Editing Benzodiazepine (section)

===Physical dependence, withdrawal and post-withdrawal syndromes===
{{Main|Benzodiazepine dependence|Benzodiazepine withdrawal syndrome|post-acute withdrawal syndrome}}
[[Image:Diazepam2mgand5mgtablets.JPG|thumb|alt=White bottle with red and black labels on a blue pad atop a desk. Also on the pad are seven small pills.|[[Diazepam]] 2&nbsp;mg and 5&nbsp;mg diazepam tablets, which are commonly used in the treatment of [[benzodiazepine withdrawal]].]]

====Tolerance====
[[drug tolerance|Tolerance]] and [[physical dependence|dependence]] are risks of chronic benzodiazepine use, and can result in doses within the therapeutic range ceasing to offer meaningful symptomatic relief after prolonged use. Tolerance develops at different rates and to different degrees to the sedative, hypnotic, anticonvulsant, muscle relaxant and [[anxiolytic]] effects of benzodiazpines. A review<ref name=":2">{{cite journal | vauthors = Vinkers CH, Olivier B | title = Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABA(A) Receptor Modulators? | journal = Advances in Pharmacological Sciences | volume = 2012 | pages = 416864 | date = 2012 | pmid = 22536226 | pmc = 3321276 | doi = 10.1155/2012/416864 | doi-access = free }}</ref> of benzodiazepine tolerance concluded that it ''"appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all",'' although the included [[randomized controlled trial]] evidence<ref>{{cite journal | vauthors = Schweizer E, Rickels K, Weiss S, Zavodnick S | title = Maintenance drug treatment of panic disorder. I. Results of a prospective, placebo-controlled comparison of alprazolam and imipramine | journal = Archives of General Psychiatry | volume = 50 | issue = 1 | pages = 51–60 | date = January 1993 | pmid = 8422222 | doi = 10.1001/archpsyc.1993.01820130053009 }}</ref><ref name=":3">{{cite journal | vauthors = Rickels K, Case WG, Downing RW, Winokur A | title = Long-term diazepam therapy and clinical outcome | journal = JAMA | volume = 250 | issue = 6 | pages = 767–771 | date = August 1983 | pmid = 6348314 | doi = 10.1001/jama.1983.03340060045024 }}</ref> is limited to 22 weeks. A review of [[clonazepam]] in the treatment of psychiatric disorders concluded that there is longitudinal data supporting anxiolytic benefit without tolerance during long-term use,<ref name="pmid16528135">{{cite journal | vauthors = Nardi AE, Perna G | title = Clonazepam in the treatment of psychiatric disorders: an update | journal = International Clinical Psychopharmacology | volume = 21 | issue = 3 | pages = 131–142 | date = May 2006 | pmid = 16528135 | doi = 10.1097/01.yic.0000194379.65460.a6 | s2cid = 29469943 }}</ref> including an [[Open-label trial|open-label study]] finding continued benefit at 3 years.<ref name=":4">{{cite journal | vauthors = Nardi AE, Valença AM, Nascimento I, Lopes FL, Mezzasalma MA, Freire RC, Veras AB, Zin WA, Versiani M | title = A three-year follow-up study of patients with the respiratory subtype of panic disorder after treatment with clonazepam | journal = Psychiatry Research | volume = 137 | issue = 1–2 | pages = 61–70 | date = November 2005 | pmid = 16226812 | doi = 10.1016/j.psychres.2005.05.011 }}</ref> However, the review concludes that long-term [[Randomized controlled trial|RCT]] evidence is scant. A study of benzodiazepine sensitivity found that patients treated chronically with alprazolam did not differ from untreated patients in terms of anxiolytic response to diazepam, suggesting a lack of anxiolytic tolerance.<ref>{{cite journal | vauthors = Cowley DS, Roy-Byrne PP, Radant A, Ritchie JC, Greenblatt DJ, Nemeroff CB, Hommer DW | title = Benzodiazepine sensitivity in panic disorder: effects of chronic alprazolam treatment | journal = Neuropsychopharmacology | volume = 12 | issue = 2 | pages = 147–157 | date = April 1995 | pmid = 7779243 | doi = 10.1016/0893-133X(94)00074-A }}</ref>

However, controversy remains regarding tolerance to anxiolytic effects, with some publications reporting that there is little evidence of continued efficacy beyond 4–6 months<ref name="pmid10779253" /> or that dependence phenomena are common.<ref name="Perugi" /><ref name="cgftmamoa2004" /> However, some of these references were published prior to the in-depth scoping reviews of benzodiazepine tolerance, and lack citations of RCT evidence of tolerance. Studies reporting on voluntary benzodiazepine cessation and withdrawal include patient reports of tolerance and worsening anxiety.<ref name="tdamobd2004" />

The question of tolerance to the amnesic effects of benzodiazepines is, likewise, unclear.<ref name="pmid15762818">{{cite journal |vauthors=Otto MW, Bruce SE, Deckersbach T |year=2005 |title=Benzodiazepine use, cognitive impairment, and cognitive-behavioral therapy for anxiety disorders: issues in the treatment of a patient in need |url=http://psychiatrist.com/supplenet/v66s02/v66s0206.pdf |url-status=dead |journal=The Journal of Clinical Psychiatry |volume=66 |issue=Suppl 2 |pages=34–38 |pmid=15762818 |archive-url=https://web.archive.org/web/20051214010100/http://psychiatrist.com/supplenet/v66s02/v66s0206.pdf |archive-date=14 December 2005 |access-date=22 June 2009}}</ref> Some evidence suggests that partial tolerance does develop, and that, "memory impairment is limited to a narrow window within 90 minutes after each dose".<ref name="pmid15078112">{{cite journal |vauthors=Chouinard G |year=2004 |title=Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound |url=http://psychiatrist.com/supplenet/v65s05/v65s0502.pdf |url-status=dead |journal=The Journal of Clinical Psychiatry |volume=65 |issue=Suppl 5 |pages=7–12 |pmid=15078112 |archive-url=https://web.archive.org/web/20051213232617/http://psychiatrist.com/supplenet/v65s05/v65s0502.pdf |archive-date=13 December 2005 |access-date=22 June 2009}}</ref>

A major disadvantage of benzodiazepines is that tolerance to therapeutic effects develops relatively quickly while many adverse effects persist. Tolerance develops to hypnotic and myorelaxant effects within days to weeks, and to anticonvulsant effects within weeks to months.<ref name="Michelini_1996">{{cite journal|title = Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders|vauthors=Michelini S, Cassano GB, Frare F |date = 1996|journal = Pharmacopsychiatry |volume=29 |issue = 4|pages=127–134 |doi=10.1055/s-2007-979558 |pmid = 8858711|s2cid=19145509 |display-authors=etal}}</ref> Therefore, benzodiazepines are unlikely to be effective long-term treatments for sleep. While BZD therapeutic effects may disappear with tolerance, depression and impulsivity with high suicidal risk commonly persist.<ref name="Michelini_1996" /> Several studies have confirmed that long-term benzodiazepines are not significantly different from placebo for sleep,<ref>{{cite journal | vauthors = Curran HV, Collins R, Fletcher S, Kee SC, Woods B, Iliffe S | title = Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life | journal = Psychological Medicine | volume = 33 | issue = 7 | pages = 1223–1237 | date = October 2003 | pmid = 14580077 | doi = 10.1017/s0033291703008213 | s2cid = 20586160 | url = http://discovery.ucl.ac.uk/14113/1/14113.pdf }}</ref><ref>{{cite journal | vauthors = Holbrook AM | title = Treating insomnia| pmid = 15550406 | doi=10.1136/bmj.329.7476.1198 | volume=329 | issue = 7476| pmc=529353 | year=2004 | journal=BMJ | pages=1198–1199}}</ref><ref>{{cite journal | vauthors = Poyares D, Guilleminault C, Ohayon MM, Tufik S | title = Chronic benzodiazepine usage and withdrawal in insomnia patients | journal = Journal of Psychiatric Research | volume = 38 | issue = 3 | pages = 327–334 | date = 1 June 2004 | pmid = 15003439 | doi = 10.1016/j.jpsychires.2003.10.003 }}</ref> and question their use for anxiety disorders such as PTSD and OCD.<ref name="Michelini_1996" /><ref>{{cite journal|title = Pharmacotherapy for posttraumatic stress disorder: a status report| vauthors = Friedman MJ |date = 1998|journal = Psychiatry and Clinical Neurosciences |volume=52 |pages=S115–S121 |doi=10.1046/j.1440-1819.1998.0520s5S115.x |s2cid = 142421768}}</ref><ref>{{cite journal|title = Randomised controlled trial of two brief interventions against long-term benzodiazepine use: outcome of intervention|vauthors=Heather N, Bowie A, Ashton H, McAvoy B, Spencer I, Brodie J, Giddings D |date = 2004|journal = Addiction Research & Theory |volume=12 |issue=2 |pages=141–154|doi = 10.1080/1606635310001634528|s2cid = 59516280}}</ref><ref>{{cite journal | vauthors = Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJ, Zohar J, Hollander E, Kasper S, Möller HJ, Bandelow B, Allgulander C, Ayuso-Gutierrez J, Baldwin DS, Buenvicius R, Cassano G, Fineberg N, Gabriels L, Hindmarch I, Kaiya H, Klein DF, Lader M, Lecrubier Y, Lépine JP, Liebowitz MR, Lopez-Ibor JJ, Marazziti D, Miguel EC, Oh KS, Preter M, Rupprecht R, Sato M, Starcevic V, Stein DJ, van Ameringen M, Vega J | title = World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders – first revision | journal = The World Journal of Biological Psychiatry | volume = 9 | issue = 4 | pages = 248–312 | date = 1 January 2008 | pmid = 18949648 | doi = 10.1080/15622970802465807 | s2cid = 39027026 | doi-access = free | title-link = doi }}</ref> This may explain why patients commonly increase doses over time and many eventually take more than one type of benzodiazepine after the first loses effectiveness.<ref name="Psychiatry_2008">{{cite book | title = Psychiatry | edition = 3rd | veditors = Tasman A, Kay J, Lieberman JA | publisher = John Wiley & Sons|year = 2008|isbn = 978-0-470-06571-6|location = Chichester, England|pages = 1186–1200, 2603–2615}}</ref><ref>{{cite journal | vauthors = Ashton H | s2cid = 1709063 | title = The diagnosis and management of benzodiazepine dependence | journal = Current Opinion in Psychiatry | volume = 18 | issue = 3 | pages = 249–255 | date = May 2005 | pmid = 16639148 | doi = 10.1097/01.yco.0000165594.60434.84 }}</ref><ref>{{cite journal | vauthors = Morin CM, Bélanger L, Bastien C, Vallières A | title = Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse | journal = Behaviour Research and Therapy | volume = 43 | issue = 1 | pages = 1–14 | date = January 2005 | pmid = 15531349 | doi = 10.1016/j.brat.2003.12.002 }}</ref> Additionally, because tolerance to benzodiazepine sedating effects develops more quickly than does tolerance to brainstem depressant effects, those taking more benzodiazepines to achieve desired effects may experience sudden respiratory depression, hypotension or death.<ref name="DSM-5">{{cite book | author = American Psychiatry Association | title = Diagnostic and statistical manual of mental disorders : DSM-5 | date = 2013 | publisher = American Psychiatric Publishing | location = Washington | isbn = 978-0-89042-555-8 | edition = 5th | url-access = registration | url = https://archive.org/details/diagnosticstatis0005unse }}</ref> Most patients with anxiety disorders and PTSD have symptoms that persist for at least several months,<ref name="DSM-5" /> making tolerance to therapeutic effects a distinct problem for them and necessitating the need for more effective long-term treatment (e.g., psychotherapy, serotonergic antidepressants).

====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/>