Etizolam is a benzodiazepine somnifacient for treating insomnia.

Somnifacient (from Latin somnus, sleep[1]), also known as sedatives or sleeping pills, is a class of medications that induces sleep. It is mainly used for treatment of insomnia. Examples of somnifacients include benzodiazepines, barbiturates and antihistamines.

Around 2-6% of adults with insomnia use somnifacients to aid sleep.[2] However, somnifacients only benefit transient or short-term insomnia but not chronic insomnia.[3] It is because somnifacients lack supportive evidence for sleep aids in chronic insomnia, and chronic use of somnifacients leads to many adverse effects.[4][5] When somnifacient is used, it should be combined with Cognitive behavioural therapy for insomnia (CBT-I) and healthy sleeping habits but not solely used due to potential severe adverse effects.[6][7]

Somnifacients are mainly in oral formulations, including tablets, capsules, solution and suspension, with an onset time within an hour.[8] One or two doses of somnifacients should be given for transient insomnia, while doses indicated for a week should be given for short-term insomnia.[9]

Types of somnifacients

Benzodiazepine Receptor Agonist

Gamma-aminobutyric acid is an inhibitory neurotransmitter for reducing excitability.

This class includes benzodiazepines and nonbenzodiazepines that have similar mechanisms of action but different chemical structures. They both act on and enhance the actions of gamma-aminobutyric acid (GABA)-A receptors, leading to an inhibitory effect on the brain and thus inducement of sleep.[10][11]

Benzodiazepine

Benzodiazepines are somnifacients for the treatment of short-term insomnia. This class of drugs is characterized by the fusion of a diazepine ring and a benzene ring in the chemical structure. Examples of benzodiazepines are diazepam, nitrazepam, triazolam and chlordiazepoxide. Long-acting benzodiazepines, such as diazepam and chlordiazepoxide, are not recommended due to their residual effects that may precipitate the next day.[12]

Withdrawal syndrome is a common drawback of benzodiazepines because of the development of a physical dependence on them after abrupt withdrawal. It is characterized by sleep disturbance, tremors, increased anxiety and tension, headache, muscular stiffness and pain, which may last 10–14 days.[13] To avoid the problem, withdrawal of benzodiazepines should be carried out at a slow reduction rate, which is determined by the initial dose, duration of use and patient tolerance, but not abruptly.[3] Three basic approaches to the taper are using the same medication for tapering, adding adjunctive medication for alleviating withdrawal symptoms, and switching to a longer-acting equivalent.[14] One of the recommended benzodiazepine taper is to reduce the dose by 50% in the first 4 weeks, maintain the dose for 1–2 months, and then reduce the dose by 25% every 2 weeks.[15] Other common side effects of benzodiazepines are drowsiness, dizziness, somnolence and increased risk of ataxia.

Benzodiazepines should not be taken with other central nervous system depressants, namely anticonvulsants, other types of somnifacients, antihistamines and alcohol, because it may potentially increase the toxic effects of benzodiazepines.[16] Besides, the US Food and Drug Administration (FDA) added a boxed warning for benzodiazepines regarding the concomitant use of opioid drugs because it may increase the risk of coma, respiratory depression, general anesthesia, and death.[17] The elderly should avoid the use of benzodiazepines due to the increased risk of cognitive impairment, falls and fractures.[18] Benzodiazepines are also contraindicated in pregnancy and breast-feeding women since they may cause floppy infant syndrome in infants, characterized by hypotonia and CNS depression.[16]

Nonbenzodiazepine

Nonbenzodiazepines, also known as benzodiazepine-like drugs or Z-drugs, are somnifacients indicated for short-term insomnia. Examples include zolpidem (Ambien, Stilnoct, Stilnox), zopiclone (Imovane, Zimovane), and zaleplon (Sonata).

Zolpidem (immediate release) is considered the first choice for patients with either sleep maintenance or sleep onset complaints. In cases where patients experience waking up at midnight or too early in the morning, zolpidem (extended release) or eszopiclone may be considered due to their longer actions. Zaleplon with the shortest half-life of the nonbenzodiazepines is suitable for patients who experience residual sedating effects in the morning.[5] However, the exact medication chosen depends on the patient's tolerance, varied efficacy in individuals and drug interactions.

Nonbenzodiazepines, theoretically, are associated with greater selectivity for several subtypes of GABA-A receptors than benzodiazepines, potentially leading to a narrower range of side effects and therapeutic outcomes.[5] However, research findings on the comparison between benzodiazepines and nonbenzodiazepines in terms of efficacy and adverse effects are conflicting. The US Agency for Healthcare Research and Quality indicates that the risk of harm from benzodiazepines is about twice as high as that from nonbenzodiazepines.[19] Another study points out that there is no significant difference between the two classes of drugs in terms of adverse effects.[20] Unlike benzodiazepines, nonbenzodiazepines appear to have little or no impact on sleep stages and do not lead to rapid-eye-movement (REM) sleep rebound.[21] However, as per a review by the National Institute for Health and Clinical Excellence (NICE), inadequate evidence supports the use of Z-drugs for treating insomnia. The review noted that clinical trials inappropriately compared short-acting nonbenzodiazepines with long-acting benzodiazepines, and there is a lack of studies that compare the effects of short-acting nonbenzodiazepines to those of short-acting benzodiazepines at equivalent doses. As a result of these findings, NICE recommended taking both the patient's preferences and the product price per dose into account when prescribing a somnifacient.[22]

Barbiturate is used as an anaesthetic medication during surgical operation.

Like benzodiazepines, nonbenzodiazepines are contraindicated in the elderly and pregnant due to potential adverse effects. Although it is hypothesized that somnifacients may help treat depression caused by insomnia, data released by the Food and Drug Administration (FDA) shows that the use of nonbenzodiazepines including zolpidem, zaleplon and eszopiclone increased the risk of depression by over two times when compared to individuals taking placebo pills.[23] Therefore, patients who suffer from or are at risk of depression may not be suitable for taking nonbenzodiazepines. The dose of nonbenzodiazepines should be reduced in patients with renal dysfunction due to the hepatic metabolism of the drugs.[24]

Barbiturates

Barbiturates are a class of sedative drugs that potentiate the action of GABA on GABA-A receptors.[25] Their effects range from moderate sedation to total anesthesia according to the doses indicated. Due to the significant adverse effects (i.e. hallucination, agitation, confusion and hangover) and higher risk of overdose, barbiturates are now mostly replaced by benzodiazepine receptor agonists or other somnifacients in clinical practice for treating insomnia.[21] Barbiturates are commonly used in epilepsy, acute migraines, general anesthesia, and assisted suicide.[26] Examples of barbiturates are phenobarbital, primidone and amobarbital.

Antihistamine

Diphenhydramine (Benadryl) is commonly used for treating allergic rhinitis and urticaria.

Antihistamines, also known as H1 antagonists, are a class of drugs which inhibit action at H1 receptors. They are clinically used to alleviate allergic reactions including allergic rhinitis, allergic conjunctivitis and urticaria mediated by histamine.[27] First generation antihistamines such as doxylamine and diphenhydramine are accompanied by sedation as the side effect, which can be utilized to treat insomnia. Some of the antihistamines, namely promethazine and doxylamine, are available for purchase over-the-counter (OTC) and can be bought by the public in some countries for the occasional relief of insomnia.[28] Low-dose doxepin is approved by the FDA for the treatment of insomnia.[5] Second generation of antihistamines such as cetirizine and loratadine have a much less sedating effect than the first ones with a much lower degree of crossing the blood–brain barrier.[29]

Common side effects of antihistamines include nausea, constipation and dry mouth.[27] Patients with severe urinary retention or untreated angle-closure glaucoma should avoid antihistamines.[5]

Melatonin/ Melatonin receptor agonist

Melatonin is an endogenous hormone synthesized in the pineal gland in the brain involved in promoting sleep.[30] It activates both melatonin receptors MT1 and MT2 to produce beneficial effects on sleep, therefore being used exogenously for mild insomnia.[31] A small improvement in sleep onset and total sleep time by using melatonin has been shown in recent systematic reviews.[32] Synthetic melatonin, also known as melatonin receptor agonist, is also used for sleeping disorders by mimicking the action of melatonin. Examples are tasimelteon and ramelteon.

Dual orexin receptor antagonist

Dual orexin receptor antagonists are drugs that block the orexin receptors OX1 and OX2, hence reducing the wakeful effect of the orexin system and inducing sleep.[33] Daridorexant, lemborexant and suvorexant have been shown in studies to improve sleep onset and sleep quality.[34][35]

Miscellaneous drugs

Antipsychotics[36]

Antidepressants[37]

Cannabinoids[38]

Miscellaneous drugs of somnifacients show sedative effects, but they are not first-line use for insomnia or they are prescribed off-label for insomnia. When prescribing these drugs for insomnia, extra care is needed due to unexpected outcomes and benefit-risk ratios compared to approved medications for insomnia.[39]

Precautions and contraindications

All somnifacients have shared risks of worsening depression, central nervous system depressant effects, abnormal thinking and behaviour changes.[5] It is not advisable to prescribe somnifacients for routine insomnia treatment, and they should only be used for short periods in patients who are severely distressed or with transient insomnia.[40] An important drawback of prolonged use is that it can result in rebound insomnia and withdrawal syndrome upon discontinuation.[40] The elderly especially those with dementia should avoid somnifacients due to potential further impairment of cognitive function according to the clinical guideline, Medication Appropriateness Tool for Comorbid Health Conditions in Dementia.[41] Most somnifacients possess Cytochrome P450 (CYP450) metabolism, a major drug metabolism pathway in the body, which may have potential drug interactions with other drugs affecting CYP450 activity, such as ketoconazole, clarithromycin and fluvoxamine.[5] Patients with polypharmacy require extra attention due to their complex medication regimens.

References

  1. ↑ "Definition of SOMNIFACIENT". www.merriam-webster.com. Retrieved 13 March 2023.
  2. ↑ Ohayon, Maurice M. (2002). "Epidemiology of insomnia: what we know and what we still need to learn". Sleep Medicine Reviews. 6 (2): 97–111. doi:10.1053/smrv.2002.0186. PMID 12531146.
  3. 1 2 "MedicinesComplete — CONTENT > BNF > Hypnotics and anxiolytics". Medicinescomplete.com. Retrieved 13 March 2023.
  4. ↑ Kripke, Daniel F. (2013). Risks of Chronic Hypnotic Use. Landes Bioscience.
  5. 1 2 3 4 5 6 7 "Pharmacotherapy for insomnia in adults". www.uptodate.com. Retrieved 13 March 2023.
  6. ↑ Qaseem, Amir; Kansagara, Devan; Forciea, Mary Ann; Cooke, Molly; Denberg, Thomas D.; Clinical Guidelines Committee of the American College of Physicians (19 July 2016). "Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians". Annals of Internal Medicine. 165 (2): 125–133. doi:10.7326/M15-2175. ISSN 1539-3704. PMID 27136449. S2CID 207538494.
  7. ↑ Sateia, Michael J.; Buysse, Daniel J.; Krystal, Andrew D.; Neubauer, David N.; Heald, Jonathan L. (15 February 2017). "Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline". Journal of Clinical Sleep Medicine. 13 (2): 307–349. doi:10.5664/jcsm.6470. ISSN 1550-9397. PMC 5263087. PMID 27998379.
  8. ↑ Donaldson, Mark; Gizzarelli, Gino; Chanpong, Brian (2007). "Oral sedation: a primer on anxiolysis for the adult patient". Anesthesia Progress. 54 (3): 118–128, quiz 129. doi:10.2344/0003-3006(2007)54[118:OSAPOA]2.0.CO;2. ISSN 0003-3006. PMC 1993866. PMID 17900211.
  9. ↑ "MedicinesComplete — CONTENT > MARTINDALE > Insomnia (Anxiolytic Sedatives Hypnotics and Antipsychotics - Sleep disorders)". Medicinescomplete.com.
  10. ↑ Griffin, Charles E.; Kaye, Adam M.; Bueno, Franklin Rivera; Kaye, Alan D. (2013). "Benzodiazepine pharmacology and central nervous system-mediated effects". The Ochsner Journal. 13 (2): 214–223. ISSN 1524-5012. PMC 3684331. PMID 23789008.
  11. ↑ Morin, Charles M.; Beaulieu-Bonneau, Simon; Cheung, Janet M.Y. (1 January 2019). "Treatment of Insomnia". Handbook of Sleep Disorders in Medical Conditions: 27–50. doi:10.1016/B978-0-12-813014-8.00002-0. ISBN 9780128130148. S2CID 87505809.
  12. ↑ "Overview | Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia | Guidance | NICE". www.nice.org.uk. 28 April 2004. Retrieved 13 March 2023.
  13. ↑ Pétursson, H. (1994). "The benzodiazepine withdrawal syndrome". Addiction. 89 (11): 1455–1459. doi:10.1111/j.1360-0443.1994.tb03743.x. ISSN 0965-2140. PMID 7841856.
  14. ↑ Ogbonna, Chinyere I.; Lembke, Anna (1 November 2017). "Tapering Patients Off of Benzodiazepines". American Family Physician. 96 (9): 606–608. PMID 29094883.
  15. ↑ "Effective Treatments for PTSD: Helping Patients Taper from Benzodiazepines" (PDF). National Center for PTSD.
  16. 1 2 "benzo.org.uk : Toxicity and Adverse Consequences of Benzodiazepine Use, Professor Ashton, 1995". www.benzo.org.uk. Retrieved 13 March 2023.
  17. ↑ "FDA adds Boxed Warning on risk of death with febuxostat". Reactions Weekly. 1742 (1): 1. 2019. doi:10.1007/s40278-019-58459-9. ISSN 0114-9954. S2CID 195088444.
  18. ↑ American Geriatrics Society 2012 Beers Criteria Update Expert Panel (2012). "American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults". Journal of the American Geriatrics Society. 60 (4): 616–631. doi:10.1111/j.1532-5415.2012.03923.x. ISSN 1532-5415. PMC 3571677. PMID 22376048.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  19. ↑ Buscemi, Nina; Vandermeer, Ben; Friesen, Carol; Bialy, Liza; Tubman, Michelle; Ospina, Maria; Klassen, Terry P.; Witmans, Manisha (June 2005). Manifestations and Management of Chronic Insomnia in Adults. Agency for Healthcare Research and Quality (US).
  20. ↑ Wagner, J.; Wagner, M. L.; Hening, W. A. (1998). "Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia". The Annals of Pharmacotherapy. 32 (6): 680–691. doi:10.1345/aph.17111. ISSN 1060-0280. PMID 9640488. S2CID 34250754.
  21. 1 2 Ramakrishnan, Kalyanakrishnan; Scheid, Dewey C. (15 August 2007). "Treatment Options for Insomnia". American Family Physician. 76 (4): 517–526. PMID 17853625.
  22. ↑ Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia (PDF). National Institute for Health and Care Excellence. April 2004. ISBN 1-84257-606-2. Archived from the original (PDF) on 3 December 2008. Retrieved 2 July 2023.
  23. ↑ Kripke, Daniel F. (21 August 2007). "Greater incidence of depression with hypnotic use than with placebo". BMC Psychiatry. 7: 42. doi:10.1186/1471-244X-7-42. ISSN 1471-244X. PMC 1994947. PMID 17711589.
  24. ↑ Toner, Laura C.; Tsambiras, Belen M.; Catalano, Glenn; Catalano, Maria C.; Cooper, David S. (2000). "Central Nervous System Side Effects Associated with Zolpidem Treatment". Clinical Neuropharmacology. 23 (1): 54–58. doi:10.1097/00002826-200001000-00011. ISSN 0362-5664. PMID 10682233.
  25. ↑ Löscher, Wolfgang; Rogawski, Michael A. (2012). "How theories evolved concerning the mechanism of action of barbiturates". Epilepsia. 53 (Suppl 8): 12–25. doi:10.1111/epi.12025. ISSN 1528-1167. PMID 23205959. S2CID 4675696.
  26. ↑ "Brochure of DIGNITAS". www.dignitas.ch. Retrieved 13 March 2023.
  27. 1 2 "MedicinesComplete — CONTENT > BNF > antihistamine". Medicinescomplete.com. Retrieved 13 March 2020.
  28. ↑ Culpepper, Larry; Wingertzahn, Mark A. (2015). "Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia: A Systematic Review of Efficacy and Safety". The Primary Care Companion for CNS Disorders. 17 (6). doi:10.4088/PCC.15r01798. ISSN 2155-7772. PMC 4805417. PMID 27057416.
  29. ↑ Slater, J. W.; Zechnich, A. D.; Haxby, D. G. (1999). "Second-generation antihistamines: a comparative review". Drugs. 57 (1): 31–47. doi:10.2165/00003495-199957010-00004. ISSN 0012-6667. PMID 9951950. S2CID 46984477.
  30. ↑ "Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders". openresearch.surrey.ac.uk.
  31. ↑ Liu, Jiabei; Clough, Shannon J.; Hutchinson, Anthony J.; Adamah-Biassi, Ekue B.; Popovska-Gorevski, Marina; Dubocovich, Margarita L. (2016). "MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective". Annual Review of Pharmacology and Toxicology. 56: 361–383. doi:10.1146/annurev-pharmtox-010814-124742. ISSN 1545-4304. PMC 5091650. PMID 26514204.
  32. ↑ Low, Tian Ling; Choo, Faith Nadine; Tan, Shian Ming (2020). "The efficacy of melatonin and melatonin agonists in insomnia - An umbrella review". Journal of Psychiatric Research. 121: 10–23. doi:10.1016/j.jpsychires.2019.10.022. ISSN 1879-1379. PMID 31715492. S2CID 207949129.
  33. ↑ Mieda, Michihiro; Tsujino, Natsuko; Sakurai, Takeshi (2013). "Differential roles of orexin receptors in the regulation of sleep/wakefulness". Frontiers in Endocrinology. 4: 57. doi:10.3389/fendo.2013.00057. ISSN 1664-2392. PMC 3656340. PMID 23730297.
  34. ↑ Kuriyama, Akira; Tabata, Hiromitsu (2017). "Suvorexant for the treatment of primary insomnia: A systematic review and meta-analysis". Sleep Medicine Reviews. 35: 1–7. doi:10.1016/j.smrv.2016.09.004. ISSN 1532-2955. PMID 28365447.
  35. ↑ Mignot, Emmanuel; Mayleben, David; Fietze, Ingo; Leger, Damien; Zammit, Gary; Bassetti, Claudio L. A.; Pain, Scott; Kinter, Dalma Seboek; Roth, Thomas; investigators (2022). "Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials". The Lancet. Neurology. 21 (2): 125–139. doi:10.1016/S1474-4422(21)00436-1. ISSN 1474-4465. PMID 35065036. S2CID 246054876.
  36. ↑ Leucht, Stefan; Cipriani, Andrea; Spineli, Loukia; Mavridis, Dimitris; Örey, Deniz; Richter, Franziska; Samara, Myrto; Barbui, Corrado; Engel, Rolf R.; Geddes, John R.; Kissling, Werner; Stapf, Marko Paul; Lässig, Bettina; Salanti, Georgia; Davis, John M. (14 September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". The Lancet. 382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3. ISSN 0140-6736. PMID 23810019. S2CID 32085212.
  37. ↑ Everitt, Hazel; Baldwin, David S.; Stuart, Beth; Lipinska, Gosia; Mayers, Andrew; Malizia, Andrea L.; Manson, Christopher Cf; Wilson, Sue (14 May 2018). "Antidepressants for insomnia in adults". The Cochrane Database of Systematic Reviews. 2018 (5): CD010753. doi:10.1002/14651858.CD010753.pub2. ISSN 1469-493X. PMC 6494576. PMID 29761479.
  38. ↑ Lavender, Isobel; McGregor, Iain S.; Suraev, Anastasia; Grunstein, Ronald R.; Hoyos, Camilla M. (2022). "Cannabinoids, Insomnia, and Other Sleep Disorders". Chest. 162 (2): 452–465. doi:10.1016/j.chest.2022.04.151. ISSN 1931-3543. PMID 35537535. S2CID 248584784.
  39. ↑ By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel (2019). "American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults". Journal of the American Geriatrics Society. 67 (4): 674–694. doi:10.1111/jgs.15767. ISSN 1532-5415. PMID 30693946. S2CID 59338182.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  40. 1 2 "MedicinesComplete — CONTENT > BNF > anxiolytics". Medicinescomplete.com. Retrieved 13 March 2023.
  41. ↑ Page, A. T.; Potter, K.; Clifford, R.; McLachlan, A. J.; Etherton-Beer, C. (2016). "Medication appropriateness tool for co-morbid health conditions in dementia: consensus recommendations from a multidisciplinary expert panel". Internal Medicine Journal. 46 (10): 1189–1197. doi:10.1111/imj.13215. ISSN 1445-5994. PMC 5129475. PMID 27527376.
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