Diazepam 234806 225653960 2008-07-14T19:20:50Z Rjwilmsi 203434 gen fixes + link/fix date fields in cite templates (explanation [[User:Rjwilmsi#My_correction_of_dates_in_templates|here]]) using [[Project:AutoWikiBrowser|AWB]] {{Drugbox| | IUPAC_name = 7-chloro-1-methyl-<br/>5-phenyl-1,3-dihydro-2''H''-<br/>1,4-benzodiazepin-2-one | image = Diazepam structure.svg | width = 180 | image2 = Diazepam-3D-balls.png | CAS_number = 439-14-5 | ATC_prefix = N05 | ATC_suffix = BA01 | ATC_supplemental = {{ATC|N05|BA17}} | PubChem = 3016 | DrugBank = APRD00642 | C = 16 | H = 13 | Cl = 1 | N = 2 | O = 1 | molecular_weight = 284.7 g/mol | molar_refractivity = 80.91 ± 0.5 cm³ | bioavailability = 93% | metabolism = [[Liver|Hepatic]] | elimination_half-life = 20–100 hours | excretion = [[Kidney|Renal]] | pregnancy_AU = C | pregnancy_US = D | legal_status = [[Schedule IV controlled substance|Schedule IV]] (International) | legal_US = Schedule IV | legal_AU = S4 | legal_CA = Schedule IV | routes_of_administration = Oral, [[Intramuscular injection|IM]], [[Intravenous therapy|IV]], [[suppository]] }} '''Diazepam''' ({{IPAEng|daɪˈæzɨpæm}}), first marketed as '''Valium''' by [[Hoffmann-La Roche]], is a [[benzodiazepine]] [[derivative (chemistry)|derivative]] [[drug]]. It possesses [[anxiolytic]], [[anticonvulsant]], [[sedative]], [[skeletal muscle relaxant]] and [[amnestic]] properties. It is commonly used for treating [[anxiety]], [[insomnia]], [[seizure]]s, [[Alcoholism#Alcohol_withdrawal|alcohol withdrawal]], and [[muscle spasms]]. It may also be used before certain medical procedures (such as [[endoscopy|endoscopies]]) to reduce tension and anxiety, and in some surgical procedures to induce [[amnesia]].<ref name="PubChem">{{cite web|author=|year= 2006|url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3016|title=Diazepam|work=[[PubChem]]| publisher=National Institute of Health: National Library of Medicine|accessdate= 2006-03-11}}</ref><ref name="NLM">{{cite web|author=|year=2006|url=http://www.nlm.nih.gov/cgi/mesh/2006/MB_cgi?mode=&term=Diazepam|title=Diazepam|work=Medical Subject Headings (MeSH)|publisher= National Library of Medicine|accessdate= 2006-03-10}}</ref> Diazepam is a ''core'' medicine in the [[World Health Organization]]'s "[[WHO Model List of Essential Medicines|Essential Drugs List]]", which is a list of minimum medical needs for a basic health care system.<ref name="essentialWHO">{{cite web | year = March 2005 | url = http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf | title = WHO Model List of Essential Medicines | format = PDF | publisher = World Health Organization | accessdate = 2006-03-12 }}</ref> Diazepam is used to treat a wide range of conditions and has been one of the most frequently prescribed medications in the world for the past 40 years. It was first synthesized by Dr. [[Leo Sternbach]]. ==History== <!-- Commented out because image was deleted: [[Image:ValiumAd.PNG|thumb|300px|A direct-to-physician advertisement for Valium, 1980.]] --> Diazepam was the second benzodiazepine to be invented by Sternbach of [[Hoffmann-La Roche]], and was approved for use in [[1963]]. It is two and a half times more potent than its predecessor, [[chlordiazepoxide]], which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.<ref name="Obituary">{{cite news | author= Sample, Ian | title= Leo Sternbach's Obituary | date= [[October 3]], [[2005]] | publisher= The Guardian (Guardian Unlimited) | url= http://www.guardian.co.uk/medicine/story/0,,1583671,00.html | accessdate= 2006-03-10 }}</ref> The benzodiazepines gained popularity among medical professionals as an improvement upon [[barbiturate]]s, which have a comparatively narrow [[therapeutic index]], and are far more sedating at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other [[depressants]] (such as alcohol or other sedatives).<ref name="Barondes1">{{cite book | first= Samuel H. | last= Barondes | year= 2003 | month= | title= Better Than Prozac | pages= 47–59 | location= New York | publisher=Oxford University Press | id= ISBN 0-19-515130-5 }}</ref> Diazepam was the top-selling pharmaceutical in the [[United States]] from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets.<ref name="Obituary" /> Diazepam along with oxazepam, nitrazepam and temazepam represent 82% of the benzodiazepine market in Australia.<ref>{{cite journal | author = Mant A | coauthors = Whicker SD, McManus P, Birkett DJ, Edmonds D, Dumbrell D. | title =Benzodiazepine utilisation in Australia: report from a new pharmacoepidemiological database. | journal = Aust J Public Health. | volume =17 | issue =4 | pages=345–9 | month =Dec | year=1993 | pmid = 7911332 }}</ref> While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the [[palliative]] treatment of certain types of epilepsy and spastic activity, e.g., forms of [[paresis]]. It is also the first line of defense for a rare disorder called [[stiff-person syndrome]].<ref name="RXL.Indications">{{cite web | year= January 24, 2005 | url= http://www.rxlist.com/cgi/generic/diazepam_ids.htm | title= Diazepam: indications | work= Rxlist.com | publisher= RxList Inc. | accessdate= 2006-03-11 }}</ref> ==Physical properties== Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The [[British Pharmacopoeia]] lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The [[United States Pharmacopoeia]] lists diazepam as soluble 1 in 16 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of [[ether]], and practically insoluble in water. The [[pH]] of diazepam is neutral (i.e. pH = 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution.<ref name="Inchem">{{cite web|author=Pere Munne/M. Ruse, Ed.|year= 1990/1998 Ed.|url= http://www.inchem.org/documents/pims/pharm/pim181.htm|title=Diazepam|work=Inchem.org|publisher=Inchem.org|accessdate=2006-03-11}}</ref> Diazepam should be stored at room temperature (15°-30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.<ref name="ElephantCare">{{cite web|author=Mikota, Susan K. and Plumb, Donald C.|year=2005|url= http://www.elephantcare.org/Drugs/diazepam.htm|title=Diazepam|work=The Elephant Formulary|publisher= Elephant Care International|accessdate=}}</ref> Diazepam can absorb into plastic, and therefore diazepam solution is not stored in plastic bottles or syringes etc. It can absorb into plastic bags and tubing used for intravenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.<ref name="ElephantCare"/> ==Pharmacology== Diazepam is a "classical" benzodiazepine. Other classical benzodiazepines include [[clonazepam]], [[lorazepam]], [[oxazepam]], [[alprazolam]], [[nitrazepam]], [[flurazepam]], [[bromazepam]] and [[clorazepate]].<ref>{{cite journal | author = Braestrup C | coauthors = Squires RF. | year = 1978 | month = Apr | day = 1 | title = Pharmacological characterization of benzodiazepine receptors in the brain. | journal = Eur J Pharmacol | volume = 48 | issue = 3 | pages = 263–70 | pmid = 639854 | doi = 10.1016/0014-2999(78)90085-7}}</ref> Diazepam has [[anticonvulsant]] properties.<ref>{{cite journal | journal = Life Sci | year = 1985| month = Feb| date = 25| volume = 36| issue = 8| pages = 737–44| title = Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines| author = Chweh AY| coauthors = Swinyard EA, Wolf HH, Kupferberg HJ| pmid = 2983169 | doi = 10.1016/0024-3205(85)90193-6}}</ref> Diazepam has no effect on GABA levels and no effect on glutamate decarboxylase activity but has a slight effect on gamma-aminobutyric acid transaminase activity. It differs insofar from some other anticonvulsive drugs, it was compared to.<ref>{{cite journal | journal = Neurochem Res | year = 1984 | month = Feb | volume = 9 | issue = 2 | pages = 225–31 | title = Effects of some anticonvulsant drugs on brain GABA level and GAD and GABA-T activities | author = Battistin L | coauthors = Varotto M, Berlese G, Roman G | pmid = 6429560 | doi = 10.1007/BF00964170}}</ref> Benzodiazepines act via [[micromolar]] benzodiazepine binding sites as [[Ca2+]] channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations.<ref>{{cite journal | journal = Proc Natl Acad Sci U S A | year = 1984 | month = May | volume = 81 | issue = 10 | pages = 3118–22 | url = http://www.pnas.org/cgi/reprint/81/10/3118.pdf | type = PDF | title = Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations | author = Taft WC |coauthors = DeLorenzo RJ | pmid = 6328498 | doi = 10.1073/pnas.81.10.3118|format=PDF}}</ref> Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. This has been found by measuring sodium-dependent high affinity choline uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo. This may play a role in explaining diazepam's anticonvulsant properties.<ref>{{cite journal | journal = Br J Pharmacol | year = 1985 | month = Jan | volume = 84 | issue = 1 | pages = 19–25 | title = Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes | author = Miller JA | coauthors = Richter JA | pmid = 3978310 | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1987204&blobtype=pdf| format = PDF }}</ref> Diazepam binds with high affinity to [[glial cells]] in animal cell cultures.<ref>{{cite journal |author=Gallager DW |coauthors=Mallorga P, Oertel W, Henneberry R, Tallman J |year=1981 |month=Feb |title=[3H]Diazepam binding in mammalian central nervous system: a pharmacological characterization |journal=J Neurosci |volume=1 |issue=2 |pages=218–25 | url=http://www.jneurosci.org/cgi/reprint/1/2/218 |type=PDF |pmid=6267221}}</ref> Diazepam binds to peripheral benzodiazepine receptors and inhibits the proliferation of rat [[thymoma]] cell cultures, mouse Swiss [[3T3 cells]] cultures, B103 and B104 rat [[neuroblastoma]] cell cultures, and Friend mouse [[erythroleukemia]] cell cultures and inhibits the uptake of radiolabeled [[thymidine]] into rat thymoma cell cultures.<ref>{{cite journal | journal = Proc Natl Acad Sci U S A | year = 1984 | month = Feb | volume = 81 | issue = 3 | pages = 753–6 | title = Benzodiazepines that bind at peripheral sites inhibit cell proliferation | author = Wang JK, Morgan JI, Spector S |pmid = 6322168 | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=344914&blobtype=pdf |format = PDF | doi = 10.1073/pnas.81.3.753 }}</ref> Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex.<ref>{{cite journal | author = Oishi R | coauthors = Nishibori M, Itoh Y, Saeki K. | year = 1986 | month = May | date = 27 | title = Diazepam-induced decrease in histamine turnover in mouse brain. | journal = Eur J Pharmacol. | volume = 124 | issue = 3 | pages = 337–42 | pmid = 3089825 | doi = 10.1016/0014-2999(86)90236-0}}</ref> Diazepam also decreases prolactin release in rats.<ref>{{cite journal |author=Grandison L |year=1982 |title=Suppression of prolactin secretion by benzodiazepines in vivo |journal=Neuroendocrinology |volume=34 |issue=5 |pages=369–73 |pmid=6979001 |doi=10.1159/000123330}}</ref> ==Mechanism of action== {{seealso|Benzodiazepine}} Diazepam is a benzodiazepine that binds to a specific subunit on the [[GABA A receptor|GABA<sub>A</sub>]] receptor at a site that is distinct from the binding site of the [[endogenous]] GABA molecule.<ref name="Barondes2">{{cite book | first= Samuel H. | last= Barondes | year= 1999 | month= MONTH | title= Molecules and Mental Illness | pages= 190–194 | publisher= New York: Scientific American Library | id= ISBN 0-7167-6033-9 }}</ref><ref name="Pharma">{{cite journal | author= Sieghart, W. | title= Pharmacology of benzodiazepine receptors: an update | journal= Journal of Psychiatry and Neuroscience | year= 1994 | month = January | pages= 24–29 | volume= 19 | issue= 1 | pmid=8148363 | url= http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1188559 | accessdate= 2006-03-10 }}</ref> The [[GABA A receptor|GABA<sub>A</sub>]] receptor is an inhibitory channel which, when activated, decreases neuronal activity. Because of the role of diazepam as a positive [[Allosteric regulation|allosteric modulator]] of GABA, when it binds to benzodiazepine receptors it causes [[inhibitory]] effects. This arises from the [[hyperpolarization (biology)|hyperpolarization]] of the post-[[synapse|synaptic]] membrane owing to the control exerted over negative [[chloride]] [[ion]]s by GABA<sub>A</sub> receptors.<ref name="Barondes2" /><ref name="Drugs.com">{{cite web | author= Thomson Healthcare (Micromedex) | year= March 2000 | url= http://www.drugs.com/pdr/diazepam.html | title= Diazepam | work= Prescription Drug Information | publisher= Drugs.com | accessdate= 2006-03-11 }}</ref> Benzodiazepines including diazepam however, do not have any effect on the levels of GABA in the brain.<ref>{{cite journal |author=Varotto M |coauthors=Roman G, Battistin L |year=1981 |month=30 April |title=[Pharmacological influences on the brain level and transport of GABA. I) Effect of various antipileptic drugs on brain levels of GABA] |volume=57 |issue=8 |pages=904–8 |pmid=7272065 |journal=Boll Soc Ital Biol Sper}}</ref> Diazepam appears to act on areas of the [[limbic system]], [[thalamus]] and [[hypothalamus]], inducing anxiolytic effects. Its actions are due to the enhancement of [[GABA]] activity.<ref name="PubChem" /><ref name="Barondes2">{{cite book | first= Samuel H. | last= Barondes | year= 1999 | month= MONTH | title= Molecules and Mental Illness | pages= 190–194 | location= New York | publisher=Scientific American Library | id= ISBN 0-7167-6033-9 }}</ref> Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.<ref>{{cite journal | author = Zakusov VV | coauthors = Ostrovskaya RU, Kozhechkin SN, Markovich VV, Molodavkin GM, Voronina TA. | year = 1977 | month = Oct | title = Further evidence for GABA-ergic mechanisms in the action of benzodiazepines. | volume = 229 | issue = 2 | pages = 313–26 | pmid = 23084 | unused_data = |Archives internationales de pharmacodynamie et de thérapie. }}</ref> The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.<ref>{{cite journal | author = McLean MJ | coauthors = Macdonald RL. | year = 1988 | month = Feb | title = Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. | volume = 244 | issue = 2 | pages = 789–95 | pmid = 2450203 | journal = J Pharmacol Exp Ther. }}</ref> The muscle relaxant properties of diazepam are produced via inhibition of [[polysynaptic]] pathways in the spinal cord.<ref>{{cite journal | author = Date SK | coauthors = Hemavathi KG, Gulati OD. | year = 1984 | month = Nov | title = Investigation of the muscle relaxant activity of nitrazepam. | volume = 272 | issue = 1 | pages = 129–39 | pmid = 6517646 | journal = Arch Int Pharmacodyn Ther. }}</ref> ==Pharmacokinetics== Diazepam can be administered orally, [[intravenous therapy|intravenous]]ly, [[intramuscular injection|intramuscular]]ly, or as a [[suppository]].<ref name="Inchem">{{cite web | author= Pere Munne/M. Ruse, Ed. | year= 1990/1998 Ed. | url= http://www.inchem.org/documents/pims/pharm/pim181.htm | title= Diazepam | work= Inchem.org | publisher= Inchem.org | accessdate= 2006-03-11}}</ref> When diazepam is administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is 1–5 minutes for IV administration and 15–30 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to 1 hour for both routes of administration.<ref name="Cuny.edu">{{cite web | author= Langsam, Yedidyah | year= <!--Unknown--> | url= http://eilat.sci.brooklyn.cuny.edu/newnyc/DRUGS/Diazepam.htm | title= DIAZEPAM (VALIUM AND OTHERS) | work= | publisher= Brooklyn College (Eilat.sci.Brooklyn.CUNY.edu) | accessdate= 2006-03-23}}</ref> Peak plasma levels are achieved 30 minutes to 2 hours after oral administration. When diazepam is administered as an intramuscular injection, absorption is slow, erratic and incomplete.<ref name="DrugBank">{{cite journal | title = Drug Bank - Diazepam | url = http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00642.txt }}</ref><ref name="ElephantCare">{{cite web | author= Mikota, Susan K. and Plumb, Donald C. | year= 2005 | url= http://www.elephantcare.org/Drugs/diazepam.htm | title= Diazepam | work= The Elephant Formulary | publisher= Elephant Care International | accessdate= }}</ref> Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the [[blood-brain barrier]] and the [[placenta]], and is excreted into breast milk. After absorption, diazepam is redistributed into [[muscle]] and [[adipose]] tissue. Continual daily doses of diazepam will quickly build up to a high concentration in the body (mainly in [[adipose tissue]]), which will be far in excess of the actual dose for any given day.<ref name="Inchem" /><ref name="ElephantCare" /> There is preferential storage of diazepam in some organs including the heart. Absortion by any administered route and the risk of accumulation is significantly increased in the [[neonate]] and there is clinical justification to recommend the withdrawal of diazepam during pregnancy and breast feeding.<ref>{{cite journal | author = Olive G | coauthors = Dreux C. | year = 1977 | month = Jan | title = Pharmacologic bases of use of benzodiazepines in peréinatal medicine. | volume = 34(1) | pages = 74–89 | pmid = 851373 | journal = Arch Fr Pediatr. }}</ref> Diazepam is metabolised via oxidative pathways in the [[liver]] via the [[cytochrome P450]] enzyme system. It has a biphasic [[half-life]] of 1–2 and 2–5 days, and has several pharmacologically active metabolites. The main active metabolite of diazepam is [[nordazepam|desmethyldiazepam]] (also known as ''nordazepam'' or ''nordiazepam''). Diazepam's other active metabolites include [[temazepam]] and [[oxazepam]]. These metabolites are conjugated with [[glucuronide]], and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug.<ref name="DrugBank" /><ref name="ElephantCare" /><ref>{{cite journal | author = Oelschläger H. | coauthors = | year = 1989 | month = Jul | date = 4 | title = [Chemical and pharmacologic aspects of benzodiazepines] | journal = Schweiz Rundsch Med Prax. | volume = 78 | issue = 27–28 | pages = 766–72 | pmid = 2570451 }}</ref> Diazepam is also metabolised to a [[benzophenone]] compound.<ref>{{cite journal | journal = Ann Biol Clin (Paris) | year = 1985| volume = 43| issue = 3| pages = 261–5| title = [Validation of a method for detecting benzodiazepines in the urine by acid extraction of their benzophenones and thin layer chromatography]| author = Vu Duc T| coauthor = Vernay A| pmid = 2862815}}</ref> Diazepam has a half-life (t1/2α) of 20–50 hours, and desmethyldiazepam has a half-life of 30–200 hours and is considered to be a long acting benzodiazepine.<ref name="ElephantCare" /> Most of the drug is metabolised; very little diazepam is excreted unchanged.<ref name="Inchem" /> In humans, the protein binding of diazepam is around 98.5%.<ref name="DrugBank" /> The elimination half life of diazepam and also the active metabolite [[desmethyldiazepam]] increases significantly in the elderly which may result in prolonged action as well as accumulation of the drug during repeated administration.<ref>{{cite journal | author = Vozeh S. | coauthors = | year = 1981 | month = Nov | date = 21 | title = [Pharmacokinetic of benzodiazepines in old age] | journal = Schweiz Med Wochenschr. | volume = 111 | issue = 47 | pages = 1789–93 | pmid = 6118950 }}</ref> ==Indications== Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute [[alcohol]] or [[opiate]] [[withdrawal]]. It is also used as a [[premedication]] for inducing sedation, anxiolysis or amnesia before certain medical procedures (e.g. [[endoscopy]]).<ref name="DrugBank" /> Diazepam is rarely used for the long-term treatment of [[epilepsy]] because tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for this purpose and also because of side-effects - in particular sedation.<ref name="Inchem" /><ref>{{cite journal | last = Isojärvi | first = JI | coauthors = Tokola RA. | year = 1998 | month = Dec | title = Benzodiazepines in the treatment of epilepsy in people with intellectual disability. | journal = J Intellect Disabil Res. | volume = 42 | issue = 1 | pages = 80–92 | pmid = 10030438 }}</ref> Diazepam has a broad spectrum of indications (most of which are off-label), including: * Treatment of [[anxiety]], [[panic attacks]], and states of [[agitation]].<ref name="DrugBank" /> * Treatment of [[status epilepticus]], adjunctive treatment of other forms of epilepsy<ref name="DrugBank" /> *Treatment of [[Vertigo (medical)|vertigo]] associated with [[Meniere's Disease]]. * Treatment of the symptoms of alcohol and opiate withdrawal<ref name="DrugBank" /> * Short-term treatment of [[insomnia]].<ref name="DrugBank" /> * Treatment of [[tetanus]], together with other measures of intensive-treatment<ref name=tetanus>{{cite journal | first = C. N. | last = Okoromah | coauthors = F. E. Lesi | year = 2004 | title = Diazepam for treating tetanus | journal = Cochrane database of systematic reviews (Online) | issue = 1 | pmid = 14974046 | doi = 10.1002/14651858.CD003954.pub2}}</ref> * Initial management of [[mania]], together with firstline drugs like [[Lithium pharmacology|lithium]], [[valproate]], [[lamotrigine]] or other [[antipsychotic]]s{{Fact|date=February 2007}} * Adjunctive treatment of painful muscle conditions<ref name="RXL.Indications" /> * Adjunctive treatment of spastic muscular [[paresis]] (para-/tetraplegia) caused by cerebral or [[spinal cord]] conditions such as [[stroke]], [[multiple sclerosis]], spinal cord injury (long-term treatment is coupled with other rehabilitative measures)<ref name="RXL.Indications" /> * Palliative treatment of [[stiff person syndrome]].<ref name="Drugs.com" /> *Used to alleviate the symptoms of [[Lesch-Nyhan Syndrome]] * Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g. before [[endoscopic]] or surgical procedures)<ref name="RXL.Indications" /> * Treatment of overdosage with [[hallucinogens]] or CNS [[stimulants]].<ref name="Inchem" /> * Adjunctive treatment of drug-induced seizures, resulting from exposure to [[sarin]], [[VX (nerve agent)|VX]], [[soman]] (or other [[organophosphate]] poisons; See [[CANA]]), [[lindane]], [[chloroquine]], [[physostigmine]], or [[pyrethroid]]s<ref name="Inchem" /> * Emergency treatment of [[eclampsia]], along with [[Intravenous therapy|IV]] [[magnesium sulfate]] * [[Prophylactic]] treatment of [[oxygen toxicity]] during [[hyperbaric oxygen therapy]].<ref name="Hyperbaric">{{cite book | first= Kindwall | last= <!--Incorrect/non-standard setup for names of authors--> | year= 1999 | coauthors= Eric P. (Ed.), Whelan, Harry T. (Ed.) | title= Hyperbaric Medicine Practice, Second Edition | pages= <!--Unknown--> | publisher= Best Publishing Company | id= ISBN 0-941332-78-0 }}</ref> * Used in the treatment for irritable bowel syndrome.<ref>Neurological Encyclopedia. http://www.answers.com/diazepam </ref> * Used to treat pain resulting from muscle spasms caused by various spastic dystonias, including blepharospasm, spasmodic dysphonia and Meige's Syndrome. ===Veterinary uses=== * Diazepam is used as a short term sedative and anxiolytic for cats and dogs. It is also used for short-term treatment of seizures in dogs and short-term and long-term treatment of seizures in cats. For emergent treatment of seizures, the typical dose is 0.5 mg/kg intravenously or 1–2 mg/kg per rectum of the injectable solution.<ref>{{cite web | last = Hines| first = Ron DVM PhD | date = 2006-01-14 | url = http://www.2ndchance.info/epilepsy.htm | title = Epilepsy In Your Dog Or Cat| publisher = 2nd Chance Sanctuary Pet Health Center | accessmonthday = May 18 | accessyear = 2006 }}</ref> * Diazepam is also used as a muscle relaxant for horses, to be given intravenously, the usual dose is 0.02 - 0.1 mg/kg in conjunction with or just after induction of general anesthesia. ===Judicial executions=== * The State of [[California]] offers Diazepam to [[Capital punishment|condemned]] inmates as a pre-execution sedative.<ref>San Quentin State Prison Operational Procedure 0-770, Execution By Lethal Injection (pp. 43 & 92). http://www.cdcr.ca.gov/News/docs/RevisedProtocol.pdf</ref> ==Dosage== Dosages should be determined on an individual basis, depending upon the condition to be treated, the severity of symptoms, the body weight of the patient, and any [[Comorbidity|comorbid]] conditions the patient may have.<ref name="Inchem" /> Typical dosages for healthy adults range from 2 mg per dose to 10 mg per dose taken 2 to 4 times per day, depending on such factors as body weight and condition being treated. For the elderly or people with liver disorders, initial dose is at the low end of the range, with the dose being increased as required.<ref name="Drugs.com" /> ==Trade names== *Valium tablets in USA and many other countries; *Valium capsules in [[Italy]], [[Spain]]; *Novodipam in [[Canada]]; *Relanium in [[Poland]]; *Seduxen in [[Hungary]], [[Russia]]; *Diazepam-Desitin rectal solution in Hungary, and other European countries; *Diazepam-Intensol; *Valrelease *Diapam in [[Finland]] *Stesolid [[Sweden]], [[Iceland]], [[Norway]] *Anxicalm [[Ireland]] *Valpam in [[Australia]] *Vival tablets in [[Norway]] *Normabel tablets in [[Croatia]] *Bensedin in [[Serbia]] *Stedon tablets in [[Greece]] *Plidex tablets in [[Uruguay]], [[Argentina]], [[Chile]] *Betapam in [[South Africa]] *Dipaz in [[Ecuador]] ===Availability=== [[Image:Diazepam(Valium) DOJ.jpg|frame|right]] Diazepam is supplied in the following forms: * For oral administration: ** Tablets - 2 mg, 5 mg, 10 mg.<ref name="Drugs.com" /> Generic versions available. ** Capsules, time-release - 15mg (marketed by Roche as '''Valrelease''')<ref name="ElephantCare" /> ** Liquid solution - 1 mg/ml in 500 ml containers and unit-dose (5 mg & 10 mg); 5 mg/ml in 30 ml dropper bottle (marketed by Roxane as '''Diazepam Intensol''')<ref name="ElephantCare" /> * For parenteral administration: ** Solution for IV/IM injection - 5 mg/ml. 2 ml ampoules and syringes; 1 ml, 2 ml, 10 ml vials; 2 ml Tel-E-Ject; also contains 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as a preservative.<ref name="RXL.Description">{{cite web | year= January 24, 2005 | url= http://www.rxlist.com/cgi/generic/diazepam.htm | title= Diazepam: description | work= Rxlist.com | publisher= RxList Inc. | accessdate= 2006-03-10 }}</ref><ref name="ElephantCare" /> Notice: IM injection is largely less effective as the drug is injected into a tetanic muscle with compressed muscular veins. This does not allow the drug to reach the circulation rapidly. <!-- Image with unknown copyright status removed: [[Image:Seduxen.jpg|frame|right]] --> Seduxen (Diazepam, in Hungary, Russia, Poland, and other Eastern-European countries) is supplied in the following forms: * For oral administration: ** Tablets 5mg ** Injection 5 mg/ml for intravenous, intramuscular or subcutaneous usage * For parenteral administration: ** Solution for IV/IM injection - 5 mg/ml. 2 ml ampoules and syringes; 1 ml, 2 ml, 10 ml vials; 2 ml Tel-E-Ject; also contains 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as a preservative.<ref name="RXL.Description">{{cite web | year= January 24, 2005 | url= http://www.rxlist.com/cgi/generic/diazepam.htm | title= Diazepam: description | work= Rxlist.com | publisher= RxList Inc. | accessdate= 2006-03-10 }}</ref><ref name="ElephantCare" /> Notice: IM injection is largely less effective as the drug is injected into a tetanic muscle with compressed muscular veins. This does not allow the drug to reach the circulation rapidly. * For rectal administration: ** Solution<ref name="Inchem" /> ** Suppositories - 5mg and 10mg<ref name="Suppositories">{{cite journal | author= Kaewnopparat, N., Kaewnopparat, S., Rojanarat, W., Ingkatawornwong, S. | title= Enhanced Release of Diazepam From Hollow-Type Suppositorie | journal= International Journal of Pharmaceutical Compounding | year= 2004 | month= July/August | pages= | volume= | issue= | id= | url= http://www.findarticles.com/p/articles/mi_qa4101/is_200407/ai_n9459054 | accessdate= 2006-03-10 | format= {{dead link|date=June 2008}} &ndash; <sup>[http://scholar.google.co.uk/scholar?hl=en&lr=&q=intitle%3AEnhanced+Release+of+Diazepam+From+Hollow-Type+Suppositorie&as_publication=International+Journal+of+Pharmaceutical+Compounding&as_ylo=2004&as_yhi=2004&btnG=Search Scholar search]</sup> }}</ref><ref name="Inchem" /> ** Rectal tubes * For inhalation administration: This method uses heating diazepam to form a vapor later producing an aerosol. This allows the drug to be passed through an inhalation route during an inhalation therapy. Provided in doses 2mg-20mg either in a single inhalation or multiple small inhalations<ref>Pharmaceutical Patents. http://www.pharmcast.com/Patents100/Yr2004/Oct2004/101904/6805853_Diazepam101904.htm </ref> * Diazepam, is available in the [[United States military]] as CANA (Convulsive Antidote, Nerve Agent). One CANA kit is typically issued to service members, along with three [[Mark I NAAK]] kits when operating in circumstances where chemical weapons in the form of [[nerve agents]] are considered a potential hazard. (Both of these kits deliver drugs using [[auto-injector]]s. They are intended for use in "buddy aid" or "self aid" administration of the drugs in the field prior to [[decontamination]] and delivery of the patient to definitive medical care.)<ref>[[United States Army Medical Research Institute of Chemical Defense|U.S. Army Medical Research Institute of Chemical Defense]], ''Medical Management of Chemical Casualties Handbook'', Third Edition (June 2000), [[Aberdeen Proving Ground]], MD, pp 118-126.</ref> ==Side effects== Diazepam has a range of side effects which are common to most benzodiazepines. Most common side effects include: * [[Somnolence]] * Suppression of REM sleep * Addiction * Impaired motor function ** Impaired coordination ** Impaired balance ** [[Dizziness]] and nausea * [[depression (mood)|Depression]] * Impaired learning * [[Anterograde amnesia]] (especially pronounced in higher doses) * [[Cognitive]] deficits<ref>{{cite journal |author=Jones DM |coauthors=Jones ME, Lewis MJ, Spriggs TL. |title=Drugs and human memory: effects of low doses of nitrazepam and hyoscine on retention. |journal=Br J Clin Pharmacol. |volume=7 |issue=5 |pages=479–83 |month=May |year=1979 |pmid=475944}}</ref> * [[Tachycardia|Reflex tachycardia]]<!--This term appears numerous times throughout Wikipedia, and yet nowhere is it properly and clearly defined.--><ref name="Cuny.edu" /> Rare paradoxical side effects can include: nervousness, irritability, insomnia, muscle cramps, and in extreme cases, rage, and violence.<ref name=rage>{{cite journal | last = Marrosu | first = F. | coauthors = G. Marrosu, M. G. Rachel, G. Biggio | month = July-September | year = 1987 | title = Paradoxical reactions elicited by diazepam in children with classic autism. | journal = Functional Neurology | volume = 2 | issue = 3 | pages = 355–361 | pmid = 2826308 | accessdate = 2006-09-24}}</ref><ref name=next_three>{{cite web | url = http://www.rxlist.com/cgi/generic/diazepam_ad.htm | title = Diazepam: Side Effects | accessmonthday = September 26 | accessyear = 2006 | work = RxList.com}}</ref><ref name=violence>{{cite journal | last = Michel | first = L. | coauthors = J. P. Lang | month = November-December | year = 2003 | title = Benzodiazépines et passage à l'acte criminel / Benzodiazepines and forensic aspects | journal = L'Encéphale | volume = 29 | issue = 6 | pages = 479–85 | pmid = 15029082 | url = http://www.masson.fr/masson/portal/bookmark?Global=1&Page=18&MenuIdSelected=106&MenuItemSelected=0&MenuSupportSelected=0&CodeProduct4=539&CodeRevue4=ENC&Path=REVUE/ENC/2003/29/6/ARTICLE11106200473.xml&Locations=}}</ref> If these side effects are present, diazepam treatment should be immediately terminated. Benzodiazepines such as diazepam impair learning and memory via their action on benzodiazepine receptors which causes a dysfunction in the cholinergic neuronal system.<ref>{{cite journal | author = Nabeshima T | coauthors = Tohyama K, Ichihara K, Kameyama T. | year = 1990 | month = Nov | title = Effects of benzodiazepines on passive avoidance response and latent learning in mice: relationship to benzodiazepine receptors and the cholinergic neuronal system. | journal = J Pharmacol Exp Ther. | volume = 255 | issue = 2 | pages = 789–94 | pmid = 2173758 }}</ref> Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.<ref name="Drugs.com" /> During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.<ref name=sedative_effect_tolerance>{{cite journal | last = Hriscu | first = A. | coauthors = F. Gherase, V. Nastasa, and E. Hriscu | month = October-December | year = 2002 | title = [An experimental study of tolerance to benzodiazepines] | journal = Revista Medico-Chirurgicală̆ a Societă̆ţ̜ii de Medici ş̧i Naturaliş̧ti din Iaş̧i | volume = 106 | issue = 4 | pages = 806–811 | pmid = 14974234 }}</ref> Patients with severe attacks of [[apnea]] during sleep may suffer [[respiratory depression]] (hypoventilation) leading to respiratory arrest and death. Organic changes such as [[leukopenia]]<ref name=leukopenia>{{cite journal | last = Haerten | first = K. | coauthors = W. Pottgen | date = [[September 19]], [[1975]] | title = [Leukopenia following benzodiazepine derivatives] | journal = Die Medizinische Welt | volume = 26 | issue = 38 | pages = 1712–1714 | pmid = 1186464 }}</ref> and liver-damage of the cholostatic type with or without [[jaundice]] ([[icterus]]) have been observed in a few cases.{{Fact|date=February 2007}} Diazepam in doses of 5 mg or more causes significant deterioration in [[alertness]] performance combined with increased feelings of sleepiness.<ref>{{cite journal | author = Kozená L | coauthors = Frantik E, Horváth M. | year = 1995 | month = May | title = Vigilance impairment after a single dose of benzodiazepines. | journal = Psychopharmacology (Berl). | volume = 119 | issue = 1 | pages = 39–45 | pmid = 7675948 | doi = 10.1007/BF02246052 }}</ref> ==Interactions== If diazepam is to be administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that enhance the effects of diazepam, such as barbiturates, [[phenothiazines]], [[narcotics]] and [[antidepressants]].<ref name="Drugs.com" /> Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. There is no evidence that would suggest diazepam alters its own metabolism with chronic administration.<ref name="Inchem" /> Agents which have an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable.<ref name="Inchem" /> * Diazepam increases the central depressive effects of alcohol, other [[hypnotic]]s/sedatives (e.g. barbiturates), narcotics, and other [[muscle relaxant]]s. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.<ref name="Holt">{{cite book| first= Gary A.| last= Holt| year= 1998| month= | title= Food and Drug Interactions: A Guide for Consumers| pages= 90–91| location= Chicago | publisher=Precept Press| id= ISBN 0-944496-59-8 }}</ref><ref name="PDRhealth">{{cite web| author= | year= 2006| url= http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/val1473.shtml| title= Diazepam| work= PDRHealth.com| publisher= PDRHealth.com| accessdate= 2006-03-10}}</ref> * [[Cimetidine]], [[omeprazole]], [[ketoconazole]], [[itraconazole]], [[disulfiram]], [[fluvoxamine]], [[isoniazid]], [[erythromycin]], [[probenecid]], [[propranolol]], [[imipramine]], [[ciprofloxacin]], [[fluoxetine]] and [[valproic acid]] prolong the action of diazepam by inhibiting its elimination.<ref name="Inchem" /><ref name="ElephantCare" /> * Alcohol ([[ethanol]]) in combination with diazepam may cause a synergistic enhancement of the [[hypotensive]] properties of benzodiazepines and alcohol.<ref>{{cite journal | author = Zácková P | coauthors = Kvĕtina J, Nĕmec J, Nĕmcová J. | year = 1982 | month = Dec | title = Cardiovascular effects of diazepam and nitrazepam in combination with ethanol. | journal = Pharmazie. | volume = 37 | issue = 12 | pages = 853–6 | pmid = 7163374 }}</ref> * Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.<ref name="PDRhealth" /><ref>{{cite journal | author = Back DJ | coauthors = Orme ML. | year = 1990 | month = Jun | title = Pharmacokinetic drug interactions with oral contraceptives. | journal = Clin Pharmacokinet. | volume = 18 | issue = 6 | pages = 472–84 | pmid = 2191822 }}</ref> * [[Rifampin]], [[phenytoin]], [[carbamazepine]] and [[phenobarbital]] increase the metabolism of diazepam, thus decreasing drug levels and effects.<ref name="Inchem" /> *Diazepam increases the serum levels of [[phenobarbital]].<ref>{{cite journal | author = Bendarzewska-Nawrocka B | coauthors = Pietruszewska E, Stepień L, Bidziński J, Bacia T. | year = 1980 | month = Jan-Feb | title = [Relationship between blood serum luminal and diphenylhydantoin level and the results of treatment and other clinical data in drug-resistant epilepsy] | journal = Neurol Neurochir Pol. | volume = 14 | issue = 1 | pages = 39–45 | pmid = 7374896 }}</ref> * [[Nefazodone]] can cause increased blood levels of benzodiazepines.<ref name="PDRhealth" /> * [[Cisapride]] may enhance the absorption, and therefore the sedative activity, of diazepam.<ref name="Cisapride">{{cite journal | author= Bateman, D.N. | title= The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam. | journal= Eur J Clin Pharmacol. | year= 1986 | pages= 205–8 | volume= 30 | issue= 2 | pmid=3709647 | doi= 10.1007/BF00614304}}</ref> * Small doses of [[theophylline]] may inhibit the action of diazepam.<ref name=theophylline>{{cite journal | last = Mattila | first = M. J. | coauthors = E. Nuotto | year = 1983 | title = Caffeine and theophylline counteract diazepam effects in man | journal = Medical Biology | volume = 61 | issue = 6 | pages = 337–343 | pmid = 6374311 }}</ref> * Diazepam may block the action of [[levodopa]] (used in the treatment of [[Parkinson's Disease]]).<ref name="Holt" /> * Diazepam may alter [[digoxin]] serum concentrations.<ref name="Inchem" /> * Other drugs that may have interactions with diazepam include: [[Antipsychotic]]s (e.g. [[chlorpromazine]]), [[MAO inhibitors]], [[ranitidine]].<ref name="PDRhealth" /> * Smoking [[tobacco]] can enhance the elimination of diazepam and decrease its action.<ref name="Holt" /> * Because it acts on the GABA receptor the herb [[Valerian (herb)|Valerian]] may produce an adverse effect.<ref>Possible Interactions with: Valerian, University of Maryland Medical Center, http://www.umm.edu/altmed/articles/valerian-000934.htm</ref> * Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.<ref name="Holt" /> * Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.<ref name="Inchem" /> * There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.<ref name="Holt" /> ==Contraindications== Use of diazepam should be avoided, when possible, in individuals with the following conditions: * [[Ataxia]] * Severe [[hypoventilation]] * Acute narrow-angle [[glaucoma]] * Severe [[hepatic]] deficiencies ([[hepatitis]] and liver [[cirrhosis]] decrease elimination by a factor of 2) * Severe [[renal]] deficiencies (e.g. patients on [[dialysis]]) * Severe [[sleep apnea]] * Severe [[clinical depression|depression]], particularly when accompanied by suicidal tendencies * Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the exception of some [[hallucinogens]], where it is occasionally used as a treatment for overdose) * [[Myasthenia gravis]] * Hypersensitivity or allergy to any drug in the [[benzodiazepine]] class ===Special caution needed=== * Pediatric patients ** Less than 18 years of age - Treatment usually not indicated, except treatment of epilepsy, and pre-/postoperative treatment. The smallest possible effective dose should be used for this group of patients.<ref name="PDRhealth" /> ** Under 6 months of age - Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.<ref name="Drugs.com" /><ref name="PDRhealth" /> * Elderly and very ill patients - Possibility that apnea and/or cardiac arrest may occur. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of patients.<ref name="Drugs.com" /><ref name="PDRhealth" /><ref name="RXL.Caution">{{cite web | year= January 24, 2005 | url= http://www.rxlist.com/cgi/generic/diazepam_wcp.htm | title= Diazepam: precautions | work= Rxlist.com | publisher= RxList Inc. | accessdate= 2006-03-10 }}</ref> Diazepam may also be dangerous in geriatric patients owing to a significant increased risk of falls.<ref>{{cite journal | author = Shats V | coauthors = Kozacov S. | year = 1995 | month = Jun | date = 1 | title = [Falls in the geriatric department: responsibility of the care-giver and the hospital] | journal = Harefuah | volume = 128 | issue = 11 | pages = 690–3 | pmid = 7557666 }}</ref> * I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.<ref name="RXL.Caution" /> * Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes and therefore rapidly crosses over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, may result in [[floppy infant syndrome]].<ref>{{cite journal | author = Kanto JH. | coauthors = | year = 1982 | month = May | title = Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations. | journal = Drugs. | volume = 23 | issue = 5 | pages = 354–80 | pmid = 6124415 | doi = 10.2165/00003495-198223050-00002}}</ref> ==Dependence== Diazepam as with other [[benzodiazepine]] drugs can cause [[physical dependence]], [[addiction]] and what is known as the [[benzodiazepine withdrawal syndrome]]. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen during alcohol and [[barbiturate]] withdrawal. The higher the dose and the longer the drug is taken for the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.<ref>{{cite journal | author = MacKinnon GL | coauthors = Parker WA. | year = 1982 | month = | title = Benzodiazepine withdrawal syndrome: a literature review and evaluation. | journal = The American journal of drug and alcohol abuse. | volume = 9 | issue = 1 | pages = 19–33 | pmid = 6133446 | doi = 10.3109/00952998209002608}}</ref> It has been shown in a clinical study that 100% of patients on low dose diazepam therapy long term are [[physically dependent]] on their medication.<ref>{{cite journal |author=Bernik MA |coauthors=Gorenstein C, Vieira Filho AH. |title=Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users. |journal=Journal of psychopharmacology (Oxford, England). |volume=12 |issue=2 |pages=146–50 |month= |year=1998 |pmid=9694026}}</ref> Increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch and panic attacks may be experienced as withdrawal symptoms in low therapeutic dose long term users of diazepam when discontinuing their diazepam medication.<ref>{{cite journal |author=Mintzer MZ |coauthors=Stoller KB, Griffiths RR. |title=A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users. |volume=147 |issue=2 |pages=200–9 |month=Nov |year=1999 |pmid=10591888}}</ref> Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines.<ref>{{cite journal |author=Chouinard G |coauthors=Labonte A, Fontaine R, Annable L |year=1983 |title=New concepts in benzodiazepine therapy: rebound anxiety and new indications for the more potent benzodiazepines |volume=7 |issue=4–6 |pages=669–73 |pmid=6141609 |journal=Prog Neuropsychopharmacol Biol Psychiatry |doi=10.1016/0278-5846(83)90043-X}}</ref> Diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction.<ref>{{cite journal |author= Lader M. |coauthors= |title=Long-term anxiolytic therapy: the issue of drug withdrawal. |journal=The Journal of clinical psychiatry. |volume=48 |issue= |pages=12–6 |month=Dec |year=1987 |pmid=2891684}}</ref> There is a significant risk of pharmacological dependence on diazepam and patients experiencing the [[benzodiazepine withdrawal syndrome]] if it is taken for 6 weeks or longer.<ref>{{cite journal |author=Murphy SM, Owen R, Tyrer P. |title=Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks' treatment with diazepam or buspirone. |journal=The [[British Journal of Psychiatry]]: the journal of mental science. |volume=154 |issue= |pages=529–34 |year=1989 |pmid=2686797}}</ref> In humans tolerance to the anticonvulsant effects of diazepam occurs frequently.<ref>{{cite journal |author=Loiseau P |year =1983 |title =[Benzodiazepines in the treatment of epilepsy] | journal =Encephale | volume =9 | issue =4 Suppl 2 | pages =287B–292B | pmid = 6373234 }}</ref> ===Patients at a high risk for abuse, dependence, tolerance, or addiction=== Diazepam can lead to [[physiological tolerance]], and psychological and/or physical dependence.<ref name="JohnHopkinsHealth.com"> {{cite web | year= 2005 | url= http://www.johnshopkinshealthalerts.com/reports/depression_anxiety/59-1.html?type=pf | title= Treating Anxiety -- Avoiding Dependence on Xanax, Klonopin, Valium, and Other Antianxiety Drugs | work= johnshopkinshealthalerts.com | publisher= Johnshopkinshealthalerts.com | accessdate= 2007-12-23}}</ref> At a particularly high risk for diazepam misuse, abuse, or dependence are: * Patients with a history of alcohol or drug abuse or dependence<ref name="Drugs.com" /><ref name="RXL.Abuse">{{cite web | year= January 24, 2005 | url= http://www.rxlist.com/cgi/generic/diazepam_ad.htm#DA | title= Diazepam: abuse and dependence | work= Rxlist.com | publisher= RxList Inc. | accessdate= 2006-03-10 }}</ref> * Patients with severe personality disorders, such as [[Borderline Personality Disorder]]<ref name=not_in_BPD>{{cite journal | last = Vorma | first = Helena | coauthors = Hannu H. Naukkarinen, Seppo J. Sarna, and Kimmo I. Kuoppasalmi | year = 2005 | title = Predictors of Benzodiazepine Discontinuation in Subjects Manifesting Complicated Dependence | journal = Substance Use & Misuse | volume = 40 | issue = 4 | pages = 499–510 | pmid = 15830732 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=pubmed_Abstract&cmd=Retrieve&db=pubmed&list_uids=15830732&dopt=ExternalLink | format = PDF | accessdate = 2006-09-25 | doi = 10.1081/JA-200052433}}</ref> * Patients with an [[anxiety disorder]]<ref name="JohnHopkinsHealth.com"> {{cite web | year= 2005 | url= http://www.johnshopkinshealthalerts.com/reports/depression_anxiety/59-1.html?type=pf | title= Treating Anxiety -- Avoiding Dependence on Xanax, Klonopin, Valium, and Other Antianxiety Drugs | work= johnshopkinshealthalerts.com | publisher= Johnshopkinshealthalerts.com | accessdate= 2007-12-23}}</ref> Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Discontinue therapy if any of these signs are noted. Long-term therapy in these patients is not recommended.<ref name="Drugs.com" /><ref name="RXL.Abuse" /> The [[American Society of Addiction Medicine]] has policy indicating that patients with addictive disease should not be prescribed benzodiazepines such as diazepam.{{Fact|date=December 2007}} Patients suspected of being physiologically addicted to benzodiazepine drugs should be very gradually tapered off the drug. Although rare, withdrawals can be life threatening particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether addiction has occurred in therapeutic or recreational contexts. A large scale nation wide USA government study conducted by [[SAMHSA]] found that benzodiazepines in the USA are the most frequently abused pharmaceutical with 35% of drug related visits to the Emergency Department involved benzodiazepines. Benzodiazepines are more commonly abused than opiate pharmaceuticals which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines. Males abuse benzodiazepines as commonly as women. Of drugs used in attempted suicide benzodiazepines are the most commonly used pharmaceutical drug with 26% of attempted suicides involving benzodiazepines. The most commonly abused benzodiazepine is however, [[alprazolam]]. Clonazepam is the 2nd most abused benzodiazepine. [[Lorazepam]] is the third most commonly abused benzodiazepine and [[diazepam]] the 4th most commonly abused benzodiazepine in the [[USA]]. Alprazolam is also commonly abused in combination with alcohol.<ref>{{cite web |url= http://dawninfo.samhsa.gov/files/DAWN2k4ED.htm |title= Drug Abuse Warning Network, 2004: National Estimates of Drug-Related Emergency Department Visits |accessdaymonth= 09 May |accessyear= 2008 |author= United States Government |authorlink= samhsa |coauthors= U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES |year= 2004 |publisher= Substance Abuse and Mental Health Services Administration}}</ref> ==Pregnancy== There is inconclusive evidence that diazepam if taken early in pregnancy may result in reduced IQ, neurodevelopmental problems, physical malformations in cardiac or facial structure as well as other malformations in some newborns, however the data is inconclusive. Diazepam when taken during late in pregnancy, the [[third trimester]], causes a definite risk of a severe [[benzodiazepine withdrawal syndrome]] in the neonate with symptoms including [[hypotonia]], and reluctance to suck, to [[apnoeic]] spells, [[cyanosis]], and impaired [[metabolic]] responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.<ref>{{cite journal | author = McElhatton PR. | coauthors = | year = 1994 | month = Nov-Dec | title = The effects of benzodiazepine use during pregnancy and lactation. | journal = Reprod Toxicol. | volume = 8 | issue = 6 | pages = 461–75 | pmid = 7881198 | doi = 10.1016/0890-6238(94)90029-9}}</ref> ==Overdose== An individual who has consumed too much diazepam will display one or more of the following symptoms:<ref name="Drugs.com" /><ref name="RXL.Overdose">{{cite web | year= January 24, 2005 | url= http://www.rxlist.com/cgi/generic/diazepam_od.htm | title= Diazepam: overdose | work= Rxlist.com | publisher= RxList Inc. | accessdate= 2006-03-10 }}</ref> * Drowsiness * Mental confusion * [[Hypotension]] * Impaired motor functions ** Impaired reflexes ** Impaired coordination ** Impaired balance ** Dizziness * [[Coma]] Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The [[antidote]] for an overdose of diazepam (or any other benzodiazepine) is [[flumazenil]] (Anexate). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug and the effects of diazepam can last for days, several doses of flumazenil may be necessary. [[Artificial respiration]] and stabilization of cardiovascular functions may also be necessary. Although not routinely indicated, [[activated charcoal]] can be used for decontamination of the stomach following a diazepam overdose. [[Emesis]] is contraindicated. [[Dialysis]] is minimally effective. Hypotension may be treated with [[levarterenol]] or [[metaraminol]].<ref name="Inchem"/><ref name="Barondes1"/><ref name="Drugs.com"/><ref name="RXL.Overdose"/> The oral [[LD50|LD<sub>50</sub>]] (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats.<ref name="Drugs.com"/> D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately deep comas, and were discharged within 48 hours without having experienced important complications in spite of having high concentrations of diazepam and its metabolites&mdash;desmethyldiazepam, oxazepam, and temazepam&mdash;according to samples taken in the hospital and as follow-up.<ref name=Greenblatt_et_al_1978>{{cite journal | last = Greenblatt | first = D. J. | coauthors = E. Woo, M. D. Allen, P. J. Orsulak, and R. I. Shader | date = [[October 20]], [[1978]] | title = Rapid recovery from massive diazepam overdose | journal = Journal of the American Medical Association | volume = 240 | issue = 17 | pages = 1872–4 | pmid = 357765 | doi = 10.1001/jama.240.17.1872 }}</ref> Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.<ref name="Barondes1"/><ref>{{cite journal | last = Lai | first = SH | coauthors = Yao YJ, Lo DS. | year = 2006 | month = Oct | title = A survey of buprenorphine related deaths in Singapore. | journal = Forensic Sci Int. | volume = 162(1–3) | pages = 80–6 | pmid = 16879940 | doi = 10.1016/j.forsciint.2006.03.037 }}</ref> ==Recreational and illicit use== Diazepam is a drug of potential dependence and addiction. Between 50 and 64% of rats will self administer diazepam.<ref>{{cite journal | author = Yoshimura K | coauthors = Horiuchi M, Inoue Y, Yamamoto K. | year = 1984 | month = Jan | title = [Pharmacological studies on drug dependence. (III): Intravenous self-administration of some CNS-affecting drugs and a new sleep-inducer, 1H-1, 2, 4-triazolyl benzophenone derivative (450191-S), in rats] | volume = 83 | issue = 1 | pages = 39–67 | pmid = 6538866 | journal = Nippon Yakurigaku Zasshi.}}</ref> Benzodiazepines including diazepam in animal studies have been shown to increase reward seeking behaviours by increasing impulsivity which may suggest an increased risk of addictive behavioural patterns with usage of diazepam or other benzodiazepines.<ref>{{cite journal | author = Thiébot MH | coauthors = Le Bihan C, Soubrié P, Simon P. | year = 1985 | month = | title = Benzodiazepines reduce the tolerance to reward delay in rats. | volume = 86 | issue = 1–2 | pages = 147–52 | pmid = 2862657 | journal = Psychopharmacology (Berl). | doi = 10.1007/BF00431700}}</ref> Diazepam has been found as an [[adulterant]] in [[heroin]].<ref name=heroin_adulterant>{{cite web | url = http://www.incb.org/incb/en/annual_report_1996_chapter2.html#IIB10 | title = CHAPTER II. OPERATION OF THE INTERNATIONAL DRUG CONTROL SYSTEM | accessmonthday = September 25 | accessyear = 2006 | author =International Narcotics Control Board | work = REPORT OF THE INTERNATIONAL NARCOTICS CONTROL BOARD FOR 1996 | year = 1996 | language = English}}</ref> This may be because diazepam greatly amplifies the effects of [[opioids]]. Sometimes diazepam is used by stimulant users to 'come down' and sleep and to help control the urge to binge.<ref name=with_meth>{{cite web | url = http://de1.erowid.org/experiences/exp.phpquery=ID=9402.html | title = Methamphetamine and Benzodiazepines: Methamphetamine & Benzodiazepines | accessmonthday = September 26 | accessyear = 2006 | author = Overclocker | work = Erowid Experience Vaults }}</ref> Benzodiazepines, including diazepam, [[nitrazepam]] and [[flunitrazepam]] account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.<ref>{{cite journal | author = Bergman U | coauthors = Dahl-Puustinen ML. | year = 1989 | month = | title = Use of prescription forgeries in a drug abuse surveillance network. | volume = 36 | issue = 6 | pages = 621–3 | pmid = 2776820 | journal = Eur J Clin Pharmacol. | doi = 10.1007/BF00637747}}</ref> Diazepam was detected in 26% of cases of people suspected of driving under the influence of drugs in Sweden and its active metabolite nordazepam was detected in 28% of cases. Other benzodiazepines and zolpidem and zopiclone also were found in high numbers. Many drivers had blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and [[zolpidem]] and [[zopiclone]].<ref>{{cite journal | author = Jones AW | coauthors = Holmgren A, Kugelberg FC. | year = 2007 | month = Apr | title = Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results. | volume = 29 | issue = 2 | pages = 248–60 | pmid = 17417081 | journal = Ther Drug Monit. | doi = 10.1097/FTD.0b013e31803d3c04}}</ref> In [[Northern Ireland]] in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found to be present in 87% of cases. Diazepam was the most commonly detected benzodiazepine.<ref>{{cite journal | author = Cosbey SH. | year = 1986 | month = Dec | title = Drugs and the impaired driver in Northern Ireland: an analytical survey. | volume = 32 | issue = 4 | pages = 245–58 | pmid = 3804143 | journal = Forensic Sci Int. | doi = 10.1016/0379-0738(86)90201-X}}</ref> ==Legal status== Internationally, diazepam is a Schedule IV drug under the [[Convention on Psychotropic Substances]].<ref name="Legal">{{cite web | author=International Narcotics Control Board | year=2003 | url= http://www.incb.org/pdf/e/list/green.pdf | title= List of psychotropic substances under international control | work= Green list | accessdate= 2006-03-11 |format=PDF}}</ref> In the UK, it is classified as a [[Misuse of Drugs Act 1971|Class C drug]]. ==Toxicity== Laboratory tests assessing the toxicity of diazepam, [[nitrazepam]] and [[chlordiazepoxide]] on mice [[spermatozoa]] found that diazepam produced toxicities in sperm including abnormalities involving both the shape and size of the sperm head. Nitrazepam however caused more profound abnormalities than diazepam.<ref>{{cite journal | author = Kar RN | coauthors = Das RK. | year = 1983 | month = | title = Induction of sperm head abnormalities in mice by three tranquilizers. | journal = Cytobios. | volume = 36 | issue = 141 | pages = 45–51 | pmid = 6132780 }}</ref> ==Further reading== <!--Information in the following references should be incorporated into the article (if it isn't already) and should be cited using the same format as the rest of this page.--> * Fachinformationen (German) for Valium, provided by Roche Pharmaceuticals * Bandelow, Borwin et al. ''Handbuch der Arzneimitteltherapie, Bd.1, Psychopharmaka'', 2nd edition. Enke, 2004. ISBN 3-13-113041-5. * Benkert, Otto et al. ''Kompendium der Psychiatrischen Pharmakotherapie'', 5th edition. Springer, 2003. ISBN 3-540-21893-9. ==References== {{Reflist|2}} ==External links== * [http://www.rocheusa.com/products/valium/tabspi.pdf Roche Pharmaceuticals (US) - Valium Product Information] <!--Not sure if this link is appropriate, but it contains a bit of information not included in the above article. * [http://www.pharmamotion.com.ar/animation-benzodiazepines-diazepam-lorazepam-alprazolam.html Flash animation about how bromazepam works (mechanism of action)] * [http://www.amc.edu/patient/ems/ems_medication.htm Albany Medical Center] - "Medication of the month" --> {{Benzodiazepines}} {{Anticonvulsants}} {{Anxiolytics}} [[Category:Benzodiazepines]] [[Category:Hoffmann-La Roche]] [[Category:Hypnotics]] {{Link FA|ja}} [[bg:Диазепам]] [[cs:Diazepam]] [[da:Diazepam]] [[de:Diazepam]] [[es:Diazepam]] [[fr:Diazépam]] [[gl:Diazepam]] [[it:Diazepam]] [[he:דיאזפאם]] [[hu:Diazepám]] [[ml:ഡയസെപാം]] [[nl:Diazepam]] [[ja:ジアゼパム]] [[no:Diazepam]] [[pl:Diazepam]] [[pt:Diazepam]] [[ru:Диазепам]] [[simple:Diazepam]] [[fi:Diatsepaami]] [[sv:Diazepam]] [[tr:Diazepam]] [[zh:地西泮]]