Hypnotic (from Greek Hypnos, sleep) or soporific drugs, commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to induce sleep and to be used in the treatment of insomnia (sleeplessness), or for surgical anesthesia.[note 1]
This group is related to sedatives. Whereas the term sedative describes drugs that serve to calm or relieve anxiety, the term hypnotic generally describes drugs whose main purpose is to initiate, sustain, or lengthen sleep. Because these two functions frequently overlap, and because drugs in this class generally produce dose-dependent effects (ranging from anxiolysis to loss of consciousness) they are often referred to collectively as sedative-hypnotic drugs.
Hypnotic drugs are regularly prescribed for insomnia and other sleep disorders, with over 95% of insomnia patients being prescribed hypnotics in some countries. Many hypnotic drugs are habit-forming and, due to a large number of factors known to disturb the human sleep pattern, a physician may instead recommend changes in the environment before and during sleep, better sleep hygiene, the avoidance of caffeine or other stimulating substances, or behavioral interventions such as Cognitive Behavioral Therapy for Insomnia (CBT-I) before prescribing medication for sleep. When prescribed, hypnotic medication should be used for the shortest period of time necessary.
Among individuals with sleep disorders, 13.7% are taking or prescribed nonbenzodiazepines, while 10.8% are taking benzodiazepines, as of 2010. Early classes of drugs, such as barbiturates, have fallen out of use in most practices but are still prescribed for some patients. In children, prescribing hypnotics is not yet acceptable unless used to treat night terrors or somnambulism. Elderly people are more sensitive to potential side effects of daytime fatigue and cognitive impairments, and a meta-analysis found that the risks generally outweigh any marginal benefits of hypnotics in the elderly. A review of the literature regarding benzodiazepine hypnotics and Z-drugs concluded that these drugs can have adverse effects, such as dependence and accidents, and that optimal treatment uses the lowest effective dose for the shortest therapeutic time period, with gradual discontinuation in order to improve health without worsening of sleep.
Hypnotica was a class of somniferous drugs and substances tested in medicine of the 1890s and later, including: Urethan, Acetal, Methylal, Sulfonal, paraldehyde, Amylenhydrate, Hypnon, Chloralurethan and Ohloralamid or Chloralimid.
Research about using medications to treat insomnia evolved throughout the last half of the 20th century. Treatment for insomnia in psychiatry dates back to 1869 when chloral hydrate was first used as a soporific. Barbiturates emerged as the first class of drugs that emerged in the early 1900s, after which chemical substitution allowed derivative compounds. Although the best drug family at the time (less toxic and with fewer side effects) they were dangerous in overdose and tended to cause physical and psychological dependence.
Benzodiazepines are not without their drawbacks; substance dependence is possible, and deaths from overdoses sometimes occur, especially in combination with alcohol and/or other depressants. Questions have been raised as to whether they disturb sleep architecture.
Nonbenzodiazepines are the most recent development (1990s–present). Although it’s clear that they are less toxic than their predecessors, barbiturates, comparative efficacy over benzodiazepines have not been established. Without longitudinal studies, it is hard to determine; however some psychiatrists recommend these drugs, citing research suggesting they are equally potent with less potential for abuse.
Other sleep remedies that may be considered “sedative-hypnotics” exist; psychiatrists will sometimes prescribe medicines off-label if they have sedating effects. Examples of these include mirtazapine (an antidepressant), clonidine (generally prescribed to regulate blood pressure), quetiapine (an antipsychotic), and the over-the-counter sleep aid diphenhydramine (Benadryl – an antihistamine). Off-label sleep remedies are particularly useful when first-line treatment is unsuccessful or deemed unsafe (for example, in patients with a history of substance abuse).
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, hypnotics, and anticonvulsalgesic effects; however, these effects are somewhat weak, preventing barbiturates from being used in surgery in the absence of other analgesics. They have dependence liability, both physical and psychological. Barbiturates have now largely been replaced by benzodiazepines in routine medical practice – for example, in the treatment of anxiety and insomnia – mainly because benzodiazepines are significantly less dangerous in overdose. However, barbiturates are still used in general anesthesia, for epilepsy, and assisted suicide. Barbiturates are derivatives of barbituric acid.
Benzodiazepines can be useful for short-term treatment of insomnia. Their use beyond 2 to 4 weeks is not recommended due to the risk of dependence. It is preferred that benzodiazepines be taken intermittently and at the lowest effective dose. They improve sleep-related problems by shortening the time spent in bed before falling asleep, prolonging the sleep time, and, in general, reducing wakefulness. Like alcohol, benzodiazepines are commonly used to treat insomnia in the short-term (both prescribed and self-medicated), but worsen sleep in the long-term. While benzodiazepines can put people to sleep (i.e., inhibit NREM stage 1 and 2 sleep), while asleep, the drugs disrupt sleep architecture: decreasing sleep time, delaying time to REM sleep, and decreasing deep slow-wave sleep (the most restorative part of sleep for both energy and mood).
Other drawbacks of hypnotics, including benzodiazepines, are possible tolerance to their effects, rebound insomnia, and reduced slow-wave sleep and a withdrawal period typified by rebound insomnia and a prolonged period of anxiety and agitation. The list of benzodiazepines approved for the treatment of insomnia is fairly similar among most countries, but which benzodiazepines are officially designated as first-line hypnotics prescribed for the treatment of insomnia can vary distinctly between countries. Longer-acting benzodiazepines such as nitrazepam and diazepam have residual effects that may persist into the next day and are, in general, not recommended.
It is not clear as to whether the new nonbenzodiazepine hypnotics (Z-drugs) are better than the short-acting benzodiazepines. The efficacy of these two groups of medications is similar. According to the US Agency for Healthcare Research and Quality, indirect comparison indicates that side-effects from benzodiazepines may be about twice as frequent as from nonbenzodiazepines. Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia. However, the UK National Institute for Health and Clinical Excellence (NICE) did not find any convincing evidence in favor of Z-drugs. A NICE review pointed out that short-acting Z-drugs were inappropriately compared in clinical trials with long-acting benzodiazepines. There have been no trials comparing short-acting Z-drugs with appropriate doses of short-acting benzodiazepines. Based on this, NICE recommended choosing the hypnotic based on cost and the patient’s preference.
Older adults should not use benzodiazepines to treat insomnia unless other treatments have failed to be effective. When benzodiazepines are used, patients, their caretakers, and their physician should discuss the increased risk of harms, including evidence which shows twice the incidence of traffic collisions among driving patients as well as falls and hip fracture for all older patients.
Nonbenzodiazepines are a class of psychoactive drugs that are very “benzodiazepine-like” in nature. Nonbenzodiazepine pharmacodynamics are almost entirely the same as benzodiazepine drugs and therefore entail similar benefits, side-effects, and risks. Nonbenzodiazepines, however, have dissimilar or entirely different chemical structures, and therefore are unrelated to benzodiazepines on a molecular level.
Research on nonbenzodiazepines is new and conflicting. A review by a team of researchers suggests the use of these drugs for people that have trouble falling asleep but not staying asleep,[note 2] as next-day impairments were minimal. The team noted that the safety of these drugs had been established, but called for more research into their long-term effectiveness in treating insomnia. Other evidence suggests that tolerance to nonbenzodiazepines may be slower to develop than with benzodiazepines.[not in citation given] A different team was more skeptical, finding little benefit over benzodiazepines.
In common use, the term antihistamine refers only to compounds that inhibit action at the H1 receptor (and not H2, etc.).
Clinically, H1 antagonists are used to treat certain allergies. Sedation is a common side-effect, and some H1 antagonists, such as diphenhydramine (Benadryl) and doxylamine, are also used to treat insomnia.
Second-generation antihistamines cross the blood–brain barrier to a much lower degree than the first ones.[medical citation needed] This results in their primarily affecting peripheral histamine receptors, and therefore having a much lower sedative effect. High doses can still induce the central nervous system effect of drowsiness.
Some antidepressants have sedating effects. Some may increase actual quality of sleep (biologically) in contrast to Benzodiazepines that decrease quality.
- When used in anesthesia to produce and maintain unconsciousness, “sleep” is metaphorical as there are no regular sleep stages or cyclical natural states; patients rarely recover from anesthesia feeling refreshed and with renewed energy.
- Because the drugs have a shorter elimination half life they are metabolized more quickly: nonbenzodiazepines zaleplon and zolpidem have a half life of 1 and 2 hours (respectively); for comparison the benzodiazepine clonazepam has a half life of about 30 hours. This makes the drug suitable for sleep-onset difficulty, but the team noted sustained sleep efficacy was not clear.
- “Dorlands Medical Dictionary:hypnotic”. Mercksource.com. Archived from the original on 2008-12-11.
- Brunton, Laurence L.; Lazo, John S.; Lazo Parker, Keith L. (2006). “17: Hypnotics and Sedatives”. Goodman & Gilman’s The Pharmacological Basis of Therapeutics (11th ed.). The McGraw-Hill Companies, Inc. ISBN 978-0-07-146804-6. Retrieved 2014-02-06.
- National Prescribing Service (2 February 2010). “NPS News 67: Addressing hypnotic medicines use in primary care”. Archived from the original on 22 February 2011. Retrieved 19 March 2010.
- Mendels, J. (September 1991). “Criteria for selection of appropriate benzodiazepine hypnotic therapy”. J Clin Psychiatry. 52. Suppl: 42–6. PMID 1680126.
- Kaufmann, Christopher N.; Spira, Adam P.; Alexander, G. Caleb; Rutkow, Lainie; Mojtabai, Ramin (2015). “Trends in prescribing of sedative-hypnotic medications in the USA: 1993–2010”. Pharmacoepidemiology and Drug Safety. 25 (6): 637–45. doi:10.1002/pds.3951. ISSN 1099-1557. PMC 4889508. PMID 26711081.
- Gelder, M.; Mayou, R.; Geddes, J. (2005). Psychiatry (3rd ed.). New York: Oxford. p. 238.
- Glass, J.; Lanctôt, K. L.; Herrmann, N.; Sproule, B. A.; Busto, U. E. (November 2005). “Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits”. BMJ. 331 (7526): 1169. doi:10.1136/bmj.38623.768588.47. PMC 1285093. PMID 16284208.
- “What’s wrong with prescribing hypnotics? Apparently just like any other drug.” Drug Ther Bull. 42 (12): 89–93. December 2004. doi:10.1136/dtb.2004.421289. PMID 15587763. (Registration required (help)).
- Zhdanova, IV (February 2005). “Melatonin as a hypnotic: pro”. Sleep Medicine Reviews. 9 (1): 51–65. doi:10.1016/j.smrv.2004.04.003. PMID 15649738.
- Pacific Record of Medicine and Surgery – Volume 5 – Page 36 1890
- Shorter, Edward (2005). “Benzodiazepines”. A Historical Dictionary of Psychiatry. Oxford University Press. pp. 41–2. ISBN 978-0-19-517668-1. Retrieved 2014-02-06.
- “Barbiturates”. Archived from the original on 7 November 2007. Retrieved 2007-10-31.
- Whitlock, F. A. (June 14, 1975). “Suicide in Brisbane, 1956 to 1973: the drug-death epidemic”. Med J Aust. 1 (24): 737–43. PMID 239307.
- Johns, M. W. (1975). “Sleep and hypnotic drugs”. Drugs. 9 (6): 448–78. doi:10.2165/00003495-197509060-00004. PMID 238826.
- Jufe, G. S. (2007). “New hypnotics: perspectives from sleep physiology”. Vertex (July–August 2007). 18 (74): 294–9. PMID 18265473.
- Barbera, J.; Shapiro, C. (2005). “Benefit-risk assessment of zaleplon in the treatment of insomnia”. Drug Saf. 28 (4): 301–18. doi:10.2165/00002018-200528040-00003. PMID 15783240.
- Wagner, J.; Wagner, M. L.; Hening, W. A. (June 1998). “Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia”. Ann Pharmacother. 32 (6): 680–91. doi:10.1345/aph.17111. PMID 9640488.
- Löscher, W.; Rogawski, M. A. (2012). “How theories evolved concerning the mechanism of action of barbiturates”. Epilepsia. 53: 12–25. doi:10.1111/epi.12025. PMID 23205959.
- Chen, K.; Wang, K.; Kirichian, A. M. (December 2006). “In silico design, synthesis, and biological evaluation of radioiodinated quinazolinone derivatives for alkaline phosphatase-mediated cancer diagnosis and therapy”. Mol. Cancer Ther. 5 (12): 3001–13. doi:10.1158/1535-7163.MCT-06-0465. PMID 17172404.
- “Technology Appraisal Guidance 77. Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia” (PDF). National Institute for Clinical Excellence. April 2004. Archived from the original (PDF) on 2008-12-03. Retrieved 2009-07-26.
- Ramakrishnan, K.; Scheid, D. C. (August 2007). “Treatment options for insomnia”. American Family Physician. 76 (4): 517–26. PMID 17853625.
- Ashton, Heather (2005-05-01). “The diagnosis and management of benzodiazepine dependence”. Current Opinion in Psychiatry. 18 (3): 249–255. doi:10.1097/01.yco.0000165594.60434.84. ISSN 0951-7367. PMID 16639148.
- Morin, Charles M.; Bélanger, Lynda; Bastien, Célyne; Vallières, Annie (2005-01-01). “Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse”. Behaviour Research and Therapy. 43 (1): 1–14. doi:10.1016/j.brat.2003.12.002. ISSN 0005-7967. PMID 15531349.
- Poyares, Dalva; Guilleminault, Christian; Ohayon, Maurice M.; Tufik, Sergio (2004-06-01). “Chronic benzodiazepine usage and withdrawal in insomnia patients”. Journal of Psychiatric Research. 38 (3): 327–334. doi:10.1016/j.jpsychires.2003.10.003. ISSN 0022-3956. PMID 15003439.
- D. Maiuro, Roland (13 December 2009). Handbook of Integrative Clinical Psychology, Psychiatry, and Behavioral Medicine: Perspectives, Practices, and Research. Springer Publishing Company. pp. 128–30. ISBN 978-0-8261-1094-7.
- Buscemi, N.; Vandermeer, B.; Friesen, C.; Bialy, L.; Tubman, M.; Ospina, M.; et al. (June 2005). “Manifestations and Management of Chronic Insomnia in Adults. Summary, Evidence Report/Technology Assessment: Number 125” (PDF). Agency for Healthcare Research and Quality.
- American Geriatrics Society. “Five Things Physicians and Patients Should Question”. Choosing Wisely: an initiative of the ABIM Foundation. American Geriatrics Society. Retrieved August 1, 2013., which cites
- Finkle, W. D.; Der, J. S.; Greenland, S.; Adams, J. L.; Ridgeway, G.; Blaschke, T.; et al. (2011). “Risk of Fractures Requiring Hospitalization After an Initial Prescription for Zolpidem, Alprazolam, Lorazepam, or Diazepam in Older Adults”. Journal of the American Geriatrics Society. 59 (10): 1883–1890. doi:10.1111/j.1532-5415.2011.03591.x. PMID 22091502.
- Allain, H.; Bentu-Ferrer, D.; Polard, E.; Akwa, Y.; Patat, A. (2005). “Postural instability and consequent falls and hip fractures associated with use of hypnotics in the elderly: A comparative review”. Drugs & Aging. 22 (9): 749–765. doi:10.2165/00002512-200522090-00004. PMID 16156679.
- 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. PMC 3571677. PMID 22376048.
- Olsen, R. W.; Betz, H. (2006). “GABA and glycine”. In Siegel, G. J.; Albers, R. W.; Brady, S.; Price, D. D. Basic Neurochemistry: Molecular, Cellular and Medical Aspects (7th ed.). Elsevier. pp. 291–302. ISBN 978-0-12-088397-4.
- Siriwardena, A. N.; Qureshi, Z.; Gibson, S.; Collier, S.; Latham, M. (December 2006). “GPs’ attitudes to benzodiazepine and ‘Z-drug’ prescribing: a barrier to implementation of evidence and guidance on hypnotics”. Br J Gen Pract. 56 (533): 964–7. PMC 1934058. PMID 17132386.
- Benca, R. M. (March 2005). “Diagnosis and treatment of chronic insomnia: a review”. Psychiatr Serv. 56 (3): 332–43. doi:10.1176/appi.ps.56.3.332. PMID 15746509.
Evidence for the utility of currently available nonbenzodiazepine hypnotics points to their primary efficacy as sleep-onset, rather than as sleep-maintenance, agents. Once again, longer-term randomized, double-blind, controlled studies that demonstrate efficacy of these agents have not been performed, but safety over the longer term has been demonstrated in open-label studies, with minimal evidence of rebound phenomena. By comparison with benzodiazepines, there has been less evidence of subjective and objective next-day residual effects associated with zolpidem or subjective next-day impairment with zaleplon, even when the latter has been delivered in the middle of the night.
- Wagner, J.; Wagner, M. L.; Hening, W. A. (June 1998). “Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia”. Ann Pharmacother. 32 (6): 680–91. doi:10.1345/aph.17111. PMID 9640488.
New developments in benzodiazepine receptor pharmacology have introduced novel nonbenzodiazepine hypnotics that provide comparable efficacy to benzodiazepines. Although they may possess theoretical advantages over benzodiazepines based on their unique pharmacologic profiles, they offer few, if any, significant advantages in terms of adverse effects.
- Arendt, J; Skene, DJ (February 2005). “Melatonin as a chronobiotic”. Sleep Med. Rev. 9 (1): 25–39. doi:10.1016/j.smrv.2004.05.002. PMID 15649736.
- Haria, M.; Fitton, A.; McTavish, D. (April 1994). “Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders”. Drugs Aging. 4 (4): 331–55. doi:10.2165/00002512-199404040-00006. PMID 8019056.
- “Levate (amitriptyline), dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 1 December 2013.
- Hajak, G.; Rodenbeck, A.; Voderholzer, U.; Riemann, D.; Cohrs, S.; Hohagen, F.; et al. (2001). “Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study”. J Clin Psychiatry. 62 (6): 453–63. doi:10.4088/JCP.v62n0609. PMID 11465523.
Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.[page needed]
- Wakeling, A. (April 1983). “Efficacy and side effects of mianserin, a tetracyclic antidepressant”. Postgrad Med J. 59 (690): 229–31. doi:10.1136/pgmj.59.690.229. PMC 2417496. PMID 6346303.
- Hartmann, P. M. (January 1999). “Mirtazapine: a newer antidepressant”. Am Fam Physician. 59 (1): 159–61. PMID 9917581.
- Jindal, R. D. (2009). “Insomnia in patients with depression: some pathophysiological and treatment considerations”. CNS Drugs. 23 (4): 309–29. doi:10.2165/00023210-200923040-00004. PMID 19374460. Archived from the original on 2013-02-09.
- Leucht, S.; Cipriani, A.; Spineli, L.; Mavridis, D.; Orey, D.; Richter, F.; et al. (September 2013). “Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis”. Lancet. 382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
- Harrison, Neil; Mendelson, Wallace B.; de Wit, Harriet (2000). “Barbiturates”. Neuropsychopharmacology. Retrieved 8 February 2014. discusses Barbs vs. benzos
- Buysse, D. J. (20 February 2013). “Insomnia”. JAMA. 309 (7): 706–16. doi:10.1001/jama.2013.193. PMC 3632369. PMID 23423416.
- Huedo-Medina, T. B.; Kirsch, I.; Middlemass, J.; Klonizakis, M.; Siriwardena, A. N. (17 December 2012). “Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration”. BMJ. 345: e8343. doi:10.1136/bmj.e8343. PMC 3544552. PMID 23248080.
- Roehrs, T.; Roth, T. (October 2012). “Insomnia pharmacotherapy”. Neurotherapeutics. 9 (4): 728–38. doi:10.1007/s13311-012-0148-3. PMC 3480571. PMID 22976558.
- Passos, G. S.; Poyares, D. L.; Santana, M. G.; Tufik, S.; Mello, M. T. (2012). “Is exercise an alternative treatment for chronic insomnia?”. Clinics (Sao Paulo). 67 (6): 653–60f. PMC 3370319. PMID 22760906.
- Becker, D. E. (Spring 2012). “Pharmacodynamic considerations for moderate and deep sedation”. Anesth Prog. 59 (1): 28–42. doi:10.2344/0003-3006-59.1.28. PMC 3309299. PMID 22428972.
- Godard, M.; Barrou, Z.; Verny, M. (December 2010). “[Geriatric approach of sleep disorders in the elderly]”. Psychol Neuropsychiatr Vieil. 8 (4): 235–41. doi:10.1684/pnv.2010.0232. PMID 21147662.
- Scammell, T. E.; Winrow, C. J. (2011). “Orexin receptors: pharmacology and therapeutic opportunities”. Annu Rev Pharmacol Toxicol. 51: 243–66. doi:10.1146/annurev-pharmtox-010510-100528. PMC 3058259. PMID 21034217.
- Sukys-Claudino, L.; Moraes, W. A.; Tufik, S.; Poyares, D. (September 2010). “[The newer sedative-hypnotics]”. Rev Bras Psiquiatr. 32 (3): 288–93. PMID 20945020.
- Uzun, S.; Kozumplik, O.; Jakovljević, M.; Sedić, B. (March 2010). “Side effects of treatment with benzodiazepines”. Psychiatr Danub. 22 (1): 90–3. PMID 20305598.
- Pigeon, W. R. (February 2010). “Diagnosis, prevalence, pathways, consequences & treatment of insomnia”. Indian J Med Res. 131: 321–32. PMC 4324320. PMID 20308757.
- Hoque, R.; Chesson Jr., A. L. (15 October 2009). “Zolpidem-induced sleepwalking, sleep related eating disorder, and sleep-driving: fluorine-18-flourodeoxyglucose positron emission tomography analysis, and a literature review of other unexpected clinical effects of zolpidem”. J Clin Sleep Med. 5 (5): 471–6. PMC 2762721. PMID 19961034.