Disturbances in circadian rhythm—the approximately 24-hour cycles that are endogenously generated by an organism—can be categorized into two main groups: transient disorders and chronic disorders. Transient disorders include jet lag or a changed sleep schedule due to work, social responsibilities, or illness.[1]
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 correlations (ie, clock polymorphisms) to circadian rhythm patterns.[2] The International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR) recognizes seven distinct circadian rhythm sleep disorders:[3]
Most physiologic systems demonstrate circadian variations. The systems with the most prominent variations are the sleep-wake cycle, thermoregulation, and the endocrine system.
Important terms associated with circadian rhythm are defined as follows:
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; it 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.
Most of the time, the biologic clock or the circadian rhythm is in synchronization with the 24-hour day-night environment. However, in some individuals, the biologic 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) 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.
A dysfunction may be present in the internal coupling mechanisms of biologic pacemakers (eg, the coupling of the sleep-wake cycle with the temperature cycle).
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
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 three or more time zones. The rate of adjustment is 1.5 hours per day after an eastward flight and 1 hour per day when the flight is in a westward direction.
Other factors that may affect the severity of jet lag are age, the ability to sleep while traveling, the time of the day at the destination, and exposure to light. Studies have even looked at cabin pressure and the slight oxygen deprivation experienced during flights as contributing factors to symptoms of jet lag.
Alzheimer disease is one of the more common examples of neurologic 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.
Circadian rhythm disturbances have been reported in children with cancer and may be seen following injury to the hypothalamus or brainstem in those with endocrine dysfunction or following cranial irradiation.[4]
In children with autism spectrum disorder, sleep onset and sleep maintenance insomnia have been described.[5] They have also been associated with abnormal sleep-wake rhythms.
Rapid shift changes and shift changes in the counterclockwise direction are most likely to cause symptoms.
Lifestyle and social pressure (to stay up late) can exacerbate a circadian rhythm disorder.
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.[6]
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.
Delayed sleep-phase syndrome (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 advanced sleep-phase syndrome (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. An irregular sleep-wake schedule is common in patients with Alzheimer disease.
Approximately 20% of US workers perform shift work, but not all of these workers develop shift-work syndrome, and individual phase tolerance is observed.
Dagan et al reported the characteristics of 322 Israeli patients with circadian rhythm sleep disorder and found that most of these patients (83.5%) had DSPS. About 90% of the patients with DSPS reported onset of the syndrome in early childhood or adolescence.[7]
A cross-sectional, nationwide epidemiologic study in Norway established an overall prevalence of DSPS of 0.17% when strict International Classification of Sleep Disorders (ICSD) criteria were used.[8]
The sex difference in circadian rhythm disorders seems to be age related. In children and adolescents, no significant prevalence based on sex is observed. Moreover, little to no difference in prevalence based on sex is observed in patients aged 20–40 years. In persons older than 40 years, however, women are 1.3 times more likely than men to report insomnia.
A systematic review of 11 studies examined sex differences in insomnia and circadian rhythm disorders. The analysis found that insomnia was more prevalent among women, who also exhibited more regular and stable sleep patterns compared to men. The impact of stress related to the COVID-19 lockdown differed between sexes, with women experiencing more stable sleep and less fragmentation, while men showed a more pronounced shift in peak activity time with age. The study concluded that risk factors for insomnia and circadian rhythm disorders affect men and women differently, which may influence long-term outcomes.[9]
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, coupled with afterschool activities and homework, are associated with sleep deprivation and phase shifting in children and adolescents. This can lead to 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 gastrointestinal (GI) and psychosomatic symptoms, increase with age.
Irregular sleep-wake rhythms can be seen in patients with neurologic impairment, including those with dementia.
Prognoses in circadian rhythm disorders include the following:
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). 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. The frequency of GI, psychosomatic, and psychiatric symptoms is also increased in shift workers. In addition, increased alcohol and drug use, as well as emotional problems, have been described.
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.
Education can play a critical role in therapeutic response; however, education in sleep hygiene without other interventions is often insufficient.
Patients should be advised of risks secondary to sleepiness and have follow-ups after treatment to determine if risk factors have been satisfactorily addressed.
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.
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.
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, > 6mo) 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.
DSPS 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 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. The sleep schedule is usually stable. 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 from 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. The principal complaints are excessive daytime sleepiness and/or insomnia.
For shift workers, the need to adjust the biologic 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 their biologic clock adjusts to the new time.
In 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.
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.
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 flight 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 three or more time zones are crossed. The likelihood of sleep disturbance during travel across time zones increases with aging.[10]
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 for obstructive sleep apnea (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.
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.
Assess impact on complex cognitive tasks such as selective attention and executive function as these will impact on risks for both work and school performance.
Perform a careful inquiry concerning the patient’s use of commonly employed 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.[11]
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.
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.
The two most commonly seen medical diseases 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.
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.
Finally, inquire about any history of motor vehicle accidents or other accidents occurring as a result of decreased alertness/excessive sleepiness.
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, obstructive sleep apnea (OSA), and neurodegenerative disease. The exam can include the following evaluations:
The consequences of poor sleep are well established. They include irritability, impaired social interactions and psychomotor coordination, poor daytime performance, and daytime sleepiness. The literature supports the relationship of poor sleep to automobile accidents, heavy machinery accidents, and other catastrophes.
Poor sleep can affect both physical and mental health at all ages. As such it is considered to be an indicator of overall health and function. In children, insomnia has been associated with poor focus, poor school performance, and behavioral changes; in adults, it is also associated with decreased cognitive functioning and accidents including falls and motor vehicle accidents.
Poor sleep can also contribute to anxiety, depreesion, hypertension and, in older adults, cardiovascular events and strokes.[12]
When assessing sleeplessness, a sleep log is often used.[3] Although not technically a laboratory test, this diary allows identification of sleep-wake cycles in the patient's normal environment and permits subjective assessment of alertness over a 2-week time period. Guidelines from the American Academy of Sleep Medicine recommend the use of sleep logs in the evaluation of the following sleep disorders:[13]
Failure to diagnose other medical conditions associated with increased daytime sleepiness, such as obstructive sleep apnea (OSA), may carry significant consequences in terms of added morbidity and mortality. Another potential treatment pitfall is failure to assess a patient’s risk for motor vehicle accidents.
Implicit in the diagnosis of circadian rhythm disorder is a desire to conform to traditionally accepted sleep-wake patterns.
Consider imaging studies if the patient is to be evaluated for neurodegenerative disease. Also consider imaging studies in patients with OSA to determine the etiology of obstruction.
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 measurement of sleep-wake cycles over time.[14]
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 the Multiple Sleep Latency Test (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.
According to the International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR), all circadian rhythm sleep-wake disorders must meet three key criteria:[3]
The MSLT allows for objective measurement of sleepiness. Normal adult values range from 10 to 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, two or more sleep-onset rapid eye movements [SOREMs]) support a diagnosis of narcolepsy.
The Epworth Sleepiness Scale (ESS) 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.
The MEQ is a self-assessment tool designed to determine an individual's circadian preference, categorizing them as morning, intermediate, or evening types. While it can provide insights into a person's chronotype, its routine use in clinical settings for evaluating CRSDs is not currently supported by sufficient evidence.
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. A combination of planned sleep scheduling, timed light exposure, and timed melatonin administration can be helpful.
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. Bright light exposure in the evening should be avoided, and regular hours of eating and other activities should be enforced.
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]).
This behavioral treatment consists of a gradual shift in sleep time in accordance with the patient's tendency. Thus, in delayed sleep-phase syndrome (DSPS), a progressive delay of 3 hours per day 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.
Tasimelteon (Hetlioz) is approved by the FDA for treatment of non–24-hour sleep-wake disorder in the totally blind. Approval was based on results of two trials: the Safety and Efficacy of Tasimelteon (SET) trial, a 26-week study that included 84 patients, and the Randomized Withdrawal study of the Safety and Efficacy of Tasimelteon (RESET), a 19-week trial that included 20 patients, all of whom had been previously screened during the SET trial and entrained during open-label tasimelteon treatment.
Entrainment of the circadian rhythm, as measured by urinary 6-hydroxymelatonin sulfate (aMT6s), a main metabolite of melatonin, was the primary efficacy endpoint for SET. Scores on the 24-hour clinical response scale were another defined endpoint for SET. Outcomes for RESET included maintenance of entrainment (aMT6s) and maintenance of clinical response. Study results demonstrated that tasimelteon entrains the master clock (both melatonin and cortisol) and has clinically meaningful effects on the sleep-wake cycle in terms of the timing and amount of sleep, and improved measure of global functioning.[15, 16]
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 to remain awake by involving them in activities and restricting sleep to conventional time periods. Encouraging a scheduled afternoon nap at a consistent time helps prevent multiple brief daytime naps and promotes consolidated sleep at 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.[17]
Studies have shown a positive association between exercise and improved sleep, including increased total sleep time, more time spent in slow-wave sleep, delayed REM onset, and reduced REM sleep. Over the long term, exercise is also linked to improved sleep efficiency. These sleep improvements are thought to result from multiple mechanisms, including a reduction in exercise-induced inflammation, alterations in core body temperature and heart rate variability, regulation of neurotransmitters, and increases in growth hormone and BDNF.
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:
Consultation with the following specialists can be useful in managing circadian rhythm disorders:
Strategies to prevent circadian rhythm disorders include the following:
Address associated psychological issues. Patients with delayed sleep-phase syndrome (DSPS) who initially respond 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 the importance of good sleep hygiene and avoidance of the use of alcohol, stimulants (eg, nicotine, caffeine), and strenuous exercise before bedtime.
The following organizations have released guidelines for the management of circadian rhythm disorders. Key diagnostic and treatment recommendations have been reviewed and integrated throughout the article.
Short-acting benzodiazepines are often prescribed in the early treatment of sleep-onset insomnia, while long-acting agents are often used to treat long-standing insomnia with sleep maintenance, as well as sleep-onset, insomnia.
Nonbenzodiazepine hypnotics have come into increased use because they do not significantly affect sleep architecture and, unlike benzodiazepines, are not associated with a rebound phenomenon.
Melatonin reportedly is effective against jet lag, as well as in the treatment of sleep-onset insomnia in elderly patients who are melatonin deficient. Melatonin agonists can be prescribed for insomnia characterized by difficulty with sleep onset.
Clinical Context: Estazolam is an intermediate-acting agent with a slow onset of action and a long duration. It is a good agent for sleep-maintenance insomnia. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Clinical Context: Flurazepam is frequently chosen as a short-term treatment of insomnia. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Clinical Context: Quazepam is used for sleep-maintenance insomnia. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Clinical Context: Temazepam's intermediate rate of absorption and duration of action make it useful for treating initial and middle insomnia. Because temazepam has no active metabolite, cognitive impairment and grogginess the following day are reduced. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Clinical Context: Triazolam is frequently chosen as a short-term adjunct to behavioral therapy. This short-acting agent is effective in helping patients fall asleep. It is not effective in persons with sleep maintenance problems.
For patients with sleep maintenance insomnia, a benzodiazepine with an intermediate half-life (eg, estazolam [ProSom]) or a long half-life (eg, quazepam) may be considered.
Clinical Context: Eszopiclone is a nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. Its precise mechanism of action is unknown, but the drug is believed to interact with the gamma-aminobutyric acid (GABA) receptor at binding domains close to or allosterically coupled to benzodiazepine receptors. It is indicated for insomnia, to decrease sleep latency and improve sleep maintenance. It has a short half-life of 6 hours.
The starting dose is 1 mg immediately before bedtime, with at least 7-8 h remaining before the planned time of awakening. The dose may be increased if clinically warranted to 2-3 mg HS in nonelderly adults, and 2 mg in elderly or debilitated patients.
Clinical Context: Zaleplon is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. It has a chemical structure unrelated to benzodiazepines, barbiturates, or other hypnotic drugs but interacts with the GABA-benzodiazepine receptor complex. It binds selectively to the omega-1 receptor situated on the alpha subunit of the GABAA receptor complex in the brain. Zaleplon potentiates t-butyl-bicyclophosphorothionate (TBPS) binding and has preferential binding to the omega-1 receptor of the GABA receptor family.
Clinical Context: Zolpidem is a nonbenzodiazepine hypnotic of the imidazopyridine class. It is rapidly absorbed, has an elimination half-life of 2.5 hours, and is a 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.
Clinical Context: Melatonin is available as an over-the-counter (OTC) preparation. It is used to enhance the natural sleep process and for resetting the body's internal time clock when an individual is traveling through different time zones. It has also been used for the treatment of circadian rhythm sleep disorders in blind people with no light perception.
No recommended daily allowance (RDA) of melatonin has been approved by the US Food and Drug Administration (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 the risks and benefits of each therapeutic option. Slow-release products are reported to be less effective. Melatonin is believed to be effective in persons crossing 5 or more time zones and is less effective in individuals traveling in a westward direction.
Clinical Context: Ramelteon is a melatonin receptor agonist with high selectivity for human melatonin MT1 and MT2 receptors. MT1 and MT2 are thought to promote sleep and to be involved in the maintenance of circadian rhythm and the normal sleep-wake cycle.
Clinical Context: Tasimelteon is a melatonin receptor agonist with high affinity for MT1 and MT2 receptors in the suprachiasmatic nucleus of the brain. MT1 and MT2 are thought to synchronize the body's melatonin and cortisol circadian rhythms with the day-night cycle in patients with non–24-hour disorder. It is indicated for non–24-hour sleep-wake disorder in the totally blind.
Clinical Context: Suvorexant is an orexin receptor antagonist. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R by suvorexant is thought to suppress wake drive. It is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.