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{{Short description|Benzodiazepine medication}}
{{Drugbox| verifiedrevid = 419095996
{{Distinguish|Loprazolam|Lormetazepam|Loratadine}}
|
{{Use dmy dates|date=February 2024}}
| IUPAC_name = (''RS'')-9-chloro-6-(2-chlorophenyl)-4-hydroxy-<br />2,5-diazabicyclo[5.4.0]undeca-<br />5,8,10,12-tetraen-3-one
{{Infobox drug
| image = Lorazepam.svg|160px
| Verifiedfields = changed
| image2 = Lorazepam 3D.png|110px
| Watchedfields = changed
| CASNo_Ref = {{cascite|correct|CAS}}
| verifiedrevid = 419619495
| UNII_Ref = {{fdacite|correct|FDA}}
| image = Lorazepam.svg
| UNII = O26FZP769L
| width = 150
| InChI = 1/C15H10Cl2N2O2/c16-8-5-6-12-10(7-8)13(19-15(21)14(20)18-12)9-3-1-2-4-11(9)17/h1-7,15,21H,(H,18,20)
| alt =
| InChIKey = DIWRORZWFLOCLC-UHFFFAOYAU
| image2 = Lorazepam ball-and-stick model.png
| smiles = Clc3ccccc3C/2=N/C(O)C(=O)Nc1c\2cc(Cl)cc1
| width2 = 150
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| alt2 =
| ChEMBL = 580
| caption = <!-- Clinical data -->
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| tradename = Ativan, Tavor, Temesta, others<ref>{{cite web|title=Lorazepam|website=The Drug Gene Interaction Database|url=http://dgidb.genome.wustl.edu/drugs/DAP000237|access-date=18 May 2016|url-status=live|archive-url=https://web.archive.org/web/20160805201939/http://dgidb.genome.wustl.edu/drugs/DAP000237|archive-date=5 August 2016}}</ref>
| StdInChI = 1S/C15H10Cl2N2O2/c16-8-5-6-12-10(7-8)13(19-15(21)14(20)18-12)9-3-1-2-4-11(9)17/h1-7,15,21H,(H,18,20)
| Drugs.com = {{drugs.com|monograph|lorazepam}}
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| MedlinePlus = a682053
| StdInChIKey = DIWRORZWFLOCLC-UHFFFAOYSA-N
| DailyMedID = Lorazepam
| CAS_number = 846-49-1
| pregnancy_AU = C
| synonyms = O-Chloroxazepam, L-Lorazepam Acetate
| pregnancy_category =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| dependency_liability = High<ref name="Edmunds-2013">{{cite book |vauthors=Edmunds M, Mayhew M |year=2013 |title=Pharmacology for the Primary Care Provider |url=https://books.google.com/books?id=8FwdEsvnw8oC&pg=PA545 |edition=4th |publisher=Mosby |page=545 |isbn=978-0-323-08790-2 |access-date=13 July 2020 |archive-date=14 January 2023 |archive-url=https://web.archive.org/web/20230114192427/https://books.google.com/books?id=8FwdEsvnw8oC&pg=PA545 |url-status=live }}</ref>
| ChemSpiderID = 3821
| addiction_liability = Moderate<ref name="Cambridge University Press-2010">{{cite book|title=Clinical Addiction Psychiatry|date=2010|publisher=Cambridge University Press|isbn=978-1-139-49169-3|page=156|url=https://books.google.com/books?id=xD-R7Z27UBEC&pg=PA156|url-status=live|archive-url=https://web.archive.org/web/20170908135445/https://books.google.com/books?id=xD-R7Z27UBEC&pg=PA156|archive-date=8 September 2017}}</ref><ref name="Ries-2009">{{cite book| vauthors = Ries RK |title= Principles of addiction medicine|date=2009|publisher=Wolters Kluwer/Lippincott Williams & Wilkins|location=Philadelphia|isbn=978-0-7817-7477-2|page=106|edition=4|url=https://books.google.com/books?id=j6GGBud8DXcC&pg=PA106|url-status=live|archive-url=https://web.archive.org/web/20170908135444/https://books.google.com/books?id=j6GGBud8DXcC&pg=PA106|archive-date=8 September 2017}}</ref>
| ATC_prefix = N05
| routes_of_administration = [[oral administration|orally]], [[intramuscular]], [[intravenous]], [[transdermal]]
| ATC_suffix = BA06
| class = [[Benzodiazepine]]
| ATC_supplemental =
| ATC_prefix = N05
| PubChem = 3958
| ATC_suffix = BA06
| DrugBank = APRD00116
| legal_AU = S4
| KEGG_Ref = {{keggcite|correct|kegg}}
| legal_BR = B1
| KEGG = D00365
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>
| C = 15 | H =10 | Cl = 2 | N = 2 | O = 2
| legal_CA = Schedule IV
| molecular_weight = 321.2 g/mol
| legal_DE = Rx-only/Anlage III
| bioavailability = 85% of oral dose
| legal_UK = CD (Benz) POM
| metabolism = [[Liver|Hepatic]] [[glucuronidation]]
| legal_US = Schedule IV
| elimination_half-life = 9–16 hours<ref name="pharmacokineticslorazepam ">{{Cite journal|author=Greenblatt DJ, Shader RI, Franke K, Maclaughlin DS, Harmatz JS, Allen MD, Werner A, Woo E |title=Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans |url=http://www3.interscience.wiley.com/cgi-bin/abstract/113291369/ABSTRACT?CRETRY=1&SRETRY=0 |journal=J Pharm Sci |volume=68 |issue=1 |pages=57–63 |year=1991 |pmid=31453 |doi=10.1002/jps.2600680119 }}</ref><ref name="Lorazepaminfusion ">{{Cite journal|author=Greenblatt DJ, von Moltke LL, Ehrenberg BL, Harmatz JS, Corbett KE, Wallace DW, Shader RI|title=Kinetics and dynamics of lorazepam during and after continuous intravenous infusion|url=http://www.ccmjournal.com/pt/re/ccm/abstract.00003246-200008000-00011.htm;jsessionid=HGxHJZZnNrV1TQp6TnmT8PwGtRJvLwT61g1pvt3TJCTTvWnpB6Sq!-667243907!181195629!8091!-1|journal=Crit Care Med|volume=28 |issue=8 |pages=2750–2757 |year=2000 |pmid=10966246 |doi=10.1097/00003246-200008000-00011}}</ref><ref name="kineticracemization">{{Cite journal|author=Papini O, da Cunha SP, da Silva Mathes Ado C, Bertucci C, Moisés EC, de Barros Duarte L, de Carvalho Cavalli R, Lanchote VL|title=Kinetic disposition of lorazepam with a focus on the glucuronidation capacity, transplacental transfer in parturients and racemization in biological samples |url=http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TGX-4H21K93-7-C&_cdi=5266&_user=308069&_orig=search&_coverDate=02%2F13%2F2006&_sk=999599997&view=c&wchp=dGLbVzz-zSkWb&md5=fe760a63ce75494ac2ad7528878afbfe&ie=/sdarticle.pdf |format=PDF|journal=J Pharm Biomed Anal|volume=40 |issue=2 |pages=397–403 |year=2006 |pmid=16143486|doi=10.1016/j.jpba.2005.07.021 }}</ref>
| legal_status = <!-- Pharmacokinetic data -->
| excretion = [[Kidney|Renal]]
| bioavailability = 85% when taken by mouth
| pregnancy_US = D
| metabolism = [[Liver]] [[glucuronidation]]
| legal_CA = Schedule IV
| elimination_half-life = 10{{ndash}}20 hours<ref>{{Cite journal |vauthors=Greenblatt DJ, Shader RI, Franke K, Maclaughlin DS, Harmatz JS, Allen MD, Werner A, Woo E | title = Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans | journal = Journal of Pharmaceutical Sciences | year = 1991 | volume = 68 | issue = 1 | pages = 57–63 | pmid = 31453 | doi = 10.1002/jps.2600680119 }}</ref><ref>{{Cite journal |vauthors=Greenblatt DJ, von Moltke LL, Ehrenberg BL, Harmatz JS, Corbett KE, Wallace DW, Shader RI | title = Kinetics and dynamics of lorazepam during and after continuous intravenous infusion | journal = Critical Care Medicine | volume = 28 | issue = 8 | pages = 2750–2757 | year = 2000 | pmid = 10966246 | doi = 10.1097/00003246-200008000-00011| s2cid = 42138460 }}</ref><ref name="kineticracemization">{{Cite journal |vauthors=Papini O, da Cunha SP, da Silva Mathes Ado C, Bertucci C, Moisés EC, de Barros Duarte L, de Carvalho Cavalli R, Lanchote VL | title = Kinetic disposition of lorazepam with a focus on the glucuronidation capacity, transplacental transfer in parturients and racemization in biological samples | journal = Journal of Pharmaceutical and Biomedical Analysis | year = 2006 | volume = 40 | issue = 2 | pages = 397–403 | pmid = 16143486 | doi = 10.1016/j.jpba.2005.07.021}}</ref>
| legal_US = Schedule IV
| excretion = [[Kidney]]
| legal_UK = CD (Benz) POM
| onset = 1{{ndash}}5 min (IV), 15{{ndash}}30 min (IM)<ref name=AHSP2016/>
| routes_of_administration = Oral, I.M., I.V., sublingual, and transdermal
| duration_of_action = 12{{ndash}}24 hours (IV, IM)<ref name=AHSP2016/>

<!-- Identifiers -->| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 846-49-1
| PubChem = 3958
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB00186
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3821
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = O26FZP769L
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00365
| ChEBI = 6539
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 580

<!-- Chemical data -->| IUPAC_name = (''RS'')-7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one
| C = 15
| H = 10
| Cl = 2
| N = 2
| O = 2
| smiles = O=C1Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C15H10Cl2N2O2/c16-8-5-6-12-10(7-8)13(19-15(21)14(20)18-12)9-3-1-2-4-11(9)17/h1-7,15,21H,(H,18,20)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DIWRORZWFLOCLC-UHFFFAOYSA-N
| synonyms = o-Chloroxazepam
}}
}}
'''Lorazepam''' (initially marketed under the brand names '''Ativan''' and '''Temesta''') is a high-potency short-to-intermediate-acting 3-hydroxy [[benzodiazepine]] drug that has all five intrinsic benzodiazepine effects: [[anxiolytic]], [[anterograde amnesia|amnesic]], [[sedative]]/[[hypnotic]], [[anticonvulsant]] and [[muscle relaxant]].<ref name="Riss-2008"/><ref name="Hindmarch">{{Cite web| last = Hindmarch | first = Ian | title = Benzodiazepines and their effects | url = http://www.benzo.org.uk/hindmarch.htm | publisher = benzo.org.uk | date = January 30, 1997 | accessdate = 2007-05-13}}</ref> Lorazepam is used for the short-term treatment of anxiety, insomnia, acute seizures including [[status epilepticus]] and sedation of hospitalised patients, as well as sedation of aggressive patients.<ref name="Hindmarch"/><ref name="Cox-2008"/><ref name="Walker-2005"/><ref name="Battaglia-2005"/>


[[File:Lorazepam Orion.jpg|thumb|a box of Lorazepam Orion (Lorazepam) tablets]]
Lorazepam is considered to be a short-acting drug which, similar to other benzodiazepines, exerts its therapeutic as well as adverse effects via its interaction at benzodiazepine binding sites, which are located on GABA<sub>A</sub> receptors in the [[central nervous system]]. After its introduction in [[1977]], lorazepam's principal use was in treating [[anxiety]]. Among benzodiazepines, lorazepam has a relatively high [[Substance use disorder|addictive]] potential.<ref name="Riss-2008"/><ref>{{Cite journal| author = Kemper N | coauthors = Poser W, Poser S. | date = December 5, 1980 | title = [Benzodiazepine dependence: addiction potential of the benzodiazepines is greater than previously assumed (author's transl)] | journal = Deutsche medizinische Wochenschrift (1980). | volume = 105 | issue = 49 | pages = 1707–12 | pmid = 7439058 | doi = 10.1055/s-2008-1070941 }}</ref> Lorazepam also has abuse potential; the main types of misuse are for recreational purposes or continued use against medical advice.<ref name="Griffiths-2005"/> The sedative-hypnotic and anterograde amnesia properties of lorazepam are sometimes used for criminal purposes.<ref name="pmid15029082"/><ref name="Kintz-2007"/>


<!-- Definition and uses -->
[[Long-term effects of benzodiazepines]] include [[drug tolerance|tolerance]], [[drug dependence|dependence]], a [[benzodiazepine withdrawal syndrome]] and cognitive impairments which may not completely reverse after cessation of treatment; however, for most patients, cognitive impairment is not severe. Withdrawal symptoms can range from [[anxiety]] and [[insomnia]] to [[seizures]] and [[psychosis]]. Due to tolerance and dependence, lorazepam is recommended for short-term use, 2–4 weeks only. Adverse effects including [[anterograde amnesia]], [[Major depression|depression]] and [[paradoxical effects]] such as excitement or worsening of seizures may occur. Children and the elderly are more sensitive to the adverse effects of benzodiazepines.<ref name="Riss-2008">{{Cite journal| last1 = Riss | first1 = J. | last2 = Cloyd | first2 = J. | last3 = Gates | first3 = J. | last4 = Collins | first4 = S. | title = Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. | journal = Acta Neurol Scand | volume = 118 | issue = 2 | pages = 69–86 | month = Aug | year = 2008 | doi = 10.1111/j.1600-0404.2008.01004.x | pmid = 18384456 }}</ref><ref name="Stewart-2005">{{Cite journal| last1 = Stewart | first1 = SA. | title = The effects of benzodiazepines on cognition. | journal = J Clin Psychiatry | volume = 66 Suppl 2 | issue = | pages = 9–13 | year = 2005 | pmid = 15762814 }}</ref><ref name=Altrx2007>{{Cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017794s034s035lbl.pdf |title=Ativan (lorazepam) Tablets Rx only |author=Food and Drug Administration |authorlink=Food and Drug Administration |coauthors=Wyeth Pharmaceuticals Inc, Biovail Pharmaceuticals, Inc. |month=March |year=2007 |publisher=Food and Drug Administration |location=USA |format=PDF |quote=In general, benzodiazepines should be prescribed for short periods only (e.g. 2–4 weeks). Extension of the treatment period should not take place without reevaluation of the need for continued therapy. Continuous long-term use of product is not recommended. }}</ref> Lorazepam impairs body balance and standing steadiness and is associated with falls and hip fractures in the elderly.<ref name="Mets-2010"/>
'''Lorazepam''', sold under the brand name '''Ativan''' among others, is a [[benzodiazepine]] medication.<ref name=AHSP2016/> It is used to treat [[anxiety]] (including [[anxiety disorder]]s), [[insomnia|trouble sleeping]], [[Psychomotor agitation|severe agitation]], active [[Epileptic seizure|seizures]] including [[status epilepticus]], [[Alcohol withdrawal syndrome|alcohol withdrawal]], and [[chemotherapy-induced nausea and vomiting]].<ref name=AHSP2016/> It is also used during surgery to [[anterograde amnesia|interfere with memory formation]] and to [[sedate]] those who are being [[mechanical ventilation|mechanically ventilated]].<ref name=AHSP2016>{{cite web|title=Lorazepam|url=https://www.drugs.com/monograph/lorazepam.html|website=drugs.com|publisher=American Society of Health-System Pharmacists|access-date=15 July 2016|date=29 June 2016|url-status=live|archive-url=https://web.archive.org/web/20160605073500/http://www.drugs.com/monograph/lorazepam.html|archive-date=5 June 2016}}</ref><ref>{{cite web|title=Lorazepam: MedlinePlus Drug Information|url=https://medlineplus.gov/druginfo/meds/a682053.html#why|website=medlineplus.gov|access-date=16 July 2016|date=1 October 2010|url-status=live|archive-url=https://web.archive.org/web/20160819014154/https://medlineplus.gov/druginfo/meds/a682053.html#why|archive-date=19 August 2016}}</ref> It is also used, along with other treatments, for [[acute coronary syndrome]] due to [[cocaine]] use.<ref name=AHSP2016/> It can be given [[oral administration|orally]] (by mouth), [[transdermal]] (on the skin via a topical gel or patch), [[intravenously]] (IV) (injection into a vein), or [[intramuscularly]] (injection into a muscle.)<ref name=AHSP2016/> When given by injection, onset of effects is between one and thirty minutes and effects last for up to a day.<ref name=AHSP2016/>


<!-- Side effects -->
==Indications==
Common side effects include weakness, sleepiness, [[hypotension|low blood pressure]], and a decreased effort to breathe.<ref name=AHSP2016/> When given intravenously, the person should be closely monitored.<ref name=AHSP2016/> Among those who are [[major depressive disorder|depressed]], there may be an increased risk of [[suicide]].<ref name=AHSP2016/><ref name=Doc2017>{{cite journal | vauthors = Dodds TJ | title = Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature | journal = The Primary Care Companion for CNS Disorders | volume = 19 | issue = 2 | date = March 2017 | pmid = 28257172 | doi = 10.4088/PCC.16r02037 | doi-access = free }}</ref> With long-term use, [[Drug tolerance|larger doses may be required for the same effect]].<ref name=AHSP2016/> [[Physical dependence]] and [[psychological dependence]] may also occur.<ref name=AHSP2016/> If stopped suddenly after long-term use, [[benzodiazepine withdrawal syndrome]] may occur.<ref name=AHSP2016/> Older people more often develop adverse effects.<ref name="Riss-2008">{{Cite journal |vauthors=Riss J, Cloyd J, Gates J, Collins S | title = Benzodiazepines in epilepsy: pharmacology and pharmacokinetics | journal = Acta Neurologica Scandinavica | volume = 118 | issue = 2 | pages = 69–86 | year = 2008 | doi = 10.1111/j.1600-0404.2008.01004.x | pmid = 18384456 | s2cid = 24453988 | doi-access = }}</ref> In this age group, lorazepam is associated with falls and [[hip fracture]]s.<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 | year = 2010 | volume = 14 | issue = 4 | pages = 259–267 | doi = 10.1016/j.smrv.2009.10.008 | pmid = 20171127 }}</ref> Due to these concerns, lorazepam use is generally only recommended for up to two to four weeks.<ref name=Altrx2007>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017794s034s035lbl.pdf |title=Ativan (lorazepam) Tablets Rx only |date=March 2007 |publisher=[[Food and Drug Administration]] |quote=In general, benzodiazepines should be prescribed for short periods only (e.g. 2–4 weeks). Extension of the treatment period should not take place without reevaluation of the need for continued therapy. Continuous long-term use of product is not recommended. |url-status=live |archive-url=https://web.archive.org/web/20110917064143/http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017794s034s035lbl.pdf |archive-date=17 September 2011 }}</ref>
[[Image:AtivanAd.jpg|thumb|200px|right|1987 Ativan advertisement. "In a world where certainties are few...no wonder Ativan (lorazepam)([[Controlled Substances Act|Schedule IV]]) is prescribed by so many caring clinicians."]]Lorazepam has relatively potent [[anxiolytic]] effects and its best-known indication is the short-term management of severe anxiety; the FDA advises against use of benzodiazepines such as lorazepam for longer than 2–4 weeks.<ref name=Altrx2007/><ref>RONI CARYN RABIN, "Disparities: Study Finds Risk in Off-Label Prescribing"[http://www.nytimes.com/2009/08/25/health/research/25disp.html?ref=science]</ref> It is fast acting, and useful in treating fast onset panic anxiety.<ref name="pmid6144459">{{Cite journal|author=Lader M |title=Short-term versus long-term benzodiazepine therapy |journal=Current Med Res Opin |volume=8 Suppl 4 |issue= |pages=120–6 |year=1984 |pmid=6144459 |doi=}}</ref>


<!-- History, society, and culture -->
Lorazepam has strong [[sedative]]/[[hypnotic]] effects, and the duration of clinical effects from a single dose makes it an appropriate choice for the short-term treatment of [[insomnia]], in particular in the presence of severe anxiety. It has a fairly short duration of action (Venable and Aschenbrenner 2009). Withdrawal symptoms, including [[rebound insomnia]] and [[rebound anxiety]], may occur after only 7 days' administration of lorazepam.<ref>{{Cite journal| doi =10.1038/clpt.1982.27| journal =Clin Pharmacol Ther| year =1982| month =February| volume =31| issue =2| pages =175–9| title =Lorazepam-efficacy, side effects, and rebound phenomena| author =Scharf MB| coauthors =Kales A, Bixler EO, Jacoby JA, Schweitzer PK| pmid =6120058}}</ref>
Lorazepam was initially patented in 1963 and went on sale in the United States in 1977.<ref>{{cite book| vauthors = Shorter E |title=A Historical Dictionary of Psychiatry|date=2005|publisher=Oxford University Press|isbn=978-0-19-029201-0|chapter-url=https://books.google.com/books?id=juAJCAAAQBAJ&pg=PT66|chapter=B|url-status=live|archive-url=https://web.archive.org/web/20170328043221/https://books.google.com/books?id=juAJCAAAQBAJ&pg=PT66|archive-date=28 March 2017}}</ref><ref>{{cite patent |country=US |number=3296249 |status=patent |title=5-monocyclic aryl-1, 3-dihydro-2h-1, 4-benzodiazepin-2-ones |pubdate=1967-01-03 |gdate=1967-01-03 |fdate=1963-06-04 |pridate=1963-06-04 |invent1=Stanley C. Bell |assign1=American Home Products |url=https://worldwide.espacenet.com/publicationDetails/biblio?II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=19670103&CC=US&NR=3296249A&KC=A}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is available as a [[Generic drug|generic medication]].<ref name=AHSP2016/> In 2021, it was the 78th most commonly prescribed medication in the United States, with more than 8{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Lorazepam - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Lorazepam | access-date = 14 January 2024}}</ref>


== Medical uses ==
Lorazepam is sometimes used for individuals receiving [[mechanical ventilation]]. However, in critically ill patients, [[propofol]] has been found to be superior to lorazepam both in effectiveness and overall cost; as a result, the use of propofol for this indication is now encouraged, whereas the use of lorazepam for this indication is discouraged.<ref name="Cox-2008">{{Cite journal| last1 = Cox | first1 = CE. | last2 = Reed | first2 = SD. | last3 = Govert | first3 = JA. | last4 = Rodgers | first4 = JE. | last5 = Campbell-Bright | first5 = S. | last6 = Kress | first6 = JP. | last7 = Carson | first7 = SS. | title = Economic evaluation of propofol and lorazepam for critically ill patients undergoing mechanical ventilation. | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763279/pdf/nihms112536.pdf | format = PDF | journal = Crit Care Med | volume = 36 | issue = 3 | pages = 706–14 | month = Mar | year = 2008 | doi = 10.1097/CCM.0B013E3181544248 | pmc = 2763279 | pmid = 18176312 }}</ref>
===Anxiety===
Lorazepam is used in the short-term management of severe anxiety. In the US, the FDA advises against use of benzodiazepines such as lorazepam for longer than four weeks.<ref name=Altrx2007 /><ref>{{ cite news | author = Rabin RC | title = Disparities: Study Finds Risk in Off-Label Prescribing | url = https://www.nytimes.com/2009/08/25/health/research/25disp.html | newspaper = [[The New York Times]] | page = D6 | date = 25 August 2009 | url-status=live | archive-url = https://web.archive.org/web/20170219121327/http://www.nytimes.com/2009/08/25/health/research/25disp.html | archive-date = 19 February 2017 }}</ref> It is fast acting, and useful in treating fast onset panic anxiety.<ref name="pmid6144459">{{Cite journal | author = Lader M | title = Short-term versus long-term benzodiazepine therapy | journal = Current Medical Research and Opinion | year = 1984 | volume = 8 | issue = Suppl 4 | pages = 120–126 | pmid = 6144459 | doi=10.1185/03007998409109550}}</ref>


Lorazepam can effectively reduce agitation and induce sleep, and the duration of effects from a single dose makes it an appropriate choice for the short-term treatment of [[insomnia]], especially in the presence of severe anxiety or night terrors. It has a fairly short duration of action.<ref>{{Cite book | vauthors = Aschenbrenner DS, Venable SJ |date=2009 |title=Drug Therapy in Nursing |edition=3rd |url=https://books.google.com/books?id=5zd_W_PUwvYC |location=Philadelphia |page=[https://books.google.com/books?id=5zd_W_PUwvYC&pg=PA273 273] |publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins |isbn=978-0-7817-6587-9 |oclc=173659630 |url-status=live |archive-url=https://web.archive.org/web/20160419091521/https://books.google.com/books?id=5zd_W_PUwvYC |archive-date=19 April 2016 }}</ref>
Its relatively potent amnesic effect,<ref name="Hindmarch"/> with its anxiolytic and sedative effects, makes lorazepam useful as [[premedication]]. It is given before a general anaesthetic to reduce the amount of anaesthetic agent required, or before unpleasant awake procedures, such as in dentistry or endoscopies, to reduce anxiety, to increase compliance, and to induce amnesia for the procedure. Oral lorazepam is given 90 to 120 minutes before procedures, and [[intravenous]] lorazepam as late as 10 minutes before procedures.<ref name="pmid8625666">Maltais F, Laberge F, Laviolette M (1996). {{PDFlink|[http://www.chestjournal.org/cgi/reprint/109/5/1195.pdf "A randomized, double-blind, placebo-controlled study of lorazepam as premedication for bronchoscopy".]|963&nbsp;KB}} ''Chest'' '''109''' (5): 1195–8. PMID 8625666.</ref><ref name="pmid238548">{{Cite journal|author=Heisterkamp DV, Cohen PJ |title=The effect of intravenous premedication with lorazepam (Ativan), pentobarbitone or diazepam on recall |journal=Br J Anaesth |volume=47 |issue=1 |pages=79–81 |year=1975 |pmid=238548|doi=10.1093/bja/47.1.79}}</ref><ref name="Tsui-2004">{{Cite journal| last1 = Tsui | first1 = BC. | last2 = Wagner | first2 = A. | last3 = Finucane | first3 = B. | title = Regional anaesthesia in the elderly: a clinical guide. | journal = Drugs Aging | volume = 21 | issue = 14 | pages = 895–910 | year = 2004 | doi = | pmid = 15554749 }}</ref> Lorazepam is sometimes used as an alternative to [[midazolam]] in [[palliative sedation]].<ref name="Verhagen-2005">{{Cite journal| last1 = Verhagen | first1 = EH. | last2 = Hesselmann | first2 = GM. | last3 = Besse | first3 = TC. | last4 = de Graeff | first4 = A. | title = [Palliative sedation] | journal = Ned Tijdschr Geneeskd | volume = 149 | issue = 9 | pages = 458–61 | month = Feb | year = 2005 | doi = | pmid = 15771339 }}</ref> In [[intensive care units]] lorazepam is sometimes used to produce [[anxiolysis]], [[hypnosis]], and [[amnesia]].<ref name="Arcangeli-2005">{{Cite journal| last1 = Arcangeli | first1 = A. | last2 = Antonelli | first2 = M. | last3 = Mignani | first3 = V. | last4 = Sandroni | first4 = C. | title = Sedation in PACU: the role of benzodiazepines. | journal = Curr Drug Targets | volume = 6 | issue = 7 | pages = 745–8 | month = Nov | year = 2005 | doi = 10.2174/138945005774574416| pmid = 16305452 }}</ref>


Withdrawal symptoms, including [[Rebound effect|rebound insomnia and rebound anxiety]], may occur after seven days' use of lorazepam.<ref>{{Cite journal |vauthors=Scharf MB, Kales A, Bixler EO, Jacoby JA, Schweitzer PK | title = Lorazepam-efficacy, side effects, and rebound phenomena | journal = Clinical Pharmacology and Therapeutics | year = 1982 | volume = 31 | issue = 2 | pages = 175–179 | doi = 10.1038/clpt.1982.27 | pmid = 6120058 | s2cid = 464310 }}</ref>
Intravenous [[diazepam]] or lorazepam are first-line treatments for convulsive [[status epilepticus]].<ref name="Walker-2005">{{Cite journal| last1 = Walker | first1 = M. | title = Status epilepticus: an evidence based guide. | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1226249/pdf/bmj33100673.pdf | format = PDF | journal = BMJ | volume = 331 | issue = 7518 | pages = 673–7 | month = Sep | year = 2005 | doi = 10.1136/bmj.331.7518.673 | pmc = 1226249 | pmid = 16179702 }}</ref><ref>{{Cite journal| last1 = Walker | first1 = M. | title = Status epilepticus: an evidence based guide. | journal = BMJ | volume = 331 | issue = 7518 | pages = 673–7 | month = Sep | year = 2005 | doi = 10.1136/bmj.331.7518.673 | pmc = 1226249 | pmid = 16179702 }}</ref> Lorazepam is more effective than diazepam in the treatment of status epilepticus.<ref name="Prasad-2005">{{Cite journal| last1 = Prasad | first1 = K. | last2 = Al-Roomi | first2 = K. | last3 = Krishnan | first3 = PR. | last4 = Sequeira | first4 = R. | last5 = Prasad | first5 = Kameshwar | title = Anticonvulsant therapy for status epilepticus. | url = http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003723/pdf_fs.html | journal = Cochrane Database Syst Rev | volume = | issue = 4 | pages = CD003723 | month = | year = 2005 | doi = 10.1002/14651858.CD003723.pub2 | pmid = 16235337 }}</ref> However, [[phenobarbitol]] has a superior success rate compared to lorazepam and other drugs, at least in the elderly.<ref name="Treiman-2006">{{Cite journal| last1 = Treiman | first1 = DM. | last2 = Walker | first2 = MC. | title = Treatment of seizure emergencies: convulsive and non-convulsive status epilepticus. | journal = Epilepsy Res | volume = 68 Suppl 1 | issue = | pages = S77–82 | month = Jan | year = 2006 | doi = 10.1016/j.eplepsyres.2005.07.020 | pmid = 16384688 }}</ref><ref name="Treiman-2007">{{Cite journal| last1 = Treiman | first1 = DM. | title = Treatment of convulsive status epilepticus. | journal = Int Rev Neurobiol | volume = 81 | pages = 273–85 | year = 2007 | doi = 10.1016/S0074-7742(06)81018-4 | pmid = 17433931 }}</ref>


===Seizures===
The marked anticonvulsant properties of lorazepam, and its [[pharmacokinetic profile]], make intravenous lorazepam a reliable agent for terminating [[status epilepticus|acute seizures]], but it has relatively prolonged sedation after-effects. Oral lorazepam, and other benzodiazepines, have a role in long-term [[prophylactic]] treatment of resistant forms of [[epilepsy|petit mal epilepsy]], but not as first-line therapies, mainly because of the development of [[Drug tolerance|tolerance]] to their effects.<ref>{{Cite journal| last = Isojärvi | first = JI | coauthors = Tokola RA. | year = 1998 | month = December | title = Benzodiazepines in the treatment of epilepsy in people with intellectual disability | journal = J Intellect Disabil Res. | volume = 42 | issue = 1 | pages = 80–92 | pmid = 10030438 }}</ref>
[[File:Lorazepam-3mg.jpg|thumb|Lorazepam 3mg scored tablets in a blister pack.]]
Intravenous [[diazepam]] or lorazepam are first-line treatments for convulsive [[status epilepticus]].<ref name="Walker-2005">{{Cite journal| author = Walker M | title = Status epilepticus: an evidence based guide | journal = BMJ | year = 2005 | volume = 331 | issue = 7518 | pages = 673–677 | doi = 10.1136/bmj.331.7518.673 | pmc = 1226249 | pmid = 16179702 }}</ref> Lorazepam is more effective than diazepam and intravenous [[phenytoin]] in the treatment of status epilepticus and has a lower risk of continuing seizures that might require additional medication.<ref>{{cite journal | vauthors = Prasad M, Krishnan PR, Sequeira R, Al-Roomi K | title = Anticonvulsant therapy for status epilepticus | journal = The Cochrane Database of Systematic Reviews | issue = 9 | pages = CD003723 | date = September 2014 | volume = 2014 | pmid = 25207925 | pmc = 7154380 | doi = 10.1002/14651858.CD003723.pub3 }}</ref> However, [[phenobarbital]] has a superior success rate compared to lorazepam and other drugs, at least in the elderly.<ref name="Treiman-2006">{{Cite journal|vauthors=Treiman DM, Walker MC | title = Treatment of seizure emergencies: convulsive and non-convulsive status epilepticus | journal = Epilepsy Research | year = 2006 | volume = 68 | issue = Suppl 1 | pages = S77–S82 | doi = 10.1016/j.eplepsyres.2005.07.020 | pmid = 16384688 | s2cid = 22205104 }}</ref><ref name="Treiman-2007">{{Cite book | author = Treiman DM | title = The Neurobiology of Epilepsy and Aging | chapter = Treatment of convulsive status epilepticus | year = 2007 | volume = 81 | pages = [https://archive.org/details/neurobiologyofep0000rams/page/273 273–285] | doi = 10.1016/S0074-7742(06)81018-4 | pmid = 17433931 | isbn = 978-0-12-374018-2 | series = International Review of Neurobiology | s2cid = 24523838 | chapter-url = https://archive.org/details/neurobiologyofep0000rams/page/273 }}</ref>


Lorazepam's [[anticonvulsant]] properties and [[Pharmacokinetics|pharmacokinetic profile]] make intravenous use reliable for terminating [[status epilepticus|acute seizures]], but induce prolonged sedation. Oral benzodiazepines, including lorazepam, are occasionally used as long-term [[Preventive healthcare|prophylactic]] treatment of resistant [[absence seizure]]s; because of gradual [[Drug tolerance|tolerance]] to their anti-seizure effects, benzodiazepines such as lorazepam are not considered first-line therapies. Additionally, common seizure characteristics (hypersalivation, jaw-clenching, involuntary swallowing, etc.) pose some difficulties with regard to oral administration.<ref>{{cite journal | vauthors = Isojärvi JI, Tokola RA | title = Benzodiazepines in the treatment of epilepsy in people with intellectual disability | journal = Journal of Intellectual Disability Research | volume = 42 | issue = 1 | pages = 80–92 | date = December 1998 | pmid = 10030438 }}</ref><ref>{{cite journal | vauthors = Kienitz R, Kay L, Beuchat I, Gelhard S, von Brauchitsch S, Mann C, Lucaciu A, Schäfer JH, Siebenbrodt K, Zöllner JP, Schubert-Bast S, Rosenow F, Strzelczyk A, Willems LM | display-authors = 6 | title = Benzodiazepines in the Management of Seizures and Status Epilepticus: A Review of Routes of Delivery, Pharmacokinetics, Efficacy, and Tolerability | journal = CNS Drugs | volume = 36 | issue = 9 | pages = 951–975 | date = September 2022 | pmid = 35971024 | doi = 10.1007/s40263-022-00940-2 | pmc = 9477921 }}</ref>
Lorazepam's anticonvulsant and CNS depressant properties are useful for the treatment and prevention of [[alcohol withdrawal syndrome]]. In this setting, it is relevant that impaired liver function is not a hazard with lorazepam since lorazepam does not require oxidation, hepatic or otherwise, for its metabolism.<ref name="pmid8700792"/><ref name="Bråthen-2005">{{Cite journal| last1 = Bråthen | first1 = G. | last2 = Ben-Menachem | first2 = E. | last3 = Brodtkorb | first3 = E. | last4 = Galvin | first4 = R. | last5 = Garcia-Monco | first5 = JC. | last6 = Halasz | first6 = P. | last7 = Hillbom | first7 = M. | last8 = Leone | first8 = MA. | last9 = Young | first9 = AB. | title = EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force. | journal = Eur J Neurol | volume = 12 | issue = 8 | pages = 575–81 | month = Aug | year = 2005 | doi = 10.1111/j.1468-1331.2005.01247.x | pmid = 16053464 }}</ref>


Lorazepam's anticonvulsant and CNS depressant properties are useful for the treatment and prevention of [[alcohol withdrawal syndrome]]. In this setting, impaired liver function is not a hazard with lorazepam, since lorazepam does not require oxidation, in the liver or otherwise, for its metabolism. Lorazepam is noted as being the most tolerable benzodiazepine in those with advanced-stage liver disease.<ref name="pmid8700792" /><ref name="Bråthen-2005">{{Cite journal|vauthors=Bråthen G, Ben-Menachem E, Brodtkorb E, Galvin R, Garcia-Monco JC, Halasz P, Hillbom M, Leone MA, Young AB | title = EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force | journal = European Journal of Neurology | year = 2005 | volume = 12 | issue = 8 | pages = 575–581 | doi = 10.1111/j.1468-1331.2005.01247.x | pmid = 16053464 | s2cid = 25904252 | doi-access = free }}</ref><ref>{{Cite book|title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet] |chapter=Lorazepam |date=2012 |url=https://www.ncbi.nlm.nih.gov/books/NBK548563/ |publisher=Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases|pmid=31643878 }}</ref>
Lorazepam is sometimes used as an alternative to [[haloperidol]] when there is the need for [[sedation|rapid sedation]] of violent or agitated individuals,<ref name="Battaglia-2005">{{Cite journal| last1 = Battaglia | first1 = J. | title = Pharmacological management of acute agitation. | journal = Drugs | volume = 65 | issue = 9 | pages = 1207–22 | month = | year = 2005 | doi = 10.2165/00003495-200565090-00003| pmid = 15916448 }}</ref><ref name="Zoupanos-2005">{{Cite journal| last1 = Zoupanos | first1 = BN. | last2 = Bryois | first2 = C. | title = [Treatment of agitation in the emergency room] | journal = Rev Med Suisse | volume = 1 | issue = 27 | pages = 1810–3 | month = Jul | year = 2005 | doi = | pmid = 16119296 }}</ref> but haloperidol plus promethazine is preferred due to better effectiveness and due to lorazepam's adverse effects on respiratory function.<ref name="Huf-2005">{{Cite journal| last1 = Huf | first1 = G. | last2 = Alexander | first2 = J. | last3 = Allen | first3 = MH. | last4 = Raveendran | first4 = Nirmal S | last5 = Huf | first5 = Gisele | title = Haloperidol plus promethazine for psychosis induced aggression. | journal = Cochrane Database Syst Rev | volume = | issue = 1 | pages = CD005146 | url = http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD005146/pdf_fs.html | format = PDF | year = 2005 | doi = 10.1002/14651858.CD005146 | pmid = 15654706 }}</ref> However, adverse effects such as behavioural disinhibition may make benzodiazepines inappropriate for some acutely psychotic patients.<ref name="Gillies-2005">{{Cite journal| last1 = Gillies | first1 = D. | last2 = Beck | first2 = A. | last3 = McCloud | first3 = A. | last4 = Rathbone | first4 = J. | last5 = Gillies | first5 = D. | title = Benzodiazepines alone or in combination with antipsychotic drugs for acute psychosis. | url = http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003079/pdf_fs.html | journal = Cochrane Database Syst Rev | volume = | issue = 4 | pages = CD003079 | month = | year = 2005 | doi = 10.1002/14651858.CD003079.pub2 | pmid = 16235313 }}</ref> Acute [[delirium]] is sometimes treated with lorazepam, but as it can cause [[paradoxical effects]], it is preferably given together with [[haloperidol]].<ref name="pmid9469682">{{Cite journal|author=Bieniek SA, Ownby RL, Penalver A, Dominguez RA |title=A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation |journal=Pharmacotherapy |volume=18 |issue=1 |pages=57–62 |year=1998 |pmid=9469682 |doi=}}</ref> Lorazepam is absorbed relatively slowly if given intramuscularly, a common route in restraint situations.


===Sedation===
[[Catatonia]] with inability to speak is responsive and sometimes controlled with a single 2&nbsp;mg oral, or slow intravenous dose of lorazepam. Symptoms may recur and treatment for some days may be necessary. Catatonia due to abrupt or too rapid withdrawal from benzodiazepines, as part of the [[benzodiazepine withdrawal syndrome]], should also respond to lorazepam treatment.<ref>{{Cite journal|author=Rosebush PI, Mazurek MF |title=Catatonia after benzodiazepine withdrawal |journal=Journal of clinical psychopharmacology |volume=16 |issue=4 |pages=315–9 |year=1996 |pmid=8835707|doi=10.1097/00004714-199608000-00007}}</ref> As lorazepam can have paradoxical effects, [[haloperidol]] is sometimes given [[concomitantly]].<ref name="pmid9469682"/><ref name="pmid16956088">{{Cite journal|author=Van Dalfsen AN, Van Den Eede F, Van Den Bossche B, Sabbe BG |title=[Benzodiazepines in the treatment of catatonia] |language=Dutch; Flemish |journal=Tijdschrift voor psychiatrie |volume=48 |issue=3 |pages=235–9 |year=2006 |pmid=16956088 |doi=}}</ref>
Lorazepam is sometimes used for individuals receiving [[mechanical ventilation]]. However, in critically ill people, [[propofol]] has been found to be superior to lorazepam both in effectiveness and overall cost; as a result, the use of propofol for this indication is now encouraged, whereas the use of lorazepam is discouraged.<ref name="Cox-2008">{{Cite journal |vauthors=Cox CE, Reed SD, Govert JA, Rodgers JE, Campbell-Bright S, Kress JP, Carson SS | title = An Economic Evaluation of Propofol and Lorazepam for Critically Ill Patients Undergoing Mechanical Ventilation | journal = Critical Care Medicine | year = 2008 | volume = 36 | issue = 3 | pages = 706–714 | doi = 10.1097/CCM.0B013E3181544248 | pmc = 2763279 | pmid = 18176312 }}</ref>


Its relative effectiveness in preventing new memory formation,<ref name="Hindmarch">{{cite web| author = Hindmarch I | title = Benzodiazepines and their effects | url = http://www.benzo.org.uk/hindmarch.htm | publisher = benzo.org.uk | date = 30 January 1997 | access-date = 13 May 2007}}</ref> along with its ability to reduce agitation and anxiety, makes lorazepam useful as [[premedication]]. It is given before a general anesthetic to reduce the amount of anesthetic required, or before unpleasant awake procedures, such as in dentistry or endoscopies, to reduce anxiety, to increase compliance, and to induce amnesia for the procedure. Lorazepam by mouth is given 90 to 120 minutes before procedures, and [[Intravenous therapy|intravenous]] lorazepam as late as 10 minutes before procedures.<ref name="pmid8625666">{{ cite journal | vauthors = Maltais F, Laberge F, Laviolette M | title = A randomized, double-blind, placebo-controlled study of lorazepam as premedication for bronchoscopy | journal = Chest | year = 1996 | volume = 109 | issue = 5 | pages = 1195–1198 | pmid = 8625666 | url = http://www.chestjournal.org/cgi/reprint/109/5/1195.pdf | doi = 10.1378/chest.109.5.1195 | url-status=dead | archive-url = https://web.archive.org/web/20080407224136/http://www.chestjournal.org/cgi/reprint/109/5/1195.pdf | archive-date = 7 April 2008 }}</ref><ref name="pmid238548">{{Cite journal |vauthors=Heisterkamp DV, Cohen PJ | title = The effect of intravenous premedication with lorazepam (Ativan), pentobarbital or diazepam on recall | journal = British Journal of Anaesthesiology | year = 1975 | volume = 47 | issue = 1 | pages = 79–81 | pmid = 238548 | doi = 10.1093/bja/47.1.79 | doi-access = free }}</ref><ref name="Tsui-2004">{{ Cite journal |vauthors=Tsui BC, Wagner A, Finucane B | title = Regional anaesthesia in the elderly: a clinical guide | journal = Drugs Aging | year = 2004 | volume = 21 | issue = 14 | pages = 895–910 | doi = 10.2165/00002512-200421140-00001| pmid = 15554749 | s2cid = 68771929 }}</ref> Lorazepam is sometimes used as an alternative to [[midazolam]] in [[palliative sedation]].<ref name="Verhagen-2005">{{Cite journal |vauthors=Verhagen EH, Hesselmann GM, Besse TC, de Graeff A |title=(title in Dutch) | trans-title = Palliative sedation | language=nl | journal = Nederlands Tijdschrift voor Geneeskunde | year = 2005 | volume = 149 | issue = 9 | pages = 458–461 | pmid = 15771339 }}</ref> In [[intensive care unit]]s lorazepam is sometimes used to produce [[Anxiolytic|anxiolysis]], [[hypnosis]], and [[amnesia]].<ref name="Arcangeli-2005">{{Cite journal |vauthors=Arcangeli A, Antonelli M, Mignani V, Sandroni C | title = Sedation in PACU: the role of benzodiazepines | journal = Current Drug Targets | year = 2005 | volume = 6 | issue = 7 | pages = 745–748 | doi = 10.2174/138945005774574416 | pmid = 16305452 }}</ref>
It is sometimes used in [[chemotherapy]] as an adjunct to [[antiemetic]]s for treating anticipatory [[nausea]] and [[vomiting]], i.e. nausea and vomiting caused or worsened by psychological sensitization to the thought of being sick.<ref name="pmid15888767">Herrstedt J, Aapro MS, Roila F, Kataja VV (2005). {{PDFlink|[http://annonc.oxfordjournals.org/cgi/reprint/16/suppl_1/i77.pdf "ESMO Minimum Clinical Recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (NV)".]|32.4&nbsp;KB}} ''Ann Oncol'' '''16 Suppl 1''': i77–9. PMID 15888767. {{doi|10.1093/annonc/mdi805}}</ref> It is also used as adjunct therapy for [[cyclic vomiting syndrome]].


===Agitation===
Also used to treat acute symptoms of vertigo and dizziness for people with [[Ménière's disease]].
Lorazepam is sometimes used as an alternative to [[haloperidol]] when there is the need for rapid [[sedation]] of violent or agitated individuals,<ref name="Battaglia-2005">{{cite journal | vauthors = Battaglia J | title = Pharmacological management of acute agitation | journal = Drugs | volume = 65 | issue = 9 | pages = 1207–1222 | year = 2005 | pmid = 15916448 | doi = 10.2165/00003495-200565090-00003 | s2cid = 692414 }}</ref><ref name="Zoupanos-2005">{{cite journal | vauthors = Zoupanos BN, Bryois C | title = [Treatment of agitation in the emergency room] | language = fr | journal = Revue Médicale Suisse | volume = 1 | issue = 27 | pages = 1810–1813 | date = July 2005 | pmid = 16119296 | trans-title = Treatment of agitation in the emergency room }}</ref> but haloperidol plus promethazine is preferred due to better effectiveness and due to lorazepam's adverse effects on respiratory function.<ref>{{cite journal | vauthors = Huf G, Alexander J, Gandhi P, Allen MH | title = Haloperidol plus promethazine for psychosis-induced aggression | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 11 | pages = CD005146 | date = November 2016 | pmid = 27885664 | pmc = 6464403 | doi = 10.1002/14651858.CD005146.pub3 }}</ref> However, adverse effects such as behavioral disinhibition may make benzodiazepines inappropriate for some people who are acutely psychotic.<ref name=":0">{{cite journal | vauthors = Gillies D, Sampson S, Beck A, Rathbone J | title = Benzodiazepines for psychosis-induced aggression or agitation | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD003079 | date = April 2013 | pmid = 23633309 | doi = 10.1002/14651858.CD003079.pub3 | doi-access = free | hdl = 10454/16512 | hdl-access = free }}</ref> Acute [[delirium]] is sometimes treated with lorazepam, but as it can cause [[Paradoxical reaction|paradoxical effects]], it is preferably given together with haloperidol.<ref name= pmid9469682>{{cite journal | vauthors = Bieniek SA, Ownby RL, Penalver A, Dominguez RA | title = A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation | journal = Pharmacotherapy | volume = 18 | issue = 1 | pages = 57–62 | year = 1998 | pmid = 9469682 | doi = 10.1002/j.1875-9114.1998.tb03827.x | s2cid = 24505811 }}</ref> Lorazepam is absorbed relatively slowly if given intramuscularly, a common route in restraint situations.


===Other===
==Formulation and administration==
[[Catatonia]] with inability to speak is responsive to lorazepam. Symptoms may recur and treatment for some days may be necessary. Catatonia due to abrupt or overly rapid withdrawal from benzodiazepines, as part of the [[benzodiazepine withdrawal syndrome]], should also respond to lorazepam treatment.<ref>{{Cite journal |vauthors=Rosebush PI, Mazurek MF | title = Catatonia after benzodiazepine withdrawal | journal = Journal of Clinical Psychopharmacology | year = 1996 | volume = 16 | issue = 4 | pages = 315–319 | pmid = 8835707 | doi = 10.1097/00004714-199608000-00007 }}</ref> As lorazepam can have paradoxical effects, [[haloperidol]] is sometimes given at the same time.<ref name="pmid9469682" /><ref name="pmid16956088">{{Cite journal |vauthors=van Dalfsen AN, van den Eede F, van den Bossche B, Sabbe BG |title=(title in Dutch) | trans-title = Benzodiazepines in the treatment of catatonia | language=nl | journal = Tijdschrift voor Psychiatrie | year = 2006 | volume = 48 | issue = 3 | pages = 235–239 | pmid = 16956088 }}</ref>
[[Image:Ativan05mg.jpg|thumb|right|0.5mg tablets of the Ativan brand of lorazepam.]]
Pure lorazepam is an almost white powder that is nearly insoluble in water and oil. In medicinal form, lorazepam is mainly available as tablets and a solution for injection, but, in some locations, it is also available as a skin patch, an oral solution, and a [[sublingual]] tablet.


It is sometimes used in [[chemotherapy]] in addition to [[antiemetic|medications used to treat nausea and vomiting]], i.e. nausea and vomiting caused or worsened by psychological sensitization to the thought of being sick.<ref name="pmid15888767">{{cite journal | vauthors = Herrstedt J, Aapro MS, Roila F, Kataja VV | title = ESMO Minimum Clinical Recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (NV) | journal = Annals of Oncology | volume = 16 | issue = Suppl 1 | pages = i77–i79 | year = 2005 | pmid = 15888767 | doi = 10.1093/annonc/mdi805 | doi-access = free }}</ref>
Lorazepam tablets and syrups are administered by mouth only. The tablets contain 0.5&nbsp;mg, 1&nbsp;mg, or 2&nbsp;mg lorazepam, with some differences between countries. Lorazepam tablets of the Ativan brand also contain [[lactose]], [[cellulose|microcrystalline cellulose]], [[polacrilin|polacrilin potassium]], [[magnesium stearate]], and colouring agents (indigo carmine—[[E132]]—in blue tablets and tartrazine—[[E102]]— in yellow tablets).


== Adverse effects ==
Lorazepam injectable solution is administered either by deep [[intramuscular injection]] or by [[intravenous therapy|intravenous]] injection. The injectable solution comes in 1 mL [[ampoule]]s containing 2&nbsp;mg or 4&nbsp;mg lorazepam. The solvents used are [[polyethylene glycol|polyethylene glycol 400]] and [[propylene glycol]]. As a preservative, the injectable solution contains [[benzyl alcohol]].<ref>[http://www.baxter.com/products/anesthesia/anesthetic_pharmaceuticals/downloads/ativan.pdf baxter.com - Lorazepam Injection Data Sheet]</ref> Toxicity from propylene glycol has been reported in the case of a patient receiving a continuous lorazepam infusion.<ref name="pmid14524641">{{Cite journal|author=Yaucher NE, Fish JT, Smith HW, Wells JA |title=Propylene glycol-associated renal toxicity from lorazepam infusion |journal=Pharmacotherapy |volume=23 |issue=9 |pages=1094–9 |year=2003 |pmid=14524641|doi=10.1592/phco.23.10.1094.32762 }}</ref> Intravenous injections should be given slowly and patients closely monitored for side effects, such as respiratory depression, hypotension, or loss of airway control.
Many beneficial effects of lorazepam (e.g., sedative, muscle relaxant, anti-anxiety, and amnesic effects) may become adverse effects when unwanted.<ref name=" Hindmarch" /> Adverse effects can include sedation and [[hypotension|low blood pressure]]; the effects of lorazepam are increased in combination with other [[Central nervous system depression|CNS depressant]] drugs.<ref name="Walker-2005" /><ref name="Battaglia-2005" /> Other adverse effects include confusion, [[ataxia]], inhibiting the formation of new memories, pupil constriction and hangover effects. With [[Effects of long-term benzodiazepine use|long-term benzodiazepine use]] it is unclear whether cognitive impairments fully return to normal after stopping lorazepam use; cognitive deficits persist for at least six months after withdrawal, but longer than six months may be required for recovery of cognitive function. Lorazepam appears to have more profound adverse effects on memory than other benzodiazepines; it impairs both [[explicit memory|explicit]] and [[implicit memory]].<ref name="Bishop, Curran 1998">{{cite journal | vauthors = Bishop KI, Curran HV | title = An investigation of the effects of benzodiazepine receptor ligands and of scopolamine on conceptual priming | journal = Psychopharmacology | volume = 140 | issue = 3 | pages = 345–353 | date = December 1998 | pmid = 9877014 | doi = 10.1007/s002130050775 | s2cid = 21940883 }}</ref><ref name="Bishop, Curran 1995">{{cite journal | vauthors = Bishop KI, Curran HV | title = Psychopharmacological analysis of implicit and explicit memory: a study with lorazepam and the benzodiazepine antagonist flumazenil | journal = Psychopharmacology | volume = 121 | issue = 2 | pages = 267–278 | date = September 1995 | pmid = 8545533 | doi = 10.1007/bf02245638 | s2cid = 24371644 }}</ref> In the elderly, falls may occur as a result of benzodiazepines. Adverse effects are more common in the elderly, and they appear at lower doses than in younger people. Benzodiazepines can cause or worsen [[Major depressive disorder|depression]]. [[Paradoxical reaction|Paradoxical effects]] can also occur, such as worsening of seizures, or paradoxical excitement; paradoxical excitement is more likely to occur in the elderly, children, those with a history of alcohol abuse, and in people with a history of aggression or anger problems.<ref name="Riss-2008" /> Lorazepam's effects are dose-dependent, meaning the higher the dose, the stronger the effects (and side effects) will be. Using the smallest dose needed to achieve desired effects lessens the risk of adverse effects. Sedative drugs and sleeping pills, including lorazepam, 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 | doi-access = free }}</ref>


Sedation is the side effect people taking lorazepam most frequently report. In a group of around 3,500 people treated for anxiety, the most common side effects complained of from lorazepam were sedation (15.9%), dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). Side effects such as sedation and unsteadiness increased with age.<ref name=RxList>{{cite web | url = http://www.rxlist.com/cgi/generic/loraz_ad.htm | title = Ativan side effects | year = 2007 | access-date = 10 August 2007 | publisher = RxList | url-status=dead | archive-url = https://web.archive.org/web/20070821134741/http://www.rxlist.com/cgi/generic/loraz_ad.htm | archive-date = 21 August 2007 }}</ref> Cognitive impairment, behavioral disinhibition and respiratory depression as well as [[hypotension]] may also occur.<ref name="Arcangeli-2005" /><ref name=":0" />
Peak effects roughly coincide with peak serum levels,<ref name="pmid8232">{{Cite journal|author=Greenblatt DJ, Schillings RT, Kyriakopoulos AA, Shader RI, Sisenwine SF, Knowles JA, Ruelius HW |title=Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam |journal=Clin Pharmacol Ther |volume=20 |issue=3 |pages=329&ndash;41 |year=1976 |pmid=8232 |doi=}}</ref> which occur 10 minutes after intravenous injection, up to 60 minutes after intramuscular injection, and 90 to 120 minutes after oral administration,<ref name="pmid8232"/><ref name="Lorzem">{{Cite web| url = http://www.medsafe.govt.nz/Profs/Datasheet/l/Lorzemtab.htm | title = Lorzem Data Sheet | date = June 4, 1999 | publisher = New Zealand Medicines and Medical Devices Safety Authority | accessdate = 2007-05-13}}</ref> but initial effects will be noted before this. A clinically relevant lorazepam dose will normally be effective for 6 to 12 hours, making it unsuitable for regular once-daily administration, so it is usually prescribed as two to four daily doses when taken regularly.
* Paradoxical effects: In some cases, paradoxical effects can occur with benzodiazepines, such as increased hostility, aggression, angry outbursts, and psychomotor agitation. These effects are seen more commonly with lorazepam than with other benzodiazepines.<ref>{{Cite journal|vauthors=Sorel L, Mechler L, Harmant J | title = Comparative trial of intravenous lorazepam and clonazepam im status epilepticus | journal = Clinical Therapeutics | year = 1981 | volume = 4 | issue = 4 | pages = 326–336 | pmid = 6120763 }}</ref> Paradoxical effects are more likely to occur with higher doses, in people with pre-existing [[personality disorder]]s and those with a psychiatric illness. Frustrating stimuli may trigger such reactions, though the drug may have been prescribed to help the person cope with such stress and frustration in the first place. As paradoxical effects appear to be dose-related, they usually subside on dose reduction or on complete withdrawal of lorazepam.<ref name="pmid3137624">{{Cite journal |vauthors=Bond A, Lader M | title = Differential effects of oxazepam and lorazepam on aggressive responding | journal = Psychopharmacology | volume = 95 | issue = 3 | pages = 369–373 | year = 1988 | pmid = 3137624 | doi = 10.1007/BF00181949 | s2cid = 35313827 }}</ref><ref name="pmid15961964">{{Cite journal |vauthors=Pietras CJ, Lieving LM, Cherek DR, Lane SD, Tcheremissine OV, Nouvion S | title = Acute effects of lorazepam on laboratory measures of aggressive and escape responses of adult male parolees | journal = Behavioral Pharmacology | year = 2005 | volume = 16 | issue = 4 | pages = 243–251 | pmid = 15961964 | doi = 10.1097/01.fbp.0000170910.53415.77 | s2cid = 44387644 }}</ref><ref name="pmid12186578">{{Cite journal |vauthors=Kalachnik JE, Hanzel TE, Sevenich R, Harder SR | title = Benzodiazepine behavioral side effects: review and implications for individuals with mental retardation | journal = American Journal on Mental Retardation| year = 2002 | volume = 107 | issue = 5 | pages = 376–410 | pmid = 12186578 | doi = 10.1352/0895-8017(2002)107<0376:BBSERA>2.0.CO;2 | issn = 0895-8017 }}</ref><ref name="pmid15029082">{{Cite journal |vauthors=Michel L, Lang JP |title=(title in French) | trans-title = Benzodiazepines and forensic aspects | language=fr | journal = L'Encéphale | volume = 29 | issue = 6 | pages = 479–485 | year = 2003 | pmid = 15029082 }}</ref><ref>{{Cite journal | vauthors = Mancuso CE, Tanzi MG, Gabay M | title = Paradoxical reactions to benzodiazepines: literature review and treatment options | journal = Pharmacotherapy | year = 2004 | volume = 24 | issue = 9 | pages = 1177–1185 | pmid = 15460178 | doi = 10.1592/phco.24.13.1177.38089 | s2cid = 38614605 | url = http://www.medscape.com/viewarticle/489358 | url-status=live | archive-url = https://web.archive.org/web/20121213142837/http://www.medscape.com/viewarticle/489358 | archive-date = 13 December 2012 }}</ref><ref name="pmid15198">{{Cite journal | author = Goldney RD | title = Paradoxical reaction to a new minor tranquilizer | journal = Medical Journal of Australia | year = 1977 | volume = 1 | issue = 5 | pages = 139–140 | pmid = 15198 | doi = 10.5694/j.1326-5377.1977.tb130567.x | s2cid = 78865613 }}</ref>
* Suicidality: Benzodiazepines are associated with increased risk of suicide, possibly due to [[disinhibition]].<ref name=Doc2017/> Higher dosages appear to confer greater risk.
* Amnesic effects: Among benzodiazepines, lorazepam has relatively strong [[anterograde amnesia|amnesic]] effects,<ref name="Hindmarch" /><ref name="pmid15483562">{{Cite journal | vauthors = Izaute M, Bacon E | title = Specific effects of an amnesic drug: effect of lorazepam on study time allocation and on judgment of learning | journal = Neuropsychopharmacology | volume = 30 | issue = 1 | pages = 196–204 | year = 2005 | pmid = 15483562 | doi = 10.1038/sj.npp.1300564 | s2cid = 18103662 | doi-access = free }}</ref> but people soon develop tolerance to this with regular use. To avoid amnesia (or excess sedation) being a problem, the initial total daily lorazepam dose should not exceed 2&nbsp;mg. This also applies to use for night sedation. Five participants in a sleep study were prescribed lorazepam 4&nbsp;mg at night, and the next evening, three subjects unexpectedly volunteered memory gaps for parts of that day, an effect that subsided completely after two to three days' use.<ref name="pmid6120058">{{Cite journal |vauthors=Scharf MB, Kales A, Bixler EO, Jacoby JA, Schweitzer PK | title = Lorazepam-efficacy, side-effects, and rebound phenomena | journal = Clinical Pharmacology and Therapeutics | year = 1982 | volume = 31 | issue = 2 | pages = 175–179 | pmid = 6120058 | doi = 10.1038/clpt.1982.27 | s2cid = 464310 }}</ref> Amnesic effects cannot be estimated from the degree of sedation present, since the two effects are unrelated.
* High-dose or prolonged parenterally-administered lorazepam with its associated [[propylene glycol|solvent]] can cause propylene glycol intoxication and poisoning.<ref name="Arcangeli-2005" /><ref name="Riker-2005">{{Cite journal |vauthors=Riker RR, Fraser GL | title = Adverse events associated with sedatives, analgesics, and other drugs that provide patient comfort in the intensive care unit | journal = Pharmacotherapy | year = 2005 | volume = 25 | issue = 5 Pt 2 | pages = 8S–18S | doi = 10.1592/phco.2005.25.5_Part_2.8S | pmid = 15899744 | s2cid = 24789150 }}</ref>


In September 2020, the U.S. [[Food and Drug Administration]] (FDA) required the [[boxed warning]] be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.<ref>{{cite web | title=FDA expands Boxed Warning to improve safe use of benzodiazepine drug | website=U.S. [[Food and Drug Administration]] (FDA) | date=23 September 2020 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class | access-date=23 September 2020}} {{PD-notice}}</ref>
==Adverse effects==
Any of the five intrinsic benzodiazepine effects possessed by lorazepam (sedative/hypnotic, muscle relaxant, anxiolytic, amnesic, and anticonvulsant) may be considered as "adverse effects," or "side effects," if unwanted.<ref name="Hindmarch"/> Adverse effects can include, [[ataxia]], sedation and [[hypotension]]; the effects of lorazepam are increased in combination with other [[CNS depressant]] drugs.<ref name="Walker-2005"/><ref name="Battaglia-2005"/> Other adverse effects include confusion, [[ataxia]], [[anterograde amnesia]] and hangover effects. With [[long-term use of benzodiazepines]] it is unclear whether cognitive impairments fully return to normal after cessation of therapy; cognitive deficits persist for at least 6 months post-withdrawal, but it is possible that longer than 6 months is required for recovery of cognitive function. Lorazepam appears to have more profound adverse effects on memory than other benzodiazepines; lorazepam impairs both explicit memory and
implicit memory. In the elderly, falls may occur as a result of benzodiazepines. Adverse effects are more common in the elderly, and they appear at lower doses than in younger patients. Benzodiazepines can cause or worsen [[Major depression|depression]]. [[Paradoxical effects]] can also occur, such as worsening of seizures, or paradoxical excitement; paradoxical excitement is more likely to occur in the elderly, children, those with a history of alcohol abuse and in people with a history of aggression or anger problems.<ref name="Riss-2008"/> Lorazepam's effects are dose-dependent, meaning the higher the dose, the stronger the effects (and side effects) will be. Using the smallest dose needed to achieve desired effects lessens the risk of adverse effects.


=== Contraindications ===
Sedation is the most complained-of side effect. In a group of around 3500 patients treated for anxiety, the most common side effects complained of from lorazepam were sedation (15.9%), dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). Side effects such as sedation and unsteadiness increased with age.<ref name=RxList>{{Cite web| url = http://www.rxlist.com/cgi/generic/loraz_ad.htm | title = Ativan side effects | year = 2007 | accessdate = 2007-08-10 | publisher = RxList}}</ref> Cognitive impairment, behavioural disinhibition and respiratory depression as well as [[hypotension]] may also occur.<ref name="Arcangeli-2005"/><ref name="Gillies-2005"/>
{{more citations needed|section|date=June 2017}}
Lorazepam should be avoided in people with:
* [[Allergy]] or [[hypersensitivity]] – Past hypersensitivity or allergy to lorazepam, to any benzodiazepine, or to any of the ingredients in lorazepam tablets or injections
* [[Respiratory failure]] – Benzodiazepines, including lorazepam, may depress central nervous system respiratory drive and are contraindicated in severe respiratory failure. An example would be the inappropriate use to relieve anxiety associated with [[acute severe asthma]]. The anxiolytic effects may also be detrimental to a person's willingness and ability to fight for breath. However, if [[mechanical ventilation]] becomes necessary, lorazepam may be used to facilitate deep sedation.
* [[Substance intoxication|Acute intoxication]] – Lorazepam may interact synergistically with the effects of [[alcohol (drug)|alcohol]], narcotics, or other psychoactive substances. It should, therefore, not be administered to a drunk or intoxicated person.
* [[Ataxia]] – This is a neurological clinical sign, consisting of unsteady and clumsy motion of the limbs and torso, due to the failure of gross muscle movement coordination, most evident on standing and walking. It is the classic way in which acute alcohol intoxication may affect a person. Benzodiazepines should not be administered to people already-ataxic.
* Acute narrow-angle [[glaucoma]] – Lorazepam has pupil-dilating effects, which may further interfere with the drainage of [[aqueous humor]] from the anterior chamber of the eye, thus worsening narrow-angle [[glaucoma]].
* [[Sleep apnea]] – Sleep apnea may be worsened by lorazepam's central nervous system depressant effects. It may further reduce the person's ability to protect his or her airway during sleep.<ref>{{cite journal | vauthors = Guilleminault C | title = Benzodiazepines, breathing, and sleep | journal = The American Journal of Medicine | volume = 88 | issue = 3A | pages = 25S–28S | date = March 1990 | pmid = 1968716 | doi = 10.1016/0002-9343(90)90282-I }}</ref>
* [[Myasthenia gravis]] – This condition is characterized by muscle weakness, so a muscle relaxant such as lorazepam may exacerbate symptoms.
* [[Pregnancy]] and [[breastfeeding]] – Lorazepam belongs to the [[Food and Drug Administration]] (FDA) pregnancy category D, which means it is likely to cause harm to the developing baby if taken during the first trimester of pregnancy. The evidence is inconclusive whether lorazepam if taken early in pregnancy results in reduced intelligence, neurodevelopmental problems, physical malformations in cardiac or facial structure, or other malformations in some newborns. Lorazepam given to pregnant women antenatally may cause [[hypotonia|floppy infant syndrome]]<ref>{{Cite journal | author = Kanto JH | title = Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations | journal = Drugs | year = 1982 | volume = 23 | issue = 5 | pages = 354–380 | pmid = 6124415 | doi = 10.2165/00003495-198223050-00002 | s2cid = 27014006 }}</ref> in the neonate, or respiratory depression necessitating ventilation. Regular lorazepam use during late pregnancy (the [[third trimester]]), carries a definite risk of [[benzodiazepine withdrawal syndrome]] in the neonate. Neonatal benzodiazepine withdrawal may include [[hypotonia]], reluctance to suck, [[apneic]] spells, [[cyanosis]], and impaired [[metabolic]] responses to cold stress. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.<ref>{{Cite journal | author = McElhatton PR | title = The effects of benzodiazepine use during pregnancy and lactation | journal = Reproductive Toxicology | year = 1994 | volume = 8 | issue = 6 | pages = 461–475 | pmid = 7881198 | doi = 10.1016/0890-6238(94)90029-9 }}</ref> Lorazepam may also inhibit fetal liver bilirubin glucuronidation, leading to neonatal jaundice. Lorazepam is present in breast milk, so caution must be exercised about breastfeeding.


=== Specific groups ===
* '''Paradoxical effects:''' In some cases, there can be [[paradox]]ical effects with benzodiazepines, such as increased hostility, aggression, angry outbursts, and psychomotor agitation. These effects are seen as more common with lorazepam than other benzodiazepines.<ref>{{Cite journal| author = Sorel L | coauthors = Mechler L, Harmant J. | year = 1981 | title = Comparative trial of intravenous lorazepam and clonazepam im status epilepticus | journal = Clin Ther. | volume = 4 | issue = 4 | pages = 326–36 | pmid = 6120763 }}</ref> Paradoxical effects are more likely to occur with higher doses, in patients with pre-existing [[personality disorder]]s and those with a psychiatric illness. It is worth noting that frustrating stimuli may trigger such reactions, even though the drug may have been prescribed to help the patient cope with such stress and frustration in the first place. As paradoxical effects appear to be dose-related, they usually subside on dose reduction or on complete withdrawal of lorazepam.<ref name="pmid3137624">{{Cite journal|author=Bond A, Lader M |title=Differential effects of oxazepam and lorazepam on aggressive responding |journal=Psychopharmacology (Berl.) |volume=95 |issue=3 |pages=369–73 |year=1988 |pmid=3137624|doi=10.1007/BF00181949}}</ref><ref name="pmid15961964">{{Cite journal|author=Pietras CJ, Lieving LM, Cherek DR, Lane SD, Tcheremissine OV, Nouvion S |title=Acute effects of lorazepam on laboratory measures of aggressive and escape responses of adult male parolees |journal=Behav Pharmacol |volume=16 |issue=4 |pages=243–51 |year=2005 |pmid=15961964|doi=10.1097/01.fbp.0000170910.53415.77}}</ref><ref name="pmid12186578">{{Cite journal|author=Kalachnik JE, Hanzel TE, Sevenich R, Harder SR |title=Benzodiazepine behavioral side effects: review and implications for individuals with mental retardation |journal=Am J Ment Retard |volume=107 |issue=5 |pages=376–410 |year=2002 |pmid=12186578|doi=10.1352/0895-8017(2002)107<0376:BBSERA>2.0.CO;2}}</ref><ref name="pmid15029082">{{Cite journal|author=Michel L, Lang JP |title=[Benzodiazepines and forensic aspects] |language=French |journal=L'Encéphale |volume=29 |issue=6 |pages=479–85 |year=2003 |pmid=15029082 |doi=}}</ref><ref>{{Cite journal|author=Mancuso CE, Tanzi MG, Gabay M |title=Paradoxical reactions to benzodiazepines: literature review and treatment options |journal=Pharmacotherapy |volume=24 |issue=9 |pages=1177–85 |year=2004 |pmid=15460178|doi=10.1592/phco.24.13.1177.38089}} [http://www.medscape.com/viewarticle/489358 Free full text with registration]</ref><ref name="pmid15198">{{Cite journal|author=Goldney RD |title=Paradoxical reaction to a new minor tranquilizer |journal=Med. J. Aust. |volume=1 |issue=5 |pages=139–40 |year=1977 |pmid=15198 |doi=}}</ref>
* Children and the elderly – The safety and effectiveness of lorazepam is not well determined in children under 18 years of age, but it is used to treat acute seizures. Dose requirements have to be individualized, especially in people who are elderly and debilitated in whom the risk of oversedation is greater. Long-term therapy may lead to cognitive deficits, especially in the elderly, which may only be partially reversible. The elderly metabolize benzodiazepines more slowly than younger people and are more sensitive to the adverse effects of benzodiazepines compared to younger individuals even at similar plasma levels. Additionally, the elderly tend to take more drugs which may interact or enhance the effects of benzodiazepines. Benzodiazepines, including lorazepam, have been found to increase the risk of falls and fractures in the elderly. As a result, dosage recommendations for the elderly are about half of those used in younger individuals and used for no longer than two weeks.<ref name="Riss-2008" /><ref name="Authier-2009">{{Cite journal|vauthors=Authier N, Balayssac D, Sautereau M, Zangarelli A, County P, Somogyi AA, Vennat B, Llorca PM, Eschalier A | title = Benzodiazepine dependence: focus on withdrawal syndrome | journal = Annales Pharmaceutiques Françaises | year = 2009 | volume = 67 | issue = 6 | pages = 408–413 | doi = 10.1016/j.pharma.2009.07.001 | pmid = 19900604 }}</ref> Lorazepam may also be slower to clear in the elderly, leading potentially to accumulation and enhanced effects.<ref name="Butler-2008">{{ Cite journal |vauthors=Butler JM, Begg EJ | title = Free drug metabolic clearance in elderly people | journal = Clinical Pharmacokinetics | year = 2008 | volume = 47 | issue = 5 | pages = 297–321 | doi = 10.2165/00003088-200847050-00002 | pmid = 18399712 | s2cid = 8473906 }}</ref> Lorazepam, similar to other benzodiazepines and [[nonbenzodiazepines]], causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. 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"/>
* '''Suicidality:''' Benzodiazepines may sometimes unmask suicidal ideation in depressed patients, possibly through disinhibition or fear reduction. The concern is that, though relatively nontoxic in themselves {{Verify source|date=September 2010}}, benzodiazepines may inadvertently become facilitators of suicidal behaviour.<ref name="pmid6109269">{{Cite journal|author=Edwards RA, Medlicott RW |title=Advantages and disadvantages of benzodiazepine prescription |journal=N Z Med J |volume=92 |issue=671 |pages=357–9 |year=1980 |pmid=6109269 |doi=}}</ref> Lorazepam should, therefore, not be prescribed in high doses or as the sole treatment in depression, but only with an appropriate antidepressant {{Specify|date=September 2010}}.
* [[Liver failure|Liver]] or [[kidney failure]] – Lorazepam may be safer than most benzodiazepines in people with [[liver failure|impaired liver function]]. Like [[oxazepam]], it does not require liver oxidation, but only liver glucuronidation into lorazepam-glucuronide. Therefore, impaired liver function is unlikely to result in lorazepam accumulation to an extent causing adverse reactions.<ref name="pmid8700792">{{Cite journal | author = Peppers MP | title = Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease | journal = Pharmacotherapy | year = 1996 | volume = 16 | issue = 1 | pages = 49–57 | pmid = 8700792 | doi=10.1002/j.1875-9114.1996.tb02915.x| s2cid = 1389910 |url = https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/j.1875-9114.1996.tb02915.x }}</ref> Similarly [[kidney]] disease has minimal effects on lorazepam levels.<ref name="Olkkola-2008" />
* '''Amnesic effects:''' Among benzodiazepines, lorazepam has relatively strong [[anterograde amnesia|amnesic]] effects,<ref name="Hindmarch"/><ref name="pmid15483562">{{Cite journal|author=Izaute M, Bacon E |title=Specific effects of an amnesic drug: effect of lorazepam on study time allocation and on judgment of learning |journal=Neuropsychopharmacology |volume=30 |issue=1 |pages=196–204 |year=2005 |pmid=15483562 |doi=10.1038/sj.npp.1300564}} [http://www.nature.com/npp/journal/v30/n1/full/1300564a.html Free full text]</ref> but patients soon develop tolerance to this with regular use. To avoid amnesia (or excess sedation) being a problem, the initial total daily lorazepam dose should not exceed 2&nbsp;mg. This also applies to use for night sedation. Five participants in a sleep study were prescribed lorazepam 4&nbsp;mg at night, and the next evening three subjects unexpectedly volunteered memory gaps for parts of that day, an effect that subsided completely after 2–3 days' use.<ref name="pmid6120058">{{Cite journal|author=Scharf MB, Kales A, Bixler EO, Jacoby JA, Schweitzer PK |title=Lorazepam-efficacy, side-effects, and rebound phenomena |journal=Clin. Pharmacol. Ther. |volume=31 |issue=2 |pages=175–9 |year=1982 |pmid=6120058 |doi=10.1038/clpt.1982.27}}</ref> Amnesic effects cannot be estimated from the degree of sedation present, since the two effects are unrelated.
* [[Drug abuse|Drug and alcohol dependence]] – The risk of abuse of lorazepam is increased in dependent people.<ref name="Authier-2009" />
*[[Comorbidity|Comorbid]] [[Mental disorder|psychiatric disorders]] also increase the risk of dependence and paradoxical adverse effects.<ref name="Authier-2009" />


=== Tolerance and dependence ===
High dose or prolonged parentally administered lorazepam is sometimes associated with propylene glycol intoxication.<ref name="Arcangeli-2005"/><ref name="Riker-2005">{{Cite journal| doi = 10.1592/phco.2005.25.5_Part_2.8S | last1 = Riker | first1 = RR. | last2 = Fraser | first2 = GL. | title = Adverse events associated with sedatives, analgesics, and other drugs that provide patient comfort in the intensive care unit. | journal = Pharmacotherapy | volume = 25 | issue = 5 Pt 2 | pages = 8S–18S | month = May | year = 2005 | pmid = 15899744 }}</ref>
Dependence typified by a withdrawal syndrome occurs in about one-third of individuals who are treated for longer than four weeks with a benzodiazepine. Higher doses and longer periods of use increase the risk of developing a [[benzodiazepine dependence]]. Potent benzodiazepines with a relatively short half life, such as lorazepam, [[alprazolam]], and [[triazolam]], have the highest risk of causing a dependence.<ref name="Riss-2008" />


If regular treatment is continued for longer than four to six months, dose increases may be necessary to maintain effects, but treatment-resistant symptoms may in fact be [[Benzodiazepine withdrawal syndrome#Signs and symptoms|benzodiazepine withdrawal symptoms]].<ref name="pmid10779253">{{Cite journal | vauthors = Longo LP, Johnson B | title = Addiction: Part I. Benzodiazepines – side effects, abuse risk and alternatives | journal = American Family Physician | year = 2000 | volume = 61 | issue = 7 | pages = 2121–2128 | pmid = 10779253 | url = http://www.aafp.org/afp/20000401/2121.html | url-status=live | archive-url = https://web.archive.org/web/20080512180747/http://www.aafp.org/afp/20000401/2121.html | archive-date = 12 May 2008 }}</ref> Due to the development of tolerance to the [[anticonvulsant]] effects, benzodiazepines are generally not recommended for long-term use for the management of epilepsy. Increasing the dose may overcome tolerance, but tolerance may then develop to the higher dose and adverse effects may persist and worsen. The mechanism of tolerance to benzodiazepines is complex and involves [[GABAA receptor|GABA<sub>A</sub> receptor]] downregulation, alterations to subunit configuration of GABA<sub>A</sub> receptors, [[Uncoupling (neuropsychopharmacology)|uncoupling]] and [[Internalization (biology)|internalisation]] of the benzodiazepine binding site from the GABA<sub>A</sub> receptor complex as well as changes in [[gene expression]].<ref name="Riss-2008" />
'''Full lists of Lorazepam side effects:'''


The likelihood of dependence is relatively high with lorazepam compared to other benzodiazepines. Lorazepam's relatively short serum half-life, its confinement mainly to blood, and its inactive metabolite can result in interdose withdrawal phenomena and next-dose cravings, that may reinforce psychological dependence. Because of its high potency, the smallest lorazepam tablet strength of 0.5&nbsp;mg is also a significant dose. To minimise the risk of physical/psychological dependence, lorazepam is best used only short-term, at the smallest effective dose. If any benzodiazepine has been used long-term, the recommendation is a gradual dose taper over a period of weeks, months or longer, according to dose and duration of use, the degree of dependence and the individual.
For lists of lorazepam side effects, refer to the manufacturers' data sheets. Please note that some may list side effects for the entire benzodiazepine class, not the specific side effect profile for lorazepam.


Coming off long-term lorazepam use may be more realistically achieved by a gradual switch to an equivalent dose of [[diazepam]] and a period of stabilization on this, and only then initiating dose reductions. The advantage of switching to diazepam is that dose reductions are felt less acutely, because of the longer half-lives (20–200 hours) of diazepam and its active metabolites.<ref>{{cite web | url = http://www.benzo.org.uk/ashvtaper.htm | title = Reasons for a diazepam (Valium) taper | author = Ashton HC |date=April 2001 | access-date = 1 June 2007 | publisher = benzo.org.uk }}</ref>
==Contraindications and special considerations==
===Contraindications===
Lorazepam should be avoided in patients with the following conditions:
* '''[[Allergy]] or [[hypersensitivity]]''' – Past hypersensitivity or allergy to lorazepam, to any benzodiazepine, or to any of the ingredients in lorazepam tablets or injections
* '''[[respiratory failure|Severe respiratory failure]]''' – Benzodiazepines, including lorazepam, may depress central nervous system respiratory drive and are contraindicated in severe respiratory failure. An example would be the inappropriate use to relieve anxiety associated with [[status asthmaticus|acute severe asthma]]. The anxiolytic effects may also be detrimental to a patient's willingness and ability to fight for breath. However, if [[mechanical ventilation]] becomes necessary, lorazepam may be used to facilitate deep sedation.
* '''[[Substance intoxication|Acute intoxication]]''' – Lorazepam may interact synergistically with the effects of alcohol, narcotics, or other psychoactive substances. It should, therefore, not be administered to a drunk or intoxicated person.
* '''[[Ataxia]]''' – This is a neurological clinical sign, consisting of unsteady and clumsy motion of the limbs and torso, due to failure of gross muscle movement coordination, most evident on standing and walking. It is the classic way in which acute alcohol intoxication may affect a person. Benzodiazepines should not be administered to already-ataxic patients.
* '''[[glaucoma|Acute narrow-angle glaucoma]]''' – Lorazepam has pupil-dilating effects, which may further interfere with the drainage of aqueous humour from the anterior chamber of the eye, thus worsening narrow-angle [[glaucoma]].
* '''[[Sleep apnea]]''' – Sleep apnea may be worsened by lorazepam's central nervous system depressant effects. It may further reduce the patient's ability to protect his or her airway during sleep.
* '''[[Myasthenia gravis]]''' – This condition is characterised by muscle weakness and a muscle relaxant such as lorazepam may exacerbate symptoms.
* '''[[Pregnancy]] and [[breast feeding]]''' – Lorazepam belongs to the [[Food and Drug Administration]] (FDA) pregnancy category D, which means that it is likely to cause harm to the developing baby, if taken during the first trimester of pregnancy. There is inconclusive evidence that lorazepam, if taken early in pregnancy, may result in reduced IQ, neurodevelopmental problems, physical malformations in cardiac or facial structure, or other malformations in some newborns. Lorazepam given to pregnant women antenatally may cause [[hypotonia|floppy infant syndrome]]<ref>{{Cite journal| author = Kanto JH. | coauthors = | year = 1982 | month = May | title = Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations | journal = Drugs. | volume = 23 | issue = 5 | pages = 354–80 | pmid = 6124415 | doi = 10.2165/00003495-198223050-00002}}</ref> in the neonate, or respiratory depression necessitating ventilation. Regular lorazepam use during late pregnancy (the [[third trimester]]), carries a definite risk of [[benzodiazepine withdrawal syndrome]] in the neonate. Neonatal benzodiazepine withdrawal may include [[hypotonia]], reluctance to suck, [[apneic]] spells, [[cyanosis]], and impaired [[metabolic]] responses to cold stress. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.<ref>{{Cite journal| author = McElhatton PR. | coauthors = | year = 1994 | month = Nov-Dec | title = The effects of benzodiazepine use during pregnancy and lactation | journal = Reprod Toxicol. | volume = 8 | issue = 6 | pages = 461–75 | pmid = 7881198 | doi = 10.1016/0890-6238(94)90029-9}}</ref> Lorazepam may also inhibit foetal liver bilirubin glucuronidation, leading to neonatal jaundice. Lorazepam is present in breast milk, so caution must be exercised about breast feeding.


===Special groups and situations===
=== Withdrawal ===
On abrupt or overly rapid discontinuation of lorazepam, anxiety, and signs of physical withdrawal have been observed, similar to those seen on withdrawal from alcohol and barbiturates. Lorazepam, as with other [[benzodiazepine]] drugs, can cause [[physical dependence]], [[Substance use disorder|addiction]], and [[benzodiazepine withdrawal syndrome]]. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can, however, occur from standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regimen.<ref>{{Cite journal|vauthors=MacKinnon GL, Parker WA | title = Benzodiazepine withdrawal syndrome: a literature review and evaluation | journal = The American Journal of Drug and Alcohol Abuse | year = 1982 | volume = 9 | issue = 1 | pages = 19–33 | pmid = 6133446 | doi = 10.3109/00952998209002608 }}</ref> [[Rebound effect]]s often resemble the condition being treated, but typically at a more intense level and may be difficult to diagnose. Withdrawal symptoms can range from mild anxiety and insomnia to more severe symptoms such as [[Epileptic seizure|seizures]] and [[psychosis]]. The risk and severity of withdrawal are increased with long-term use, use of high doses, abrupt or over-rapid reduction, among other factors. Short-acting benzodiazepines such as lorazepam are more likely to cause a more severe withdrawal syndrome compared to longer-acting benzodiazepines.<ref name="Riss-2008" />
* '''Children and the elderly''' – The safety and effectiveness of lorazepam is not well determined in children under 18 years of age, but it is used to treat acute seizures. Dose requirements have to be individualized, especially in the elderly and debilitated patients in whom the risk of oversedation is greater. Long-term therapy may lead to cognitive deficits, especially in the elderly, which may only be partially reversible. The elderly metabolise benzodiazepines more slowly than younger people and are more sensitive to the adverse effects of benzodiazepines compared to younger individuals even at similar plasma levels. Additionally the elderly tend to take more drugs which may interact or enhance the effects of benzodiazepines. Benzodiazepines, including lorazepam, have been found to increase the risk of falls and fractures in the elderly. As a result dosage recommendations for the elderly are about half of those used in younger individuals and used for no longer than two weeks.<ref name="Riss-2008"/><ref name="Authier-2009">{{Cite journal| last1 = Authier | first1 = N. | last2 = Balayssac | first2 = D. | last3 = Sautereau | first3 = M. | last4 = Zangarelli | first4 = A. | last5 = Courty | first5 = P. | last6 = Somogyi | first6 = AA. | last7 = Vennat | first7 = B. | last8 = Llorca | first8 = PM. | last9 = Eschalier | first9 = A. | title = Benzodiazepine dependence: focus on withdrawal syndrome. | journal = Ann Pharm Fr | volume = 67 | issue = 6 | pages = 408–13 | month= November| year = 2009 | doi = 10.1016/j.pharma.2009.07.001 | pmid = 19900604 }}</ref> Lorazepam may also be slower to clear in the elderly leading potentially to accumulation and enhanced effects.<ref name="Butler-2008">{{Cite journal| doi = 10.2165/00003088-200847050-00002 | last1 = Butler | first1 = JM. | last2 = Begg | first2 = EJ. | title = Free drug metabolic clearance in elderly people. | journal = Clin Pharmacokinet | volume = 47 | issue = 5 | pages = 297–321 | month = | year = 2008 | pmid = 18399712 }}</ref> Lorazepam, similar to other benzodiazepines and [[nonbenzodiazepines]] causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. 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| last1 = Mets | first1 = MA. | last2 = Volkerts | first2 = ER. | last3 = Olivier | first3 = B. | last4 = Verster | first4 = JC. | title = Effect of hypnotic drugs on body balance and standing steadiness. | journal = Sleep Med Rev | volume = 14 | month = Feb | issue = 4 | pages = 259–67 | year = 2010 | doi = 10.1016/j.smrv.2009.10.008 | pmid = 20171127 }}</ref>
* '''Liver or kidney failure''' – Lorazepam may be safer than most benzodiazepines in patients with [[liver failure|impaired liver function]]. Like [[oxazepam]], it does not require hepatic oxidation, but only hepatic glucuronidation into lorazepam-glucuronide. Therefore, impaired liver function is unlikely to result in lorazepam accumulation to an extent causing adverse reactions.<ref name="pmid8700792">{{Cite journal|author=Peppers MP |title=Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease |journal=Pharmacotherapy |volume=16 |issue=1 |pages=49–57 |year=1996 |pmid=8700792 |doi=}}</ref> Similarly [[renal]] disease has minimal effects on lorazepam levels.<ref name="Olkkola-2008"/>
* '''Surgical premedication''' – [[Informed consent]] that was given only ''after'' receiving lorazepam [[premedication]] could have its validity challenged later. Staff must use [[Chaperone (clinical)|chaperone]]s to guard against allegations of abuse during treatment. Such allegations may arise because of incomplete amnesia, disinhibition, and impaired ability to process cues. Because of its relative long duration of residual effects ([[sedation]], [[ataxia]], [[hypotension]], and [[anterograde amnesia|amnesia]]), lorazepam premedication is best suited for hospital inpatient use. Patients should not be discharged from the hospital within 24 hours of receiving lorazepam premedication, unless accompanied by a caregiver. They should also not drive, operate machinery, or use alcohol within this period.
* '''[[Drug abuse|Drug and alcohol dependence]]''' – There is an increased risk of abuse of lorazepam.<ref name="Authier-2009"/>
* '''[[Comorbid]] [[psychiatric disorders]]''' – Increased risk of dependence and paradoxical adverse effects<ref name="Authier-2009"/>


Withdrawal symptoms can occur after taking therapeutic doses of lorazepam for as little as one week.{{citation needed|date=June 2023}} Withdrawal symptoms include headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, [[dysphoria]], dizziness, [[derealization]], depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, [[myalgia]], agitation, palpitations, [[tachycardia]], panic attacks, short-term memory loss, and hyperthermia. It takes about 18–36 hours for the benzodiazepine to be removed from the body.<ref>{{cite web | url = https://www.fda.gov/medwatch/safety/2007/Apr_PI/Ativan_PI.pdf | title = Ativan Labeling Revision | date = April 2007 | access-date = 3 October 2007 | publisher = FDA | url-status=live | archive-url = https://web.archive.org/web/20080307080808/https://www.fda.gov/medwatch/safety/2007/Apr_PI/Ativan_PI.pdf | archive-date = 7 March 2008 }}</ref> The ease of physical dependence to lorazepam, (Ativan brand was particularly cited), and its withdrawal were brought to the attention of the British public during the early 1980s in Esther Rantzen's BBC TV series ''[[That's Life!]]'', in a feature on the drug over a number of episodes.
===Tolerance and dependence===
Dependence typified by a withdrawal syndrome occurs in approximately one third of individuals who are treated for longer than 4 weeks with a benzodiazepines. The higher doses and the longer periods benzodiazepines are taken increase the risk of developing a [[benzodiazepine dependence]]. Potent benzodiazepines such as lorazepam, [[alprazolam]] and [[triazolam]] have the highest risk of causing a dependence.<ref name="Riss-2008"/> Tolerance to benzodiazepine effects develops with regular use. This is desirable with amnesic and sedative effects, undesirable with anxiolytic, hypnotic, and anticonvulsant effects. Patients at first experience drastic relief from anxiety and sleeplessness, but symptoms gradually return, relatively soon in the case of insomnia but more slowly in the case of anxiety symptoms. After four to six months of regular benzodiazepine use, there is little evidence of continued efficacy. If regular treatment is continued for longer than this, dose increases may be necessary to maintain effects, but treatment-resistant symptoms may in fact be [[Benzodiazepine withdrawal#Withdrawal symptoms|benzodiazepine withdrawal symptoms]].<ref name="pmid10779253">{{Cite journal|author=Longo LP, Johnson B |title=Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives |journal=American Family Physician |volume=61 |issue=7 |pages=2121–8 |year=2000 |pmid=10779253 |doi=}} [http://www.aafp.org/afp/20000401/2121.html Free full text]</ref> Due to the development of tolerance to the [[anticonvulsant]] effects, benzodiazepines are generally not recommended for long-term use for the management of epilepsy. Increasing the dose may overcome tolerance, but tolerance may then develop to the higher dose and adverse effects may persist and worsen. The mechanism of tolerance to benzodiazepines is complex and involves [[GABAA receptor|GABA<sub>A</sub> receptor]] downregulation, alterations to subunit configuration of GABA<sub>A</sub> receptors, [[uncoupling]] and [[internalisation]] of the benzodiazepine binding site from the GABA<sub>A</sub> receptor complex as well as changes in [[gene expression]].<ref name="Riss-2008"/>


=== Interactions ===
The likelihood of dependence is relatively high with lorazepam compared to other [[benzodiazepine]]s. Lorazepam's relatively short serum half-life, its confinement mainly to the vascular space, and its inactive metabolite results in interdose withdrawal phenomena and next-dose cravings. This may reinforce psychological dependence. Because of its high potency, the smallest lorazepam tablet strength of 0.5&nbsp;mg is also a significant dose reduction (in the UK, the smallest tablet strength is 1.0&nbsp;mg, which further accentuates this difficulty). To minimise the risk of physical/psychological dependence, lorazepam is best used only short-term, at the smallest effective dose. If any benzodiazepine has been used long-term, the recommendation is a gradual dose taper over a period of weeks, months or longer, according to dose and duration of use, degree of dependence and the individual. Coming off long-term lorazepam may be more realistically achieved by a gradual switch to an equivalent dose of [[diazepam]], a period of stabilization on this and only then initiating dose reductions. The advantage of switching to diazepam is that dose reductions are felt less acutely, because of the longer half lives (20–200 hours) of diazepam and its active metabolites.<ref>{{Cite web| url = http://www.benzo.org.uk/ashvtaper.htm | title = Reasons for a diazepam (Valium) taper | last = Heather Ashton | first = C | month = April | year = 2001 | accessdate = 2007-06-01 | publisher = benzo.org.uk}}</ref>
Lorazepam is not usually fatal in overdose, but may cause respiratory depression if taken in overdose with alcohol. The combination also causes greater enhancement of the [[disinhibition|disinhibitory]] and [[anterograde amnesia|amnesic]] effects of both drugs, with potentially embarrassing or criminal consequences. Some experts advise that people should be warned against drinking alcohol while on lorazepam treatment,<ref name="Hindmarch" /><ref name="PI">{{cite web | publisher = Genus Pharmaceuticals | title = Lorazepam: Patient Information Leaflet, UK, 1998 | url = http://www.benzo.org.uk/lorazepam.htm | date = 21 January 1998 | access-date = 14 May 2007 }}</ref> but such clear warnings are not universal.<ref>{{cite web | url = http://www.patient.co.uk/showdoc/30002635 | title = Lorazepam | publisher = Patient UK | date = 25 October 2006 | access-date = 14 May 2007 | url-status=live | archive-url = https://web.archive.org/web/20070927173700/http://www.patient.co.uk/showdoc/30002635 | archive-date = 27 September 2007 }}</ref>


Greater adverse effects may also occur when lorazepam is used with other drugs, such as [[opioids]] or other [[hypnotic]]s.<ref name="Olkkola-2008" /> Lorazepam may also interact with [[rifabutin]].<ref name="Baciewicz-2008">{{Cite journal |vauthors=Baciewicz AM, Chrisman CR, Finch CK, Self TH | title = Update on rifampin and rifabutin drug interactions | journal = American Journal of the Medical Sciences | year = 2008 | volume = 335 | issue = 2 | pages = 126–136 | doi = 10.1097/MAJ.0b013e31814a586a | pmid = 18277121 | s2cid = 42918932 }}</ref> [[Valproate]] inhibits the metabolism of lorazepam, whereas [[carbamazepine]], [[lamotrigine]], [[phenobarbital]], [[phenytoin]], and [[Rifampicin|rifampin]] increase its rate of metabolism. Some antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opiates, antipsychotics and alcohol, when taken with lorazepam may result in enhanced sedative effects.<ref name="Riss-2008" />
====Withdrawal====
On abrupt, or overly rapid discontinuation of lorazepam, anxiety and signs of physical withdrawal have been observed, similar to those seen on withdrawal from alcohol and barbiturates. Lorazepam, as with other [[benzodiazepine]] drugs, can cause [[physical dependence]], [[Substance use disorder|addiction]], and what is known as the [[benzodiazepine withdrawal syndrome]]. The higher the dose and the longer the drug is taken for, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can, however, occur from standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regimen.<ref>{{Cite journal| author = MacKinnon GL | coauthors = Parker WA. | year = 1982 | title = Benzodiazepine withdrawal syndrome: a literature review and evaluation | journal = The American journal of drug and alcohol abuse. | volume = 9 | issue = 1 | pages = 19–33 | pmid = 6133446 | doi = 10.3109/00952998209002608}}</ref> [[Rebound effects]] often resemble the condition being treated but typically at a more intense level and may be difficult to diagnose. Withdrawal symptoms can range from mild anxiety and insomnia to more severe symptoms such as [[seizures]] and [[psychosis]]. The risk and severity of withdrawal is increased with long-term use, use of high doses, abrupt or over-rapid reduction, among other factors. Short-acting benzodiazepines such as lorazepam are more likely to cause a more severe withdrawal syndrome compared to longer-acting benzodiazepines.<ref name="Riss-2008"/>


=== Overdose ===
Withdrawal symptoms can occur after taking therapeutic doses of Ativan for as little as one week. Withdrawal symptoms include headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, [[dysphoria]], dizziness, [[derealization]], depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, [[myalgia]], agitation, palpitations, [[tachycardia]], panic attacks, short-term memory loss, and hyperthermia. It takes approximately 18–36 hours for the benzodiazepine to remove itself from the body.<ref>{{Cite web| url = http://www.fda.gov/medwatch/safety/2007/Apr_PI/Ativan_PI.pdf |format=PDF| title = Labeling Revision | last = FDA | month = April | year = 2007 | accessdate = 2007-10-03 | publisher = fda.gov}}</ref> The ease of addiction to Lorazepam, (the Ativan brand was particularly cited), and its withdrawal were brought to the attention of the British public during the early 1980s in Esther Rantzen's BBC TV series "''[[That's Life!]]''", in a feature on the drug over a number of episodes.
{{See also|Benzodiazepine overdose}}
In cases of a suspected lorazepam overdose, it is important to establish whether the person is a regular user of lorazepam or other benzodiazepines since regular use causes tolerance to develop. Also, one must ascertain whether other substances were also ingested.


Signs of overdose range through mental confusion, [[dysarthria]], [[paradoxical reaction]]s, [[Somnolence|drowsiness]], [[hypotonia]], [[ataxia]], [[hypotension]], [[Hypnosis|hypnotic state]], [[coma]], cardiovascular depression, [[Hypoventilation|respiratory depression]], and [[death]]. However, fatal overdoses on benzodiazepines alone are rare and less common than with [[barbiturate]]s.<ref>{{cite journal | vauthors = Löscher W, Rogawski MA | title = How theories evolved concerning the mechanism of action of barbiturates | journal = Epilepsia | volume = 53 | issue = Suppl 8 | pages = 12–25 | date = December 2012 | pmid = 23205959 | doi = 10.1111/epi.12025 | s2cid = 4675696 | doi-access = free }}</ref> Such a difference is largely due to benzodiazepine activity as a neuroreceptor [[Allosteric modulator|modulator]], and not as an activator per se. Lorazepam and similar medications do however act in synergy with alcohol, which increases the risk of overdose.
==Pharmacology==
Lorazepam has [[anxiolytic]], [[sedative]], [[hypnotic]], [[amnesic]], [[anticonvulsant]] as well as [[muscle relaxant]] properties.<ref name="Mandrioli-2008">{{Cite journal| last1 = Mandrioli | first1 = R. | last2 = Mercolini | first2 = L. | last3 = Raggi | first3 = MA. | title = Benzodiazepine metabolism: an analytical perspective. | journal = Curr Drug Metab | volume = 9 | issue = 8 | pages = 827–44 | month = Oct | year = 2008 | doi = 10.2174/138920008786049258| pmid = 18855614 }}</ref> Lorazepam is high-potency and an intermediate-acting benzodiazepine and its uniqueness,<ref>Pompéia S, Manzano GM, Tufik S, Bueno OF (2005). {{PDFlink|[http://www.blackwell-synergy.com/doi/pdf/10.1113/jphysiol.2005.569005 "What makes lorazepam different from other benzodiazepines?"]}} ''J Physiol'' '''569''' (2): 709. PMID 16322061. {{doi|10.1113/jphysiol.2005.569005}}. [[Letter to the editor|Letter]].</ref><ref>{{Cite journal|author=Chouinard G |title=Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound |journal=J Clin Psychiatry |volume=65 Suppl 5 |issue= |pages=7–12 |year=2004 |pmid=15078112 |doi= |url=http://article.psychiatrist.com/?ContentType=START&ID=10000770}}</ref> advantages and disadvantages are largely explained by its pharmacokinetic properties (poor water and lipid solubility, high protein binding and non-oxidative metabolism to a pharmacologically inactive glucuronide form) and by its high relative potency (lorazepam 1&nbsp;mg is equal in effect to [[diazepam]] 10&nbsp;mg).<ref>{{Cite book| author = [[British Medical Association]] and [[Royal Pharmaceutical Society of Great Britain]] | title = [[British National Formulary]] | year = 2007 | month = March | edition = v53 | isbn = 0-85369-731-0 | publisher = BMJ and RPS Pub. | location = London}}</ref><ref>{{Cite web| last = Nimmo | first = Ray | coauthors = C. Heather Ashton | title = Benzodiazepine Equivalence Table | url = http://www.benzo.org.uk/bzequiv.htm | publisher = benzo.org.uk | year = 2007 | month = March | accessdate = 2007-05-13}}</ref> The half life of lorazepam is 10–20 hours.<ref>{{Cite web| url = http://www.bcnc.org.uk/equivalence.html | title = Benzodiazepine equivalency table | accessdate = September 23, 2007 | author = Professor heather Ashton | year = 2007 | month = April }}</ref>


Early management of people under alert includes [[Vomiting|emetics]], [[gastric lavage]], and [[Activated carbon|activated charcoal]]. Otherwise, management is by observation, including of vital signs, support and, only if necessary, considering the hazards of doing so, giving [[Intravenous therapy|intravenous]] [[flumazenil]].
===Pharmacokinetics===
Lorazepam is highly protein bound and is extensively metabolised into pharmacologically inactive metabolites.<ref name="Riss-2008"/> Due to its poor lipid solubility lorazepam is absorbed relatively slowly by mouth and is unsuitable for rectal administration. But its poor lipid solubility and high degree of protein binding (85-90%<ref name="Lorzem"/>) mean that lorazepam's volume of distribution is mainly the [[Circulatory system|vascular]] compartment, causing relatively prolonged peak effects. This contrasts with the highly lipid-soluble [[diazepam]], which, although rapidly absorbed orally or rectally, soon redistributes from the serum to other parts of the body, in particular body fat. This explains why one lorazepam dose, despite lorazepam's shorter serum half-life, has more prolonged peak effects than an equivalent diazepam dose.<ref name="pmid3234245">{{Cite journal| author = Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A, Liebson IA, Nemeth-Coslett R | title = Relative abuse liability of lorazepam and diazepam: an evaluation in 'recreational' drug users | journal = Drug and alcohol dependence | volume = 22 | issue = 3 | pages = 215–22 | year = 1988 | pmid = 3234245| doi = 10.1016/0376-8716(88)90021-X}}</ref> On regular administration diazepam will, however, accumulate more, since it has a longer half-life and active metabolites with even longer half-lives.


People are ideally nursed in a kind, frustration-free environment, since, when given or taken in high doses, benzodiazepines are more likely to cause paradoxical reactions. If shown sympathy, even quite crudely feigned, people may respond solicitously, but they may respond with disproportionate aggression to frustrating cues.<ref>{{ cite book | publisher = Council of Europe, Pompidou Group | location = Strassbourg | year = 2002 | title = Contribution to the sensible use of benzodiazepines | isbn = 978-92-871-4751-6 }}</ref> Opportunistic [[List of counseling topics|counseling]] has limited value here, as the person is unlikely to recall this later, owing to drug-induced anterograde amnesia.
'''Clinical example:''' Diazepam has long been a drug of choice for [[status epilepticus]]: Its high lipid solubility means it gets absorbed with equal speed whether given intravenously, orally, or rectally (non-intravenous routes are convenient in non-hospital settings). But diazepam's high lipid solubility also means it does not remain in the vascular space but soon redistributes into other body tissues. So it may be necessary to repeat diazepam doses to maintain peak anticonvulsant effects, resulting in excess body accumulation. Lorazepam is a different case: Its low lipid solubility makes it relatively slowly absorbed by any route other than intravenously, but once injected will not get significantly redistributed beyond the vascular space. Therefore, lorazepam's anticonvulsant effects are more durable, thus reducing the need for repeated doses. If a patient is known to usually stop convulsing after only one or two diazepam doses, diazepam may be preferable because sedative after-effects will be less than if a single dose of lorazepam is given (diazepam anticonvulsant/sedative effects wear off after 15–30 minutes, but lorazepam effects last 12–24 hours).<ref name="pmid11898891">{{Cite journal|author=Lackner TE |title=Strategies for optimizing antiepileptic drug therapy in elderly people |journal=Pharmacotherapy |volume=22 |issue=3 |pages=329–64 |year=2002 |pmid=11898891|doi=10.1592/phco.22.5.329.33192}} [http://www.medscape.com/viewarticle/430209_3 Free full text with registration at Medscape]</ref> The prolonged sedation from lorazepam may, however, be an acceptable trade-off for its reliable duration of effects, particularly if the patient needs to be transferred to another facility. Although lorazepam is not necessarily better than diazepam at initially terminating seizures,<ref name="pmid16714516">{{Cite journal|author=Choudhery V, Townend W |title=Best evidence topic reports. Lorazepam or diazepam in paediatric status epilepticus |journal=Emergency Medicine Journal |volume=23 |issue=6 |pages=472&ndash;3 |year=2006 |url=http://emj.bmj.com/cgi/content/extract/23/6/472 |pmid=16714516 |pmc=2564351 |doi=10.1136/emj.2006.037606}}</ref> lorazepam is, nevertheless, replacing diazepam as the ''intravenous'' agent of choice in [[status epilepticus]].<ref>Henry JC, Holloway R (2006). {{PDFlink|[http://ebm.bmj.com/cgi/reprint/11/2/54.pdf "Review: lorazepam provides the best control for status epilepticus".]|115&nbsp;KB}} ''Evid Based Med'' '''11''' (2): 54. PMID 17213084. {{doi|10.1136/ebm.11.2.54}}</ref><ref name="pmid11937649">{{Cite journal|author=Cock HR, Schapira AH |title=A comparison of lorazepam and diazepam as initial therapy in convulsive status epilepticus |journal=QJM |volume=95 |issue=4 |pages=225–31 |year=2002 |url=http://qjmed.oxfordjournals.org/cgi/content/full/95/4/225 |pmid=11937649|doi=10.1093/qjmed/95.4.225}}</ref>


=== Detection in body fluids ===
Lorazepam serum levels are proportional to the dose administered. Giving 2&nbsp;mg oral lorazepam will result in a peak total serum lorazepam level of around 20 nanograms/ml around two hours later,<ref name="pmid8232"/><ref name="Lorzem"/> half of which is lorazepam, half its inactive metabolite, lorazepam-glucuronide.<ref name="pmid16243469">{{Cite journal|author=Papini O, Bertucci C, da Cunha SP, dos Santos NA, Lanchote VL |title=Quantitative assay of lorazepam and its metabolite glucuronide by reverse-phase liquid chromatography-tandem mass spectrometry in human plasma and urine samples |journal=Journal of pharmaceutical and biomedical analysis |volume=40 |issue=2 |pages=389–96 |year=2006 |pmid=16243469 |doi=10.1016/j.jpba.2005.07.033}}</ref> A similar lorazepam dose given intravenously will result in an earlier and higher peak serum level, with a higher relative proportion of unmetabolised (active) lorazepam.<ref name="pmid2743706">{{Cite journal|author=Herman RJ, Van Pham JD, Szakacs CB |title=Disposition of lorazepam in human beings: enterohepatic recirculation and first-pass effect |journal=Clin Pharmacol Ther |volume=46 |issue=1 |pages=18–25 |year=1989 |pmid=2743706 |doi=10.1038/clpt.1989.101}}</ref> On regular administration, maximum lorazepam serum levels are attained after three days. Longer-term use, up to six months, does not result in further accumulation.<ref name="Lorzem"/> On discontinuation, lorazepam serum levels become negligible after 3 days and undetectable after about a week. Lorazepam is metabolised in the liver by conjugation into inactive lorazepam-glucuronide. This metabolism does not involve hepatic oxidation and, therefore, is relatively unaffected by reduced liver function. Lorazepam-glucuronide is more water-soluble than its precursor and, therefore, gets more widely distributed in the body, leading to a longer half-life than lorazepam. Lorazepam-glucuronide is eventually excreted by the kidneys,<ref name="Lorzem"/> and, because of its tissue accumulation, it remains detectable - particularly in the urine - for substantially longer than lorazepam.
Lorazepam may be quantitated in blood or plasma to confirm poisoning in hospitalized people, provide evidence of an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma concentrations are usually in a range of 10–300 μg/L in persons either receiving the drug therapeutically or in those arrested for impaired driving. Approximately 300–1000 μg/L is found in people after acute overdosage.<ref>{{ cite book | author =Baselt R | title = Disposition of Toxic Drugs and Chemicals in Man | edition = 8th | publisher = Biomedical Publications | location = Foster City, CA | year = 2008 | pages = 860–862 }}</ref> Lorazepam may not be detected by commonly used [[drug test|urine drug screenings]] for benzodiazepines. This is due to the fact that the majority of these screening tests are only able to detect benzodiazepines that undergo [[oxazepam]] [[glucuronide]] metabolism.<ref>{{cite book | vauthors = Shaw LM |title=The Clinical Toxicology Laboratory: Contemporary Practice of Poisoning Evaluation |date=2001 |publisher=Amer. Assoc. for Clinical Chemistry |isbn=9781890883539 |page=216 |url=https://books.google.com/books?id=pXvFGqz44pYC&pg=PA216 }}</ref><ref>{{cite book | vauthors = Ries RK, Miller SC, Fiellin DA |title=Principles of Addiction Medicine |date=2009 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-7477-2 |page=301 |url=https://books.google.com/books?id=j6GGBud8DXcC&pg=PA301 }}</ref><ref>{{cite book | vauthors = Kang M, Galuska MA, Ghassemzadeh S | chapter = Benzodiazepine Toxicity |date=2023 | chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK482238/ | title = StatPearls |access-date=13 June 2023 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29489152 }}</ref>


== Pharmacology ==
===Pharmacodynamics===
Lorazepam has [[anxiolytic]], [[sedative]], [[hypnotic]], [[amnesic]], [[anticonvulsant]], and [[muscle relaxant]] properties.<ref name="Mandrioli-2008">{{Cite journal |vauthors=Mandrioli R, Mercolini L, Raggi MA | title = Benzodiazepine metabolism: an analytical perspective | journal = Current Drug Metabolism | year = 2008 | volume = 9 | issue = 8 | pages = 827–844 | doi = 10.2174/138920008786049258 | pmid = 18855614 | url = https://zenodo.org/record/1067769 }}</ref> It is a high-potency and an {{Clarify | text = intermediate-acting | date = January 2020 | reason = What is intermediate acting? Duration? The anxiety section above says it is of short duration. Speed? One of the references to follow mentions that it has a fast onset.}} benzodiazepine, and its uniqueness,<ref>{{cite journal |vauthors=Pompéia S, Manzano GM, Tufik S, Bueno OF | title = What makes lorazepam different from other benzodiazepines? | journal = Journal of Physiology | volume = 569 | issue = Pt 2 | pages = 709; author reply 710 | year = 2005 | pmid = 16322061 | pmc = 1464231 | doi = 10.1113/jphysiol.2005.569005 }}</ref><ref>{{Cite journal | author = Chouinard G | title = Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound | journal = Journal of Clinical Psychiatry | year = 2004 | volume = 65 | issue = Suppl 5 | pages = 7–12 | pmid = 15078112 | url = http://article.psychiatrist.com/?ContentType=START&ID=10000770 }}</ref> advantages, and disadvantages are largely explained by its pharmacokinetic properties (poor water and lipid solubility, high protein binding and anoxidative metabolism to a pharmacologically inactive glucuronide form) and by its high relative potency (lorazepam 1&nbsp;mg is equal in effect to [[diazepam]] 10&nbsp;mg).<ref>{{Cite book| author = [[British Medical Association]] and [[Royal Pharmaceutical Society of Great Britain]] | title = British National Formulary |date=March 2007 | edition = v53 | isbn = 978-0-85369-731-2 | publisher = BMJ and RPS Pub. | location = London| title-link = British National Formulary }}</ref><ref>{{cite web|vauthors=Nimmo R, Ashton CH | title = Benzodiazepine Equivalence Table | url = http://www.benzo.org.uk/bzequiv.htm | publisher = benzo.org.uk |date=March 2007 | access-date = 13 May 2007}}</ref> The [[biological half-life]] of lorazepam is 10–20 hours.<ref>{{cite web | url = http://www.bcnc.org.uk/equivalence.html | title = Benzodiazepine equivalency table | access-date = 23 September 2007 | author = Ashton CH | date = April 2007 | url-status=live | archive-url = https://web.archive.org/web/20070928121055/http://www.bcnc.org.uk/equivalence.html | archive-date = 28 September 2007 }}</ref>
Relative to other benzodiazepines, lorazepam is thought to have high affinity for [[GABA receptor]]s,<ref name="pmid7708722">{{Cite journal|author=Matthew E, Andreason P, Pettigrew K, ''et al.'' |title=Benzodiazepine receptors mediate regional blood flow changes in the living human brain |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue=7 |pages=2775–9 |year=1995 |pmid=7708722 |pmc=42301|doi=10.1073/pnas.92.7.2775}} {{PMC|42301}}</ref> which may also explain its marked<ref name="Hindmarch"/> amnesic effects. The main pharmacological effects of lorazepam are the enhancement of the effects of [[GABA]] at the GABA<sub>A</sub> receptor.<ref name="Riss-2008"/> Benzodiazepines, such as lorazepam enhance the effects of GABA at the GABA<sub>A</sub> receptor via increasing the frequency of opening of the chloride ion channel on the GABA<sub>A</sub> receptors; which results in the therapeutic actions of benzodiazepines. Benzodiazepines, however, do not on their own enhance the GABA<sub>A</sub> receptors but require the [[neurotransmitter]] GABA to be present. Thus the effect of benzodiazepines is to enhance the effects of the neurotransmitter GABA.<ref name="Riss-2008"/><ref name="Olkkola-2008">{{Cite journal| last1 = Olkkola | first1 = KT. | last2 = Ahonen | first2 = J. | title = Midazolam and other benzodiazepines. | journal = Handb Exp Pharmacol | volume = 182| issue = 182 | pages = 335–60 | year = 2008 | doi = 10.1007/978-3-540-74806-9_16 | pmid = 18175099 }}</ref>


=== Pharmacokinetics ===
The magnitude and duration of lorazepam effects are dose-related, meaning that larger doses have stronger and longer-lasting effects. This is because the brain has spare benzodiazepine drug receptor capacity, with single, clinical doses leading only to an occupancy of some 3% of the available receptors.<ref name="pmid8395663">{{Cite journal|author=Sybirska E, Seibyl JP, Bremner JD, ''et al.'' |title=[123I]iomazenil SPECT imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain |journal=Neuropharmacology |volume=32 |issue=7 |pages=671–80 |year=1993 |pmid=8395663|doi=10.1016/0028-3908(93)90080-M}}</ref>
Lorazepam is highly protein bound and is extensively metabolized into pharmacologically inactive metabolites.<ref name="Riss-2008" /> Due to its poor lipid solubility, lorazepam is absorbed relatively slowly by mouth and is unsuitable for rectal administration. However, its poor lipid solubility and high degree of protein binding (85–90%<ref name="Lorzem" />) mean its volume of distribution is mainly the [[Circulatory system|vascular]] compartment, causing relatively prolonged peak effects. This contrasts with the highly lipid-soluble [[diazepam]], which, although rapidly absorbed orally or rectally, soon redistributes from the serum to other parts of the body, in particular, body fat. This explains why one lorazepam dose, despite its shorter serum half-life, has more prolonged peak effects than an equivalent diazepam dose.<ref name="pmid3234245">{{Cite journal |vauthors=Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A, Liebson IA, Nemeth-Coslett R | title = Relative abuse liability of lorazepam and diazepam: an evaluation in 'recreational' drug users | journal = Drug and Alcohol Dependence | volume = 22 | issue = 3 | pages = 215–222 | year = 1988 | pmid = 3234245| doi = 10.1016/0376-8716(88)90021-X | doi-access = free }}</ref> Lorazepam is rapidly conjugated at its 3-hydroxy group into lorazepam [[glucuronide]] which is then excreted in the urine. Lorazepam glucuronide has no demonstrable CNS activity in animals. The plasma levels of lorazepam are proportional to the dose given. There is no evidence of accumulation of lorazepam on administration up to six months. On regular administration, diazepam will accumulate, since it has a longer half-life and active metabolites, these metabolites also have long half-lives.


'''Clinical example:''' Diazepam has long been a drug of choice for [[status epilepticus]]; its high lipid solubility means it gets absorbed with equal speed whether given orally, or rectally (nonintravenous routes are convenient outside of hospital settings), but diazepam's high lipid solubility also means it does not remain in the vascular space, but soon redistributes into other body tissues. So, it may be necessary to repeat diazepam doses to maintain peak anticonvulsant effects, resulting in excess body accumulation. Lorazepam is a different case; its low lipid solubility makes it relatively slowly absorbed by any route other than intravenously, but once injected, it will not get significantly redistributed beyond the vascular space. Therefore, lorazepam's anticonvulsant effects are more durable, thus reducing the need for repeated doses. If a person is known to usually stop convulsing after only one or two diazepam doses, it may be preferable because sedative after effects will be less than if a single dose of lorazepam is given (diazepam anticonvulsant/sedative effects wear off after 15–30 minutes, but lorazepam effects last 12–24 hours).<ref name="pmid11898891">{{Cite journal | author = Lackner TE | title = Strategies for optimizing antiepileptic drug therapy in elderly people | journal = Pharmacotherapy | volume = 22 | issue = 3 | pages = 329–364 | year = 2002 | pmid = 11898891 | doi = 10.1592/phco.22.5.329.33192 | s2cid = 45073171 | url = http://www.medscape.com/viewarticle/430209_3 | url-status=live | archive-url = https://web.archive.org/web/20031015072253/http://www.medscape.com/viewarticle/430209_3 | archive-date = 15 October 2003 }}</ref> The prolonged sedation from lorazepam may, however, be an acceptable trade-off for its reliable duration of effects, particularly if the person needs to be transferred to another facility. Although lorazepam is not necessarily better than diazepam at initially terminating seizures,<ref name="pmid16714516">{{Cite journal | vauthors = Choudhery V, Townend W | title = Lorazepam or diazepam in paediatric status epilepticus | journal = Emergency Medicine Journal | year = 2006 | volume = 23 | issue = 6 | pages = 472–473 | pmid = 16714516 | pmc = 2564351 | doi = 10.1136/emj.2006.037606 }}</ref> lorazepam is, nevertheless, replacing diazepam as the intravenous agent of choice in status epilepticus.<ref>{{cite journal | vauthors = Henry JC, Holloway R | title = Review: lorazepam provides the best control for status epilepticus | journal = Evidence Based Medicine | year = 2006 | volume = 11 | issue = 2 | page = 54 | pmid = 17213084 | doi = 10.1136/ebm.11.2.54 | s2cid = 30618719 | url = http://ebm.bmj.com/cgi/reprint/11/2/54.pdf | url-status=live | archive-url = https://web.archive.org/web/20061212072448/http://ebm.bmj.com/cgi/reprint/11/2/54.pdf | archive-date = 12 December 2006 | doi-access = free }}</ref><ref name="pmid11937649">{{Cite journal | vauthors = Cock HR, Schapira AH | title = A comparison of lorazepam and diazepam as initial therapy in convulsive status epilepticus | journal = QJM | year = 2002 | volume = 95 | issue = 4 | pages = 225–231 | pmid = 11937649 | doi = 10.1093/qjmed/95.4.225 | doi-access = }}</ref>
The anticonvulsant properties of lorazepam and other benzodiazepines may be, in part or entirely, due to binding to voltage-dependent [[sodium channels]] rather than benzodiazepine receptors. Sustained repetitive firing seems to get limited, by the benzodiazepine effect of slowing recovery of sodium channels from inactivation in mouse spinal cord cell cultures.<ref>{{Cite journal| author = McLean MJ | coauthors = Macdonald RL. | year = 1988 | month = February | title = Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture | volume = 244 | issue = 2 | pages = 789–95 | pmid = 2450203 | journal = J Pharmacol Exp Ther. }}</ref>


Lorazepam serum levels are proportional to the dose administered. Giving 2&nbsp;mg oral lorazepam will result in a peak total serum level of around 20&nbsp;ng/mL around two hours later,<ref name="Lorzem" /><ref name="pmid8232" /> half of which is lorazepam, half its inactive metabolite, lorazepam-glucuronide.<ref name="pmid16243469">{{Cite journal |vauthors=Papini O, Bertucci C, da Cunha SP, dos Santos NA, Lanchote VL | title = Quantitative assay of lorazepam and its metabolite glucuronide by reverse-phase liquid chromatography-tandem mass spectrometry in human plasma and urine samples | journal = Journal of Pharmaceutical and Biomedical Analysis | year = 2006 | volume = 40 | issue = 2 | pages = 389–396 | pmid = 16243469 | doi = 10.1016/j.jpba.2005.07.033 }}</ref> A similar lorazepam dose given intravenously will result in an earlier and higher peak serum level, with a higher relative proportion of unmetabolised (active) lorazepam.<ref name="pmid2743706">{{Cite journal |vauthors=Herman RJ, Van Pham JD, Szakacs CB | title = Disposition of lorazepam in human beings: enterohepatic recirculation and first-pass effect | journal = Clinical Pharmacology and Therapeutics | year = 1989 | volume = 46 | issue = 1 | pages = 18–25 | pmid = 2743706 | doi = 10.1038/clpt.1989.101 | s2cid = 2092144 }}</ref> On regular administration, maximum serum levels are attained after three days. Longer-term use, up to six months, does not result in further accumulation.<ref name="Lorzem" /> On discontinuation, lorazepam serum levels become negligible after three days and undetectable after about a week. Lorazepam is metabolized in the liver by conjugation into inactive lorazepam-glucuronide. This metabolism does not involve liver oxidation, so is relatively unaffected by reduced liver function. Lorazepam-glucuronide is more water-soluble than its precursor, so gets more widely distributed in the body, leading to a longer half-life than lorazepam. Lorazepam-glucuronide is eventually excreted by the kidneys,<ref name="Lorzem" /> and, because of its tissue accumulation, it remains detectable, particularly in the urine, for substantially longer than lorazepam.
==Interactions==
Lorazepam is not usually fatal in overdose, but may cause fatal respiratory depression if taken in overdose with alcohol. The combination also causes synergistic enhancement of the [[disinhibition|disinhibitory]] and [[anterograde amnesia|amnesic]] effects of both drugs, with potentially embarrassing or criminal consequences. Some experts advise that patients should be warned against drinking alcohol while on lorazepam treatment,<ref name="Hindmarch"/><ref name="PI">{{Cite web| author = Genus Pharmaceuticals | title = Lorazepam: Patient Information Leaflet, UK, 1998 | url = http://www.benzo.org.uk/lorazepam.htm | publisher = benzo.org.uk | date = January 21, 1998 | accessdate = 2007-05-14}}</ref> but such clear warnings are not universal.<ref>{{Cite web| url = http://www.patient.co.uk/showdoc/30002635 | title = Lorazepam | publisher = Patient UK | date = October 25, 2006 | accessdate = 2007-05-14}}</ref> Synergistic adverse effects may also occur when lorazepam is administered with other drugs such as [[opioids]] or other [[hypnotics]].<ref name="Olkkola-2008"/> Lorazepam may also interact with [[rifabutin]].<ref name="Baciewicz-2008">{{Cite journal| last1 = Baciewicz | first1 = AM. | last2 = Chrisman | first2 = CR. | last3 = Finch | first3 = CK. | last4 = Self | first4 = TH. | title = Update on rifampin and rifabutin drug interactions. | journal = Am J Med Sci | volume = 335 | issue = 2 | pages = 126–36 | month = Feb | year = 2008 | doi = 10.1097/MAJ.0b013e31814a586a | pmid = 18277121 }}</ref> [[Valproate]], inhibits the metabolism of lorazepam, whereas [[carbamazepine]], [[lamotrigine]], [[phenobarbital]], [[phenytoin]], [[rifampin]] increases the rate of metabolism of lorazepam. Some antidepressants, anti-epileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opiates, antipsychotics and alcohol when taken with lorazepam may result in enhanced sedative effects.<ref name="Riss-2008"/>


=== Pharmacodynamics ===
==Overdose==
Relative to other benzodiazepines, lorazepam is thought to have high affinity for [[GABA receptor]]s,<ref name="pmid7708722">{{Cite journal |vauthors=Matthew E, Andreason P, Pettigrew K, etal | title = Benzodiazepine receptors mediate regional blood flow changes in the living human brain | journal = Proc. Natl. Acad. Sci. U.S.A. | year = 1995 | volume = 92 | issue = 7 | pages = 2775–2779 | pmid = 7708722 | pmc = 42301 | doi = 10.1073/pnas.92.7.2775 | bibcode = 1995PNAS...92.2775M | doi-access = free }}</ref> which may also explain its marked amnesic effects.<ref name="Hindmarch" /> Its main pharmacological effects are the enhancement of the effects of the neurotransmitter [[Gamma-Aminobutyric acid|GABA]] at the GABA<sub>A</sub> receptor.<ref name="Riss-2008" /> Benzodiazepines, such as lorazepam, enhance the effects of GABA at the GABA<sub>A</sub> receptor via increasing the frequency of opening of the chloride ion channel on the GABA<sub>A</sub> receptors; which results in the therapeutic actions of benzodiazepines. They, however, do not on their own activate the GABA<sub>A</sub> receptors, but require the [[neurotransmitter]] GABA to be present. Thus, the effect of benzodiazepines is to enhance the effects of the neurotransmitter GABA.<ref name="Riss-2008" /><ref name="Olkkola-2008">{{Cite book |vauthors=Olkkola KT, Ahonen J | chapter = Midazolam and Other Benzodiazepines | year = 2008 | volume = 182 | issue = 182 | pages = 335–360 | doi = 10.1007/978-3-540-74806-9_16 | pmid = 18175099 | isbn = 978-3-540-72813-9 | series = Handbook of Experimental Pharmacology | title = Modern Anesthetics }}</ref>
{{See also|Benzodiazepine overdose}}
In cases of a suspected lorazepam overdose, it is important to establish whether the patient is a regular user of lorazepam or other benzodiazepines, since regular use causes tolerance to develop. Also, one must ascertain whether other drugs were also ingested.


The magnitude and duration of lorazepam effects are dose-related, meaning larger doses have stronger and longer-lasting effects, because the brain has spare benzodiazepine drug receptor capacity, with single, clinical doses leading only to an occupancy of some 3% of the available receptors.<ref name="pmid8395663">{{Cite journal |vauthors=Sybirska E, Seibyl JP, Bremner JD, etal | title = <nowiki>[</nowiki><sup>123</sup>I<nowiki>]</nowiki>Iomazenil SPECT imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain | journal = Neuropharmacology | year = 1993 | volume = 32 | issue = 7 | pages = 671–680 | pmid = 8395663 | doi = 10.1016/0028-3908(93)90080-M | s2cid = 43017514 | doi-access = free }}</ref>
Signs of overdose range through mental confusion, [[dysarthria]], [[paradoxical reaction]]s, [[drowsiness]], [[hypotonia]], [[ataxia]], [[hypotension]], [[hypnotic state]], [[coma]], cardiovascular depression, [[respiratory depression]], and [[death]].


The anticonvulsant properties of lorazepam and other benzodiazepines may be, in part or entirely, due to binding to voltage-dependent [[sodium channel]]s rather than benzodiazepine receptors. Sustained repetitive firing seems to get limited, by the benzodiazepine effect of slowing recovery of sodium channels [[Action potential#Biophysical basis|from inactivation to deactivation]] in mouse spinal cord cell cultures, hence prolonging the [[Refractory period (physiology)|refractory period]].<ref>{{Cite journal |vauthors=McLean MJ, Macdonald RL | title = Benzodiazepines, but not beta-carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture | journal = Journal of Pharmacology and Experimental Therapeutics | year = 1988 | volume = 244 | issue = 2 | pages = 789–795 | pmid = 2450203 }}</ref>
Early management of alert patients includes [[emetics]], [[gastric lavage]], and [[activated charcoal]]. Otherwise, management is by observation, including of vital signs, support and, only if necessary, considering the hazards of doing so, giving [[intravenous]] [[flumazenil]].


== Physical properties and formulations ==
Patients are ideally nursed in a kind, non-frustrating environment, since, when given or taken in high doses, benzodiazepines are more likely to cause paradoxical reactions. If shown sympathy, even quite crudely feigned, patients may respond solicitously, but they may respond with disproportionate aggression to frustrating cues.<ref>Coundil of Europe, Pompidou Group (Strassbourg, 2002) ''Contribution to the sensible use of benzodiazepines.'' ISBN 9789287147516.</ref> Opportunistic [[counseling]] has limited value here, as the patient is unlikely to recall this later, owing to drug-induced [[anterograde amnesia]].
[[File:Ativan05mg.jpg|thumb|0.5 mg tablets of the Ativan brand of lorazepam]]
Pure lorazepam is an almost white powder that is nearly insoluble in water and oil. In medicinal form, it is mainly available as tablets and a solution for injection, but, in some locations, it is also available as a skin patch, an oral solution, and a [[Sublingual administration|sublingual]] tablet.


Lorazepam tablets and syrups are administered orally. Lorazepam tablets of the Ativan brand also contain [[lactose]], [[cellulose|microcrystalline cellulose]], [[polacrilin]], [[magnesium stearate]], and coloring agents ([[indigo carmine]] in blue tablets and [[tartrazine]] in yellow tablets). Lorazepam for injection formulated with [[polyethylene glycol]] 400 in [[propylene glycol]] with 2.0% [[benzyl alcohol]] as preservative.
===Detection in body fluids===
Lorazepam may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma lorazepam concentrations are usually in a range of 10-300&nbsp;ug/L in persons either receiving the drug therapeutically or in those arrested for impaired driving, and 300-1000&nbsp;ug/L in victims of acute overdosage.<ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 860–862.</ref>


Lorazepam injectable solution is administered either by deep [[intramuscular injection]] or by [[intravenous therapy|intravenous]] injection. The injectable solution comes in 1 mL [[ampoule]]s containing 2 or 4&nbsp;mg of lorazepam. The solvents used are [[polyethylene glycol]] 400 and [[propylene glycol]]. As a preservative, the injectable solution contains [[benzyl alcohol]].<ref>[http://www.baxter.com/products/anesthesia/anesthetic_pharmaceuticals/downloads/ativan.pdf baxter.com – Lorazepam Injection Data Sheet] {{webarchive |url=https://web.archive.org/web/20070507201447/http://www.baxter.com/products/anesthesia/anesthetic_pharmaceuticals/downloads/ativan.pdf |date=7 May 2007 }}</ref> Toxicity from propylene glycol has been reported in the case of a person receiving a continuous lorazepam infusion.<ref name="pmid14524641">{{Cite journal |vauthors=Yaucher NE, Fish JT, Smith HW, Wells JA | title = Propylene glycol-associated renal toxicity from lorazepam infusion | journal = Pharmacotherapy | volume = 23 | issue = 9 | pages = 1094–1099 | year = 2003 | pmid = 14524641 | doi = 10.1592/phco.23.10.1094.32762 | s2cid = 20496680 }}</ref> Intravenous injections should be given slowly and they should be closely monitored for side effects, such as respiratory depression, hypotension, or loss of airway control.
==Other use==
{{See also|Nonmedical benzodiazepine drug use}}
Lorazepam is also used for other purposes. Recreational use, wherein the drug is taken to achieve a high, or when the drug is continued long term against medical advice.<ref name="Griffiths-2005">{{Cite journal|author=Griffiths RR, Johnson MW |title=Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds |journal=J Clin Psychiatry |volume=66 Suppl 9 |issue= |pages=31–41 |year=2005 |pmid=16336040 }}</ref>


Peak effects roughly coincide with peak serum levels,<ref name="pmid8232">{{Cite journal |vauthors=Greenblatt DJ, Schillings RT, Kyriakopoulos AA, Shader RI, Sisenwine SF, Knowles JA, Ruelius HW | title = Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam | journal = Clinical Pharmacology and Therapeutics | volume = 20 | issue = 3 | pages = 329–341 | year = 1976 | pmid = 8232 | doi = 10.1002/cpt1976203329 | s2cid = 76854489 }}</ref> which occur 10 minutes after intravenous injection, up to 60 minutes after intramuscular injection, and 90 to 120 minutes after oral administration,<ref name="Lorzem">{{cite web | url = http://www.medsafe.govt.nz/Profs/Datasheet/l/Lorzemtab.htm | title = Lorzem Data Sheet | date = 4 June 1999 | publisher = New Zealand Medicines and Medical Devices Safety Authority | access-date = 13 May 2007 | url-status=dead | archive-url = https://web.archive.org/web/20070928070833/http://www.medsafe.govt.nz/Profs/Datasheet/l/Lorzemtab.htm | archive-date = 28 September 2007 }}</ref><ref name="pmid8232" /> but initial effects will be noted before this. A clinically relevant lorazepam dose will normally be effective for six to 12 hours, making it unsuitable for regular once-daily administration, so it is usually prescribed as two to four daily doses when taken regularly, but this may be extended to five or six, especially in the case of elderly people who could not handle large doses at once.
In addition to recreational use, benzodiazepines may be diverted and used to facilitate crime: Criminals may take them to deliberately seek disinhibition before committing crimes<ref name="pmid15029082"/> (which increases their potential for violence). The [[anterograde amnesia]] and sedative-hypnotic effects of benzodiazepines such as lorazepam are sometimes used by predators on unwitting victims as [[date rape drug]]s, or for the purpose of [[robbery]]; however, alcohol is the most common drug involved in such crimes.<ref name="Kintz-2007">{{Cite journal| last1 = Kintz | first1 = P. | title = Bioanalytical procedures for detection of chemical agents in hair in the case of drug-facilitated crimes. | url = http://www.springerlink.com/content/k6w77661421pr404/fulltext.pdf | format = PDF | journal = Anal Bioanal Chem | volume = 388 | issue = 7 | pages = 1467–74 | month = Aug | year = 2007 | doi = 10.1007/s00216-007-1209-z | pmid = 17340077 }}</ref>


[[Topical medication|Topical formulations]] of lorazepam, while sometimes used as treatment for nausea especially in people in [[hospice]], has been advised against by the [[American Academy of Hospice and Palliative Medicine]] for this purpose as it has not been proven effective.<ref name="AAHPMfive">{{Citation |author1 = American Academy of Hospice and Palliative Medicine |author1-link = American Academy of Hospice and Palliative Medicine |title = Five Things Physicians and Patients Should Question |publisher = [[American Academy of Hospice and Palliative Medicine]] |work = [[Choosing Wisely]]: an initiative of the [[ABIM Foundation]] |url = http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-hospice-palliative-medicine/ |access-date = 1 August 2013 |url-status = dead |archive-url = https://web.archive.org/web/20130901101934/http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-hospice-palliative-medicine/ |archive-date = 1 September 2013 }}, which cites
A large-scale, nationwide, U.S. government study of pharmaceutical-related ED visits by [[SAMHSA]] found that sedative-hypnotics in the United States are the pharmaceuticals most frequently used outside of their prescribed medical purpose, with 35% of drug-related emergency room visits involving sedative-hypnotics. In this category, benzodiazepines are most commonly used. Males and females use benzodiazepines for nonmedical purposes equally. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceutical drug, with 26% of attempted suicides involving benzodiazepines. Lorazepam was the third-most-common benzodiazepine used outside of prescription in these ED visit statistics.<ref name=dawn2neodredv>{{Cite web|url= http://dawninfo.samhsa.gov/files/ed2006/DAWN2k6ED.htm |title= Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits |accessdate= 9 February 2009 |author= United States Government |authorlink= samhsa |coauthors= U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES |year= 2006 |publisher= Substance Abuse and Mental Health Services Administration}}</ref>
* {{cite journal | vauthors = Smith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, Parker G | title = ABH gel is not absorbed from the skin of normal volunteers | journal = Journal of Pain and Symptom Management | volume = 43 | issue = 5 | pages = 961–966 | date = May 2012 | pmid = 22560361 | doi = 10.1016/j.jpainsymman.2011.05.017 | doi-access = free }}
* {{cite journal | vauthors = Weschules DJ | title = Tolerability of the compound ABHR in hospice patients | journal = Journal of Palliative Medicine | volume = 8 | issue = 6 | pages = 1135–1143 | date = December 2005 | pmid = 16351526 | doi = 10.1089/jpm.2005.8.1135 }}</ref>


==History and legal status==
== History ==
[[File:AtivanAd.jpg|thumb|1987 advertisement. "In a world where certainties are few...no wonder Ativan is prescribed by so many caring clinicians."]]
[[Image:Ativan77.jpg|thumb|right|Early lorazepam marketing, a 1977 direct-to-patient advertisement implying its positive effects: "Now it can be yours - The Ativan Experience."]]
Historically, lorazepam is one of the "classical" benzodiazepines. Other classical benzodiazepines include [[diazepam]], [[clonazepam]], [[oxazepam]], [[nitrazepam]], [[flurazepam]], [[bromazepam]] and [[clorazepate]].<ref>{{Cite journal| author = Braestrup C | coauthors = Squires RF. | date=1 April 1978| title = Pharmacological characterization of benzodiazepine receptors in the brain | journal = Eur J Pharmacol | volume = 48 | issue = 3 | pages = 263–70 | pmid = 639854 | doi = 10.1016/0014-2999(78)90085-7}}</ref> Lorazepam was first introduced by [[Wyeth Pharmaceuticals]] in 1971 under the brand names of '''Ativan''' and '''Temesta'''.<ref>{{Cite web| url= http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html| title=Benzodiazepine Names| accessdate=2008-12-29| publisher=non-benzodiazepines.org.uk}}</ref> The drug was developed by President of Research, D.J. Richards. [[Wyeth]]'s original [[patent]] on lorazepam is expired in the United States but the drug continues to be commercially viable. As a measure of its ongoing success, it has been marketed under more than seventy [[generic brand]]s since then:
Historically, lorazepam is one of the "classical" benzodiazepines. Others include [[diazepam]], [[clonazepam]], [[oxazepam]], [[nitrazepam]], [[flurazepam]], [[bromazepam]], and [[clorazepate]].<ref>{{Cite journal |vauthors=Braestrup C, Squires RF | title = Pharmacological characterization of benzodiazepine receptors in the brain | journal = European Journal of Pharmacology | year = 1978 | volume = 48 | issue = 3 | pages = 263–270 | pmid = 639854 | doi = 10.1016/0014-2999(78)90085-7 }}</ref> Lorazepam was first introduced by [[Wyeth|Wyeth Pharmaceuticals]] in 1977 under the brand names Ativan and Temesta.<ref>{{cite web|url=http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html |title=Benzodiazepine Names |access-date=29 December 2008 |publisher=non-benzodiazepines.org.uk |url-status=dead |archive-url=https://web.archive.org/web/20081208054743/http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html |archive-date=8 December 2008 }}</ref> The drug was developed by D.J. Richards, president of research. [[Wyeth]]'s original [[patent]] on lorazepam is expired in the United States.


== Society and culture ==
''Almazine, Alzapam, Anxiedin, Anxira, Anzepam, Aplacasse, Aplacassee, Apo-Lorazepam, Aripax, Azurogen, Bonatranquan, Bonton, Control, Donix, Duralozam, Efasedan, Emotion, Emotival, Idalprem, Kalmalin, Larpose, Laubeel, Lopam, Lorabenz, Loram, Lorans, Lorapam, Lorat, Lorax, Lorazene, Lorazep, Lorazepam, Lorazin, Lorafen (PL), Lorazon, Lorenin, Loridem, Lorivan, Lorsedal, Lorzem, Lozepam, Merlit, Nervistop L, Nervistopl, NIC, Novhepar, Novolorazem, Orfidal, Piralone, Placidia, Placinoral, Punktyl, Quait, Renaquil, Rocosgen, Securit, Sedarkey, Sedatival, Sedizepan, Sidenar, Silence, Sinestron, Somnium, Stapam, Tavor, Titus, Tolid, Tranqil, Tranqipam, Trapax, Trapaxm, Trapex, Upan, Wintin'', and ''Wypax''.


=== Recreational use ===
In 2000, the [[United States|U.S.]] drug company [[Mylan Laboratories Inc.|Mylan]] agreed to pay $147 million to settle accusations by the [[Federal Trade Commission|F.T.C.]] that they had raised the price of generic lorazepam by 2600 percent and generic [[clorazepate]] by 3200 percent in 1998 after having obtained exclusive licensing agreements for certain ingredients.<ref>{{Cite news| last = Labaton | first = Stephen | title = Generic-Drug Maker Agrees to Settlement In Price-Fixing Case | work = [[The New York Times]] | date = July 13, 2000 | url = http://query.nytimes.com/gst/fullpage.html?sec=health&res=9806E7DB1F38F930A25754C0A9669C8B63 | accessdate = 2007-05-14}}</ref>
{{See also|Benzodiazepine misuse}}
Lorazepam is also used for other purposes, such as [[recreational drug|recreational]] use, wherein the drug is taken to achieve a high, or when the drug is continued long-term against medical advice.<ref name="Griffiths-2005">{{Cite journal |vauthors=Griffiths RR, Johnson MW | title = Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds | journal = Journal of Clinical Psychiatry | year = 2005 | volume = 66 | issue = Suppl 9 | pages = 31–41 | pmid = 16336040 }}</ref>


A 2006 large-scale, nationwide, US government study of pharmaceutical-related [[emergency department]] visits by [[Substance Abuse and Mental Health Services Administration|SAMHSA]] found sedative-hypnotics are the pharmaceuticals most frequently used outside of their prescribed medical purpose in the United States, with 35% of drug-related emergency department visits involving sedative-hypnotics. In this category, benzodiazepines are most commonly used. Males and females use benzodiazepines for nonmedical purposes equally. Of drugs used in attempted [[suicide in the United States|suicide]], benzodiazepines are the most commonly used pharmaceutical drugs, with 26% of attempted suicides involving them. Lorazepam was the third-most-common benzodiazepine used outside of prescription in these ER visit statistics.<ref name=dawn2neodredv>{{cite web | url = http://www.samhsa.gov/data/DAWN/files/ED2006/DAWN2k6ED.htm | title = Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits | access-date = 21 February 2014 | year = 2006 | publisher = [[Substance Abuse and Mental Health Services Administration]] | url-status = dead | archive-url = https://web.archive.org/web/20140316023656/http://www.samhsa.gov/data/DAWN/files/ED2006/DAWN2k6ED.htm | archive-date = 16 March 2014 }}</ref>
Lorazepam is a Schedule IV drug under the [[Controlled Substances Act]] in the U.S. and internationally under the United Nations [[Convention on Psychotropic Substances]].<ref>[[International Narcotics Control Board]] (August 2003). {{PDFlink|[http://www.incb.org/pdf/e/list/green.pdf ''List of psychotropic substances under international control: Green List'']|1.63&nbsp;MB}}, 23<sup>rd</sup> ed., Vienna: International Narcotics Control Board, p.7.</ref> Lorazepam is a [[Controlled Drugs and Substances Act#Schedule IV|Schedule IV]] drug under the [[Controlled Drugs and Substances Act]] in Canada. In the United Kingdom, lorazepam is a Class C, Schedule 4 Controlled Drug under the Misuse of Drugs Regulations 2001.<ref>{{Cite web| title = List of Controlled Drugs | url=http://www.homeoffice.gov.uk/documents/cdlist.pdf | publisher = UK Home Office |date=January 2006}}</ref>
==Chemistry==
Lorazepam is synthesized according to a scheme containing some of the same
elements for the synthesis of [[chlordiazepoxide]] and [[oxazepam]].
#2-amino-2′,5-dichlorobenzophenone is reacted with [[hydroxylamine]].
#The intermediate [[oxime]] is then reacted with [[chloracetyl chloride]], and upon heterocyclization 6-chloro-2-chlormethyl-4-(2′-chlorophenyl)quinazolin-3-oxide is formed.
#The above product is reacted with [[methylamine]], as in the case of chlordiazepoxide, this leads to rearrangement and a ring expansion, forming 7-chloro-2-methylamino-5-(2′-chlorphenyl)-3H-1,4-benzodiazepin-4-oxide.
#The resulting benzodiazepin-4-oxide undergoes acetylation by [[acetic anhydride]] at the secondary nitrogen atom, and is further hydrolyzed by hydrochloric acid into 7-chloro-5-(2′-chlorophenyl)-1,2- dihydro-3H-1,4-benzodiazepin-2-on-4-oxide.
#Reaction of the above product with [[acetic anhydride]] leads to a Polonovski type rearrangement reaction, giving a 3-acetoxylated benzodiazepine, 7-chloro-1,3-dihydro-3-acetoxy-5-(2′-chlorphenyl)-2H-benzodiazepin-2-one.
#Hydrolysis of thee above product forms the desired product lorazepam.
[[File:Lorazepam synthesis.png|600px]]
*S.C. Bell, {{US Patent|3176009}} (1965).
*American Home Products Corp., {{Cite patent|GB|1022642}} (1962).
*S.C. Bell, {{US Patent|3296249}} (1967).
*S.C. Bell, {{Cite patent|GB|1057492}} (1967).
*S.J. Childress, M.I. Gluckman, J. Pharm. Sci., 53, 577 (1964).
*{{Cite doi|10.1021/jm00309a010}}


==See also==
=== Legal status ===
Lorazepam is a Schedule IV drug under the [[Controlled Substances Act]] in the U.S. and internationally under the United Nations [[Convention on Psychotropic Substances]].<ref>{{cite web|publisher=[[International Narcotics Control Board]] |date=August 2003 |url=http://www.incb.org/pdf/e/list/green.pdf |title=List of psychotropic substances under international control: Green List 23rd ed |location=Vienna |page=7 |url-status=dead |archive-url=https://web.archive.org/web/20051205125434/http://www.incb.org/pdf/e/list/green.pdf |archive-date=5 December 2005 }}</ref> It is a Schedule IV drug under the [[Controlled Drugs and Substances Act]] in Canada. In the United Kingdom, it is a Class C, Schedule 4 Controlled Drug under the Misuse of Drugs Regulations 2001.<ref>{{cite web | title = List of Controlled Drugs | url = http://www.homeoffice.gov.uk/documents/cdlist.pdf | publisher = UK Home Office | date = January 2006 | url-status=dead | archive-url = https://web.archive.org/web/20090711025428/http://www.homeoffice.gov.uk/documents/cdlist.pdf | archive-date = 11 July 2009 }}</ref>
* [[Benzodiazepine]]
* [[Benzodiazepine dependence]]
* [[Benzodiazepine withdrawal syndrome]]
* [[Long term effects of benzodiazepines]]


==References==
=== Pricing ===
In 2000, the US drug company [[Mylan]] agreed to pay $147 million to settle accusations by the [[Federal Trade Commission|FTC]] that they had raised the price of generic lorazepam by 2600% and generic [[clorazepate]] by 3200% in 1998 after having obtained exclusive licensing agreements for certain ingredients.<ref>{{ Cite news | author = Labaton S | title = Generic-Drug Maker Agrees to Settlement In Price-Fixing Case | newspaper = [[The New York Times]] | date = 13 July 2000 | url = https://www.nytimes.com/2000/07/13/business/generic-drug-maker-agrees-to-settlement-in-price-fixing-case.html | access-date = 14 May 2007 | url-status=live | archive-url = https://web.archive.org/web/20071014185951/http://query.nytimes.com/gst/fullpage.html?sec=health&res=9806E7DB1F38F930A25754C0A9669C8B63 | archive-date = 14 October 2007 }}</ref>
{{Reflist|2}}


==External links==
== References ==
{{Reflist}}
* [http://www.inchem.org/documents/pims/pharm/pim223.htm inchem.org - Lorazepam data sheet]

* [http://www.rxlist.com/cgi/generic/loraz.htm rxlist.com - Lorazepam data sheet]
== External links ==
* [http://www.drugs.com/lorazepam.html drugs.com - Lorazepam data sheet]
* [http://www.inchem.org/documents/pims/pharm/pim223.htm Lorazepam data sheet] IPCS INCHEM
* [http://www.baxter.com/products/anesthesia/anesthetic_pharmaceuticals/downloads/ativan.pdf baxter.com - Lorazepam Injection Data Sheet]
* [http://www.medsafe.govt.nz/Profs/Datasheet/l/Lorzemtab.htm NZ medsafe.govt.nz - Lorzem Data Sheet]
* [http://www.benzo.org.uk/lorazepam.htm benzo.org.uk - Genus/Wyeth 1998 UK Lorazepam Data Sheet]
* [http://benzo.org.uk/manual/index.htm benzo.org.uk - Ashton H. Benzodiazepines: How They Work And How to Withdraw. August 2002 (The "Ashton Manual")].
* [http://www.ndaa.org/pdf/ntlc_benzodiazepines.pdf ndaa.org - Drummer, OH. 'Benzodiazepines: Effects on Human Performance and Behavior'(Central Police University Press, 2002)].
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Lorazepam U.S. National Library of Medicine: Drug Information Portal - Lorazepam]


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