Comparison of Insomnia Treatments

 

Full update May 2020

 

Insomnia is a very common disorder that can present in a number of different ways. Patients may have difficulty falling asleep (sleep latency), difficulty staying asleep (sleep maintenance), or may not feel rested by a night’s sleep (sleep quality).1 Insomnia can be transient (lasting days to weeks) or chronic (occurring at least three times per week for at least three months).1 Approximately 30% to 50% of Americans have symptoms of insomnia at some time in their lives, with distress or impairment in about 10% to 15%.1 First-line treatment of chronic insomnia should focus on nonpharmacologic interventions (e.g., sleep hygiene).2-4 Pharmacologic treatments are added only if necessary.2-4 Studies show medications are only modestly effective, helping patients fall asleep about five to 15 minutes faster and/or stay asleep about 30 to 60 minutes longer.1 In general, benzodiazepines have more side effects and a higher potential for dependence, tolerance, and rebound insomnia than the newer nonbenzodiazepine hypnotics.5 Hypnotics have a risk of complex sleep-related behaviors (e.g., sleepwalking, sleep driving) with amnesia; however they appear to be more common with the nonbenzodiazepine “Z” drugs (e.g., zolpidem, eszopiclone, zaleplon).6 For most patients, medications should be started at the low end of the dose range and increased as necessary based on effect. The chart below provides a comparison of medications that are commonly used to treat insomnia. See our patient education handout, Strategies for a Good Night’s Sleep, which provides information about sleep hygiene. See our Benzodiazepine Toolkit, for more information on the comparison of benzodiazepines. Also see our commentary, Melatonin for Insomnia, and our CE, Natural Medicines in the Clinical Management of Insomnia Disorder, for information on melatonin, valerian, and other supplements.

 

-Information pertains to U.S. products-


Generic
(Brand)

Usual Dose
(mg/day)a
,g
Elderlye/
Adult

Costb

Onset
(min)
c

Half-life
(hours)
a,c

Commentsa

Nonprescription Antihistamines

Diphenhydramine
(Benadryl, Sleep Tabs, ZzzQuil, etc; generics)

 

 

Avoid1,4,5/
25-507

 

~$0.10/25 mg

15-308

 

2-88

 

 

 

  • Anticholinergic side effects can occur.4
  • Not recommended due to poor evidence of efficacy.1

Doxylamine
(Unisom, generics)

 

 

Avoid1,4,5/
259

 

~$0.13/25 mg

308,f

108

  • Anticholinergic side effects can occur.1
  • Not recommended due to poor evidence of efficacy.1

 

Antidepressants

Doxepin
(Silenor, generics)

3/
6

$12.59/3 mg,
6 mg

 

 

3010

15

 

31
(primary metabolite)

  • Approved for insomnia, to improve sleep maintenance.
  • Maximum dose is 3 mg in patients taking cimetidine.
  • Dose-dependent anticholinergic adverse effects.10
  • Do not take within three hours of a meal due to delayed onset and potential for next day drowsiness.
  • Little evidence of rebound insomnia.
  • Dispense with a MedGuide.

 

Mirtazapine
(Remeron, Remeron Soltab, generics)

15/
1511


 

Tablet:
~$0.38/15 mg

 

Disintegrating tablet:
~$1.78/15 mg

 

Not available

 

 

20-40

  • Off-label use.
  • Some evidence on reducing insomnia in patients with depression, especially early in treatment.12
  • Increased risk of restless legs syndrome and periodic limb movements in sleep.12
  • Low anticholinergic activity compared to doxepin.13
  • Dispense with a MedGuide.

 

Trazodone
(generics)

Start with 2514/
25-1003

~$0.06/50 mg
~$0.11/100 mg

 

 

 

3015,f

 

 

 

6.4 in younger patients,
11.6 in elderly10

 

 

 

  • Off-label use.
  • Limited efficacy data, especially in primary insomnia.2,12
  • Not recommended for insomnia as harms outweigh the benefits.1,3
  • Low anticholinergic effects compared to doxepin.11,12
  • Anticholinergic effects can be significant in the elderly.3
  • Can cause priapism, even at low doses.10,16
  • Dispense with a MedGuide.

Benzodiazepines

Estazolam
(generics)

0.5-1/
1-2

$0.54/1 mg
$0.60/2 mg

 

60-12010

 

 

10-24

  • Approved for the short-termd treatment of insomnia, to improve sleep onset and maintenance.
  • Concurrent administration with strong CYP450 3A4 inhibitors such as the azole antifungals is contraindicated.
  • Duration six to ten hours.17
  • Dispense with a MedGuide.

 

 

Flurazepam
(generics)

 

 

15/
15-30

 

(start with 15 in women)

~$0.29/15 mg
~$0.35/30 mg

<605,18

 

>100
(including active metabolite)10

  • Approved for insomnia, to improve sleep onset and maintenance.
  • Avoid in elderly due to active metabolite with long half-life.10
  • Duration ten to 20 hours.17
  • Risk of daytime drowsiness and impaired functioning.
  • Dispense with a MedGuide.

Lorazepam

(Ativan, generics)

0.25-1/
0.5-419,20

~$0.06/0.5 mg
~$0.08/1 mg
~$0.15/2 mg

30-6020


 

12

 

18 (primary metabolite)

  • Off-label use.
  • Generally used for secondary insomnia (e.g., due to anxiety).21
  • Useful to improve sleep maintenance, not sleep onset.21
  • Dispense with a MedGuide.

Oxazepam
(generics)

10-15/
15-3010

~$1.38/10 mg
~$1.58/15 mg
~$2.20/30 mg

45-6020

 

5.7-10.9

  • Off-label use.

     

  • May be effective for sleep-onset insomnia.19

     

Quazepam
(Doral, generics)

7.5-15/
7.5-15

~$21.07/15 mg

30-6010

 

 

39-73
(including active metabolites)

  • Approved for insomnia, to improve sleep onset and maintenance.
  • Avoid in the elderly due to long half-life.10
  • Duration ten to 20 hours.17
  • Risk of daytime drowsiness and impaired functioning.
  • Dispense with a MedGuide.

 

Temazepam
(Restoril, generics)

Start with 7.5/
7.5-30

~$4.21/7.5 mg
~$0.10/15 mg
~$6.23/22.5 mg
~$0.12/30 mg

 

60-12010

3.5-18.4

  • Approved for short-termd treatment of insomnia.
  • No cytochrome P450 interactions.
  • Improves sleep onset and sleep maintenance.1,10
  • If a benzodiazepine is to be used in the elderly, temazepam may be one of the better options if appropriately dosed.22
  • Duration six to ten hours.17
  • Dispense with a MedGuide.

Triazolam
(Halcion, generics)

0.125-0.25/
0.125-0.5

$2.93/0.125 mg
~$2.32/0.25 mg

 

 

15-3010

1.5-5.5

  • Approved for short-termd treatment of insomnia.
  • Contraindicated with CYP3A4 inhibitors such as azole antifungals and HIV protease inhibitors.
  • Avoid in elderly due to risk of cognitive and behavioral side effects.22
  • Duration two to five hours.17
  • Dispense with a MedGuide.

Nonbenzodiazepine Hypnotics (“Z” Drugs)

Eszopiclone
(Lunesta, generics)

1-2/
1-3

 

(start with 1 in all patients)

~$0.52/1 mg,
2 mg, 3 mg

 

3010

6

  • Approved for insomnia, to improve sleep onset and maintenance.
  • Not limited to short-term use, studies up to six months duration.
  • Nonbenzodiazepine benzodiazepine receptor agonist.
  • Dose should not exceed 2 mg in patients with severe hepatic impairment or those taking strong CYP3A4 inhibitors.
  • Do not take with or immediately after a meal due to delayed onset.
  • Can cause a dose-dependent unpleasant taste.
  • Duration about seven to eight hours.
  • Dispense with a MedGuide.

 

 

 

 

 

Zolpidem
immediate-release
(Ambien, generics)

5/
5-10

 

(start with 5 in women)

 

~$0.08/5 mg, 10 mg

 

3010

1.4-4.5

 

 

 

  • Approved for the short-termd treatment of insomnia, to improve sleep onset.
  • Nonbenzodiazepine benzodiazepine receptor agonist.
  • Rebound insomnia is not associated with stopping zolpidem.
  • Reports of withdrawal after rapid dose reduction or abruptly stopping.
  • May have a lower risk of dependence than benzodiazepines.10
  • Taking with CYP3A4  inducers can reduce effects.
  • Taking with or immediately after a meal results in delayed onset.
  • Dose is 5 mg in patients with mild to moderate hepatic impairment.
  • Duration about seven to eight hours.
  • Dispense with a MedGuide.

 

 

 

 

 

Zolpidem controlled-release
(Ambien CR, generics)

6.25/
6.25-12.5

 

(start with 6.25 in women)

~$0.98/
6.25 mg,
12.5 mg

 

3010

1.62-4.05

 

  • Approved for insomnia, to improve sleep onset and maintenance.
  • Not limited to short-term use.
  • Biphasic absorption with rapid initial absorption similar to immediate-release tablet, but with extended plasma concentration beyond three hours.
  • No clear clinical advantage of controlled-release zolpidem vs immediate-release zolpidem.10
  • Taking with CYP3A4 inducers can reduce effects.
  • Taking with or immediately after a meal results in delayed onset.
  • Dose is 6.25 mg in patients with mild to moderate hepatic impairment.
  • Duration about seven to eight hours.
  • Dispense with a MedGuide.

 

 

Zolpidem
sublingual
(Edluar)

5/
5-10

 

(start with 5 in women)

 

 

~$12.47/5 mg, 10 mg

 

3010

1.57-6.73
(for 5 mg dose)

 

1.75-3.77
(for 10 mg dose)

 

 

 

  • Approved for the short-termd treatment of insomnia, to improve sleep onset.
  • To be dissolved under the tongue. Should not be swallowed whole or taken with water.
  • Taking with or immediately after a meal results in delayed onset.
  • Dose is 5 mg in patients with hepatic impairment.
  • Duration about seven to eight hours.
  • Dispense with a MedGuide.

 

Zolpidem
sublingual
(Intermezzo, generics)

1.75/
1.75 (women)
3.5 (men)

 

~$7.90/1.75 mg
~$7.90/3.5 mg

20-3810

 

1.4-3.6

  • Approved for insomnia associated with middle-of-the-night awakening.
  • Take only if there are at least four hours remaining before planned wake time.
  • To be dissolved under the tongue, not to be swallowed whole
  • Taking with or immediately after a meal results in delayed onset
  • Duration about four hours.24
  • Dispense with a MedGuide.

Zolpidem
oral spray
(Zolpimist)


5/
5-10

 

(start with 5 in women)

$10.98/5 mg

 

1010

 

1.7-5
(for 5 mg dose)

 

1.7-8.4
(for 10 mg dose)

 

  • Approved for the short-termd treatment of insomnia, to improve sleep onset.
  • Do not take with or immediately after a meal due to delayed onset.
  • Dose is 5 mg in patients with hepatic impairment.
  • Duration about seven to eight hours.
  • Dispense with a MedGuide.

Zaleplon
(Sonata [brand discontinued], generics)

5-10/
10-20

 

 

~$0.43/5 mg
~$0.50/10 mg

3010

1

  • Approved for the short-termd treatment of insomnia, to improve sleep onset.
  • Nonbenzodiazepine benzodiazepine receptor agonist.
  • No apparent withdrawal symptoms, daytime anxiety, next-day sedation, or psychomotor impairment.
  • Mild dose-dependent rebound insomnia.
  • May have a lower risk of dependence than benzodiazepines.10
  • Taking with or immediately after a heavy, high-fat meal may decrease absorption and delay onset.
  • Dose is 5 mg in patients taking cimetidine, with mild to moderate hepatic impairment, and low-weight patients.
  • Duration about two to four hours.17
  • Dispense with a MedGuide.

 

Melatonin Receptor Agonist

Ramelteon
(Rozerem, generics)

8/
8

 

 

 

~$6.13/8 mg

 

3010

 

 

1-2.6

 

2-5
(active metabolite)

  • Approved for insomnia, to improve sleep onset.
  • Not limited to short-term use, studies up to six months duration.
  • Melatonin receptor agonist.
  • Not a controlled substance.
  • Metabolized by CYP1A2. Use with fluvoxamine is contraindicated.
  • Do not take with or immediately after a high-fat meal due to delayed onset.
  • Duration about six to eight hours.17
  • Dispense with a MedGuide.

Orexin Receptor Antagonists

Lemborexant
(Dayvigo)

 


5-10/
5-10

 

(use caution with doses over 5 in the elderly)

Not yet available.

<30f

17-19

  • Approved for insomnia, to improve sleep onset and maintenance.
  • Orexin receptor antagonist.
  • Taking with or immediately after a meal results in delayed onset.
  • Not associated with rebound insomnia when stopped.
  • No apparent withdrawal symptoms.
  • Risk of sleep paralysis.
  • Avoid taking with moderate or strong CYP3A inhibitors and inducers.
  • The max dose is 5 mg in patients taking weak CYP3A inhibitors and with moderate hepatic impairment.
  • Duration about seven hours.
  • Dispense with a MedGuide.

 

 

Suvorexant
(Belsomra)

Not specified/
10-20

$12.19/5 mg,
10 mg, 15 mg, 20 mg

3010

 

12

  • Approved for insomnia, to improve sleep onset and maintenance.
  • Orexin receptor antagonist.
  • Taking with or immediately after a meal results in delayed onset.
  • Not associated with rebound insomnia when stopped.
  • No apparent withdrawal symptoms.
  • Risk of sleep paralysis.
  • Taking with strong CYP3A inhibitors is not recommended.
  • Dose is 5 to 10 mg with moderate CYP3A inhibitors.
  • Duration about seven hours.
  • Dose-related adverse effects are greater in obese patients and women. Use caution if increasing dose above 10 mg.
  • Dispense with a MedGuide.

 

 

  1. The following U.S. product labeling was used for the above chart unless otherwise noted: Ambien (August 2019), Ambien CR (August 2019), Ativan (September 2018), Belsomra (March 2020), Dayvigo (December 2019), Doral (April 2019), estazolam (Actavis, October 2019), Edluar (May 2017), flurazepam (Mylan, December 2018), Halcion (October 2019), Intermezzo (August 2019), Lunesta (August 2019), oxazepam (Actavis, September 2016), trazodone (Teva, May 2019), Remeron/Remeron Soltab (March 2020), Restoril (September 2017), Rozerem (December 2018), Silenor (August 2019), zaleplon (Teva, August 2015), Zolpimist (August 2019).
  2. Pricing based on the average wholesale acquisition cost (WAC) per dose for generic (if available), by Elsevier, accessed April 2020.
  3. Administration of a drug with a fast onset and short half-life decreases the risk of adverse daytime effects such as falls.23
  4. Generally, should not be used for more than seven to ten consecutive days.
  5. In general, when dosing sedatives in elderly patients, some experts recommend starting with half the usual adult dose and titrating up as necessary.19
  6. Based on recommendations on the timing of the bedtime dose.
  7. For otherwise healthy individuals with normal hepatic/renal function.

Project Leader in preparation of this clinical resource (360507): Annette Murray, BScPharm

References

  1. Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 2017;13:307-49.
  2. Qaseem A, Kansagara D, Forciea MA, et al. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2016;165:125-33.
  3. Patel D, Steinberg J, Patel P. Insomnia in the elderly: a review. J Clin Sleep Med 2018;14:1017-24.
  4. Brewster GS, Riegel B, Gehrman PR. Insomnia in the older adult. Sleep Med Clin 2018;13:13-9.
  5. Tariq SH, Pulisetty S. Pharmacotherapy for insomnia. Clin Geriatr Med 2008;24:93-105.
  6. Bonnet MH, Arand DL. Behavioral and pharmacologic therapies for chronic insomnia in adults. Last updated January 7, 2020. In UpToDate, Post TW (ed), UpToDate, Waltham, MA 02013.
  7. Product information for ZzzQuil Nighttime Sleep-Aid. Proctor & Gamble. September 2019.
  8. Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2020. http://www.clinicalkey.com. (Accessed April 17, 2020).
  9. Sanofi. Unisom. https://www.unisom.com/our-products/unisom-sleeptabs/. (Accessed April 15, 2020).
  10. Sherwood DA, Morin AK. Chapter 84. Sleep disorders. In: Zeind CS, Carvalho MG, Eds. Applied Therapeutics: The Clinical Use of Drugs. 11th ed. Philadelphia: Wolters Kluwer Health. 2018.
  11. Wiegand MH. Antidepressants for the treatment of insomnia: a suitable approach? Drugs 2008;68:2411-7.
  12. Wilson SJ, Nutt DJ, Alford C, et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol 2010;24:1577-601.
  13. Mendelson WB. A review of the evidence for efficacy and safety of trazodone in insomnia. J Clin Psychiatry 2005;66:469-76.
  14. Agostini JV, Zhang Y, Inouye SK. Use of a computer-based reminder to improve sedative-hypnotic prescribing in older hospitalized patients. J Am Geriatr Soc 2007;55:43-8.
  15. Generali JA, Cada DJ. Trazodone: insomnia (adults). Hosp Pharm 2015;50:367-9.
  16. Jayaram G, Rao P. Safety of trazodone as a sleep agent for inpatients. Psychosomatics 2005;46:367-9.
  17. Bain KT. Management of chronic insomnia in elderly persons. Am J Geriatr Pharmacother 2006;4:168-92.
  18. eCPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2020. http://www.e-therapeutics.ca. (Accessed April 20, 2020).
  19. Wolkove N, Elkholy O, Baltzan M, Palayew M. Sleep and aging: 2. Management of sleep disorders in older people. CMAJ 2007;176:1449-54.
  20. Lenhart SE, Buysse DJ. Treatment of insomnia in hospitalized patients. Ann Pharmacother 2001;35:1449-57.
  21. Rosenberg RP. Sleep maintenance insomnia: strengths and weaknesses of current pharmacologic therapies. Ann Clin Psychiatry 2006;18:49-56.
  22. Clinical Resource, Benzodiazepine Toolbox. Pharmacist’s Letter/Prescriber’s Letter. August 2014.
  23. Sateia MJ, Nowell PD. Insomnia. Lancet 2004;364:1959-73.
  24. Roth T, Mayleben D, Corser BC, Singh NN. Daytime pharmacodynamic and pharmacokinetic evaluation of low-dose sublingual transmucosal zolpidem hemitartrate. Hum Psychopharmacol 2008;23:13-20.

Cite this document as follows: Clinical Resource, Comparison of Insomnia Treatments. Pharmacist’s Letter/Prescriber’s Letter. May 2020.

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