Skip to main content
SpringerLink
Log in

A New Class of Hypnotic Compounds for the Treatment of Insomnia: The Dual Orexin Receptor Antagonists

  • Chapter
  • First Online:
Orexin and Sleep

Abstract

Insomnia is a widespread, debilitating disorder responsible for enormous individual and societal costs. Currently available pharmacologic treatments for insomnia, including allosteric modulators of the gamma-aminobutyric acid type A receptor (GABAA), such as zolpidem (Ambien®) and eszopiclone (Lunesta®), have undesirable effects that limit their tolerability and utility. The dual orexin receptor antagonists (DORAs), possessing novel mechanisms of action, have demonstrated efficacy in improving sleep latency and quantity in several preclinical species, healthy human volunteers, and patients with insomnia. Importantly, accumulating data suggest that DORAs may be better tolerated than allosteric modulators of the GABAA receptor with respect to cognitive impairment and motor side effects. A greater understanding of the differences between these drug classes is warranted. This chapter attempts to explain some of their key differences in mechanisms of action as well as describe areas where greater experimentation is warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Allain H, Patat A et al (1995) Comparative study of the effects of zopiclone (7.5 mg), zolpidem, flunitrazepam and a placebo on nocturnal cognitive performance in healthy subjects, in relation to pharmacokinetics. Eur Psychiatry 10(Suppl 3):129s–135s

    Article  PubMed  Google Scholar 

  • Allain H, Bentue-Ferrer D et al (2005) Postural instability and consequent falls and hip fractures associated with use of hypnotics in the elderly: a comparative review. Drugs Aging 22(9):749–765

    Article  PubMed  Google Scholar 

  • Balkin TJ, O’Donnell VM et al (1992) Comparison of the daytime sleep and performance effects of zolpidem versus triazolam. Psychopharmacology 107(1):83–88

    Article  CAS  PubMed  Google Scholar 

  • Balter MB, Uhlenhuth EH (1991) The beneficial and adverse effects of hypnotics. J Clin Psychiatry 52(Suppl):16–23

    PubMed  Google Scholar 

  • Berlin I, Warot D et al (1993) Comparison of the effects of zolpidem and triazolam on memory functions, psychomotor performances, and postural sway in healthy subjects. J Clin Psychopharmacol 13(2):100–106

    Article  CAS  PubMed  Google Scholar 

  • Bettica P, Squassante L et al (2012) Differential effects of a dual orexin receptor antagonist (SB-649868) and zolpidem on sleep initiation and consolidation, SWS, REM sleep, and EEG power spectra in a model of situational insomnia. Neuropsychopharmacology 37(5):1224–1233

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bonnet MH (1983) Memory for events occurring during arousal from sleep. Psychophysiology 20(1):81–87

    Article  CAS  PubMed  Google Scholar 

  • Brisbare-Roch C, Dingemanse J et al (2007) Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13(2):150–155

    Article  CAS  PubMed  Google Scholar 

  • Broughton RJ (1968) Sleep disorders: disorders of arousal? Enuresis, somnambulism, and nightmares occur in confusional states of arousal, not in “dreaming sleep”. Science 159(3819):1070–1078

    Article  CAS  PubMed  Google Scholar 

  • Brunner DP, Dijk DJ et al (1991) Effect of zolpidem on sleep and sleep EEG spectra in healthy young men. Psychopharmacology 104(1):1–5

    Article  CAS  PubMed  Google Scholar 

  • Chemelli RM, Willie JT et al (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98(4):437–451

    Article  CAS  PubMed  Google Scholar 

  • Chong Y, Fryer CD et al (2013) Prescription sleep aid use among adults: United States, 2005–2010. NCHS Data Brief 127:1–8

    PubMed  Google Scholar 

  • de Haas SL, Schoemaker RC et al (2010) Pharmacokinetics, pharmacodynamics and the pharmacokinetic/pharmacodynamic relationship of zolpidem in healthy subjects. J Psychopharmacol 24(11):1619–1629

    Article  PubMed  Google Scholar 

  • de Lecea L, Kilduff TS et al (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95(1):322–327

    Article  PubMed Central  PubMed  Google Scholar 

  • Dijk DJ, James LM et al (2010) Sex differences and the effect of gaboxadol and zolpidem on EEG power spectra in NREM and REM sleep. J Psychopharmacol 24(11):1613–1618

    Article  CAS  PubMed  Google Scholar 

  • Dinges DF (1984) The nature and timing of sleep. Trans Stud Coll Physicians Phila 6(3):177–206

    CAS  PubMed  Google Scholar 

  • Drover DR (2004) Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet 43(4):227–238

    Article  CAS  PubMed  Google Scholar 

  • Foundation NS (2006) Sleep in America poll, Washington DC

    Google Scholar 

  • Fox SV, Gotter AL et al (2013) Quantitative electroencephalography within sleep/wake states differentiates GABAA modulators eszopiclone and zolpidem from dual orexin receptor antagonists in rats. Neuropsychopharmacology 38(12):2401–2408

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gotter AL, Roecker AJ et al (2013a) Orexin receptors as therapeutic drug targets. Prog Brain Res 198:163–188

    Article  Google Scholar 

  • Gotter AL, Winrow CJ et al (2013b) The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold. BMC Neurosci 14:90

    Article  PubMed Central  PubMed  Google Scholar 

  • Hajak G, Petukhova M et al (2011) Days-out-of-role associated with insomnia and comorbid conditions in the America Insomnia Survey. Biol Psychiatry 70(11):1063–1073

    Article  PubMed  Google Scholar 

  • Herculano-Houzel S (2012) Brains matter, bodies maybe not: the case for examining neuron numbers irrespective of body size. Ann N Y Acad Sci 1225:191–199

    Article  Google Scholar 

  • Herculano-Houzel S, Lent R (2005) Isotropic fractionator: a simple, rapid method for the quantification of total cell and neuron numbers in the brain. J Neurosci 25:2518–2521

    Article  CAS  PubMed  Google Scholar 

  • Herring WJ, Snyder E et al (2012) Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 79(23):2265–2274

    Article  CAS  PubMed  Google Scholar 

  • Hoch M, Hay JL et al (2013) Dual orexin receptor antagonism by almorexant does not potentiate impairing effects of alcohol in humans. Eur Neuropsychopharmacol 23(2):107–117

    Article  CAS  PubMed  Google Scholar 

  • Hoever P, de Haas S et al (2010) Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant. Clin Pharmacol Ther 87(5):593–600

    Article  CAS  PubMed  Google Scholar 

  • Hoever P, de Haas SL et al (2012) Orexin receptor antagonism: an ascending multiple-dose study with almorexant. J Psychopharmacol 26(8):1071–1080

    Article  PubMed  Google Scholar 

  • Johnson LC, Spinweber CL et al (1987) Dose level effects of triazolam on sleep and response to a smoke detector alarm. Psychopharmacology 91(4):397–402

    Article  CAS  PubMed  Google Scholar 

  • Kanno O, Sasaki T et al (2000) Comparison of the effects of zolpidem and triazolam on nocturnal sleep and sleep latency in the morning: a cross-over study in healthy young volunteers. Prog Neuropsychopharmacol Biol Psychiatry 24(6):897–910

    Article  CAS  PubMed  Google Scholar 

  • Kessler RC, Berglund PA et al (2011) Insomnia and the performance of US workers: results from the America insomnia survey. Sleep 34(9):1161–1171

    PubMed Central  PubMed  Google Scholar 

  • Kuitunen T, Mattila MJ et al (1990) Actions and interactions of hypnotics on human performance: single doses of zopiclone, triazolam and alcohol. Int Clin Psychopharmacol 5(Suppl 2):115–130

    PubMed  Google Scholar 

  • Kuppermann M, Lubeck DP et al (1995) Sleep problems and their correlates in a working population. J Gen Intern Med 10(1):25–32

    Article  CAS  PubMed  Google Scholar 

  • Lancel M (1999) Role of GABAA receptors in the regulation of sleep: initial sleep responses to peripherally administered modulators and agonists. Sleep 22(1):33–42

    CAS  PubMed  Google Scholar 

  • Leufkens TR, Lund JS et al (2009) Highway driving performance and cognitive functioning the morning after bedtime and middle-of-the-night use of gaboxadol, zopiclone and zolpidem. J Sleep Res 18(4):387–396

    Article  PubMed  Google Scholar 

  • Lin L, Faraco J et al (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98(3):365–376

    Article  CAS  PubMed  Google Scholar 

  • Loomis AL, Harvey EN et al (1936) Brain potentials during hypnosis. Science 83(2149):239–241

    Article  CAS  PubMed  Google Scholar 

  • Lubin A, Hord DJ et al (1976) Effects of exercise, bedrest and napping on performance decrement during 40 hours. Psychophysiology 13(4):334–339

    Article  CAS  PubMed  Google Scholar 

  • Mai E, Buysse DJ (2008) Insomnia: prevalence, impact, pathogenesis, differential diagnosis, and evaluation. Sleep Med Clin 3(2):167–174

    Article  PubMed Central  PubMed  Google Scholar 

  • Marcus JN, Aschkenasi CJ et al (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435(1):6–25

    Article  CAS  PubMed  Google Scholar 

  • Mendelson WB, Martin JV et al (1988) Effects of flurazepam on sleep, arousal threshold, and the perception of being asleep. Psychopharmacology 95(2):258–262

    Article  CAS  PubMed  Google Scholar 

  • Michelson D, Snyder E et al (2013) Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 13(5):461–471

    Article  Google Scholar 

  • Mohler H, Fritschy JM et al (2002) A new benzodiazepine pharmacology. J Pharmacol Exp Ther 300(1):2–8

    Article  CAS  PubMed  Google Scholar 

  • Montgomery P, Dennis J (2004) A systematic review of non-pharmacological therapies for sleep problems in later life. Sleep Med Rev 8(1):47–62

    Article  PubMed  Google Scholar 

  • Morairty SR, Wilk AJ et al (2014) The hypocretin/orexin antagonist almorexant promotes sleep without impairment of performance in rats. Front Neurosci 8:3

    Article  PubMed Central  PubMed  Google Scholar 

  • Morin CM, Belanger L et al (2009) The natural history of insomnia: a population-based 3-year longitudinal study. Arch Intern Med 169(5):447–453

    Article  PubMed  Google Scholar 

  • Nishino S, Ripley B et al (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355(9197):39–40

    Article  CAS  PubMed  Google Scholar 

  • Nutt DJ, Malizia AL (2001) New insights into the role of the GABA(A)-benzodiazepine receptor in psychiatric disorder. 179:390–396

    Google Scholar 

  • Ohayon MM (2002) Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev 6(2):97–111

    Article  PubMed  Google Scholar 

  • Ohayon MM, Guilleminault C et al (2010) Sleep epidemiology 30 years later: where are we? Sleep Med 11(10):961–962

    Article  PubMed  Google Scholar 

  • Ramirez AD, Gotter AL et al (2013) Dual orexin receptor antagonists show distinct effects on locomotor performance, ethanol interaction and sleep architecture relative to gamma-aminobutyric acid-A receptor modulators. Front Neurosci 7:254

    Article  PubMed Central  PubMed  Google Scholar 

  • Rechtschaffen A, Kales A (1968) A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects, Los Angeles: Brain Information Service/Brain Research Institute, University of California

    Google Scholar 

  • Roehrs T, Merlotti L et al (1994) Sedative, memory, and performance effects of hypnotics. Psychopharmacology 116(2):130–134

    Article  CAS  PubMed  Google Scholar 

  • Roth T, Ancoli-Israel S (1999) Daytime consequences and correlates of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. II. Sleep 22(Suppl 2):S354–S358

    Google Scholar 

  • Roth T, Franklin M et al (2007) The state of insomnia and emerging trends. Am J Manag Care 13(5 Suppl):S117–S120

    PubMed  Google Scholar 

  • Roth T, Coulouvrat C et al (2011) Prevalence and perceived health associated with insomnia based on DSM-IV-TR; international statistical classification of diseases and related health problems, tenth revision; and research diagnostic criteria/international classification of sleep disorders, second edition criteria: results from the America Insomnia Survey. Biol Psychiatry 69(6):592–600

    Article  PubMed  Google Scholar 

  • Rudolph U, Crestani F et al (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401(6755):796–800

    Article  CAS  PubMed  Google Scholar 

  • Rush CR, Griffiths RR (1996) Zolpidem, triazolam, and temazepam: behavioral and subject-rated effects in normal volunteers. J Clin Psychopharmacol 16(2):146–157

    Article  CAS  PubMed  Google Scholar 

  • Sakurai T (2007) The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 8(3):171–181

    Article  CAS  PubMed  Google Scholar 

  • Sakurai T, Amemiya A et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92(4):573–585

    Article  CAS  PubMed  Google Scholar 

  • Schoenborn CA, Adams PF et al (2004) Health behaviors of adults: United States, 1999-2001. Vital Health Stat 10(219):1–79

    Google Scholar 

  • Scott EM (1968) Dreams of alcoholics. Percept Mot Skills 26(Suppl 3):1315–1318

    Google Scholar 

  • Steiner MA, Lecourt H et al (2011) Differential effects of the dual orexin receptor antagonist almorexant and the GABA(A)-alpha1 receptor modulator zolpidem, alone or combined with ethanol, on motor performance in the rat. Neuropsychopharmacology 36(4):848–856

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Stones MJ (1977) Memory performance after arousal from different sleep stages. Br J Psychol 68(2):177–181

    Article  CAS  PubMed  Google Scholar 

  • Sun H, Kennedy WP et al (2013) Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep 36(2):259–267

    PubMed Central  PubMed  Google Scholar 

  • Tannenbaum PL, Stevens J, Tye SJ, Fox SV, Binns J, Savitz AT, Kuduk SD, Uslaner JM, Winrow CJ, Renger JJ (2013) Dual orexin receptor antagonist sleep retains the ability to wake with emotionally salient acoustic stimuli yet sleep through neutral stimuli in dog and monkey models. Poster 0062 presented at the 27th Annual Meeting of the Associated Professional Sleep Societies, Baltimore, Maryland, USA, 1 June–5 June

    Google Scholar 

  • Tannenbaum PL, Stevens J et al (2014) Orexin receptor antagonist-induced sleep does not impair the ability to wake in response to emotionally salient acoustic stimuli in dogs. Front Behav Neurosci 8:182

    Article  PubMed Central  PubMed  Google Scholar 

  • Thannickal TC, Moore RY et al (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27(3):469–474

    Article  CAS  PubMed  Google Scholar 

  • Uslaner JM, Tye SJ et al 2013 Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition. Sci Transl Med 5(179):179ra44

    Google Scholar 

  • Vermeeren A (2004) Residual effects of hypnotics: epidemiology and clinical implications. CNS Drugs 18(5):297–328

    Article  CAS  PubMed  Google Scholar 

  • Verster JC, Volkerts ER et al (2002) Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance. J Clin Psychopharmacol 22(6):576–583

    Article  CAS  PubMed  Google Scholar 

  • Warot D, Bensimon G et al (1987) Comparative effects of zopiclone, triazolam and placebo on memory and psychomotor performance in healthy volunteers. Fundam Clin Pharmacol 1(2):145–152

    Article  CAS  PubMed  Google Scholar 

  • Wesensten NJ, Balkin TJ et al (1995) Effects of daytime administration of zolpidem versus triazolam on memory. Eur J Clin Pharmacol 48(2):115–122

    Article  CAS  PubMed  Google Scholar 

  • Winrow CJ, Gotter AL et al (2011) Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist. J Neurogenet 25(1–2):52–61

    Article  CAS  PubMed  Google Scholar 

  • Zammit G, Wang-Weigand S et al (2008) Use of computerized dynamic posturography to assess balance in older adults after nighttime awakenings using zolpidem as a reference. BMC Geriatr 8:15

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Merck Co. Inc, WP 46-100. Sumneytown Pike, P.O. Box 4, West Point, PA, 19486, USA

    Jason M. Uslaner, John J. Renger, Paul J. Coleman & Chris J. Winrow

Authors
  1. Jason M. Uslaner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John J. Renger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul J. Coleman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chris J. Winrow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jason M. Uslaner .

Editor information

Editors and Affiliations

  1. Dept. of Molecular Neurosci. & Integrati, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan

    Takeshi Sakurai

  2. Somnogen Canada Inc, President and Chief Executive Officer, Toronto, Ontario, Canada

    S.R. Pandi-Perumal

  3. Dept. Pharmacology & Therapeutics, Clinics Hospital Montevideo School of Medicine, Montevideo, Uruguay

    Jaime M. Monti

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Uslaner, J.M., Renger, J.J., Coleman, P.J., Winrow, C.J. (2015). A New Class of Hypnotic Compounds for the Treatment of Insomnia: The Dual Orexin Receptor Antagonists. In: Sakurai, T., Pandi-Perumal, S., Monti, J. (eds) Orexin and Sleep. Springer, Cham. https://doi.org/10.1007/978-3-319-23078-8_17

Download citation

Publish with us

Policies and ethics

Search

Navigation