Insomnia

Author: Jasvinder Chawla, MD, MBA; Chief Editor: Selim R Benbadis, MD

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.

Essential update: FDA approves dosing changes for zolpidem products

In a follow-up to its January 2013 update, the FDA announced approval for label changes
specifying new dosing for products containing zolpidem (Ambien, Ambien CR, and Edluar),
because of the known risk for next-morning impairment with these drugs.[1]

The FDA now recommends that the initial dose of 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.

Signs and symptoms

The 2008 American Academy of Sleep Medicine (AASM) guideline consensus is that, at a
minimum, patients with insomnia should complete the following evaluations[2] :

 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
 Stimulants
 Over-the-counter and herbal remedies

Physical examination may offer clues to underlying medical disorders predisposing to

insomnia.[2] 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[3] )
See Workup for more detail.

Management

The 2008 AASM guidelines list 2 primary treatment goals, as follows[2] :

 To improve sleep quality

 To improve related daytime impairments

The AASM guidelines recommend including at least 1 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.[2, 4, 5, 6]

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 commonly 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

Sedating antidepressants used in the treatment of insomnia include the following:

 Amitriptyline
 Nortriptyline
 Doxepin
 Mirtazapine
 Trazodone

Other measures that may be helpful include the following:

 Acupressure
 Dietary modification
 Exercise (at least 6 hours before bedtime)

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.[7] 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.[8]

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.[9] 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.[10] 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.[2]

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.[7] 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.[11] 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.[12]

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.[13]

In 2005, the National Institutes of Health held a State of the Science Conference on the
Manifestations of Chronic Insomnia in Adults.[14] 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)[15, 16] and a short course of a sedative-hypnotic
or melatonin receptor agonist (see Treatment).

Primary insomnia is a diagnosis of exclusion. Thus, the differential diagnosis of primary

insomnia requires ruling out several other conditions, including medical, psychiatric, or
circadian-rhythm disorders (eg, delayed sleep-phase syndrome) or other sleep-related disorders,
such as periodic limb movement disorder or restless-legs syndrome. The treatment of primary
insomnia begins with education about the sleep problem and appropriate sleep hygiene measures.
CBT is now considered the most appropriate treatment for patients with primary insomnia.[4, 5, 6]

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 forebrainThe 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.[17] 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.[18] 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.[19]

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.[20]

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.[21, 22] (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 GABA A 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 GABA A 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.[23]

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.[23]

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.[24] The evidence supporting this theory is that compared with persons who have normal
sleep, persons with insomnia have the following[25] :

 Higher rates of depression and anxiety

 Higher scores on scales of arousal
 Longer daytime sleep latency
 Increased 24-hour metabolic rates[26]
 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.[27]

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.[28, 29] 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.[30] 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.[31]

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.[32] 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. [33]
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.[34] 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.[35, 36, 37]

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.[38]

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.[39]

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.[40] 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.[41] 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)[42] 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[43] :

 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[43] :

 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 4th Edition, Text Revision
(DSM-IV-TR). The insomnia must be temporally associated with the mental disorder; however,
in some cases, insomnia may appear a few days or weeks before the emergence of the underlying
mental disorder.

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

Insomnia due to drug/substance abuse

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

 The patient has current, ongoing dependence on or abuse of a drug or substance known to
have sleep-disruptive properties either during periods of use or intoxication or during
periods of withdrawal
 The patient has current ongoing use of or exposure to a medication, food, or toxin known
to have sleep-disruptive properties in susceptible individuals

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

Insomnia not due to substance or known physiologic condition, unspecified

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

Inadequate sleep hygiene

Inadequate sleep hygiene practices are evident by the presence of at least 1 of the following:

 Improper sleep scheduling consisting of frequent daytime napping, selecting highly

variable bed or rising times, or spending excessive amounts of time in bed
 Routine use of products containing alcohol, nicotine, or caffeine, especially in the period
preceding bedtime
 Engagement in mentally stimulating, physically activating, or emotionally upsetting
activities too close to bedtime
 Frequent use of the bed for activities other than sleep (eg, television watching, reading,
studying, snacking, thinking, planning)
 Failure to maintain a comfortable sleeping environment

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

Idiopathic insomnia

This sleep disturbance is a long-standing complaint of insomnia, with insidious onset in infancy
or childhood. No precipitant or cause is identifiable. The course is persistent, with no sustained
periods of remission. This condition is present in 0.7% of adolescents and 1% of very young
adults.[44]

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.[45]

In an epidemiologic study from Quebec, 29.9% of 2001 respondents reported insomnia

symptoms, and 9.5% met criteria for insomnia syndrome.[46] 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%.[47] 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.[48] Epidemiologic data
indicate that 40% of women between the ages of 40 and 55 years report recent sleep difficulty
resembling insomnia.[49]

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.[50] 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.[51]

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.[52]

Prognosis

Treatment of insomnia can improve these patients’ perceived health, function, and quality of
life.[53] 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.[54]
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.[55] Other studies, however, indicate an association
between short sleep or sleep restriction and hypertension.[56, 57]

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.[58] 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.[59]

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.[60]

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.[41] 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.[41] 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.[61]

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.[62] 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
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[2] :

 A general medical and psychiatric questionnaire to detect comorbid disorders

 A sleepiness assessment, such as the Epworth Sleepiness Scale
 A 2-week sleep log to define sleep-wake patterns and their variability

Sleep history

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

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

 Is the difficulty with falling asleep, frequent awakenings, or early morning awakening?
 If the problem is at sleep onset, are you sleepy when you get into bed?

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

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

 Do you go to bed and get up at the same times every day? How about during off days?
 Has this schedule changed recently?

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

 What are the temperature, bed comfort, and noise and light levels?
 Do you sleep better in a chair or when away from home (eg, hotel) than in your own bed?

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

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

 Do you read or watch television in bed?
 Is the television or a light kept on during the night?
 What do you do if you cannot fall asleep?
 If you wake up in the middle of the night, do you fall back to sleep easily? If not, what do
you do?
 Do you take daytime naps?
 Do you exercise? If so, at what time?
Ask patients about symptoms of other sleep disorders, such as obstructive sleep apnea (eg,
snoring, witnessed apneas, gasping) and restless legs syndrome/periodic limb movement disorder
(eg, restless feeling in legs on lying down, which improves with movement; rhythmic kicking
during the night; sheets in disarray in the morning).

Ask about daytime effects, which should be present if the patient is truly not sleeping at night. In
fact, a patient who has no daytime effects is probably getting adequate sleep and may have sleep-
state misperception insomnia (sometimes called paradoxical insomnia). This rare condition,
which appears to constitute less than 5% of insomnia cases, is defined by a marked discrepancy
between the subjective complaint of insomnia and the objective polysomnographic findings.[7]

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.

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.

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.[2]

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.

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)

Approach Considerations
The 2008 American Association of Sleep Medicine (AASM) guideline states that the 2 primary
goals of treatment are to improve sleep quality and to improve related daytime impairments. [2]
Strategies for achieving these goals will vary depending on the underlying etiology. If the patient
has a medical, neurologic, or sleep disorder, treat the disorder. In particular, adequate pain
control can greatly relieve the insomnia associated with pain syndromes.

The AASM 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.[2]

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.[65, 66, 67] 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[15] and a short course of a sedative-hypnotic or melatonin receptor agonist. In the case of a
psychiatric disorder (eg, depression[68] 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.[2]

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.[69] 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.[70] 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.[71] An
Internet-based CBT learning program for patients is also available for a nominal cost (see
CBTforINSOMNIA.com).

The components of CBT include the following:

 Sleep hygiene education

 Cognitive therapy
 Relaxation therapy
 Stimulus-control therapy
 Sleep-restriction therapy

CBT for insomnia (CBT-I) is a term for the combination of cognitive therapy and behavioral
therapy, such as stimulus-control therapy or sleep-restriction therapy (with or without relaxation
therapy).[2]

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.[2]

Sleep hygiene education

Sleep hygiene education addresses behaviors that are incompatible with sleep. These include
caffeine or alcohol use, environmental noise, inappropriate room temperature, and watching TV
in bed. The 2008 AASM guideline recommends adherence to sleep hygiene rules for all patients
with chronic insomnia but finds insufficient evidence of effectiveness when following these
sleep hygiene rules as monotherapy and, thus, advises its use as adjunctive therapy.[2]

Cognitive therapy and relaxation therapy

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

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

Stimulus-control therapy

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

 Use the bed only for sleeping and sexual activity (no reading, TV, eating, or working in
bed)
 Go to bed only when sleepy
 If unable to fall asleep in 15-20 minutes, get out of bed to do something relaxing until
sleepy; this can be repeated as often as needed
 Do not spend more time in bed than is needed by establishing a standard wake-up time
 Refrain from daytime napping

Sleep-restriction therapy

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

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

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

Several randomized trials comparing CBT against hypnotics for primary insomnia have been
published. Morin and colleagues compared temazepam with CBT in older patients and found
similar short-term effects, but there was continued efficacy after discontinuation of therapy in the
CBT group only. A study by Jacobs et al comparing zolpidem with CBT showed continued
efficacy for the patients treated with CBT.[66]

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.[72] 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.[73]

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.[73]

Pharmacologic Treatment of Insomnia

The pharmacologic treatment of insomnia has made great advances in the last 2 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.

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.[74, 75] Another study demonstrated continued efficacy at 12 months.[76]

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.[77] 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.[78, 79] 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 a 5-mg dose for women for immediate-release
products (Ambien, Edluar, and ZolpiMist) and 6.25 mg for extended-release products (Ambien
CR); the recommendations also urge prescribers to consider lower doses in men.[79]

Eszopiclone has a half-life of 5-7 hours and can be used for sleep-maintenance insomnia. It can
be started at a dose of 2 or 3 mg at bedtime or 1 mg in elderly or debilitated patients.

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.[2] Long-term administration of hypnotics may be
intermittent, as needed, or nightly.[2] If possible, during long-term therapy, patients should
receive an adequate trial of CBT.[2]

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[80, 81] )
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.[82] 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 2008 AASM guideline states that these
measures are aided by concurrent CBT for insomnia (CBT-I).[2]

Ramelteon

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

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

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

This medication is suited for patients with sleep-onset insomnia, particularly for elderly patients
with gait disorders who have an increased risk of falls and in patients with a history of substance
abuse. The typical starting dose is 8 mg before bedtime. Ramelteon is not effective for sleep-
maintenance insomnia.

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.[86] .

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.[87]

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.[88]

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.[2]

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.[17] Most of the data,
however, seem to suggest that melatonin taken before bedtime decreases sleep latency, may
increase total sleep time,[89, 90] 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.[2]

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.[91]

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.[92]

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. [93]
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.[94]

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.[95]

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.[96] For these reasons, the 2008 AASM
guideline states that valerian and other alternative or herbal medications are not recommended
for treatment of chronic insomnia.[2]

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.[97]

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.[98]

However, aging should not be assumed to be the explanation for insomnia.[99] 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.[100]

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.[2] 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.[101]

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.

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.[2]
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.

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.

Eszopiclone is indicated for insomnia to decrease sleep latency and improve sleep maintenance.
It has a short half-life (6 hours). Higher doses (ie, 2 mg for elderly adults and 3 mg for
nonelderly adults) are more effective for sleep maintenance, whereas lower doses (ie, 1 mg for
elderly adults and 2 mg for nonelderly adults) are suitable for difficulty in falling asleep.

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.