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Postgraduate Education Corner: Contemporary Reviews in Sleep Medicine |

Sleep Medicine Pharmacotherapeutics OverviewSleep Medicine Pharmacotherapeutics, Part 1: Today, Tomorrow, and the Future (Part 1: Insomnia and Circadian Rhythm Disorders) FREE TO VIEW

Seema Gulyani, PhD, NP; Rachel E. Salas, MD; Charlene E. Gamaldo, MD
Author and Funding Information

From the Division of Pulmonary and Critical Care Medicine (Dr Gulyani) and Department of Neurology (Drs Salas and Gamaldo), Johns Hopkins University, Baltimore, MD.

Correspondence to: Seema Gulyani, PhD, NP, Johns Hopkins University, 601 N Caroline St, Ste 1261, Baltimore, MD 21287; e-mail: sgulyan1@jhmi.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(6):1659-1668. doi:10.1378/chest.12-0465
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Over the past 10 years, significant strides have been made in the understanding, development, and availability of sleep disorder therapeutics. In this review series, we discuss the current evidence surrounding the mechanisms of actions, indications, efficacy, and adverse side effects associated with the available armamentarium of sleep over-the-counter and pharmacotherapeutics. This article is the first of a two-part series that covers the therapeutics for insomnia and circadian rhythm disorders.

Figures in this Article

Insomnia is the most common sleep disorder, affecting millions worldwide. The International Classification of Sleep Disorders–Second Edition (ICSD-2) defines insomnia as a functionally debilitating condition characterized by repeated difficulty with sleep initiation, maintenance, or quality despite adequate sleep opportunity.1 Currently, the ICSD-2 subclassifies insomnia as either primary insomnia or insomnia due to a secondary medical, psychiatric, or medication-induced etiology. Primary insomnia symptoms can be acute and self-limiting or chronic and persistent. In the case of adjustment insomnia, sleep complaints develop abruptly as the result of a tangible event, such as the loss of a loved one. Individuals classified with this acute form of insomnia, however, will typically report resolution of their sleep complaints within 1 month. When the symptoms of primary insomnia persist beyond 3 months, the insomnia is reclassified as one of the following three chronic primary insomnia subtypes: psychophysiologic insomnia, paradoxical insomnia, or idiopathic insomnia.

Epidemiology

The lifetime prevalence of insomnia is approximately 4% to 24%, depending on the study design and diagnostic criteria used.2-5 Studies have shown that the prevalence of insomnia varies with age and by sex, with women having a lifetime risk 1.5- to 2-times higher than men. Additional demographic factors associated with increased risk of insomnia include employment status, obesity, and an employment history associated with a rotating shift. When insomnia evolves into a chronic and debilitating condition, the estimated prevalence ranges from 6% to 10%.4

Neurobiology of Insomnia

The sleep-wake state represents a dynamic interaction between arousing and sleep-inducing physiologic systems (Table 1). These interconnected neurotransmitter systems, which include noradrenaline, serotonin, acetylcholine, dopamine, histamine, and orexin, promote wakefulness, whereas γ-aminobutyric acid (GABA), glycine, melatonin, and adenosine promote sleepiness.6,7

Table Graphic Jump Location
Table 1 —Neurotransmitters Involved in Sleep and Arousal

GABA = γ-aminobutyric acid.

Over-the-counter Insomnia Treatments

Most of the over-the-counter sleep-promoting agents contain antihistamines that block histamine 1 receptors, thus decreasing arousal. These drugs have low efficacy, which can generally be explained by the fact that they target only one of the parallel arousing systems (Table 2). Although antihistamine-based medications may improve mild insomnia for a short period of time, they are not likely to significantly improve symptoms over an extended period and, thus, are not ideal. Side effects are mainly due to the diffuse and systemic anticholinergic properties. Common side effects of antihistamines typically include dry mouth, dizziness, daytime sedation, and memory problems. These medications are not recommended for pregnant women or breast-feeding mothers. People aged >65 years are particularly sensitive to the anticholinergic side effects, making these medications a less desirable option for this age group.

Table Graphic Jump Location
Table 2 —Common Over-the-counter Sleep Aids

FDA = Food and Drug Administration; H = histamine; MT = melatonin; N/A = not applicable.

a 

Made by various companies as a combination product as a sleep aid.

b 

N/A because different ingredients in combination drugs have different half-lives.

Melatonin is another commonly used over-the-counter sleep aid for insomnia. It is a sleep-promoting hormone made by the pineal gland that regulates the circadian rhythm by its action on melatonin receptors in the suprachiasmatic nucleus.8,9 Although melatonin often is used and viewed as a natural supplement, patients should be alerted to the potentially serious side effects that can be encountered, including alterations in cardiac rhythmicity, BP, GI motility, and glucose metabolism.10

Food and Drug Administration-Approved Medications for Insomnia

The current US Food and Drug Administration (FDA)-approved medications for insomnia use either the GABAergic pathway or the central melatonergic pathway (Table 3). These medications often are prescribed to individuals with chronic insomnia. Although acute and adjustment insomnia often are self-limited, these medications can also be used during the symptomatic period in severe cases. A major issue regarding the use of hypnotic agents for chronic insomnia is the duration of treatment. Nearly all published placebo-controlled studies have reported efficacy and tolerability based on 2- to 6-week trials.11

Table Graphic Jump Location
Table 3 —FDA-Approved Drugs for Insomnia

See Table 1 and 2 legends for expansion of abbreviations.

a 

Produces a metabolite with a longer half-life (40-250 h).

b 

Specific ranges: intermezzo sublingual, 1.75-3.5 mg; oral spray, 10 mg; immediate release, 10 mg; extended release, 12.5 mg.

Although insomnia could last for years or decades, longitudinal treatment studies evaluating the efficacy and outcomes of these medications beyond 1 year are limited. Two studies done with eszopiclone 3 mg provided placebo-controlled data for 6 months of treatment and found that tolerance and withdrawal did not occur in up to 1 year of continuous therapy. The paucity of information regarding the safety and efficacy of these medications as a long-term therapeutic suggests further investigation.

Most of the current insomnia pharmacotherapeutics target the GABAergic system. These agents are GABAA receptor agonists that activate the receptor by binding to the benzodiazepine (BZD) receptor site. Activation of the GABAA receptors reduces the neuronal excitability of the wake/arousal centers, resulting in sleep. The GABAA receptor comprises five subunits that form a central chloride channel. Most receptor subtypes consist of two α and two β subunits and one γ subunit. The α subunits have six variants, and α1 is of interest in insomnia because agents binding to this subunit mediate sedation (Fig 1). The BZD receptor agonist (BZRA) insomnia agents (eg, zolpidem, eszopiclone) demonstrate improvements over the earlier generation of BZDs primarily because of their faster elimination rates and more-selective binding affinity to specific α subunits. The BZRA drugs have half-lives <6 h, optimally allowing for the presence of peak therapeutic levels during the sleep period while minimizing the risk of residual daytime sedation (Table 4).

Figure Jump LinkFigure 1. The five subunits of a GABAA receptor. In addition to a Cl channel pore and two GABA active binding sites, a BZD allosteric binding site exists at the interface of the γ2 subunit and one of four isoforms of the α subunit (α1, α2, α3, and α5). BZDs have nonselective binding affinity for the BZD site regardless of the α-subunit isoform, whereas newer BZD receptor agonist insomnia medications have more selective affinity to the BZD binding sites that contain specific α-subunit isoforms as depicted in the key. This selectivity allows for not only greater control of clinical effects but also association with specific side effect profiles (Table 4). BZD = benzodiazepine; Cl = chloride ion; GABA = γ-aminobutyric acid.Grahic Jump Location
Table Graphic Jump Location
Table 4 —Effects Mediated by GABAA Receptor α Subunits

See Table 1 legend for expansion of abbreviation.

On the other hand, the classic BZDs have roughly equivalent affinities for all of the α subunits that can be represented in the BZD receptor. Clinical use of BZDs, such as temazepam, continues but is limited by side effects likely because of its indiscriminate binding to GABAA receptors and unfavorable pharmacokinetics.12 BZDs are known to be involved in mediating amnesic and ataxic effects in addition to sedation (triazolam, flurazepam) (Table 3) and, therefore, must be prescribed with caution in vulnerable populations, such as elderly people.

Ramelteon was the first approved melatonergic drug for the treatment of insomnia. It acts on melatonin receptors MT1 and MT2, showing higher affinities for these receptors than the natural ligand melatonin. In chronic insomnia, ramelteon decreases sleep onset latency and increases total sleep time and sleep efficiency without causing residual sleepiness, psychomotor complaints, addiction, or withdrawal symptoms.13

Currently, there are no FDA-approved pharmacotherapies for insomnia in the pediatric population. Doxepin, however, was approved in the adult population for sleep maintenance insomnia and has long been used safely in the pediatric population for anxiety and depression.

As discussed in a previous section, insomnia often presents as a chronic condition requiring treatment that far exceeds the duration approved by the FDA for any of the currently available agents. This often sparks questions and concerns by both patients and providers regarding the long-term consequences of these medications. Dependence risk depends on both the agent and the dose and may vary among individuals on the basis of comorbid psychiatric illness or polypharmacy. Studies have found that nightly treatment in adults with eszopiclone 3 mg or zaleplon 5 to 10 mg for up to 1 year did not result in tolerance or withdrawal symptoms.14 Another study of nightly zaleplon use in older adults demonstrated safety with minimal risk of withdrawal upon discontinuation.15

Non-FDA-Approved (Off-label) Medications for Insomnia

The recognition of the prevalence and negative consequences of insomnia predates the introduction of FDA-approved therapeutics. For this reason, clinicians have long prescribed and continue to prescribe several off-label medications for insomnia in lieu of the FDA-approved options. Tricyclic antidepressants, BZDs, and, more recently, atypical antipsychotics are three of the most common classes prescribed strictly for sleep promotion. Unlike most FDA-approved therapeutics with half-lives in the 2- to 6-h range, most off-label options have half-lives of >6 h (eg, nortriptyline) (Table 5), increasing the likelihood of residual grogginess or hangover sensations in the morning. This was particularly the case with the older BZDs, such as nitrazepam, which was associated with daytime sedation and falls in elderly people.16,17 As shown in Table 5, the utility of these medications for sleep promotion is limited by their side effects profile, which is considered to outweigh their sleep-promoting benefits based on current sleep expert consensus.12,18,19

Table Graphic Jump Location
Table 5 —Non-FDA-Approved Antidepressant Medications Used as Sleep Aids

5-HT =5-hydroxytryptamine (serotonin); D2 =dopamine; SNRI =serotonin-norepinephrine reuptake inhibitor. See Table 2 legend for expansion of other abbreviation.

New Insomnia Drugs in Clinical Trials or Newly Approved

Clinical trials targeting insomnia remain robust, despite the overall drop in economic resources and investments targeting pharmacotherapeutics (Table 6). Increased understanding of complex neuronal networks involved in sleep and wake has led to the development of new hypnotics that target a diverse range of receptors with increasing selectivity. Potential agents under investigation are targeting mechanisms and pathways, including histamine 1 receptors and orexin receptors.

Table Graphic Jump Location
Table 6 —New Drugs Under Clinical Trials

NK-1 =neurokinin 1; OX =orexin. See Table 1, 2, and 5 legends for expansion of other abbreviations.

Special Consideration: Insomnia Pharmacotherapy and Obstructive Sleep Apnea

Insomnia and sleep-disordered breathing represent the two most common sleep disorders. Although they may occur separately in a patient, they can also occur concurrently. As such, the prevalence of these conditions often results in the sleep practitioner raising clinical questions regarding the impact of insomnia on (1) altering the respiratory arousal thresholds and apnea-hypopnea index, (2) CPAP adherence, and (3) treatment of insomnia in the setting of obstructive sleep apnea. Current clinical trials are evaluating the answers to these questions. A recent double-blind, placebo-controlled study found that eszopiclone 3 mg significantly improved sleep quality and duration while lowering the stage N2 sleep respiratory arousal threshold and apnea-hypopnea index without prolonging respiratory events or worsening hypoxemia.20 Trazodone at doses as high as 100 mg has been found to increase the arousal threshold in response to hypercapnia in patients with obstructive sleep apnea and allows these patients to tolerate higher CO2 levels.21 One randomized, double-blind, placebo-controlled pilot trial examined the effectiveness of ramelteon on improving sleep parameters in older people starting on autotitrating positive airway pressure (APAP) therapy.22 This study found that ramelteon resulted in statistically reduced sleep onset latency relative to placebo without any change in subjective sleep onset latency, sleep quality, APAP adherence, or daytime functioning parameters. These results suggest that ramelteon may improve sleep onset latency in this population, particularly during the critical initial phase of starting APAP therapy. Another randomized trial showed that subjects assigned to the eszopiclone group had greater CPAP adherence, demonstrating 1.3 h more of CPAP use per night for all nights.23,24 Another study by the same authors reported that premedication with eszopiclone during a CPAP titration study significantly improved short-term CPAP compliance. Premedication also improved sleep efficiency, decreased sleep onset latency, and decreased the number of residual obstructive events observed at the final CPAP pressure.25

Special Consideration: Insomnia and Comorbid Depression

Insomnia is one of the diagnostic features for mood instability in depression and anxiety. For this reason, clinicians have long struggled with whether to treat insomnia as a distinct condition or as a secondary phenomenon related to mood stability. Data suggest that insomnia may in fact predate complaints related to mood. In a review of epidemiologic studies, it was reported that insomnia predicted future risks of depression, anxiety, substance abuse, and suicide.26 A community-based study in adolescents reported that 69% of insomnia cases preceded comorbid depression, whereas anxiety disorder preceded insomnia 73% of the time.27,28 Findings suggest that long-term outcomes significantly improve when the sleep disruption is concurrently and aggressively managed along with the primary mood complaints in individuals with significant sleep disruption. Enhanced rate of mood stabilization and a decline in relapse rates have been found with this dual approach.29 Studies have shown that more-sedating antidepressants, such as nefazodone and amitriptyline, improve sleep symptoms and polysomnographic findings compared with selective serotonin reuptake inhibitors alone.30 Thus, among patients who present with significant insomnia at the time of depression, selection of more-sedating antidepressants, such as mirtazapine and trazodone, may be reasonable.31 Among patients with comorbid insomnia, BZRA hypnotics could also be an effective adjunctive treatment. The combination of eszopiclone with fluoxetine has been associated with greater sleep improvements and depression responses compared with fluoxetine alone.32 Adding a small dose of trazodone (50-100 mg) to a selective serotonin reuptake inhibitor has been shown to improve insomnia comorbid with depression.33

Circadian rhythm sleep disorders (CRSDs) are characterized by a misalignment between one’s sleep period and physical or social 24-h environmental cycle.34,35 Both exogenous and endogenous factors can contribute to the misalignment.36 Circadian and homeostatic processes interact to regulate sleep and wakefulness. Light is the strongest cue that synchronizes the circadian clock to the external environment. The master clock regulating the endogenous circadian rhythm is located in the suprachiasmatic nucleus, which receives information about light through the retinohypothalamic tract. Melatonin, which is regulated by the suprachiasmatic nucleus, begins to rise 1 to 3 h before the habitual sleep time and peaks prior to core body temperature nadir. In contrast to light, melatonin given in the evening shifts the circadian rhythm to an earlier time.

Six distinct CRSDs are currently recognized in the ICSD-21: (1) delayed sleep phase disorder (DSPD), (2) advanced sleep phase disorder (ASPD), (3) shift work disorder, (4) jet lag disorder (JLD), (5) free-running disorder, and (6) irregular sleep-wake rhythm (ISWR). The core of the biologic clock is believed to consist of interactions among about 10 clock genes, including Per1, Per2, and Per3 (circadian clock protein period 1, 2, and 3); Cry1 and Cry2 (cryptochrome 1 and 2 [photolyase-like]); Bmal1 (aryl hydrocarbon receptor nuclear translocator-like); CLOCK (mammalian clock gene); and CK1δ/ε (casein kinase 1 δ/χ).7Per1, 2, and 3, Cry 1 and 2, Bmal1, and CLOCK code for transcriptional factors, whereas CK1δ/ε code for kinases that phosphorylate these transcriptional factors. Functional abnormalities of these clock genes affect the circadian phenotype in various species, including insects, mice, hamsters, and humans.37

In most cases, CRSD treatment involves a combination of behavioral, over-the-counter, and pharmacologic therapies. General statements regarding behavioral strategies are discussed as they apply to the specific CRSD conditions. In-depth discussion of the behavioral strategies, however, are beyond the scope of this review.

Delayed Sleep Phase Disorder

DSPD is one of the most common CRSDs, affecting an estimated 1.7% of the general population and up to 16% of adolescents and young adults. Nearly 10% of those with DSPD also develop chronic insomnia38,39 because of their unsuccessful attempts to conform to conventional work or other social demands. Treatment of DSPD involves a multimodal approach that uses both behavioral and pharmacologic treatments. Behavioral approaches usually involve the introduction of zeitgebers (environmental variables capable of entraining the circadian rhythm) at appropriate times in the sleep-wake cycle to assist in anchoring and shifting forward the individual’s inherent circadian clock. In general, techniques such as sleep restriction with stringent wake time and timed light exposure have proven effective.34,40 Melatonin remains effective in advancing the sleep-wake rhythm and endogenous melatonin rhythm in DSPD.8,36

Advanced Sleep Phase Disorder

ASPD is characterized by a stable sleep schedule that is several hours earlier than the conventional or desired time. Conventionally viewed as morning larks, individuals with this circadian rhythm usually do not encounter the same difficulties related to work performance, attendance, or punctuality experienced by those with DSPD. In severe cases, however, they present with concerns of inability to fully participate in evening social events with friends and family. Several pedigrees have exhibited a familial preponderance for ASPD. So far, causative mutations of clock genes have been found in two of the familial ASPD pedigrees. The mutation of Per2 cosegregated with affected patients in one of the familial ASPD pedigrees. Although there is rationale indicated in American Academy of Sleep Medicine guidelines for timed melatonin administration, there is no clear supporting evidence of its effectiveness.34

Shift Work Disorder

An estimated 20% of the US workforce does some form of shift work, with women doing more than men. Shift work disorder has been linked to increased morbidity (sleep-wake disturbances, GI disturbances, infertility, glucose metabolism dysregulation) and mortality (malignancy and vehicular or occupational accidents).41 Many therapeutic modalities ranging from behavioral to pharmacologic have been found to be effective.42 Behavioral modifications include planned napping and timed light exposure in the work environment. Restricting light in the morning has also been shown to improve alertness, vigilance, mood, and work time tasks.35 A meta-analysis concluded that caffeine may be an effective intervention for improving performance in shift workers.43 Administration of melatonin 5 to 6 mg prior to daytime sleep is indicated to promote daytime sleep among night shift workers, although the evidence is mixed.35 Melatonin 3 mg or 0.5 mg given before naps and sleep periods results in a significant phase advancement compared with placebo in a randomized controlled trial of simulated night workers.44

BZDs (Table 7) have been evaluated as a potential sleep aid for shift work disorder. Studies have shown zopiclone 7.5 mg,45 triazolam 0.25 to 0.5 mg,46 and temazepam 20 mg47 to be effective in increasing daytime sleep duration with both subjective and objective measures. One study with zolpidem 5 to 10 mg reported improvement in night shift-related sleep quality over placebo; however, mood was worsened during the following work period compared with placebo.48 A double-blinded randomized controlled trial of modafinil 200 mg given 30 to 60 min before the start of a night shift resulted in objective improvement in sleepiness and improved performance on psychomotor vigilance testing.49 Armodafinil 150 mg given 30 to 60 min prior to beginning the night shift resulted in reduced self-reported sleepiness during work and the morning commute.50 Significant improvement in performance on standardized memory and attention testing was also demonstrated. No worsening in daytime sleep parameters occurred with armodafinil. Both modafinil and armodafinil are FDA approved for the treatment of shift work disorder.

Table Graphic Jump Location
Table 7 —Commonly Used Medication to Treat Circadian Rhythm Disorders

OTC =over-the-counter. See Table 2 for expansion of other abbreviations.

Jet Lag Disorder

The symptoms of JLD are due to circadian misalignment when crossing time zones too rapidly for the circadian system to keep pace. Depending on the number and direction of time zones crossed, it may take days for the circadian system to resynchronize. The intensity and duration of the disorder are related to (1) the number of time zones crossed, (2) the direction of travel, (3) the ability to sleep while traveling, (4) the availability and intensity of local circadian time cues, and (5) individual differences in phase tolerance.35 In addition to sleep complaints, JLD can be associated with the following somatic complaints: GI disturbance, light-headedness, weakness, and physical clumsiness.51 The administration of melatonin 5 to 8 mg is the most extensively studied treatment of JLD, with demonstrated efficacy in reducing symptoms of jet lag and improving sleep when traveling across multiple time zones.52,53 Efficacy of this treatment has been studied primarily under the context of eastward travel,54-56 but a few studies have also provided evidence that melatonin is useful in westward travel.57 One study showed that ramelteon 1 mg taken before bedtime reduced sleep onset latency after a 5-h phase advance due to eastward jet travel.55

A short course of a hypnotic medication has been shown in randomized trials to reduce insomnia related to jet lag. Eastward travelers from the United States taking zolpidem 10 mg reported better sleep posttravel than those taking placebo, particularly on the first 2 posttravel nights. After trans-Atlantic travel crossing five to nine time zones, zolpidem was associated with improved sleep quality and increased total sleep time.34,52

Free-Running Disorder

The earliest studies of human subjects in time-free environments concluded that most people have an intrinsic circadian period >24 h, averaging about 24.2 h. Patients with free-running rhythms have circadian cycles that mimic those of individuals in time-free environments and, thus, are believed to reflect a failure of entrainment. The condition is rare in people with normal sight, but quite common in people with retinal blindness who have no access to the entraining effects of the light/dark cycle.58 Data from limited studies show that both appropriately timed bright light exposure and melatonin administration entrain sighted patients with free-running disorder. Melatonin 0.5 to 10 mg has also been shown to entrain people with total or retinal blindness with free-running disorder.58,59

Irregular Sleep-Wake Rhythm

ISWR is characterized by the relative absence of a circadian pattern to the sleep-wake cycle. Total sleep time could be normal, but instead of being consolidated into a distinct sleep and wake bout, sleep times are shortened, and in extreme cases, sleep cycles are almost randomly distributed throughout the day and night. ISWR is commonly associated with neurologic and psychiatric illness, such as mental retardation and dementia in older adults, especially in people with Alzheimer disease. There is no proven pharmacotherapy to treat ISWR.

Sleep medicine remains an area of active research. There has been an increase in the number of sleep over-the-counter and pharmacotherapeutics, particularly for insomnia. Although the GABAergic system remains the primary target for the current insomnia pharmacotherapeutics, agents targeting more-diverse mechanisms (melatonin, orexin, and histamine) are either in the clinical trial pipeline or have recently entered the market. Longitudinal outcome studies evaluating the long-term use of sleep pharmacotherapeutics remain sparse; thus, further studies are warranted. Insomnia and circadian rhythm disorders are two common conditions associated with several medical, psychiatric, and other primary sleep conditions. Therefore, treatment strategies should involve a strong emphasis on individualized therapies based on comorbid conditions and the available efficacy and outcomes data.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

APAP

autotitrating positive airway pressure

ASPD

advanced sleep phase disorder

BZD

benzodiazepine

BZRA

benzodiazepine receptor agonist

CRSD

circadian rhythm sleep disorder

DSPD

delayed sleep phase disorder

FDA

Food and Drug Administration

GABA

γ-aminobutyric acid

ICSD-2

International Classification of Sleep Disorders–Second Edition

ISWR

irregular sleep-wake rhythm

JLD

jet lag disorder

International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.
 
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Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry. 2006;59(11):1052-1060. [CrossRef] [PubMed]
 
Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M. Trazodone for antidepressant-associated insomnia. Am J Psychiatry. 1994;151(7):1069-1072. [PubMed]
 
Sack RL, Auckley D, Auger RR, et al; American Academy of Sleep Medicine. Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm. An American Academy of Sleep Medicine review. Sleep. 2007;30(11):1484-1501. [PubMed]
 
Sack RL, Auckley D, Auger RR, et al; American Academy of Sleep Medicine. Circadian rhythm sleep disorders: part I, basic principles, shift work and jet lag disorders. An American Academy of Sleep Medicine review. Sleep. 2007;30(11):1460-1483. [PubMed]
 
Morgenthaler TI, Lee-Chiong T, Alessi C, et al; Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007;30(11):1445-1459. [PubMed]
 
Ebisawa T. Circadian rhythms in the CNS and peripheral clock disorders: human sleep disorders and clock genes. J Pharmacol Sci. 2007;103(2):150-154. [CrossRef] [PubMed]
 
Schrader H, Bovim G, Sand T. The prevalence of delayed and advanced sleep phase syndromes. J Sleep Res. 1993;2(1):51-55. [CrossRef] [PubMed]
 
Dagan Y, Eisenstein M. Circadian rhythm sleep disorders: toward a more precise definition and diagnosis. Chronobiol Int. 1999;16(2):213-222. [CrossRef] [PubMed]
 
Sharkey KM, Carskadon MA, Figueiro MG, Zhu Y, Rea MS. Effects of an advanced sleep schedule and morning short wavelength light exposure on circadian phase in young adults with late sleep schedules. Sleep Med. 2011;12(7):685-692. [CrossRef] [PubMed]
 
Schwartz JR, Roth T. Shift work sleep disorder: burden of illness and approaches to management. Drugs. 2006;66(18):2357-2370. [CrossRef] [PubMed]
 
Zee PC, Goldstein CA. Treatment of shift work disorder and jet lag. Curr Treat Options Neurol. 2010;12(5):396-411. [CrossRef] [PubMed]
 
Ker K, Edwards PJ, Felix LM, Blackhall K, Roberts I. Caffeine for the prevention of injuries and errors in shift workers. Cochrane Database Syst Rev. 2010;;(5): CD008508.
 
Sharkey KM, Eastman CI. Melatonin phase shifts human circadian rhythms in a placebo-controlled simulated night-work study. Am J Physiol Regul Integr Comp Physiol. 2002;282(2):R454-R463. [PubMed]
 
Monchesky TC, Billings BJ, Phillips R, Bourgouin J. Zopiclone in insomniac shiftworkers. Evaluation of its hypnotic properties and its effects on mood and work performance. Int Arch Occup Environ Health. 1989;61(4):255-259. [CrossRef] [PubMed]
 
Walsh JK, Schweitzer PK, Anch AM, Muehlbach MJ, Jenkins NA, Dickins QS. Sleepiness/alertness on a simulated night shift following sleep at home with triazolam. Sleep. 1991;14(2):140-146. [PubMed]
 
Porcù S, Bellatreccia A, Ferrara M, Casagrande M. Performance, ability to stay awake, and tendency to fall asleep during the night after a diurnal sleep with temazepam or placebo. Sleep. 1997;20(7):535-541. [PubMed]
 
Hart CL, Ward AS, Haney M, Foltin RW. Zolpidem-related effects on performance and mood during simulated night-shift work. Exp Clin Psychopharmacol. 2003;11(4):259-268. [CrossRef] [PubMed]
 
Czeisler CA, Walsh JK, Roth T, et al;; U.S. Modafinil in Shift Work Sleep Disorder Study Group U.S. Modafinil in Shift Work Sleep Disorder Study Group. Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med. 2005;353(5):476-486. [CrossRef] [PubMed]
 
Czeisler CA, Walsh JK, Wesnes KA, Arora S, Roth T. Armodafinil for treatment of excessive sleepiness associated with shift work disorder: a randomized controlled study. Mayo Clin Proc. 2009;84(11):958-972. [PubMed]
 
Drake CL, Roehrs T, Richardson G, Walsh JK, Roth T. Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep. 2004;27(8):1453-1462. [PubMed]
 
Sack RL. Clinical practice. Jet lag. N Engl J Med. 2010;362(5):440-447. [CrossRef] [PubMed]
 
Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;;(2): CD001520.
 
Takahashi T, Sasaki M, Itoh H, et al. Melatonin alleviates jet lag symptoms caused by an 11-hour eastward flight. Psychiatry Clin Neurosci. 2002;56(3):301-302. [CrossRef] [PubMed]
 
Zee PC, Wang-Weigand S, Wright KP Jr, Peng X, Roth T. Effects of ramelteon on insomnia symptoms induced by rapid, eastward travel. Sleep Med. 2010;11(6):525-533. [CrossRef] [PubMed]
 
Suhner A, Schlagenhauf P, Höfer I, Johnson R, Tschopp A, Steffen R. Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag. Aviat Space Environ Med. 2001;72(7):638-646. [PubMed]
 
Paul MA, Miller JC, Gray GW, Love RJ, Lieberman HR, Arendt J. Melatonin treatment for eastward and westward travel preparation. Psychopharmacology (Berl). 2010;208(3):377-386. [CrossRef] [PubMed]
 
Sack RL, Lewy AJ, Blood ML, Keith LD, Nakagawa H. Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. J Clin Endocrinol Metab. 1992;75(1):127-134. [CrossRef] [PubMed]
 
Arendt J, Aldhous M, Wright J. Synchronisation of a disturbed sleep-wake cycle in a blind man by melatonin treatment. Lancet. 1988;331(8588):772-773. [CrossRef]
 

Figures

Figure Jump LinkFigure 1. The five subunits of a GABAA receptor. In addition to a Cl channel pore and two GABA active binding sites, a BZD allosteric binding site exists at the interface of the γ2 subunit and one of four isoforms of the α subunit (α1, α2, α3, and α5). BZDs have nonselective binding affinity for the BZD site regardless of the α-subunit isoform, whereas newer BZD receptor agonist insomnia medications have more selective affinity to the BZD binding sites that contain specific α-subunit isoforms as depicted in the key. This selectivity allows for not only greater control of clinical effects but also association with specific side effect profiles (Table 4). BZD = benzodiazepine; Cl = chloride ion; GABA = γ-aminobutyric acid.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Neurotransmitters Involved in Sleep and Arousal

GABA = γ-aminobutyric acid.

Table Graphic Jump Location
Table 2 —Common Over-the-counter Sleep Aids

FDA = Food and Drug Administration; H = histamine; MT = melatonin; N/A = not applicable.

a 

Made by various companies as a combination product as a sleep aid.

b 

N/A because different ingredients in combination drugs have different half-lives.

Table Graphic Jump Location
Table 3 —FDA-Approved Drugs for Insomnia

See Table 1 and 2 legends for expansion of abbreviations.

a 

Produces a metabolite with a longer half-life (40-250 h).

b 

Specific ranges: intermezzo sublingual, 1.75-3.5 mg; oral spray, 10 mg; immediate release, 10 mg; extended release, 12.5 mg.

Table Graphic Jump Location
Table 4 —Effects Mediated by GABAA Receptor α Subunits

See Table 1 legend for expansion of abbreviation.

Table Graphic Jump Location
Table 5 —Non-FDA-Approved Antidepressant Medications Used as Sleep Aids

5-HT =5-hydroxytryptamine (serotonin); D2 =dopamine; SNRI =serotonin-norepinephrine reuptake inhibitor. See Table 2 legend for expansion of other abbreviation.

Table Graphic Jump Location
Table 6 —New Drugs Under Clinical Trials

NK-1 =neurokinin 1; OX =orexin. See Table 1, 2, and 5 legends for expansion of other abbreviations.

Table Graphic Jump Location
Table 7 —Commonly Used Medication to Treat Circadian Rhythm Disorders

OTC =over-the-counter. See Table 2 for expansion of other abbreviations.

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Sullivan SS, Guilleminault C. Emerging drugs for insomnia: new frontiers for old and novel targets. Expert Opin Emerg Drugs. 2009;14(3):411-422. [CrossRef] [PubMed]
 
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Eckert DJ, Owens RL, Kehlmann GB, et al. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clin Sci (Lond). 2011;120(12):505-514. [CrossRef] [PubMed]
 
Heinzer RC, White DP, Jordan AS, et al. Trazodone increases arousal threshold in obstructive sleep apnoea. Eur Respir J. 2008;31(6):1308-1312. [CrossRef] [PubMed]
 
Gooneratne NS, Gehrman P, Gurubhagavatula I, Al-Shehabi E, Marie E, Schwab R. Effectiveness of ramelteon for insomnia symptoms in older adults with obstructive sleep apnea: a randomized placebo-controlled pilot study. J Clin Sleep Med. 2010;6(6):572-580. [PubMed]
 
Lettieri CJ, Shah AA, Holley AB, Kelly WF, Chang AS, Roop SA; CPAP Promotion and Prognosis-The Army Sleep Apnea Program Trial CPAP Promotion and Prognosis-The Army Sleep Apnea Program Trial. Effects of a short course of eszopiclone on continuous positive airway pressure adherence: a randomized trial. Ann Intern Med. 2009;151(10):696-702. [PubMed]
 
Bradshaw DA, Ruff GA, Murphy DP. An oral hypnotic medication does not improve continuous positive airway pressure compliance in men with obstructive sleep apnea. Chest. 2006;130(5):1369-1376. [CrossRef] [PubMed]
 
Lettieri CJ, Collen JF, Eliasson AH, Quast TM. Sedative use during continuous positive airway pressure titration improves subsequent compliance: a randomized, double-blind, placebo-controlled trial. Chest. 2009;136(5):1263-1268. [CrossRef] [PubMed]
 
Taylor DJ, Lichstein KL, Durrence HH. Insomnia as a health risk factor. Behav Sleep Med. 2003;1(4):227-247. [CrossRef] [PubMed]
 
Mindell JA, Emslie G, Blumer J, et al. Pharmacologic management of insomnia in children and adolescents: consensus statement. Pediatrics. 2006;117(6):e1223-e1232. [CrossRef] [PubMed]
 
Johnson EO, Roth T, Schultz L, Breslau N. Epidemiology of DSM-IV insomnia in adolescence: lifetime prevalence, chronicity, and an emergent gender difference. Pediatrics. 2006;117(2):e247-e256. [CrossRef] [PubMed]
 
Riemann D; Workshop Participants Workshop Participants. Does effective management of sleep disorders reduce depressive symptoms and the risk of depression?. Drugs. 2009;69(suppl 2):43-64. [CrossRef] [PubMed]
 
Rush AJ, Armitage R, Gillin JC, et al. Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder. Biol Psychiatry. 1998;44(1):3-14. [CrossRef] [PubMed]
 
Franzen PL, Buysse DJ. Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications. Dialogues Clin Neurosci. 2008;10(4):473-481. [PubMed]
 
Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry. 2006;59(11):1052-1060. [CrossRef] [PubMed]
 
Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M. Trazodone for antidepressant-associated insomnia. Am J Psychiatry. 1994;151(7):1069-1072. [PubMed]
 
Sack RL, Auckley D, Auger RR, et al; American Academy of Sleep Medicine. Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm. An American Academy of Sleep Medicine review. Sleep. 2007;30(11):1484-1501. [PubMed]
 
Sack RL, Auckley D, Auger RR, et al; American Academy of Sleep Medicine. Circadian rhythm sleep disorders: part I, basic principles, shift work and jet lag disorders. An American Academy of Sleep Medicine review. Sleep. 2007;30(11):1460-1483. [PubMed]
 
Morgenthaler TI, Lee-Chiong T, Alessi C, et al; Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007;30(11):1445-1459. [PubMed]
 
Ebisawa T. Circadian rhythms in the CNS and peripheral clock disorders: human sleep disorders and clock genes. J Pharmacol Sci. 2007;103(2):150-154. [CrossRef] [PubMed]
 
Schrader H, Bovim G, Sand T. The prevalence of delayed and advanced sleep phase syndromes. J Sleep Res. 1993;2(1):51-55. [CrossRef] [PubMed]
 
Dagan Y, Eisenstein M. Circadian rhythm sleep disorders: toward a more precise definition and diagnosis. Chronobiol Int. 1999;16(2):213-222. [CrossRef] [PubMed]
 
Sharkey KM, Carskadon MA, Figueiro MG, Zhu Y, Rea MS. Effects of an advanced sleep schedule and morning short wavelength light exposure on circadian phase in young adults with late sleep schedules. Sleep Med. 2011;12(7):685-692. [CrossRef] [PubMed]
 
Schwartz JR, Roth T. Shift work sleep disorder: burden of illness and approaches to management. Drugs. 2006;66(18):2357-2370. [CrossRef] [PubMed]
 
Zee PC, Goldstein CA. Treatment of shift work disorder and jet lag. Curr Treat Options Neurol. 2010;12(5):396-411. [CrossRef] [PubMed]
 
Ker K, Edwards PJ, Felix LM, Blackhall K, Roberts I. Caffeine for the prevention of injuries and errors in shift workers. Cochrane Database Syst Rev. 2010;;(5): CD008508.
 
Sharkey KM, Eastman CI. Melatonin phase shifts human circadian rhythms in a placebo-controlled simulated night-work study. Am J Physiol Regul Integr Comp Physiol. 2002;282(2):R454-R463. [PubMed]
 
Monchesky TC, Billings BJ, Phillips R, Bourgouin J. Zopiclone in insomniac shiftworkers. Evaluation of its hypnotic properties and its effects on mood and work performance. Int Arch Occup Environ Health. 1989;61(4):255-259. [CrossRef] [PubMed]
 
Walsh JK, Schweitzer PK, Anch AM, Muehlbach MJ, Jenkins NA, Dickins QS. Sleepiness/alertness on a simulated night shift following sleep at home with triazolam. Sleep. 1991;14(2):140-146. [PubMed]
 
Porcù S, Bellatreccia A, Ferrara M, Casagrande M. Performance, ability to stay awake, and tendency to fall asleep during the night after a diurnal sleep with temazepam or placebo. Sleep. 1997;20(7):535-541. [PubMed]
 
Hart CL, Ward AS, Haney M, Foltin RW. Zolpidem-related effects on performance and mood during simulated night-shift work. Exp Clin Psychopharmacol. 2003;11(4):259-268. [CrossRef] [PubMed]
 
Czeisler CA, Walsh JK, Roth T, et al;; U.S. Modafinil in Shift Work Sleep Disorder Study Group U.S. Modafinil in Shift Work Sleep Disorder Study Group. Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med. 2005;353(5):476-486. [CrossRef] [PubMed]
 
Czeisler CA, Walsh JK, Wesnes KA, Arora S, Roth T. Armodafinil for treatment of excessive sleepiness associated with shift work disorder: a randomized controlled study. Mayo Clin Proc. 2009;84(11):958-972. [PubMed]
 
Drake CL, Roehrs T, Richardson G, Walsh JK, Roth T. Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep. 2004;27(8):1453-1462. [PubMed]
 
Sack RL. Clinical practice. Jet lag. N Engl J Med. 2010;362(5):440-447. [CrossRef] [PubMed]
 
Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;;(2): CD001520.
 
Takahashi T, Sasaki M, Itoh H, et al. Melatonin alleviates jet lag symptoms caused by an 11-hour eastward flight. Psychiatry Clin Neurosci. 2002;56(3):301-302. [CrossRef] [PubMed]
 
Zee PC, Wang-Weigand S, Wright KP Jr, Peng X, Roth T. Effects of ramelteon on insomnia symptoms induced by rapid, eastward travel. Sleep Med. 2010;11(6):525-533. [CrossRef] [PubMed]
 
Suhner A, Schlagenhauf P, Höfer I, Johnson R, Tschopp A, Steffen R. Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag. Aviat Space Environ Med. 2001;72(7):638-646. [PubMed]
 
Paul MA, Miller JC, Gray GW, Love RJ, Lieberman HR, Arendt J. Melatonin treatment for eastward and westward travel preparation. Psychopharmacology (Berl). 2010;208(3):377-386. [CrossRef] [PubMed]
 
Sack RL, Lewy AJ, Blood ML, Keith LD, Nakagawa H. Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. J Clin Endocrinol Metab. 1992;75(1):127-134. [CrossRef] [PubMed]
 
Arendt J, Aldhous M, Wright J. Synchronisation of a disturbed sleep-wake cycle in a blind man by melatonin treatment. Lancet. 1988;331(8588):772-773. [CrossRef]
 
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