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Insomnia Medication

  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Selim R Benbadis, MD  more...
 
Updated: Jul 06, 2016
 

Medication Summary

Medications used in the treatment of insomnia include nonbenzodiazepine receptor agonists, benzodiazepine receptor agonists, the selective melatonin receptor agonist ramelteon, and sedating antidepressants. All can be considered first-line agents for insomnia; agent choice is largely dictated by past trials, cost, side-effect profile, drug interactions, and patient preference.[1] Pharmacologic therapy is used in concert with behavioral and psychological interventions.

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Sedative-Hypnotics

Class Summary

Sedative-hypnotics include nonbenzodiazepine receptor agonists (zaleplon, zolpidem, eszopiclone); short-acting benzodiazepine receptor agonists (triazolam); intermediate-acting benzodiazepine receptor agonists (estazolam, temazepam); and selective melatonin agonists (ramelteon).

Nonbenzodiazepine receptor agonists have a nonbenzodiazepine structure and bind more specifically to the alpha-1 subunit of the gamma-aminobutyric acid–A (GABAA) receptor, which is associated with sedation. 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 of up to 6 months as compared with nonselective benzodiazepine receptor agonists.

Short-acting (eg, triazolam) and intermediate-acting (eg, estazolam, temazepam) benzodiazepine receptor agonists are useful for sleep-onset insomnia. These agents have been the hypnotics of choice for many years because of their relative safety compared with the barbiturates, as well as their low cost. 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.

Benzodiazepines are on the Beer’s List of potentially inappropriate medications for older patients. They are not recommended in the elderly because of the risk of falls; if used, they should be given at the lowest effective dose for the shortest amount of time. The older sedative-hypnotics that have a prolonged half-life increase the risk for next-day sedation and daytime psychomotor impairment and pose an increased risk for abuse and dependence. Other complications of benzodiazepine use include tolerance, withdrawal, abuse, and rebound insomnia.

Selective melatonin agonists are indicated for insomnia characterized by difficulty with sleep onset, particularly for individuals who lack dim-light melatonin-onset stimulation. Melatonin itself is not regulated by the US Food and Drug Administration (FDA) and is thus not approved for treatment of insomnia. Melatonin does not appear to have obvious side effects other than sedation. Currently, ramelteon is the only melatonin receptor agonist approved by the FDA for treatment of insomnia and is available by prescription.

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 the night without residual sedation in the morning (this is believed to be an advantage of this hypnotic over others).

Zolpidem (Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist)

 

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 produces no significant residual sedation in the 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 higher-dose sublingual product (Edluar) is available as 5- and 10-mg tablets; an oral spray (Zolpimist) is also available for sleep-onset and/or sleep-maintenance insomnia. The low-dose sublingual product (Intermezzo) is indicated for middle-of-the-night awakening.

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 receptors 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 (6 h).

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.

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. Triazolam was the first short-acting benzodiazepine for promoting sleep but fell out of favor after high-profile reports of amnesia with its use.

Estazolam

 

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.

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 than in sleep-onset insomnia.

Ramelteon (Rozerem)

 

Ramelteon is a melatonin receptor agonist that is indicated for insomnia characterized by difficulty with sleep onset. This agent has high selectivity for human melatonin MT1 and MT2 receptors. MT1 and MT2 are thought to promote sleep and to be involved in maintenance of the circadian rhythm and normal sleep-wake cycle. Stimulation of the MT1 receptor in the suprachiasmatic nucleus (SCN) inhibits neuronal firing (reduces alerting effect of the SCN), and stimulation of the MT2 receptor in the SCN affects the circadian rhythm, causing a phase advance (earlier sleep time).

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.

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Antidepressants, TCAs

Class Summary

Except for low-dose doxepin (Silenor), drugs in this category are not approved for treatment of insomnia by the US Food and Drug Administration (FDA), and there have been few randomized, placebo-controlled trials demonstrating efficacy for insomnia. Nevertheless, these agents can be useful, especially in patients with comorbid depression or anxiety.

Amitriptyline

 

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

Doxepin (Silenor)

 

Low-dose doxepin is FDA approved for sleep-maintenance insomnia. It is available in 3- and 6-mg tablets.

Nortriptyline (Pamelor)

 

Nortriptyline has demonstrated effectiveness in the treatment of chronic pain.

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

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Antidepressants, Other

Class Summary

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

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 reuptake inhibitors (SSRIs). In patients with depression, the sedative properties of mirtazapine may help with sleep-onset insomnia. This drug is not an FDA-approved treatment for insomnia, and no randomized, placebo-controlled trials have demonstrated its efficacy for insomnia.

Trazodone (Oleptro)

 

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.

Nefazodone

 

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. The FDA has added a Black Box warning regarding rare cases of liver failure with this drug.

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Contributor Information and Disclosures
Author

Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

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

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

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: UCB; Sunovion.

Youngsook Park, MD Co-Director in SLEEP Lab, Hines Veterans Affairs Medical Center; Assistant Professor of Neurology, Loyola University, Chicago Stritch School of Medicine

Youngsook Park, MD is a member of the following medical societies: American Academy of Neurology, Willis-Ekbom Disease Foundation, American Academy of Sleep Medicine

Disclosure: Received none from Hines VA Hospital for none.

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

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 Medscape Reference 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.

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.

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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