treatment of insomnia?
What is the focus of cognitive therapy for insomnia?
What is relaxation therapy for insomnia?
What is stimulus-control therapy for insomnia?
What is sleep-restriction therapy for insomnia?
What is the efficacy of cognitive-behavioral therapy (CBT) compared to sedative hypnotics for treatment of insomnia?
What is the efficacy of combined cognitive-behavioral therapy (CBT) and sedative hypnotics for insomnia?
What is the role of medications in the treatment of insomnia?
What is the role of sedative-hypnotic drugs in the treatment of insomnia?
What is the efficacy of sedative-hypnotic drugs for the treatment of insomnia?
What is the recommended dosage for sedative-hypnotic drugs in the treatment of insomnia?
What are general precautions regarding the use of sedative-hypnotics for insomnia?
What is the role of long-term hypnotic drug treatment for insomnia?
What are risks associated with the use of sedative-hypnotics for insomnia?
What is the role of suvorexant (Belsomra) in the treatment of insomnia?
What is the role of ramelteon (Rozerem) in the treatment of insomnia?
What is the role of sedating antidepressants in the treatment of insomnia?
What is the role of antihistamines in the treatment of insomnia?
What is the role of melatonin in the treatment of insomnia?
What is the role of alternative and herbal medications in the treatment of insomnia?
What is the role of acupressure for insomnia?
What is the Cerêve Sleep System for the treatment of insomnia?
Which dietary modifications are used in the treatment of insomnia?
What are treatment options for insomnia in elderly patients?
When is referral to a sleep specialist indicated for the treatment of insomnia?
Guidelines
What are the AASM Choosing Wisely® recommendations regarding insomnia?
What are the AASM guidelines for the evaluation of insomnia?
What are the American Thoracic Society (ATS) guidelines for managing insomnia?
Medications
Which medications are used in the treatment of insomnia?
Which medications in the drug class Antidepressants, Other are used in the treatment of Insomnia?
Which medications in the drug class Antidepressants, TCAs are used in the treatment of Insomnia?
Which medications in the drug class Sedative-Hypnotics are used in the treatment of Insomnia?
Which medications in the drug class Orexin Antagonists are used in the treatment of Insomnia?
Contributor Information and Disclosures
Author
Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University
Medical Center
Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American
Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American
Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)
Youngsook Park, MD Co-Director in SLEEP Lab, Hines Veterans Affairs Medical Center; Assistant Professor of Neurology,
Loyola University, Chicago Stritch School of Medicine
Youngsook Park, MD is a member of the following medical societies: American Academy of Neurology, Willis-Ekbom
Disease Foundation, American Academy of Sleep Medicine
Disclosure: Received none from Hines VA Hospital for none.
Erasmo A Passaro, MD, FAAN, FAES, FAASM, FACNS Director, Comprehensive Epilepsy Program/Clinical
Neurophysiology Lab, Bayfront Health System, Florida Center for Neurology; Director, Epilepsy Surgery Program, Johns
Hopkins All Children's Hospital
Erasmo A Passaro, MD, FAAN, FAES, FAASM, FACNS is a member of the following medical societies: American Academy
of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society,
American Medical Association, American Society of Neuroimaging
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: UCB; Sunovion; Eisai, GWPharma.
Chief Editor
Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and
Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy
of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Bioserenity, Catalyst,
Ceribell, Eisai, Jazz, LivaNova, Neurelis, Neuropace, SK Life Science Science, Sunovion, Takeda, UCB<br/>Serve(d) as a
speaker or a member of a speakers bureau for: Catalyst, Jazz, LivaNova, Neurelis, SK Life Science, Stratus,
UCB<br/>Received research grant from: Cerevel Therapeutics; Ovid Therapeutics; Neuropace; Jazz; SK Life Science,
Xenon Pharmaceuticals, UCB, Marinus, Longboard.
Acknowledgements
Carmel Armon, MD, MSc, MHS Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology,
Baystate Medical Center
Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American
Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical
Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association,
American Neurological Association, American Stroke Association, Massachusetts Medical Society, Movement Disorders
Society, and Sigma Xi
Disclosure: Avanir Pharmaceuticals Consulting fee Consulting
Kendra Becker, MD, MPH Sleep Medicine Department, Kaiser Permanente Fontana Medical Center
Kendra Becker, MD, MPH is a member of the following medical societies: American Academy of Sleep Medicine, American
College of Physicians, and American Medical Association
Jose E Cavazos, MD, PhD, FAAN Associate Professor with Tenure, Departments of Neurology, Pharmacology, and
Physiology, Program Director of the Clinical Neurophysiology Fellowship, University of Texas School of Medicine at San
Antonio; Co-Director, South Texas Comprehensive Epilepsy Center, University Hospital System; Director of the San Antonio
Veterans Affairs Epilepsy Center of Excellence and Neurodiagnostic Centers, Audie L Murphy Veterans Affairs Medical
Center
Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology,
American Clinical Neurophysiology Society, American Epilepsy Society, and American Neurological Association
Disclosure: GXC Global, Inc. Intellectual property rights Medical Director - company is to develop a seizure detecting device.
No conflict with any of the Medscape Reference articles that I wrote or edited.
Zab Mosenifar, MD Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease
Institute, Professor and Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center, University of California,
Los Angeles, David Geffen School of Medicine
Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College
of Physicians, American Federation for Medical Research, and American Thoracic Society
Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University School of Medicine; Consulting
Staff, Pulmonary Disease and Critical Care Medicine Service, Henry Ford Health System
Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians and
American Thoracic Society
James A Rowley, MD Professor, Fellowship Program Director, Department of Medicine, Division of Pulmonary, Critical Care
and Sleep Medicine, Wayne State University School of Medicine
James A Rowley, MD is a member of the following medical societies: American Academy of Sleep Medicine, American
College of Chest Physicians, American College of Physicians, and American Thoracic Society
Silverio M Santiago, MD Clinical Professor of Medicine, University of California at Los Angeles School of Medicine; Chief,
Department of Pulmonary and Critical Care Medicine, Medical Director, Sleep Disorders Center, Veterans Affairs Medical
Center of West Los Angeles
Silverio M Santiago, MD is a member of the following medical societies: American Academy of Sleep Medicine, American
College of Chest Physicians, and American Thoracic Society
Ron A Shatzmiller, MD, MSc Assistant Clinical Professor, Department of Neurology, Keck School of Medicine of the
University of Southern California; Specialty Lead Physician, Healthcare Partners Medical Group, Arcadia, California
Ron A Shatzmiller, MD, MSc is a member of the following medical societies: American Academy of Neurology and American
Academy of Sleep Medicine
Peter Smethurst, MD Attending Physician, Pulmonary, Critical Care and Sleep Medicine, St Joseph's Medical Center
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy;
Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Gregory Tino, MD Director of Pulmonary Outpatient Practices, Associate Professor, Department of Medicine, Division of
Pulmonary, Allergy, and Critical Care, University of Pennsylvania Medical Center and Hospital
Gregory Tino, MD is a member of the following medical societies: American College of Chest Physicians, American College
of Physicians, and American Thoracic Society
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08/03/2024, 15:43 emedicine.medscape.

Signs and symptoms

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

A careful sleep history should be obtained, addressing the following:

Patient’s sleep habits (commonly referred to as sleep hygiene)

Presence or absence of symptoms of sleep disorders associated with insomnia

A thorough medical history should be obtained, including a review of systems.

A family history should be obtained, with particular attention to the following:

A social history should be obtained, addressing the following:

Transient or short-term insomnia: Recent situational stresses

Chronic insomnia: Past stresses or medical illnesses

Use of tobacco, caffeinated products, alcohol, and illegal drugs

Certain antidepressants (eg, protriptyline, fluoxetine)

Over-the-counter and herbal remedies

History suggestive of sleep apnea: Careful head and neck examination

See Clinical Presentation for more detail.

Studies for hypoxemia

Polysomnography and daytime multiple sleep latency testing (MSLT)

Genetic testing (eg, for FFI)

Brain imaging (eg, to assist in the diagnosis of FFI[2] )

See Workup for more detail.

The AASM guidelines list two primary treatment goals, as follows:[1, 3]

To improve sleep quality

To improve related daytime impairments

The components of CBT include the following:

Sleep hygiene education

Short- and intermediate-acting benzodiazepines (eg, triazolam, temazepam, estazolam)

Avoid using for more than 2-4 weeks if possible

Counsel patients to allow for at least 8 hours of sleep

Never use hypnotics with alcohol

Avoid using in pregnant patients

Avoid using benzodiazepines in patients with known or possible sleep apnea

Use lower doses in elderly patients

Other pharmacological therapies use for insomnia include the following:

Tricyclic antidepressants (ie, amitriptyline, nortriptyline)

Heterocyclics (ie, doxepin, trazodone)

Other antidepressants (ie, mirtazapine)

Melatonin agonist (ramelteon)

Orexin antagonists (eg, daridorexant, lemborexant, suvorexant)

Other measures that may be helpful include the following:

Exercise (at least 6 hours before bedtime)

See Treatment and Medication for more detail.

Classification (DSM-5 and ICSD-3)

Difficulty initiating sleep

Early-morning awakening with inability to return to sleep

Other criteria include the following:

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

Acute and chronic insomnia

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 homeostatic and circadian processes

Melatonin and the circadian process

The flip-flop switch model

Mechanisms of action of insomnia medication

Benzodiazepines and benzodiazepine receptor agonists

GABAA receptor subunit function(s).

Melatonin and melatonin receptor agonists