View source for Benzodiazepine

{{Benzos}}
A '''benzodiazepine''' ({{pron-en|ˌbɛnzɵdaɪˈæzɨpiːn}}, sometimes colloquially referred to as a "'''benzo'''", and often abbreviated in the literature as a "'''BZD'''") is a [[psychoactive drug]] whose core chemical structure is the fusion of a [[benzene]] ring and a [[diazepine]] ring. The first benzodiazepine, [[chlordiazepoxide]] (Librium), was [[Serendipity|discovered accidentally]] by [[Leo Sternbach]] in 1955, and made available in 1960 by [[Hoffmann–La Roche]], which has also marketed [[diazepam]] (Valium) since 1963.<ref name=isbn0-19-517668-5/>

Benzodiazepines enhance the effect of the [[neurotransmitter]] [[gamma-Aminobutyric acid|gamma-aminobutyric acid]], which results in [[sedative]], [[hypnotic]] (sleep-inducing), [[anxiolytic]] (anti-anxiety), [[anticonvulsant]], [[muscle relaxant]] and [[anterograde amnesia|amnesic]] action.<ref name=ip2002/> These properties make benzodiazepines useful in treating [[anxiety]], [[insomnia]], [[Psychomotor agitation|agitation]], [[seizure]]s, [[Spasm|muscle spasms]], [[alcohol withdrawal]] and as a [[premedication]] for medical or dental procedures.<ref name=pmid18175099/> Benzodiazepines are categorized as either short-, intermediate- or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety.<ref name=sddat/>

In general, benzodiazepines are safe and effective in the short term, although cognitive impairments and [[paradoxical effect]]s such as aggression or behavioral [[disinhibition]] occasionally occur.<ref name=pmid18922233/> Long-term use is controversial due to concerns about adverse psychological and physical effects, increased questioning of effectiveness and because benzodiazepines are prone to cause [[drug tolerance|tolerance]], [[physical dependence]] and upon cessation of use, a [[benzodiazepine withdrawal syndrome|withdrawal syndrome]].<ref name=pmid18671662/><ref name=pmid19062773/> Due to adverse effects asscoiated with the long-term use of benzodiazepines withdrawal from benzodiazepines in general leads to improved physical and mental health.<ref name=tdamobd2004 /><ref name=asapdacg /> The elderly are at an increased risk of suffering from both short- and long-term [[adverse drug reaction|adverse effects]].<ref name=tdamobd2004/><ref name=ohop/>

There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not major [[teratogens]], uncertainty remains as to whether they cause [[cleft palate]] in a small number of babies and whether neurobehavioural effects occur as a result of prenatal exposure;<ref name=ACOG /> they are known to cause [[Neonatal withdrawal|withdrawal symptoms in the newborn]]. Benzodiazepines can be taken in [[overdose]]s and can cause dangerous [[coma|deep unconsciousness]]. However, they are much less toxic than their predecessors, the [[barbiturate]]s, and death rarely results when a benzodiazepine is the only drug taken. When combined with other [[central nervous system depressants]] such as [[Alcoholic beverage|alcohol]] and [[opiates]], the potential for toxicity increases.<ref name=pmid9780123/> Benzodiazepines are commonly misused and taken in combination with other [[Drug abuse|drugs of abuse]].<ref name=Charlson_2009/><ref name=pmid10707430/><ref name=pmid10622686/>

==History==
[[File:Chlordiazepoxide 2.png|thumb|left|alt=Chemical structure diagram of a benzene ring fused to a diazepine ring. Cl is attached to the benzene, N H CH3 and O are attached to the diazepine.|The molecular structure of [[chlordiazepoxide]], the first benzodiazepine. It was marketed by [[Hoffmann–La Roche]] from 1960 branded as ''Librium''.]]

The first benzodiazepine, [[chlordiazepoxide]] (''Librium''), was synthesized in 1955 by [[Leo Sternbach]] while working at [[Hoffmann–La Roche]] on the development of tranquilizers. The pharmacological properties of the compounds prepared initially were disappointing, and Sternbach abandoned the project. Two years later, in April 1957, co-worker Earl Reeder noticed a "nicely crystalline" compound left over from the discontinued project while spring cleaning in the lab. This compound, later named chlordiazepoxide, had not been tested in 1955 because of Sternbach's focus on other issues. Expecting the pharmacology results to be negative and hoping to publish the chemistry-related findings, researchers submitted it for a standard battery of animal tests. Unexpectedly, the compound showed very strong [[sedative]], [[anticonvulsant]] and [[muscle relaxant]] effects. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name ''Librium''.<ref name="pmid34039">{{cite journal |author=Sternbach LH |title=The benzodiazepine story |journal=J Med Chem |volume=22 |issue=1 |pages=1–7 |year=1979 |pmid=34039 |doi=10.1021/jm00187a001 |quote=During this cleanup operation, my co-worker, Earl Reeder, drew my attention to a few hundred milligrams of two products, a nicely crystalline base and its hydrochloride. Both the base, which had been prepared by treating the quinazoline N-oxide 11 with methylamine, and its hydrochloride had been made sometime in 1955. The products were not submitted for pharmacological testing at that time because of our involvement with other problems }}</ref><ref name=Miller-Gold>{{cite journal |author=Miller NS, Gold MS |title=Benzodiazepines: reconsidered |journal=Adv Alcohol Subst Abuse |volume=8 |issue=3–4 |pages=67–84 |year=1990 |pmid=1971487 }}</ref> Following chlordiazepoxide, [[diazepam]] was marketed by Hoffmann–La Roche under the brand name ''Valium'' in 1963, and for a while the two were the most commercially successful drugs. The introduction of benzodiazepines led to a decrease in the prescription of [[barbiturate]]s, and by the 1970s they had largely replaced the older drugs for sedative and [[hypnotic]] uses.<ref name=isbn0-19-517668-5>{{cite book |author=Shorter E |title=A Historical Dictionary of Psychiatry |publisher=Oxford University Press |year=2005 |chapter=Benzodiazepines |pages=41–2 |isbn=0-19-517668-5 }}</ref>

The new group of drugs was initially greeted with optimism by the medical profession, but gradually concerns arose; in particular, the risk of dependence became evident in the 1980s. Benzodiazepines have a unique history in that they were responsible for the largest-ever [[class-action lawsuit]] against [[drugs manufacturers|drug manufacturers]] in the United Kingdom, involving 14,000 patients and 1,800 [[law firms]] that alleged the manufacturers knew of the dependence potential but intentionally withheld this information from doctors. At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of [[benzodiazepine dependence|dependence]] and [[withdrawal]]. This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines.<ref>{{cite journal |author=King MB |title=Is there still a role for benzodiazepines in general practice? |journal=Br J Gen Pract |volume=42 |issue=358 |pages=202–5 |year=1992 |pmid=1389432 |pmc=1372025 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1372025&blobtype=pdf |format=PDF }}</ref> The court case against the drug manufacturers never reached a verdict; [[legal aid]] had been withdrawn and there were allegations that the consultant psychiatrists, the expert witnesses, had a conflict of interest. This litigation led to changes in the [[British law]], making class action law suits more difficult.<ref name="urlHouse of Commons">{{cite web |url=http://www.publications.parliament.uk/pa/cm199899/cmselect/cmhealth/549/99072723.htm |title=Memorandum by Dr Reg Peart |author=Peart R |date=1999-06-01 |work=Minutes of Evidence |publisher=Select Committee on Health, House of Commons, UK Parliament |accessdate=2009-05-27 }}</ref>

Although antidepressants with anxiolytic properties have been introduced, and there is increasing awareness of the adverse effects of benzodiazepines, prescriptions for short term anxiety relief have not significantly dropped.<ref name=pmid18671662>{{cite journal |author=Lader M |title=Effectiveness of benzodiazepines: do they work or not? |journal=Expert Rev Neurother |volume=8 |issue=8 |pages=1189–91 |year=2008 |pmid=18671662 |doi=10.1586/14737175.8.8.1189 |url=http://www.expert-reviews.com/doi/full/10.1586/14737175.8.8.1189 }}</ref> For treatment of insomnia, benzodiazepines are now less popular than [[nonbenzodiazepine]]s, which include [[zolpidem]], [[zaleplon]] and [[eszopiclone]].<ref>{{Cite journal | last1 = Jufe | first1 = GS. | title = [New hypnotics: perspectives from sleep physiology] | journal = Vertex | volume = 18 | issue = 74 | pages = 294–9 | month = Jul-Aug | year = 2007 | pmid = 18265473 }}</ref> Nonbenzodiazepines are molecularly distinct, but nonetheless, they work on benzodiazepine receptors.<ref name=wake>{{cite journal |author=Lemmer B |title=The sleep–wake cycle and sleeping pills |journal=Physiol Behav |volume=90 |issue=2–3 |pages=285–93 |year=2007 |pmid=17049955 |doi=10.1016/j.physbeh.2006.09.006 }}</ref>

==Therapeutic uses==
{{See also|List of benzodiazepines}}
[[File:Midazolam.JPG|thumb|alt=Two 10 mL bottles labeled Midazolam. The bottle on the left has a label in red and says 1 mg/mL; the one on the right is in green and says 5 mg/mL. Both bottles have much fine print.|Injectable midazolam in 1&nbsp;mg/ml and 5&nbsp;mg/ml strengths]]

Benzodiazepines possess sedative, hypnotic, [[anxiolytic]], anticonvulsant, muscle relaxant, and [[anterograde amnesia|amnesic]] actions,<ref name=ip2002>{{cite book |author=Page C, Michael C, Sutter M, Walker M, Hoffman BB |title=Integrated Pharmacology |edition=2nd |year=2002 |publisher=C.V. Mosby |isbn=978-0723432210 }}</ref><ref name=pmid18175099>{{cite journal |author=Olkkola KT, Ahonen J |title=Midazolam and other benzodiazepines |journal=Handb Exp Pharmacol |volume=182 |issue=182 |pages=335–60 |year=2008 |pmid=18175099 |doi=10.1007/978-3-540-74806-9_16 }}</ref> which are useful in a variety of indications such as [[alcohol dependence]], [[seizures]], [[anxiety]], [[panic]], [[psychomotor agitation|agitation]] and insomnia. Most are administered orally; however, they can also be given [[intravenous therapy|intravenously]], [[intramuscular injection|intramuscularly]] or [[rectal]]ly.<ref name="BNF_2009">{{cite book |title=[[British National Formulary]] (BNF 57) |author=Royal Pharmaceutical Society of Great Britain |publisher=BMJ Group and RPS Publishing |year=2009 |isbn=9780853698456 }}</ref>{{rp|189}} In general, benzodiazepines are well-tolerated and are safe and effective drugs in the short term for a wide range of conditions.<ref name=Perugi>{{cite journal |author=Perugi G, Frare F, Toni C |title=Diagnosis and treatment of agoraphobia with panic disorder |journal=CNS Drugs |volume=21 |issue=9 |pages=741–64 |year=2007 |pmid=17696574 |doi=10.2165/00023210-200721090-00004 }}</ref><ref name=Tesar>{{cite journal |author=Tesar GE |title=High-potency benzodiazepines for short-term management of panic disorder: the U.S. experience |journal=J Clin Psychiatry |volume=51 |issue=Suppl |pages=4–10; discussion 50–3 |year=1990 |pmid=1970816 }}</ref> Tolerance can develop to their effects and there is also a risk of [[drug dependence|dependence]], and upon discontinuation a withdrawal syndrome may occur. These factors, combined with other possible secondary effects after prolonged use such as psychomotor, cognitive or memory impairments, limit their long term applicability.<ref>{{cite journal |author=Faught E |title=Treatment of refractory primary generalized epilepsy |journal=Rev Neurol Dis |volume=1 |issue=Suppl 1 |pages=S34–43 |year=2004 |pmid=16400293 }}</ref><ref>{{cite journal |author=Allgulander C, Bandelow B, Hollander E |title=WCA recommendations for the long-term treatment of generalized anxiety disorder |journal=CNS Spectr |volume=8 |issue=Suppl 1 |pages=53–61 |year=2003 |pmid=14767398 }}</ref> [[Long-term effects of benzodiazepines|The effects of long-term use]] or misuse include the tendency to cause or worsen [[cognitive deficit]]s, [[Clinical depression|depression]] and anxiety.<ref name=tdamobd2004>{{cite journal |author=Ashton H |title=The diagnosis and management of benzodiazepine dependence |journal=Curr Opin Psychiatry |volume=18 |issue=3 |pages=249–55 |year=2005 |pmid=16639148 |doi=10.1097/01.yco.0000165594.60434.84 |url=http://www.benzo.org.uk/amisc/ashdiag.pdf |format=PDF }}</ref><ref name=ohop/>

===Panic disorder===
Due to their effectiveness, tolerability and rapid onset of anxiolytic action, benzodiazepines are frequently used for the treatment of anxiety associated with panic disorder.<ref name="pmid15762816">{{cite journal |author=Stevens JC, Pollack MH |title=Benzodiazepines in clinical practice: consideration of their long-term use and alternative agents |journal=Journal of Clinical Psychiatry |volume=66 |issue=Suppl 2 |pages=21–27 |year=2005 |pmid=15762816|quote=The frequent use of benzodiazepines for the treatment of anxiety is likely a reflection of their effectiveness, rapid onset of anxiolytic effect, and tolerability.}}</ref> However, there is disagreement among expert bodies regarding the long-term use of benzodiazepines for panic disorder. The views range from those that hold that benzodiazepines are not effective long-term <ref name=cgftmamoa2004/> and that they should be reserved for treatment-resistant cases<ref>{{cite journal |author=Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJ |title=World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders |journal=World J. Biol. Psychiatry |volume=3 |issue=4 |pages=171–99 |year=2002 |month=October |pmid=12516310 |doi= 10.3109/15622970209150621|url=}}</ref> to that they are as effective in the long-term as [[selective serotonin reuptake inhibitors]].<ref name=APA/>

The [[American Psychiatric Association]] (APA) guidelines<ref name="APA">{{cite web |url=http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=PanicDisorder_2e_PracticeGuideline |format=PDF |title= APA Practice Guideline for the Treatment of Patients With Panic Disorder, Second Edition |author=Work Group on Panic Disorder |date=January 2009 |accessdate=07/12/09}}</ref> note that, in general, benzodiazepines are well tolerated, and their use for the initial treatment for panic disorder is strongly supported by numerous controlled trials. APA states that there is insufficient evidence to recommend any of the established panic disorder treatments over another. The choice of treatment between benzodiazepines, [[SSRI]]s, [[serotonin–norepinephrine reuptake inhibitors]], [[tricyclic antidepressant]]s or psychotherapy should be based on the patient's history, preference and other individual characteristics. Selective serotonin reuptake inhibitors are likely to be the best choice of pharmacotherapy for many patients with panic disorder, but benzodiazepines are also often used, and some studies suggest that these medications are still used with greater frequency than the SSRIs. One advantage of benzodiazepines is that they alleviate the anxiety symptoms much faster than antidepressants, and therefore may be preferred in patients for whom rapid symptom control is critical. However, this advantage is offset by the possibility of developing [[benzodiazepine dependence]]. APA does not recommend benzodiazepines for persons with depressive symptoms or a recent history of [[substance abuse]]. The APA guidelines state that, in general, pharmacotherapy of panic disorder should be continued for at least a year, and that clinical experience support continuing benzodiazepine treatment to prevent recurrence. Although major concerns about benzodiazepine tolerance and withdrawal have been raised, there is no evidence for significant dose escalation in patients using benzodiazepines long-term. For many such patients stable doses of benzodiazepines retain their efficacy over several years.<ref name=APA/>

Guidelines issued by the UK-based [[National Institute for Health and Clinical Excellence]] (NICE), carried out a systematic review using different methodology and came to a different conclusion. They questioned the accuracy of studies which were not placebo controlled and based on the findings of [[placebo-controlled studies]] they do not recommend use of benzodiazepines beyond two to four weeks, as tolerance and [[physical dependence]] develop rapidly, with withdrawal symptoms including [[rebound anxiety]] occurring after six weeks or more of use.<ref name=cgftmamoa2004>{{cite web |author=McIntosh A, Cohen A, Turnbull N ''et al.'' |title=Clinical guidelines and evidence review for panic disorder and generalised anxiety disorder |url=http://www.nice.org.uk/nicemedia/pdf/cg022fullguideline.pdf |publisher=National Collaborating Centre for Primary Care |format=PDF |year=2004 |accessdate=2009-06-16 }}</ref><ref>{{cite web |author=Barbui C, Cipriani A |title=Proposal for the inclusion in the WHO Model List of Essential Medicines of a selective serotonin-reuptake inhibitor for Generalised Anxiety Disorder |url=http://who.int/selection_medicines/committees/expert/17/application/Section24_GAD.pdf |publisher=WHO Collaborating Centre for Research and Training in Mental Health |format=PDF |year=2009 |accessdate=2009-06-23 }}</ref> Nevertheless, benzodiazepines continue to be prescribed for the long-term treatment of [[anxiety disorders]], although specific [[antidepressants]] and psychological therapies are recommended as the [[First-line treatment|first line]] treatment options with the [[anticonvulsant]] drug [[pregabalin]] indicated as a second or third line treatment and suitable for long term use.<ref>{{cite journal |author=Cloos JM, Ferreira V |title=Current use of benzodiazepines in anxiety disorders |journal=Current Opinion in Psychiatry |volume=22 |issue=1 |pages=90–95 |year=2009 |pmid=19122540 |doi=10.1097/YCO.0b013e32831a473d }}</ref> NICE stated that long-term use of benzodiazepines for panic disorder with or without [[agoraphobia]] is an unlicensed indication, does not have long term efficacy, and is therefore not recommended by clinical guidelines. Psychological therapies such as [[cognitive behavioural therapy]] are recommended as a first line therapy for panic disorder; benzodiazepine use has been found to interfere with therapeutic gains from these therapies.<ref name=cgftmamoa2004 />

Benzodiazepines are usually administered orally; however, very occasionally lorazepam or diazepam may be given intravenously for the treatment of [[panic attacks]].<ref name="BNF_2009"/>

===Generalized anxiety disorder===
Benzodiazepines have robust efficacy in the short-term management of [[generalized anxiety disorder]] (GAD), but were not shown to be effective in producing long-term improvement overall.<ref name="pmid17881433">{{cite journal |author=Martin JL, Sainz-Pardo M, Furukawa TA, Martín-Sánchez E, Seoane T, Galán C |title=Benzodiazepines in generalized anxiety disorder: heterogeneity of outcomes based on a systematic review and meta-analysis of clinical trials |journal=J. Psychopharmacol. (Oxford) |volume=21 |issue=7 |pages=774–82 |year=2007 |month=September |pmid=17881433 |doi=10.1177/0269881107077355}}</ref> According to [[National Institute for Health and Clinical Excellence]] (NICE), benzodiazepines can be used in the immediate management of GAD, if necessary. However, they should not usually be given for longer than 2–4 weeks. The only medications NICE recommends for the longer term management of GAD are antidepressants.<ref name=NICECG022>{{cite web |author=|title=Clinical Guideline 22 (amended). Anxiety: management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care |pages=23–25| url=http://www.nice.org.uk/nicemedia/pdf/CG022NICEguidelineamended.pdf |publisher=National Institute for Health and Clinical Excellence |format=PDF |year=2007 |accessdate=2009-08-08 }}</ref>

Similarly, Canadian Psychiatric Association (CPA) recommends benzodiazepines [[alprazolam]], [[bromazepam]], [[lorazepam]], and [[diazepam]] only as a second-line choice, if the treatment with two different antidepressants was unsuccessful. Although they are second-line agents, benzodiazepines can be used for a limited time to relieve severe anxiety and agitation. CPA guidelines note that after 4–6 weeks the effect of benzodiazepines may decrease to the level of placebo, and that benzodiazepines are less effective than antidepressants in alleviating [[rumination (psychology)|ruminative worry]], the core symptom of GAD. However, in some cases a prolonged treatment with benzodiazepines as the add-on to an antidepressant may be justified.<ref name="pmid16933543">{{cite journal |author=Canadian Psychiatric Association |title=Clinical practice guidelines. Management of anxiety disorders |journal=Can J Psychiatry |volume=51 |issue=8 Suppl 2 |pages=51S–55S |year=2006 |month=July |pmid=16933543 |url=http://publications.cpa-apc.org/media.php?mid=440&xwm=true |format=PDF |accessdate=2009-08-08}}</ref>

===Insomnia===
Benzodiazepines can be useful for short-term treatment of insomnia. Their use beyond two to four weeks is not recommended due to the risk of dependence. Preferably, benzodiazepines are taken intermittently and at the lowest effective dose. They improve sleep related problems by shortening the time spent in bed before falling asleep, prolonging the sleep time and, in general, reducing wakefulness.<ref name=nice-hypnotics>{{cite web |author=|title=Technology Appraisal Guidance 77. Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia |url=http://www.nice.org.uk/nicemedia/pdf/TA077fullguidance.pdf |publisher=National Institute for Clinical Excellence |format=PDF |year=2004 |month=April|accessdate=2009-07-26}}</ref><ref name="pmid17853625">{{cite journal |author=Ramakrishnan K, Scheid DC |title=Treatment options for insomnia |journal=Am Fam Physician |volume=76 |issue=4 |pages=517–26 |year=2007 |month=August |pmid=17853625 |url=http://www.aafp.org/afp/20070815/517.html}}</ref> However, they worsen sleep quality by increasing light sleep and decreasing deep sleep. Other drawbacks of hypnotics, including benzodiazepines, are possible tolerance to their effects, [[rebound insomnia]] and reduced slow wave sleep and a withdrawal period typified by [[rebound insomnia]] and a prolonged period of anxiety and agitation.<ref name="handbook_of_integrative">{{Cite book | last1 = D. Maiuro PhD | first1 = Roland | title = Handbook of Integrative Clinical Psychology, Psychiatry, and Behavioral Medicine: Perspectives, Practices, and Research | date = 13 December 2009 | publisher = Springer Publishing Company | url = http://books.google.com/?id=4Tkdm1vRFbUC | isbn = 0-8261-1094-0 | pages = 128–130 }}</ref><ref name="ahrq"/> Among the benzodiazepines approved in the US for the treatment of insomnia, the fast acting ones with short half-lives such as [[estazolam]], [[triazolam]], and [[temazepam]] are recommended.<ref name="pmid17853625"/> Longer-acting benzodiazepines such as [[nitrazepam]] and [[diazepam]] have residual effects that may persist into the next day and are, in general, not recommended.<ref name=nice-hypnotics/>

It is not clear whether the new [[nonbenzodiazepine]] hypnotics (Z-drugs) are better than the short-acting benzodiazepines. The efficacy of these two groups of medications is similar.<ref name=nice-hypnotics/><ref name="ahrq"/> According to the US [[Agency for Healthcare Research and Quality]], indirect comparison indicates that side effects from benzodiazepines may be about twice as frequent as from nonbenzodiazepines.<ref name="ahrq">{{cite web |author=Buscemi N, Vandermeer B, Friesen C, Bialy L, Tubman M, Ospina M, Klassen TP, Witmans M |title=Manifestations and Management of Chronic Insomnia in Adults. Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment Number 125 |year=2005 |month=June |format =PDF |url=http://www.ahrq.gov/clinic/epcsums/insomnsum.htm}}</ref> This may make the non-benzodiazepines preferable as the first-line long-term treatment of insomnia.<ref name="pmid17853625"/> However, the UK [[National Institute for Health and Clinical Excellence]] did not find any convincing evidence in favor of Z-drugs. NICE review pointed out that short-acting Z-drugs were inappropriately compared in clinical trials with long-acting benzodiazepines. There have been no trials comparing short-acting Z-drugs with appropriate doses of short-acting benzodiazepines. Based on this, NICE recommended choosing the hypnotic based on cost and the patient's preference.<ref name=nice-hypnotics/>

It has been argued that long term use of [[hypnotics]] and over prescribing of these drugs represents an unjustifiable risk, especially to the elderly, and is harmful for the [[public health]] in general.<ref name="therbull">{{cite journal |title=What's wrong with prescribing hypnotics? |journal=Drug Ther Bull |volume=42 |issue=12 |pages=89–93 |year=2004 |pmid=15587763 |doi=10.1136/dtb.2004.421289 }} [http://www.nelm.nhs.uk/en/NeLM-Area/Evidence/Drug-Class-Focused-Reviews/Whats-wrong-with-prescribing-hypnotics/ NeLM summary].</ref>

===Seizures===
Prolonged convulsive [[epileptic seizure]]s are a [[medical emergency]] that can usually be dealt with effectively by administering fast-acting benzodiazepines, which are potent [[anticonvulsants]]. In a hospital environment, [[intravenous]] [[lorazepam]] and [[diazepam]] are first-line choices, diazepam due to its faster onset and lorazepam for its longer duration of action. In the community, intravenous administration is not practical and so [[rectal]] diazepam or (more recently) [[buccal mucosa|buccal]] [[midazolam]] are used, with a preference for midazolam as its administration is easier and more socially acceptable.<ref name=SIGN70>{{cite web |url=http://sign.ac.uk/pdf/sign70.pdf |format=PDF |title=Diagnosis and management of epilepsy in adults |accessdate=2009-06-05 |author=Scottish Intercollegiate Guidelines Network |year=2005 |pages=17–19 }}</ref><ref name=NICECG020>{{cite web |url=http://www.nice.org.uk/nicemedia/pdf/CG020fullguideline.pdf |format=PDF |title=Clinical Guidelines and Evidence Review for the Epilepsies: diagnosis and management in adults and children in primary and secondary care |accessdate=2009-06-02 |author=Stokes T, Shaw EJ, Juarez-Garcia A, Camosso-Stefinovic J, Baker R |year=2004 |publisher=Royal College of General Practitioners |pages=61, 64–65 }}</ref>

When benzodiazepines were first introduced, they were enthusiastically adopted for treating all forms of [[epilepsy]]. However, drowsiness and [[drug tolerance|tolerance]] become problems with continued use and none are now considered [[first-line treatment|first-line]] choices for long-term epilepsy therapy.<ref name="pmid19298435">{{cite journal |author=Shorvon SD |title=Drug treatment of epilepsy in the century of the ILAE: the second 50 years, 1959–2009 |journal=Epilepsia |volume=50 |issue=Suppl 3 |pages=93–130 |year=2009 |pmid=19298435 |doi=10.1111/j.1528-1167.2009.02042.x |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/122250225/HTMLSTART }}</ref> Clobazam is widely used by specialist epilepsy clinics worldwide (but it is not available in the US) and clonazepam is popular in France.<ref name="pmid19298435"/> In the UK, both clobazam and clonazepam are second-line choices for treating many forms of epilepsy.<ref name=NICECG020b>{{cite web |url=http://www.nice.org.uk/nicemedia/pdf/CG020fullguideline_appendixB.pdf |format=PDF |title=Clinical Guidelines and Evidence Review for the Epilepsies: diagnosis and management in adults and children in primary and secondary care (Appendix B) |accessdate=2009-06-02 |author=Stokes T, Shaw EJ, Juarez-Garcia A, Camosso-Stefinovic J, Baker R |year=2004 |publisher=Royal College of General Practitioners |page=432 }}</ref> Clobazam also has a useful role for very short-term seizure [[prophylaxis]] and in [[catamenial epilepsy]].<ref name="pmid19298435"/> Discontinuation after long term use in epilepsy requires additional caution because of the risks of rebound seizures. Therefore, the dose is slowly tapered over a period of up to six months or longer.<ref name=NICECG020/>

===Alcohol withdrawal===
[[Chlordiazepoxide]] is the most commonly used benzodiazepine for [[alcohol detoxification]],<ref>{{cite journal |author=Ashworth M, Gerada C |title=ABC of mental health. Addiction and dependence--II: Alcohol |journal=BMJ |volume=315 |issue=7104 |pages=358–60 |year=1997 |pmid=9270461 |pmc=2127236 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2127236&blobtype=pdf |format=PDF }}</ref> but [[diazepam]] may be used as an alternative. Both are used in the detoxification of individuals who are motivated to stop drinking, and are prescribed for a short period of time to reduce the risks of developing tolerance and dependence to the benzodiazepine medication itself.<ref name="BNF_2009"/>{{rp|275}} The benzodiazepines with a longer half-life make detoxification more tolerable, and dangerous alcohol withdrawal effects are less likely to occur. On the other hand, short-acting benzodiazepines may lead to [[breakthrough seizure]]s, and are therefore not recommended for detoxification in an outpatient setting. [[Oxazepam]] and [[lorazepam]] are often used in patients at risk of drug accumulation, particularly the elderly and those with [[cirrhosis]], because they are metabolized differently from other benzodiazepines, through [[Glucuronic acid#Glucuronidation|conjugation]].<ref>{{cite journal |author=Kraemer KL, Conigliaro J, Saitz R |title=Managing alcohol withdrawal in the elderly |journal=Drugs Aging |volume=14 |issue=6 |pages=409–25 |year=1999 |pmid=10408740 |doi=10.2165/00002512-199914060-00002 }}</ref><ref>{{cite journal |author=Prater CD, Miller KE, Zylstra RG |title=Outpatient detoxification of the addicted or alcoholic patient |journal=Am Fam Physician |volume=60 |issue=4 |pages=1175–83 |year=1999 |pmid=10507746 |url=http://www.aafp.org/afp/990915ap/1175.html }}</ref>

Benzodiazepines are the preferred choice in the management of [[alcohol withdrawal syndrome]], particularly for the prevention and treatment of the dangerous complication of seizures and in subduing severe [[delirium]].<ref>{{cite journal |author=Ebell MH |title=Benzodiazepines for alcohol withdrawal |journal=Am Fam Physician |volume=73 |issue=7 |pages=1191 |year=2006 |pmid=16623205 |url=http://www.aafp.org/afp/20060401/cochrane.html#c2 }}</ref> Lorazepam is the only benzodiazepine with predictable intramuscular absorption and it is the most effective in preventing and controlling acute seizures.<ref>{{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 }}</ref>

===Anxiety===
Benzodiazepines are sometimes used in the treatment of acute anxiety as they bring about rapid and marked or moderate relief of symptoms in most individuals<ref name=cgftmamoa2004/>; however, they are not recommended beyond 2–4 weeks of use due to risks of tolerance and dependence and a lack of long-term effectiveness. Compared to other pharmacological treatments benzodiazepines are twice as likely to lead to a relapse of the underlying condition upon discontinuation. Psychological therapies and other pharmacological therapies are recommended for the long-term treatment of generalised anxiety disorder. Antidepressants have higher remission rates and are, in general, safe and effective in the short and long-term.<ref name=cgftmamoa2004/>

===Other indications===
Benzodiazepines are often prescribed for a wide range of conditions, including the following:
* They can be very useful in intensive care to sedate patients receiving [[mechanical ventilation]] or those in extreme distress. Caution is exercised in this situation due to the occasional occurrence of [[respiratory depression]] and it is recommended that [[benzodiazepine overdose]] treatment facilities should be available.<ref>{{Cite journal | last1 = Devlin | first1 = JW. | last2 = Roberts | first2 = RJ. | title = Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids. | journal = Crit Care Clin | volume = 25 | issue = 3 | pages = 431–49, vii | month = Jul | year = 2009 | doi = 10.1016/j.ccc.2009.03.003 | pmid = 19576523 }}</ref>
* Benzodiazepines are effective as medication given a couple of hours before surgery to relieve anxiety. They also produce [[amnesia]], which can be useful as patients will not be able to remember any unpleasantness from the procedure.<ref name="Broscheit-2008">{{Cite journal | last1 = Broscheit | first1 = J. | last2 = Kranke | first2 = P. | title = [The preoperative medication: background and specific indications for the selection of the drugs] | journal = Anasthesiol Intensivmed Notfallmed Schmerzther | volume = 43 | issue = 2 | pages = 134–43 | month = Feb | year = 2008 | doi = 10.1055/s-2008-1060547 | pmid = 18293248 }}</ref> They are also used in patients with [[dental phobia]] as well as some ophthalmic procedures like refractive surgery; although such use is controversial and only recommended for those who are very anxious.<ref>{{Cite journal | last1 = Berthold | first1 = C. | title = Enteral sedation: safety, efficacy, and controversy. | journal = Compend Contin Educ Dent | volume = 28 | issue = 5 | pages = 264–71; quiz 272, 282 | month = May | year = 2007 | pmid = 17607891 }}</ref> Midazolam is the most commonly prescribed for this use because of its strong sedative actions and fast recovery time, as well as its water solubility, which reduces pain upon injection. Diazepam and lorazepam are sometimes used. Lorazepam has particularly marked amnesic properties that may make it more effective when amesia is the desired effect.<ref name="BNF_2009"/>{{rp|693}}
* Benzodiazepines are well known for their strong muscle-relaxing properties and can be useful in the treatment of muscle spasms,<ref name="BNF_2009"/>{{rp|577–578}} although tolerance often develops to their muscle relaxant effects.<ref name=tdamobd2004 /> [[Baclofen]]<ref>{{cite journal |author=Mañon-Espaillat R, Mandel S |title=Diagnostic algorithms for neuromuscular diseases |journal=Clin Podiatr Med Surg |volume=16 |issue=1 |pages=67–79 |year=1999 |pmid=9929772 }}</ref> or [[tizanidine]] are sometimes used as an alternative to benzodiazepines. Tizanidine has been found to have superior tolerability compared to diazepam and baclofen.<ref name="Kamen-2008">{{Cite journal | last1 = Kamen | first1 = L. | last2 = Henney | first2 = HR. | last3 = Runyan | first3 = JD. | title = A practical overview of tizanidine use for spasticity secondary to multiple sclerosis, stroke, and spinal cord injury. | journal = Curr Med Res Opin | volume = 24 | issue = 2 | pages = 425–39 | month = Feb | year = 2008 | doi = 10.1185/030079908X261113 | pmid = 18167175 }}</ref>
* Benzodiazepines are also used to treat the acute panic caused by [[hallucinogen]] intoxication.<ref>{{cite book |author=Wyatt JP, Illingworth RN, Robertson CE, Clancy MJ, Munro PT |title=Oxford Handbook of Accident and Emergency Medicine |edition=2nd |year=2005 |publisher=Oxford University Press |isbn=978-0198526230 |pages=173–208 |chapter=Poisoning }}</ref> Benzodiazepines are also used to calm the acutely agitated individual and can, if required, be given via an intramuscular injection.<ref>{{cite journal |author=Zimbroff DL |title=Pharmacological control of acute agitation: focus on intramuscular preparations |journal=CNS Drugs |volume=22 |issue=3 |pages=199–212 |year=2008 |pmid=18278976 |doi=10.2165/00023210-200822030-00002 }}</ref> They can sometimes be effective in the short-term treatment of psychiatric emergencies such as acute [[psychosis]] as in [[schizophrenia]] or [[mania]], bringing about rapid tranquillization and sedation until the effects of [[Lithium pharmacology|lithium]] or [[neuroleptics]] (antipsychotics) take effect. [[Lorazepam]] is most commonly used but [[clonazepam]] is sometimes prescribed for acute psychosis or mania;<ref>{{cite journal |author=Curtin F, Schulz P |journal=J Affect Disord |title=Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis |volume=78 |issue=3 |pages=201–8 |year=2004 |pmid=15013244 |doi=10.1016/S0165-0327(02)00317-8 }}</ref><ref>{{cite journal |author=Gillies D, Beck A, McCloud A, Rathbone J, Gillies D |title=Benzodiazepines alone or in combination with antipsychotic drugs for acute psychosis |journal=Cochrane Database Syst Rev |issue=4 |pages=CD003079 |year=2005 |pmid=16235313 |doi=10.1002/14651858.CD003079.pub2 }}</ref> their long-term use is not recommended due to risks of dependence.<ref name="BNF_2009"/>{{rp|204}}
* [[Clonazepam]], a benzodiazepine is used to treat many forms of [[parasomnia]].<ref>{{Cite journal | last1 = Schenck | first1 = CH. | last2 = Arnulf | first2 = I. | last3 = Mahowald | first3 = MW. | title = Sleep and sex: what can go wrong? A review of the literature on sleep related disorders and abnormal sexual behaviors and experiences. | journal = Sleep | volume = 30 | issue = 6 | pages = 683–702 | month = Jun | year = 2007 | doi = | pmid = 17580590 | pmc = 1978350 }}</ref> [[Rapid eye movement behavior disorder]] responds well to low doses of clonazepam.<ref>{{Cite journal | last1 = Ferini-Strambi | first1 = L. | last2 = Zucconi | first2 = M. | title = REM sleep behavior disorder. | journal = Clin Neurophysiol | volume = 111 Suppl 2 | pages = S136–40 | month = Sep | year = 2000 | pmid = 10996567 }}</ref><ref>{{Cite journal | last1 = Silber | first1 = MH. | title = Sleep disorders. | journal = Neurol Clin | volume = 19 | issue = 1 | pages = 173–86 | month = Feb | year = 2001 | pmid = 11471763 | doi = 10.1016/S0733-8619(05)70011-6 }}</ref> [[Restless legs syndrome]] can be treated using clonazepam as a third line treatment option as the use of clonazepam is still investigational.<ref>{{Cite journal | title = [Restless legs syndrome: diagnosis and treatment. Opinion of Brazilian experts] | journal = Arq Neuropsiquiatr | volume = 65 | issue = 3A | pages = 721–7 | month = Sep | year = 2007 | pmid = 17876423 }}</ref><ref>{{Cite journal | last1 = Trenkwalder | first1 = C. | last2 = Hening | first2 = WA. | last3 = Montagna | first3 = P. | last4 = Oertel | first4 = WH. | last5 = Allen | first5 = RP. | last6 = Walters | first6 = AS. | last7 = Costa | first7 = J. | last8 = Stiasny-Kolster | first8 = K. | last9 = Sampaio | first9 = C. | title = Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. | journal = Mov Disord | volume = 23 | issue = 16 | pages = 2267–302 | month = Dec | year = 2008 | doi = 10.1002/mds.22254 | url = http://www.movementdisorders.org/publications/ebm_reviews/treatmentofrls.pdf | format = PDF | pmid = 18925578 }}</ref>
* Benzodiazepines are sometimes used for [[obsessive compulsive disorder]], although they are generally believed to be ineffective for this indication; effectiveness was however, found in one small study.<ref>{{Cite book |first1=Alan |last1=F. |first2=MD |last2=Schatzberg |first3=Charles B. |last3=Nemeroff |first4=Jacob |last4=Ballon | title = The American Psychiatric Publishing Textbook of Psychopharmacology (Schatzberg, American Psychiatric Publishing Textbook of Psychopharmacology) | date = 31 July 2009 | edition = 4 | publisher = American Psychiatric Publishing, Inc. | url = http://books.google.com/?id=Xx7iNGdV25IC&pg=PA470 | isbn = 978-1-58562-309-9 | page = 470 }}</ref> Benzodiazepines can be considered as a treatment option in treatment resistant cases.<ref>{{Cite journal | last1 = Bandelow | first1 = B. | title = The medical treatment of obsessive-compulsive disorder and anxiety. | journal = CNS Spectr | volume = 13 | issue = 9 Suppl 14 | pages = 37–46 | month = Sep | year = 2008 | pmid = 18849910 }}</ref>
* [[Antipsychotics]] are generally a first-line treatment for delirium; however, when [[delirium]] is caused by alcohol or sedative hypnotic [[withdrawal]], benzodiazepines are a first-line treatment.<ref name="Attard-2008">{{Cite journal | last1 = Attard | first1 = A. | last2 = Ranjith | first2 = G. | last3 = Taylor | first3 = D. | title = Delirium and its treatment. | journal = CNS Drugs | volume = 22 | issue = 8 | pages = 631–44 | month =  | year = 2008 | pmid = 18601302 | doi = 10.2165/00023210-200822080-00002 }}</ref>

==Side effects==
{{See also|Long-term effects of benzodiazepines|Paradoxical reaction#Benzodiazepines|}}
The most common side effects of benzodiazepines are related to their sedating and muscle-relaxing action. They include [[drowsiness]], dizziness and decreased alertness and concentration. Lack of [[motor coordination|coordination]] may result in falls and injuries, particularly in the elderly.<ref name="isbn0-683-30128-4">{{cite book |author=Ballenger JC |editor=Sadock VA, Sadock BJ, Kaplan HI (eds.) |title=Kaplan & Sadock's Comprehensive Textbook of Psychiatry |edition=7th |chapter=Benzodiazepine receptors agonists and antagonists |publisher=Lippincott Williams & Wilkins |pages=2317–23 |year=2000 |isbn=0-683-30128-4 }}</ref><ref name="isbn0-470-02821-1">{{cite book |author=Tasman A, Lieberman JA |title=Handbook of Psychiatric Drugs |publisher=Wiley |year=2006 |page=151 |isbn=0-470-02821-1 }}</ref><ref name="pmid18929314">{{cite journal | author = Stone KL, Ensrud KE, Ancoli-Israel S | title = Sleep, insomnia and falls in elderly patients | journal = Sleep Med. | volume = 9 Suppl 1 | issue = | pages = S18–22 | year = 2008 | month = September | pmid = 18929314 | doi = 10.1016/S1389-9457(08)70012-1 }}</ref> Another result is impairment of driving skills and increased likelihood of road traffic accidents.<ref>{{cite journal |author=Rapoport MJ, Lanctôt KL, Streiner DL |title=Benzodiazepine use and driving: a meta-analysis |journal=J Clin Psychiatry |year=2009 |volume=70 |issue=5 |pages=663–73 |pmid=19389334 |doi=10.4088/JCP.08m04325 }}</ref><ref>{{cite journal |author=Orriols L, Salmi LR, Philip P |title=The impact of medicinal drugs on traffic safety: a systematic review of epidemiological studies |journal=Pharmacoepidemiol Drug Saf |year=2009 |pmid=19418468 |doi=10.1002/pds.1763 |volume=18 |issue=8 |pages=647–58 |pmc=2780583 }}</ref> Decreased libido and erection problems are a common side effect. Depression and [[disinhibition]] may emerge. [[Hypotension]] and suppressed breathing may be encountered with intravenous use.<ref name="isbn0-683-30128-4"/><ref name="isbn0-470-02821-1"/> Less common side effects include nausea and changes in appetite, blurred vision, confusion, [[euphoria (emotion)|euphoria]], [[depersonalization]] and nightmares. Cases of [[liver toxicity]] have been described but are very rare.<ref name="BNF_2009"/>{{rp|183–189}}<ref>{{cite web |url=http://www.medicinenet.com/benzodiazepines-oral/article.htm |title=Benzodiazepines–oral |year=2005 |accessdate=2008-04-10 |publisher=MedicineNet }}</ref>

===Paradoxical effects===
[[Paradoxical reactions]], such as increased seizures in epileptics,<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. | url = http://www3.interscience.wiley.com/cgi-bin/fulltext/120119477/PDFSTART | format = PDF | 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> [[aggression]], violence, [[impulsivity]], [[irritability]] and suicidal behavior sometimes occur. These reactions have been explained as consequences of disinhibition, that is loss of control over socially unacceptable behavior. Paradoxical reactions are rare in the general population, with an incidence rate below 1% and similar to placebo.<ref name=pmid18922233>{{cite journal |author=Saïas T, Gallarda T |title=[Paradoxical aggressive reactions to benzodiazepine use: a review] |language=French |journal=Encephale |volume=34 |issue=4 |pages=330–6 |year=2008 |pmid=18922233 |doi=10.1016/j.encep.2007.05.005 }}</ref><ref name=badar2002>{{cite journal |author=Paton C |title=Benzodiazepines and disinhibition: a review |journal=Psychiatr Bull R Coll Psychiatr |volume=26 |issue=12 |pages=460–2 |year=2002 |doi=10.1192/pb.26.12.460 |url=http://pb.rcpsych.org/cgi/content/full/26/12/460 }}</ref> However, they occur with greater frequency in recreational abusers, individuals with [[borderline personality disorder]], children, and patients on high-dosage regimes.<ref name="Bond_1998">{{cite journal |author=Bond AJ |title=Drug-induced behavioural disinhibition: incidence, mechanisms and therapeutic implications |journal=CNS Drugs |volume=9 |issue=1 |pages=41–57 |year=1998 |doi=10.2165/00023210-199809010-00005 }}</ref><ref name="Drummer_2002">{{cite journal |author=Drummer OH |title=Benzodiazepines—effects on human performance and behavior |journal=Forensic Sci Rev |volume=14 |issue=1–2 |pages=1–14 |year=2002 |url=http://www.ndaa.org/pdf/ntlc_benzodiazepines.pdf |format=PDF |accessdate=2009-05-27 }}</ref> In these groups, [[impulse control]] problems are perhaps the most important risk factor for disinhibition; learning disabilities and neurological disorders are also significant risks. Most reports of disinhibition involve high doses of high-potency benzodiazepines.<ref name=badar2002 /> Paradoxical effects may also appear after chronic use of benzodiazepines.<ref name=cbpham>{{cite book |author=Ashton H |editor=Ayers S, Baum A, McManus C, Newman S (eds.) |title=Cambridge Handbook of Psychology, Health and Medicine |edition=2nd |year=2007 |publisher=Cambridge University Press |isbn=978-0521879972 |pages=675–8 |chapter=Drug dependency: benzodiazepines }}</ref>

===Cognitive effects===
The short-term use of benzodiazepines adversely affects multiple areas of cognition; most notably, it interferes with the formation and consolidation of memories of new material and may induce complete anterograde amnesia.<ref name="isbn0-683-30128-4"/> However, researchers hold contrary opinions regarding the effects of long-term administration. One view is that many of the short-term effects continue into the long-term and may even worsen, and are not resolved after quitting benzodiazepines. Another view maintains that cognitive deficits in chronic benzodiazepine users occur only for a short period after the dose, or that the anxiety disorders is the cause of these deficits. While the definitive studies are lacking, the former view recently received support from a meta-analysis of 13 small studies.<ref name="pmid14731058">{{cite journal |author=Barker MJ, Greenwood KM, Jackson M, Crowe SF |title=Cognitive effects of long-term benzodiazepine use: a meta-analysis |journal=CNS Drugs |volume=18 |issue=1 |pages=37–48 |year=2004 |pmid=14731058 |doi=10.2165/00023210-200418010-00004}}</ref><ref name="pmid15762814">{{cite journal |author= Stewart SA |title= The effects of benzodiazepines on cognition |journal= J Clin Psychiatry |volume=66 |issue= Suppl 2 |pages=9–13 |year=2005 |pmid=15762814 |url=http://psychiatrist.com/supplenet/v66s02/v66s0202.pdf |format=PDF}}</ref> This meta-analysis found that long-term use of benzodiazepines was associated with moderate to large adverse effects on all areas of cognition, with [[visuospatial]] memory being the most commonly detected impairment. Some of the other impairments reported were decreased IQ, visiomotor coordination, information processing, verbal learning and concentration. The authors of the meta-analysis<ref name="pmid14731058"/> and a later reviewer<ref name="pmid15762814"/> noted that the applicability of this meta-analysis is limited because the subjects were taken mostly from withdrawal clinics, the coexisting drug, alcohol use, and psychiatric disorders were not defined, and several of the included studies conducted the cognitive measurements during the withdrawal period.

===Long-term effects===
The [[long-term adverse effects of benzodiazepines]] include a general deterioration in physical and [[mental health]] and tend to increase with time. Not everyone, however, experiences problems with long-term use. The adverse effects can include [[cognitive impairment]], as well as affective and behavioural problems. Feelings of turmoil, difficulty in thinking constructively, loss of sex-drive, agoraphobia and social phobia, increasing anxiety and depression, loss of interest in leisure pursuits and interests, and an inability to experience or express feelings can also occur.<ref name=asapdacg>{{cite book |editor=Haddad P, Dursun S, Deakin B (eds.) |title=Adverse Syndromes and Psychiatric Drugs: A Clinical Guide |year=2004 |publisher=Oxford University Press |isbn=978-0198527480 |pages=239–60 |author=Ashton H |chapter=Benzodiazepine dependence }}</ref><ref>{{cite book |editor=Palmer S, Dainow S, Milner P (eds.) |title=Counselling: The BACP Counselling Reader |volume=1 |year=1996 |publisher=Sage |isbn=978-0803974777 |pages=211–4 |url=http://books.google.com/?id=wnIBEQKQi7IC |author=Hammersley D, Beeley L |chapter=The effects of medication on counselling }}</ref> Additionally an altered perception of self, environment and relationships may occur.<ref name="pmid15762814" />

===Withdrawal syndrome===
{{Main|Benzodiazepine dependence|Benzodiazepine withdrawal syndrome}}

====Tolerance, dependence and withdrawal====
[[Image:Diazepam2mgand5mgtablets.JPG|thumb|right|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]].]]

The main problem of the chronic use of benzodiazepines is the development of [[drug tolerance|tolerance]] and [[physical dependence|dependence]]. Tolerance manifests itself as diminished pharmacological effect and develops relatively quickly to the sedative, hypnotic, anticonvulsant and muscle relaxant actions of benzodiazepines. Tolerance to anti-anxiety effects develops more slowly with little evidence of continued effectiveness beyond four to six months of continued use. In general, tolerance to the amnesic effects does not occur.<ref name=tdamobd2004 /><ref>{{cite journal |author=Longo LP, Johnson B |title=Addiction: part I. Benzodiazepines—side effects, abuse risk and alternatives |journal=Am Fam Physician |volume=61 |issue=7 |pages=2121–8 |year=2000 |pmid=10779253 |url=http://www.aafp.org/afp/20000401/2121.html }}</ref> However, controversy exists as to tolerance to the anxiolytic effects with some evidence that benzodiazepines retain efficacy<ref name="pmid16528135">{{cite journal |author=Nardi AE, Perna G |title=Clonazepam in the treatment of psychiatric disorders: an update |journal=Int Clin Psychopharmacol |volume=21 |issue=3 |pages=131–42 |year=2006 |month=May |pmid=16528135 |doi=10.1097/01.yic.0000194379.65460.a6 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0268-1315&volume=21&issue=3&spage=131}}</ref> and opposing evidence from a systematic review of the literature that tolerance frequently occurs<ref name=Perugi /><ref name=cgftmamoa2004 /> and some evidence that anxiety may worsen with long-term use.<ref name=tdamobd2004 /> The question of tolerance to the amnesic effects of benzodiazepines is similarly unclear.<ref name="pmid15762818">{{cite journal |author=Otto MW, Bruce SE, Deckersbach T |title=Benzodiazepine use, cognitive impairment, and cognitive-behavioral therapy for anxiety disorders: issues in the treatment of a patient in need |journal=J Clin Psychiatry |volume=66 |issue=Suppl 2 |pages=34–8 |year=2005 |pmid=15762818 |url=http://psychiatrist.com/supplenet/v66s02/v66s0206.pdf |format=PDF }}</ref> Some evidence suggests that partial tolerance does develop, and "the memory impairment is limited to a narrow window within 90 minutes after each dose".<ref name="pmid15078112">{{cite journal |author=Chouinard G |title=Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound |journal=J Clin Psychiatry |volume=65 |issue=Suppl 5 |pages=7–12 |year=2004 |pmid=15078112 |url=http://psychiatrist.com/supplenet/v65s05/v65s0502.pdf |format=PDF }}</ref>

Discontinuation of benzodiazepines or abrupt reduction of the dose, even after a relatively short course of treatment (three 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"/>

====Withdrawal symptoms and management====
[[File:Chlordiazepoxidetabletsgeneric.JPG|thumb|right|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]].]]

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 (mood)|depression]], [[suicidal]] behavior, [[psychosis]], [[seizures]] and [[delirium tremens]].<ref name="isbn0-19-856667-0">{{cite book |author=Harrison PC, Gelder MG, Cowen P |title=Shorter Oxford Textbook of Psychiatry |edition=5th |publisher=Oxford University Press |year=2006 |pages=461–2 |chapter=The misuse of alcohol and drugs |isbn=0-19-856667-0 }}</ref> Severe symptoms usually occur as a result of abrupt or over-rapid withdrawal. Abrupt withdrawal can be dangerous, therefore a gradual reduction regime is recommended.<ref name=pmid19062773>{{cite journal |author=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 }}</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 |author=Longmore M, Scally P, Collier J |edition=6th |title=Oxford Handbook of Clinical Specialties |publisher=Oxford University Press |year=2003 |page=366<!--Please replace this with "pages=" and the pages of the chapter.--> |chapter=Chapter 4<!--Please replace this with the chapter title.--> |isbn=0-19-852518-4 }}</ref> Approximately 10% of patients will 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 |journal=J Subst Abuse Treat |year=1991 |volume=8 |issue=1–2 |pages=19–28 |title=Protracted withdrawal syndromes from benzodiazepines |author=Ashton H |pmid=1675688 |url=http://benzo.org.uk/ashpws.htm |doi=10.1016/0740-5472(91)90023-4 }}</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's being poorly managed. Over-rapid withdrawal from benzodiazepines increases the severity of the withdrawal syndrome and increases the failure rate. A slow and gradual [[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}} 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 web |url=http://benzo.org.uk/manual/ |title=Benzodiazepines: how they work & how to withdraw |author=Ashton CH |year=2002 |work=The Ashton Manual |publisher=benzo.org.uk |accessdate=2009-05-27 }}</ref><ref>{{cite book |author=Lal R, Gupta S, Rao R, Kattimani S |title=Substance Use Disorder |url=http://www.whoindia.org/en/Section20/Section22_1674.htm |format=PDF |accessdate=2009-06-06 |year=2007 |publisher=World Health Organisation |page=82 |chapter=Emergency management of substance overdose and withdrawal |chapterurl=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 }}</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. 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 name="manual" /> 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 |last1=Ebadi |first1=Manuchair |title=Desk Reference for Clinical Pharmacology |url=http://books.google.com/?id=ihxyHbnj3qYC |edition=2nd |date=23 October 2007 |publisher=CRC Press |location=USA |isbn=978-1420047431 |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/>

==Contraindications==
Because of their muscle relaxant action, benzodiazepines may cause [[hypoventilation|respiratory depression]] in susceptible individuals. For that reason, they are contraindicated in people with [[myasthenia gravis]], [[sleep apnea]], [[bronchitis]] and [[Chronic obstructive pulmonary disease|COPD]].<ref name="isbn0-683-30128-4"/><ref name="isbn0-444-50998-4"/> Caution is required when benzodiazepines are used in people with [[personality disorders]] or [[mental retardation]] because of frequent [[paradoxical reactions]].<ref name="isbn0-683-30128-4"/><ref name="isbn0-444-50998-4"/> In [[major depressive disorder|major depression]], they may precipitate [[suicidal tendencies]]<ref>{{cite web |author=Committee on Safety of Medicines |year=1988 |url=http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=CON2024428&RevisionSelectionMethod=LatestReleased |format=PDF |title=Benzodiazepines, dependence and withdrawal symptoms |publisher=Medicines and Healthcare products Regulatory Agency |accessdate=2009-05-28 }}</ref> and are sometimes used for suicidal overdoses.<ref name="isbn0-444-50998-4"/> Individuals with a history of alcohol, [[opioid]] and [[barbiturate]] abuse should avoid benzodiazepines, as there is a risk of life-threatening interactions with these drugs.<ref name="isbn1-58829-211-8"/>

===Pregnancy===
{{See also|Long term effects of benzodiazepines#Neonatal effects|l1=Effects of benzodiazepines on newborns}}
[[File:Pregnant woman2.jpg|thumb|alt=Exposed belly of a pregnant woman.|Benzodiazepines taken during pregnancy have adverse effects on the baby. Abrupt withdrawal in [[benzodiazepine dependent]] pregnant women may result in [[spontaneous abortions]] and provoke [[suicidal ideation]].]]

In the United States, the [[Food and Drug Administration (United States)|Food and Drug Administration]] has categorized benzodiazepines into either [[Pregnancy category|category D or X]] meaning potential for harm in the unborn has been demonstrated.<ref>{{cite book |author=Roach SS, Ford SM |title=Introductory Clinical Pharmacology |edition=8th |year=2006 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-7595-3 |page=236 |chapter=Sedatives and hypnotics }}</ref>

Exposure to benzodiazepines during pregnancy has been associated with a slightly increased (from 0.06 to 0.07%) risk of [[cleft lip and palate|cleft palate]] in newborns, a controversial conclusion as some studies find no association between benzodiazepines and cleft palate. Their use by expectant mothers shortly before the delivery may result in a [[Hypotonia#Floppy baby syndrome|floppy infant syndrome]], with the newborns suffering from [[hypotonia]], [[hypothermia]], [[lethargy]] and breathing and feeding difficulties.<ref name=ACOG>{{cite journal |author=American College of Obstetricians and Gynecologists Committee on Practice Bulletins—Obstetrics |title=ACOG Practice Bulletin no. 92: Use of psychiatric medications during pregnancy and lactation |journal=Obstet Gynecol |volume=111 |issue=4 |pages=1001–20 |year=2008 |pmid=18378767 |doi=10.1097/AOG.0b013e31816fd910 |doi_brokendate=2009-06-14 |url=http://whb.ncpublichealth.com/provPart/docs/psychmeds.pdf |format=PDF |accessdate=2009-06-14 }}</ref><ref name=pmid9748174>{{cite journal |author=Dolovich LR, Addis A, Vaillancourt JM, Power JD, Koren G, Einarson TR |title=Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies |journal=BMJ |volume=317 |issue=7162 |pages=839–43 |year=1998 |pmid=9748174 |pmc=31092 |url=http://www.bmj.com/cgi/content/full/317/7162/839 }}</ref> Cases of [[neonatal withdrawal syndrome]] have been described in infants chronically exposed to benzodiazepines [[in utero]]. This syndrome may be hard to recognize as it starts several days after delivery, for example, as late as 21 day for chlordiazepoxide. The symptoms include [[tremor]]s, [[hypertonia]], [[hyperreflexia]], [[hyperactivity]] and vomiting and may last for up to three to six months.<ref name=ACOG/><ref name=pmid9614425>{{cite journal |title=Neonatal drug withdrawal |author=American Academy of Pediatrics Committee on Drugs |journal=Pediatrics |volume=101 |issue=6 |pages=1079–88 |year=1998 |pmid=9614425 |url=http://pediatrics.aappublications.org/cgi/content/full/101/6/1079 }}</ref> Tapering down the dose during pregnancy may lessen its severity. If used in pregnancy, those benzodiazepines with a better and longer safety record, such as [[diazepam]] or [[chlordiazepoxide]], are recommended over potentially more harmful benzodiazepines, such as [[alprazolam]] or [[triazolam]]. Using the lowest effective dose for the shortest period of time minimizes the risks to the unborn child.<ref>{{cite journal |author=Iqbal MM, Sobhan T, Ryals T |title=Effects of commonly used benzodiazepines on the fetus, the neonate and the nursing infant |journal=Psychiatr Serv |volume=53 |issue=1 |pages=39–49 |year=2002 |pmid=11773648 |doi=10.1176/appi.ps.53.1.39 |url=http://ps.psychiatryonline.org/cgi/content/full/53/1/39 }}</ref>

===Elderly===
[[File:Nurse in geriatry.jpg|thumb|alt=Seated elderly woman in glasses and sweater, viewing a birthday cake being placed in front of her by a nurse. The square cake has a single lit candle.|Adverse effects of benzodiazepines are increased and the benefits are decreased in the elderly. Adverse effects on cognition can be mistaken for the effects of old age.<ref name="pmid15001721" /><ref name=pmid18035234>{{cite journal |author=Tariq SH, Pulisetty S |title=Pharmacotherapy for insomnia |journal=Clin Geriatr Med |volume=24 |issue=1 |pages=93–105, vii |year=2008 |pmid=18035234 |doi=10.1016/j.cger.2007.08.009 }}</ref>]]

The benefits of benzodiazepines are least and the risks are greatest in the elderly.<ref name=pmid18035234/><ref>{{cite journal |journal=Am J Geriatr Pharmacother |year=2006 |volume=4 |issue=2 |pages=168–92 |title=Management of chronic insomnia in elderly persons |author=Bain KT |pmid=16860264 |doi=10.1016/j.amjopharm.2006.06.006 }}</ref> The elderly are at an increased risk of [[drug dependence|dependence]] and are more sensitive to the adverse effects such as memory problems, daytime sedation, impaired motor coordination and increased risk of motor vehicle accidents and falls.<ref name=pmid16156679>{{cite journal |author=Allain H, Bentué-Ferrer D, Polard E, Akwa Y, Patat A |title=Postural instability and consequent falls and hip fractures associated with use of hypnotics in the elderly: a comparative review |journal=Drugs Aging |volume=22 |issue=9 |pages=749–65 |year=2005 |pmid=16156679 |doi=10.2165/00002512-200522090-00004 }}</ref> The [[long-term effects of benzodiazepines]] and [[benzodiazepine dependence]] in the elderly can resemble [[dementia]], [[clinical depression|depression]] or [[anxiety syndromes]] and progressively worsens over time. Adverse effects on cognition can be mistaken for the effects of old age. The benefits of withdrawal include improved cognition, alertness, mobility, reduced risk incontinance and a reduced risk of falls and fractures. The success of gradual-tapering benzodiazepines is as great in the elderly as in younger people. Benzodiazepines should be prescribed to the elderly only with caution and only for a short period at low doses.<ref name="pmid15001721">{{cite journal |author=Bogunovic OJ, Greenfield SF |title=Practical geriatrics: Use of benzodiazepines among elderly patients |journal=Psychiatr Serv |volume=55 |issue=3 |pages=233–5 |year=2004 |pmid=15001721 |doi=10.1176/appi.ps.55.3.233 |url=http://psychservices.psychiatryonline.org/cgi/content/full/55/3/233 }}</ref><ref name="prescribing_for_elderly_patients"/> Short to intermediate-acting benzodiazepines are preferred in the elderly such as [[oxazepam]] and [[temazepam]]. The high potency benzodiazepines [[alprazolam]] and [[triazolam]] and long-acting benzodiazepines are not recommended in the elderly due to increased adverse effects. [[Nonbenzodiazepines]] such as [[zaleplon]] and [[zolpidem]] and low doses of sedating antidepressants are sometimes used as alternatives to benzodiazepines.<ref name="prescribing_for_elderly_patients">{{Cite book | last1 = Jackson | first1 = Stephen G. | last2 = Jansen | first2 = Paul | last3 = Mangoni | first3 = Arduino | title = Prescribing for Elderly Patients | url = http://books.google.com/?id=A38nZY3vp2wC | date =22 May 2009 | publisher = Wiley | isbn = 0-470-02428-3 | pages = 47–48}}</ref><ref>{{Cite book | last1 = Rosenthal | first1 = Thomas C. | last2 = Williams | first2 = Mark | last3 = Naughton | first3 = Bruce J. | title = Office care geriatrics | year = 2006 | publisher = Lippincott Williams Wilkins | location = Philadelphia | url = http://books.google.com/?id=iyZfvfo-M2wC&pg=PA260 | isbn = 0-7817-6196-4 | pages = 260–262 }}</ref>

Long-term use of benzodiazepines has been associated with increased risk of cognitive impairment, but its relationship with dementia remains inconclusive.<ref name="pmid16240487">{{cite journal |author=Hulse GK, Lautenschlager NT, Tait RJ, Almeida OP |title=Dementia associated with alcohol and other drug use |journal=Int Psychogeriatr |volume=17 |issue=Suppl 1 |pages=S109–27 |year=2005 |doi=10.1017/S1041610205001985 |pmid=16240487 }}</ref> The association of a past history of benzodiazepine use and cognitive decline is unclear, with some studies reporting a lower risk of cognitive decline in former users, some finding no association and some indicating an increased risk of cognitive decline.<ref>{{cite journal |author=Verdoux H, Lagnaoui R, Begaud B |title=Is benzodiazepine use a risk factor for cognitive decline and dementia? A literature review of epidemiological studies |journal=Psychol Med |volume=35 |issue=3 |pages=307–15 |year=2005 |pmid=15841867 |doi=10.1017/S0033291704003897 }}</ref>

Benzodiazepines are sometimes prescribed to treat behavioral symptoms of dementia. However, similarly to [[antidepressant]]s they have little evidence of effectiveness, although [[antipsychotic]]s have shown some benefit.<ref>{{cite journal |author=Snowden M, Sato K, Roy-Byrne P |title=Assessment and treatment of nursing home residents with depression or behavioral symptoms associated with dementia: a review of the literature |journal=J Am Geriatr Soc |volume=51 |issue=9 |pages=1305–17 |year=2003 |pmid=12919245 |doi=10.1046/j.1532-5415.2003.51417.x }}</ref><ref>{{cite journal |author=Wang PS, Brookhart MA, Setoguchi S, Patrick AR, Schneeweiss S |title=Psychotropic medication use for behavioral symptoms of dementia |journal=Curr Neurol Neurosci Rep |volume=6 |issue=6 |pages=490–5 |year=2006 |pmid=17074284 |doi=10.1007/s11910-006-0051-6 }}</ref> Cognitive impairing effects of benzodiazepines that occur frequently in the elderly can also worsen dementia.<ref name="pmid10779253">{{cite journal |author=Longo LP, Johnson B |title=Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives |journal=Am Fam Physician |volume=61 |issue=7 |pages=2121–8 |year=2000 |month=April |pmid=10779253 |url=http://www.aafp.org/afp/20000401/2121.html}}</ref>

==Pharmacology==
Benzodiazepines share a similar chemical structure and their effects in humans are mainly produced by the [[allosteric]] modification of a specific kind of [[neurotransmitter receptor]], the [[GABAA receptor|GABA<sub>A</sub> receptor]], which increases the conductance of this inhibitory channel; this results in the various therapeutic effects as well as adverse effects of benzodiazepines.<ref name="isbn0-12-088397-X"/> Other less important mechanisms of action are also known.<ref name="pmid9504140"/><ref name="pmid16780077"/>

===Chemistry===
{{FixBunching|beg}}
[[File:Benzodiazepine3.png|thumb|250px|right|alt=On the left is the chemical structure of the parent benzodiazepine ring system, which consists of a seven membered ring containing two nitrogen atoms fused to a six membered ring. The two nitrogen atoms are labeled one and four. On the right is the chemical structure of a pharmacologically active benzodiazepine in which alkyl, phenyl, and halogen groups are attached to the one, five, and seven positions respectively and the carbon atom at position two is double bonded to an exocyclic oxygen atom. The ortho and para positions of the phenyl substituent are labeled two-prime and 4-prime respectively.|'''Left''': The 1,4-benzodiazepine ring system. '''Right''': 5-phenyl-1''H''-benzo[''e''][1,4]diazepin-2(3''H'')-one forms the skeleton of many of the most common benzodiazepine pharmaceuticals, such as [[diazepam]] (7-chloro-1-methyl substituted).]]
{{FixBunching|mid}}
[[File:Bzr pm.png|thumb|right|250px|alt=Superposition of the chemical structures of a benzodiazepine and nonbenzodiazepine ligand and their interactions with binding sites within the receptor.|A [[pharmacophore]] model of the benzodiazepine binding site on the GABA<sub>A</sub> receptor.<ref name="isbn0-471-21384-5"/> White sticks represent the carbon atoms of the benzodi-azepine [[diazepam]] while green represents carbon atoms of the nonbenzodiazepine [[CGS-9896]]. Red and blue sticks are oxygen and nitrogen atoms that are present in both structures. The red spheres labeled H1 and H2/A3 are respectively [[hydrogen bond]] donating and accepting sites in the receptor while L1, L2, and L3 denote [[lipophilicity|lipophilic]] binding sites.]]
{{FixBunching|end}}

The term benzodiazepine is the [[IUPAC nomenclature|chemical name]] for the [[heterocycle|heterocyclic]] ring system (see figure to the right), which is a fusion between the [[benzene]] and [[diazepine]] ring systems.<ref name=IUPAC>{{BlueBook1993 |pages=40–3 }}; {{cite journal |author=Moss GP |year=1998 |title=Nomenclature of fused and bridged fused ring systems (IUPAC Recommendations 1998) |url=http://media.iupac.org/publications/pac/1998/pdf/7001x0143.pdf |format=PDF |journal=Pure Appl Chem |volume=70 |issue=1 |pages=143–216 |doi=10.1351/pac199870010143 }}</ref> Under [[Hantzsch–Widman nomenclature]], a [[diazepine]] is a heterocycle with two [[nitrogen]] atoms, five [[carbon]] atom and the maximum possible number of cumulative [[double bond]]s. The "benzo" prefix indicates the [[benzene]] ring fused onto the diazepine ring.<ref name="IUPAC" />

Benzodiazepine drugs are substituted 1,4-benzodiazepines, although the chemical term can refer to many other compounds that do not have useful pharmacological properties. Different benzodiazepine drugs have different side groups attached to this central structure. The different side groups affect the binding of the molecule to the GABA<sub>A</sub> receptor and so modulate the pharmacological properties.<ref name="isbn0-12-088397-X"/> Many of the pharmacologically active "classical" benzodiazepine drugs contain the 5-phenyl-1''H''-benzo[''e''][1,4]diazepin-2(3''H'')-one substructure (see figure to the right).<ref name=CAS>[[CAS registry number]]:{{CAS|2898-08-0|1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one}}; other names: Ro 05-2921, dechlorodemethyldiazepam.</ref>

[[Nonbenzodiazepine]]s also bind to the benzodiazepine binding site on the GABA<sub>A</sub> receptor and possess similar pharmacological properties. While the nonbenzodiazepines are by definition structurally unrelated to the benzodiazepines, both classes of drugs share a common [[pharmacophore]] (see figure to the lower right), which explains their binding to a common receptor site.<ref name="isbn0-471-21384-5">{{cite book |author=Madsen U, Bräuner-Osborne H, Greenwood JR, Johansen TN, Krogsgaard-Larsen P, Liljefors T, Nielsen M, Frølund B |editor=Gad SC |title=Drug Discovery Handbook |publisher=Wiley-Interscience/J. Wiley |location=Hoboken, N.J |year=2005 |pages=797–907 |chapter=GABA and Glutamate receptor ligands and their therapeutic potential in CNS disorders |isbn=0-471-21384-5 }}</ref>

===Mechanism of action===
Benzodiazepines work by increasing the efficiency of a natural brain chemical, [[gamma-Aminobutyric acid|GABA]], to decrease the excitability of certain types of brain cells called [[neuron]]s. This reduces the communication between neurons and therefore has a calming effect on many of the functions of the brain.

[[Image:GABAA-receptor-protein-example.png|thumb|190px|left|alt=Figure of the GABA<sub>A</sub> receptor complex where the five subunits (two alpha, two beta, and one gamma) are symmetrically arranged in a pentagon shape about a central ion conduction pore. The location of the two GABA binding sites are located between the alpha and beta subunit while the single benzodiazepine binding site is located between the alpha and gamma subunits.|Schematic diagram of the (α1)<sub>2</sub>(β2)<sub>2</sub>(γ2) GABA<sub>A</sub> receptor complex that depicts the five-protein subunits that form the receptor, the chloride (Cl<sup>-</sup>) ion channel pore at the center, the two GABA active binding sites at the α1 and β2 interfaces and the benzodiazepine (BZD) allosteric binding site at the α1 and γ2 interface.]]

GABA controls the excitability of neurons by binding to the [[GABAA receptor|GABA<sub>A</sub> receptor]].<ref name="isbn0-12-088397-X">{{cite book |author=Olsen RW, Betz H |editor=Siegel GJ, Albers RW, Brady S, Price DD (eds.) |title=Basic Neurochemistry: Molecular, Cellular and Medical Aspects |edition=7th |publisher=Elsevier |year=2006 |pages=291–302 |chapter=GABA and glycine |isbn=0-12-088397-X }}</ref> The GABA<sub>A</sub> receptor is a [[multiprotein complex|protein complex]] located in the [[chemical synapse|synapses]] of neurons. All GABA<sub>A</sub> receptors contain an [[ion channel]] that conducts [[chloride]] ions across neuronal [[cell membrane]]s and two binding sites for the [[neurotransmitter]] gamma-aminobutyric acid (GABA), while a subset of GABA<sub>A</sub> receptor complexes also contain a single binding site for benzodiazepines. Binding of benzodiazepines to this receptor complex promotes binding of GABA, which in turn increases the conduction of chloride ions across the neuronal cell membrane. This increased conductance raises the [[membrane potential]] of the neuron resulting in inhibition of neuronal [[action potential|firing]]. In addition, different GABA<sub>A</sub> receptor subtypes have varying distributions within different regions of the brain and therefore control distinct [[biological neural network|neuronal circuits]]. Hence, activation of different GABA<sub>A</sub> receptor subtypes by benzodiazepines may result in distinct pharmacological actions.<ref name="pmid16376150">{{cite journal |author=Rudolph U, Möhler H |title=GABA-based therapeutic approaches: GABA<sub>A</sub> receptor subtype functions |journal=Curr Opin Pharmacol |volume=6 |issue=1 |pages=18–23 |year=2006 |pmid=16376150 |doi=10.1016/j.coph.2005.10.003 }}</ref> In terms of the mechanism of action of benzodiazepines, their similarities are too great to separate them into individual categories such as anxiolytic or hypnotic. For example, a hypnotic administered in low doses will produce anxiety relieving effects, whereas a benzodiazepine marketed as an anti-anxiety drug will at higher doses induce sleep.<ref>{{cite book |last1=Puri |first1=Basant K. |last2=Tyrer |first2=Peter |title=Sciences Basic to Psychiatry |url=http://books.google.com/?id=KTbfRIqjLtUC |accessdate=11-07-2009 |edition=2nd |date=28 August 1998 |publisher=Churchill Livingstone |isbn=978-0443055140 |pages=155–156 |chapter=Clinical psychopharmacology |chapterurl=http://books.google.co.uk/books?id=KTbfRIqjLtUC&pg=PA149 }}</ref>

The subset of GABA<sub>A</sub> receptors that also bind benzodiazepines are referred to as benzodiazepine receptors (BzR). The GABA<sub>A</sub> receptor is a [[heteromer]] composed of five subunits, most commonly two α's, two β's and one γ (α<sub>2</sub>β<sub>2</sub>γ). For each subunit, many subtypes exist (α<sub>1-6</sub>, β<sub>1-3</sub> and γ<sub>1-3</sub>). GABA<sub>A</sub> receptors that are made up of different combinations of subunit subtypes have different properties, different distributions in the brain and different activities relative to pharmacological and clinical effects.<ref name="pmid8783370">{{cite journal |author=Johnston GA |title=GABA<sub>A</sub> receptor pharmacology |journal=Pharmacol Ther |volume=69 |issue=3 |pages=173–98 |year=1996 |pmid=8783370 |doi=10.1016/0163-7258(95)02043-8 }}</ref> Benzodiazepines bind at the interface of the α and γ subunits on the GABA<sub>A</sub> receptor. Binding also requires that alpha subunits contain a [[histidine]] amino acid residue, (''i.e.'', [[GABRA1|α<sub>1</sub>]], [[GABRA2|α<sub>2</sub>]], [[GABRA3|α<sub>3</sub>]] and [[GABRA5|α<sub>5</sub>]] containing GABA<sub>A</sub> receptors). For this reason, benzodiazepines show no affinity for GABA<sub>A</sub> receptors containing [[GABRA4|α<sub>4</sub>]] and [[GABRA6|α<sub>6</sub>]] subunits with an [[arginine]] instead of a histidine residue.<ref name="pmid15157182">{{cite journal |author=Wafford KA, Macaulay AJ, Fradley R, O'Meara GF, Reynolds DS, Rosahl TW |title=Differentiating the role of gamma-aminobutyric acid type A (GABA<sub>A</sub>) receptor subtypes |journal=Biochem Soc Trans |volume=32 |issue=Pt3 |pages=553–6 |year=2004 |pmid=15157182 |doi=10.1042/BST0320553 }}</ref>

Once bound to the benzodiazepine receptor, the benzodiazepine [[ligand (biochemistry)|ligand]] locks the benzodiazepine receptor into a conformation in which it has a greater affinity for the [[gamma-aminobutyric acid|GABA]] [[neurotransmitter]]. This increases the frequency of the opening of the associated chloride [[ion channel]] and [[hyperpolarization (biology)|hyperpolarizes]] the membrane of the associated neuron. The inhibitory effect of the available GABA is potentiated, leading to sedatory and anxiolytic effects. Furthermore, different benzodiazepines can have different affinities for BzRs made up of different collection of subunits. For instance, those with high activity at the α<sub>1</sub> are associated with stronger [[hypnotic]] effects, whereas those with higher affinity for GABA<sub>A</sub> receptors containing α<sub>2</sub> and/or α<sub>3</sub> subunits have good anti-anxiety activity.<ref name="pmid9824848">{{cite journal |author=Hevers W, Lüddens H |title=The diversity of GABA<sub>A</sub> receptors. Pharmacological and electrophysiological properties of GABA<sub>A</sub> channel subtypes |journal=Mol Neurobiol |volume=18 |issue=1 |pages=35–86 |year=1998 |pmid=9824848 |doi=10.1007/BF02741459 }}</ref>

The benzodiazepine class of drugs also interact with [[translocator protein|peripheral benzodiazepine receptors]]. Peripheral benzodiazepine receptors are present in [[peripheral nervous system]] tissues, [[glial cells]] and to a lesser extent the central nervous system.<ref name="pmid12240908">{{cite journal |author=Arvat E, Giordano R, Grottoli S, Ghigo E |title=Benzodiazepines and anterior pituitary function |journal=J Endocrinol Invest |volume=25 |issue=8 |pages=735–47 |year=2002 |pmid=12240908 }}</ref> These peripheral receptors are not structurally related nor coupled to GABA<sub>A</sub> receptors. They modulate the [[immune system]] and are involved in the body response to injury.<ref name="pmid9504140">{{cite journal |author=Zavala F |title=Benzodiazepines, anxiety and immunity |journal=Pharmacol Ther |volume=75 |issue=3 |pages=199–216 |year=1997 |pmid=9504140 |doi=10.1016/S0163-7258(97)00055-7 }}</ref><ref name="pmid9378234">{{cite journal |author=Zisterer DM, Williams DC |title=Peripheral-type benzodiazepine receptors |journal=Gen Pharmacol |volume=29 |issue=3 |pages=305–14 |year=1997 |pmid=9378234 |doi=10.1016/S0306-3623(96)00473-9 }}</ref> Benzodiazepines also function as weak [[adenosine reuptake inhibitor]]s. It has been suggested that some of their anticonvulsant, anxiolytic and muscle relaxant effects may be in part mediated by this action.<ref name="pmid16780077">{{cite journal |author=Narimatsu E, Niiya T, Kawamata M, Namiki A |title=[The mechanisms of depression by benzodiazepines, barbiturates and propofol of excitatory synaptic transmissions mediated by adenosine neuromodulation] |journal=Masui |volume=55 |issue=6 |pages=684–91 |year=2006 |pmid=16780077 |language=Japanese }}</ref>

==Pharmacokinetics==
A benzodiazepine can be placed into one of three groups by its [[elimination half-life]], or time it takes for the body to eliminate half of the dose. Some benzodiazepines have long-acting [[active metabolites]] such as diazepam and chlordiazepoxide, which are metabolised into [[desmethyldiazepam]]. Desmethyldiazepam has a half-life of 36–200 hours, and flurazepam, with the main active metabolite of desalkylflurazepam, with a half life of 40-250 hours. These long-acting metabolites are [[partial agonists]].<ref name=sddat>{{cite book |author=Dikeos DG, Theleritis CG, Soldatos CR |chapter=Benzodiazepines: effects on sleep |pages=220–2 |title=Sleep Disorders: Diagnosis and Therapeutics |editor=Pandi-Perumal SR, Verster JC, Monti JM, Lader M, Langer SZ (eds.) |publisher=Informa Healthcare |year=2008 |isbn=0-415-43818-7 }}</ref><ref name="manual" />
* Short-acting compounds have a median half-life of 1–12 hours. They have few residual effects if taken before bedtime, [[rebound insomnia]] may occur upon discontinuation and they might cause day time withdrawal symptoms such as next day [[rebound anxiety]] with prolonged usage. Examples are [[brotizolam]], [[midazolam]], [[triazolam]], and [[alprazolam]].
* Intermediate-acting compounds have a median half-life of 12–40 hours. They may have some residual effects in the first half of the day if used as a [[hypnotic]]. Rebound insomnia, however, is more common upon discontinuation of intermediate-acting benzodiazepines than longer acting benzodiazepines. Examples are [[estazolam]], [[flunitrazepam]], [[clonazepam]], [[lormetazepam]], [[lorazepam]], [[nitrazepam]] and [[temazepam]].
* Long-acting compounds have a half-life of 40–250 hours. They have a risk of accumulation in the elderly and in individuals with severely impaired liver function, but they have a reduced severity of [[rebound effects]] and [[withdrawal]]. Examples are [[diazepam]], [[chlordiazepoxide]], and [[flurazepam]].

==Interactions==
Individual benzodiazepines may have different [[drug interaction|interactions]] with certain drugs. Depending on their [[metabolism]] pathway, benzodiazepines can be roughly divided into two groups. The largest group consists of those that are metabolized by [[cytochrome P450]] (CYP450) enzymes and possess significant potential for interactions with other drugs. The other group comprises those that are metabolized through [[Glucuronic acid#Glucuronidation|glucuronidation]], such as [[lorazepam]], [[oxazepam]], and [[temazepam]] and, in general, have few drug interactions.<ref name="isbn0-444-50998-4">{{cite book |editor=Meyler L, Aronson JK |title=Meyler's Side Effects of Drugs: the International Encyclopedia of Adverse Drug Reactions and Interactions |edition=15th |publisher=Elsevier |year=2006 |pages=429–43 |isbn=0-444-50998-4 }}</ref>

Many drugs, including [[combined oral contraceptive pill|oral contraceptives]], some [[antibiotic]]s, [[antidepressant]]s and [[antifungal]] agents, inhibit cytochrome enzymes in the liver. They reduce the rate of elimination of the benzodiazepines that are metabolized by CYP450, leading to possibly excessive drug accumulation and increased side effects. In contrast, drugs that induce cytochrome P450 enzymes, such as [[St John's wort]], the antibiotic [[rifampicin]] and the [[anticonvulsants]] [[carbamazepine]] and [[phenytoin]], accelerate elimination of many benzodiazepines and decrease their action.<ref name="isbn1-58829-211-8"/><ref name="biadmtad">{{cite journal |author=Norman TR, Ellen SR, Burrows GD |title=Benzodiazepines in anxiety disorders: managing therapeutics and dependence |journal=Med J Aust |volume=167 |issue=9 |pages=490–5 |year=1997 |pmid=9397065 |url=http://www.mja.com.au/public/mentalhealth/course/06norman.pdf |format=PDF }}</ref> Taking benzodiazepines with alcohol, [[opioid]]s and other [[depressant|central nervous system depressants]] potentiates their action. This often results in increased sedation, impaired motor coordination, suppressed breathing and other adverse effects that may potentially be lethal.<ref name="isbn1-58829-211-8">{{cite book |author=Moody D |editor=Raymon LP, Mozayani A (eds.) |title=Handbook of Drug Interactions: a Clinical and Forensic Guide |publisher=Humana |year=2004 |pages=3–88 |chapter=Drug interactions with benzodiazepines |isbn=1-58829-211-8 }}</ref><ref name=biadmtad/> [[Antacids]] may slow down absorption of some benzodiazepines; however, this effect is marginal and inconsistent.<ref name="isbn1-58829-211-8"/>

==Overdose==
{{main|Benzodiazepine overdose}}
[[Image:Flumazenil3.png|thumb|right|alt=Chemical structure of the benzodiazepine flumazenil, which contains a imidazole ring fused to positions one and two, a methyl group at position four, an exocylic carbonyl oxygen atom a position five, and a fluorine atom at position seven.|The use of [[Flumazenil]] is controversial following benzodiazepine overdose.]]

Although benzodiazepines are much safer in overdose than their predecessors, the [[barbiturate]]s, they can still cause problems in overdose.<ref name=pmid9780123>{{cite journal |author=Fraser AD |title=Use and abuse of the benzodiazepines |journal=Ther Drug Monit |volume=20 |issue=5 |pages=481–9 |year=1998 |pmid=9780123 |doi=10.1097/00007691-199810000-00007 }}</ref> Taken alone, they rarely cause severe complications in [[Drug overdose|overdose]];<ref>{{cite journal |author=Gaudreault P, Guay J, Thivierge RL, Verdy I |title=Benzodiazepine poisoning. Clinical and pharmacological considerations and treatment |journal=Drug Saf |volume=6 |issue=4 |pages=247–65 |year=1991 |pmid=1888441 |doi=10.2165/00002018-199106040-00003 }}</ref> statistics in England showed that benzodiazepines were responsible for 3.8% of all deaths by poisoning from a single drug.<ref name=Charlson_2009/> However, combining these drugs with [[Ethanol|alcohol]], [[opiates]] or [[tricyclic antidepressants]] markedly raises the toxicity.<ref name=pmid10707430>{{cite journal |author=White JM, Irvine RJ |title=Mechanisms of fatal opioid overdose |journal=Addiction |volume=94 |issue=7 |pages=961–72 |year=1999 |pmid=10707430 |doi=10.1046/j.1360-0443.1999.9479612.x }}</ref><ref>{{cite web |author=Green RS, Godsoe SK, Sharma S, Palatnick W |title=Toxicity, benzodiazepine |url=http://emedicine.medscape.com/article/165645-print |work=eMedicine |year=2008 |accessdate=2008-06-10 }}</ref><ref name=ohoam>{{cite book |author=Ramrakha P, Moore K |title=Oxford Handbook of Acute Medicine |edition=2nd |year=2004 |publisher=Oxford University Press |pages=791–838 (798) |chapter=Chapter 14: Drug overdoses |isbn=0198520727 }}</ref> The elderly are more sensitive to the side effects of benzodiazepines, and poisoning may even occur from their long-term use.<ref>{{cite journal |author=Klein-Schwartz W, Oderda GM |title=Poisoning in the elderly. Epidemiological, clinical and management considerations |journal=Drugs Aging |volume=1 |issue=1 |pages=67–89 |year=1991 |pmid=1794007 |doi=10.2165/00002512-199101010-00008 }}</ref> The various benzodiazepines differ in their toxicity; [[alprazolam]] appears to be most toxic in overdose and when used with other drugs.<ref>{{cite journal |journal=Curr Psychiatr |volume=5 |issue=5 |pages=16–28 |year=2006 |author=Ramadan MI, Werder SF, Preskorn SH |title=Protect against drug–drug interactions with anxiolytics |url=http://www.jfponline.com/Pages.asp?AID=4065 }}</ref> The symptoms of a benzodiazepine overdose may include; [[drowsiness]], [[slurred speech]], [[Pathologic nystagmus|nystagmus]], [[hypotension]], [[ataxia]], [[coma]], [[respiratory depression]] and [[cardiorespiratory arrest]].<ref name=ohoam />

A reversal agent for benzodiazepines exists, [[flumazenil]] (Anexate). Its use as an [[antidote]] is not routinely recommended due to the high risk of resedation and seizures.<ref>{{cite journal |author=Seger DL |title=Flumazenil—treatment or toxin |journal=J Toxicol Clin Toxicol |volume=42 |issue=2 |pages=209–16 |year=2004 |pmid=15214628 |doi=10.1081/CLT-120030946 }}</ref> In a double-blind, placebo-controlled trial of 326 patients, 4 patients suffered serious adverse events and 61% became resedated following the use of flumazenil.<ref>{{cite journal |title=Treatment of benzodiazepine overdose with flumazenil. The flumazenil in benzodiazepine intoxication multicenter study group |journal=Clin Ther| volume=14|issue=6|pages=978–95|year=1992|pmid=1286503}}</ref> Numerous contraindications to its use exist. It is contraindicated in patients with a history of long term use of benzodiazepines, those who have ingested a substance that lowers the seizure threshold or may cause an [[arrhythmia]], and in those with abnormal vital signs.<ref>{{cite journal |author=Spivey WH |title=Flumazenil and seizures: analysis of 43 cases |journal=Clin Ther |volume=14 |issue=2 |pages=292–305 |year=1992 |pmid=1611650 }}</ref> One study found that only 10% of the patient population presenting with a [[benzodiazepine overdose]] are suitable candidates for treatment with flumazenil.<ref name="isbn0-07-136001-8">{{cite book |author=Goldfrank LR |title=Goldfrank's Toxicologic Emergencies |publisher=McGraw-Hill |year=2002 |isbn=0-07-136001-8 }}</ref>

==Drug misuse==
{{Main|Benzodiazepine drug misuse|Drug-related crime}}
[[File:Xanax2mg.jpg|thumb|alt=A picture of alprazolam (Xanax) "bars"|[[Alprazolam]] 2mg [[tablet]]s, manufactured by [[Sandoz]] Pharma (imprint GG/2/4/9), commonly known as "bars" due to shape. Scored to easily break in to four 0.5mg pieces.]]

Benzodiazepines are considered to be major drugs of abuse.<ref name=pmid10622686>{{cite journal |author=Lader MH |title=Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified? |journal=Eur Neuropsychopharmacol |volume=9 |issue=Suppl 6 |pages=S399–405 |year=1999 |pmid=10622686 |doi=10.1016/S0924-977X(99)00051-6 }}</ref> Benzodiazepine abuse is mostly limited to individuals who abuse other drugs, i.e. poly-drug abusers. The majority of prescribed users do not abuse their medication.<ref>{{cite book |editor1-first=Woody |editor1-last=Caan |editor2-first=Jackie de |editor2-last=Belleroche |title=Drink, Drugs and Dependence: From Science to Clinical Practice |url=http://books.google.com/?id=nPvbDUw4w5QC |edition=1st |date=11 April 2002 |publisher=Routledge |isbn=978-0415278911 |pages=197–211 |chapter=Benzodiazepine abuse |chapterurl=http://books.google.co.uk/books?id=nPvbDUw4w5QC&pg=PA197 }}</ref> Internationally, [[Benzodiazepine drug misuse#Legal status|benzodiazepines are categorized]] as [[Convention on Psychotropic Substances#Schedules of Controlled Substances|Schedule IV]] controlled drugs by the [[INCB]], apart from [[flunitrazepam]], which is a [[Convention on Psychotropic Substances#Schedules of Controlled Substances|Schedule III]] drug under the [[Convention on Psychotropic Substances]].<ref>{{cite web |url=http://www.incb.org/pdf/e/list/green.pdf |title=List of psychotropic substances under international control |accessdate=2008-12-17 |author=[[International Narcotics Control Board]] |year=2003 |format=PDF }}</ref> Some variation in drug scheduling exists in individual countries; for example in the United Kingdom [[midazolam]] and [[temazepam]] are Schedule III controlled drugs.<ref>{{cite web |url=http://www.homeoffice.gov.uk/documents/cdlist.pdf?view=Binary |format=PDF |title=List of drugs currently controlled under the misuse of drugs legislation |date=2009-01-28 |accessdate=2009-05-27 |publisher=UK Government Home Office }}</ref> Benzodiazepine abuse ranges from occasional binges on large doses, to chronic and compulsive drug abuse of high doses.<ref>{{cite book |last1=Karch |first1=Steven B. |title=Drug Abuse Handbook |url=http://books.google.com/?id=F0mUte90ATUC |edition=2nd |date=20 December 2006 |publisher=CRC Press |location=United States of America |isbn=978-0849316906 |page=217}}</ref>

Benzodiazepines are used recreationally and by problematic drug misusers. [[Death|Mortality]] is higher among [[Poly drug use|poly-drug misusers]] that also use benzodiazepines. Heavy alcohol use also increases [[Mortality rate|mortality]] among poly-drug users.<ref name="Charlson_2009">{{cite journal |author=Charlson F, Degenhardt L, McLaren J, Hall W, Lynskey M |title=A systematic review of research examining benzodiazepine-related mortality |journal=Pharmacoepidemiol Drug Saf |volume=18 |issue=2 |pages=93–103 |year=2009 |pmid=19125401 |doi=10.1002/pds.1694 }}</ref> Dependence and tolerance, often coupled with dosage escalation, to benzodiazepines can develop rapidly among drug misusers; withdrawal syndrome may appear after as little as three weeks of continuous use. Long-term use has the potential to cause both physical and psychological dependence and severe withdrawal symptoms such as [[Clinical depression|depression]], anxiety and panic attacks, and [[agoraphobia]].<ref name=ohop>{{cite book |author=McIntosh A, Semple D, Smyth R, Burns J, Darjee R |title=Oxford Handbook of Psychiatry |edition=1st |publisher=Oxford University Press |year=2005 |page=540 |chapter=Depressants |isbn=0-19-852783-7 }}</ref> Benzodiazepines and in particular [[temazepam]], are sometimes used intravenously, which if done incorrectly or in an unsterile manner, can lead to medical complications including [[abscess]]es, [[cellulitis]], [[thrombophlebitis]], arterial puncture, [[deep vein thrombosis]] and [[gangrene]]. Sharing syringes and needles for this purpose also brings up the possibility of transmission of [[hepatitis]], [[HIV]] and other diseases. Benzodiazepines are also misused [[intranasally]], which may have additional health consequences. Once benzodiazepine dependence has been established, a clinician usually converts the patient to an equivalent dose of diazepam before beginning a gradual reduction program.<ref>{{cite journal |author=Gerada C, Ashworth M |title=ABC of mental health. Addiction and dependence—I: Illicit drugs |journal=BMJ |volume=315 |issue=7103 |pages=297–300 |year=1997 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2127199&blobtype=pdf |format=PDF |pmid=9274553 |pmc=2127199 }}</ref>

A 1999–2005 Australian police survey of detainees reported preliminary findings that self-reported users of benzodiazepines were less likely than non-user detainees to work full-time and more likely to receive government benefits, use methamphetamine or heroin and be arrested or imprisoned.<ref>{{cite journal |url=http://www.aic.gov.au/documents/4/3/3/%7B4336A1AE-AFEC-4D82-A1D9-EB94ECC5B008%7Dtandi336.pdf |title=Benzodiazepine use and harms among police detainees in Australia |author=Loxley W |year=2007 |format=PDF |issn=0817-8542 |journal=Trends Issues Crime Crim Justice |issue=336 |accessdate=2009-06-10 |publisher=Australian Institute of Criminology |location=Canberra, A.C.T. }}</ref> Benzodiazepines are sometimes used for criminal purposes; they serve to incapacitate a victim in cases of [[drug assisted rape]] or robbery.<ref>{{cite journal |author=Kintz P |title=Bioanalytical procedures for detection of chemical agents in hair in the case of drug-facilitated crimes |journal=Anal Bioanal Chem |volume=388 |issue=7 |pages=1467–74 |year=2007 |pmid=17340077 |doi=10.1007/s00216-007-1209-z }}</ref>

==Veterinary use==
Benzodiazepines are used in [[veterinary]] practice in the treatment of various disorders and conditions. As in humans, they are used in the first-line management of [[seizures]], [[status epilepticus]] and [[tetanus]], and as maintenance therapy in epilepsy (particularly in cats).<ref name = MVM>{{cite book |editor=Kahn CM, Line S, Aiello SE |title=[[Merck Veterinary Manual|The Merck Veterinary Manual]]|year=2005 |publisher=Wiley |edition=9th |isbn=0-911910-50-6 |url=http://www.merckvetmanual.com/mvm/index.jsp |accessdate=2009-06-08 |author=Editor, Cynthia M. Kahn; associate editor Scott Line }}</ref><ref>{{cite journal |author=Frey HH |title=Anticonvulsant drugs used in the treatment of epilepsy |journal=Probl Vet Med |volume=1 |issue=4 |pages=558–77 |year=1989 |pmid=2520134 }}</ref><ref>{{cite journal |author=Podell M |journal=Vet Clin North Am Small Anim Pract |title=Seizures in dogs |volume=26 |issue=4 |pages=779–809 |year=1996 |pmid=8813750 }}</ref> They are widely used in small and large animals (including horses, swine, cattle and exotic and wild animals) for their anxiolytic and sedative effects, as pre medication before surgery, for induction of [[anesthesia]] and as adjuncts to anaesthesia.<ref name = MVM/><ref name=Adams>{{cite book |author=Gross ME |chapter=Tranquilizers, &alpha;<sub>2</sub>-adrenergic agonists, and related agents |editor=Adams RH (ed.) |title=Veterinary Pharmacology and Therapeutics |edition=8th |publisher=Iowa State University Press |year=2001 |pages=325–33 |isbn=0-8138-1743-9 |accessdate=2009-06-08 }}</ref>

==See also==
*[[List_of_benzodiazepines|Benzodiazepine Comparison Chart]]
*[[Endozepines]]
*[[Z-drugs]]

==References==
{{Reflist|colwidth=30em}}

==Further reading==
* {{cite web |url=http://benzo.org.uk/manual/ |title=Benzodiazepines: how they work & how to withdraw |author=Ashton CH |year=2002 |work=The Ashton Manual |publisher=benzo.org.uk |accessdate=2009-06-09 }}
* {{cite web |url=http://benzo.org.uk/bzequiv.htm |title=Benzodiazepine equivalence table |author=Ashton CH |year=2007 |publisher=benzo.org.uk |accessdate=2009-06-09 }}
* {{cite web |url=http://www.inchem.org/documents/pims/pharm/pimg008.htm |title=Benzodiazepines |author=Fruchtengarten L |year=1998 |work=PIM G008 |publisher=International Programme on Chemical Safety (IPCS) INCHEM |accessdate=2009-06-09 }}
* {{cite journal |url=http://www.aafp.org/afp/20000401/2121.html |title=Addiction: part I. Benzodiazepines—side effects, abuse risk and alternatives |author=Longo LP, Johnson B |journal=Am Fam Physician |volume=61 |issue=7 |pages=2121–8 |year=2000 |pmid=10779253 }}
* {{cite web |url=http://www.etfrc.com/benzos1.htm |title=The complete story of the benzodiazepines |year=2005 |publisher=The Eaton T. Fores Research Center |accessdate=2009-06-09 }}
* {{cite web |url=http://www.drugs.com/cons/benzodiazepines.html |title=Benzodiazepines advanced consumer information |date=2005-02-24 |publisher=Drugs.com |accessdate=2009-06-09 }}
* [http://www.rcpsych.ac.uk/mentalhealthinfoforall/treatments/benzodiazepines.aspx Benzodiazepines] - information from mental health charity The Royal College of Psychiatrists

{{GABAergics}}
{{Benzodiazepines}}
{{Anticonvulsants}}
{{Anxiolytics}}
{{Hypnotics and sedatives}}

[[Category:Benzodiazepines| ]]
[[Category:Pharmacology]]

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