{{Short description|Class of psychoactive drugs}} [[File:Zolpidem.svg|thumb|right|220px|class=skin-invert-image|Chemical structure of a typical Z-drug, zolpidem]]
'''Nonbenzodiazepines''' ({{IPAc-en|ˌ|n|ɒ|n|ˌ|b|ɛ|n|z|oʊ|d|aɪ|ˈ|æ|z|ᵻ|p|iː|n|,_|-|ˈ|eɪ|-}}{{refn|{{cite web |url=https://www.oxforddictionaries.com/definition/english/benzodiazepine |archive-url=https://web.archive.org/web/20120828134823/http://oxforddictionaries.com/definition/english/benzodiazepine |archive-date=August 28, 2012 |title=benzodiazepine - definition of benzodiazepine in English from the Oxford dictionary |publisher=OxfordDictionaries.com |access-date=2016-01-20 }} }}{{refn|{{MerriamWebsterDictionary|benzodiazepine}}}}), sometimes referred to colloquially as '''Z-drugs''' (as some of the more well-known drugs begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are '''benzodiazepine-like''' in uses, such as for treating insomnia<ref>{{cite journal | title = What's wrong with prescribing hypnotics? | journal = Drug and Therapeutics Bulletin | volume = 42 | issue = 12 | pages = 89–93 | date = December 2004 | pmid = 15587763 | doi = 10.1136/dtb.2004.421289 | s2cid = 40188442 | url = http://dtb.bmj.com/cgi/content/full/42/12/89 | url-access = subscription }}</ref> and anxiety.<ref name="pmid22981367">{{cite journal | vauthors = Skolnick P | title = Anxioselective anxiolytics: on a quest for the Holy Grail | journal = Trends Pharmacol Sci | volume = 33 | issue = 11 | pages = 611–20 | date = November 2012 | pmid = 22981367 | pmc = 3482271 | doi = 10.1016/j.tips.2012.08.003 | url = }}</ref>
Nonbenzodiazepine pharmacodynamics are similar in mechanism of action to benzodiazepine drugs, acting as GABA<sub>A</sub> receptor positive allosteric modulators of the benzodiazepine site, and therefore exhibit similar benefits, side effects, and risks. However, nonbenzodiazepines have dissimilar or entirely different chemical structures, so are unrelated to benzodiazepines on a molecular level.<ref name="pmid17132386">{{cite journal | vauthors = Siriwardena AN, Qureshi Z, Gibson S, Collier S, Latham M | title = GPs' attitudes to benzodiazepine and 'Z-drug' prescribing: a barrier to implementation of evidence and guidance on hypnotics | journal = The British Journal of General Practice | volume = 56 | issue = 533 | pages = 964–7 | date = December 2006 | pmid = 17132386 | pmc = 1934058 }}</ref><ref name="pmid9640488">{{cite journal | vauthors = Wagner J, Wagner ML, Hening WA | title = Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia | journal = The Annals of Pharmacotherapy | volume = 32 | issue = 6 | pages = 680–91 | date = June 1998 | pmid = 9640488 | doi = 10.1345/aph.17111 | s2cid = 34250754 }}</ref>
==Background== Nonbenzodiazepines have demonstrated efficacy in treating sleep disorders. There is some limited evidence that suggests that tolerance to nonbenzodiazepines is slower to develop than with benzodiazepines.<ref>{{Citation |last=Owens |first=Judith A. |title=Chapter 7 - Pharmacology of Sleep |date=2014-01-01 |url=https://www.sciencedirect.com/science/article/pii/B9781455703180000073 |work=Principles and Practice of Pediatric Sleep Medicine (Second Edition) |pages=53–61 |editor-last=Sheldon |editor-first=Stephen H. |access-date=2023-06-17 |place=Philadelphia |publisher=W.B. Saunders |language=en |isbn=978-1-4557-0318-0 |editor2-last=Ferber |editor2-first=Richard |editor3-last=Kryger |editor3-first=Meir H. |editor4-last=Gozal |editor4-first=David}}</ref> However, data are limited, so no conclusions can be drawn. Data are also limited into the long-term effects of nonbenzodiazepines. Further research into the safety of nonbenzodiazepines and long-term effectiveness of nonbenzodiazepines has been recommended in a review of the literature.<ref name="pmid15746509">{{cite journal | vauthors = Benca RM | title = Diagnosis and treatment of chronic insomnia: a review | journal = Psychiatric Services | volume = 56 | issue = 3 | pages = 332–43 | date = March 2005 | pmid = 15746509 | doi = 10.1176/appi.ps.56.3.332 }}</ref> Some differences exist between the Z-drugs, for example tolerance and rebound effects may not occur with zaleplon.<ref name="pmid11219327">{{cite journal | vauthors = Lader MH | title = Implications of hypnotic flexibility on patterns of clinical use | journal = International Journal of Clinical Practice. Supplement | issue = 116 | pages = 14–9 | date = January 2001 | pmid = 11219327 }}</ref>
==Classes== thumb|651px|class=skin-invert-image|Core structures of selected nonbenzodiazepines (left three diagrams) and the structure of benzodiazepines (right) for comparison.
Currently, the major chemical classes of nonbenzodiazepines are:
'''Imidazopyridines''' * Alpidem * Necopidem * Saripidem * Zolpidem (Ambien, Ambien CR, Intermezzo, Zolpimist, Edluar, Ivadal, Sanval, Stilnox, etc.) '''Pyrazolopyrimidines''' * Divaplon * Fasiplon * Indiplon * Lorediplon * Ocinaplon * Panadiplon * Taniplon * Zaleplon (Sonata, Starnoc, Andante) {{Col-begin}} {{Col-break}} '''Cyclopyrrolones''' * Eszopiclone (Lunesta, Valnoc, etc.) * Pagoclone * Pazinaclone * Suproclone * Suriclone * Zopiclone (Imovane, Zimovane, Somnol, etc.) {{Col-break}} '''β-Carbolines''' * Abecarnil * Azocarnil (photoswitchable)<ref>{{cite journal | vauthors = Maleeva G, Nin-Hill A, Wirth U, Rustler K, Ranucci M, Opar E, Rovira C, Bregestovski P, Zeilhofer HU, König B, Alfonso-Prieto M, Gorostiza P | title = Light-Activated Agonist-Potentiator of GABA<sub>A</sub> Receptors for Reversible Neuroinhibition in Wildtype Mice | journal = Journal of the American Chemical Society | date = October 2024 | volume = 146 | issue = 42 | pages = 28822–28831 | pmid = 39383450 | doi = 10.1021/jacs.4c08446 | pmc = 11503767 | bibcode = 2024JAChS.14628822M }}</ref> * Gedocarnil * SL-651,498 * ZK-93423 {{col-end}} {{Col-begin}} {{Col-break}} '''Others''' * AXS-17 (BAER-101, AZD-7325) * CGS-20625 * CGS-9896 * CL-218,872 * ELB-139 * GBLD-345 * HIE-124 * L-838,417 {{Col-break}} * NS-2664 * NS-2710 * Pipequaline * RWJ-51204 * SB-205,384 * SL-651,498 * SX-3228 {{Col-break}} * TCS-1205 * TP-003 * TP-13 * TPA-023 * Y-23684 * Etifoxine {{col-end}}
==Pharmacology== The nonbenzodiazepines are positive allosteric modulators of the GABA<sub>A</sub> receptor. Like the benzodiazepines, they exert their effects by binding to and activating the benzodiazepine site of the receptor complex.
=== Functional selectivity === Some nonbenzodiazepines can be subtype-selective, possibly providing anxiolytic effects with little to no hypnotic or amnesic effects or providing hypnotic effects with little or no anxiolytic effect.
More recently, a range of non-sedating anxiolytic drugs derived from the same structural families as the Z-drugs have been developed, such as alpidem (Ananxyl) and pagoclone, and approved for clinical prescription. The new drugs are much more selective than the older benzodiazepine anxiolytics, producing effective relief of anxiety/panic with little or no sedation, anterograde amnesia, or anticonvulsant effects, and are thus potentially more precise than older, anti-anxiety drugs. However, anxiolytic nonbenzodiazepines are not widely prescribed and many have collapsed after initial clinical trials and consumption halted many projects, including but not limited to alpidem, indiplon, and suriclone.
A number of non-sedating benzodiazepine anxiolytics such as imidazenil and clobazam also exist, with the caveat that neither is a traditional 1,4-benzodiazepine. The functional selectivity is not unique to the nonbenzodiazepine structural class and has more to do with selectivity among different types of GABA<sub>A</sub> receptors or partial agonism, though this structural class does have more drug candidates.<ref name="pmid22981367"/>
==Pharmaceuticals== {| class="wikitable" style="float:right; width:40em; margin:0 0 1em 1em;" |- ! colspan="5" | Comparison of nonbenzodiazepines<ref name="BBDinsomnia">{{Cite web |title=Evaluating Newer Sleeping Pills Used to Treat: Insomnia: Comparing Effectiveness, Safety, and Price|date=January 2012 |publisher=Consumer Reports |page=14 |url=http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/InsomniaUpdate-FINAL-July2008.pdf |access-date=4 June 2013}}</ref><ref name="pmid23248080">{{cite journal | vauthors = Huedo-Medina TB, Kirsch I, Middlemass J, Klonizakis M, Siriwardena AN | title = Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration | journal = BMJ | volume = 345 | article-number = e8343 | date = December 2012 | pmid = 23248080 | pmc = 3544552 | doi = 10.1136/bmj.e8343 }}</ref> |- ! Drug ! Reduces sleep onset latency? ! Encourages sleep maintenance? ! Observed causing rebound insomnia? ! Observed causing physical dependence? |- | Zolpidem instant-release | Yes | Maybe | Maybe | Yes |- | Zolpidem extended-release | Yes | Yes | Yes | Yes |- | Sublingual zolpidem | Yes | Maybe | Maybe | Yes |- | Zolpidem oral spray | Yes | Maybe | Maybe | Yes |- | Eszopiclone | Yes | Yes | Yes | Yes |- | Zaleplon | Yes | Maybe | No | Yes |- |}
The first three nonbenzodiazepine drugs to enter the market were the "Z-drugs", zopiclone, zolpidem and zaleplon. These three drugs are all sedatives used exclusively for the treatment of mild insomnia. They are safer than the older barbiturates especially in overdosage and they may, when compared to the benzodiazepines, have less of a tendency to induce physical dependence and addiction, although these issues can still become a problem. This has led to the Z-drugs becoming widely prescribed for the treatment of insomnia particularly in elderly patients.<ref name="pmid16871130">{{cite journal | vauthors = Neubauer DN | title = New approaches in managing chronic insomnia | journal = CNS Spectrums | volume = 11 | issue = 8 Suppl 8 | pages = 1–13 | year = 2006 | pmid = 16871130 | doi = 10.1017/S1092852900026687 | s2cid = 141232890 }}</ref><ref name="pmid16750462">{{cite journal | vauthors = Najib J | title = Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia | journal = Clinical Therapeutics | volume = 28 | issue = 4 | pages = 491–516 | date = April 2006 | pmid = 16750462 | doi = 10.1016/j.clinthera.2006.04.014 }}</ref><ref name="pmid17599165">{{cite journal | vauthors = Lieberman JA | title = Update on the safety considerations in the management of insomnia with hypnotics: incorporating modified-release formulations into primary care | journal = Primary Care Companion to the Journal of Clinical Psychiatry | volume = 9 | issue = 1 | pages = 25–31 | year = 2007 | pmid = 17599165 | pmc = 1894851 | doi = 10.4088/pcc.v09n0105 | url = http://www.psychiatrist.com/pcc/pccpdf/v09n01/v09n0105.pdf | access-date = 2007-10-07 | archive-date = 2013-05-15 | archive-url = https://web.archive.org/web/20130515044935/http://www.psychiatrist.com/pcc/pccpdf/v09n01/v09n0105.pdf }}</ref> Almost a third of all prescriptions written for Z-drugs are for adults over the age of 65.<ref>{{cite journal | vauthors = Kaufmann CN, Spira AP, Alexander GC, Rutkow L, Mojtabai R | title = Trends in prescribing of sedative-hypnotic medications in the USA: 1993-2010 | journal = Pharmacoepidemiology and Drug Safety | volume = 25 | issue = 6 | pages = 637–45 | date = June 2016 | pmid = 26711081 | pmc = 4889508 | doi = 10.1002/pds.3951 }}</ref>
Long-term use is not recommended as tolerance and addiction can occur.<ref>{{cite journal | vauthors = Touitou Y | title = [Sleep disorders and hypnotic agents: medical, social and economical impact] | language = fr | journal = Annales Pharmaceutiques Françaises | volume = 65 | issue = 4 | pages = 230–8 | date = July 2007 | pmid = 17652991 | doi = 10.1016/s0003-4509(07)90041-3 }}</ref> Zolpidem and zaleplon are, in the US, indicated for 7–10 days of use only. Longer periods of use lead to loss of efficacy from tolerance.<ref>{{cite web |title=Literature Review of Nonbenzodiazepine Hypnotics |url=https://www.orpdl.org/durm/drug_articles/reviews/dur_review_2001_02_21_nonbenzodiazepine.pdf |website=Oregon State College of Pharmacy}}</ref> Tolerance has also been demonstrated with zopiclone,<ref>{{cite journal |last1=Sivertsen |first1=B |last2=Omvik |first2=S |last3=Pallesen |first3=S |last4=Nordhus |first4=IH |last5=Bjorvatn |first5=B |title=Sleep and sleep disorders in chronic users of zopiclone and drug-free insomniacs. |journal=Journal of Clinical Sleep Medicine |date=2009-08-15 |volume=5 |issue=4 |pages=349–54 |doi=10.5664/jcsm.27546 |pmid=19968013|pmc=2725254 }}</ref> which is indicated for a maximum of 4 weeks of use in New Zealand.<ref>{{cite web |title=Zopiclone – Indicated for short-term use only |url=https://www.medsafe.govt.nz/profs/PUArticles/June2019/Zopiclone-Indicated-for-short-term-use-only.htm |website=www.medsafe.govt.nz |language=en-nz}}</ref>
A survey of patients using nonbenzodiazepine Z-drugs and benzodiazepine hypnotic users found that there was no difference in reports of adverse effects that were reported in over 41% of users and, in fact, Z-drug users were more likely to report that they had tried to quit their hypnotic drug and were more likely to want to stop taking Z-drugs than benzodiazepine users. Efficacy also did not differ between benzodiazepine and Z-drug users.<ref>{{cite journal | vauthors = Siriwardena AN, Qureshi MZ, Dyas JV, Middleton H, Orner R | title = Magic bullets for insomnia? Patients' use and experiences of newer (Z drugs) versus older (benzodiazepine) hypnotics for sleep problems in primary care | journal = The British Journal of General Practice | volume = 58 | issue = 551 | pages = 417–22 | date = June 2008 | pmid = 18505619 | pmc = 2418994 | doi = 10.3399/bjgp08X299290 }}</ref>
===Effectiveness=== A major systematic review and network meta-analysis of medications for the treatment of insomnia was published in 2022.<ref name="pmid35843245">{{cite journal | vauthors = De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A | display-authors = 6 | title = Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis | journal = Lancet | volume = 400 | issue = 10347 | pages = 170–184 | date = July 2022 | pmid = 35843245 | doi = 10.1016/S0140-6736(22)00878-9 | s2cid = 250536370 | doi-access = free | hdl = 11380/1288245 | hdl-access = free }}</ref> It included the Z-drugs and found effect sizes (standardized mean difference (SMD)) ranging from 0.03 to 0.63 for these agents.<ref name="pmid35843245" /> More specifically, the SMDs were 0.45 (4{{nbsp}}weeks) and 0.03 (3{{nbsp}}months) for zolpidem, 0.51 (4{{nbsp}}weeks) for zopiclone, 0.51 (4{{nbsp}}weeks) and 0.63 (3{{nbsp}}months) for eszopiclone, and 0.19 (4{{nbsp}}weeks) for zaleplon.<ref name="pmid35843245" /> Eszopiclone had the most favorable profile and best evidence to support its use.<ref name="pmid35843245" /> For comparison, benzodiazepines had SMDs of 0.58 to 0.83, sedative antidepressants and antihistamines had SMDs of 0.30 to 0.55, the antipsychotic quetiapine had an SMD of 0.07, orexin receptor antagonists had SMDs of 0.23 to 0.44, and melatonin receptor agonists had SMDs of 0.00 to 0.13.<ref name="pmid35843245" /> The certainty of evidence varied and ranged from high to very low depending on the medication.<ref name="pmid35843245" />
==Side effects== The Z-drugs are not without disadvantages, and all three compounds are notable for producing side effects such as pronounced amnesia and more rarely hallucinations,<ref name="pmid17852167">{{cite journal | vauthors = Stone JR, Zorick TS, Tsuang J | title = Dose-related illusions and hallucinations with zaleplon | journal = Clinical Toxicology | volume = 46 | issue = 4 | pages = 344–5 | date = April 2008 | pmid = 17852167 | doi = 10.1080/15563650701517442 | doi-access = free }}</ref><ref name="pmid10682233">{{cite journal | vauthors = Toner LC, Tsambiras BM, Catalano G, Catalano MC, Cooper DS | title = Central nervous system side effects associated with zolpidem treatment | journal = Clinical Neuropharmacology | volume = 23 | issue = 1 | pages = 54–8 | year = 2000 | pmid = 10682233 | doi = 10.1097/00002826-200001000-00011 }}</ref> especially when used in large doses. On rare occasions, these drugs can produce a fugue state, wherein the patient sleepwalks and may perform relatively complex actions, including cooking meals or driving cars, while effectively unconscious and with no recollection of the events upon awakening. While this effect is rare (and has also been reported to occur with some of the older sedative drugs such as temazepam and secobarbital), it can be potentially hazardous, and so further development of this class of drugs has continued in an effort to find new compounds with further improved profiles.<ref name="pmid17117195">{{cite journal | vauthors = Mellingsaeter TC, Bramness JG, Slørdal L | title = [Are z-hypnotics better and safer sleeping pills than benzodiazepines?] | language = no | journal = Tidsskrift for den Norske Laegeforening | volume = 126 | issue = 22 | pages = 2954–6 | date = November 2006 | pmid = 17117195 | url = http://www.tidsskriftet.no/pls/lts/pa_lt.visSeksjon?vp_SEKS_ID=1453732 | archive-url = https://web.archive.org/web/20071028084351/http://www.tidsskriftet.no/pls/lts/pa_lt.visSeksjon?vp_SEKS_ID=1453732 | archive-date = 2007-10-28 }}</ref><ref name="pmid15954071">{{cite journal | vauthors = Yang W, Dollear M, Muthukrishnan SR | title = One rare side effect of zolpidem--sleepwalking: a case report | journal = Archives of Physical Medicine and Rehabilitation | volume = 86 | issue = 6 | pages = 1265–6 | date = June 2005 | pmid = 15954071 | doi = 10.1016/j.apmr.2004.11.022 }}</ref><ref name="pmid15725964">{{cite journal | vauthors = Lange CL | title = Medication-associated somnambulism | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 44 | issue = 3 | pages = 211–2 | date = March 2005 | pmid = 15725964 | doi = 10.1097/01.chi.0000150618.67559.48 }}</ref><ref name="pmid14592194">{{cite journal | vauthors = Morgenthaler TI, Silber MH | title = Amnestic sleep-related eating disorder associated with zolpidem | journal = Sleep Medicine | volume = 3 | issue = 4 | pages = 323–7 | date = July 2002 | pmid = 14592194 | doi = 10.1016/S1389-9457(02)00007-2 }}</ref><ref name="pmid15266187">{{cite journal | vauthors = Liskow B, Pikalov A | title = Zaleplon overdose associated with sleepwalking and complex behavior | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 43 | issue = 8 | pages = 927–8 | date = August 2004 | pmid = 15266187 | doi = 10.1097/01.chi.0000129219.66563.aa }}</ref>
Daytime withdrawal-related anxiety can also occur from chronic nightly nonbenzodiazepine hypnotic usage such as with zopiclone.<ref name="pmid2230061">{{cite journal | vauthors = Fontaine R, Beaudry P, Le Morvan P, Beauclair L, Chouinard G | title = Zopiclone and triazolam in insomnia associated with generalized anxiety disorder: a placebo-controlled evaluation of efficacy and daytime anxiety | journal = International Clinical Psychopharmacology | volume = 5 | issue = 3 | pages = 173–83 | date = July 1990 | pmid = 2230061 | doi = 10.1097/00004850-199007000-00002 }}</ref>
Side effects can differ within the drug class due to differences in metabolism and pharmacology. For example, long-acting benzodiazepines have problems of drug accumulation especially in the elderly or those with liver disease, and shorter-acting benzodiazepines have a higher risk of more severe withdrawal symptoms.<ref>{{cite journal | vauthors = Shader RI, Greenblatt DJ | title = Clinical implications of benzodiazepine pharmacokinetics | journal = The American Journal of Psychiatry | volume = 134 | issue = 6 | pages = 652–6 | date = June 1977 | pmid = 17302 | doi = 10.1176/ajp.134.6.652 }}</ref><ref>{{cite journal | vauthors = Noyes R, Perry PJ, Crowe RR, Coryell WH, Clancy J, Yamada T, Gabel J | title = Seizures following the withdrawal of alprazolam | journal = The Journal of Nervous and Mental Disease | volume = 174 | issue = 1 | pages = 50–2 | date = January 1986 | pmid = 2867122 | doi = 10.1097/00005053-198601000-00009 }}</ref> In the case of the nonbenzodiazepines, zaleplon may be the safest in terms of next-day sedation, and − unlike zolpidem and zopiclone − zaleplon has been found to have no association with increased motor vehicle accidents even when taken for middle-of-the-night insomnia due to its ultrashort elimination half-life.<ref>{{cite journal | vauthors = Menzin J, Lang KM, Levy P, Levy E | title = A general model of the effects of sleep medications on the risk and cost of motor vehicle accidents and its application to France | journal = PharmacoEconomics | volume = 19 | issue = 1 | pages = 69–78 | date = January 2001 | pmid = 11252547 | doi = 10.2165/00019053-200119010-00005 | title-link = motor vehicle accidents | s2cid = 45013069 }}</ref><ref>{{cite journal | vauthors = Vermeeren A, Riedel WJ, van Boxtel MP, Darwish M, Paty I, Patat A | title = Differential residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol | journal = Sleep | volume = 25 | issue = 2 | pages = 224–31 | date = March 2002 | pmid = 11905433 }}</ref><ref>{{cite journal | vauthors = Walsh JK, Pollak CP, Scharf MB, Schweitzer PK, Vogel GW | title = Lack of residual sedation following middle-of-the-night zaleplon administration in sleep maintenance insomnia | journal = Clinical Neuropharmacology | volume = 23 | issue = 1 | pages = 17–21 | date = January–February 2000 | pmid = 10682226 | doi = 10.1097/00002826-200001000-00004 | s2cid = 33929400 }}</ref><ref>{{cite journal | vauthors = Verster JC, Veldhuijzen DS, Volkerts ER | title = Residual effects of sleep medication on driving ability | journal = Sleep Medicine Reviews | volume = 8 | issue = 4 | pages = 309–25 | date = August 2004 | pmid = 15233958 | doi = 10.1016/j.smrv.2004.02.001 | hdl-access = free | hdl = 1874/11902 | s2cid = 22856696 }}</ref>
===Increased risk of depression=== It has been claimed that insomnia causes depression and hypothesized that insomnia medications may help to treat depression. However, an analysis of data of clinical trials submitted to the Food and Drug Administration (FDA) concerning the drugs zolpidem, zaleplon, and eszopiclone found that these sedative hypnotic drugs more than doubled the risks of developing depression compared to those taking placebo pills.<ref name="pmid17711589">{{cite journal | vauthors = Kripke DF | title = Greater incidence of depression with hypnotic use than with placebo | journal = BMC Psychiatry | volume = 7 | page = 42 | date = August 2007 | pmid = 17711589 | pmc = 1994947 | doi = 10.1186/1471-244X-7-42 | doi-access = free }}</ref> Hypnotic drugs, therefore, may be contraindicated in patients with or at risk of depression. Hypnotics were found to be more likely to cause depression than to help it. Studies have found that long-term users of sedative hypnotic drugs have a markedly raised suicide risk as well as an overall increased mortality risk. Cognitive-behavioral therapy (CBT) for insomnia, on the other hand, has been found to both improve sleep quality as well as general mental health.<ref name="pmid17711589" />
===Other risks=== Sleeping pills, including the Z-drugs, have been associated with an increased risk of death.<ref>{{cite journal | vauthors = Kripke DF | title = Mortality Risk of Hypnotics: Strengths and Limits of Evidence | journal = Drug Safety | volume = 39 | issue = 2 | pages = 93–107 | date = February 2016 | pmid = 26563222 | doi = 10.1007/s40264-015-0362-0 | s2cid = 7946506 | url = https://escholarship.org/content/qt08d9f3d5/qt08d9f3d5.pdf?t=nz1gjv | doi-access = free }}</ref>
In older people this family of medications increases the risk of fractures and falls.<ref name=Tre2018>{{cite journal | vauthors = Treves N, Perlman A, Kolenberg Geron L, Asaly A, Matok I | title = Z-drugs and risk for falls and fractures in older adults-a systematic review and meta-analysis | journal = Age and Ageing | volume = 47 | issue = 2 | pages = 201–208 | date = March 2018 | pmid = 29077902 | doi = 10.1093/ageing/afx167 | doi-access = free }}</ref> The 2023 Beers criteria lists all three Z-drugs approved in the US (zolpidem, zaleplon, eszolpiclon) as unsuitable for older people.<ref>{{cite journal |title=American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults |journal=Journal of the American Geriatrics Society |date=July 2023 |volume=71 |issue=7 |pages=2052–2081 |doi=10.1111/jgs.18372|pmid=37139824 |author1=By the 2023 American Geriatrics Society Beers Criteria® Update Expert Panel }}</ref>
The Z-drug zaleplon may have fewer side effects compared to benzodiazepines.<ref>{{cite journal | vauthors = Barbera J, Shapiro C | title = Benefit-risk assessment of zaleplon in the treatment of insomnia | journal = Drug Safety | volume = 28 | issue = 4 | pages = 301–18 | year = 2005 | pmid = 15783240 | doi = 10.2165/00002018-200528040-00003 | s2cid = 24222535 }}</ref><!-- why only Benzodiazepines? -->
Much like benzodiazepines, Z-drugs are associated with an increased incidence of dementia. There is overall a 20% increase in dementia risk after adjusting for confounding factors. The effect is more profound in women.<ref>{{cite journal |last1=Torres-Bondia |first1=F |last2=Dakterzada |first2=F |last3=Galván |first3=L |last4=Buti |first4=M |last5=Besanson |first5=G |last6=Grill |first6=E |last7=Buil |first7=R |last8=de Batlle |first8=J |last9=Piñol-Ripoll |first9=G |title=Benzodiazepine and Z-Drug Use and the Risk of Developing Dementia. |journal=The International Journal of Neuropsychopharmacology |date=19 April 2022 |volume=25 |issue=4 |pages=261–268 |doi=10.1093/ijnp/pyab073 |pmid=34727174|pmc=9017765 }}</ref>
==Dependence and withdrawal management== Nonbenzodiazepines should not be discontinued abruptly if taken for more than a few weeks due to the risk of rebound withdrawal effects and acute withdrawal reactions, which may resemble those seen during benzodiazepine withdrawal. Treatment usually entails gradually reducing the dosage over a period of weeks or several months depending on the individual, dosage, and length of time the drug has been taken. If this approach fails, a crossover to a benzodiazepine equivalent dose of a long-acting benzodiazepine (such as chlordiazepoxide or more preferably diazepam) can be tried followed by a gradual reduction in dosage. In extreme cases and, in particular, where severe addiction and/or abuse is manifested, an inpatient detoxification may be required, with flumazenil as a possible detoxification tool.<ref>{{cite web |url=https://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a605009.html |title=Eszopiclone |access-date=21 March 2008 |author=MedlinePlus |date=January 8, 2001 |publisher=National Institutes of Health |archive-url=https://web.archive.org/web/20080227024716/http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a605009.html |archive-date=February 27, 2008}}</ref><ref>{{cite web |url=http://www.benzo.org.uk/manual/ |title=Benzodiazepines: How They Work and How to Withdraw |author=Professor Heather Ashton}}</ref><ref>{{cite journal | vauthors = Quaglio G, Lugoboni F, Fornasiero A, Lechi A, Gerra G, Mezzelani P | title = Dependence on zolpidem: two case reports of detoxification with flumazenil infusion | journal = International Clinical Psychopharmacology | volume = 20 | issue = 5 | pages = 285–7 | date = September 2005 | pmid = 16096519 | doi = 10.1097/01.yic.0000166404.41850.b4 }}</ref>
==Elderly== Nonbenzodiazepine hypnotic drugs, similar to benzodiazepines, cause impairments in body balance and standing steadiness upon waking; falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial but incomplete tolerance develops to these impairments.<ref name="Mets-2010">{{cite journal | vauthors = Mets MA, Volkerts ER, Olivier B, Verster JC | title = Effect of hypnotic drugs on body balance and standing steadiness | journal = Sleep Medicine Reviews | volume = 14 | issue = 4 | pages = 259–67 | date = August 2010 | pmid = 20171127 | doi = 10.1016/j.smrv.2009.10.008 }}</ref> In general, nonbenzodiazepines are not recommended for older patients due to the increased risk of falls and fractures.<ref>{{cite journal | vauthors = Antai-Otong D | title = The art of prescribing. Risks and benefits of non-benzodiazepine receptor agonists in the treatment of acute primary insomnia in older adults | journal = Perspectives in Psychiatric Care | volume = 42 | issue = 3 | pages = 196–200 | date = August 2006 | pmid = 16916422 | doi = 10.1111/j.1744-6163.2006.00070.x | doi-access = free }}</ref> An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and lasting benefits of non-drug treatments for insomnia in adults of all age groups and that these interventions are underused. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics offer little if any advantages in efficacy or tolerability in elderly persons. It was found that newer agents such as the melatonin agonists may be more suitable and effective for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and is discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that further research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.<ref>{{cite journal | vauthors = Bain KT | title = Management of chronic insomnia in elderly persons | journal = The American Journal of Geriatric Pharmacotherapy | volume = 4 | issue = 2 | pages = 168–92 | date = June 2006 | pmid = 16860264 | doi = 10.1016/j.amjopharm.2006.06.006 }}</ref>
==Safety== A review of the literature regarding hypnotics including the nonbenzodiazepine Z-drugs concluded that these drugs carry a significant risk to the individual. The risks include dependence, accidents, and other adverse effects. Gradual discontinuation of hypnotics may lead to improved health without worsening of sleep. It is preferred that they should be prescribed for only a few days at the lowest effective dose and avoided wherever possible in the elderly.<ref>{{cite journal | title = What's wrong with prescribing hypnotics? | journal = Drug and Therapeutics Bulletin | volume = 42 | issue = 12 | pages = 89–93 | date = December 2004 | pmid = 15587763 | doi = 10.1136/dtb.2004.421289 | s2cid = 40188442 }}</ref>
==History== Z-drugs emerged in the last years of the 1980s and early 1990s, with zopiclone (Imovane) approved by the British National Health Service as early as 1989, quickly followed by Sanofi with zolpidem (Ambien). By 1999, King Pharmaceuticals had finalized approval with the American Food and Drug Administration (FDA) to market zaleplon (Sonata, Starnoc) across the US. In 2005, the FDA approved eszopiclone (Lunesta) the (''S'')-enantiomer of zopiclone. That same year, 2005, the FDA finalized approval for Ambien CR, or extended-release zolpidem. Most recently, in 2012 the FDA approved Intermezzo (zolpidem tartate sublingual), which is marketed for middle-of-the-night insomnia, available in doses only half of the strength of immediate-release zolpidem tartrate to avoid residual next-day sedation.
==References== {{Reflist}}
{{Hypnotics and sedatives}} {{Insomnia pharmacotherapies}} {{Anxiolytics}} {{GABAAR PAMs}} {{Chemical classes of psychoactive drugs}}
Category:Cyclopyrrolones Category:Imidazopyridines Category:Pyrazolopyrimidines Category:Nonbenzodiazepines Category:GABAA receptor positive allosteric modulators Category:Hypnotics Category:Sedatives