Neurotherapeutics

, Volume 9, Issue 4, pp 728–738

Insomnia Pharmacotherapy

Article

Summary

The benzodiazepine receptor agonists (BzRAs) a melatonin receptor agonist and a histamine antagonist have all been approved as hypnotics. Beyond their differing mechanisms of action, they have differences in pharmacokinetics, and among the BzRAs differences in receptor subtype affinity and formulations, which provides the physician with broad options for tailoring therapy to each patient’s specific needs. Consistent with their specific pharmacokinetics and formulations, these Food and Drug Administration-approved hypnotics have been shown to improve sleep with no evidence of tolerance development in long-term use. In addition, emerging data indicate these drugs also improve aspects of daytime function. Their side effects are either associated with the direct sedating effects of the drugs, doses greater than clinical doses, or a combination with alcohol or other sedating drugs. Anxiolytic BzRAs, sedating antidepressants and antipsychotics have been used off-label as hypnotics. However, in the absence of information regarding their dose range for efficacy and safety, their use as hypnotics is ill-advised.

Keywords

Hypnotic efficacy Hypnotic safety Hypnotic pharmacology Off-label use Treatment considerations 

Supplementary material

13311_2012_148_MOESM1_ESM.pdf (511 kb)
ESM 1(PDF 510 kb)

References

  1. 1.
    Gallup. Sleep in America. Princeton: Gallup, 1995:1–78.Google Scholar
  2. 2.
    Johnson EO, Roehrs T, Roth T, et al. Epidemiology of alcohol and medication as aids to sleep in early adulthood. Sleep 1998;21:178–186.PubMedGoogle Scholar
  3. 3.
    Roehrs T, Hollebeek E, Drake C, et al. Substance use for insomnia in Metropolitan Detroit. J Psychosom Res 2003;53:571–576.CrossRefGoogle Scholar
  4. 4.
    Roehrs T, Roth T. Sleep, sleepiness, sleep disorders and alcohol use and abuse. Sleep Med Rev 2001;5:287–297.PubMedCrossRefGoogle Scholar
  5. 5.
    National Institutes of Health. State of the science conference statement on manifestations and management of chronic insomnia in adults June 13-15, 2005. Sleep 2005;28:1049–1057.Google Scholar
  6. 6.
    Mohler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther 2002;300:2–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Mendelson WB, Thompson C, Franko T. Adverse reactions to sedative hypnotics: three years’ experience. Sleep 1996;19:702–706.PubMedGoogle Scholar
  8. 8.
    Nutt D. GABA-A receptors: subtypes, regional distribution, and function. J Clin Sleep Med 2006;2:S7–S11.PubMedGoogle Scholar
  9. 9.
    Fava M, Schaefer K, Huang H, Wilson A, et al. A post hoc analysis of the effect of nightly administration of eszopiclone and a selective serotonin reuptake inhibitor in patients with insomnia and anxious depression. J Clin Psychiat 2011;72:473–479.CrossRefGoogle Scholar
  10. 10.
    Pollack M, Kinrys G, Krystal A, et al. Eszopiclone co-administered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder. Arch Gen Psychiat 2009;65:551–562.CrossRefGoogle Scholar
  11. 11.
    Fava M, Asnis GM, Shrivastava RK, et al. Improved insomnia symptoms and sleep-related next-day functioning in patients with comorbid major depressive disorder and insomnia following concomitant zolpidem extended-release 12.5 mg and escitalopram treatment: a randomized controlled trial. J Clin Psychiat 2011;72:914–928.CrossRefGoogle Scholar
  12. 12.
    Fava M, Asnis GM, Shrivastava R, Lydiard B, et al. Zolpidem extended-release improves sleep and next-day symptoms in comorbid insomnia and generalized anxiety disorder. J Clin Psychopharm 2009;29:222–230.CrossRefGoogle Scholar
  13. 13.
    Nowell PD, Mazumdar S, Buysse DJ, et al. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA 1997;278:2170–2177.PubMedCrossRefGoogle Scholar
  14. 14.
    Holbrook AM, Crowther R, Lotter A, et al. Meta-anlysis of benzodiazepine use in the treatment of insomnia. Can Med Assoc J 2000;162:225–233.Google Scholar
  15. 15.
    Merlotti L, Roehrs T, Koshorek G, Zorick F, Lamphere J, Roth T. The dose effects of zolpidem on the sleep of healthy normals. J of Clin Psychopharm 1989;9:9–14.Google Scholar
  16. 16.
    Lamphere JK, Roehrs TA, Zorick FJ, Koshorek G, Roth T. The dose effects of zopiclone. Hum Psychopharm 1989;4:41–46.CrossRefGoogle Scholar
  17. 17.
    Roth T, Hull SG, Lankford DA, et al. Low-dose sublingual zolpidem tartrate is associated with dose-related improvement in sleep onset and duration in insomnia characterized by middle-of-the-night [MOTN] awakenings. Sleep 2008;31:277–1284.Google Scholar
  18. 18.
    Krystal AD, Walsh JK, Laska E, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, doubled blinded, placebo controlled study in adults with chronic insomnia. Sleep 2003;26:793–799.PubMedGoogle Scholar
  19. 19.
    Walsh JK., Krystal AD, Amato DA, et al. Nightly treatment of primary insomnia with eszopiclone for six months: effects on sleep, quality of life, and work limitations. Sleep 2007;30:959–968.PubMedGoogle Scholar
  20. 20.
    Randall S, Roehrs T, Roth T. Efficacy of eight months of nightly zolpidem: a prospective placebo controlled study. Sleep (in press).Google Scholar
  21. 21.
    Karin A, Tolbert D, Cao C. Disposition kinetics and tolerance of escalating single doses of remelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia. J Clin Pharmacol 2006;46:140–148.CrossRefGoogle Scholar
  22. 22.
    Roth T, Roehrs T. Issues in the use of benzodiazepine therapy. J Clin Psychiatry 1992;53:S14–S18.Google Scholar
  23. 23.
    Mendelson WB, Thompson C, Franko T. Adverse reactions to sedative/hypnotics: three years’ experience. Sleep 1996;9:702–706.Google Scholar
  24. 24.
    Rush CR, Griffiths RR. Zolpidem, triazolam and temazepam: behavioral and subject-rated effects in normal volunteers. J Clin Psychopharmacol 1996;6:46–57.Google Scholar
  25. 25.
    Roehrs T, Merlotti L, Zorick F, et al. Sedative, memory and performance effects of hypnotics. Psychpharmacology [Berl] 1994;16:30–34.Google Scholar
  26. 26.
    Danjou P, Fruncillo PR, Worthington P, et al. A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2 h before awakening. Br J Clin Pharmacol 1999;48:367–374.PubMedCrossRefGoogle Scholar
  27. 27.
    Carskadon MA, Seidel WF, Greenblatt DJ, et al. Daytime carryover of triazolam and flurazepam in elderly insomniacs. Sleep 1982;5:362–371.Google Scholar
  28. 28.
    Riedel BW, Lichstein KL. Insomnia and daytime functioning. Sleep Med Rev 2000;4:277–298.PubMedCrossRefGoogle Scholar
  29. 29.
    Kelly KD, Pickett W, Yiannakaoulias N, et al. Medication use and falls in community-dwelling older persons. Age Ageing 2003;32:503–509.PubMedCrossRefGoogle Scholar
  30. 30.
    Ensrud KE, Blackwell T, Mangione CM, et al. Central nervous system active medications and risk for fractures in older women. Arch Intern Med 2003;163:949–957.PubMedCrossRefGoogle Scholar
  31. 31.
    Brassington GS, King AC, Bliwise DL. Sleep problems as a risk factor for falls in a sample of community-dwelling adults aged 64-99 years. J Am Ger Soc 2000;48:1234–1240.Google Scholar
  32. 32.
    Avidan AY, Fries BE, James ML, Szafara KL, Wright GT, Chervin RD. Insomnia and hypnotic use recorded in the minimum data set as predictors of fall and hip fractures in Michigan nursing homes. J Am Ger Soc 2005;53:955–962.CrossRefGoogle Scholar
  33. 33.
    Roehrs T, Zorick F, Sicklesteel J, et al. Effects of hypnotics on memory. J Clin Psychopharmacol 1983;3:310–313.PubMedGoogle Scholar
  34. 34.
    Green JF, McElholm A, King DJ. A comparison of the sedative and amnestic effects of chlorpromazine and lorazepam. Psychopharmacology [Berl] 1996;128:67–73.CrossRefGoogle Scholar
  35. 35.
    Mohler H, Crestani F, Rudolph U. GABA-A receptor subtypes: a new pharmacology. Curr Opin Pharmacol 2001;1:22–25.PubMedCrossRefGoogle Scholar
  36. 36.
    Guillmineau C, Dement WC. Amnesia and disorders of excessive sleepiness. In: Drucker-Colin RR, McGaugh JL, eds. Neurobiology of sleep and memory. London: Academic Press, 1977.Google Scholar
  37. 37.
    Roehrs TA, Vogel G, Roth T. Rebound insomnia: Its determinants and significance. Am J Med 1990;88:43S–46S.PubMedGoogle Scholar
  38. 38.
    Roehrs T, Zorick F, Wittig R, et al. Dose determinants of rebound insomnia. Brit J Clin Pharmacology 1986;22:143–147.CrossRefGoogle Scholar
  39. 39.
    Roehrs TA, Randall S, Harris E, et al. Twelve months of nightly zolpidem does not lead to rebound insomnia or withdrawal symptoms: a prospective placebo-controlled study. J Psychopharm 2012;26:1088–1095.Google Scholar
  40. 40.
    Merlotti L, Roehrs T, Zorick F, et al. Rebound insomnia: duration of use and individual differences. J Clin Psychopharm 1991;11:368–373.CrossRefGoogle Scholar
  41. 41.
    Roehrs T, Merlotti L, Zorick F, et al. Rebound insomnia and hypnotic self administration. Psychopharmacology 1992;107:480–484.PubMedCrossRefGoogle Scholar
  42. 42.
    Woods JH, Winger G. Current benzodiazepine issues. Psychopharmacology 1995;118:103–107.Google Scholar
  43. 43.
    Kan CC, Hilldebrink SR, Breteier MHM. Determination of the main risk factors for benzodiazepine dependence using a multidimensional approach. Compr Psychiatry 2004;45:88–94.PubMedCrossRefGoogle Scholar
  44. 44.
    Mellinger GD, Balter MB, Uhlenhuth EH. Insomnia and its treatment. Arch Gen Psychiatry 1985;42:225–232.PubMedCrossRefGoogle Scholar
  45. 45.
    Roehrs T, Pedrosi B, Rosenthal L, et al. Hypnotic self administration and dose escalation. Psychopharmacology [Berl] 1996;127:150–154.CrossRefGoogle Scholar
  46. 46.
    Roehrs T, Bonahoom A, Pedrosi B, et al. Nighttime versus daytime hypnotic self-administration. Psychopharmacology 2002;161:137–142.PubMedCrossRefGoogle Scholar
  47. 47.
    Roehrs T, Bonahoom A, Pedrosi B, et al. Disturbed sleep predicts hypnotic self administration. Sleep Med 2002;3:61–66.PubMedCrossRefGoogle Scholar
  48. 48.
    Roehrs TA, Randall S, Harris E, et al. Twelve months of nightly zolpidem does not lead to dose escalation: a prospective placebo-controlled study. Sleep 2011;34:201–212.Google Scholar
  49. 49.
    Roth T, Singh NN, Steinbert FJ, Rosenberg R, Krystal A. Absence of tolerance, dependence potential, and rebound during PRN treatment of middle-of-the-night awakening with zolpidem tartrate sublingual tablet 3.5 MG. Sleep Med 2011;12(suppl 1):S58.CrossRefGoogle Scholar
  50. 50.
    Roth T, Zammit GK, Scharf MB, Farber R. Efficacy and safety of as-needed, post bedtime dosing with Indiplon in insomnia patients with chronic difficulty maintaining sleep. Sleep 2007;30:1731–1738.PubMedGoogle Scholar
  51. 51.
    Lisko B, Pikalov A. Zaleplon overdose associated with sleepwalking and complex behavior. J Am Acad Child Adolesc Psychiatry 2004;43:927–928.CrossRefGoogle Scholar
  52. 52.
    Menkes DB. Triazolam-induced nocturnal bingeing with amnesia. Aust N Z J Psychaitry 1992;26:320–321.CrossRefGoogle Scholar
  53. 53.
    Morgenthaler TI, Silber MH. Amnestic sleep-related eating disorder associated with zolpidem. Sleep Med 2002;3:323–327.PubMedCrossRefGoogle Scholar
  54. 54.
    Yang W, Dollear M, Muthukrishnan SR. One rare side effect of zolpidem – sleepwalking: a case report. Arch Phys Med Rehabil 2005;86:1265–1266.PubMedCrossRefGoogle Scholar
  55. 55.
    Lange CL. Medication-associated somnambulism. J Am Acad Child Adoles Psychiatry 2005;44:211–212.CrossRefGoogle Scholar
  56. 56.
    Lauerma H. Nocturnal wandering caused by restless legs and short-acting benzodiazepines. Acta Psychiatr Scand 1991;83:492–493.PubMedCrossRefGoogle Scholar
  57. 57.
    Roehrs TA, Roth T. Safety of insomnia pharmacotherapy. Sleep Med Clinics 2006;1:399–407.CrossRefGoogle Scholar
  58. 58.
    Kato K, Hirai K, Nichiyama K, et al. Neurochemical properties of ramelteon [TAK-375], a selective MT1 and MT2 receptor agonist. Neuropharmacology 2005;48:301–310.PubMedCrossRefGoogle Scholar
  59. 59.
    Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and dose-response study of remelteon in patients with chronic primary insomnia. Sleep Med 2006;7:17–24.PubMedCrossRefGoogle Scholar
  60. 60.
    Roth T, Seiden D, Saimati S, et al. Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia. Sleep Med 2006;7:312–318.PubMedCrossRefGoogle Scholar
  61. 61.
    Roth T, Seiden D, Wang-Weigand S, et al. A 2-night, 3-period crossover study of ramelteon’s efficacy and safety in older adults with chronic insomnia. Curr Med Res Opin 2007;23:1005–1014.PubMedCrossRefGoogle Scholar
  62. 62.
    Zammit G, Erman M, Wang-Weigand S, et al. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med 2007;3:495–504.PubMedGoogle Scholar
  63. 63.
    Mayer G, Wang-Weigand S, Roth-Schechter B, et al. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep 2009;32:351–360.PubMedGoogle Scholar
  64. 64.
    DeMicco M, Wang-Weigand S, Zhang J. Long-term therapeutic effects of ramelteon treatment in adults with chronic insomnia: a 1 year study. Sleep 2006;29(suppl):A234.Google Scholar
  65. 65.
    Richardson GS, Zee PC, Wang-Weigand S, et al. Circadian phase-shifting effects of repeated ramelteon administration in healthy adults. J Clin Sleep Med 2008;4:456–461.PubMedGoogle Scholar
  66. 66.
    Roth T, Stubbs C, Walsh J. Ramelteon [TAK-375], a selective MT1/MT2 receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep 2005;28:303–307.PubMedGoogle Scholar
  67. 67.
    Griffiths R, Suess P, Johnson M. Ramelteon and triazolam in humans: behavioral effects and abuse potential. Sleep 2005;28:A44.Google Scholar
  68. 68.
    Roth T, Seiden D, Sainati S, et al. Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia. Sleep Med 2006;7:312–318.PubMedCrossRefGoogle Scholar
  69. 69.
    Zammit G, Roth T, Erman M, et al. Double-blind, placebo-controlled polysomnography and outpatient trial to evaluate the efficacy and safety of ramelteon in adult patients with chronic insomnia. Sleep 2005;28(suppl):A228–A229.Google Scholar
  70. 70.
    Johnson MW, Suess PE, Griffiths RR. Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. Arch Gen Psychiatry 2006;63:1149–1157.PubMedCrossRefGoogle Scholar
  71. 71.
    Hajak G, Rodenbeck A, Voderholzer U, et al. Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry 2001;62:453–463.PubMedCrossRefGoogle Scholar
  72. 72.
    Roth T, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep 2007;30:1555–1561.PubMedGoogle Scholar
  73. 73.
    Scharf M, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebo-controlled crossover study. J Clin Psychiatry 2008;69:1557–1564.PubMedCrossRefGoogle Scholar
  74. 74.
    Owen RT. Selective histamine H[1] antagonism: a novel approach to insomnia using low-dose doxepin. Drugs Today 2009;45:261–267.PubMedCrossRefGoogle Scholar
  75. 75.
    Wolf B, Guarino JJ, Preston KL, Griffiths RR. Abuse liability of diphenhydramine in sedative abuser. NIDA Res Monogr 1989;95:486–487.PubMedGoogle Scholar
  76. 76.
    Walsh JK. Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-based medicine. Sleep 2004;27:1441–1442.PubMedGoogle Scholar
  77. 77.
    Jenck F, Moreau JL, Mutel V, et al. Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs. Eur J Pharmacol 1993;231:223–229.PubMedCrossRefGoogle Scholar
  78. 78.
    Richelson E. The pharmacology of antidepressants at the synapse: focus on newer compounds. J Clin Psychiatry 1994;55(suppl A):34–39PubMedGoogle Scholar
  79. 79.
    Montgomery I, Oswald I, Morgan K, et al. Trazodone enhances sleep in subjective quality but not in objective duration. Br J Clin Pharmacol 1983;16:139–144.PubMedCrossRefGoogle Scholar
  80. 80.
    Walsh JK, Erman M, Erwin CW, et al. Subjective hypnotic efficacy of trazodone and zolpidem in DSM-III-R primary insomnia. Hum Psychopharmacol 1998:13:191–198.CrossRefGoogle Scholar
  81. 81.
    Golden RN, Dawkins K, Nicholas L. Trazadone and nefazodone. In: Schatzberg A, Nemeroff C, eds. The American Psychiatric Textbook Of Psychopharmacology. Washington, DC: American Psychiatric Textbook, Inc., 2004:315–325.Google Scholar
  82. 82.
    Levenson JL. Prolonged QT interval after trazodone overdose. Am J Psychiatry 1999;156:969–970.PubMedGoogle Scholar
  83. 83.
    Haria M, Fitton A, McTavish D. Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders. Drugs Aging 1994;4:331–355.PubMedCrossRefGoogle Scholar
  84. 84.
    Wiegard M, Landry T, Bruckner T, et al. Quetiapine in primary insomnia: a pilot study. Psychopharmacology 2008;196:337–338.CrossRefGoogle Scholar
  85. 85.
    Juni C, Chana P, Tapia J, et al. Quetiapine for insomnia in Parkinson Disease: results from an open-label trial. Clin Neuropharmacol 2005;28:185–187.CrossRefGoogle Scholar
  86. 86.
    Estivill E, de la Fuente V, Segarra F, et al. The use of olanzapine in sleep disorders. An open trial with nine patients. Rev Neurol 2004;38:829–831.PubMedGoogle Scholar
  87. 87.
    Cates ME, Jackson CW, Feldman JM, et al. Metabolic consequences of using low-dose quetiapine for insomnia in psychiatric patients. Community Ment Health J 2009;45:251–254.PubMedCrossRefGoogle Scholar
  88. 88.
    Roehrs T, Roth T. “Hypnotic” prescription patterns in a large managed-care population: Sleep Med 2004;5:463–466.PubMedCrossRefGoogle Scholar
  89. 89.
    Breslau N, Roth T, Rosenthal L, et al. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 1996;39:411–418.PubMedCrossRefGoogle Scholar
  90. 90.
    Perlis ML, Giles DE, Buysse DJ, et al. Self-reported sleep disturbance as a prodromal symptom in recurrent depression. J Affect Disord 1997;42:209–212.PubMedCrossRefGoogle Scholar
  91. 91.
    Hall RC, Platt DE. Suicide risk assessment: a review of risk factors for suicide in 100 patients who made severe suicide attempts. Evaluation of suicide risk in a time of managed care. Psychosomatics 1999;40:18–27.PubMedCrossRefGoogle Scholar
  92. 92.
    Roehrs TA. Does effective management of sleep disorders improve pain symptoms? Drugs 2009;69:S5–S11.CrossRefGoogle Scholar
  93. 93.
    Stark P, Hardison CD. A review of multicenter controlled studies of fluoxetine vs. imipramine and placebo in outpatients with major depressive disorder. J Clin Psychiatry 1985;46:53–58.PubMedGoogle Scholar
  94. 94.
    Walsh JK, Roth T, Randazzo AC, et al. Eight weeks of non-nightly use of zolpidem for primary insomnia. Sleep 2000;23:1087–1096.PubMedGoogle Scholar
  95. 95.
    Roehrs T, Bonahoom A, Pedrosi B, Rosenthal L, Roth T. Treatment regimen and hypnotic self-administration. Psychopharmacology 2001;155:11–17.PubMedCrossRefGoogle Scholar
  96. 96.
    Bettica P, Squassante L, Zamuner S, Nucci G, Danker-Hopfe H, Ratti E. The orexin antagonist SB-649868 promotes and maintains sleep in men with primary insomnia. Sleep 2012;35:1097–1104.PubMedGoogle Scholar
  97. 97.
    Landolt HHP, Meier V, Burgess HJ, et al. Serotonin-2 receptors and human sleep: effect of a selective antagonist on EEG power spectra. Neuropsychopharmacology 1999;21:455–466.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2012

Authors and Affiliations

  1. 1.Sleep Disorders and Research Center, Henry Ford HospitalDetroitUSA
  2. 2.Department of Psychiatry and Behavioral Neuroscience, School of MedicineWayne State UniversityDetroitUSA

Personalised recommendations