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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief:  Adnan Ezici, M.D[2]

## Overview

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Pharmacologic medical therapies for insomnia include (either) benzodiazepines (e.g., triazolam, temazepam, etc.), nonbenzodiazepine receptor agonists (e.g., zaleplon, zolpidem, eszopiclone), antidepressants (doxepin), melatonin, melatonin agonists (ramelteon), orexin receptor antagonists (i.e., lemborexant, suvorexant), and/or antihistamines.

## Medical Therapy

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Many insomniacs rely on sleeping tablets and other sedatives to get rest. All sedative drugs have the potential of causing psychological dependence where the individual cannot psychologically accept that they can sleep without drugs. Certain classes of sedatives such as benzodiazepines and newer nonbenzodiazepine drugs can also cause physical dependence which manifests in withdrawal symptoms if the drug is not carefully titrated down.

In comparing the options, systematic reviews:

* 2022 reported "eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce"[1]

* 2007 found that benzodiazepines and nonbenzodiazepines have similar efficacy which was  insignificantly more than for antidepressants.[2] Benzodiazepines had an  insignificant tendency for more adverse drug reactions.[2]

### Benzodiazepines

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Main article: Benzodiazepine

The most commonly used class of hypnotics prescribed for insomnia are the benzodiazepines. Benzodiazepines bind unselectively to the GABAA receptor.[2] This includes drugs such as triazolam, temazepam, diazepam, lorazepam, flurazepam, nitrazepam and midazolam. These medications can be addictive, especially after taking them over long periods of time.[3]

* Preferred regimen (1): Triazolam 0.125, 0.25 mg PO
* A benzodiazepine with rapid onset and short duration that might be prescribed for sleep onset insomnia
* Preferred regimen (2): Temazepam 7.5, 15, 22.5, 30 mg PO
* A benzodiazepine with slow onset and intermediate duration that might be prescribed for both sleep onset and sleep maintenance insomnia.

### Non-benzodiazepine Receptor Agonists

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Main article: Nonbenzodiazepine

Nonbenzodiazepine Receptor Agonists prescription drugs, including the zolpidem, zaleplon, and eszopiclone, are more selective for the GABAA receptor[2] and may have a cleaner side effect profile than the older benzodiazepines; however, there are controversies over whether these non-benzodiazepine drugs are superior to benzodiazepines. These drugs appear to cause both psychological dependence and physical dependence, and can also cause the same memory and cognitive disturbances as the benzodiazepines along with morning sedation.[3]

* Preferred regimen (1): Zaleplon 5 or 10 mg PO
* A non–benzodiazepine receptor agonist with rapid onset and ultra-short duration that might be prescribed for sleep-onset insomnia
* Preferred regimen (2): Zolpidem with different routes of administration (the lower dose is recommended for women to reduce effects on the next day)
* 1.75, 3.5 mg immediate-release sublingual tablet
* A non–benzodiazepine receptor agonist with rapid onset and ultra-short duration that might be prescribed for night-time awakening
* 5, 10 mg PO
* A non–benzodiazepine receptor agonist with rapid onset and short duration that might be prescribed for both sleep onset and sleep maintenance insomnia
* 5, 10 mg sublingual tablet
* A non–benzodiazepine receptor agonist with rapid onset and short duration that might be prescribed for both sleep onset and sleep maintenance insomnia
* 6.25, 12.5 mg controlled-release tablet
* A non–benzodiazepine receptor agonist with rapid onset and short duration that might be prescribed for both sleep onset and sleep maintenance insomnia
* Preferred regimen (3): Eszopiclone 1, 2, 3 mg PO (Initial dose is 1 mg)
* A non–benzodiazepine receptor agonist with rapid onset and intermediate duration that might be prescribed for both sleep onset and sleep maintenance insomnia

Randomized controlled trial of treatment options for insomnia.[4] Treatment | Outcome at 6 months

|

Responders | Remitters
6 weeks of CBT | 55% | 40%
6 months of CBT | 63% | 44%
6 months of CBT
6 weeks of zolpidem | 81% | 68%
6 months of CBT
6 months of zolpidem | 65% | 42%
Adapted from Table 4 of Morin et al.[4]

### Antidepressants

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Main article: Antidepressants

Some antidepressants such as mirtazapine, trazodone and doxepin have a sedative effect, and are prescribed off label to treat insomnia. The major drawback of these drugs is that they have antihistaminergic, anticholinergic and antiadrenergic properties which can lead to many side effects. Some also alter sleep architecture.

* Preferred regimen (1): doxepin 3, 6 mg PO[3]
* A tricyclic antidepressant with slow onset and long duration that might be prescribed for sleep maintenance insomnia

### Melatonin and Melatonin Agonists

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Melatonin has proved effective for some insomniacs in regulating the sleep/waking cycle, but lacks definitive data regarding efficacy in the treatment of insomnia. Melatonin agonists, including ramelteon (Rozerem), seem to lack the potential for abuse and dependence. This class of drugs has a relatively mild side effect profile and a lower likelihood of causing morning sedation.

* Preferred regimen (1): ramelteon 8 mg PO[3]
* A melatonin agonist with rapid onset and short duration that might be prescribed for sleep-onset insomnia

### Orexin Receptor Antagonists

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* Preferred regimen (1): Lemborexant 5, 10 mg PO (initial dose is 5 mg)[3]
* An orexin receptor antagonist with slow onset and long duration that might be prescribed for sleep maintenance insomnia
* Preferred regimen (2): Suvorexant 5, 10, 20 mg PO (initial dose is 10 mg)
* An orexin receptor antagonist with slow onset and long duration that might be prescribed for sleep maintenance insomnia

### Antihistamines

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The antihistamine diphenhydramine is widely used in nonprescription sleep aids, with a 50 mg recommended dose mandated by the FDA. In the United Kingdom, Australia, New Zealand, South Africa, and other countries, a 50 to 100 mg recommended dose is permitted. While it is available over the counter, the effectiveness of these agents may decrease over time and the incidence of next-day sedation is higher than for most of the newer prescription drugs. Dependence does not seem to be an issue with this class of drugs.

### Atypical antipsychotics

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Low doses of certain atypical antipsychotics such as quetiapine (Seroquel) are also prescribed for their sedative effect but the danger of neurological and cognitive side effects make these drugs a poor choice to treat insomnia.

### Herbal medicines

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Some insomniacs use herbs such as valerian, chamomile, lavender, hops, and passion-flower. Valerian has undergone multiple studies and appears to be modestly effective.[5][6][7]

### Other substances

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Cannabis has also been suggested as a very effective treatment for insomnia. [8]

Alcohol may have sedative properties, but the REM sleep suppressing effects of the drug prevent restful, quality sleep. Middle-of-the-night awakenings due to polyuria or other effects from alcohol consumption are common, and hangovers can also lead to morning grogginess.

Insomnia may be a symptom of magnesium deficiency, or lower magnesium levels. A healthy diet containing magnesium, can help to improve sleep in individuals without an adequate intake of magnesium.[9]

Other reports cite the use of an elixir of cider vinegar and honey but the evidence for this is only anecdotal. [10]

## References

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1. ↑ De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N; et al. (2022). "Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis". Lancet. 400 (10347): 170–184. doi:10.1016/S0140-6736(22)00878-9. PMID 35843245 Check `|pmid=` value (help).CS1 maint: Multiple names: authors list (link)
2. ↑ 2.0 2.1 2.2 2.3 Buscemi N, Vandermeer B, Friesen C, Bialy L, Tubman M, Ospina M, Klassen TP, Witmans M. The efficacy and safety of drug treatments for chronic insomnia in adults: a meta-analysis of RCTs. J Gen Intern Med. 2007 Sep;22(9):1335-50. Epub 2007 Jul 10. PMID 17619935
3. ↑ 3.0 3.1 3.2 3.3 3.4 Sutton EL (March 2021). "Insomnia". Ann Intern Med. 174 (3): ITC33–ITC48. doi:10.7326/AITC202103160. PMID 33683929 Check `|pmid=` value (help).
4. ↑ 4.0 4.1 Morin CM, Vallières A, Guay B, Ivers H, Savard J, Mérette C; et al. (2009). "Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial". JAMA. 301 (19): 2005–15. doi:10.1001/jama.2009.682. PMID 19454639.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
5. ↑ Donath F, Quispe S, Diefenbach K, Maurer A, Fietze I, Roots I (2000). "Critical evaluation of the effect of valerian extract on sleep structure and sleep quality". Pharmacopsychiatry. 33 (2): 47–53. PMID 10761819.CS1 maint: Multiple names: authors list (link)
6. ↑ Morin CM, Koetter U, Bastien C, Ware JC, Wooten V (2005). "Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial". Sleep. 28 (11): 1465–71. PMID 16335333.CS1 maint: Multiple names: authors list (link)
7. ↑ Meolie AL, Rosen C, Kristo D; et al. (2005). "Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence". Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 1 (2): 173–87. PMID 17561634.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
8. ↑ http://www.cannabis.net/medical-marijuana/pot-docs.html
9. ↑ Hornyak M, Voderholzer U, Hohagen F, Berger M, Riemann D (1998). "Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: an open pilot study". Sleep. 21 (5): 501–5. PMID 9703590.CS1 maint: Multiple names: authors list (link)
10. ↑ "Cider Vinegar and Insomnia".