Temazepam: Difference between revisions
Thegoodson (talk | contribs) the article is in good condition aside from things here and there; Nothing will be taken out - this is a very well referenced article |
|||
Line 26: | Line 26: | ||
|routes_of_administration=Oral |
|routes_of_administration=Oral |
||
}} |
}} |
||
'''Temazepam''' (marketed under brand names '''Restoril''', '''Euhypnos''', '''Normison''', '''Remestan''', '''Tenox''' and '''Norkotral''') is a |
'''Temazepam''' (marketed under brand names '''Restoril''', '''Euhypnos''', '''Normison''', '''Remestan''', '''Tenox''' and '''Norkotral''') is a type of [[benzodiazepine]] drug. It is a powerful hypnotic benzodiazepine which possesses strong [[sedative]], [[amnestic]] and motor impairing properties.<ref>{{cite journal |author=Yasui M |coauthors=Kato A, Kanemasa T, Murata S, Nishitomi K, Koike K, Tai N, Shinohara S, Tokomura M, Horiuchi M, Abe K |title=[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes] |Nihon Shinkei Seishin Yakurigaku Zasshi |volume=25 |issue=3 |pages=143-51 |month=Jun |year=2005 |pmid=16045197}}</ref> In addition, temazepam also has strong [[anxiolytic]], [[anticonvulsant]], and [[skeletal muscle relaxant]] properties. Temazepam, which is an intermediate acting benzodiazepine, acts quickly to induce sleep. It is generally prescribed for the treatment of short-term severe or debilitating [[insomnia]] in patients who have difficulty falling asleep or maintaining sleep.<ref>{{cite journal |author=Rickels K |year=1986 |title=The clinical use of hypnotics: indications for use and the need for a variety of hypnotics |journal=Acta Psychiatr Scand Suppl |volume=332 |pages=132-41 |pmid=2883820}}</ref> |
||
==History== |
==History== |
||
Temazepam first came into use in the 1960's, but it was not until 1969 that its usefulness to counter insomnia was realized, and by the year [[1981]], the [[Food and Drug Administration]] approved temazepam as a sedative-hypnotic for the treatment of [[insomnia]] and other [[sleep disorders]] under the trade name Restoril. Its powerful sedative and amnesic effects got the attention of several Secret Intelligence agencies, especially the former [[Soviet Union]]. It was utilized as a [[Truth drug|truth serum]] during interrogations because of its strong hypnotic properties. Given to the subject, temazepam weakens the resolve of the subject and makes him or her more compliant to pressure. As a [[Truth drug|truth serum]], temazepam was not often used. It was mainly utilized by the [[Soviet Union]] and [[East Germany]] in the 1970's during the [[Cold War]]. It also saw limited use as a truth serum in some parts of [[East Asia]] and [[Southeast Asia]]. The preferred drugs used as [[Truth drug|truth serum]]s were, and still are [[barbiturates]], particularly [[sodium thiopental]] (Sodium Pentothal). Temazepam was also one of several drugs used in the research of [[mind control]], [[brainwashing]] and mass-scale [[social engineering]] by Secret Intelligence agencies of several different federal governments. Other drugs used for this same purpose were, [[barbiturates]], [[morphine]], [[LSD]], [[amphetamines]], and [[neuroleptics]].<ref>O'Neal, Maryadele J. Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. Merck. October 18, 2006.</ref> In former [[Soviet Union]], temazepam was extensively used, along with other drugs like [[haloperidol]] (Haldol), [[thorazine]], barbiturates, and [[morphine]] to keep political dissidents housed in [[Punitive psychiatry in the Soviet Union|psikhushkas]] (mental asylums and psychiatric hospitals) in a constant vegetative state.<ref>{{cite book |author=Yevgenia Albats and Catherine A. Fitzpatrick |title=The State Within a State: The KGB and Its Hold on Russia - Past, Present, and Future |year=1994 |publsiher=Farrar Straus Giroux |isbn=0374527385}}</ref><ref>{{cite book |author=Sidney Bloch and Peter Reddaway |year=1984 |title=Soviet Psychiatric Abuse: The Shadow over World Psychiatry |publisher=Victor Gollancz |location=London |isbn=0813302099}}</ref> |
|||
Temazepam was approved by the [[Food and Drug Administration]] for the treatment of [[insomnia]] and other [[sleep disorders]] under the trade name Restoril. |
|||
By the late 1980's, temazepam was one of the most widely prescribed drugs for insomnia and other sleep disorders. |
By the late 1980's, temazepam was one of the most effective hypnotics on the market and it became one of the most widely prescribed drugs for insomnia and other sleep disorders. With that however, the abuse of temazepam became widespread in much of Europe, East and Southeast Asia, Australia and [[New Zealand]]. It quickly superseded other benzodiazepines like [[diazepam]] (Valium) and [[nitrazepam]] (Mogadon), which were also commonly diverted to the black market and abused by drug addicts. In [[North America]], its abuse did not become as widespread as it did elsewhere in the world due to the fact that [[triazolam]] and [[flurazepam]] were by far the most commonly prescribed hypnotic benzodiazepines. Diazepam, [[alprazolam]], and [[lorazepam]], though not hypnotics and aren't usually indicated for sleep, were also more widely prescribed to patients having trouble sleeping then was temazepam.<ref>{{cite web |title=Prescription Drugs: Their Use and Abuse |url=http://teacher.scholastic.com/scholasticnews/indepth/headsup/support/prescription.pdf |format=PDF |date= |publisher=[[Scholastic Corporation]] and [[National Institute on Drug Abuse]], [[National Institutes of Health|NIH]] |accessdate=2007-11-25}}</ref> It was not until the mid to late 1990's that temazepam became more widely prescribed in the United States. |
||
Until recently, temazepam was produced as a gel-filled capsule intended to be taken orally. However, it gained notoriety in Europe, especially in [[United Kingdom]] and [[Scotland]], when it was discovered that if the capsules were melted and injected, the effects were more powerful and the onset was quicker. However, the liquid has a tendency to congeal in arteries and cause [[thrombosis]] and [[gangrene]], in some cases requiring [[amputation]]. Despite the risks, injection of temazepam quickly spread throughout some parts [[Europe]] and then to [[Australia]], [[New Zealand]], and many parts of [[Asia]]. In [[Malaysia]], [[nimetazepam]] is the only benzodiazepine that's more commonly abused or sought after by drug addicts than temazepam according to government data and seizures made by police. To curb the diversion of temazepam into the black market and stop abuse, many countries have placed temazepam under more strict drug schedules. In Australia, instead of being a [[Standard for the Uniform Scheduling of Drugs and Poisons|Schedule 4 drug]] like all other benzodiazepines, temazepam is placed in [[Standard for the Uniform Scheduling of Drugs and Poisons|Schedule 8]], along side drugs like [[morphine]], [[cocaine]], [[methamphetamine]], and [[methylphenidate]] (Ritalin). In the [[United Kingdom]], temazepam (and [[flunitrazepam]]) is a Class B drug, meanwhile all other benzodiazepines are Class C, a much less restrictive category. In the United States, temazepam is the only benzodiazepine which requires specially coded prescriptions in certain states.<ref>{{cite web |title=What are the UK drug laws? |url=http://www.drugscope.org.uk/resources/faqs/faqpages/what-are-the-uk-drug-laws.htm |date=February 2007 |publisher=DrugsScope |accessdate=2007-11-25}}</ref> Despite the much more stringent restrictions put on temazepam compared to most other benzodiazepines, temazepam remains to be the most sought after and abused benzodiazepine worldwide with more kilograms of diverted temazepam being seized than any other benzodiazepine, followed by [[flunitrazepam]], [[diazepam]], [[nimetazepam]], and then [[nitrazepam]].<ref>{{cite journal |author= Woody GE |coauthors= Mc Lellan AT O'Brien CP |title=Development of psychiatric illness in drug abusers. Possible role of drug preference |journal=The New England journal of medicine |volume=301 |issue=24 |pages=1310-4 |year=1979 |pmid=41182}}</ref> Pharmacy burglaries and prescription forgeries in Scotland, Australia, Ireland, Sweden, and several Asian countries report that temazepam is often a main target, whilst other benzodiazepines are rarely targeted.<ref>{{cite journal |author=Duddu V, Saleem PT, Green K |title=Sedative-hypnotic prescription in an out-patient mental health service in the north-west |journal=Clinical Governance |year=2003 |volume=8 |issue=1 |pages=65-8 |doi=10.1108/14777270310459986}}</ref><ref name="pmid10940604">{{cite journal |author=Rasanen I, Neuvonen M, Ojanperä I, Vuori E |title=Benzodiazepine findings in blood and urine by gas chromatography and immunoassay |journal=Forensic Sci. Int. |volume=112 |issue=2-3 |pages=191–200 |year=2000 |pmid=10940604 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0379073800002735}}</ref><ref> |
|||
Oral doses of temazepam were initially supplied as gel-filled capsules. However, this generated concern in the medical community, especially in the [[United Kingdom]] and [[Scotland]], when it was discovered that some addicts were melting and injecting the product intravenously. This preparation, not intended for parenteral administration, was reported to congeal in blood vessels, causing [[thrombosis]] and [[gangrene]], rarely requiring [[amputation]]. This practice also spread to some parts of [[Europe]], [[Australia]], [[New Zealand]], and [[Asia]]. |
|||
{{cite web |author=Australian Institute of Criminology |title=Benzodiazepine use and harms among police detainees in Australia |url=http://www.aic.gov.au/publications/tandi2/tandi336.pdf |format=PDF |publisher=Australian Government |date=May 2007}}</ref> |
|||
== |
==Pharmacology== |
||
Temazepam is classed as a 1,4 benzodiazepine, with the chemical name ''7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1-4-benzodiazepin-2-one''. It's structurally most closely related to [[diazepam]] and [[oxazepam]]. In its pharmacological properties however, temazepam is most closely related to [[nimetazepam]], [[nitrazepam]], and [[flunitrazepam]].<ref>{{cite journal |author=K. Bronisz |coauthors= M. Ostafin |year=2006 |month=Nov |title=Studies of the electronic structure and biological activity of chosen 1,4-benzodiazepines by 35Cl NQR spectroscopy and DFT calculations |journal=Chemical Physics |volume= |issue=1-2 |pages=301-306}}</ref> It is a white, crystalline substance, is very slightly soluble in water and sparingly soluble in alcohol. It is [[lipophilic]] and is metabolized hepatically via oxidative pathways. The main pharmacological action of temazepam is the enhancement of the [[neurotransmitter]], [[GABA]] at the GABA<sub>A</sub> receptor.<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> The half life of temazepam is 8-22 hours.<ref>{{cite web |url=http://www.bcnc.org.uk/equivalence.html |title=Benzodiazepine Equivalency Table |accessmonthday=Sept 23 |accessyear=2007 |author=Ashton, H |year=2007 |month=April}}</ref> It is a full agonist of the benzodiazepine receptor.<ref>{{cite journal |author=Podhorna J |coauthors=Krsiak M |year=2000 |title=Behavioural effects of a benzodiazepine receptor partial agonist, Ro 19-8022, in the social conflict test in mice |journal=Behavioural pharmacology |volume=11 |issue =2 |pages=143-51 |pmid=10877119}}</ref> An opioid mechanism of action may play a role in some of the pharmacological properties of temazepam.<ref>{{cite journal |author=Nowakowska E |coauthors=Chodera A |year=1991 |month=Feb |title=Studies on the involvement of opioid mechanism in the locomotor effects of benzodiazepines in rats |journal=Pharmacology, biochemistry, and behavior |volume=38 |issue=2 |pages=265-6 |pmid=1676167}}</ref> |
|||
In attempt to mitigate the diversion of temazepam into the black market and prevent abuse, many countries have placed temazepam under more strict regulation than most other drugs in its class. |
|||
Temazepam triggers the release of [[vasopressin]] into the rat hypothalamic paraventricular nucleus. <ref name="pmid16395302">{{cite journal |author=Welt T, Engelmann M, Renner U, ''et al'' |title=Temazepam triggers the release of vasopressin into the rat hypothalamic paraventricular nucleus: novel insight into benzodiazepine action on hypothalamic-pituitary-adrenocortical system activity during stress |journal=Neuropsychopharmacology |volume=31 |issue=12 |pages=2573–9 |year=2006 |pmid=16395302 |doi=10.1038/sj.npp.1301006 |url=http://www.nature.com/npp/journal/v31/n12/full/1301006a.html}}</ref> Adult male Wistar rats were intravenously administered with temazepam (0.5, 1, and 3 mg/kg body weight) and plasma concentrations of [[corticotropin]] (ACTH) and [[vasopressin]] (AVP) were measured in blood samples collected via chronically implanted jugular venous catheters. Simultaneously, the release of AVP within the hypothalamic paraventricular nucleus (PVN) was monitored via microdialysis. [[Plasma]] AVP levels remained unaffected by the different treatment conditions. Temazepam blunted the stressor exposure-induced secretion of ACTH in a dose-dependent manner. Concurrently, and also in a dose-dependent manner temazepam enhanced the intra-PVN release of AVP, known to originate from magnocellular neurons of the hypothalamic neurohypophyseal system. Furthermore, temazepam did not affect the in vitro secretion of ACTH from the adenohypophyseal cells. Taken together, the results of this study suggest that temazepam modulates the central nervous regulation of the HPA axis by altering intra-PVN AVP release. An increasingly released AVP of magnocellular origin seems to provide a negative tonus on ACTH secretion most probably via inhibiting the release of ACTH secretagogues from the median eminence into hypophyseal portal blood.<ref>{{cite journal |author=Engelmann M |coauthors=M., Renner, U., Erhardt, A., Muller, M.B., Landgraf, R., Holsboer, F., Keck, M.E |year=2006 |month=Dec |title=Temazepam triggers the release of vasopressin into the rat hypothalamic paraventricular nucleus: novel insight into benzodiazepine action on hypothalamic-pituitary-adrenocortical system activity during stress |journal= Neuropsychopharmacology |volume=31 |issue=12 |pages=2573-9 |pmid=16395302}}</ref> |
|||
In the [[United States|USA]], temazepam is a [[Schedule IV controlled substance|Schedule IV drug]] and is only available by prescription. Some states require specially coded prescriptions. |
|||
Temazepam and other [[benzodiazepines]] may influence [[neurosteroid]] metabolism and [[progesterone]] levels which in turn may influence the functions of the [[brain]] and [[reproductive system]]. The [[pharmacological]] actions of benzodiazepines at the GABAa receptor are similar to those of [[neurosteroids]]. [[Neuroactive]] steroids are positive [[allosteric]] modulators of the GABAa receptor, enhancing [[GABA]] function. Many benzodiazepines ([[diazepam]], [[medazepam]], [[estazolam]], [[nitrazepam]] [[flunitrazepam]] and temazepam) potently inhibit the [[enzymes]] involved in the [[metabolism]] of neurosteroids. Long-term administration of benzodiazepines may influence the concentrations of [[endogenous]] neurosteroids, and thereby would modulate the emotional state. Factors which effects the ability of individual benzodiazepines to alter neurosteroid levels depend on the molecular make up of the individual benzodiazepine drug. Presence of a substituent at N1 position of the diazepine ring and/or the chloro or nitro group at position 7 of the [[benzene]] ring contribute to potent inhibition of the isoenzymes, and in turn a [[bromo]] group at position 7 (for bromazepam) and additional substituents (3-hydroxy group for [[oxazepam]] and tetrahydroxazole ring for [[cloxazolam]] and [[oxazolam]]) decrease the [[inhibitory]] potency of benzodiazepines on neurosteroids.<ref>{{cite journal |author=Usami N |coauthors=Yamamoto T, Shintani S, Ishikura S, Higaki Y, Katagiri Y, Hara A |year=2002 |month=Apr |title=Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines |journal=Biol Pharm Bull |volume=25 |issue=4 |pages=441-5 |pmid=11995921 |url=http://www.jstage.jst.go.jp/article/bpb/25/4/441/_pdf |format=pdf}}</ref> |
|||
In [[Canada]], Temazepam is a Schedule IV controlled substance requiring a doctors prescription. |
|||
In [[Ireland]], Temazepam is a Schedule 3 controlled substance with strict restrictions.<ref>{{cite web |title=Misuse Of Drugs (Amendment) Regulations |year=1993 |url=http://www.irishstatutebook.ie/1993/en/si/0342.html |work=Irish Statute Book |publisher=Office of the Attorney General}}</ref> |
|||
In [[Australia]], temazepam in liquid form is restricted as a Schedule 8 controlled drug. As a Schedule 8 controlled substance, it is illegal to have this drug in possession without an authority prescription from a registered doctor. In tablet form, it is a Schedule 4 prescription only medicine. |
|||
In [[South Africa]], temazepam is a Schedule 6 drug, requiring a prescription, and restricted to 10-20 mg doses. |
|||
In [[Sweden]], temazepam is available in 10-20 mg capsules and tablets but are rarely prescribed. The most commonly prescribed hypnotics in Sweden are [[zopiclone]], [[nitrazepam]], and [[flunitrazepam]]. Temazepam is only prescribed if for any reason the three above hypnotics fail to work. As such, temazepam is second line treatment for severe insomnia where the other hypnotics have failed. |
|||
Temazepam has an inhibitory effect on plasma [[cholinesterase]] of 60--90 per cent.<ref>{{cite journal | author = Holmes JH | coauthors = Kanfer I, Zwarenstein H. | year = 1978 | month = Aug | title = Effect of benzodiazepine derivatives on human blood cholinesterase in vitro. | journal = Res Commun Chem Pathol Pharmacol | volume = 21 | issue = 2 | pages = 367-70 | pmid = 29327 }}</ref> |
|||
In [[Hong Kong]], Temazepam is regulated under Schedule 1 of [[Hong Kong|Hong Kong's]] Chapter 134 ''Dangerous Drugs Ordinance''. |
|||
Internationally, temazepam is a Schedule IV drug under the [[Convention on Psychotropic Substances]]. Though it is classed as a Schedule IV internationally, penalties for its possession and/or trafficking are more severe, unlike all other benzodiazepines (except for [[flunitrazepam]], which is treated in the same manner as temazepam is.<ref>{{cite web |title=Green List -- List of psychotropic substances under international control |url=http://www.incb.org/pdf/e/list/green.pdf |format=PDF |date=23rd edition, August 2003 |publisher=International Narcotics Control Board |accessdate=2007-11-25}}</ref> |
|||
==Clinical Pharmacology== |
|||
Specifically, temazepam is classed as a 1,4 benzodiazepine with the chemical name ''7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1-4-benzodiazepin-2-one''. It is a white, crystalline solid, very sparingly soluble in water and sparingly soluble in alcohol. It is [[lipophilic]] and is metabolized hepatically via oxidative pathways.<ref>{{cite journal |author=K. Bronisz |coauthors= M. Ostafin |year=2006 |month=Nov |title=Studies of the electronic structure and biological activity of chosen 1,4-benzodiazepines by 35Cl NQR spectroscopy and DFT calculations |journal=Chemical Physics |volume= |issue=1-2 |pages=301-306}}</ref> |
|||
As with all benzodiazepines, the main pharmacological action of temazepam is the enhancement of the [[neurotransmitter]], [[GABA]] at the GABA<sub>A</sub> receptor. Unlike other similarly classified drugs, it is active at both the Omega-1 and Omega-2 benzodiazepine recetors, which modulate its hypnotic and anxiolytic effects, respectively.<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> The half life of temazepam is 8-22 hours.<ref>{{cite web |url=http://www.bcnc.org.uk/equivalence.html |title=Benzodiazepine Equivalency Table |accessmonthday=Sept 23 |accessyear=2007 |author=Ashton, H |year=2007 |month=April}}</ref>. It has been suggested that an opioid mechanism of action may play a role in the properties of benzodiazepines, including temazepam.<ref>{{cite journal |author=Nowakowska E |coauthors=Chodera A |year=1991 |month=Feb |title=Studies on the involvement of opioid mechanism in the locomotor effects of benzodiazepines in rats |journal=Pharmacology, biochemistry, and behavior |volume=38 |issue=2 |pages=265-6 |pmid=1676167}}</ref> |
|||
Temazepam has been shown to trigger the release of [[vasopressin]] into the rat hypothalamic paraventricular nucleus. <ref name="pmid16395302">{{cite journal |author=Welt T, Engelmann M, Renner U, ''et al'' |title=Temazepam triggers the release of vasopressin into the rat hypothalamic paraventricular nucleus: novel insight into benzodiazepine action on hypothalamic-pituitary-adrenocortical system activity during stress |journal=Neuropsychopharmacology |volume=31 |issue=12 |pages=2573–9 |year=2006 |pmid=16395302 |doi=10.1038/sj.npp.1301006 |url=http://www.nature.com/npp/journal/v31/n12/full/1301006a.html}}</ref> This suggests that temazepam may modulate the central nervous regulation of the HPA axis by altering vasopressin release. |
|||
Temazepam has also been shown to have an inhibitory effect on plasma [[cholinesterase]].<ref>{{cite journal | author = Holmes JH | coauthors = Kanfer I, Zwarenstein H. | year = 1978 | month = Aug | title = Effect of benzodiazepine derivatives on human blood cholinesterase in vitro. | journal = Res Commun Chem Pathol Pharmacol | volume = 21 | issue = 2 | pages = 367-70 | pmid = 29327 }}</ref> |
|||
==Pharmacokinetics== |
==Pharmacokinetics== |
||
In a single and multiple dose absorption, distribution, metabolism, and excretion (ADME) study, using [[tritium]] (3H) labelled drug, temazepam was well absorbed and found to have minimal (8%) first pass metabolism. There were no active metabolites formed and the only significant metabolite present in blood was the O-conjugate. The unchanged drug was 96% bound to plasma proteins. The blood level decline of the parent drug was biphasic with the short half-life ranging from 0.4-0.6 hours and the terminal half-life from 3.5-18.4 hours (mean 8.8 hours), depending on the study population and method of determination.<ref name="pmid2891534">{{cite journal |author=Müller FO, Van Dyk M, Hundt HK, ''et al'' |title=Pharmacokinetics of temazepam after day-time and night-time oral administration |journal=Eur. J. Clin. Pharmacol |volume=33 |issue=2 |pages=211–4 |year=1987 |pmid=2891534 |doi=10.1007/BF00544571}}</ref> Metabolites were formed with a half-life of 10 hours and excreted with a half-life of approximately 2 hours. Thus, formation of the major metabolite is the rate limiting step in the biodisposition of temazepam. There is no accumulation of metabolites. A dose-proportional relationship has been established for the area under the plasma concentration/time curve over the 15-30 mg dose range.<ref name="RxList">{{cite web |title=Restoril -- Clinical Pharmacology |url=http://www.rxlist.com/cgi/generic/temaz_cp.htm |publisher=RxList.com |accessdate=2007-11-25}}</ref> |
|||
Temazepam |
Temazepam was completely metabolized through conjugation prior to excretion; 80%-90% of the dose appeared in the urine. The major metabolite was the O-conjugate of temazepam (90%); the O-conjugate of N-desmethyl temazepam was a minor metabolite (7%).<ref>{{cite journal |author=Schwarz HJ |year=1979 |month=Aug |date=1 |title=Pharmacokinetics and metabolism of temazepam in man and several animal species |volume=23 |issue=29 |pmid=41539}}</ref> |
||
===Bioavailability, Induction, and Plasma Levels=== |
===Bioavailability, Induction, and Plasma Levels=== |
||
Following ingestion of |
After oral administration, temazepam is rapidly absorbed and fast acting. Following ingestion of 30 mg temazepam, measurable plasma concentrations are achieved 10-20 minutes after dosing with peak plasma levels ranging from 666-982 ng/mL (mean 865 ng/mL) occurring approximately 1.2-1.6 hours (mean 1.5 hours) after dosing. Strong hypnotic, sedative and anticonvulsant effects are noticeable 20-30 minutes after ingestion. <ref name="pmid598411">{{cite journal |author=Fuccella LM, Bolcioni G, Tamassia V, Ferrario L, Tognoni G |title=Human pharmacokinetics and bioavailability of temazepam administered in soft gelatin capsules |journal=Eur. J. Clin. Pharmacol |volume=12 |issue=5 |pages=383–6 |year=1977 |month=Sept |pmid=598411 |doi=10.1007/BF00562455}}</ref> |
||
In a 7 day study, in which subjects were given a 30 mg temazepam capsule 1 hour before retiring, steady-state (as measured by the attainment of maximal trough concentrations) was achieved by the third dose. Mean plasma levels of temazepam (for days 2-7) were 260±210 ng/mL at 9 hours and 75±80 ng/mL at 24 hours after dosing. A slight trend toward declining 24 hour plasma levels was seen after day 4 in the study, however, the 24 hour plasma levels were quite variable. .<ref name="RxList" /> |
|||
==Other Uses== |
|||
At a dose of 30 mg once-a-day for 8 weeks, no evidence of enzyme induction was found in man. |
|||
Temazepam also possesses strong [[anticonvulsant]] properties and it has been used to manage seizure disorders in adults. Though a highly-effective anti-epileptic, such use is relatively rare due to its sedative and motor-impairing properties. Temazepam is also a potent [[anxiolytic]] and [[skeletal muscle relaxant]]. Again, such off-label is rare due to its side-effect profile. |
|||
==Indications, Uses & Efficacy== |
|||
As with most benzodiazepines, temazepam has been shown to produce anterograde [[amnesia]]. It has been speculated that the former [[Soviet Union]] utilized temazepam in KGP, espionage, and interrogation practices.<ref>{{cite book |author=Yevgenia Albats and Catherine A. Fitzpatrick |title=The State Within a State: The KGB and Its Hold on Russia - Past, Present, and Future |year=1994 |publsiher=Farrar Straus Giroux |isbn=0374527385}}</ref><ref>{{cite book |author=Sidney Bloch and Peter Reddaway |year=1984 |title=Soviet Psychiatric Abuse: The Shadow over World Psychiatry |publisher=Victor Gollancz |location=London |isbn=0813302099}}</ref> |
|||
Temazepam is a full agonist of the [[benzodiazepine]] receptor.<ref>{{cite journal |author=Podhorna J |coauthors=Krsiak M |year=2000 |title=Behavioural effects of a benzodiazepine receptor partial agonist, Ro 19-8022, in the social conflict test in mice |journal=Behavioural pharmacology |volume=11 |issue =2 |pages=143-51 |pmid=10877119}}</ref> It is a powerful [[hypnotic]] agent. In sleep laboratory studies, temazepam dramatically decreased the number of nightly awakenings.<ref name="pmid342551">{{cite journal |author=Bixler EO, Kales A, Soldatos CR, Scharf MB, Kales JD |title=Effectiveness of temazepam with short-intermediate-, and long-term use: sleep laboratory evaluation |journal=J Clin Pharmacol |volume=18 |issue=2-3 |pages=110–8 |year=1978 |pmid=342551 |doi= |url=http://jcp.sagepub.com/cgi/pmidlookup?view=long&pmid=342551}}</ref> Rebound [[insomnia]] was observed only occasionally after withdrawal of the drug. Temazepam decreased [[Sleep#Stages of sleep|stage 3]], and combined stage 3 and 4 sleep, accompanied by a compensatory increase in stage 2 sleep, but did not alter REM sleep. |
|||
Temazepam also possesses strong [[anticonvulsant]] properties and it has been used to manage seizures in adults. Though it is highly effective, its use as an anticonvulsant is rare due to its strong sedative and motor impairing properties. Temazepam is also a potent [[anxiolytic]], [[skeletal muscle relaxant]], and a strong [[amnestic]]. Its use as an anticonvulsant, anxiolytic, and skeletal muscle relaxant would be considered off-label, and though highly effective, its sedative, motor impairing, and hypnotic properties make it undesirable for such uses. |
|||
Temazepam is officially indicated for severe [[insomnia]] and other severe or disabling [[sleep disorder]]s, where other sleep aids and treatments have failed. Despite this however, it is a widely prescribed first line hypnotic for short periods of time (usually no more than 7-10 days). The failure of insomnia to remit after 7-10 days of treatment may indicate the presence of a primary [[psychiatric]] and/or medical illness that should be evaluated. Temazepam taken for longer than 2 - 4 weeks may result in a strong [[physical dependence]] with a resultant [[benzodiazepine withdrawal syndrome]] developing when dosage is decreased or the drug is stopped. |
|||
====Military Use==== |
====Military Use==== |
||
The [[United States Air Force]] uses temazepam under trade name Restoril as "no-go pills" to help pilots sleep after a mission. Another drug used for the same purpose is a short acting [[nonbenzodiazepine]] [[zolpidem]] ([[Ambien]]) (''Cf.'' "go-pills"; [[dextroamphetamine]], or recently [[modafinil]], used as a stimulant for pilots). |
The [[United States Air Force]] uses temazepam under trade name Restoril as "no-go pills" to help pilots sleep after a mission. Another drug used for the same purpose is a short acting [[nonbenzodiazepine]] [[zolpidem]] ([[Ambien]]) (''Cf.'' "go-pills"; [[dextroamphetamine]], or recently [[modafinil]], used as a stimulant for pilots). |
||
====Utilization==== |
|||
Temazepam, despite being the most highly restricted benzodiazepine in Australia (along with [[flunitrazepam]]) is commonly prescribed for severe insomnia. Temazepam along with diazepam, nitrazepam and oxazepam 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 |pages=345-9 |pmid=7911332}}</ref> |
|||
==Dosage== |
==Dosage== |
||
Line 93: | Line 83: | ||
In Australia it is only available in 10mg tablets under the trade name "Normison" and the generic name "Temaze" and "Temtabs". 20mg tablets and Temazepam in capsule or gelcap form is no longer available in that country. |
In Australia it is only available in 10mg tablets under the trade name "Normison" and the generic name "Temaze" and "Temtabs". 20mg tablets and Temazepam in capsule or gelcap form is no longer available in that country. |
||
Usual UK doses (from [[British National Formulary|BNF]]) are 10-20mg at bedtime, max 30-40mg in exceptional circumstances. |
|||
==Tolerance== |
==Tolerance== |
||
Although tolerance to the sleep inducing properties of temazepam develops within a matter of days, so too does tolerance to the residual performance impairment. After 6 days of use, tolerance to temazepam's sleep inducing effects and performance impairing effects occurs.<ref>{{cite journal |author=Griffiths AN |coauthors=Tedeschi G, Richens A |title=The effects of repeated doses of temazepam and nitrazepam on several measures of human performance |journal=Acta psychiatrica Scandinavica. Supplementum |volume=332 |issue= |pages=119-26 |month= |year=1986 |pmid=2883819}}</ref> One study demonstrated tolerance to the sleep promoting effects of [[nitrazepam]] and temazepam after 7 days nightly administration. Quality of sleep was found to be increased after the first nights administration of either nitrazepam or temazepam but by day 7 quality of sleep was found to have returned to baseline suggesting the development of complete tolerance after 7 days use.<ref>{{cite journal |author=Cook PJ |coauthors=Huggett A, Graham-Pole R, Savage IT, James IM |year=1983 |month=8 Jan |title=Hypnotic accumulation and hangover in elderly inpatients: a controlled double-blind study of temazepam and nitrazepam |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1546430&blobtype=pdf |format=pdf |journal=Br Med J (Clin Res Ed) |volume=286 |issue=6359 |pages=100-2 |pmid=6129914}}</ref> In mice tolerance to the anticonvulsant properties of temazepam developed profoundly and rapidly over 6 days, although some anticonvulsant effects were still apparent after 6 days administration.<ref name="pmid2894998">{{cite journal |author=Garratt JC, Gent JP, Feely M, Haigh JR |title=Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential? |journal=Eur. J. Pharmacol. |volume=145 |issue=1 |pages=75–80 |year=1988 |month=Jan |pmid=2894998 |doi=}}</ref> |
|||
Temazepam shares cross tolerance with barbiturates and [[barbiturates]] can easily be substituted for temazepam in those who are habituated to barbiturate sedative hypnotics.<ref>{{cite journal |author=Rooke KC |coauthors= |year=1976 |month= |title=The use of flurazepam (dalmane) as a substitute for barbiturates and methaqualone/diphenhydramine (mandrax) in general practice |journal=J Int Med Res |volume=4 |issue=5 |pages=355-9 |pmid=18375}}</ref> |
|||
==Dependence== |
==Dependence== |
||
Line 101: | Line 94: | ||
''See also'' [[benzodiazepine withdrawal syndrome]] |
''See also'' [[benzodiazepine withdrawal syndrome]] |
||
Temazepam as with other [[benzodiazepine]] drugs can lead to |
Temazepam as with other [[benzodiazepine]] drugs can lead to [[physical dependence]], [[addiction]] and what is known as the [[benzodiazepine withdrawal syndrome]]. Withdrawal from temazepam or other benzodiazepines after regular use 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 however occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction 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}}</ref> |
||
Dependence on temazepam and other benzodiazepine hypnotics like [[nitrazepam]], [[flunitrazepam]], or [[nimetazepam]] often occurs due to discharging patients from hospital on benzodiazepines who were started on benzodiazepine hypnotics in hospital. It was recommended that hypnotics in hospital be limited to 5 nights use only to avoid the development of the [[benzodiazepine withdrawal syndrome]] eg withdrawal insomnia.<ref>{{cite journal |author=Hecker R |coauthors=Burr M, Newbury G |year=1992 |title=Risk of benzodiazepine dependence resulting from hospital admission |journal=Drug Alcohol Rev |volume=11 |issue=2 |pages=131-5 |pmid=16840267}}</ref> |
|||
After discontinuation of temazepam, a [[rebound effect]] may occur immediately after abruptly stopping.<ref>{{cite journal |author=Hindmarch I |coauthors= |year=1977 |month=Nov |title=A repeated dose comparison of three benzodiazepine derivative (nitrazepam, temazepam and flunitrazepam) on subjective appraisals of sleep and measures of psychomotor performance the morning following night-time medication |journal=Acta Psychiatr Scand |volume=56 |issue=5 |pages=373-81 |pmid=22990}}</ref> Temazepam tends to have more side effects than other hypnotic drugs and tolerance to the sedative properties and [[rebound insomnia]] after discontinuation occurs after only 3-5 days administration.<ref>{{cite journal |author=Viukari M |coauthors=Linnoila M, Aalto U |year=1978 |month=Jan |title=Efficacy and side effects of flurazepam, temazepam, and nitrazepam as sleeping aids in psychogeriatric patients |journal=Acta Psychiatr Scand |volume=57 |issue=1 |pages=27-35 |pmid=24980}}</ref> Tolerance to the [[anticonvulsant]] and [[anxiolytic]] effects also develops rapidly during daily administration.<ref>{{cite journal |author=Nowakowska E |coauthors=Chodera A, Cenajek-Musiał D, Szczawińska K |year=1987 |month=May-Jun |title=Differences in the development of tolerance to various benzodiazepines |journal=Pol J Pharmacol Pharm |volume=39 |issue=3 |pages=245-52 |pmid=2894019}}</ref> |
|||
Abrupt withdrawal after long term use from therapeutic doses of temazepam may result in a very severe [[benzodiazepine withdrawal syndrome]]. There are reports in the medical literature of at least six psychotic states developing after abrupt withdrawal from temazepam including delirium after abrupt withdrawal of only 30 mg of temazepam and in another case, auditory hallucinations and visual cognitive disorder developed after abrupt withdrawal from 10 mg of temazepam, 5 mg of nitrazepam and 0.5 mg of triazolam. Gradual and careful reduction of the dosage, preferably with a milder long-acting benzodiazepine such as clonazepam or diazepam, or even a milder short to intermediate acting benzodiazepine such as oxazepam or alprazolam, was recommended to prevent severe withdrawal syndromes from developing. Other strong hypnotic benzodiazepines, whether short, intermediate or long-acting are not recommended.<ref name="pmid2902678">{{cite journal |author=Terao T, Tani Y |title=[Two cases of psychotic state following normal-dose benzodiazepine withdrawal] |language=Japanese |journal=J. UOEH |volume=10 |issue=3 |pages=337–40 |year=1988 |pmid=2902678 |doi=}}</ref> Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions.<ref name="pmid6118452">{{cite journal |author=Tagashira E, Hiramori T, Urano T, Nakao K, Yanaura S |title=Enhancement of drug withdrawal convulsion by combinations of phenobarbital and antipsychotic agents |journal=Jpn. J. Pharmacol |volume=31 |issue=5 |pages=689–99 |year=1981 |pmid=6118452 |doi=}}</ref> [[Depersonalisation]] has also been reported as a benzodiazepine withdrawal effect from temazepam.<ref name="pmid1737083">{{cite journal |author=Terao T, Yoshimura R, Terao M, Abe K |title=Depersonalization following nitrazepam withdrawal |journal=Biol. Psychiatry |volume=31 |issue=2 |pages=212–3 |year=1992 |pmid=1737083 |doi=}}</ref> |
|||
Abrupt withdrawal from very high doses is even more likely to cause severe withdrawal effects. Withdrawal from very high doses of temazepam will cause severe [[hypoperfusion]] of the whole brain with [[diffuse]] slow activity on [[EEG]]. After withdrawal, abnormalities in hypofrontal brain wave patterns may persist beyond the withdrawal syndrome suggesting that organic [[brain damage]] may occur from chronic high dose abuse of temazepam. Temazepam withdrawal has been well known to cause a sudden and often violent death.<ref name="pmid11900604">{{cite journal |author=Kitabayashi Y, Ueda H, Narumoto J, ''et al'' |title=Chronic high-dose temazepam dependence 123I-IMP SPECT and EEG studies |journal=Addict Biol |volume=6 |issue=3 |pages=257–261 |year=2001 |pmid=11900604 |doi=10.1080/13556210120056507}}</ref> |
|||
==Cognitive Behavioural Therapy== |
|||
Temazepam, [[nitrazepam]] and [[zopiclone]] are the most frequently prescribed hypnotics in the United Kingdom. Hypnotic drugs are of poor value for the management of chronic insomnia. It is widely accepted that hypnotic drug usage beyond 4 weeks is undesirable for all age groups of patients. Many continuous sedative hypnotic users exhibit disturbed sleep as a consequence of tolerance but experience worsening rebound or withdrawal insomnia when the dose is reduced too quickly which compounds the problem of chronic hypnotic drug use. Chronic hypnotic drug consumption has been shown to reduce work performance increase absenteeism increase road traffic accidents, increased [[morbidity]], increased [[mortality]] and is associated with increased deliberate [[self harm]]. In the elderly increases in falls and fractures associated with sedative hypnotic drug use has been found. CBT have been found to be more effective for the long term management of insomnia than sedative hypnotic drugs. No formal withdrawal programs for benzodiazepines exists with local providers. A meta-analysis of published data on psychological treatments for insomnia show a success rate between 70 and 80%. A large scale trial utilising [[cognitive behavioural therapy]] in chronic users of sedative hypnotics including nitrazepam, temazepam and zopiclone found that [[CBT]] to be a more effective long term treatment for chronic insomnia. Persisting improvements in sleep quality, sleep latency, increased total sleep, improvements in sleep efficiency, significant improvements in vitality, physical and mental health at 3, 6 and 12 month follow up was found in those receiving cognitive behavioural therapy. A marked reduction in total sedative hypnotic drug use was found in those receiving CBT, with 33% reporting zero hypnotic drug use. Age has been found not to be a barrier to successful outcome of CBT. It was concluded that CBT for the management of chronic insomnia was flexible, practical and cost effective treatment for the treatment of insomnia and that CBT leads to a reduction of benzodiazepine drug intake in significant number of patients.<ref>{{cite journal |author=Morgan K |coauthors=Dixon S, Mathers N, Thompson J, Tomeny M |year=2004 |month=Feb |title=Psychological treatment for insomnia in the regulation of long-term hypnotic drug use |journal=Health Technol Assess |volume=8 |issue=8 |pages=1-68 |publisher=National Institute for Health Research |pmid=14960254 |url=http://www.hta.ac.uk/fullmono/mon808.pdf |format=PDF}}</ref> |
|||
==Toxicity== |
==Toxicity== |
||
Benzodiazepines |
Benzodiazepines are generally thought to be safe in overdose.<ref name="pmid1888441">{{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=}}</ref> Death after admission is rare and due to respiratory depression with aspiration of gastric contents. <ref name="pmid2769176">{{cite journal |author=Höjer J, Baehrendtz S, Gustafsson L |title=Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period |journal=J. Intern. Med |volume=226 |issue=2 |pages=117–22 |year=1989 |pmid=2769176 |doi=}}</ref> Over 10 years in the United Kingdom, however, 1512 fatal poisonings have been attributed to benzodiazepines with or without alcohol.<ref name="pmid8104653">{{cite journal |author=Serfaty M, Masterton G |title=Fatal poisonings attributed to benzodiazepines in Britain during the 1980s |journal=Br J Psychiatry |volume=163 |issue= |pages=386–93 |year=1993 |pmid=8104653 |doi=}}</ref> These were compared with prescription data to establish a fatal toxicity index (deaths per million prescriptions) for each benzodiazepine. Similar indices have been derived for [[antidepressants]]<ref name="pmid3690249">{{cite journal |author=Cassidy S, Henry J |title=Fatal toxicity of antidepressant drugs in overdose |journal=Br Med J (Clin Res Ed) |volume=295 |issue=6605 |pages=1021–4 |year=1987 |pmid=3690249 |doi= |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=3690249}}</ref> and [[barbiturates]].<ref name="pmid861497">{{cite journal |author=Johns MW |title=Self-poisoning with barbiturates in England and Wales during 1959-74 |journal=Br Med J |volume=1 |issue=6069 |pages=1128–30 |year=1977 |pmid=861497 |doi= |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=861497}}</ref> There were clear differences between benzodiazepines. Of drugs frequently prescribed, temazepam by far had the highest number of deaths per million prescriptions at 11.9 (95% confidence interval 10.9 to 12.8); above that of some tricyclic antidepressants.<ref name="pmid8104653"/><ref name="pmid3690249"/> In contrast, oxazepam had an index of 2.3 (1.2 to 3.4), and the average index for all benzodiazepines combined was 5.7. |
||
Although there are potential sources of error in these studies,<ref name="pmid6480013">{{cite journal |author=Dwyer PS, Jones IF |title=Fatal self-poisoning in the UK and the paracetamol/dextropropoxyphene combination |journal=Hum Toxicol |volume=3 Suppl |issue= |pages=145S–174S |year=1984 |pmid=6480013 |doi= |url= http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=861497}}</ref> a bias that would lead to differences between compounds was not identified.<ref name="pmid8104653"/> Clinical studies can adjust for potential confounders which studies that use coronial data are unable to take into account. If differences between the benzodiazepines are supported by data from clinical studies this also adds credence to the fatal toxicity index which first noted these findings. |
|||
The aim was therefore to determine if temazepam caused more sedation and oxazepam less sedation than other benzodiazepines. |
|||
During 1991-3, 542 patients with [[benzodiazepine]] poisoning presented to the hospital, 239 of these patients, however, had ingested either more than one benzodiazepine or co-ingested other sedating drugs. The drugs ingested by the remainder were temazepam (64), [[oxazepam]] (45), [[diazepam]] (113), [[clonazepam]] (24), [[flunitrazepam]] (21), [[nitrazepam]] (18), others (18). |
|||
Details of coma scores and odds ratios of the benzodiazepines ingested showed that temazepam was significantly more toxic than most other benzodiazepines.<ref name="pmid7866122">{{cite journal |author=Buckley NA, Dawson AH, Whyte IM, O'Connell DL |title=Relative toxicity of benzodiazepines in overdose |journal=BMJ |volume=310 |issue=6974 |pages=219–21 |year=1995 |pmid=7866122 |doi= |url= http://www.bmj.com/cgi/content/full/310/6974/219}}</ref> Two out of the 45 subjects (4%) who ingested [[oxazepam]] were stuporous or comatose, 38 out of the 194 subjects (19%) who ingested other benzodiazepines (clonazepam, diazepam, flunitrazepam, nitrazepam and others) were stuporous or comatose, while 16 out of the 64 subjects (25%) who ingested temazepam were stuporous or comatose. None of the [[oxazepam]] subjects were comatose, 16 out of the 194 subjects (8%) who ingested other benzodiazepines were fully comatose, and 9 out of 64 subjects (14%) who ingested temazepam were fully comatose. |
|||
The results show that there are differences between temazepam, oxazepam, and other benzodiazepines in the degree of sedation they cause in overdose, and the observed differences are not due to confounding by age, sex, dose ingested, co-ingestion of alcohol, chronic benzodiazepine use, or history of drug or [[alcohol abuse]]. This provides a plausible explanation why temazepam and oxazepam have different fatal toxicity indices from other benzodiazepines.<ref name="pmid8104653"/> |
|||
The [[sedation]] produced by benzodiazepines in therapeutic doses and overdose has a poor correlation with measured drug concentration but is increased with rapid absorption.<ref name="pmid1888441">{{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=}}</ref><ref name="pmid6101526">{{cite journal |author=Busto U, Kaplan HL, Sellers EM |title=Benzodiazepine-associated emergencies in Toronto |journal=Am J Psychiatry |volume=137 |issue=2 |pages=224–7 |year=1980 |pmid=6101526 |doi=}}</ref><ref name="pmid598411">{{cite journal |author=Fuccella LM, Bolcioni G, Tamassia V, Ferrario L, Tognoni G |title=Human pharmacokinetics and bioavailability of temazepam administered in soft gelatin capsules |journal=Eur. J. Clin. Pharmacol |volume=12 |issue=5 |pages=383–6 |year=1977 |pmid=598411 |doi=}}</ref><ref name="pmid2564763">{{cite journal |author=Greenblatt DJ, Harmatz JS, Engelhardt N, Shader RI |title=Pharmacokinetic determinants of dynamic differences among three benzodiazepine hypnotics. Flurazepam, temazepam, and triazolam |journal=Arch. Gen. Psychiatry |volume=46 |issue=4 |pages=326–32 |year=1989 |pmid=2564763 |doi=}}</ref> Temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than other benzodiazepines.<ref name="pmid1888441"/><ref name="pmid6101526"/><ref name="pmid598411"/><ref name="pmid2564763"/><ref name="pmid6152815">{{cite journal |author=Mitler MM |title=Evaluation of temazepam as a hypnotic |journal=Pharmacotherapy |volume=1 |issue=1 |pages=3–13 |year=1981 |pmid=6152815 |doi=}}</ref> Further research is required to determine if the rate of absorption is different in overdose and is sufficient to explain the differences in sedation. Slowing the rate of absorption may reduce toxicity, but this would also reduce their sedative effect in therapeutic doses.<ref name="pmid598411"/> Drug regulatory authorities should be aware that changes in formulation of benzodiazepines may affect toxicity in overdose. |
|||
Pharmacodynamic factors such as benzodiazepine receptor affinity and potency may also be important. Because of the wide variations in half life, adjustments for dose by conversion into defined daily doses or [[diazepam]] equivalents is imperfect.<ref name="pmid1675694">{{cite journal |author=Alexander B, Perry PJ |title=Detoxification from benzodiazepines: schedules and strategies |journal=J Subst Abuse Treat |volume=8 |issue=1-2 |pages=9–17 |year=1991 |pmid=1675694 |doi=}}</ref> These are designed to compare use rather than potency. Though they correlate reasonably well with sizes of prescriptions and tablets, they may not account for potency per tablet taken in overdose.<ref name="pmid8104653"/> |
|||
==Abuse and misuse== |
|||
In [[Australia]], temazepam accounts for most benzodiazepine sought by forgery of prescriptions and through pharmacy burglary. Pharmacists and their staff often encounter aggressive and threatening behaviour from people seeking temazepam. There were 537 burglaries on Victoria's 1200 pharmacies from 1 January to 30 August 2001, including 'ram raids' (using stolen cars to smash through windows). Temazepam appears to be the main target in many pharmacy burglaries. Temazepam is sought in 85% of all reported benzodiazepine forgeries.<ref>{{cite web |title= Injecting Temazepam -- Temazepam Injection and Diversion |url=http://www.health.vic.gov.au/drugservices/pubs/temazepam/facts.htm |date= 29 March, 2007 |publisher=Victorian Governmant Health Information |accessdate=2007-11-25}}</ref> |
|||
Unprescribed temazepam is often detected in urine samples of drug misusers which suggests a high misuse potential of temazepam.<ref>{{cite journal |author=Garretty DJ |coauthors=Wolff K, Hay AW, Raistrick D |year=1997 |month=Jan |title=Benzodiazepine misuse by drug addicts |journal=Annals of clinical biochemistry |volume=34 |issue=Pt 1 |pages=68-73 |pmid=9022890}}</ref> |
|||
Studies suggest that temazepam is a particularily euphoric [[benzodiazepine]], and along with other [[hypnotic]] benzodiazepines, particularly [[flunitrazepam]], [[nitrazepam]], and [[nimetazepam]], it is considered to have the highest abuse potential of all benzodiazepines. In the UK, temazepam has superseded [[diazepam]], [[nitrazepam]] and [[flurazepam]] as the most commonly abused benzodiazepine, in line with the increase in temazepam prescriptions and possibly (until recently) because of the availability of easily injectable forms of temazepam from capsules, 'jellies', 'eggs' (Stark et al. 1987). Benzodiazepines have been injected but at present temazepam is mainly involved. Strang et al. (1994) conducted a questionnaire survey of subjects attending drug clinics in seven British cities. Of 208 subjects returning the questionnaire, 186 had used benzodiazepines and 103 had injected them intravenously. Temazepam was the most commonly used and had been injected from preparations of capsules, tablets and syrup.<ref name="Ashton">{{cite book |author=Ashton H |title=Drugs and Dependence |chapter= Benzodiazepine Abuse |chapterurl=http://www.benzo.org.uk/ashbzab.htm |date=2002 |publisher=Harwood Academic Publishers |location=London & New York |accessdate=2007-11-25}}</ref> |
|||
Temazepam (whether obtained from capsules, tablets or elixir), is extremely irritating and likely to cause tissue damage. When arm veins become occluded due to local irritation, users may proceed to injecting in the groin, where inadvertent intra-arterial injection has led to amputation. The severity of the addiction which can develop to temazepam is illustrated by the case of a temazepam injector who needed his leg amputated but was later admitted for a second amputation since he had continued injecting into his remaining leg.<ref>{{cite journal |author=Parrott, A |title=Psychoactive drugs of use and abuse: Wobble, rave, inhale or crave |year=1995 |journal=J. Psvchopharmacol |volume=9 |pages=390-1}}</ref> A second subject, following a leg amputation, injected temazepam gel into his eye, resulting in bilateral blindness.<ref name="Ashton"/> |
|||
In [[Northern Ireland]] in cases where drugs were found in tests on impaired drivers who had low alcohol readings but were suspected of driving under the influence of drugs benzodiazepines were found to be present in 87% of cases, with temazepam accounting for the vast majority of cases.<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.}}</ref> |
|||
==Side effects== |
|||
===Common side effects include=== |
|||
[[Central nervous system|CNS]] depression typical of hypnotic benzodiazepine are common and include, [[somnolence]], [[dizziness]], [[Fatigue (medical)|fatigue]], [[ataxia]], [[headache]], [[lethargy]], impairment of memory, impairment of motor functions, slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, blurred vision, and inattention. [[Euphoria]], which is very uncommon among the vast majority of benzodiazepines, was consistently reported with the use of temazepam. According to the [[Food and Drug Administration|FDA]], temazepam had the highest incidences of euphoria among the few benzodiazepines that reported it during clinical trials.<ref name="DrugsCom"/> Unpleasant dreams and rebound insomnia have also been reported. High levels of [[confusion]], [[clumsiness]] also occurs after administration of temazepam.<ref>{{cite journal |author=Sanders LD |coauthors=Yeomans WA, Rees J, Rosen M, Robinson JO |year=1988 |month=Nov |title=A double-blind comparison between nitrazepam, lorazepam, lormetazepam and placebo as preoperative night sedatives |journal=Eur J Anaesthesiol |volume=5 |issue=6 |pages=377-83 |pmid=2907315}}</ref> Increased reaction time, co-ordination problems and impaired learning and memory.<ref name="pmid38627 ">{{cite journal |author=Liljequist R |coauthors=Mattila MJ |year=1979 |month=May |title=Acute effects of temazepam and nitrazepam on psychomotor skills and memory |journal=Acta Pharmacol Toxicol (Copenh) |volume=44 |issue=5 |pages=364-9 |pmid=38627}}</ref> |
|||
* [[Somnolence]] |
|||
*Impaired motor function |
|||
** Impaired coordination.<ref name="pmid38627 "/> |
|||
** Impaired balance |
|||
*Impaired learning and memory<ref name="pmid38627 "/> |
|||
* [[Euphoria]] (temazepam had one of the highest incidence of euphoria among the few that reported euphoria from any benzodiazepines according to the FDA)<ref name="DrugsCom">{{cite web |title= Temazepam |url=http://www.drugs.com/pro/temazepam.html |date= 10/2007 |publisher=Drugs.com |accessdate=2007-11-25}}</ref> |
|||
* [[Dizziness]] |
|||
* [[Anterograde amnesia]] |
|||
* [[Respiratory depression]] in higher doses (According to the FDA, temazepam may pose a serious risk to respiratory function even when taken alone, this is due to its much higher toxicity index relative to other benzodiazepines) |
|||
* Blurred vision (in higher doses) |
|||
* Confusion |
|||
* Lack of [[concentration]] |
|||
* Slurred speech |
|||
===Less Common Side Effects=== |
|||
[[Hyperhidrosis]], [[hypotension]], burning eyes, changes in [[libido]], hallucinations, faintness, horizontal nystagmus, vomiting, [[pruritus]], gastrointestinal disturbances, nightmares, [[palpitation]] and paradoxical reactions including restlessness, aggression, violence, over stimulation and agitation have been reported, but are rare (less than 0.5%). |
|||
Before taking temazepam, one should ensure that at least 8 hours are available to dedicate to sleep. Failing to do so can increase the side effects of the drug. |
|||
Long-term use of temazepam can result in psychological and physical dependence and the appearance of [[benzodiazepine withdrawal symptoms]] when the drug is discontinued or the dose reduced. Temazepam impairs [[cognitive]] and psychomotor functions, affecting reaction time and driving skill. The use of this drug in combination with alcohol potentiates these side effects, and can lead to [[toxicity]] and [[death]]. |
|||
In a clinical study conducted in the [[United Kingdom]] between the years 1991-1993, it was found that temazepam was the most toxic of all benzodiazepines, easily causing death in an overdose, even when not combined with any other [[Depressant|CNS Depressant]], unlike most other benzodiazepines, especially the anxiolytics which all have a much lower toxicity profile. [[Oxazepam]] had the lowest toxicity profile of all benzodiazepines. Others with low toxicity profiles were [[diazepam]], [[alprazolam]], [[lorazepam]], [[bromazepam]], and [[clonazepam]]. Besides temazepam, other hypnotic benzodiazepines were tested ([[flunitrazepam]], [[nitrazepam]], [[flurazepam]], [[midazolam]], and [[triazolam]]) and all had a high toxicity profile. The reason was that the hypnotics more strongly reduced the rate of respiration, caused more sedation, were more likely to induce [[coma]], amnesia, and [[hypotension]]. All the hypnotic benzodiazepines that were tested in the study showed that they can cause death without ingesting other CNS depressants, very much like [[barbiturates]]. [[Nimetazepam]], though was not part of the British study is believed to have a toxicity profile similar to temazepam's.<ref name="pmid8104653"/><ref name="pmid3690249"/> |
|||
Though rare, residual 'hangover' effects after night time administration of temazepam such as sleepiness, impaired psychomotor and [[cognitive]] functions may persist into the next day which may impair the ability of users to drive safely or may increase the risks of falls and [[hip fractures]].<ref>{{cite journal |author=Vermeeren A |coauthors= |year=2004 |month= |title=Residual effects of hypnotics: epidemiology and clinical implications |journal=CNS Drugs |volume=18 |issue=5 |pages=297-328 |pmid=15089115}}</ref> |
|||
==Interactions== |
==Interactions== |
||
Temazepam produces additive CNS depressant effects when co-administered with other medications which themselves produce CNS depression, e.g. [[barbiturates]], [[alcohol]], [[opiates]], [[tricyclic antidepressants]], nonselective MAO inhibitors, [[phenothiazines]] and other [[antipsychotic]]s, skeletal muscle relaxants, [[antihistamines]] and [[anaesthetics]]. Administration of [[theophylline]] or [[aminophylline]] have been shown to reduce the sedative effects of temazepam and other benzodiazepines. |
Temazepam produces additive CNS depressant effects when co-administered with other medications which themselves produce CNS depression, e.g. [[barbiturates]], [[alcohol]], [[opiates]], [[tricyclic antidepressants]], nonselective MAO inhibitors, [[phenothiazines]] and other |
||
[[antipsychotic]]s, skeletal muscle relaxants, [[antihistamines]] and [[anaesthetics]]. Administration of [[theophylline]] or [[aminophylline]] have been shown to reduce the sedative effects of temazepam and other benzodiazepines. |
|||
The [[cytochrome]] P450 system has not been shown to be involved in the disposition of temazepam and, unlike many benzodiazepines, [[pharmacokinetic]] interactions involving the P450 system have not been observed with temazepam. Temazepam shows no significant interaction with 3A4 inhibitors (e.g. [[itraconazole]], [[erythromycin]]).<ref name="pmid8721273">{{cite journal |author=Ahonen J, Olkkola KT, Neuvonen PJ |title=Lack of effect of antimycotic itraconazole on the pharmacokinetics or pharmacodynamics of temazepam |journal=Ther Drug Monit |volume=18 |issue=2 |pages=124–7 |year=1996 |pmid=8721273 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0163-4356&volume=18&issue=2&spage=124}}</ref> |
The [[cytochrome]] P450 system has not been shown to be involved in the disposition of temazepam |
||
and, unlike many benzodiazepines, [[pharmacokinetic]] interactions involving the P450 system have not been observed with temazepam. Temazepam shows no significant interaction with 3A4 inhibitors (e.g. [[itraconazole]], [[erythromycin]]).<ref name="pmid8721273">{{cite journal |author=Ahonen J, Olkkola KT, Neuvonen PJ |title=Lack of effect of antimycotic itraconazole on the pharmacokinetics or pharmacodynamics of temazepam |journal=Ther Drug Monit |volume=18 |issue=2 |pages=124–7 |year=1996 |pmid=8721273 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0163-4356&volume=18&issue=2&spage=124}}</ref> |
|||
Interactions have been reported between temazepam and anticonvulsants, with changes in the serum concentration of the temazepam or anticonvulsant. It is recommended that patients be observed for altered responses when temazepam and anticonvulsants are prescribed together, and that serum level monitoring of the anticonvulsant be performed more frequently. |
Interactions have been reported between temazepam and anticonvulsants, with changes in the serum concentration of the temazepam or anticonvulsant. It is recommended that patients be observed for altered responses when temazepam and anticonvulsants are prescribed together, and that serum level monitoring of the anticonvulsant be performed more frequently. |
||
Line 126: | Line 183: | ||
* Hypersensitivity or allergy to any drug in the [[benzodiazepine]] class |
* Hypersensitivity or allergy to any drug in the [[benzodiazepine]] class |
||
====Special caution needed==== |
|||
Other individuals at risk: |
|||
* |
*Pregnant Women - temazepam may cause fetal damage when administered during pregnancy. |
||
* Pediatric patients |
* Pediatric patients |
||
** Less than 18 years of age - Safety and effectiveness have not been established; temazepam should generally not be given to individuals under 18 years of age |
|||
** Under 6 months of age - Safety and effectiveness have not been established; temazepam should not be given to individuals in this age group. |
|||
* 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. |
* 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. |
||
===Pregnancy=== |
====Pregnancy==== |
||
Temazepam belongs to the Pregnancy Category X of the FDA, and as such it is known to cause serious birth defects and fetal abnormalities. Temazepam increased risk of congenital malformations associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy. |
Temazepam belongs to the Pregnancy Category X of the FDA, and as such it is known to cause serious birth defects and fetal abnormalities. Temazepam increased risk of congenital malformations associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy. |
||
Line 138: | Line 198: | ||
Temazepam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving Temazepam, she should be warned of the potential risk to the fetus. Patients should be instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered.<ref name="DrugsCom">{{cite web |title= Temazepam |url=http://www.drugs.com/pro/temazepam.html |date= 10/2007 |publisher=Drugs.com |accessdate=2007-11-25}}</ref> |
Temazepam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving Temazepam, she should be warned of the potential risk to the fetus. Patients should be instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered.<ref name="DrugsCom">{{cite web |title= Temazepam |url=http://www.drugs.com/pro/temazepam.html |date= 10/2007 |publisher=Drugs.com |accessdate=2007-11-25}}</ref> |
||
====Patients at a high risk for abuse and dependence==== |
|||
===Renal/hepatic function=== |
|||
Temazepam can lead to [[physiological tolerance]], and psychological and/or physical dependence. At a particularly high risk for temazepam misuse, abuse, and dependence are: |
|||
* Patients with a history of alcohol or drug abuse or dependence |
|||
* Emotionally unstable patients |
|||
* Patients with severe personality disorders, such as [[Borderline Personality Disorder]] |
|||
* Patients with chronic pain or other physical disorders |
|||
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. |
|||
==Special Precautions== |
|||
Complex behaviours such as "sleep-driving" (i.e. driving while not fully awake after taking a temazepam, with amnesia for the event) have been reported with its use. These events can occur in temazepam naive as well as in experienced temazepam persons. These events can occur at normal therapeutic doses, and the risk appears to be increased when temazepam is combined with alcohol or other [[depressant|CNS depressants]] or used at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of temazepam should be strongly considered for patients who report a "sleep-driving" episode. Other complex behaviours (eg. preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking temazepam. As with "sleep driving", patients usually do not remember these events. As with all patients taking CNS depressant medications, patients receiving temazepam should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy or dizzy from temazepam therapy.<ref name="Temaze">{{cite web |title= Temaze (Temazepam) – Product Information |url=http://www.pbs.gov.au/pi/afptemaz10307.pdf |format=PDF |date= 23 March 2007 |publisher= Therapeutic Goods Administration}}</ref> Abilities may be impaired on the day following use. In sleep laboratory studies in volunteers, doses of 10 and 20 mg did not significantly affect morning performance, however the 30 mg dose produced impairment of psychomotor behaviour on the morning following night time administration. Patients should be advised that their tolerance for alcohol and other CNS depressants will be diminished and that these medications should either be eliminated or given in reduced dosage in the presence of temazepam. Rare cases of [[angioedema]] involving the [[tongue]], [[glottis]] or [[larynx]] have been reported in patients after taking the first or subsequent doses of temazepam. Some patients have had additional symptoms such as [[dyspnea]], throat closing, or [[nausea]] and [[vomiting]] that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be [[fatal]].<ref name="Temaze"/> |
|||
===Impaired renal/hepatic function and blood dyscrasias=== |
|||
Patients with impaired [[renal]] or [[hepatic]] function should use temazepam with caution, and dosage reduction may be advisable. In rare instances, some patients taking temazepam have developed blood dyscrasias, and some have had elevations of hepatic [[enzymes]]. As with other benzodiazepines, periodic blood counts and liver function tests are recommended. The use of temazepam may worsen hepatic [[encephalopathy]]; therefore, temazepam should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy.<ref name="Temaze"/> |
Patients with impaired [[renal]] or [[hepatic]] function should use temazepam with caution, and dosage reduction may be advisable. In rare instances, some patients taking temazepam have developed blood dyscrasias, and some have had elevations of hepatic [[enzymes]]. As with other benzodiazepines, periodic blood counts and liver function tests are recommended. The use of temazepam may worsen hepatic [[encephalopathy]]; therefore, temazepam should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy.<ref name="Temaze"/> |
||
===Depression, psychosis and schizophrenia=== |
===Depression, psychosis and schizophrenia=== |
||
Temazepam is not recommended as primary therapy in patients with [[Clinical depression|depression]] and [[psychosis]]. In such conditions, psychiatric assessment and supervision are necessary if temazepam is indicated. Temazepam may increase depression in some patients, and may contribute to deterioration in severely disturbed schizophrenic patients with confusion and withdrawal. [[suicide|Suicidal]] tendencies may be present or uncovered, and protective measures may be required. Paradoxical reactions such as acute rage, stimulation or excitement may occur; should such reactions occur, temazepam should be discontinued. Such reactions may be more likely to occur in children and the elderly.<ref |
Temazepam is not recommended as primary therapy in patients with [[Clinical depression|depression]] and [[psychosis]]. In such conditions, psychiatric assessment and supervision are necessary if temazepam is indicated. Temazepam may increase depression in some patients, and may contribute to deterioration in severely disturbed schizophrenic patients with confusion and withdrawal. [[suicide|Suicidal]] tendencies may be present or uncovered, and protective measures may be required. Paradoxical reactions such as acute rage, stimulation or excitement may occur; should such reactions occur, temazepam should be discontinued. Such reactions may be more likely to occur in children and the elderly.<ref name="pmid2896665">{{cite journal |author=Dietch JT, Jennings RK |title=Aggressive dyscontrol in patients treated with benzodiazepines |journal=J Clin Psychiatry |volume=49 |issue=5 |pages=184–8 |year=1988 |pmid=2896665 |doi=}}</ref> |
||
===Impaired respiratory function=== |
===Impaired respiratory function=== |
||
Use of temazepam may lead to potentially fatal respiratory depression. Hence, caution in the use of temazepam is recommended in patients with respiratory depression. In patients with chronic obstructive pulmonary disease, temazepam can cause increased arterial carbon dioxide tension and decreased arterial oxygen tension. |
Use of temazepam may lead to potentially fatal respiratory depression. Hence, caution in the use of temazepam is recommended in patients with respiratory depression. In patients with chronic obstructive pulmonary disease, temazepam can cause increased arterial carbon dioxide tension and decreased arterial oxygen tension.<ref name="Temaze"/> |
||
===Epilepsy=== |
===Epilepsy=== |
||
Abrupt withdrawal of temazepam in patients with convulsive disorders may be associated with a temporary increase in the frequency and/or severity of seizures. |
Abrupt withdrawal of temazepam in patients with convulsive disorders may be associated with a temporary increase in the frequency and/or severity of seizures. |
||
===Carcinogenesis, |
===Carcinogenesis, Mutagenesis, Impairment of Fertility=== |
||
Carcinogenicity studies were conducted in rats at dietary temazepam doses up to 160 mg/kg/day for 24 months and in mice at dietary dose of 160 mg/kg/day for 18 months. No evidence of [[carcinogenicity]] was observed although hyperplastic [[liver]] nodules were observed in female mice exposed to the highest dose. The clinical significance of this finding is not known. No mutagenicity tests have been done with temazepam.<ref>{{cite web |title=Restoril (temazepam) capsule |url=http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=2871 |date= 03/2006 |work=DailyMed |publisher=National Institutes of Health |accessdate=2007-11-25}}</ref> In animal studies, an increased perinatal [[mortality]] has been seen following concomitant administration of temazepam and [[diphenhydramine]] to rabbits in the later stages of gestation compared with rabbits that received either drug alone. It is recommended that the use of temazepam be avoided in pregnant women receiving antihistamines. [[Fertility]] in male and female rats was not adversely affected by temazepam. |
Carcinogenicity studies were conducted in rats at dietary temazepam doses up to 160 mg/kg/day for 24 months and in mice at dietary dose of 160 mg/kg/day for 18 months. No evidence of [[carcinogenicity]] was observed although hyperplastic [[liver]] nodules were observed in female mice exposed to the highest dose. The clinical significance of this finding is not known. No mutagenicity tests have been done with temazepam.<ref>{{cite web |title=Restoril (temazepam) capsule |url=http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=2871 |date= 03/2006 |work=DailyMed |publisher=National Institutes of Health |accessdate=2007-11-25}}</ref> In animal studies, an increased perinatal [[mortality]] has been seen following concomitant administration of temazepam and [[diphenhydramine]] to rabbits in the later stages of gestation compared with rabbits that received either drug alone. It is recommended that the use of temazepam be avoided in pregnant women receiving antihistamines. [[Fertility]] in male and female rats was not adversely affected by temazepam.<ref name="Temaze"/> |
||
==Overdose== |
==Overdose== |
||
Line 168: | Line 240: | ||
Temazepam overdose is considered a serious medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of temazepam (or any other benzodiazepine) is [[flumazenil]] (Anexate). |
Temazepam overdose is considered a serious medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of temazepam (or any other benzodiazepine) is [[flumazenil]] (Anexate). |
||
If the patient is conscious, vomiting should be induced mechanically or with emetics (e.g., syrup of ipecac 20 to 30 mL). Gastric lavage should be employed as soon as possible, utilizing concurrently a cuffed endotracheal tube if the patient is unconscious, in order to prevent aspiration and pulmonary complications. Maintenance of adequate pulmonary ventilation is essential and fluids should be administered IV to encourage diuresis. The use of pressor agents IV, may be necessary to combat [[hypotension]] but only if considered essential. The value of dialysis in emergency therapy for benzodiazepine overdosage has not been determined. If excitation occurs, barbiturates should not be used. It should be borne in mind that multiple agents may have been ingested. |
|||
The oral [[LD50|LD<sub>50</sub>]] of temazepam was 1963 mg/kg in mice, 1833 mg/kg in rats, and >2400 mg/kg in rabbits. |
The oral [[LD50|LD<sub>50</sub>]] of temazepam was 1963 mg/kg in mice, 1833 mg/kg in rats, and >2400 mg/kg in rabbits. |
||
Temazepam is a drug which is very frequently involved in drug intoxication, including overdose.<ref name="pmid12474705">{{cite journal |author=Zevzikovas A, Kiliuviene G, Ivanauskas L, Dirse V |title=[Analysis of benzodiazepine derivative mixture by gas-liquid chromatography] |language=Lithuanian |journal=Medicina (Kaunas) |volume=38 |issue=3 |pages=316–20 |year=2002 |pmid=12474705 |doi= |url=http://medicina.kmu.lt/0203/0203-12l.pdf}}</ref> Overdose of temazepam may result in excessive sedation, impairment of balance and speech. This may progress in severe overdoses to respiratory depression or coma and possibly death. The risk of overdose is increased if temazepam is taken in combination with alcohol, opiates or other CNS depressants. Temazepam overdose responds to the benzodiazepine receptor antagonist [[flumazenil]]. |
Temazepam is a drug which is very frequently involved in drug intoxication, including overdose.<ref name="pmid12474705">{{cite journal |author=Zevzikovas A, Kiliuviene G, Ivanauskas L, Dirse V |title=[Analysis of benzodiazepine derivative mixture by gas-liquid chromatography] |language=Lithuanian |journal=Medicina (Kaunas) |volume=38 |issue=3 |pages=316–20 |year=2002 |pmid=12474705 |doi= |url=http://medicina.kmu.lt/0203/0203-12l.pdf}}</ref> Overdose of temazepam may result in excessive sedation, impairment of balance and speech. This may progress in severe overdoses to respiratory depression or coma and possibly death. The risk of overdose is increased if temazepam is taken in combination with alcohol, opiates or other CNS depressants. Temazepam overdose responds to the benzodiazepine receptor antagonist [[flumazenil]]. |
||
Benzodiazepines were implicated in 39% of suicides by drug poisoning in [[Sweden]], with temazepam, nitrazepam and flunitrazepam accounting for 90% of benzodiazepine implicated suicides, in the elderly over a period of 2 decades. In three quarters of cases death was due to drowning, typically in the bath. Benzodiazepines were the predominant drug class used in suicides in this review of Swedish [[death certificates]] with 72% of benzodiazepine overdoses showing that benzodiazepines were the sole drug used in deaths by overdose. Benzodiazepines and in particular temazepam, nitrazepam and flunitrazepam should therefore be prescribed with caution in the elderly.<ref>{{cite journal |last=Carlsten |first=A |coauthors=Waern M, Holmgren P, Allebeck P |year=2003 |month= |title=The role of benzodiazepines in elderly suicides |journal=Scand J Public Health |volume=31 |issue=3 |pages=224-8 |pmid=12850977}}</ref> [[Nitrazepam]], and especially temazepam were the benzodiazepines most commonly detected in overdose related drug deaths in an [[Australian]] study of drug deaths. The two benzodiazepines were found to be the sole cause of death in one third of cases.<ref>{{cite journal |author=Drummer OH |coauthors=Ranson DL |year=1996 |month=Dec |title=Sudden death and benzodiazepines |journal=Am J Forensic Med Pathol |volume=17 |issue=4 |pages=336-42 |pmid=8947361}}</ref> |
|||
In a retrospective study of deaths, when benzodiazepines were implicated in the deaths, the benzodiazepines [[flunitrazepam]], temazepam and [[nitrazepam]] were the most common benzodiazepines involved. Benzodiazepines were a factor in all deaths caused by drug addiction in the study. Temazepam, [[nitrazepam]] and [[flunitrazepam]] were significantly more commonly implicated in suicide related deaths than natural deaths. In four of the cases benzodiazepines alone were the only cause of death. It was concluded that flunitrazepam, nitrazepam, and temazepam were significantly more toxic than other benzodiazepines.<ref name="pmid8231567">{{cite journal |author=Ericsson HR, Holmgren P, Jakobsson SW, Lafolie P, De Rees B |title=[Benzodiazepine findings in autopsy material. A study shows interacting factors in fatal cases] |language=Swedish |journal=Lakartidningen |volume=90 |issue=45 |pages=3954–7 |year=1993 |pmid=8231567 |doi=}}</ref> |
|||
From a research perspective, there are several data acquired through scientific research that suggest temazepam is more frequently involved in drug-related deaths than are all other benzodiazepines. Temazepam is also the benzodiazepine that is by far the most commonly targeted in pharmacy burglaries and prescription forgeries.<ref>{{cite web |title= Injecting Temazepam -- Temazepam Injection and Diversion |url=http://www.health.vic.gov.au/drugservices/pubs/temazepam/facts.htm |date= 29 March, 2007 |publisher=Victorian Governmant Health Information |accessdate=2007-11-25}}</ref> Seized diverted temazepam tablets and/or capsules account for half of all police seizures of benzodiazepines.<ref name="pmid7663317">{{cite journal |author=Hammersley R, Cassidy MT, Oliver J |title=Drugs associated with drug-related deaths in Edinburgh and Glasgow, November 1990 to October 1992 |journal=Addiction |volume=90 |issue=7 |pages=959–65 |year=1995 |pmid=7663317 |doi= |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0965-2140&date=1995&volume=90&issue=7&spage=959}}</ref> |
|||
==Legal Status== |
|||
In the [[United Kingdom]], the drug is available only by prescription and is a controlled drug. Temazepam is a [[Misuse of Drugs Act 1971#Class B drugs|Class B drug]] in the United Kingdom and possession is illegal without a [[Medical prescription|prescription]]. Additionally, all manufacturers in the UK have replaced the gel-capsules with solid tablets. Temazepam prepared for injection is classed as a [[Misuse of Drugs Act 1971#Class A drugs|Class A drug]]. |
In the [[United Kingdom]], the drug is available only by prescription and is a controlled drug. Temazepam is a [[Misuse of Drugs Act 1971#Class B drugs|Class B drug]] in the United Kingdom and possession is illegal without a [[Medical prescription|prescription]]. Additionally, all manufacturers in the UK have replaced the gel-capsules with solid tablets. Temazepam prepared for injection is classed as a [[Misuse of Drugs Act 1971#Class A drugs|Class A drug]]. |
||
In the [[United States|USA]], temazepam is a [[Schedule IV controlled substance|Schedule IV drug]] and is only available by prescription. Temazepam is the only benzodiazepine which requires specially coded prescriptions in certain States. |
|||
In [[Canada]], Temazepam is a Schedule IV controlled substance requiring a doctors prescription. |
|||
In [[Ireland]], Temazepam is a Schedule 3 controlled substance with strict restrictions.<ref>{{cite web |title=Misuse Of Drugs (Amendment) Regulations |year=1993 |url=http://www.irishstatutebook.ie/1993/en/si/0342.html |work=Irish Statute Book |publisher=Office of the Attorney General}}</ref> |
|||
In [[Australia]], temazepam in liquid form is restricted as a Schedule 8 controlled drug. As a Schedule 8 controlled substance, it is illegal to have this drug in possession without an authority prescription from a registered doctor. In tablet form, it is a Schedule 4 prescription only medicine. |
|||
In [[South Africa]], temazepam is a Schedule 6 drug, requiring a prescription, and restricted to 10-20 mg doses. |
|||
In [[Sweden]], temazepam is available in 10-20 mg capsules and tablets but are rarely prescribed. The most commonly prescribed hypnotics in Sweden are [[zopiclone]], [[nitrazepam]], and [[flunitrazepam]]. Temazepam is only prescribed if for any reason the three above hypnotics fail to work. As such, temazepam is second line treatment for severe insomnia where the other hypnotics have failed. |
|||
In [[Hong Kong]], Temazepam is regulated under Schedule 1 of [[Hong Kong|Hong Kong's]] Chapter 134 ''Dangerous Drugs Ordinance''. [[Nimetazepam]] is also regulated under Schedule 1 of [[Hong Kong|Hong Kong's]] Chapter 134 ''Dangerous Drugs Ordinance''. All other benzodiazepines are regulated under a much less restrictive Schedule category. Temazepam can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 ([[Hong Kong dollar|HKD]]) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.<ref>{{cite web |title=Bilingual Laws Information System |url=http://www.legislation.gov.hk/eng/index.htm |format=English |publisher=The Government of the Hong Kong Special Administrative Region of the People's Republic of China}}</ref> |
|||
Internationally, temazepam is a Schedule IV drug under the [[Convention on Psychotropic Substances]]. Though it is classed as a Schedule IV internationally, penalties for its possession and/or trafficking are more severe, unlike all other benzodiazepines (except for [[flunitrazepam]], which is treated in the same manner as temazepam is.<ref>{{cite web |title=Green List -- List of psychotropic substances under international control |url=http://www.incb.org/pdf/e/list/green.pdf |format=PDF |date=23rd edition, August 2003 |publisher=International Narcotics Control Board |accessdate=2007-11-25}}</ref> |
|||
==Temazepam in Popular Culture== |
|||
Temazepam tablets are called Jellies, Tams, Terms, Temazzies, Eggs, Green Eggs, Norries, and Rugby balls. |
|||
The recreational effects of the drug were documented on the [[Black Grape]] album, ''[[It's Great When You're Straight... Yeah]]''. The track 'Tramazi Parti' contains the lyric: ''I got my boots on the back of my head / It's full of jellies in the good old bed / And no one knows what no one said''. Although there is no medical research confirming this behaviour, it is not inconsistent with the known side effects of the drug. |
|||
On the BBC radio series ''[[The Archers]]'', Jolyon Gibson's Christmas present to Kate Aldridge was a bottle of temazepam capsules. Feeling depressed on New Year's Eve 1995, Kate took whisky and the "jellies" together and ended up in hospital.<ref>{{cite web |
|||
|url= http://www.bbc.co.uk/radio4/archers/backstage/kate_children.shtml |
|||
|title= The latest from Kate |
|||
|accessdate= 2008-01-07 |
|||
|date= 2007-01-25 |
|||
|publisher= [[BBC Radio 4]] |
|||
}}</ref><ref>{{cite archers episode|date=1995-12-31}}</ref> |
|||
==See also== |
==See also== |
Revision as of 18:34, 10 January 2008
![]() | |
![]() | |
Clinical data | |
---|---|
Pregnancy category |
|
Routes of administration | Oral |
ATC code | |
Legal status | |
Legal status |
|
Pharmacokinetic data | |
Bioavailability | 96% |
Metabolism | Hepatic |
Elimination half-life | 8-20 hours |
Excretion | Renal |
Identifiers | |
| |
CAS Number | |
PubChem CID | |
DrugBank | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.011.535 |
Chemical and physical data | |
Formula | C16H13ClN2O2 |
Molar mass | 300.7 g/mol g·mol−1 |
Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is a type of benzodiazepine drug. It is a powerful hypnotic benzodiazepine which possesses strong sedative, amnestic and motor impairing properties.[1] In addition, temazepam also has strong anxiolytic, anticonvulsant, and skeletal muscle relaxant properties. Temazepam, which is an intermediate acting benzodiazepine, acts quickly to induce sleep. It is generally prescribed for the treatment of short-term severe or debilitating insomnia in patients who have difficulty falling asleep or maintaining sleep.[2]
History
Temazepam first came into use in the 1960's, but it was not until 1969 that its usefulness to counter insomnia was realized, and by the year 1981, the Food and Drug Administration approved temazepam as a sedative-hypnotic for the treatment of insomnia and other sleep disorders under the trade name Restoril. Its powerful sedative and amnesic effects got the attention of several Secret Intelligence agencies, especially the former Soviet Union. It was utilized as a truth serum during interrogations because of its strong hypnotic properties. Given to the subject, temazepam weakens the resolve of the subject and makes him or her more compliant to pressure. As a truth serum, temazepam was not often used. It was mainly utilized by the Soviet Union and East Germany in the 1970's during the Cold War. It also saw limited use as a truth serum in some parts of East Asia and Southeast Asia. The preferred drugs used as truth serums were, and still are barbiturates, particularly sodium thiopental (Sodium Pentothal). Temazepam was also one of several drugs used in the research of mind control, brainwashing and mass-scale social engineering by Secret Intelligence agencies of several different federal governments. Other drugs used for this same purpose were, barbiturates, morphine, LSD, amphetamines, and neuroleptics.[3] In former Soviet Union, temazepam was extensively used, along with other drugs like haloperidol (Haldol), thorazine, barbiturates, and morphine to keep political dissidents housed in psikhushkas (mental asylums and psychiatric hospitals) in a constant vegetative state.[4][5]
By the late 1980's, temazepam was one of the most effective hypnotics on the market and it became one of the most widely prescribed drugs for insomnia and other sleep disorders. With that however, the abuse of temazepam became widespread in much of Europe, East and Southeast Asia, Australia and New Zealand. It quickly superseded other benzodiazepines like diazepam (Valium) and nitrazepam (Mogadon), which were also commonly diverted to the black market and abused by drug addicts. In North America, its abuse did not become as widespread as it did elsewhere in the world due to the fact that triazolam and flurazepam were by far the most commonly prescribed hypnotic benzodiazepines. Diazepam, alprazolam, and lorazepam, though not hypnotics and aren't usually indicated for sleep, were also more widely prescribed to patients having trouble sleeping then was temazepam.[6] It was not until the mid to late 1990's that temazepam became more widely prescribed in the United States.
Until recently, temazepam was produced as a gel-filled capsule intended to be taken orally. However, it gained notoriety in Europe, especially in United Kingdom and Scotland, when it was discovered that if the capsules were melted and injected, the effects were more powerful and the onset was quicker. However, the liquid has a tendency to congeal in arteries and cause thrombosis and gangrene, in some cases requiring amputation. Despite the risks, injection of temazepam quickly spread throughout some parts Europe and then to Australia, New Zealand, and many parts of Asia. In Malaysia, nimetazepam is the only benzodiazepine that's more commonly abused or sought after by drug addicts than temazepam according to government data and seizures made by police. To curb the diversion of temazepam into the black market and stop abuse, many countries have placed temazepam under more strict drug schedules. In Australia, instead of being a Schedule 4 drug like all other benzodiazepines, temazepam is placed in Schedule 8, along side drugs like morphine, cocaine, methamphetamine, and methylphenidate (Ritalin). In the United Kingdom, temazepam (and flunitrazepam) is a Class B drug, meanwhile all other benzodiazepines are Class C, a much less restrictive category. In the United States, temazepam is the only benzodiazepine which requires specially coded prescriptions in certain states.[7] Despite the much more stringent restrictions put on temazepam compared to most other benzodiazepines, temazepam remains to be the most sought after and abused benzodiazepine worldwide with more kilograms of diverted temazepam being seized than any other benzodiazepine, followed by flunitrazepam, diazepam, nimetazepam, and then nitrazepam.[8] Pharmacy burglaries and prescription forgeries in Scotland, Australia, Ireland, Sweden, and several Asian countries report that temazepam is often a main target, whilst other benzodiazepines are rarely targeted.[9][10][11]
Pharmacology
Temazepam is classed as a 1,4 benzodiazepine, with the chemical name 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1-4-benzodiazepin-2-one. It's structurally most closely related to diazepam and oxazepam. In its pharmacological properties however, temazepam is most closely related to nimetazepam, nitrazepam, and flunitrazepam.[12] It is a white, crystalline substance, is very slightly soluble in water and sparingly soluble in alcohol. It is lipophilic and is metabolized hepatically via oxidative pathways. The main pharmacological action of temazepam is the enhancement of the neurotransmitter, GABA at the GABAA receptor.[13] The half life of temazepam is 8-22 hours.[14] It is a full agonist of the benzodiazepine receptor.[15] An opioid mechanism of action may play a role in some of the pharmacological properties of temazepam.[16]
Temazepam triggers the release of vasopressin into the rat hypothalamic paraventricular nucleus. [17] Adult male Wistar rats were intravenously administered with temazepam (0.5, 1, and 3 mg/kg body weight) and plasma concentrations of corticotropin (ACTH) and vasopressin (AVP) were measured in blood samples collected via chronically implanted jugular venous catheters. Simultaneously, the release of AVP within the hypothalamic paraventricular nucleus (PVN) was monitored via microdialysis. Plasma AVP levels remained unaffected by the different treatment conditions. Temazepam blunted the stressor exposure-induced secretion of ACTH in a dose-dependent manner. Concurrently, and also in a dose-dependent manner temazepam enhanced the intra-PVN release of AVP, known to originate from magnocellular neurons of the hypothalamic neurohypophyseal system. Furthermore, temazepam did not affect the in vitro secretion of ACTH from the adenohypophyseal cells. Taken together, the results of this study suggest that temazepam modulates the central nervous regulation of the HPA axis by altering intra-PVN AVP release. An increasingly released AVP of magnocellular origin seems to provide a negative tonus on ACTH secretion most probably via inhibiting the release of ACTH secretagogues from the median eminence into hypophyseal portal blood.[18]
Temazepam and other benzodiazepines may influence neurosteroid metabolism and progesterone levels which in turn may influence the functions of the brain and reproductive system. The pharmacological actions of benzodiazepines at the GABAa receptor are similar to those of neurosteroids. Neuroactive steroids are positive allosteric modulators of the GABAa receptor, enhancing GABA function. Many benzodiazepines (diazepam, medazepam, estazolam, nitrazepam flunitrazepam and temazepam) potently inhibit the enzymes involved in the metabolism of neurosteroids. Long-term administration of benzodiazepines may influence the concentrations of endogenous neurosteroids, and thereby would modulate the emotional state. Factors which effects the ability of individual benzodiazepines to alter neurosteroid levels depend on the molecular make up of the individual benzodiazepine drug. Presence of a substituent at N1 position of the diazepine ring and/or the chloro or nitro group at position 7 of the benzene ring contribute to potent inhibition of the isoenzymes, and in turn a bromo group at position 7 (for bromazepam) and additional substituents (3-hydroxy group for oxazepam and tetrahydroxazole ring for cloxazolam and oxazolam) decrease the inhibitory potency of benzodiazepines on neurosteroids.[19]
Temazepam has an inhibitory effect on plasma cholinesterase of 60--90 per cent.[20]
Pharmacokinetics
In a single and multiple dose absorption, distribution, metabolism, and excretion (ADME) study, using tritium (3H) labelled drug, temazepam was well absorbed and found to have minimal (8%) first pass metabolism. There were no active metabolites formed and the only significant metabolite present in blood was the O-conjugate. The unchanged drug was 96% bound to plasma proteins. The blood level decline of the parent drug was biphasic with the short half-life ranging from 0.4-0.6 hours and the terminal half-life from 3.5-18.4 hours (mean 8.8 hours), depending on the study population and method of determination.[21] Metabolites were formed with a half-life of 10 hours and excreted with a half-life of approximately 2 hours. Thus, formation of the major metabolite is the rate limiting step in the biodisposition of temazepam. There is no accumulation of metabolites. A dose-proportional relationship has been established for the area under the plasma concentration/time curve over the 15-30 mg dose range.[22]
Temazepam was completely metabolized through conjugation prior to excretion; 80%-90% of the dose appeared in the urine. The major metabolite was the O-conjugate of temazepam (90%); the O-conjugate of N-desmethyl temazepam was a minor metabolite (7%).[23]
Bioavailability, Induction, and Plasma Levels
After oral administration, temazepam is rapidly absorbed and fast acting. Following ingestion of 30 mg temazepam, measurable plasma concentrations are achieved 10-20 minutes after dosing with peak plasma levels ranging from 666-982 ng/mL (mean 865 ng/mL) occurring approximately 1.2-1.6 hours (mean 1.5 hours) after dosing. Strong hypnotic, sedative and anticonvulsant effects are noticeable 20-30 minutes after ingestion. [24]
In a 7 day study, in which subjects were given a 30 mg temazepam capsule 1 hour before retiring, steady-state (as measured by the attainment of maximal trough concentrations) was achieved by the third dose. Mean plasma levels of temazepam (for days 2-7) were 260±210 ng/mL at 9 hours and 75±80 ng/mL at 24 hours after dosing. A slight trend toward declining 24 hour plasma levels was seen after day 4 in the study, however, the 24 hour plasma levels were quite variable. .[22]
At a dose of 30 mg once-a-day for 8 weeks, no evidence of enzyme induction was found in man.
Indications, Uses & Efficacy
Temazepam is a full agonist of the benzodiazepine receptor.[25] It is a powerful hypnotic agent. In sleep laboratory studies, temazepam dramatically decreased the number of nightly awakenings.[26] Rebound insomnia was observed only occasionally after withdrawal of the drug. Temazepam decreased stage 3, and combined stage 3 and 4 sleep, accompanied by a compensatory increase in stage 2 sleep, but did not alter REM sleep.
Temazepam also possesses strong anticonvulsant properties and it has been used to manage seizures in adults. Though it is highly effective, its use as an anticonvulsant is rare due to its strong sedative and motor impairing properties. Temazepam is also a potent anxiolytic, skeletal muscle relaxant, and a strong amnestic. Its use as an anticonvulsant, anxiolytic, and skeletal muscle relaxant would be considered off-label, and though highly effective, its sedative, motor impairing, and hypnotic properties make it undesirable for such uses.
Temazepam is officially indicated for severe insomnia and other severe or disabling sleep disorders, where other sleep aids and treatments have failed. Despite this however, it is a widely prescribed first line hypnotic for short periods of time (usually no more than 7-10 days). The failure of insomnia to remit after 7-10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Temazepam taken for longer than 2 - 4 weeks may result in a strong physical dependence with a resultant benzodiazepine withdrawal syndrome developing when dosage is decreased or the drug is stopped.
Military Use
The United States Air Force uses temazepam under trade name Restoril as "no-go pills" to help pilots sleep after a mission. Another drug used for the same purpose is a short acting nonbenzodiazepine zolpidem (Ambien) (Cf. "go-pills"; dextroamphetamine, or recently modafinil, used as a stimulant for pilots).
Utilization
Temazepam, despite being the most highly restricted benzodiazepine in Australia (along with flunitrazepam) is commonly prescribed for severe insomnia. Temazepam along with diazepam, nitrazepam and oxazepam represent 82% of the benzodiazepine market in Australia.[27]
Dosage
When used for treatment of insomnia, the usual dose is 7.5mg to 15mg taken at bedtime but can be used at doses up to 30mg.
In the United States, temazepam is available in 7.5mg, 15mg, 22.5mg and 30mg capsules.
It is available as 10 and 20mg tablets in Finland, but also in at least some countries in the rest of Europe.
In the United Kingdom Temazepam is currently available in doses of 10mg and 20mg tablets.
In Australia it is only available in 10mg tablets under the trade name "Normison" and the generic name "Temaze" and "Temtabs". 20mg tablets and Temazepam in capsule or gelcap form is no longer available in that country.
Usual UK doses (from BNF) are 10-20mg at bedtime, max 30-40mg in exceptional circumstances.
Tolerance
Although tolerance to the sleep inducing properties of temazepam develops within a matter of days, so too does tolerance to the residual performance impairment. After 6 days of use, tolerance to temazepam's sleep inducing effects and performance impairing effects occurs.[28] One study demonstrated tolerance to the sleep promoting effects of nitrazepam and temazepam after 7 days nightly administration. Quality of sleep was found to be increased after the first nights administration of either nitrazepam or temazepam but by day 7 quality of sleep was found to have returned to baseline suggesting the development of complete tolerance after 7 days use.[29] In mice tolerance to the anticonvulsant properties of temazepam developed profoundly and rapidly over 6 days, although some anticonvulsant effects were still apparent after 6 days administration.[30]
Temazepam shares cross tolerance with barbiturates and barbiturates can easily be substituted for temazepam in those who are habituated to barbiturate sedative hypnotics.[31]
Dependence
See also benzodiazepine withdrawal syndrome
Temazepam as with other benzodiazepine drugs can lead to physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from temazepam or other benzodiazepines after regular use 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 however occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.[32] Dependence on temazepam and other benzodiazepine hypnotics like nitrazepam, flunitrazepam, or nimetazepam often occurs due to discharging patients from hospital on benzodiazepines who were started on benzodiazepine hypnotics in hospital. It was recommended that hypnotics in hospital be limited to 5 nights use only to avoid the development of the benzodiazepine withdrawal syndrome eg withdrawal insomnia.[33]
After discontinuation of temazepam, a rebound effect may occur immediately after abruptly stopping.[34] Temazepam tends to have more side effects than other hypnotic drugs and tolerance to the sedative properties and rebound insomnia after discontinuation occurs after only 3-5 days administration.[35] Tolerance to the anticonvulsant and anxiolytic effects also develops rapidly during daily administration.[36]
Abrupt withdrawal after long term use from therapeutic doses of temazepam may result in a very severe benzodiazepine withdrawal syndrome. There are reports in the medical literature of at least six psychotic states developing after abrupt withdrawal from temazepam including delirium after abrupt withdrawal of only 30 mg of temazepam and in another case, auditory hallucinations and visual cognitive disorder developed after abrupt withdrawal from 10 mg of temazepam, 5 mg of nitrazepam and 0.5 mg of triazolam. Gradual and careful reduction of the dosage, preferably with a milder long-acting benzodiazepine such as clonazepam or diazepam, or even a milder short to intermediate acting benzodiazepine such as oxazepam or alprazolam, was recommended to prevent severe withdrawal syndromes from developing. Other strong hypnotic benzodiazepines, whether short, intermediate or long-acting are not recommended.[37] Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions.[38] Depersonalisation has also been reported as a benzodiazepine withdrawal effect from temazepam.[39]
Abrupt withdrawal from very high doses is even more likely to cause severe withdrawal effects. Withdrawal from very high doses of temazepam will cause severe hypoperfusion of the whole brain with diffuse slow activity on EEG. After withdrawal, abnormalities in hypofrontal brain wave patterns may persist beyond the withdrawal syndrome suggesting that organic brain damage may occur from chronic high dose abuse of temazepam. Temazepam withdrawal has been well known to cause a sudden and often violent death.[40]
Cognitive Behavioural Therapy
Temazepam, nitrazepam and zopiclone are the most frequently prescribed hypnotics in the United Kingdom. Hypnotic drugs are of poor value for the management of chronic insomnia. It is widely accepted that hypnotic drug usage beyond 4 weeks is undesirable for all age groups of patients. Many continuous sedative hypnotic users exhibit disturbed sleep as a consequence of tolerance but experience worsening rebound or withdrawal insomnia when the dose is reduced too quickly which compounds the problem of chronic hypnotic drug use. Chronic hypnotic drug consumption has been shown to reduce work performance increase absenteeism increase road traffic accidents, increased morbidity, increased mortality and is associated with increased deliberate self harm. In the elderly increases in falls and fractures associated with sedative hypnotic drug use has been found. CBT have been found to be more effective for the long term management of insomnia than sedative hypnotic drugs. No formal withdrawal programs for benzodiazepines exists with local providers. A meta-analysis of published data on psychological treatments for insomnia show a success rate between 70 and 80%. A large scale trial utilising cognitive behavioural therapy in chronic users of sedative hypnotics including nitrazepam, temazepam and zopiclone found that CBT to be a more effective long term treatment for chronic insomnia. Persisting improvements in sleep quality, sleep latency, increased total sleep, improvements in sleep efficiency, significant improvements in vitality, physical and mental health at 3, 6 and 12 month follow up was found in those receiving cognitive behavioural therapy. A marked reduction in total sedative hypnotic drug use was found in those receiving CBT, with 33% reporting zero hypnotic drug use. Age has been found not to be a barrier to successful outcome of CBT. It was concluded that CBT for the management of chronic insomnia was flexible, practical and cost effective treatment for the treatment of insomnia and that CBT leads to a reduction of benzodiazepine drug intake in significant number of patients.[41]
Toxicity
Benzodiazepines are generally thought to be safe in overdose.[42] Death after admission is rare and due to respiratory depression with aspiration of gastric contents. [43] Over 10 years in the United Kingdom, however, 1512 fatal poisonings have been attributed to benzodiazepines with or without alcohol.[44] These were compared with prescription data to establish a fatal toxicity index (deaths per million prescriptions) for each benzodiazepine. Similar indices have been derived for antidepressants[45] and barbiturates.[46] There were clear differences between benzodiazepines. Of drugs frequently prescribed, temazepam by far had the highest number of deaths per million prescriptions at 11.9 (95% confidence interval 10.9 to 12.8); above that of some tricyclic antidepressants.[44][45] In contrast, oxazepam had an index of 2.3 (1.2 to 3.4), and the average index for all benzodiazepines combined was 5.7.
Although there are potential sources of error in these studies,[47] a bias that would lead to differences between compounds was not identified.[44] Clinical studies can adjust for potential confounders which studies that use coronial data are unable to take into account. If differences between the benzodiazepines are supported by data from clinical studies this also adds credence to the fatal toxicity index which first noted these findings.
The aim was therefore to determine if temazepam caused more sedation and oxazepam less sedation than other benzodiazepines.
During 1991-3, 542 patients with benzodiazepine poisoning presented to the hospital, 239 of these patients, however, had ingested either more than one benzodiazepine or co-ingested other sedating drugs. The drugs ingested by the remainder were temazepam (64), oxazepam (45), diazepam (113), clonazepam (24), flunitrazepam (21), nitrazepam (18), others (18).
Details of coma scores and odds ratios of the benzodiazepines ingested showed that temazepam was significantly more toxic than most other benzodiazepines.[48] Two out of the 45 subjects (4%) who ingested oxazepam were stuporous or comatose, 38 out of the 194 subjects (19%) who ingested other benzodiazepines (clonazepam, diazepam, flunitrazepam, nitrazepam and others) were stuporous or comatose, while 16 out of the 64 subjects (25%) who ingested temazepam were stuporous or comatose. None of the oxazepam subjects were comatose, 16 out of the 194 subjects (8%) who ingested other benzodiazepines were fully comatose, and 9 out of 64 subjects (14%) who ingested temazepam were fully comatose.
The results show that there are differences between temazepam, oxazepam, and other benzodiazepines in the degree of sedation they cause in overdose, and the observed differences are not due to confounding by age, sex, dose ingested, co-ingestion of alcohol, chronic benzodiazepine use, or history of drug or alcohol abuse. This provides a plausible explanation why temazepam and oxazepam have different fatal toxicity indices from other benzodiazepines.[44]
The sedation produced by benzodiazepines in therapeutic doses and overdose has a poor correlation with measured drug concentration but is increased with rapid absorption.[42][49][24][50] Temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than other benzodiazepines.[42][49][24][50][51] Further research is required to determine if the rate of absorption is different in overdose and is sufficient to explain the differences in sedation. Slowing the rate of absorption may reduce toxicity, but this would also reduce their sedative effect in therapeutic doses.[24] Drug regulatory authorities should be aware that changes in formulation of benzodiazepines may affect toxicity in overdose.
Pharmacodynamic factors such as benzodiazepine receptor affinity and potency may also be important. Because of the wide variations in half life, adjustments for dose by conversion into defined daily doses or diazepam equivalents is imperfect.[52] These are designed to compare use rather than potency. Though they correlate reasonably well with sizes of prescriptions and tablets, they may not account for potency per tablet taken in overdose.[44]
Abuse and misuse
In Australia, temazepam accounts for most benzodiazepine sought by forgery of prescriptions and through pharmacy burglary. Pharmacists and their staff often encounter aggressive and threatening behaviour from people seeking temazepam. There were 537 burglaries on Victoria's 1200 pharmacies from 1 January to 30 August 2001, including 'ram raids' (using stolen cars to smash through windows). Temazepam appears to be the main target in many pharmacy burglaries. Temazepam is sought in 85% of all reported benzodiazepine forgeries.[53]
Unprescribed temazepam is often detected in urine samples of drug misusers which suggests a high misuse potential of temazepam.[54] Studies suggest that temazepam is a particularily euphoric benzodiazepine, and along with other hypnotic benzodiazepines, particularly flunitrazepam, nitrazepam, and nimetazepam, it is considered to have the highest abuse potential of all benzodiazepines. In the UK, temazepam has superseded diazepam, nitrazepam and flurazepam as the most commonly abused benzodiazepine, in line with the increase in temazepam prescriptions and possibly (until recently) because of the availability of easily injectable forms of temazepam from capsules, 'jellies', 'eggs' (Stark et al. 1987). Benzodiazepines have been injected but at present temazepam is mainly involved. Strang et al. (1994) conducted a questionnaire survey of subjects attending drug clinics in seven British cities. Of 208 subjects returning the questionnaire, 186 had used benzodiazepines and 103 had injected them intravenously. Temazepam was the most commonly used and had been injected from preparations of capsules, tablets and syrup.[55] Temazepam (whether obtained from capsules, tablets or elixir), is extremely irritating and likely to cause tissue damage. When arm veins become occluded due to local irritation, users may proceed to injecting in the groin, where inadvertent intra-arterial injection has led to amputation. The severity of the addiction which can develop to temazepam is illustrated by the case of a temazepam injector who needed his leg amputated but was later admitted for a second amputation since he had continued injecting into his remaining leg.[56] A second subject, following a leg amputation, injected temazepam gel into his eye, resulting in bilateral blindness.[55]
In Northern Ireland in cases where drugs were found in tests on impaired drivers who had low alcohol readings but were suspected of driving under the influence of drugs benzodiazepines were found to be present in 87% of cases, with temazepam accounting for the vast majority of cases.[57]
Side effects
Common side effects include
CNS depression typical of hypnotic benzodiazepine are common and include, somnolence, dizziness, fatigue, ataxia, headache, lethargy, impairment of memory, impairment of motor functions, slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, blurred vision, and inattention. Euphoria, which is very uncommon among the vast majority of benzodiazepines, was consistently reported with the use of temazepam. According to the FDA, temazepam had the highest incidences of euphoria among the few benzodiazepines that reported it during clinical trials.[58] Unpleasant dreams and rebound insomnia have also been reported. High levels of confusion, clumsiness also occurs after administration of temazepam.[59] Increased reaction time, co-ordination problems and impaired learning and memory.[60]
- Somnolence
- Impaired motor function
- Impaired coordination.[60]
- Impaired balance
- Impaired learning and memory[60]
- Euphoria (temazepam had one of the highest incidence of euphoria among the few that reported euphoria from any benzodiazepines according to the FDA)[58]
- Dizziness
- Anterograde amnesia
- Respiratory depression in higher doses (According to the FDA, temazepam may pose a serious risk to respiratory function even when taken alone, this is due to its much higher toxicity index relative to other benzodiazepines)
- Blurred vision (in higher doses)
- Confusion
- Lack of concentration
- Slurred speech
Less Common Side Effects
Hyperhidrosis, hypotension, burning eyes, changes in libido, hallucinations, faintness, horizontal nystagmus, vomiting, pruritus, gastrointestinal disturbances, nightmares, palpitation and paradoxical reactions including restlessness, aggression, violence, over stimulation and agitation have been reported, but are rare (less than 0.5%).
Before taking temazepam, one should ensure that at least 8 hours are available to dedicate to sleep. Failing to do so can increase the side effects of the drug.
Long-term use of temazepam can result in psychological and physical dependence and the appearance of benzodiazepine withdrawal symptoms when the drug is discontinued or the dose reduced. Temazepam impairs cognitive and psychomotor functions, affecting reaction time and driving skill. The use of this drug in combination with alcohol potentiates these side effects, and can lead to toxicity and death.
In a clinical study conducted in the United Kingdom between the years 1991-1993, it was found that temazepam was the most toxic of all benzodiazepines, easily causing death in an overdose, even when not combined with any other CNS Depressant, unlike most other benzodiazepines, especially the anxiolytics which all have a much lower toxicity profile. Oxazepam had the lowest toxicity profile of all benzodiazepines. Others with low toxicity profiles were diazepam, alprazolam, lorazepam, bromazepam, and clonazepam. Besides temazepam, other hypnotic benzodiazepines were tested (flunitrazepam, nitrazepam, flurazepam, midazolam, and triazolam) and all had a high toxicity profile. The reason was that the hypnotics more strongly reduced the rate of respiration, caused more sedation, were more likely to induce coma, amnesia, and hypotension. All the hypnotic benzodiazepines that were tested in the study showed that they can cause death without ingesting other CNS depressants, very much like barbiturates. Nimetazepam, though was not part of the British study is believed to have a toxicity profile similar to temazepam's.[44][45]
Though rare, residual 'hangover' effects after night time administration of temazepam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may impair the ability of users to drive safely or may increase the risks of falls and hip fractures.[61]
Interactions
Temazepam produces additive CNS depressant effects when co-administered with other medications which themselves produce CNS depression, e.g. barbiturates, alcohol, opiates, tricyclic antidepressants, nonselective MAO inhibitors, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines and anaesthetics. Administration of theophylline or aminophylline have been shown to reduce the sedative effects of temazepam and other benzodiazepines.
The cytochrome P450 system has not been shown to be involved in the disposition of temazepam and, unlike many benzodiazepines, pharmacokinetic interactions involving the P450 system have not been observed with temazepam. Temazepam shows no significant interaction with 3A4 inhibitors (e.g. itraconazole, erythromycin).[62]
Interactions have been reported between temazepam and anticonvulsants, with changes in the serum concentration of the temazepam or anticonvulsant. It is recommended that patients be observed for altered responses when temazepam and anticonvulsants are prescribed together, and that serum level monitoring of the anticonvulsant be performed more frequently.
Contraindications
Use of temazepam 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 depression, particularly when accompanied by suicidal tendencies
- Acute intoxication with alcohol, narcotics, or other psychoactive substances
- Myasthenia gravis
- Hypersensitivity or allergy to any drug in the benzodiazepine class
Special caution needed
- Pregnant Women - temazepam may cause fetal damage when administered during pregnancy.
- Pediatric patients
- Less than 18 years of age - Safety and effectiveness have not been established; temazepam should generally not be given to individuals under 18 years of age
- Under 6 months of age - Safety and effectiveness have not been established; temazepam should not be given to individuals in this age group.
- 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.
Pregnancy
Temazepam belongs to the Pregnancy Category X of the FDA, and as such it is known to cause serious birth defects and fetal abnormalities. Temazepam increased risk of congenital malformations associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy.
Reproduction studies in animals with Temazepam were performed in rats and rabbits. In a perinatal-postnatal study in rats, oral doses of 60 mg/kg/day resulted in increasing nursling mortality. Teratology studies in rats demonstrated increased fetal resorptions at doses of 30 and 120 mg/kg in one study and increased occurrence of rudimentary ribs, which are considered skeletal variants, in a second study at doses of 240 mg/kg or higher. In rabbits, occasional abnormalities such as exencephaly and fusion or asymmetry of ribs were reported without dose relationship. Although these abnormalities were not found in the concurrent control group, they have been reported to occur randomly in historical controls. At doses of 40 mg/kg or higher, there was an increased incidence of the 13th rib variant when compared to the incidence in concurrent and historical controls.
Temazepam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving Temazepam, she should be warned of the potential risk to the fetus. Patients should be instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered.[58]
Patients at a high risk for abuse and dependence
Temazepam can lead to physiological tolerance, and psychological and/or physical dependence. At a particularly high risk for temazepam misuse, abuse, and dependence are:
- Patients with a history of alcohol or drug abuse or dependence
- Emotionally unstable patients
- Patients with severe personality disorders, such as Borderline Personality Disorder
- Patients with chronic pain or other physical disorders
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.
Special Precautions
Complex behaviours such as "sleep-driving" (i.e. driving while not fully awake after taking a temazepam, with amnesia for the event) have been reported with its use. These events can occur in temazepam naive as well as in experienced temazepam persons. These events can occur at normal therapeutic doses, and the risk appears to be increased when temazepam is combined with alcohol or other CNS depressants or used at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of temazepam should be strongly considered for patients who report a "sleep-driving" episode. Other complex behaviours (eg. preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking temazepam. As with "sleep driving", patients usually do not remember these events. As with all patients taking CNS depressant medications, patients receiving temazepam should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy or dizzy from temazepam therapy.[63] Abilities may be impaired on the day following use. In sleep laboratory studies in volunteers, doses of 10 and 20 mg did not significantly affect morning performance, however the 30 mg dose produced impairment of psychomotor behaviour on the morning following night time administration. Patients should be advised that their tolerance for alcohol and other CNS depressants will be diminished and that these medications should either be eliminated or given in reduced dosage in the presence of temazepam. Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of temazepam. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal.[63]
Impaired renal/hepatic function and blood dyscrasias
Patients with impaired renal or hepatic function should use temazepam with caution, and dosage reduction may be advisable. In rare instances, some patients taking temazepam have developed blood dyscrasias, and some have had elevations of hepatic enzymes. As with other benzodiazepines, periodic blood counts and liver function tests are recommended. The use of temazepam may worsen hepatic encephalopathy; therefore, temazepam should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy.[63]
Depression, psychosis and schizophrenia
Temazepam is not recommended as primary therapy in patients with depression and psychosis. In such conditions, psychiatric assessment and supervision are necessary if temazepam is indicated. Temazepam may increase depression in some patients, and may contribute to deterioration in severely disturbed schizophrenic patients with confusion and withdrawal. Suicidal tendencies may be present or uncovered, and protective measures may be required. Paradoxical reactions such as acute rage, stimulation or excitement may occur; should such reactions occur, temazepam should be discontinued. Such reactions may be more likely to occur in children and the elderly.[64]
Impaired respiratory function
Use of temazepam may lead to potentially fatal respiratory depression. Hence, caution in the use of temazepam is recommended in patients with respiratory depression. In patients with chronic obstructive pulmonary disease, temazepam can cause increased arterial carbon dioxide tension and decreased arterial oxygen tension.[63]
Epilepsy
Abrupt withdrawal of temazepam in patients with convulsive disorders may be associated with a temporary increase in the frequency and/or severity of seizures.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in rats at dietary temazepam doses up to 160 mg/kg/day for 24 months and in mice at dietary dose of 160 mg/kg/day for 18 months. No evidence of carcinogenicity was observed although hyperplastic liver nodules were observed in female mice exposed to the highest dose. The clinical significance of this finding is not known. No mutagenicity tests have been done with temazepam.[65] In animal studies, an increased perinatal mortality has been seen following concomitant administration of temazepam and diphenhydramine to rabbits in the later stages of gestation compared with rabbits that received either drug alone. It is recommended that the use of temazepam be avoided in pregnant women receiving antihistamines. Fertility in male and female rats was not adversely affected by temazepam.[63]
Overdose
Manifestations of acute overdosage of temazepam can be expected to reflect the increasing CNS effects of the drug and include:
- Somnolence (difficulty staying awake)
- Mental confusion
- Respiratory depression
- Hypotension
- Impaired motor functions
- Impaired or absent reflexes
- Impaired coordination
- Impaired balance
- Dizziness
- Coma
- Death
Temazepam overdose is considered a serious medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of temazepam (or any other benzodiazepine) is flumazenil (Anexate).
If the patient is conscious, vomiting should be induced mechanically or with emetics (e.g., syrup of ipecac 20 to 30 mL). Gastric lavage should be employed as soon as possible, utilizing concurrently a cuffed endotracheal tube if the patient is unconscious, in order to prevent aspiration and pulmonary complications. Maintenance of adequate pulmonary ventilation is essential and fluids should be administered IV to encourage diuresis. The use of pressor agents IV, may be necessary to combat hypotension but only if considered essential. The value of dialysis in emergency therapy for benzodiazepine overdosage has not been determined. If excitation occurs, barbiturates should not be used. It should be borne in mind that multiple agents may have been ingested.
The oral LD50 of temazepam was 1963 mg/kg in mice, 1833 mg/kg in rats, and >2400 mg/kg in rabbits.
Temazepam is a drug which is very frequently involved in drug intoxication, including overdose.[66] Overdose of temazepam may result in excessive sedation, impairment of balance and speech. This may progress in severe overdoses to respiratory depression or coma and possibly death. The risk of overdose is increased if temazepam is taken in combination with alcohol, opiates or other CNS depressants. Temazepam overdose responds to the benzodiazepine receptor antagonist flumazenil.
Benzodiazepines were implicated in 39% of suicides by drug poisoning in Sweden, with temazepam, nitrazepam and flunitrazepam accounting for 90% of benzodiazepine implicated suicides, in the elderly over a period of 2 decades. In three quarters of cases death was due to drowning, typically in the bath. Benzodiazepines were the predominant drug class used in suicides in this review of Swedish death certificates with 72% of benzodiazepine overdoses showing that benzodiazepines were the sole drug used in deaths by overdose. Benzodiazepines and in particular temazepam, nitrazepam and flunitrazepam should therefore be prescribed with caution in the elderly.[67] Nitrazepam, and especially temazepam were the benzodiazepines most commonly detected in overdose related drug deaths in an Australian study of drug deaths. The two benzodiazepines were found to be the sole cause of death in one third of cases.[68]
In a retrospective study of deaths, when benzodiazepines were implicated in the deaths, the benzodiazepines flunitrazepam, temazepam and nitrazepam were the most common benzodiazepines involved. Benzodiazepines were a factor in all deaths caused by drug addiction in the study. Temazepam, nitrazepam and flunitrazepam were significantly more commonly implicated in suicide related deaths than natural deaths. In four of the cases benzodiazepines alone were the only cause of death. It was concluded that flunitrazepam, nitrazepam, and temazepam were significantly more toxic than other benzodiazepines.[69]
From a research perspective, there are several data acquired through scientific research that suggest temazepam is more frequently involved in drug-related deaths than are all other benzodiazepines. Temazepam is also the benzodiazepine that is by far the most commonly targeted in pharmacy burglaries and prescription forgeries.[70] Seized diverted temazepam tablets and/or capsules account for half of all police seizures of benzodiazepines.[71]
Legal Status
In the United Kingdom, the drug is available only by prescription and is a controlled drug. Temazepam is a Class B drug in the United Kingdom and possession is illegal without a prescription. Additionally, all manufacturers in the UK have replaced the gel-capsules with solid tablets. Temazepam prepared for injection is classed as a Class A drug.
In the USA, temazepam is a Schedule IV drug and is only available by prescription. Temazepam is the only benzodiazepine which requires specially coded prescriptions in certain States.
In Canada, Temazepam is a Schedule IV controlled substance requiring a doctors prescription.
In Ireland, Temazepam is a Schedule 3 controlled substance with strict restrictions.[72]
In Australia, temazepam in liquid form is restricted as a Schedule 8 controlled drug. As a Schedule 8 controlled substance, it is illegal to have this drug in possession without an authority prescription from a registered doctor. In tablet form, it is a Schedule 4 prescription only medicine.
In South Africa, temazepam is a Schedule 6 drug, requiring a prescription, and restricted to 10-20 mg doses.
In Sweden, temazepam is available in 10-20 mg capsules and tablets but are rarely prescribed. The most commonly prescribed hypnotics in Sweden are zopiclone, nitrazepam, and flunitrazepam. Temazepam is only prescribed if for any reason the three above hypnotics fail to work. As such, temazepam is second line treatment for severe insomnia where the other hypnotics have failed.
In Hong Kong, Temazepam is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. Nimetazepam is also regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. All other benzodiazepines are regulated under a much less restrictive Schedule category. Temazepam can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.[73]
Internationally, temazepam is a Schedule IV drug under the Convention on Psychotropic Substances. Though it is classed as a Schedule IV internationally, penalties for its possession and/or trafficking are more severe, unlike all other benzodiazepines (except for flunitrazepam, which is treated in the same manner as temazepam is.[74]
Temazepam in Popular Culture
Temazepam tablets are called Jellies, Tams, Terms, Temazzies, Eggs, Green Eggs, Norries, and Rugby balls.
The recreational effects of the drug were documented on the Black Grape album, It's Great When You're Straight... Yeah. The track 'Tramazi Parti' contains the lyric: I got my boots on the back of my head / It's full of jellies in the good old bed / And no one knows what no one said. Although there is no medical research confirming this behaviour, it is not inconsistent with the known side effects of the drug.
On the BBC radio series The Archers, Jolyon Gibson's Christmas present to Kate Aldridge was a bottle of temazepam capsules. Feeling depressed on New Year's Eve 1995, Kate took whisky and the "jellies" together and ended up in hospital.[75][76]
See also
References
- ^ Yasui M (2005). "[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes]". 25 (3): 143–51. PMID 16045197.
{{cite journal}}
: Cite journal requires|journal=
(help); Text "Nihon Shinkei Seishin Yakurigaku Zasshi" ignored (help) - ^ Rickels K (1986). "The clinical use of hypnotics: indications for use and the need for a variety of hypnotics". Acta Psychiatr Scand Suppl. 332: 132–41. PMID 2883820.
- ^ O'Neal, Maryadele J. Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. Merck. October 18, 2006.
- ^ Yevgenia Albats and Catherine A. Fitzpatrick (1994). The State Within a State: The KGB and Its Hold on Russia - Past, Present, and Future. ISBN 0374527385.
{{cite book}}
: Unknown parameter|publsiher=
ignored (|publisher=
suggested) (help) - ^ Sidney Bloch and Peter Reddaway (1984). Soviet Psychiatric Abuse: The Shadow over World Psychiatry. London: Victor Gollancz. ISBN 0813302099.
- ^ "Prescription Drugs: Their Use and Abuse" (PDF). Scholastic Corporation and National Institute on Drug Abuse, NIH. Retrieved 2007-11-25.
- ^ "What are the UK drug laws?". DrugsScope. February 2007. Retrieved 2007-11-25.
- ^ Woody GE (1979). "Development of psychiatric illness in drug abusers. Possible role of drug preference". The New England journal of medicine. 301 (24): 1310–4. PMID 41182.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Duddu V, Saleem PT, Green K (2003). "Sedative-hypnotic prescription in an out-patient mental health service in the north-west". Clinical Governance. 8 (1): 65–8. doi:10.1108/14777270310459986.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Rasanen I, Neuvonen M, Ojanperä I, Vuori E (2000). "Benzodiazepine findings in blood and urine by gas chromatography and immunoassay". Forensic Sci. Int. 112 (2–3): 191–200. PMID 10940604.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Australian Institute of Criminology (May 2007). "Benzodiazepine use and harms among police detainees in Australia" (PDF). Australian Government.
- ^ K. Bronisz (2006). "Studies of the electronic structure and biological activity of chosen 1,4-benzodiazepines by 35Cl NQR spectroscopy and DFT calculations". Chemical Physics (1–2): 301–306.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ Oelschläger H (4). "[Chemical and pharmacologic aspects of benzodiazepines]". Schweiz Rundsch Med Prax. 78 (27–28): 766–72. PMID 2570451.
{{cite journal}}
: Check date values in:|date=
and|year=
/|date=
mismatch (help); Cite has empty unknown parameter:|coauthors=
(help); Unknown parameter|month=
ignored (help) - ^ Ashton, H (2007). "Benzodiazepine Equivalency Table".
{{cite web}}
: Unknown parameter|accessmonthday=
ignored (help); Unknown parameter|accessyear=
ignored (|access-date=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ Podhorna J (2000). "Behavioural effects of a benzodiazepine receptor partial agonist, Ro 19-8022, in the social conflict test in mice". Behavioural pharmacology. 11 (2): 143–51. PMID 10877119.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Nowakowska E (1991). "Studies on the involvement of opioid mechanism in the locomotor effects of benzodiazepines in rats". Pharmacology, biochemistry, and behavior. 38 (2): 265–6. PMID 1676167.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ Welt T, Engelmann M, Renner U; et al. (2006). "Temazepam triggers the release of vasopressin into the rat hypothalamic paraventricular nucleus: novel insight into benzodiazepine action on hypothalamic-pituitary-adrenocortical system activity during stress". Neuropsychopharmacology. 31 (12): 2573–9. doi:10.1038/sj.npp.1301006. PMID 16395302.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - ^ Engelmann M (2006). "Temazepam triggers the release of vasopressin into the rat hypothalamic paraventricular nucleus: novel insight into benzodiazepine action on hypothalamic-pituitary-adrenocortical system activity during stress". Neuropsychopharmacology. 31 (12): 2573–9. PMID 16395302.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ Usami N (2002). "Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines" (pdf). Biol Pharm Bull. 25 (4): 441–5. PMID 11995921.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ Holmes JH (1978). "Effect of benzodiazepine derivatives on human blood cholinesterase in vitro". Res Commun Chem Pathol Pharmacol. 21 (2): 367–70. PMID 29327.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ Müller FO, Van Dyk M, Hundt HK; et al. (1987). "Pharmacokinetics of temazepam after day-time and night-time oral administration". Eur. J. Clin. Pharmacol. 33 (2): 211–4. doi:10.1007/BF00544571. PMID 2891534.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - ^ a b "Restoril -- Clinical Pharmacology". RxList.com. Retrieved 2007-11-25.
- ^ Schwarz HJ (1). "Pharmacokinetics and metabolism of temazepam in man and several animal species". 23 (29). PMID 41539.
{{cite journal}}
: Check date values in:|date=
and|year=
/|date=
mismatch (help); Cite journal requires|journal=
(help); Unknown parameter|month=
ignored (help) - ^ a b c d Fuccella LM, Bolcioni G, Tamassia V, Ferrario L, Tognoni G (1977). "Human pharmacokinetics and bioavailability of temazepam administered in soft gelatin capsules". Eur. J. Clin. Pharmacol. 12 (5): 383–6. doi:10.1007/BF00562455. PMID 598411.
{{cite journal}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid598411" was defined multiple times with different content (see the help page). - ^ Podhorna J (2000). "Behavioural effects of a benzodiazepine receptor partial agonist, Ro 19-8022, in the social conflict test in mice". Behavioural pharmacology. 11 (2): 143–51. PMID 10877119.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Bixler EO, Kales A, Soldatos CR, Scharf MB, Kales JD (1978). "Effectiveness of temazepam with short-intermediate-, and long-term use: sleep laboratory evaluation". J Clin Pharmacol. 18 (2–3): 110–8. PMID 342551.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Mant A (1993). "Benzodiazepine utilisation in Australia: report from a new pharmacoepidemiological database". Aust J Public Health. 17 (4): 345–9. PMID 7911332.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ Griffiths AN (1986). "The effects of repeated doses of temazepam and nitrazepam on several measures of human performance". Acta psychiatrica Scandinavica. Supplementum. 332: 119–26. PMID 2883819.
{{cite journal}}
: Cite has empty unknown parameter:|month=
(help); Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Cook PJ (1983). "Hypnotic accumulation and hangover in elderly inpatients: a controlled double-blind study of temazepam and nitrazepam" (pdf). Br Med J (Clin Res Ed). 286 (6359): 100–2. PMID 6129914.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ Garratt JC, Gent JP, Feely M, Haigh JR (1988). "Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential?". Eur. J. Pharmacol. 145 (1): 75–80. PMID 2894998.
{{cite journal}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ Rooke KC (1976). "The use of flurazepam (dalmane) as a substitute for barbiturates and methaqualone/diphenhydramine (mandrax) in general practice". J Int Med Res. 4 (5): 355–9. PMID 18375.
{{cite journal}}
: Cite has empty unknown parameters:|month=
and|coauthors=
(help) - ^ MacKinnon GL (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation". The American journal of drug and alcohol abuse. 9 (1): 19–33. PMID 6133446.
{{cite journal}}
: Cite has empty unknown parameter:|month=
(help); Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Hecker R (1992). "Risk of benzodiazepine dependence resulting from hospital admission". Drug Alcohol Rev. 11 (2): 131–5. PMID 16840267.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Hindmarch I (1977). "A repeated dose comparison of three benzodiazepine derivative (nitrazepam, temazepam and flunitrazepam) on subjective appraisals of sleep and measures of psychomotor performance the morning following night-time medication". Acta Psychiatr Scand. 56 (5): 373–81. PMID 22990.
{{cite journal}}
: Cite has empty unknown parameter:|coauthors=
(help); Unknown parameter|month=
ignored (help) - ^ Viukari M (1978). "Efficacy and side effects of flurazepam, temazepam, and nitrazepam as sleeping aids in psychogeriatric patients". Acta Psychiatr Scand. 57 (1): 27–35. PMID 24980.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ Nowakowska E (1987). "Differences in the development of tolerance to various benzodiazepines". Pol J Pharmacol Pharm. 39 (3): 245–52. PMID 2894019.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ Terao T, Tani Y (1988). "[Two cases of psychotic state following normal-dose benzodiazepine withdrawal]". J. UOEH (in Japanese). 10 (3): 337–40. PMID 2902678.
- ^ Tagashira E, Hiramori T, Urano T, Nakao K, Yanaura S (1981). "Enhancement of drug withdrawal convulsion by combinations of phenobarbital and antipsychotic agents". Jpn. J. Pharmacol. 31 (5): 689–99. PMID 6118452.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Terao T, Yoshimura R, Terao M, Abe K (1992). "Depersonalization following nitrazepam withdrawal". Biol. Psychiatry. 31 (2): 212–3. PMID 1737083.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Kitabayashi Y, Ueda H, Narumoto J; et al. (2001). "Chronic high-dose temazepam dependence 123I-IMP SPECT and EEG studies". Addict Biol. 6 (3): 257–261. doi:10.1080/13556210120056507. PMID 11900604.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - ^ Morgan K (2004). "Psychological treatment for insomnia in the regulation of long-term hypnotic drug use" (PDF). Health Technol Assess. 8 (8). National Institute for Health Research: 1–68. PMID 14960254.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ a b c Gaudreault P, Guay J, Thivierge RL, Verdy I (1991). "Benzodiazepine poisoning. Clinical and pharmacological considerations and treatment". Drug Saf. 6 (4): 247–65. PMID 1888441.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Höjer J, Baehrendtz S, Gustafsson L (1989). "Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period". J. Intern. Med. 226 (2): 117–22. PMID 2769176.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ a b c d e f Serfaty M, Masterton G (1993). "Fatal poisonings attributed to benzodiazepines in Britain during the 1980s". Br J Psychiatry. 163: 386–93. PMID 8104653.
- ^ a b c Cassidy S, Henry J (1987). "Fatal toxicity of antidepressant drugs in overdose". Br Med J (Clin Res Ed). 295 (6605): 1021–4. PMID 3690249.
- ^ Johns MW (1977). "Self-poisoning with barbiturates in England and Wales during 1959-74". Br Med J. 1 (6069): 1128–30. PMID 861497.
- ^ Dwyer PS, Jones IF (1984). "Fatal self-poisoning in the UK and the paracetamol/dextropropoxyphene combination". Hum Toxicol. 3 Suppl: 145S–174S. PMID 6480013.
- ^ Buckley NA, Dawson AH, Whyte IM, O'Connell DL (1995). "Relative toxicity of benzodiazepines in overdose". BMJ. 310 (6974): 219–21. PMID 7866122.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ a b Busto U, Kaplan HL, Sellers EM (1980). "Benzodiazepine-associated emergencies in Toronto". Am J Psychiatry. 137 (2): 224–7. PMID 6101526.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ a b Greenblatt DJ, Harmatz JS, Engelhardt N, Shader RI (1989). "Pharmacokinetic determinants of dynamic differences among three benzodiazepine hypnotics. Flurazepam, temazepam, and triazolam". Arch. Gen. Psychiatry. 46 (4): 326–32. PMID 2564763.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Mitler MM (1981). "Evaluation of temazepam as a hypnotic". Pharmacotherapy. 1 (1): 3–13. PMID 6152815.
- ^ Alexander B, Perry PJ (1991). "Detoxification from benzodiazepines: schedules and strategies". J Subst Abuse Treat. 8 (1–2): 9–17. PMID 1675694.
- ^ "Injecting Temazepam -- Temazepam Injection and Diversion". Victorian Governmant Health Information. 29 March, 2007. Retrieved 2007-11-25.
{{cite web}}
: Check date values in:|date=
(help) - ^ Garretty DJ (1997). "Benzodiazepine misuse by drug addicts". Annals of clinical biochemistry. 34 (Pt 1): 68–73. PMID 9022890.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ a b Ashton H (2002). "Benzodiazepine Abuse". Drugs and Dependence. London & New York: Harwood Academic Publishers.
{{cite book}}
:|access-date=
requires|url=
(help); External link in
(help); Unknown parameter|chapterurl=
|chapterurl=
ignored (|chapter-url=
suggested) (help) - ^ Parrott, A (1995). "Psychoactive drugs of use and abuse: Wobble, rave, inhale or crave". J. Psvchopharmacol. 9: 390–1.
- ^ Cosbey SH (1986). "Drugs and the impaired driver in Northern Ireland: an analytical survey". Forensic Sci Int. 32 (4): 245–58. PMID 3804143.
{{cite journal}}
: Unknown parameter|month=
ignored (help) - ^ a b c "Temazepam". Drugs.com. 10/2007. Retrieved 2007-11-25.
{{cite web}}
: Check date values in:|date=
(help) - ^ Sanders LD (1988). "A double-blind comparison between nitrazepam, lorazepam, lormetazepam and placebo as preoperative night sedatives". Eur J Anaesthesiol. 5 (6): 377–83. PMID 2907315.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ a b c Liljequist R (1979). "Acute effects of temazepam and nitrazepam on psychomotor skills and memory". Acta Pharmacol Toxicol (Copenh). 44 (5): 364–9. PMID 38627.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ Vermeeren A (2004). "Residual effects of hypnotics: epidemiology and clinical implications". CNS Drugs. 18 (5): 297–328. PMID 15089115.
{{cite journal}}
: Cite has empty unknown parameters:|month=
and|coauthors=
(help) - ^ Ahonen J, Olkkola KT, Neuvonen PJ (1996). "Lack of effect of antimycotic itraconazole on the pharmacokinetics or pharmacodynamics of temazepam". Ther Drug Monit. 18 (2): 124–7. PMID 8721273.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ a b c d e "Temaze (Temazepam) – Product Information" (PDF). Therapeutic Goods Administration. 23 March 2007.
- ^ Dietch JT, Jennings RK (1988). "Aggressive dyscontrol in patients treated with benzodiazepines". J Clin Psychiatry. 49 (5): 184–8. PMID 2896665.
- ^ "Restoril (temazepam) capsule". DailyMed. National Institutes of Health. 03/2006. Retrieved 2007-11-25.
{{cite web}}
: Check date values in:|date=
(help) - ^ Zevzikovas A, Kiliuviene G, Ivanauskas L, Dirse V (2002). "[Analysis of benzodiazepine derivative mixture by gas-liquid chromatography]" (PDF). Medicina (Kaunas) (in Lithuanian). 38 (3): 316–20. PMID 12474705.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Carlsten, A (2003). "The role of benzodiazepines in elderly suicides". Scand J Public Health. 31 (3): 224–8. PMID 12850977.
{{cite journal}}
: Cite has empty unknown parameter:|month=
(help); Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Drummer OH (1996). "Sudden death and benzodiazepines". Am J Forensic Med Pathol. 17 (4): 336–42. PMID 8947361.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help); Unknown parameter|month=
ignored (help) - ^ Ericsson HR, Holmgren P, Jakobsson SW, Lafolie P, De Rees B (1993). "[Benzodiazepine findings in autopsy material. A study shows interacting factors in fatal cases]". Lakartidningen (in Swedish). 90 (45): 3954–7. PMID 8231567.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ "Injecting Temazepam -- Temazepam Injection and Diversion". Victorian Governmant Health Information. 29 March, 2007. Retrieved 2007-11-25.
{{cite web}}
: Check date values in:|date=
(help) - ^ Hammersley R, Cassidy MT, Oliver J (1995). "Drugs associated with drug-related deaths in Edinburgh and Glasgow, November 1990 to October 1992". Addiction. 90 (7): 959–65. PMID 7663317.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ "Misuse Of Drugs (Amendment) Regulations". Irish Statute Book. Office of the Attorney General. 1993.
- ^ "Bilingual Laws Information System" (English). The Government of the Hong Kong Special Administrative Region of the People's Republic of China.
- ^ "Green List -- List of psychotropic substances under international control" (PDF). International Narcotics Control Board. 23rd edition, August 2003. Retrieved 2007-11-25.
{{cite web}}
: Check date values in:|date=
(help) - ^ "The latest from Kate". BBC Radio 4. 2007-01-25. Retrieved 2008-01-07.
- ^ Template:Cite archers episode