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.
Similar content being viewed by others
References
Gallup. Sleep in America. Princeton: Gallup, 1995:1–78.
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.
Roehrs T, Hollebeek E, Drake C, et al. Substance use for insomnia in Metropolitan Detroit. J Psychosom Res 2003;53:571–576.
Roehrs T, Roth T. Sleep, sleepiness, sleep disorders and alcohol use and abuse. Sleep Med Rev 2001;5:287–297.
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.
Mohler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther 2002;300:2–8.
Mendelson WB, Thompson C, Franko T. Adverse reactions to sedative hypnotics: three years’ experience. Sleep 1996;19:702–706.
Nutt D. GABA-A receptors: subtypes, regional distribution, and function. J Clin Sleep Med 2006;2:S7–S11.
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.
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.
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.
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.
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.
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.
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.
Lamphere JK, Roehrs TA, Zorick FJ, Koshorek G, Roth T. The dose effects of zopiclone. Hum Psychopharm 1989;4:41–46.
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.
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.
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.
Randall S, Roehrs T, Roth T. Efficacy of eight months of nightly zolpidem: a prospective placebo controlled study. Sleep (in press).
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.
Roth T, Roehrs T. Issues in the use of benzodiazepine therapy. J Clin Psychiatry 1992;53:S14–S18.
Mendelson WB, Thompson C, Franko T. Adverse reactions to sedative/hypnotics: three years’ experience. Sleep 1996;9:702–706.
Rush CR, Griffiths RR. Zolpidem, triazolam and temazepam: behavioral and subject-rated effects in normal volunteers. J Clin Psychopharmacol 1996;6:46–57.
Roehrs T, Merlotti L, Zorick F, et al. Sedative, memory and performance effects of hypnotics. Psychpharmacology [Berl] 1994;16:30–34.
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.
Carskadon MA, Seidel WF, Greenblatt DJ, et al. Daytime carryover of triazolam and flurazepam in elderly insomniacs. Sleep 1982;5:362–371.
Riedel BW, Lichstein KL. Insomnia and daytime functioning. Sleep Med Rev 2000;4:277–298.
Kelly KD, Pickett W, Yiannakaoulias N, et al. Medication use and falls in community-dwelling older persons. Age Ageing 2003;32:503–509.
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.
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.
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.
Roehrs T, Zorick F, Sicklesteel J, et al. Effects of hypnotics on memory. J Clin Psychopharmacol 1983;3:310–313.
Green JF, McElholm A, King DJ. A comparison of the sedative and amnestic effects of chlorpromazine and lorazepam. Psychopharmacology [Berl] 1996;128:67–73.
Mohler H, Crestani F, Rudolph U. GABA-A receptor subtypes: a new pharmacology. Curr Opin Pharmacol 2001;1:22–25.
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.
Roehrs TA, Vogel G, Roth T. Rebound insomnia: Its determinants and significance. Am J Med 1990;88:43S–46S.
Roehrs T, Zorick F, Wittig R, et al. Dose determinants of rebound insomnia. Brit J Clin Pharmacology 1986;22:143–147.
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.
Merlotti L, Roehrs T, Zorick F, et al. Rebound insomnia: duration of use and individual differences. J Clin Psychopharm 1991;11:368–373.
Roehrs T, Merlotti L, Zorick F, et al. Rebound insomnia and hypnotic self administration. Psychopharmacology 1992;107:480–484.
Woods JH, Winger G. Current benzodiazepine issues. Psychopharmacology 1995;118:103–107.
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.
Mellinger GD, Balter MB, Uhlenhuth EH. Insomnia and its treatment. Arch Gen Psychiatry 1985;42:225–232.
Roehrs T, Pedrosi B, Rosenthal L, et al. Hypnotic self administration and dose escalation. Psychopharmacology [Berl] 1996;127:150–154.
Roehrs T, Bonahoom A, Pedrosi B, et al. Nighttime versus daytime hypnotic self-administration. Psychopharmacology 2002;161:137–142.
Roehrs T, Bonahoom A, Pedrosi B, et al. Disturbed sleep predicts hypnotic self administration. Sleep Med 2002;3:61–66.
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.
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.
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.
Lisko B, Pikalov A. Zaleplon overdose associated with sleepwalking and complex behavior. J Am Acad Child Adolesc Psychiatry 2004;43:927–928.
Menkes DB. Triazolam-induced nocturnal bingeing with amnesia. Aust N Z J Psychaitry 1992;26:320–321.
Morgenthaler TI, Silber MH. Amnestic sleep-related eating disorder associated with zolpidem. Sleep Med 2002;3:323–327.
Yang W, Dollear M, Muthukrishnan SR. One rare side effect of zolpidem – sleepwalking: a case report. Arch Phys Med Rehabil 2005;86:1265–1266.
Lange CL. Medication-associated somnambulism. J Am Acad Child Adoles Psychiatry 2005;44:211–212.
Lauerma H. Nocturnal wandering caused by restless legs and short-acting benzodiazepines. Acta Psychiatr Scand 1991;83:492–493.
Roehrs TA, Roth T. Safety of insomnia pharmacotherapy. Sleep Med Clinics 2006;1:399–407.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Griffiths R, Suess P, Johnson M. Ramelteon and triazolam in humans: behavioral effects and abuse potential. Sleep 2005;28:A44.
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.
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.
Johnson MW, Suess PE, Griffiths RR. Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. Arch Gen Psychiatry 2006;63:1149–1157.
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.
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.
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.
Owen RT. Selective histamine H[1] antagonism: a novel approach to insomnia using low-dose doxepin. Drugs Today 2009;45:261–267.
Wolf B, Guarino JJ, Preston KL, Griffiths RR. Abuse liability of diphenhydramine in sedative abuser. NIDA Res Monogr 1989;95:486–487.
Walsh JK. Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-based medicine. Sleep 2004;27:1441–1442.
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.
Richelson E. The pharmacology of antidepressants at the synapse: focus on newer compounds. J Clin Psychiatry 1994;55(suppl A):34–39
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.
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.
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.
Levenson JL. Prolonged QT interval after trazodone overdose. Am J Psychiatry 1999;156:969–970.
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.
Wiegard M, Landry T, Bruckner T, et al. Quetiapine in primary insomnia: a pilot study. Psychopharmacology 2008;196:337–338.
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.
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.
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.
Roehrs T, Roth T. “Hypnotic” prescription patterns in a large managed-care population: Sleep Med 2004;5:463–466.
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.
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.
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.
Roehrs TA. Does effective management of sleep disorders improve pain symptoms? Drugs 2009;69:S5–S11.
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.
Walsh JK, Roth T, Randazzo AC, et al. Eight weeks of non-nightly use of zolpidem for primary insomnia. Sleep 2000;23:1087–1096.
Roehrs T, Bonahoom A, Pedrosi B, Rosenthal L, Roth T. Treatment regimen and hypnotic self-administration. Psychopharmacology 2001;155:11–17.
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.
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.
Required Author Forms
Disclosure forms provided by the authors are available with the online version of this article.
Author information
Authors and Affiliations
Corresponding author
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
ESM 1
(PDF 510 kb)
Rights and permissions
About this article
Cite this article
Roehrs, T., Roth, T. Insomnia Pharmacotherapy. Neurotherapeutics 9, 728–738 (2012). https://doi.org/10.1007/s13311-012-0148-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13311-012-0148-3