Editing Benzodiazepine (section)

====Withdrawal symptoms and management====
[[File:Chlordiazepoxidetabletsgeneric.JPG|thumb|alt=White bottle on blue pad atop a desk. The bottle cap is off, and is upside down on the pad in front of the bottle. In the cap are a dozen black-and-yellow capsules.|[[Chlordiazepoxide]] 5&nbsp;mg capsules, which are sometimes used as an alternative to [[diazepam]] for [[benzodiazepine withdrawal]]. Like diazepam it has a long [[elimination half-life]] and long-acting [[active metabolites]].]]

Discontinuation of benzodiazepines or abrupt reduction of the dose, even after a relatively short course of treatment (two to four weeks), may result in two groups of symptoms, [[Rebound effect|rebound]] and [[benzodiazepine withdrawal syndrome|withdrawal]]. Rebound symptoms are the return of the symptoms for which the patient was treated but worse than before. Withdrawal symptoms are the new symptoms that occur when the benzodiazepine is stopped. They are the main sign of [[physical dependence]].<ref name="pmid15078112" />

The most frequent symptoms of withdrawal from benzodiazepines are insomnia, gastric problems, [[tremor]]s, agitation, fearfulness, and [[Spasm|muscle spasms]].<ref name="pmid15078112" /> The less frequent effects are irritability, sweating, [[depersonalization]], [[derealization]], hypersensitivity to stimuli, depression, [[suicidal]] behavior, [[psychosis]], [[seizures]], and [[delirium tremens]].<ref name="isbn0-19-856667-0">{{cite book |vauthors=Harrison PC, Gelder MG, Cowen P |title=Shorter Oxford Textbook of Psychiatry |edition=5th |publisher=Oxford University Press |year=2006 |pages=461–462 |chapter=The misuse of alcohol and drugs |isbn=978-0-19-856667-0 }}</ref> Severe symptoms usually occur as a result of abrupt or over-rapid withdrawal. Abrupt withdrawal can be dangerous and lead to [[excitotoxicity]], causing damage and even death to nerve cells as a result of excessive levels of the excitatory neurotransmitter [[glutamate (neurotransmitter)|glutamate]]. Increased glutamatergic activity is thought to be part of a compensatory mechanism to chronic GABAergic inhibition from benzodiazepines.<ref name="gaba-glutamate-adapt">{{cite journal | vauthors = Allison C, Pratt JA | title = Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence| journal = Pharmacology & Therapeutics | volume = 98 | issue = 2 | pages = 171–195 | date = May 2003 | pmid = 12725868 | doi = 10.1016/s0163-7258(03)00029-9 }}</ref><ref name="gabaa-dependence">{{cite journal | vauthors = Cheng T, Wallace DM, Ponteri B, Tuli M | title = Valium without dependence? Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects | journal = Neuropsychiatric Disease and Treatment | volume = 14 | issue = 1 | pages = 1351–1361 | date = 23 May 2018 | pmid = 29872302 | doi = 10.2147/NDT.S164307 | pmc = 5973310 | doi-access = free | title-link = doi }}</ref> Therefore, a gradual reduction regimen is recommended.<ref name="pmid19062773">{{cite journal | vauthors = Lader M, Tylee A, Donoghue J | title = Withdrawing benzodiazepines in primary care | journal = CNS Drugs | volume = 23 | issue = 1 | pages = 19–34 | year = 2009 | pmid = 19062773 | doi = 10.2165/0023210-200923010-00002 | s2cid = 113206 }}</ref>

Symptoms may also occur during a gradual dosage reduction, but are typically less severe and may persist as part of a protracted [[Benzodiazepine withdrawal syndrome|withdrawal syndrome]] for months after cessation of benzodiazepines.<ref name="isbn0-19-852518-4">{{cite book | vauthors = Collier J, Longmore M, Amarakone K | title = Oxford Handbook of Clinical Specialties|chapter-url=https://books.google.com/books?id=HCxoAgAAQBAJ&pg=PA368|year= 2013|publisher=OUP Oxford|isbn=978-0-19-150476-1|page=368 |chapter=Psychiatry }}</ref> Approximately 10% of patients experience a notable protracted withdrawal syndrome, which can persist for many months or in some cases a year or longer. Protracted symptoms tend to resemble those seen during the first couple of months of withdrawal but usually are of a sub-acute level of severity. Such symptoms do gradually lessen over time, eventually disappearing altogether.<ref name=pmid1675688>{{cite journal | vauthors = Ashton H | title = Protracted withdrawal syndromes from benzodiazepines | journal = Journal of Substance Abuse Treatment | volume = 8 | issue = 1–2 | pages = 19–28 | year = 1991 | pmid = 1675688 | doi = 10.1016/0740-5472(91)90023-4 | url = http://benzo.org.uk/ashpws.htm }}</ref>

Benzodiazepines have a reputation with patients and doctors for causing a severe and traumatic withdrawal; however, this is in large part due to the withdrawal process being poorly managed. Over-rapid withdrawal from benzodiazepines increases the severity of the withdrawal syndrome and increases the failure rate. A slow and gradual [[Drug withdrawal|withdrawal]] customised to the individual and, if indicated, psychological support is the most effective way of managing the withdrawal. Opinion as to the time needed to complete withdrawal ranges from four weeks to several years. A goal of less than six months has been suggested,<ref name=pmid19062773 /> but due to factors such as dosage and type of benzodiazepine, reasons for prescription, lifestyle, personality, [[environmental stresses]], and amount of available support, a year or more may be needed to withdraw.<ref name=tdamobd2004 /><ref name="BNF_2009"/>{{rp|183–184|date=November 2012}}

Withdrawal is best managed by transferring the physically dependent patient to an equivalent dose of diazepam because it has the longest half-life of all of the benzodiazepines, is metabolised into long-acting active metabolites and is available in low-potency tablets, which can be quartered for smaller doses.<ref name="manual" /> A further benefit is that it is available in liquid form, which allows for even smaller reductions.<ref name=pmid19062773/> [[Chlordiazepoxide]], which also has a long half-life and long-acting [[active metabolites]], can be used as an alternative.<ref name="manual">{{cite book |url=http://benzo.org.uk/manual/ |title=Benzodiazepines: how they work & how to withdraw (aka The Ashton Manual) |publisher=Ashton CH |year=2002 |access-date=27 May 2009 }}</ref><ref>{{cite book |vauthors=Lal R, Gupta S, Rao R, Kattimani S |title=Substance Use Disorder |url=http://www.whoindia.org/en/Section20/Section22_1674.htm |access-date=6 June 2009 |year=2007 |publisher=[[World Health Organization]] (WHO) |page=82 |chapter=Emergency management of substance overdose and withdrawal |chapter-url=http://www.whoindia.org/LinkFiles/Mental_Health_&_substance_Abuse_Emergency_management_of_Substance_Overdose_and_Withdrawal-Manual_For_Nursing_Personnel.pdf |quote=Generally, a longer-acting benzodiazepine such as chlordiazepoxide or diazepam is used and the initial dose titrated downward |archive-url=https://web.archive.org/web/20100613203853/http://whoindia.org/LinkFiles/Mental_Health_%26_substance_Abuse_Emergency_management_of_Substance_Overdose_and_Withdrawal-Manual_For_Nursing_Personnel.pdf |archive-date=13 June 2010 |url-status=dead }}</ref>

[[Nonbenzodiazepine]]s are contraindicated during benzodiazepine withdrawal as they are [[cross tolerant]] with benzodiazepines and can induce dependence.<ref name=tdamobd2004 /> Alcohol is also cross tolerant with benzodiazepines and more toxic and thus caution is needed to avoid replacing one dependence with another.<ref name="manual" /> During withdrawal, [[fluoroquinolone]]-based antibiotics are best avoided if possible; they displace benzodiazepines from their binding site and reduce GABA function and, thus, may aggravate withdrawal symptoms.<ref>{{cite web | url = http://www.smmgp.org.uk/download/guidance/guidance025.pdf | title = Guidance for the use and reduction of misuse of benzodiazepines and other hypnotics and anxiolytics in general practice | vauthors = Ford C, Law F | date = July 2014 | website = smmgp.org.uk | access-date = 18 October 2015 | archive-url = https://web.archive.org/web/20170706085219/http://www.smmgp.org.uk/download/guidance/guidance025.pdf | archive-date = 6 July 2017 | url-status = dead }}</ref> Antipsychotics are not recommended for benzodiazepine withdrawal (or other CNS depressant withdrawal states) especially [[clozapine]], [[olanzapine]] or low potency [[phenothiazines]], e.g., [[chlorpromazine]] as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required.<ref>{{cite book | vauthors = Ebadi M | title = Desk Reference for Clinical Pharmacology |chapter-url=https://books.google.com/books?id=ihxyHbnj3qYC |edition=2nd |year= 2007 |publisher=CRC Press |location=US|isbn=978-1-4200-4743-1 |page=512 |chapter=Alphabetical presentation of drugs }}</ref>

Withdrawal from long term benzodiazepines is beneficial for most individuals.<ref name=cbpham /> Withdrawal of benzodiazepines from long-term users, in general, leads to improved physical and [[mental health]] particularly in the elderly; although some long term users report continued benefit from taking benzodiazepines, this may be the result of suppression of withdrawal effects.<ref name=tdamobd2004 /><ref name=asapdacg/>