eMedicine Specialties > Neurology > Sleep-Related Diseases

Insomnia

Erasmo A Passaro, MD, Director, Comprehensive Epilepsy Program/Clinical Neurophysiology Lab, Bayfront Medical Center Florida Center for Neurology

Updated: Aug 3, 2009

Introduction

Background

Insomnia is defined as repeated difficulty with the initiation, duration, maintenance, or quality of sleep that occurs despite adequate time and opportunity for sleep that results in some form of daytime impairment. Approximately one third of adults report some difficulty falling asleep and/or staying asleep during the past 12 months, with 17% reporting this problem as a significant one. Insomnia can be acute or chronic. Acute adjustment insomnia occurs in the context of an identifiable stressor (eg, personal loss, change in interpersonal relationships, bereavement, occupational stress, job loss) that acts as a precipitating factor. It typically lasts 3 months or less, and resolves as the stressor is no longer present or as the individual adapts to the stressor. The 1-year prevalence of adjustment insomnia in adults is approximately 10-15%.

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 physiological state of hyperarousal (see Pathophysiology). In fact, despite not getting adequate sleep, patients with insomnia oftentimes have difficulty falling asleep even during daytime naps.

Chronic insomnia also has numerous health consequences. For example, patients with chronic insomnia report reduced quality of life comparable to other conditions such as diabetes, arthritis, and heart disease. Quality of life improves with treatment but still does not reach the level seen in the general population. In addition, chronic insomnia is associated with impaired occupational and social performance and an elevated absenteeism rate that is 10-fold greater than controls. Furthermore, insomnia is associated with higher healthcare use, including a 2-fold increase in hospitalizations and office visits.

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 at $12 billion dollars for healthcare and $2 billion dollars for sleep promoting agents.

In 2005, the National Institutes of Health held a State of the Science Conference on the Manifestations of Chronic Insomnia in Adults. This conference focused on the definition, classification, etiology, prevalence, risk factors, consequences, comorbidities, public health consequences and the available treatments and evidence for their efficacy. A summary of this conference can be obtained at the NIH Consensus Development Program home page. Prior to this conference, most cases of chronic insomnia were widely believed to be secondary to another medical or psychiatric condition and effective treatment of the primary condition was believed to effectively address secondary insomnia. However, at this 2005 conference, based on the review of the literature and the panel experts, the following was concluded:

Most causes of insomnia are co-morbid with other conditions. Historically, this has been termed secondary insomnia. However, the limited understanding of the mechanistic pathways precludes drawing firm conclusions about the nature of these associations or directions of causality. Furthermore, there is concern that the term secondary insomnia may promote under treatment. Therefore, we propose the term comorbid insomnia.

Pathophysiology

In the late 1980s, Spielman created a model of insomnia in terms of predisposing, precipitating, and perpetuating factors.
 
Predisposing factors

Genetic and neurobiologic factors likely determine a person’s risk of developing insomnia in the context of a precipitating factor (psychosocial, medical, or psychiatric). Many of these have not been identified. Sleep and wakefulness is an active, tightly regulated process that may differ between individuals who have different susceptibilities to exogenous influences. 

Recent 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. The ADORA2A 1083T>C genotype determined how closely the caffeine-induced changes in brain electrical activity (increased beta activity) during sleep resembled the alterations observed in patients with insomnia. 

In addition, circadian clock genes (Clock, Per2) have been identified that regulate the circadian rhythm. For example, a mutation or functional polymorphism in the clock gene (Per2) can lead to circadian rhythm disorders such as advance sleep phase syndrome (sleep and morning awakening occur earlier than normal), and delayed sleep phase syndrome (sleep and morning awakening are delayed). Furthermore, a study examining the association between Clock gene polymorphisms and insomnia revealed a higher recurrence of initial, middle, and terminal insomnia in patients homozygous for the Clock genotype. 

A missense mutation has been found in the gene encoding the GABA_A beta 3 subunit in a patient with chronic insomnia. 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 5-HT2 receptor promotes slow wave sleep. Therefore, preliminary basic science evidence indicates a possible genetic predisposition to hyperarousal and insomnia.

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 NREM sleep, an EEG sign of hyperarousal, and evidence of reduced deactivation in key sleep/wake regions during NREM sleep when compared with controls. Furthermore, patients with insomnia have higher day and night body temperatures, urinary cortisol and adrenaline secretion, and ACTH than patients with normal sleep. A study of normal sleepers demonstrated that these changes were not due to sleep deprivation. Only a fraction of patients with medical and psychiatric conditions develop insomnia, which suggests that some patients have an inherent susceptibility (whether psychosocial, medical, or psychiatric) to develop insomnia in the context of a stressful event.

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. These factors include depression, anxiety, sleep-wake schedule changes, medications, other sleep disorders, and medical conditions. In addition, positive or negative family, work-related, and health events are common insomnia precipitants.

Perpetuating factors
 
Insomnia, regardless of how it is triggered, is generally accepted to be perpetuated by cognitive and behavioral mechanisms. Cognitive mechanisms include misconceptions about normal sleep requirements and excessive worry about the ramifications of the daytime effects of inadequate sleep. As a result, these 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 late, which in turn reduces their 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 the 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. Thus, conditioned environmental cues causing insomnia develop from the continued association of sleeplessness with situations and behaviors that are typically related to sleep.

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.

Overview of mechanisms of normal sleep and wakefulness

A basic understanding of mechanisms of sleep and wakefulness is essential to understanding potential mechanisms of insomnia and how insomnia medications affect these pathways to promote sleep.

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.

Sleep-wake cycle.

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 increases between 8 and 10 am and peaks between 2 and 4 am, then declines gradually over the morning. Melatonin acts via specific melatonin receptors MT1 which attenuates the alerting signal and MT2 which phase shifts the SCN clock. The novel sleep-promoting drug ramelteon acts specifically at the MT1 and MT2 receptors to promote sleep.

Brain areas critical for wakefulness include the tuberomammillary nucleus (TMN) in the posterior hypothalamus that contains histamine neurons, which project stimulatory inputs to brainstem arousal centers such as the locus coeruleus (LC) (norepinephrine), the dorsal raphe nuclei (DRN) (serotonin), the ventral tegmental area (VTA) (dopamine), and the basal forebrain (acetylcholine), which project diffusely to cortical areas to promote arousal.

The TMN also inhibits sleep-promoting areas, such as the anterior hypothalamus. Similarly, the brainstem arousal regions inhibit sleep-promoting regions in the anterior hypothalamus. Adenosine, a neurotransmitter, accumulates in the brain during prolonged wakefulness and inhibits wake-promoting regions in the posterior hypothalamus and the basal forebrain. Acetylcholine in the basal forebrain also projects diffusely to cortical areas and the TMN to promote wakefulness.

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

The anterior hypothalamus, which includes the ventrolateral preoptic nucleus (VLPO) contains GABA and the peptide galanin, which are inhibitory and promote sleep. They project to the TMN and the brainstem arousal regions to inhibit wakefulness. GABA is the predominant inhibitory neurotransmitter in the central nervous system.

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

Saper and colleagues proposed the flip-flop switch model of sleep-wake regulation.¹ 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.

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.² For example, patients with narcolepsy with cataplexy have a greater than 90% loss of hypocretin neurons, and they have sleep-wake state instability with bouts of NREM/REM sleep intruding into wakefulness.

Benzodiazepine receptor agonists (BZRAs) and nonbenzodiazepine receptor agonists (NBZRAs), for example, work through GABA_A 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 (see Medication for further information about BZRAs and NBZRAs).

In summary, sleep and wakefulness is a tightly regulated process with reciprocal connections that produce consolidated periods of wakefulness and sleep that are entrained by environmental light to occur at specific times of the 24-hour cycle.

Frequency

United States

In a 1991 survey, 30-35% of American adults 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 physician specifically to discuss their insomnia. Only 26% discussed their insomnia during a visit made for another problem.

International

A study from Quebec indicated an overall prevalence of insomnia of approximately 20% of French Canadians. A study of young adults in Switzerland indicated a 9% prevalence of chronic insomnia. A World Health Organization (WHO) study conducted in 15 centers found a prevalence of approximately 27% for the complaint "difficulty sleeping."

Mortality/Morbidity

Consequences of chronic insomnia 

• Patients with insomnia report decreased quality of life compared with normal controls in all dimension of the SF-36.
• Patients with insomnia report excessive fatigue as measure by the Fatigue Severity Scale and the Profiles of Mood Status (POMS).
• Patients with insomnia are more than twice as likely as the general population to have a fatigue-related motor vehicle accident.
• Increased occupational dysfunction and decreased work performance are likely due to chronic hyperarousal state or perceptions of sleep deprivation rather than actual sleep loss from insomnia. For example, unlike patients with chronic sleep deprivation from other causes, patients with insomnia report less excessive daytime sleepiness and less psychomotor and cognitive impairment.
• Knutson et al found that the quantity and quality of sleep correlate with future blood pressure. In an ancillary 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 (P<0.05).³

Associations of insomnia with depression and anxiety

One of the early descriptions of an association between insomnia and depression and anxiety was by Ford and Kamerow.⁴  What is still unknown is the nature of the association. For example, does insomnia presage the development of an incipient mood disorder and/or do mood disorders independently predispose to insomnia.

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 who did not have insomnia.

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.⁵

In contrast, insomnia symptoms were reported to occur before a 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.

Race

At this time, no data are available to suggest an association for or against race as a risk factor for insomnia.

Sex

The prevalence of chronic insomnia is 1.2-2.0 times greater in women than men. One study by Strine and colleagues indicated that women who have menstrual-related problems are more likely to have insomnia as compared with women without such problems.⁶ 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 than women without such problems. At this time, whether social factors or neurobiologic factors contribute to the increased prevalence in women is not known.

Age

Chronic insomnia increases in frequency with age and is more common in the elderly. This is presumed due to greater psychosocial stressors, losses, and medical illnesses. Recent epidemiologic data indicate that the prevalence of chronic insomnia increases form 25% in the adult population to 50% in the elderly population.

Clinical

History

The history is the most important part of evaluating insomnia. It must include a complete sleep history, medical history, psychiatric history, social history, and careful medication review.

Sleep history

Determining the timing of insomnia, the patient's sleep habits (commonly referred to as sleep hygiene), and symptoms of sleep disorders associated with insomnia is important.

• Timing of insomnia: Patients should be asked about any difficulty falling asleep, frequent or early morning awakening, problems in sleep onset, and whether they feel sleepy when getting into bed.
• Sleep schedule: Patients must be asked what time they go to bed and rise from bed in the morning. Determine whether the sleep schedule is consistent and if the schedule has changed recently.
• Sleep environment: Patients should be asked about temperature, bed comfort, noise, and light levels. Ask whether the patient sleeps better in his or her own bed or in a chair or a foreign environment (like a hotel).
• Sleep habits: Patients with insomnia often have poor sleep hygiene. They should be asked about activities prior to bedtime (ie, relaxation or work), whether they read or watch TV in bed, and whether the TV or light is kept on during the night. Also, ask patients what they do if unable to fall asleep and whether they fall asleep after waking up in the middle of the night. Ask patients about daytime naps and whether they exercise and the time of exercise.
• Patients should be asked about symptoms of other sleep disorders such as obstructive sleep apnea (eg, snoring, witnessed apneas, gasping) and restless legs syndrome/periodic limb movement disorder (ie, restless feeling in legs on lying down, which improves with movement; rhythmic kicking during the night; sheets in disarray in the morning).
• Daytime effects: Patients should experience daytime effects if they truly are not sleeping at night. In fact, if a patient is having no daytime effects, he or she is probably getting adequate sleep and the complaint of insomnia is truly subjective. Common complaints are fatigue, tiredness, lack of energy, irritability, reduced work performance, and difficulty concentrating. These complaints should be distinguished from the complaint of excessive sleepiness, which is uncommon in insomnia. For example, if a patient complains of excessive daytime sleepiness (ie Epworth Sleepiness Scale Score >10), another sleep disorder should also be considered. (See Media file 12 for the Epworth Sleepiness Scale.)

Medical history

A thorough medical history and review of systems should be performed, with particular emphasis on those disorders mentioned in Causes.

Psychiatric history

A review of signs and symptoms of anxiety or depression should be sought. A 2-question case-finding instrument can help screen for depression.

Diagnostic algorithm for major depression.

Diagnostic criteria for generalized anxiety disorder.

Social history

For transient or short-term insomnia, inquire about new 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 tobacco, caffeinated products, alcohol, and illegal drug use.

Medication history

Medications that commonly cause insomnia include beta-blockers, clonidine, theophylline (acutely), certain antidepressants (protriptyline or fluoxetine), decongestants, and stimulants. Also inquire about over-the-counter and herbal remedies that the patient may be taking.

Physical

The physical examination can provide clues to comorbid insomnia.

• A large neck size of 18 inches or greater in males, elevated BMI of 30 kg/m², enlarged tonsils, Mallampati airway score of 3 or 4 (see Media file 2), low lying soft palate particularly in patients with hypertension or cardiac disease, and obstructive sleep apnea/hypopnea syndrome should be considered. Other features include enlarged tongue, retrognathia, micrognathia, or a steep mandibular angle.
• If patients have evidence of peripheral neuropathy (ie, stocking distribution loss of temperature sensation) with or without trophic changes, they should be asked about painful symptoms (ie, burning sensation) in their feet, and history of diabetes, alcohol abuse, and neurologic consultation should be requested.
• If patients complain of symptoms of restless legs syndrome or symptoms suggestive of a neurologic disorder, such as nocturnal seizures, Parkinson disease, or a neuromuscular disorder, a neurologic consultation should be requested.
• In patients with chronic pain syndromes or rheumatologic syndromes, referral to a pain management specialist and/or rheumatologist should be considered.
• If chest examination shows reduced breath sounds; clubbing or wheezing in the setting of clinical signs; and symptoms suggestive of chronic obstructive pulmonary disease, asthma, or obesity hypoventilation syndrome, pulmonary consultation should be requested.

Causes

Many clinicians often assume that insomnia is secondary to a psychiatric disorder, However, a large epidemiologic survey showed that half of insomnia diagnoses were not related to a primary psychiatric disorder. As mentioned earlier, an insomnia diagnosis does increase the future risk for depression or anxiety (see Morbidity).

Frequency of insomnia causes.

Classification of Insomnia

1. Repeated difficulty with the initiation, duration, maintenance, or quality of sleep that occurs despite adequate time and opportunity for sleep that results in some form of daytime impairment.
2. Number 1 must be present for at least 1 month.

Psychophysiologic insomnia (primary insomnia)

• The patient has 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 either by 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.

• 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 show an average sleep time often with no sleep at all indicated for several nights each week; typically daytime naps are absent following such nights.
  • The patients typically show a mismatch between objective findings from polysomnography or actigraphy and subjective sleep estimates from 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.

• The patient has a coexisting medical condition known to disrupt sleep.
• The insomnia is clearly associated with the medical condition. The insomnia began near the time of onset or with significant progression of the medical condition and waxes and wanes with the severity of this condition.
• The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance abuse disorder.

Insomnia due to mental disorder

• A mental disorder has been diagnosed according to the criteria of DSM-IV-TR.
• The insomnia is 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 or substance abuse

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

Insomnia not due to substance or known physiological condition, unspecified

This diagnosis is used for forms of insomnia that cannot be classified elsewhere in ICSD-2, but are suspected to be due to 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

A longstanding complaint of insomnia with insidious onset in infancy or childhood. No precipitant or cause is identifiable. There is a persistent course with no sustained periods of remission. This condition is present in 0.7% of adolescents and 1% of very young adults.

Behavioral insomnia of childhood

• A child's symptoms meet the criteria for insomnia based on parents or other adult caregivers observations.
• The child shows a pattern consistent with either sleep-onset association or limit-setting type of insomnia:
  • Sleep onset association type
    • 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.
    • Nightime awakenings require caregiver intervention for the child to return to sleep.
  • Limit-setting type
    • The individual has difficulty initiating or maintaining sleep.
    • The individual 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

• 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.
  • The urge to move or the unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting.
  • The urge to move or the unpleasant sensations are partially or totally relieved by moving, such as walking or stretching, at least as long as the activity continues.
  • The urge to move or the unpleasant sensations are worse or only occur in the evening or the night.
• Obstructive sleep apnea/hypopnea syndrome:A minority of patients complain of insomnia rather than hypersomnolence. They frequently complain of multiple awakenings or sleep-maintenance difficulties. They may also have nocturia causing frequent nocturnal awakenings.
• Circadian rhythm disorders
  • Advanced sleep phase syndrome: The patient feels sleepy earlier than their desired bedtime (ie, 8 pm) and they wake up earlier than they would like to (ie, 4-5 am). This condition is more common in the elderly. These patients typically complain of sleep maintenance insomnia.
  • Delayed sleep phase syndrome: The patient does not feel sleepy until much later than the desired bedtime, and he or she wakes 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. This condition 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 the school or work week.
  • Shift work sleep disorder: A complaint of insomnia or excessive sleepiness is typically temporally related to a recurring work schedule that overlaps the usual sleep time. This can occur with early morning shifts (4-6 am), where the patient is 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 in that the patient may need some time to wind down from work before retiring to bed. Night shift can be associated with both sleep onset and maintenance insomnia due to exposure to sunlight on their drive home from work, daylight exposure in their bedroom, and social and environmental cues (picking up children at school, paying bills, household chores, etc).
  • Irregular sleep-wake rhythm: This is typically seen in patients with poor sleep hygiene, patients who live or work alone with minimal exposure to light, activity, and social cues. 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.

Differential Diagnoses

Other Problems to Be Considered

Medications associated with insomnia are as follows:

Central nervous system stimulants
Dextroamphetamine
Methylphenidate

Antihypertensives
Alpha-antagonists
Beta-antagonists

Respiratory medications
Albuterol
Theophylline

Decongestants
Phenylephrine
Pseudoephedrine

Hormones
Corticosteroids
Thyroid medications

Anti-epileptic medications
Lamotrigine

Other noncontrolled substances
Caffeine
Alcohol
Nicotine

Workup

Laboratory Studies

• Patients with a history suggestive of sleep apnea or restless legs syndrome (RLS)/periodic limb movement disorder (PLMD) should be referred to a sleep center for polysomnography.
• Patients with a history suggestive of COPD and insomnia should have an arterial blood gases (ABG) study performed to determine if they are hypoxemic.
  • Insomnia in chronic obstructive pulmonary disease (COPD) frequently begins with the development of nocturnal hypoxemia (though nocturnal, hypoxemia is not required for insomnia to occur).
  • Treatment with oxygen may improve but rarely eliminates the insomnia.
  • Nocturnal hypoxemia is present if the patient has daytime hypoxemia or, frequently, exercise-related hypoxemia.
  • If the ABG result is negative for hypoxemia, an exercise desaturation study or overnight oximetry may be helpful to determine if the patient needs oxygen.
• Neurologic testing may be indicated in patients with signs and symptoms of neurologic disease.

Other Tests

Actigraphy

Actigraphy uses a portable device worn around the wrist like a watch to record movement over extended periods, making it highly useful to study sleep patterns and circadian rhythms. Distinguishing primary insomnia from circadian rhythm disorders and identifying paradoxical insomnia is useful, particularly in those patients who are refractory to treatment. This study provides an indirect objective measure of sleep and wake time.

Sleep diary

Patients are asked to complete a daily diary for 2 weeks, estimating the time (1) that they go to bed, (2) fall asleep, (3) awaken during the night, (4) spend in bed awake, and (5) that they are out of bed in the morning. They also record time spent exercising, taking medications, and consuming caffeinated and alcoholic beverages. While the sleep diary provides detailed information about sleep patterns, it can be confounded by the patient's subjective assessment of when they fall asleep and awaken during the night. Click on the following image to download a sample sleep diary.

Sleep diary.

Treatment

Medical Care

Practical management of insomnia
 
Even when comorbid causes of insomnia (ie, medical, psychiatric) are treated, variable degrees of insomnia persist that require additional interventions.

• The management of insomnia depends upon its etiology. However, even comorbid insomnia can benefit from cognitive behavioral therapy and a short-term course of a sedative-hypnotic or melatonin receptor agonist.
  • If the patient has a comorbid medical, neurologic, or sleep disorder, treatment should be directed at that disorder.
  • In the case of a psychiatric disorder (eg, depression or anxiety), treatment should be directed at the disorder. This may involve medications, psychotherapy, and, if possible, referral to a psychiatrist, psychologist, or therapist. A short-term sedative-hypnotic in conjunction with an antidepressant can be beneficial.
  • If the insomnia is related to medication or drug abuse, the offending medication or drug must be slowly tapered and withdrawn.
• The treatment of primary insomnia begins with education about the sleep problem and appropriate sleep hygiene measures (elements of good sleep hygiene are described in Patient Education).
• Before instituting therapy, most patients are asked to maintain a sleep diary for 2-4 weeks (see Sleep diary). This gives the physician a clearer picture of the degree of sleep disturbance and allows him or her to better tailor the treatment.

Cognitive behavior therapy (CBT) 

CBT is a group of techniques that regardless of predisposing or precipitating factors is 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 and the consequences of insomnia. While CBT is most effective for primary insomnia, it can also be effective for comorbid insomnia as adjunctive therapy.

CBT consists of the following components:

• Sleep hygiene education addresses behaviors that are incompatible with sleep (eg, caffeine or alcohol use, environmental noise, room temperature, watching TV in bed) (see Patient Education).
• 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: 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 the patient with immediate feedback regarding his or her level of tension and rapidly teaching the patient how to relax.
• Stimulus control therapy: This 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 15-30 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: This is based upon the fact that excessive time in bed often perpetuates the insomnia. Limiting time 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 h) and increasing it by 20 minutes for a given week when the patient estimates that their 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 20 minutes for a given week when the SE is less than 85%. Periodic (weekly) adjustments are made until the optimal sleep duration is achieved.

Multiple, randomized, controlled trials have demonstrated the efficacy of CBT. Sleep latency, total sleep time, duration of wakefulness, and sleep quality improve compared with placebo treatment. 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 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.⁷ CBT has also been shown to be better in weaning patients from hypnotics compared with tapering medications alone. Most studies of CBT used trained psychologists to work with patients over an average of 5.7 sessions over 6.5 weeks. At this time, how practical or effective this treatment can be when administered by a healthcare provider is not known.

Preliminary evidence by Morin indicated that providing written information about CBT can be helpful.⁸ In summary, CBT should be an integral component of therapy for any patient with insomnia, whether it be primary insomnia or comorbid insomnia.

Surgical Care

No surgical intervention is warranted, unless the patient has another medical condition or sleep disorder contributing to insomnia that warrants surgical therapy.

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 when primary or associated with a sleep or psychiatric disorder, referral to an appropriate specialist may be indicated.

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

• If 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 if 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. Furthermore, patients with a history of substance abuse or another major psychiatric disorder should also be referred to a psychiatrist.

Diet

• 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 in patients with gastroesophageal reflux disease or delayed gastric emptying.

Activity

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.

Medication

Pharmacology of sedative-hypnotic medications

Gamma-aminobutyric acid (GABA) is the most widely distributed inhibitory neurotransmitter in the central nervous system (CNS). The GABA_A receptor consists of 5 protein subunits arranged in a ring around a central pore. Most GABA_A receptors consist of 2 alpha, 2 beta, and 1 gamma subunits. Upon GABA_A receptor activation, chloride ions flow into the cell, resulting in neuronal hyperpolarization. 

Benzodiazepine receptor agonists (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 receptors that is distinct from the GABA binding site and changes 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.

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

Synaptic GABA_A  receptors typically contain a γ in combination with an α₁, α₂, and α₃ subunit. Most GABA_A receptors expressed in the CNS are α₁ β₂ γ₂, α₂ β₃ γ₂, α₃ β₃ γ₂, α₅ β₃ γ_2. While GABA binds at the junction between subunits α and β, BZRAs bind at the interface between α and γ. The alpha subunits of the GABA_A receptor mediate sedative, amnestic, anxiolytic, myorelaxant, ataxic, and sedative effects. GABA_A 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 GABA_A receptors containing the α₁ subunit, thereby producing fewer adverse effects (ie, ataxia, anxiolytic, myorelaxation properties) than nonselective BZRAs.

GABA_A receptor subunit function(s).

Practical medical management of insomnia

The pharmacologic treatment of insomnia has made great advances in the last 2 decades. In the early 19^th century, alcohol and opioids were used as sleeping medications. In the late 19^th century, chloral hydrate and alcohol were used in combination “Mickey Finn,” and in the early 20^th century, barbiturates were used until the early 1960s when benzodiazepine receptor agonists (BZRAs) were first FDA-approved for the treatment of insomnia (flurazepam and quazepam).

Typically, BZRAs include long-acting forms (flurazepam and quazepam that are rarely used today for insomnia because of daytime sedation, cognitive impairment, and increased risk for falls in elderly patients); intermediate-acting forms (temazepam, estazolam) and short-acting (triazolam). BZRAs were commonly used until the 1980s, when concerns about 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, days to 1-2 w). 
 
Subsequently, in the 1990s, antidepressants were widely used for primary insomnia, and they continue to be widely used, despite the fact that no randomized controlled trials have demonstrated their efficacy in treating primary insomnia.

Sedative-hypnotic medications do not cure insomnia, but they can provide symptomatic relief as  sole therapy or as an adjunct with cognitive behavioral therapy (CBT). Furthermore, some patients cannot adhere or do not respond to CBT and are candidates for these agents, particularly NBRAs. The most appropriate use of BZRA drugs 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. However, recent studies have indicated that nonbenzodiazepine benzodiazepine receptor agonists (NBBRAs) have long-term efficacy for 6-12 months without the development of tolerance. Eszopiclone was the first sedative-hypnotic to be tested over a 6-month period.¹³ This study showed continued efficacy over the 6-month period. Recent evidence shows continued efficacy at 12 months.

More recently, Krystal et al showed long-term efficacy and safety of zolpidem-CR for 6 months in a double-blind, placebo-controlled trial.¹⁴  A multicenter, randomized, placebo-controlled trial of long-term (6 mo) eszopiclone showed improved quality of life, reduced work limitations and reduced global insomnia severity.¹⁵  In summary, eszopiclone and zolpidem are believed to be less habit forming than benzodiazepines and, therefore, represent important advances in the long-term treatment of chronic insomnia.
 
Zolpidem can be dosed at 5 or 10 mg at bedtime for sleep-onset insomnia, and zolpidem-controlled release at doses of 6.25 mg or 12.5 mg can be used for patients with sleep maintenance insomnia or patients with both sleep onset and maintenance insomnia. Eszopiclone has a half-life of 5-7 hours, and can be used for sleep-maintenance insomnia. It can be used starting with either a 2 mg or 3 mg dose at bedtime or a 1 mg starting dose in elderly or debilitated patients. Zaleplon has a very short half-life of 1 hour 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.

Intermediate-acting BZRAs, such as temazepam, are still sometimes used in a short course at a dose of 15-30 mg at bedtime.

Some general precautions should be followed for the use of sedative-hypnotics, as follows:

• Therapy should be instituted and maintained with the smallest effective dose.
• Nightly use should be discouraged in most patients.
• It can be used for 3-4 weeks, however, the need for long-term use needs to be assessed on a regular basis.
• A hypnotic free of residual effects in the morning is preferable (eg, zolpidem, zaleplon, triazolam, eszopiclone, ramelteon).
• Hypnotics with a rapid onset of action, such as zolpidem, zaleplon, triazolam, and eszopiclone, are preferable when the problem is falling asleep. If the problem is staying asleep, a hypnotic with longer actions, such as zolpidem-CR or eszopiclone, can be used. Alternatively, zaleplon can be used for sleep maintenance insomnia with a dose given at the time of awakening as long as the time for remaining sleep is at least 4 hours in duration. If the patient is depressed, an antidepressant with sedative properties, such as trazodone or mirtazapine, may be useful.
• Hypnotics should never be used with alcohol since this can produce excess sedation or the development of parasomnias.
• In general, pregnancy is a contraindication.
• Benzodiazepines should be used with caution in patients with mild sleep apnea and avoided in patients with known or suspected moderate to severe sleep apnea since they can worsen sleep apnea or render their usual continuous positive airway pressure (CPAP) settings less effective.
• Smaller doses should be used in elderly patients, and used very cautiously, if at all, in patients with gait disorders or a history of recurrent falls.
• In most patients, the risk of dependency is low (most rarely escalate the dose or use more frequently than prescribed). However, avoid use in patients with a history of substance abuse.
• Rebound insomnia may develop when the medication is withdrawn abruptly in some patients. This is more likely to occur with large doses,  short-acting agents, and long-term use. Using smaller doses and tapering the drug can avoid rebound insomnia.

Sedating antidepressants

Although there is a paucity of clinical data for the treatment of primary insomnia without mood disorders, sedating antidepressants are still sometimes used. Many clinicians believe that sedating antidepressants have fewer side effects that NBZRAs; however, this is not the case. Sedating tricyclic antidepressants, such as amitriptyline, nortriptyline, and doxepin and the tetracyclic drug mirtazapine have been used. Tricyclic drugs and mirtazapine can cause daytime sedation, weight gain, dry mouth, postural hypotension, and cardiac arrhythmias. Trazodone can cause priapism in men, daytime sedation, and hypotension.

Melatonin has become a popular over-the-counter 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 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.

However, 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. Therefore, at this time, most authorities do not recommend melatonin for the treatment of chronic insomnia.

Melatonin receptor agonists

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. This medication is suited for patients with sleep-onset insomnia, and particularly for elderly patients with gait disorders who have an increased fall risk and in patients with a history of substance abuse.

The typical starting dose is 8 mg prior to bedtime. It is effective for sleep-onset insomnia and not for sleep maintenance insomnia.

Common OTC remedies ¹⁶

First generation H1-receptor antagonists (eg, diphenhydramine, hydroxyzine, doxylamine) are not indicated for the treatment of insomnia. Antihistamines are the major ingredient of OTC sleep aids and are the ingredient in cold and sinus formulas sold as bedtime-use medications. While H1-receptor antagonists have sedative effects in healthy individuals, no study has established a dose range over which the hypnotic effect is effective in patients with insomnia. Thus, their regular use in individuals with insomnia is not advised. These agents may have some subjective benefit, but long-term efficacy has not been demonstrated and they are not recommended. 

Studies of melatonin can reduce sleep latency in patients with circadian rhythm disorders but have conflicting efficacy in primary insomnia. Herbal remedies, such as chamomile and St. Johns Wort, have also not shown efficacy for insomnia with the exception of valerian root where some evidence suggests some benefit. Furthermore, potential risks were associated with the use of some OTC remedies such as dogwood, kava kava, alcohol, and l-tryptophan.¹⁶

Sedative Hypnotics, Nonbenzodiazepine Receptor Agonists

These agents have a nonbenzodiazepine structure and bind more specifically to the alpha 1 subunit of the GABA _A receptor, which is associated with sedation. This class of drugs is called nonbenzodiazepine receptor agonists. They are excellent choices for treatment of sleep-onset insomnia.

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

Zaleplon (Sonata)

Sedative-hypnotic of pyrazolopyrimidine class; rapid onset of action with ultra-short duration of action; good choice for treatment of sleep-onset insomnia. Second dose can be used during middle of night without residual sedation in morning (believed to be an advantage of this hypnotic over others).

Dosing

Adult

10 mg PO hs; 5 mg PO hs in elderly adults

Pediatric

Not established

Interactions

Cimetidine significantly increases levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Failure of insomnia to remit after 7-10 d of treatment may indicate need for evaluation of primary psychiatric or medical illness; limit treatment to 7-10 d of use, and reevaluate patient if to be taken for >2-3 wk (do not prescribe in quantities exceeding 1-month supply); in hepatic function impairment, reduce dose to 5 mg PO hs; caution in patients exhibiting signs or symptoms of depression; headaches may occur if taking 20 mg hs

Zolpidem (Ambien, Ambien CR)

Sedative-hypnotic of imidazopyridine class; has rapid onset and duration of action; good first choice for treatment of sleep-onset insomnia; has no significant residual sedation in 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.

Dosing

Adult

10 mg PO hs; 5 mg PO hs in elderly adults
Extended-release: 12.5 mg PO hs
Extended-release in elderly patients: 6.25 mg PO hs

Pediatric

Not established

Interactions

Increases toxicity of alcohol and CNS depressants; effect may be delayed if taken with food or shortly after a meal

Contraindications

Documented hypersensitivity; lactation

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor elderly persons for impaired cognitive or motor performance; extended-release dosage form must be swallowed whole (do not divide, chew, or crush)

Eszopiclone (Lunesta)

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

Dosing

Adult

Nonelderly adults: 2 mg PO hs; may increase to 3 mg PO hs prn
Elderly adults: 1 mg PO hs initially; not to exceed 2 mg PO hs
Severe hepatic impairment: Not to exceed 2 mg PO hs

Pediatric

<18 years: Not established
>18 years: Administer as in adults

Interactions

CYP3A4 and CYP2E1 substrate; potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, nelfinavir) increases AUC, C_max, and t_1/2 and therefore potential toxicity (decrease dose); potent CYP3A4 inducers (eg, rifampicin) increase clearance; coadministration with alcohol or other CNS depressants may increase effect and toxicity (decrease dose); coadministration with olanzapine may decrease DSST scores; sleep onset may be delayed if taken with or immediately after a high-fat or heavy meal

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause dysgeusia, headache, or coldlike symptoms; rare adverse effects associated with hypnotics include short-term amnesia, confusion, agitation, hallucinations, worsened depression, or suicidal thoughts; high doses (ie, 6-12 mg) produce euphoric effects similar to those of diazepam 20 mg; anxiety, abnormal dreams, nausea, and upset stomach may occur within 48 h after discontinuing; alertness may be affected the following day, use caution while operating machinery or driving a car

Sedative hypnotic, short-acting benzodiazepine receptor agonists

Useful in sleep onset insomnia.

Triazolam (Halcion)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.

Dosing

Adult

0.125-0.25 mg PO hs
Elderly: 0.125 mg PO qhs

Pediatric

Not established

Interactions

Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; untreated obstructive sleep apnea; history of substance abuse

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution and close monitoring needed in hepatic dysfunction, low albumin levels, renal or pulmonary disease
Cause residual daytime sedation, impair cognition, and increase risk of falls especially in older people; caution with other CNS depressants

Sedative hypnotics, intermediate-acting benzodiazepine receptor agonists

These agents have been the hypnotics of choice for many years because of their relative safety compared with the barbiturates. By binding to specific subunits of GABA_A receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission by increasing the frequency of chloride channel opening. The older sedative hypnotics have prolonged half-life with an increased risk for next day sedation, daytime psychomotor impairment, and an increased risk for abuse and dependence.

Useful in sleep-onset insomnia.

Estazolam (ProSom)

Intermediate acting with slow onset of action and long duration; good agent for sleep-maintenance insomnia.

Dosing

Adult

1-2 mg PO hs; 0.5-1 mg PO hs in elderly persons

Pediatric

Not established

Interactions

Phenothiazines, barbiturates, alcohols, and MAOIs increase CNS toxicity

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; untreated obstructive sleep apnea; history of substance abuse

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients with depression; most common adverse effects include drowsiness, hypokinesia, dizziness, and abnormal coordination; may have more significant respiratory depressive effects than other agents in its class; caution and close monitoring needed in hepatic dysfunction, low albumin levels, renal or pulmonary disease; may cause residual daytime sedation, impair cognition, and increase risk of falls, especially in older people

Temazepam (Restoril)

Short to intermediate acting with longer latency to onset and half-life; may be more helpful in sleep-maintenance insomnia.

Dosing

Adult

15-30 mg PO hs; 7.5-15 mg PO hs in elderly persons

Pediatric

Not established

Interactions

Phenothiazines, barbiturates, alcohols, and MAOIs increase CNS toxicity

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; untreated obstructive sleep apnea; history of substance abuse; severe uncontrolled pain

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Use cautiously in patients with depression; adverse effects are generally mild and include drowsiness, headache, nervousness, and dizziness; caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity)

Tricyclic antidepressants

Drugs in this category are not FDA approved treatment of insomnia, and there have been no randomized placebo controlled trials demonstrating efficacy for insomnia.

Amitriptyline (Elavil)

Tricyclic antidepressant with sedative effects. Inhibits reuptake of serotonin and/or norepinephrine at presynaptic neuronal membrane, which increases concentration in CNS.

Dosing

Adult

50-100 mg PO hs
Start at 25 mg qhs and then gradually titrate dose by 25 mg qwk as needed to achieve target dose

Pediatric

Not established

Interactions

Phenobarbital may decrease effects; CYP2D6 enzyme system inhibitors (eg, cimetidine, quinidine) may increase levels; inhibits hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram

Contraindications

Documented hypersensitivity; MAOIs in past 14 d; history of seizures, cardiac arrhythmias, glaucoma, or urinary retention

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Most common adverse effects are anticholinergic (urinary retention, constipation, and blurred vision); caution in cardiac conduction disturbances and history of hyperthyroidism, renal or hepatic impairment; avoid use in elderly persons

Doxepin (Adapin, Sinequan)

Increases concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. These effects are associated with a decrease in symptoms of depression.

Dosing

Adult

30-150 mg/d PO hs or 2-3 divided doses; gradually increase dose to 300 mg/d prn

Pediatric

<12 years: Not recommended
>12 years: 25-50 mg/d PO hs or bid/tid and increase gradually to 100 mg/d

Interactions

Decreases antihypertensive effects of clonidine but increases effects of sympathomimetics and benzodiazepines; effects of desipramine increase with phenytoin, carbamazepine, and barbiturates

Contraindications

Documented hypersensitivity; urinary retention; acute recovery phase following myocardial infarction; glaucoma

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, and patients receiving thyroid replacement

Nortriptyline (Aventyl HCl, Pamelor)

Has demonstrated effectiveness in the treatment of chronic pain.
By inhibiting the re-uptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, this drug increases the synaptic concentration of these neurotransmitters in the CNS.
Pharmacodynamic effects such as the desensitization of adenyl cyclase and downregulation of beta-adrenergic receptors and serotonin receptors also appear to play a role in its mechanisms of action.

Dosing

Adult

25 mg PO qhs and increase weekly increments to target dose of 50-100 mg PO qhs

Pediatric

Not established

Interactions

Cimetidine may increase nortriptyline levels when used concurrently; nortriptyline may increase prothrombin time in patients stabilized with warfarin

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; do not administer to patients that have taken MAOIs in past 14 days

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in cardiac conduction disturbances and history of hyperthyroidism, renal or hepatic impairment; due to pronounced effects in cardiovascular system, best to avoid in elderly

Non-tricyclic antidepressants

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

Trazodone (Desyrel)

Nontricyclic antidepressant with short onset of action; consolidates sleep. Antagonist at 5-HT2 receptor and inhibits reuptake of 5-HT. Also has negligible affinity for cholinergic and histaminergic receptors.

Dosing

Adult

50-100 mg PO hs

Pediatric

Not established

Interactions

May enhance response to alcohol, barbiturates, and other CNS depressants; may increase digoxin and phenytoin serum levels; may decrease hypoprothrombinemic effects of warfarin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include dry mouth, blurred vision, constipation, and urinary retention; priapism has been reported; hypotension, including orthostatic hypotension and syncope, have occurred; may produce drowsiness or dizziness; patients taking this medication should observe caution while driving or performing other tasks requiring alertness, coordination, or dexterity

Nefazodone (Serzone)

Withdrawn from market in May 2004 due to hepatotoxicity risk. Inhibits serotonin reuptake and is potent antagonist at type 2 serotonin (5-HT) receptor. Also has negligible affinity for cholinergic, histaminic, or alpha-adrenergic receptors.

Dosing

Adult

50-150 mg PO qhs

Pediatric

Not established

Interactions

Decreases effects of anticoagulants, oral hypoglycemics, diuretics, clonidine, and methyldopa; increases effects of digoxin, carbamazepine, and MAOIs; toxicity may increase when used concurrently with amiodarone, cimetidine, fluoxetine, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, metronidazole, zafirlukast, or zileuton

Contraindications

Documented hypersensitivity; use of MAOIs within 14 d of initiating treatment; concurrent use with astemizole, carbamazepine, cisapride, or terfenadine

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in cardiac disease, cerebrovascular disease, or seizures; discontinue therapy and reevaluate if priapism occurs
This medication was withdrawn from the market in 2004 by Bristol Myers-Squibb due to an increased risk of hepatotoxicity of one in 250,000-300,000 patients

Antidepressant, alpha-2 antagonists

This drug is not an FDA approved treatment for insomnia, and no randomized, placebo-controlled trials have demonstrated its efficacy for insomnia.

In patients with depression, the sedative properties of the drug may help with sleep-onset insomnia.

Mirtazapine (Remeron, Remeron SolTab)

Exhibits both noradrenergic and serotonergic activity. In cases of depression associated with severe insomnia and anxiety, shown to be superior to other SSRI drugs.

Dosing

Adult

15 mg PO hs initially; may increase by 15 mg increments q1-2wk, not to exceed 45 mg hs

Pediatric

Not established

Interactions

May increase effect of CNS depressants; concurrent administration with MAOI may trigger hypertensive crisis

Contraindications

Documented hypersensitivity; MAOI within 14 d

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause drowsiness; discontinue use if patient develops sore throat, fever, or other signs of infection; suicide ideation is inherent in depression and may persist until significant remission occurs; severe neutropenia reported in clinical trials

Selective melatonin agonists

Indicated for insomnia characterized by difficulty with sleep onset.

Ramelteon (Rozerem)

Melatonin receptor agonist with high selectivity for human melatonin MT₁ and MT₂ receptors. MT₁ and MT₂ are thought to promote sleep and be involved in maintenance of circadian rhythm and normal sleep-wake cycle. Stimulation of the MT1 receptor in the suprachiasmatic nucleus (SCN) inhibits neuronal firing (reduces alerting affect of the SCN) and stimulation of the MT2 receptor in the SCN affects the circadian rhythm causing a phase advance (earlier sleep time).
Ramelteon has a short half-life of 1-2.6 hours. Its active metabolite M-II has a half-life of 2-5 hours. It has a 3-5 times greater affinity for the melatonin receptor and is up to 17 times more potent than melatonin.

Dosing

Adult

8 mg PO 30 min before bedtime on empty stomach

Pediatric

Not established

Interactions

Major substrate of cytochrome P450 CYP1A2 and minor substrate of CYP2C and CYP3A4; strong CYP1A2 inhibitors (eg, fluvoxamine) increase AUC up to 190-fold and C_max 70-fold; strong CYP inducers (eg, rifampin) decrease total exposure by mean of 80%; strong CYP3A4 inhibitors (eg, ketoconazole) and strong CYP2C9 inhibitors (eg, fluconazole) may increase serum levels

Contraindications

Documented hypersensitivity; strong cytochrome P450 CYP1A2 inhibitors (eg, fluvoxamine) should be avoided; severe hepatic impairment

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution with mild hepatic impairment; adverse effects leading to discontinuation in clinical trials included dizziness, nausea, fatigue, headache, and worsening insomnia

Follow-up

Patient Education

• 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. Daytime naps should be avoided. If a nap is necessary, keep it short (less than 1 hour) and avoid napping after 3 pm. Avoid staying in bed in the morning to catch up on sleep.
• Keep a regular 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 nonstimulating TV program). Avoid watching the clock or worrying about the perceived consequences of not getting enough sleep.

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

See eMedicine's Mental Health and Behavior Center, and Sleep Disorders Center. Also, see eMedicine's patient education articles Insomnia, Primary Insomnia, Understanding Insomnia Medications, Sleep Disorders in Women, Sleep Disorders and Aging, and Sleeplessness and Circadian Rhythm Disorder.

Miscellaneous

Medicolegal Pitfalls

• Use sedative hypnotics with caution in patients with a prior history of drug or alcohol abuse.
• Sedative hypnotics should also 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).
• Counsel patients to allow for at least 8 hours of sleep and avoid concomitant alcohol use when using sedative hypnotic medications. 
• Use sleep restriction therapy with caution in commercial truck drivers, those that operate heavy machinery, pilots, and those in occupations where sleep deprivation can have devastating consequences.

Special Concerns

Insomnia in the elderly

• 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.
• However, aging should not be assumed to be the explanation for insomnia. Multiple factors affect sleep in the elderly, including nocturia, pain syndromes, and many medical disorders (eg, heart failure, COPD, Parkinson disease). Other factors include restless legs syndrome, periodic leg movement disorder, 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.
• As in younger patients, nonpharmacologic treatment should take precedence over pharmacologic treatment.
• Hypnotics should be prescribed cautiously and in lower doses than for younger patients. Drugs tend to have longer duration of effect due to changes in metabolism and elimination. This can lead to increased incidence of falls and bone fractures at night (if the patient gets up to use the bathroom not fully awake or ataxic) and decrements in daytime alertness and performance (including increased incidence of motor vehicle accidents).

Multimedia

Media file 1: 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.

Media file 2: Mallampati airway scoring.

Media file 3: Diagnostic algorithm for major depression.

Media file 4: Diagnostic criteria for generalized anxiety disorder.

Media file 5: Sleep diary.

Media file 6: GABA_A receptor subunit function(s).

Media file 7: GABA_A receptor complex subunits and schematic representation of agonist binding sites.

Media file 8: Sleep-wake cycle.

Media file 9: The ascending arousal system. Adapted from Saper et al. Hypothalamic Regulation of Sleep and Circadian Rhythms. Nature 2005;437:1257-1263.

Media file 10: Ventrolateral pre-optic nucleus inhibitory projections to main components of the arousal system to promote sleep.

Media file 11: Schematic flip-flop switch model. Adapted from Saper C et al. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257-1263.

Media file 12: Epworth Sleepiness Scale.

Media file 13: Frequency of insomnia causes.

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Keywords

insomnia, sleep disorder, sleep problem, sleep symptom, sleep complaint, sleeplessness, inability to sleep, transient insomnia, short-term insomnia, chronic insomnia, insomnia, sedative, hypnotic, melatonin, sleep loss 

Contributor Information and Disclosures

Author

Erasmo A Passaro, MD, Director, Comprehensive Epilepsy Program/Clinical Neurophysiology Lab, Bayfront Medical Center Florida Center for Neurology
Erasmo A Passaro, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association, and American Society of Neuroimaging
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; Takeda Honoraria Speaking and teaching

Medical Editor

Carmel Armon, MD, MSc, MHS, Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center
Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Movement Disorders Society, and Sigma Xi
Disclosure: Nothing to disclose.

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Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Jose E Cavazos, MD, PhD, FAAN, Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, University of Texas Health Science Center at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center; Director of the Epilepsy Center, Audie L Murphy Veterans Affairs Medical Center
Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and Society for Neuroscience
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author James A Rowley, MD to the development and writing of this article.

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