Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Sleeplessness and Circadian Rhythm Disorder Medication

  • Author: Mary E Cataletto, MD; Chief Editor: Selim R Benbadis, MD  more...
 
Updated: Jan 07, 2015
 

Medication Summary

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.

Next

Benzodiazepines

Class Summary

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)

 

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.

Temazepam (Restoril)

 

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.

Estazolam

 

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.

Quazepam (Doral)

 

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.

Flurazepam

 

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.

Previous
Next

Nonbenzodiazepine hypnotics

Class Summary

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

Zolpidem (Ambien, Ambien CR, Edluar)

 

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.

Eszopiclone (Lunesta)

 

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.

Zaleplon (Sonata)

 

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.

Previous
Next

Melatonin Receptor Agonists

Class Summary

Melatonin receptor agonists (tasimelteon, ramelteon) have been approved by the FDA. Tasimelteon is indicated for non–24-hour sleep-wake disorder. Ramelteon is indicated for insomnia characterized by difficulty with sleep onset.

Melatonin (herbal/alternative) 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.[12]

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 melatonin 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.

Tasimelteon (Hetlioz)

 

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.

Ramelteon (Rozerem)

 

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.

Melatonin

 

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.

Previous
Next

Orexin Receptor Antagonists

Class Summary

Orexin promotes wakefulness. Antagonism of the orexin receptor suppresses this action by orexin.

Suvorexant (Belsomra)

 

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.

Previous
 
Contributor Information and Disclosures
Author

Mary E Cataletto, MD Professor of Clinical Pediatrics, State University of New York at Stony Brook

Mary E Cataletto, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians

Disclosure: Nothing to disclose.

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, American Psychological Association

Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cyberonics; Eisai; Lundbeck; Sunovion; UCB; Upsher-Smith<br/>Serve(d) as a speaker or a member of a speakers bureau for: Cyberonics; Eisai; Glaxo Smith Kline; Lundbeck; Sunovion; UCB<br/>Received research grant from: Cyberonics; Lundbeck; Sepracor; Sunovion; UCB; Upsher-Smith.

Acknowledgements

Norberto Alvarez, MD Assistant Professor, Department of Neurology, Harvard Medical School; Consulting Staff, Department of Neurology, Boston Children's Hospital; Medical Director, Wrentham Developmental Center

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.

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

Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Movement Disorders Society, and Sigma Xi

Disclosure: Avanir Pharmaceuticals Consulting fee Consulting

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References
  1. US Food and Drug Administration. FDA approves Hetlioz: first treatment for non-24 hour sleep-wake disorder in blind individuals [news release]. January 31, 2014. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm384092.htm. Accessed: February 3, 2014.

  2. Katzenberg D, Young T, Finn L, et al. A CLOCK polymorphism associated with human diurnal preference. Sleep. 1998 Sep 15. 21(6):569-76. [Medline].

  3. Rosen GM, Shor AC, Geller TJ. Sleep in children with cancer. Curr Opin Pediatr. 2008 Dec. 20(6):676-81. [Medline].

  4. Ming X, Walters AS. Autism spectrum disorders, attention deficit/hyperactivity disorder, and sleep disorders. Curr Opin Pulm Med. 2009 Aug 26. [Medline].

  5. Dagan Y, Eisenstein M. Circadian rhythm sleep disorders: toward a more precise definition and diagnosis. Chronobiol Int. 1999 Mar. 16(2):213-22. [Medline].

  6. Schrader H, Bovim G, Sand T. The prevalence of delayed and advanced sleep phase syndromes. J Sleep Res. 1993 Mar. 2(1):51-55. [Medline].

  7. Sack RL, Auckley D, Auger RR, et al. Circadian rhythm sleep disorders: part I, basic principles, shift work and jet lag disorders. An American Academy of Sleep Medicine review. Sleep. 2007 Nov. 30(11):1460-83. [Medline]. [Full Text].

  8. Johnson EO, Roehrs T, Roth T, Breslau N. Epidemiology of alcohol and medication as aids to sleep in early adulthood. Sleep. 1998 Mar 15. 21(2):178-86. [Medline].

  9. Morgenthaler TI, Lee-Chiong T, Alessi C, Friedman L, Aurora RN, Boehlecke B. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007 Nov 1. 30(11):1445-59. [Medline].

  10. Lockley S, Dressman M, Xiao C, Fisher D, Torres R, Lavedan C, et al. Tasimelteon treatment entrains the circadian clock and demonstrates a clinically meaningful benefit blind individuals with non-24-hour circadian rhythms. Presented at ENDO 2013: the Endocrinology Society 95th Annual Meeting. San Francisco. (SUN-134).

  11. Lockley S, Dressman M, Xiao C, Licamele L, Polymeropoulos M. RESET study demonstrates that tasimelteon maintains entrainment of melatonin and cortisol in totally blind individuals with non-24-hour circadian rhythms. Presented at ENDO 2013: the Endocrinology Society 95th Annual Meeting. San Francisco. (SUN-137).

  12. Herxheimer A, Petrie KJ. Cochrane Review. Oxford: Cochrane; 2001.

  13. Allen R. Development of the human circadian cycle. Loughlin G, et al, eds. Sleep and Breathing in Children. 2000. 313-32.

  14. Ancoli-Israel S, Klauber MR, Jones DW, et al. Variations in circadian rhythms of activity, sleep, and light exposure related to dementia in nursing-home patients. Sleep. 1997 Jan. 20(1):18-23. [Medline].

  15. Boggild H, Suadicani P, Hein HO, et al. Shift work, social class, and ischaemic heart disease in middle aged and elderly men; a 22 year follow up in the Copenhagen Male Study. Occup Environ Med. 1999 Sep. 56(9):640-5. [Medline].

  16. Chesson AL Jr, Littner M, Davila D, et al. Practice parameters for the use of light therapy in the treatment of sleep disorders. Standards of Practice Committee, American Academy of Sleep Medicine. Sleep. 1999 Aug 1. 22(5):641-60. [Medline].

  17. Chesson AL, Anderson WM, Littner M, et al. Practice parameters for the nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 1999 Dec 15. 22(8):1128-33. [Medline].

  18. Epstein R, Chillag N, Lavie P. Starting times of school: effects on daytime functioning of fifth-grade children in Israel. Sleep. 1998 May 1. 21(3):250-6. [Medline].

  19. Glaze DG. Childhood insomnia: why Chris can't sleep. Pediatr Clin North Am. 2004 Feb. 51(1):33-50, vi. [Medline].

  20. Hauri PJ. Insomnia. Clin Chest Med. 1998 Mar. 19(1):157-68. [Medline].

  21. Morin C, ed. Insomnia: Psychological Assessment and Management. New York, NY: Guilford Press; 1993.

  22. Manni R, Ratti MT, Tartara A. Nocturnal eating: prevalence and features in 120 insomniac referrals. Sleep. 1997 Sep. 20(9):734-8. [Medline].

  23. Martin SK, Eastman CI. Medium-intensity light produces circadian rhythm adaptation to simulated night-shift work. Sleep. 1998 Mar 15. 21(2):154-65. [Medline].

  24. Meltzer LJ, Mindell JA. Nonpharmacologic treatments for pediatric sleeplessness. Pediatr Clin North Am. 2004 Feb. 51(1):135-51. [Medline].

  25. Mulrooney DA, Ness KK, Neglia JP, Whitton JA, Green DM, Zeltzer LK. Fatigue and sleep disturbance in adult survivors of childhood cancer: a report from the childhood cancer survivor study (CCSS). Sleep. 2008 Feb 1. 31(2):271-81. [Medline].

  26. Natale D, Sabrine W. Melatonin. Clin Tox Rev. 1997. 20 (1):

  27. Roehrs T, Roth T. Chronic insomnias associated with circadian rhythm disorders. Kryger M, Roth T, Dement W, eds. Principles and Practice of Sleep Medicine. 2nd ed. Philadelphia, PA: WB Saunders; 1994.

  28. Vgontzas AN, Bixler EO, Lin HM, et al. Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab. 2001 Aug. 86(8):3787-94. [Medline].

  29. Walsh JK, Engelhardt CL. The direct economic costs of insomnia in the United States for 1995. Sleep. 1999 May 1. 22 Suppl 2:S386-93. [Medline].

  30. Yazaki M, Shirakawa S, Okawa M, et al. Demography of sleep disturbances associated with circadian rhythm disorders in Japan. Psychiatry Clin Neurosci. 1999 Apr. 53(2):267-8. [Medline].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.