eMedicine Specialties > Neurology > Sleep-Related Diseases

Sleeplessness and Circadian Rhythm Disorder

Mary E Cataletto, MD, Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Professor of Clinical Pediatrics, State University of New York at Stony Brook; Director of Children's Sleep Services, Winthrop University Hospital
Gila Hertz, PhD, ABSM, Director, Center for Insomnia and Sleep Disorders, Clinical Associate Professor of Psychiatry and Behavioral Sciences, State University of New York at Stony Brook

Updated: Aug 22, 2008

Introduction

Background

Circadian rhythm describes the approximately 24-hour cycles that are generated by an organism. Most physiological systems demonstrate circadian variations. The systems with the most prominent variations are the sleep-wake cycle, thermoregulation, and the endocrine system. Circadian rhythm disturbances can be categorized into 2 main groups: transient disorders (eg, jet lag; changed sleep schedule due to work, social responsibilities, illness) and chronic disorders. The most common chronic disorders are delayed sleep-phase syndrome (DSPS), advanced sleep-phase syndrome (ASPS), and irregular sleep-wake cycle. Katzenberg et al suggested genetic correlation (ie, clock polymorphisms) to circadian rhythm patterns.¹

Important terms are defined as follows:

Circadian rhythm (from circa, meaning "about" and dies, meaning day) - Approximately 24-hour cycles endogenously generated by an organism (eg, sleep-wake cycle)
Ultradian rhythm - Biological rhythms shorter than a 24-hour cycle (eg, sleep stages)
Entrainment - Synchronization of the circadian rhythms with environmental cues
Free-running clock - Persistence of circadian rhythms in the absence of environmental cues (eg in patients with impaired ability to entrain or in those without time cues)
Zeitgeber (time giver) - Specific environmental variables that provide time cues (eg, light, food-availability cycles)
Sleeplessness (insomnia) - Difficulty initiating or maintaining sleep
Circadian rhythm disorders - Malfunction of the circadian timing system or the biological clock

DSPS is characterized by a persistent inability (>6 mo) to fall asleep and awaken at socially accepted times. Once asleep, these patients are able to maintain their sleep and have normal total sleep times. In contrast, patients with insomnia have a lower than normal total sleep time due to difficulties in initiating or maintaining sleep.

ASPS is characterized by persistent, early evening sleep onset (between 6:00 pm and 9:00 pm), with an early morning wake-up time, generally between 3:00 am and 5:00 am. ASPS is less common than DSPS and most frequently occurs in elderly patients and in individuals who are depressed.

An irregular sleep-wake schedule features multiple sleep episodes without evidence of recognizable ultradian or circadian features of sleep and wakefulness. As with ASPS and DSPS, total sleep time is normal. Daily sleep logs demonstrate irregularity not only of sleep but also of daytime activities, including eating.

Pathophysiology

The neural basis of the circadian rhythm, the suprachiasmatic nuclei (SCN), is located in the anterior ventral hypothalamus and has been identified as the substrate that generates circadian activity. SCN lesions produce loss of circadian rhythmicity of the sleep-wake cycle, the activity-rest cycle, skin temperature, and corticosteroid secretion. Other pacemakers that are not located in the SCN are observed. For instance, core body temperature rhythm persists despite bilateral ablation of SCN. Furthermore, free-running studies have provided evidence for multiple circadian oscillators. Under free-running conditions, circadian rhythm may split into independent components.

Frequency

United States

DSPS is common. Approximately 7-10% of patients who complain of insomnia are diagnosed with a circadian rhythm disorder, most often DSPS. The prevalence of DSPS is probably higher than that because the total sleep time is typically normal in patients with DSPS and because patients with DSPS adjust their lifestyle to accommodate their sleep schedule and do not seek medical treatment. In adolescence, the prevalence is approximately 7%.

True ASPS is probably quite rare. However, an age-related phase advance is common in elderly patients because they tend to go to sleep early and get up early.

The prevalence of irregular sleep-wake schedules has not been established but is said to be quite high. Irregular sleep-wake schedule is common in patients with Alzheimer disease.

Approximately 20% of US workers perform shift work; not all of these works develop shift work syndrome, and individual phase tolerance is observed.

International

Dagan et al reported the characteristics of 322 Israeli patients with circadian rhythm disorder.² Most patients (85%) with circadian rhythm disorder who seek medical help have DSPS. About 90% of patients with DSPS in the study by Dagan et al reported onset of DSPS in early childhood or adolescence. A cross-sectional nationwide epidemiologic study in Norway established an overall prevalence of DSPS to be 0.17% when strict International Classification of Sleep Disorders (ICSD) criteria were used.³

Mortality/Morbidity

The mortality rates associated with circadian rhythms are difficult to assess. Many deaths related to circadian rhythm disorders are the result of impaired performance secondary to sleep deprivation; therefore, many times, the deaths are categorized into different headings (eg, motor vehicle accidents, heavy machinery accidents, other accidents). Sometimes, deaths are sequelae of the use of hypnotics, alcohol, or both to treat insomnia.

Shift workers have been found to have a 40% greater cardiovascular disease risk than nonshift workers. Frequency of GI symptoms, other psychosomatic symptoms, and psychiatric symptoms is also increased in shift workers.
Daytime sleepiness in students with DSPS has been correlated with negative mood and increased smoking and alcohol consumption.
Some of the features of depressive disorders, such as early morning awakening and decreased rapid eye movement (REM) latency, are suggestive of ASPS. Whether these changes are secondary to depression or actually cause it has not been established.

Race

Race has been associated with variations in incidence of obstructive sleep apnea (OSA); however, many variables may be associated with these differences, and further research is necessary to evaluate this.

Sex

The sex difference in circadian rhythm disorders seems to be age related.

In children and adolescents, no significant prevalence based on sex is observed.
In patients aged 20-40 years, little to no difference in prevalence based on sex is observed.
In those older than 40 years, women are 1.3 times more likely to report insomnia than men.

Age

Circadian rhythm cycles undergo changes during puberty, as do other physiologic systems. At this time, increased daytime sleepiness is seen along with the development of sleep-phase delay. Early school start times at this critically important developmental phase can be associated with symptoms of daytime sleepiness, poor concentration, and impaired performance.
DSPS is the most common circadian rhythm disorder in children and adolescents. ASPS is more likely to appear in elderly individuals.
Health risks associated with shift work, such as GI and psychosomatic symptoms, increase with age.
Irregular sleep-wake rhythms can be seen in patients with neurological impairment, including those with dementia.

Clinical

History

The diagnosis of circadian rhythm disorders is primarily based on a thorough history. Differentiation of transient disorders from chronic disorders and primary disorders from secondary disorders influences the direction of evaluation and treatment plans. As with all medical and psychiatric histories, the nature of the complaint is the first order of business. In cases of sleeplessness, distinguishing individuals with difficulty initiating sleep from those with difficulty maintaining sleep, those with significant daytime impairment, and those with nonrestorative sleep is important.

Duration of symptoms: Transient changes can be seen with air flights of long duration, jet lag, transient stresses (eg, illnesses), and short-term sleep schedule disruptions (eg, shift work). Chronic circadian changes can be seen with advanced sleep-phase syndrome (ASPS), delayed sleep-phase syndrome (DSPS), and irregular sleep-wake cycles.
Pattern of sleep-wake cycle: This is an important part of the history in patients with circadian rhythm disturbances. The pattern of the sleep-wake cycle allows diagnosis within the chronic subtypes. DSPS is characterized by a persistent inability (ie, >6 mo) to fall asleep and awaken at socially accepted times. Once asleep, these patients are able to maintain their sleep and have normal total sleep times. This disorder is most frequently identified in adolescents, college students, and night workers. Differential diagnosis includes lifestyle preference, inadequate sleep hygiene, primary insomnia, jet lag, and psychophysiologic insomnia. Teenagers with DSPS are at increased risk for behavioral problems and depression.
ASPS: This syndrome is characterized by persistent, early evening sleep onset (between 6:00 pm and 9:00 pm) with an early morning wake-up time, generally between 3:00 and 5:00 am. ASPS occurs much less frequently than DSPS and is seen most commonly in the elderly and in persons who are depressed. It needs to be differentiated from exogenous depression and excessive daytime sleepiness (EDS), which is associated with other sleep disorders (eg, obstructive sleep apnea [OSA]). An irregular sleep-wake schedule features multiple sleep episodes without evidence of recognizable ultradian or circadian features of sleep and wakefulness. As with APSD and DPSD, total sleep time is normal. Daily sleep logs demonstrate irregularity not only of sleep but also of daytime activities including eating. Body temperature also randomly fluctuates.
Shift workers: For shift workers, the need to adjust the biological clock is coupled with the social pressure of more noise and disturbance during the day, leading to difficulties in sleeping. This is most difficult for workers who must switch their schedule and rotate between morning, evening, and night shifts. For those who consistently work the same shift, only environmental issues affect sleep quality once the biological clock adjusts to the new time.
Total sleep time: In both ASPS and DSPS delays, total sleep time is normal. Shift workers, even those who work a consistent night shift, tend to have shorter sleep times.
Peak alertness: Patients with DSPS have their peak alertness in late evening and night, whereas patients with ASPS have their peak alertness in the early morning. Patients with irregular sleep-wake cycles demonstrate no consistent pattern of alertness.
Concern about sleep pattern: Implicit in the diagnosis of circadian rhythm disorder is a desire to conform to traditionally accepted sleep-wake patterns.
Recent travel: Jet lag is a form of transient circadian rhythm disturbance. It results from an inability to synchronize one's normal rhythm to rapidly changing time shifts of environmental cues. Although many of the symptoms have been associated with high-altitude flying in general, the distinguishing factor seems to be the length of symptoms. Symptoms related to flight generally last less than 24 hours, whereas those of jet lag may persist for days. The duration of the flight is the primary determinant of the intensity and duration of the jet lag. In general, jet lag is most likely to be experienced if 3 or more time zones are crossed.
Daytime sleepiness: Daytime sleepiness is seen in all circadian rhythm disorders, although the severity may vary from individual to individual and from day to day. Assess for the presence of consequences of daytime sleepiness, which include poor concentration, impaired performance (including a decrease in cognitive skills), and poor psychomotor coordination. Headaches may also be present. The presence of early morning headaches should suggest further investigation of OSA. For children and adolescents, early school hours are associated with shorter total sleep time and increased daytime sleepiness. This is more prominent in teenagers.
Psychological assessment: Psychophysiological insomnia, depressive disorders, and other psychiatric disorders may present with symptom profiles similar to those of circadian rhythm disorders. Assess patients for these disorders.
Patient attempts at treatment: Perform a careful inquiry concerning the use of commonly used sleep aids, including alcohol, herbal preparations, and over-the-counter (OTC) sleep aids. Residual sleepiness can be seen with some of these preparations as well as with prescription hypnotics and some of the allergy preparations. Johnson et al reported that 13% of the general population had used alcohol as a short-term sleep aid during the previous year.⁴
Medication history: Obtain a careful medication history regarding the timing of administration of drugs. For example, beta-adrenergic drugs, typically used in the treatment of asthma, can delay sleep because of their stimulant effect. Amphetamines, caffeine, selective serotonin reuptake inhibitor (SSRI) antidepressants, steroids, nicotine, theophylline, and clonidine can also affect sleep.
Snoring: Chronic loud snoring with or without witnessed apnea should direct the physician to evaluate the patient for risk factors for upper airway resistance syndrome and OSA.
Other medical or psychiatric problems: The 2 most commonly seen medical diseases and disorders that affect sleep and daytime function are congestive heart failure and chronic obstructive pulmonary disease. Chronic pain syndromes and thyroid disease also affect sleep and daytime function. Hyperthyroidism is associated with sleep disruption, whereas hypothyroidism is associated with daytime sleepiness and fatigue.
Environmental cues and sleep hygiene: This is particularly important to assess in shift workers. The intensity of light, level of noise, and environmental temperature can influence sleep. Exercise and stimulant intake prior to bedtime are frequent lapses in good sleep hygiene and can be easily addressed.

Physical

The physical examination complements the history in patients with insomnia. Focus the physical examination on identifying risk factors for other conditions that may precipitate, exacerbate, or mimic insomnia. These may include depression, OSA, and neurodegenerative disease.

Affect: Assess general affect and sense of well-being in patients presenting with insomnia as a primary sleep complaint.
Body mass index: Patients with obesity who have increased body mass indices are at increased risk for OSA.
Craniofacial morphology: The head and neck examination is important in assessing risk for OSA. Patients with large tonsils, narrow oropharyngeal spaces, and large necks are at risk for OSA.
Chest: Barrel chest (ie, increased anteroposterior diameter) is associated with chronic lung disease. Crackles, murmurs, and cardiac enlargement evinced by displaced point of maximum impulse (PMI) suggest congestive heart failure.
Digital clubbing: Clubbing may be associated with chronic lung disease or congenital heart disease, or it may be familial. This finding should suggest a need for further medical evaluation.
Neurologic examination: Alzheimer disease and other neurodegenerative diseases frequently are associated with irregular sleep-wake cycles.

Causes

Most of the time, the biological clock or the circadian rhythm is in synchronization with the 24-hour day-night environment. However, in some individuals, the biological circadian rhythm of sleep and wakefulness is out of phase with the conventional or desired sleep-wake schedule. Postulated reasons for that breakdown are as follows:

Sensitivity to zeitgebers (ie, environmental cues): This may be altered or disrupted, which can be demonstrated under free-running conditions. Altered or disrupted sensitivity to zeitgebers is probably the most common cause of circadian rhythm disorder.
Disrupted pacemaker function: A dysfunction may be present in the internal coupling mechanisms of biological pacemakers (eg, the coupling of the sleep-wake cycle with temperature cycle).
Environment: Light, higher levels of noise, and elevated room temperature are not conducive to good sleep and are important variables to consider in shift and night workers
Travel: The severity of jet lag is related to the direction of travel (ie, more frequently seen when traveling in an eastward direction) and the number of time zones crossed. Most patients experience jet lag if they cross 3 or more time zones. The rate of adjustment is 1.5 h/d after an eastward flight and 1 h/d when the flight is in a westward direction. Other factors that may affect severity of jet lag are age, ability to sleep while traveling, the time of the day at destination, and exposure to light. More recent studies even look at cabin pressure and the slight oxygen deprivation experienced during flights as contributing factors to symptoms of jet lag.
Neurologic disease: Alzheimer disease is one of the more common examples of neurological disease associated with circadian rhythm disturbance; however, irregular sleep-wake cycles also can be seen in other neurodegenerative diseases. The phenomenon of sundowning is best described in Alzheimer disease and is characterized by sleep disruptions with awakenings and confusion.
Shift work: Rapid shift changes and shift changes in the counterclockwise direction are most likely to cause symptoms.
Other factors: Lifestyle and social pressure (to stay up late) can exacerbate circadian rhythm disorder.

Differential Diagnoses

Insomnia
Narcolepsy

Workup

Laboratory Studies

When assessing sleeplessness, a sleep log is often used. Although not technically a laboratory test, this diary allows identification of sleep-wake cycles in the patient's normal environment and allows subjective assessment of alertness over a 2-week time period. The Practice Parameters (2007) recommend the use of sleep logs in the evaluation of the following sleep disorders:⁵

Shift work syndrome
Jet lag
Advanced sleep-phase syndrome (ASPS)
Delayed sleep-phase syndrome (DSPS)
Free-running disorder
Irregular sleep-wake rhythm

Imaging Studies

Consider imaging studies if the patient is to be evaluated for neurodegenerative disease.
Also consider imaging studies in patients with obstructive sleep apnea (OSA) to determine the etiology of obstruction.

Other Tests

Multiple sleep latency test (MSLT): This test allows for objective measurement of sleepiness. Normal adult values range from 10-20 minutes, whereas sleep latencies of less than 5 minutes indicate abnormal sleepiness. MSLT is indicated when suspicion of narcolepsy is raised by the clinical history. Following a normal night's sleep documented by overnight polysomnography, specific abnormalities in MSLT (ie, 2 or more sleep-onset rapid eye movements [SOREMs]) support a diagnosis of narcolepsy.
Epworth sleepiness scale (ESS): This scale is based on a questionnaire that asks patients to rate their responses to 8 situations on a scale of 0-3 based on whether the situation was likely to be associated with dozing behavior. It was designed to give an indication of sleepiness and has been correlated with sleep apnea.
Morningness eveningness questionnaire (MEQ): The evidence is insufficient to recommend the routine use of this questionnaire for the evaluation of circadian rhythm disturbances.

Procedures

Actigraphy: An Actigraph is a small motion-sensing device worn on the nondominant wrist, generally for 1 week. It is based on the premise that wrist motion is decreased during sleep. This allows a very gross measure of sleep-wake cycles over time. It is not routinely indicated to treat jet lag.
Overnight polysomnography: This study is of value in identifying the patient with OSA, periodic limb movements of sleep (PLMS), or sleep-state misperception. It also is used in conjunction with MSLT to evaluate patients with narcolepsy. It is not routinely used in the diagnostic evaluation of patients with insomnia or in the diagnostic evaluation of patients with circadian rhythm disturbances.

Treatment

Medical Care

Behavioral and light therapy are the mainstays of treatment of circadian rhythm disturbances. Emphasize good sleep hygiene and discourage maladaptive behaviors.

Bright light therapy: Circadian rhythm disturbances respond very well to light therapy, especially bright light (>600 lux). For entrainment purposes, bright room light over time may be sufficient; however, a higher intensity of light (>6000 lux over 30-60 min) is often necessary to accomplish acute phase shifts. The timing of light therapy is also important because it affects the degree and direction of the rhythm shift. For example, light therapy applied in the early evening and nighttime hours delays the cycle (in patients with advanced sleep-phase syndrome [ASPS]), whereas therapy given in the early morning stimulates morning alertness and an earlier bedtime (in patients with delayed sleep-phase syndrome [DSPS]).
Chronotherapy: This behavioral treatment consists of a gradual shift in sleep time in accordance with the patient's tendency. Thus, in DSPS, a progressive delay of 3 h/d is prescribed, followed by strict maintenance of a regular bedtime hour once the desired schedule is achieved. In ASPS, chronotherapy focuses on advancing bedtime by 2-3 hours per night over 1 week until a desired schedule is achieved.
Enhancing environmental cues: This is an important part of the treatment of circadian rhythm disorders. Patients are encouraged to keep a dark quiet room during sleep and a well-lit room upon awakening. Avoid bright light exposure in the evening. Enforce regular hours of eating and other activities.
Lifestyle: Patients may respond to shifts in their active phases by exhibiting signs of sleep deprivation. For example, teenagers may have difficulty keeping late hours and getting up for an early morning class. Shift workers may have difficulty if shifts are changed too rapidly before they have had a chance to adjust.

Surgical Care

Sleep disturbances associated with obstructive sleep apnea (OSA) syndrome may be amenable to surgical intervention. See Obstructive Sleep Apnea and Sleep Dysfunction in Women.

Consultations

Sleep medicine specialist
Neurologist
Psychiatrist
Pulmonologist

Diet

Nocturnal eating disorder is an entity distinct from circadian rhythm disorders and is characterized by an inability to maintain sleep over the night. Sleep is interrupted and patients are unable to return to sleep without eating or drinking.
Dietary advice includes the following:
- Limit large meals.
- Avoid intake of excessive fluids before bedtime. This is an element that is generally emphasized when attempting to improve sleep hygiene.
- Discourage obesity.

Activity

In patients with irregular sleep-wake cycles, behavioral modification has been shown to be helpful. This includes encouraging structured daytime activity, even in the presence of fatigue. Attendants in nursing homes can help elderly patients remain awake by involving them in activities and restricting sleep to conventional time periods. Encourage afternoon naps scheduled daily at a regular time. This helps to avoid multiple brief daytime naps and to consolidate sleep to the desired time.
Emphasizing a program of regular morning exercise is a component of promoting sleep hygiene. Advise patients to avoid strenuous exercise before bedtime.

Medication

Therapy for circadian rhythm disturbances is largely behavioral. Light therapy has been shown to be an effective modifier of circadian cycles. Mixed modalities may be effective in elderly patients with dementia who have irregular sleep-wake rhythms. Combination of planned sleep scheduling, timed light exposure, or timed melatonin administration can be helpful.

Benzodiazepines

These agents are recommended in preference to barbiturates because of their low toxicity and clinical efficacy. They have a rapid onset of action. Concerns remain with regard to rebound insomnia, residual daytime effects, and addictive potential. Short-acting benzodiazepines are often chosen in the early treatment of sleep-onset insomnia and are used in conjunction with behavioral therapy. Long-standing insomnia with sleep maintenance as well as sleep-onset insomnia often requires long-acting agents.

Triazolam (Halcion)

Frequently chosen as short-term adjunct to behavioral therapy. This short-acting agent is effective in helping patients fall asleep. Not effective in those with sleep maintenance problems. For patients with sleep maintenance insomnia, a benzodiazepine with intermediate (eg, estazolam [ProSom]) or long half-life (eg, quazepam) may be considered. Information given here is for triazolam. For longer-acting agents, please consult PDR.

Dosing

Adult

Initial dose: 0.25 mg PO qhs
Elderly patients: 0.125-0.25 mg PO qhs

Pediatric

Not established

Interactions

Phenothiazines, barbiturates, alcohols, and MAOIs increase toxicity of benzodiazepines in CNS

Contraindications

Documented hypersensitivity; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

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

Nonbenzodiazepine hypnotics

These agents are gaining popularity because they do not have significant effect on sleep architecture and are not associated with the rebound phenomenon seen with the benzodiazepines.

Zolpidem (Ambien, Ambien CR)

Nonbenzodiazepine hypnotic of imidazopyridine class. Rapidly absorbed, has elimination half-life of 2.5 h, and is good short-term option for patients with sleep-onset insomnia who require pharmacologic support. 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 qhs
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 patients for impaired cognitive or motor performance; adverse effects include drowsiness, dizziness, lightheadedness, and impaired coordination; patients should be cautioned about operating heavy machinery and driving; 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: Do not 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

Zaleplon

Nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. Has a chemical structure unrelated to benzodiazepines, barbiturates, or other hypnotic drugs but interacts with the GABA-BZ receptor complex. Binds selectively to the omega-1 receptor situated on the alpha subunit of the GABAA receptor complex in the brain. Potentiates t-butyl-bicyclophosphorothionate (TBPS) binding. Has preferential binding to the omega-1 receptor of the GABA receptor family.

Dosing

Adult

10 mg PO hs; may increase to 20 mg prn if tolerated
Start with 5 mg PO hs in elderly and debilitated patients; doses >10 mg are not recommended in these populations

Pediatric

Not established

Interactions

Cimetidine significantly increases effect of zaleplon; contraindicated in patients receiving Sodium oxybate

Contraindications

Documented hypersensitivity; anaphylaxis may occur with first dose

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 a 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 zaleplon in quantities exceeding a 1-mo supply); in hepatic function impairment, reduce dose to 5 mg PO hs; caution in patients exhibiting signs or symptoms of depression; 5-mg and 10-mg cap contain tartrazine and may trigger bronchospasm in susceptible individuals particularly those with aspirin sensitivity.

Pineal gland hormones

Melatonin has been reported to be useful in the treatment of jet lag and in the treatment of sleep-onset insomnia in elderly patients who are melatonin deficient. Recommendations regarding melatonin are based on the extensive literature review from the Cochrane Library.⁶ However, because of the phenomenon of publication bias, studies showing efficacy are more likely to be available for review than those that do not show efficacy. Furthermore, potential users of these agents should be cautioned that variations in quality, purity, and quantity of active ingredient in natural pharmaceuticals make interpretation of studies difficult and raises concerns about interactions and contaminants.

Melatonin

Available as OTC preparation. Used to enhance natural sleep process and for resetting body's internal time clock when traveling through different time zones. Has also been used for treatment of circadian rhythm sleep disorders in blind people with no light perception. No RDA of melatonin has been approved by the FDA, nor is FDA-approved prescribing information available for any of the doses discussed here. Individual patients may or may not experience the reported benefits of melatonin.
Physicians and patients should consider risks and benefits of each therapeutic option. Slow-release products are reported to be less effective. Melatonin is believed to be effective when crossing 5 or more time zones and is less effective when traveling in westward direction.

Dosing

Adult

Jet lag: 0.5-5 mg PO qhs with improved efficacy suggested at higher doses; may be initiated several nights prior to travel
Elderly melatonin-deficient patients with sleep-onset insomnia: 1-2 mg PO qhs

Pediatric

Not established

Interactions

Fluvoxamine increases levels, thus increasing drowsiness; nifedipine increases HR and BP

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

Adverse effects include suppression of male libido, hypothermia, retinal damage, headache, nightmares, and worsening of depression; caution in patients who have epilepsy, are taking warfarin, have autoimmune or endocrine disorders, or are pregnant or lactating (such individuals should consult a physician before using melatonin, as should individuals taking other medications)

Melatonin agonists

These agents are 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.

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); 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

Further Outpatient Care

Address associated psychological issues. Patients with delayed sleep-phase syndrome (DSPS) who initially responded to chronotherapy may gradually shift back to their old sleep pattern. Often, chronotherapy must be repeated every few months to maintain long-lasting results.
Emphasize importance of good sleep hygiene.
Avoid use of alcohol, stimulants (eg, nicotine, caffeine), and strenuous exercise before bedtime.

Inpatient & Outpatient Medications

See Medication.

Transfer

The overwhelming majority of patients with insomnia (except elderly patients) are treated as outpatients.
In the elderly, in whom numerous other physical, psychiatric, and pharmacological concerns are present, institutional care is often necessary. The presence of significant sleep disruption is often a predictor for which patients require institutionalization.

Deterrence/Prevention

Encourage good sleep hygiene.
Control of sleep environment with regulation of light/dark exposure has been helpful to shift workers in maintaining sleep.
For patients anticipating jet lag, advise scheduling to the time of the new location prior to departure. This can modify effects of jet lag.
For shift workers, advise shifting the schedule in a clockwise direction; this is often better tolerated.

Complications

Sleeplessness may have various consequences, which have been discussed above. These consequences include poor daytime performance, daytime sleepiness, impaired social interactions, and irritability.

Prognosis

Jet lag: This is a transient condition that has a good prognosis.
Shift work: Abrupt changes in schedule and counterclockwise shifts are associated with daytime sleepiness and impaired performance. Older patients may not adjust well to shift work.
DSPS: This is typically seen in adolescents and young adults. This sleep pattern often resolves in adulthood.
Advanced sleep-phase syndrome (ASPS): This is prominent in the elderly and often responds well to a combination of behavioral and pharmacological intervention.
Other conditions: Children with special needs, including attention deficit hyperactivity disorder and developmental disabilities, generally respond well to behavioral intervention.

Patient Education

Many of the consequences of sleep disturbances related to circadian rhythm can be modified with the use of chronobiotics. Education can play a critical role in therapeutic response; however, education in sleep hygiene without other interventions is often insufficient.
For excellent patient education resources, visit 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

The consequences of poor sleep are well established. Among other symptoms, they include impaired social interactions and psychomotor coordination. The literature supports the relationship of poor sleep to automobile accidents, heavy machinery accidents, and other catastrophes.
Failure to diagnose other medical conditions associated with increased daytime sleepiness, such as obstructive sleep apnea (OSA), may also carry significant consequences in terms of added morbidity and mortality.
Failure to assess patient risk for motor vehicle accidents is a pitfall. Patients should be advised of risks secondary to sleepiness and have follow-ups after treatment to determine if risk factors have been satisfactorily addressed.

Special Concerns

Children and adolescents: Early start times for school coupled with after school activities and homework are associated with sleep deprivation and phase shifting in children and adolescents. Subsequent daytime sleepiness and impaired performance have been documented.
Children with special needs: These children have a higher incidence of sleeplessness. This impacts children, parents, and their families. Positive routines are superior to extinction techniques in this population; however, these children may take longer than other children to achieve the desired results.
Elderly persons: The decision to institutionalize elderly individuals is often based on sleep disruption. This decision often involves the need for the caregiver to be able to obtain adequate sleep. Concerns about the elderly patient wandering and falling are also important when making the decision to institutionalize the patient
Shift workers: Numerous health risks have been described in association with shift work. These include GI symptoms, psychosomatic symptoms, increased alcohol and drug use, and emotional problems.

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Keywords

sleeplessness, circadian rhythms, ultradian rhythm, entrainment, free-running clock, zeitgeber, insomnia, biological clock, jet lag, sleep disorders, sleep deprivation, daytime sleepiness, biological rhythms, delayed sleep-phase syndrome, DSPS, advanced sleep-phase syndrome, ASPS, irregular sleep-wake cycle, suprachiasmatic nuclei, SCN, suprachiasmatic nuclei lesions, SCN lesions, Alzheimer disease, Alzheimer's disease, shift work syndrome, circadian rhythm disorder, motor vehicle accidents, heavy machinery accidents, obstructive sleep apnea, OSA, excessive daytime sleepiness, EDS, upper airway resistance syndrome, congestive heart failure, chronic obstructive pulmonary disease, neurodegenerative disease, chronic lung disease

Contributor Information and Disclosures

Author

Mary E Cataletto, MD, Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Professor of Clinical Pediatrics, State University of New York at Stony Brook; Director of Children's Sleep Services, Winthrop University Hospital
Mary E Cataletto, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Chest Physicians
Disclosure: Shering Plough Pharmaceuticals Honoraria Consulting

Coauthor(s)

Gila Hertz, PhD, ABSM, Director, Center for Insomnia and Sleep Disorders, Clinical Associate Professor of Psychiatry and Behavioral Sciences, State University of New York at Stony Brook
Gila Hertz, PhD, ABSM is a member of the following medical societies: American Academy of Sleep Medicine and American Psychological Association
Disclosure: Nothing to disclose.

Medical Editor

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

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Norberto Alvarez, MD, Assistant Professor, Department of Neurology, Harvard Medical School; Consulting Staff, Department of Neurology, Boston Children's Hospital
Norberto Alvarez, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, and Child Neurology Society
Disclosure: Nothing to disclose.

CME 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.

Chief Editor

Further Reading

eMedicine Specialties > Neurology > Sleep-Related Diseases

Sleeplessness and Circadian Rhythm Disorder

Introduction

Background

Pathophysiology

Frequency

United States

International

Mortality/Morbidity

Race

Sex

Age

Clinical

History

Physical

Causes

Differential Diagnoses

Other Problems to Be Considered

Workup

Laboratory Studies

Imaging Studies

Other Tests

Procedures

Treatment

Medical Care

Surgical Care

Consultations

Diet

Activity

Medication

Benzodiazepines

Triazolam (Halcion)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Nonbenzodiazepine hypnotics

Zolpidem (Ambien, Ambien CR)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Eszopiclone (Lunesta)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Zaleplon

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Pineal gland hormones

Melatonin

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Melatonin agonists

Ramelteon (Rozerem)