Insomnia Medication

  • Author: Ron A Shatzmiller, MD, MSc; Chief Editor: Selim R Benbadis, MD   more...
 
Updated: Jan 17, 2012
 

Medication Summary

These agents have a nonbenzodiazepine structure and bind more specifically to the alpha 1 subunit of the GABAA receptor, which is associated with sedation. This class of drugs is called nonbenzodiazepine receptor agonists. They are excellent choices for treatment of sleep-onset insomnia.Both eszopiclone and sustained-release zolpidem are effective for both sleep-onset and sleep-maintenance insomnia, with a reduced abuse potential and long-term efficacy up to 6 months as compared with nonselective benzodiazepine receptor agonists.

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Sedative Hypnotics, Nonbenzodiazepine Receptor Agonists

Class Summary

These agents have a nonbenzodiazepine structure and bind more specifically to the alpha 1 subunit of the GABAA receptor, which is associated with sedation. This class of drugs is called nonbenzodiazepine receptor agonists. They are excellent choices for treatment of sleep-onset insomnia. The low-dose sublingual product is indicated for as-needed use for middle of the night awakening.

Both eszopiclone and sustained-release zolpidem are effective for both sleep-onset and sleep-maintenance insomnia, with a reduced abuse potential and long-term efficacy up to 6 months as compared with nonselective benzodiazepine receptor agonists.

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Zaleplon (Sonata)

 

A sedative-hypnotic of the pyrazolopyrimidine class, zaleplon has a rapid onset of action and an ultra-short duration of action, making it a good choice for treatment of sleep-onset insomnia. A second dose can be used during the middle of night without residual sedation in morning (this is believed to be an advantage of this hypnotic over others).

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Zolpidem (Ambien, Ambien CR, Intermezzo)

 

A sedative-hypnotic of the imidazopyridine class, zolpidem has a rapid onset and short duration of action; it is a good first choice for treatment of sleep-onset insomnia and has no significant residual sedation in morning. 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. The low-dose sublingual product (Intermezzo) is indicated for middle of night awakening.

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Eszopiclone (Lunesta)

 

Eszopiclone is a nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. The precise mechanism of action is unknown but this agent is believed to interact with GABA-receptor at binding domains close to or allosterically coupled to benzodiazepine receptors.

Eszopiclone is indicated for insomnia to decrease sleep latency and improve sleep maintenance. It has a short half-life of 6 h. Higher doses (ie, 2 mg for elderly adults and 3 mg for nonelderly adults) are more effective for sleep maintenance, whereas lower doses (ie, 1 mg for elderly adults and 2 mg for nonelderly adults) are suitable for difficulty in falling asleep.

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Sedative hypnotic, short-acting benzodiazepine receptor agonists

Class Summary

Useful in sleep onset insomnia.

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Triazolam (Halcion)

 

Triazolam depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. It is indicated for short-term insomnia.

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Sedative hypnotics, intermediate-acting benzodiazepine receptor agonists

Class Summary

Useful in sleep-onset insomnia, these agents have been the hypnotics of choice for many years because of their relative safety compared with the barbiturates. By binding to specific subunits of GABAA receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission by increasing the frequency of chloride channel opening.

The older sedative-hypnotics have a prolonged half-life with an increased risk for next-day sedation, daytime psychomotor impairment, and an increased risk for abuse and dependence.

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Estazolam (ProSom)

 

Estazolam is an intermediate-acting benzodiazepine with a slow onset of action and a long duration. Estazolam is a good agent for sleep-maintenance insomnia.

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Temazepam (Restoril)

 

Temazepam is a short- to intermediate-acting benzodiazepine with longer latency to onset and half-life. Temazepam may be more helpful in sleep-maintenance insomnia.

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Tricyclic antidepressants

Class Summary

Drugs in this category are not FDA-approved for treatment of insomnia, and there have been no randomized placebo-controlled trials demonstrating efficacy for insomnia.

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Amitriptyline (Elavil)

 

Amitriptyline is a tricyclic antidepressant with sedative effects. It inhibits reuptake of serotonin and/or norepinephrine at the presynaptic neuronal membrane, which increases concentration in CNS.

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Doxepin (Adapin, Sinequan)

 

Doxepin increases the concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake by the presynaptic neuronal membrane. These effects are associated with a decrease in symptoms of depression.

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Nortriptyline (Aventyl HCl, Pamelor)

 

Nortriptyline has demonstrated effectiveness in the treatment of chronic pain.

By inhibiting the re-uptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, this drug increases the synaptic concentration of these neurotransmitters in the CNS.

Pharmacodynamic effects such as the desensitization of adenyl cyclase and downregulation of beta-adrenergic receptors and serotonin receptors also appear to play a role in its mechanisms of action.

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Non-tricyclic antidepressants

Class Summary

The side effect of drowsiness seen with some antidepressants can be used to benefit the patient in the treatment of sleep-maintenance insomnia or insomnia associated with depression.

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Trazodone (Desyrel)

 

A nontricyclic antidepressant with short onset of action, trazodone consolidates sleep. It is an antagonist at the type 2 serotonin (5-HT2) receptor and inhibits reuptake of 5-HT; it also has negligible affinity for cholinergic and histaminergic receptors.

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Nefazodone (Serzone)

 

Nefazodone inhibits serotonin reuptake and is a potent antagonist at the 5-HT2 receptor. It also has negligible affinity for cholinergic, histaminic, or alpha-adrenergic receptors.

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Antidepressant, alpha-2 antagonists

Class Summary

This drug is not an FDA approved treatment for insomnia, and no randomized, placebo-controlled trials have demonstrated its efficacy for insomnia.

In patients with depression, the sedative properties of the drug may help with sleep-onset insomnia.

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Mirtazapine (Remeron, Remeron SolTab)

 

Mirtazapine exhibits both noradrenergic and serotonergic activity. In cases of depression associated with severe insomnia and anxiety, it has been shown to be superior to other selective serotonin receptor inhibitors (SSRIs).

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Selective melatonin agonists

Class Summary

This agent is indicated for insomnia characterized by difficulty with sleep onset.

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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 be involved in maintenance of circadian rhythm and normal sleep-wake cycle. Stimulation of the MT1 receptor in the suprachiasmatic nucleus (SCN) inhibits neuronal firing (reduces alerting affect of the SCN) and stimulation of the MT2 receptor in the SCN affects the circadian rhythm causing a phase advance (earlier sleep time).

Ramelteon has a short half-life of 1-2.6 hours. Its active metabolite M-II has a half-life of 2-5 hours. It has a 3-5 times greater affinity for the melatonin receptor and is up to 17 times more potent than melatonin.

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Contributor Information and Disclosures
Author

Ron A Shatzmiller, MD, MSc  Assistant Clinical Professor, Department of Neurology, Keck School of Medicine of the University of Southern California; Specialty Lead Physician, Healthcare Partners Medical Group, Arcadia, California

Ron A Shatzmiller, MD, MSc is a member of the following medical societies: American Academy of Neurology and American Academy of Sleep Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Erasmo A Passaro, MD, FAAN  Director, Comprehensive Epilepsy Program/Clinical Neurophysiology Lab, Bayfront Medical Center, Florida Center for Neurology

Erasmo A Passaro, MD, FAAN is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association, and American Society of Neuroimaging

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; Forest Honoraria Speaking and teaching

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 Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting

Additional Contributors

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

Kendra Becker, MD, MPH Sleep Medicine Department, Kaiser Permanente Fontana Medical Center

Kendra Becker, MD, MPH is a member of the following medical societies: American Academy of Sleep Medicine, American College of Physicians, and American Medical Association

Disclosure: Nothing to disclose.

Jose E Cavazos, MD, PhD, FAAN Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, Program Director of the Clinical Neurophysiology Fellowship, University of Texas School of Medicine at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center, University Hospital System; Director of the San Antonio Veterans Affairs Epilepsy Center of Excellence and Neurodiagnostic Centers, Audie L Murphy Veterans Affairs Medical Center

Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and American Neurological Association

Disclosure: GXC Global, Inc. Intellectual property rights Medical Director - company is to develop a seizure detecting device. No conflict with any of the eMedicine articles that I wrote or edited.

Zab Mosenifar, MD Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Professor and Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society

Disclosure: Nothing to disclose.

Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University School of Medicine; Consulting Staff, Pulmonary Disease and Critical Care Medicine Service, Henry Ford Health System

Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians and American Thoracic Society

Disclosure: Nothing to disclose.

James A Rowley, MD Professor, Fellowship Program Director, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine

James A Rowley, MD is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Silverio M Santiago, MD Clinical Professor of Medicine, University of California at Los Angeles School of Medicine; Chief, Department of Pulmonary and Critical Care Medicine, Medical Director, Sleep Disorders Center, Veterans Affairs Medical Center of West Los Angeles

Silverio M Santiago, MD is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Peter Smethurst, MD Attending Physician, Pulmonary, Critical Care and Sleep Medicine, St Joseph's Medical Center

Disclosure: Nothing to disclose.

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

Gregory Tino, MD Director of Pulmonary Outpatient Practices, Associate Professor, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Medical Center and Hospital

Gregory Tino, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

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Theoretical model of the factors causing chronic insomnia. Chronic insomnia is believed to primarily occur in patients with predisposing or constitutional factors. These factors may cause the occasional night of poor sleep but not chronic insomnia. A precipitating factor, such as a major life event, causes the patient to have acute insomnia. If poor sleep habits or other perpetuating factors occur in the following weeks to months, chronic insomnia develops despite the removal of the precipitating factor. Adapted from Spielman AJ, Caruso LS, Glovinsky PB: A behavioral perspective on insomnia treatment. Psychiatr Clin North Am. 1987 Dec;10(4):541-53.
Mallampati airway scoring.
Diagnostic algorithm for major depression.
Diagnostic criteria for generalized anxiety disorder.
Sleep diary.
GABAA receptor subunit function(s).
GABAA receptor complex subunits and schematic representation of agonist binding sites.
Sleep-wake cycle.
The ascending arousal system. Adapted from Saper et al. Hypothalamic Regulation of Sleep and Circadian Rhythms. Nature 2005;437:1257-1263.
Ventrolateral pre-optic nucleus inhibitory projections to main components of the arousal system to promote sleep.
Schematic flip-flop switch model. Adapted from Saper C et al. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257-1263.
Epworth Sleepiness Scale.
Frequency of insomnia causes.
 
 
 
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