Temazepam detailed information

Overview
Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is a powerful intermediate-acting benzodiazepine drug of the 3-hydroxy category. Therapeutic and supratherapeutic doses of the drug can manifest clinical effects of strong hypnosis, sedation, amnesia, and ataxia. In addition, temazepam is an effective anxiolytic, anticonvulsant, and skeletal muscle relaxant. After an oral dose of temazepam, absorption occurs rapidly to induce sleep and preserve sleep architecture. It is generally prescribed for the treatment of short-term severe or debilitating insomnia in patients who have difficulty falling asleep or maintaining sleep.

History
Temazepam first came into use in the 1960s, 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 mainly because the onset of its powerful sedative-hypnotic effects were quick, rendering the subject asleep. It was still, however, utilized by the Soviet Union and East Germany in the 1970s 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, including the KGB and the CIA. Temazepam was used under the code name MKSEARCH, which was the CIA's successor project to MKULTRA. In former Soviet Union, temazepam was one of several drugs that was extensively used to keep political dissidents housed in psikhushkas (mental asylums and psychiatric hospitals) in a constant vegetative state.

By the late 1980s, 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. In North America, its abuse was not initially as widespread as it was elsewhere in the world since other hypnotic benzodiazepines such as triazolam and flurazepam were more commonly prescribed for insomnia. Benzodiazepines such as alprazolam and lorazepam, medications indicated for anxiety and panic disorders, were also more likely to be prescribed to patients suffering from insomnia than was temazepam. The 1990s saw an increase in temazepam prescriptions in the United States.

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 is structurally most closely related to diazepam and oxazepam. In its clinical effects however, temazepam is most closely related to nimetazepam, nitrazepam, and flunitrazepam. 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. Temazepam is a powerful agonist of the α1 subunit of the GABAA receptor. Modulation of the α1 is associated with sedation, motor-impairment, ataxia, and reinforcing behavior. The half life of temazepam is 8-22 hours. It is a full agonist of the benzodiazepine receptor. An opioid mechanism of action may play a role in some of the pharmacological properties of temazepam.

Temazepam triggers the release of vasopressin into the rat hypothalamic paraventricular nucleus. 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.

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.

Temazepam has an inhibitory effect on plasma cholinesterase of 60--90 per cent. Temazepam also inhibits Swiss 3T3 cells.

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. 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.

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%).

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.

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. .

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. It is a powerful hypnotic agent. In sleep laboratory studies, temazepam dramatically decreased the number of nightly awakenings. 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.

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 Netherlands, temazepam is available as 10mg and 20mg gelcaps under the brand name Normison, and as generic by several manufacturers, and as 10mg and 20mg generic tablets by several manufacturers. Temazepam is only indicated for the temporary treatment of insomnia, usually in doses of 10mg or 20mg, though higher doses may also be prescribed, if the prescribing doctor finds it necesarry.

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 Belgium, Germany, France, the United Kingdom and Finland, but also in most other European countries.

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. 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. 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.

Temazepam shares cross tolerance with barbiturates and barbiturates can easily be substituted for temazepam in those who are habituated to barbiturate sedative hypnotics.

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. 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.

After discontinuation of temazepam, a rebound effect may occur immediately after abruptly stopping. 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. Tolerance to the anticonvulsant and anxiolytic effects also develops rapidly during daily administration.

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. Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions. Depersonalisation has also been reported as a benzodiazepine withdrawal effect from temazepam.

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.

Elderly
An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines including temazepam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

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 a significant number of patients.

Toxicity
Benzodiazepines have a relatively high therapeutic index. Death after admission is rare and due to respiratory depression with aspiration of gastric contents. Over 10 years in the United Kingdom, however, 1512 fatal poisonings have been attributed to benzodiazepines with or without alcohol. 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 and barbiturates. 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. 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, a bias that would lead to differences between compounds was not identified. 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. 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.

The sedation produced by benzodiazepines in therapeutic doses and overdose has a poor correlation with measured drug concentration but is increased with rapid absorption. Temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than other benzodiazepines. 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. 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. 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.

Abuse epidemic
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. As a result of its rampant abuse, the Australian government made a decision to restrict temazepam and put it under a much more restrictive schedule than it previously was. Since March 2004 temazepam capsules have been withdrawn from the Australian market amidst studies linking that particular form of dose to abuse, particularly by intravenous drug users. As a result, temazepam has been rescheduled to an S4 drug (Prescription Only).

In the United States, temazepam is the fifth most prescribed benzodiazepine, with only alprazolam, lorazepam, clonazepam, and diazepam being more commonly prescribed in that order. Individuals abusing temazepam obtain the drug by getting prescriptions from several doctors, forging prescriptions, or buying diverted pharmaceutical products on the illicit market. Seizures of diverted temazepam in the United States rivals that of the top four most prescribed benzodiazepines, despite the fact that temazepam is considerably less prescribed.

Unprescribed temazepam is often detected in urine samples of drug misusers which suggests a high misuse potential of temazepam. Studies suggest that temazepam is a particularly 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. 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. A second subject, following a leg amputation, injected temazepam gel into his eye, resulting in bilateral blindness.

Until recently, temazepam was produced as a gel-filled capsule intended to be taken orally. However, it gained notoriety in Europe, especially in the United Kingdom, most prominently in 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 of Europe and then to Australia, New Zealand, and many parts of Asia. In Malaysia and Singapore, 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, but its demands worldwide increased and were supplied by highly organized crime syndicates and drug barons in Eastern Europe and Asia who are illicitly manufacturing temazepam in clandestine laboratories. In the United Kingdom, temazepam is a Class C drug under the Schedule 2 of the Misuse of Drugs Act 1971. In the United States, temazepam is the only benzodiazepine which requires specially coded prescriptions in certain states. 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. Temazepam is becoming increasingly more difficult to contain and curb its abuse. The 1990s saw a dramatic increase in temazepam abuse, especially among heroin injectors, crack cocaine smokers, methamphetamine, and dextroamphetamine users. In Europe, and especially in the United Kingdom it was at its worst. The media quickly pointed out the dangers associated with temazepam abuse, and temazepam was quickly publicized as an extremely addictive, dangerous, and destructive drug, both mentally and physically. Claims that the abuse of temazepam eventually lead to brain damage, psychosis, homicidal and suicidal thoughts.

In the United States, concern over temazepam's abuse elsewhere in the world caused concern. However, instead of placing it under Schedule III, as was proposed in the late 1990s, certain American states have made laws which require prescriptions for temazepam to be written on specially coded prescriptions, no other benzodiazepine has such requirement by law. Pharmacy burglaries and prescription forgeries in Scotland, Australia, Ireland, Finland, and several Asian countries report that temazepam is often a main target, whilst other benzodiazepines are rarely targeted.

International Trend
The misuse of temazepam remained a concern in the United Kingdom, Europe, South Africa, Russia, China, and Southeast Asia. More recently though, South America has seen a significant spike of temazepam abuse. Temazepam is believed to be the main contributing factor to crime waves in Argentina and Peru. Clandestine laboratories which illegally manufacture temazepam through chemical alteration of diazepam have contributed to the continued global consumption. North America is also becoming increasingly vulnerable to the illicit trade of temazepam, despite the fact that North America never had a serious problem with temazepam abuse as seen elsewhere in the world.

In South Africa, the continued availability of illicitly manufactured and diverted pharmaceutical products containing temazepam remained a concern. The low price and ready availability of temazepam in Northern Africa has seen a rise in their popularity. According to drug use surveys conducted in Argentina, Chile and Uruguay, the use of temazepam now ranks second after cannabis, with stimulant use levels in these countries being similar to that of cocaine. According to UNODC research on drug use in the East Asia and the Pacific regions, nimetazepam—a benzodiazepine previously unranked in previous studies—is now the most commonly used drug in Singapore, with temazepam being second most commonly used. In Brunei, temazepam was the most commonly used, with nitrazepam being second and nimetazepam in third. In Malaysia, more than a quarter of a million capsules of temazepam were seized in 2005. During that same year in Malaysia there were over half a million nimetazepam tablets seized. Nine temazepam seizures (which where en route to Western Europe and South America), equalling 1,430,231 capsules, between July and December 2005 were recorded in Turkey.

In Finland, the import of drugs is an international crime and in recent years, 20–30% of those suspected of aggravated temazepam offences in Finland have been foreigners (28% in 2005). Among these, the largest groups in 2005 consisted of Estonians (32% of foreign suspects) and Russians (25%). Organised crime groups led from Estonia play an important role in acquiring temazepam and other drugs from abroad and smuggling almost all drugs to Finland. The largest groups of foreign citizens suspected of aggravated temazepam offences were Estonians and Russians, whose proportion increased significantly from the end of the 1990s up to 85% of foreign suspects. However, since 2003, their share has clearly decreased to 57% of foreign suspects and 16% of all persons suspected of aggravated temazepam offences in 2005.

In 2005, the total number of samples of suspected cases of driving while intoxicated came to 3,420. temazepam was the most common substances detected in the samples, comprising of over 82% of the cases. These findings have increased almost fivefold when compared to 2003. Temazepam is increasingly found and used either as a sole drug or as part of a polydrug regimen.

In Japan, temazepam, triazolam, flutoprazepam, and nimetazepam are by far the most common benzodiazepines of abuse.

Illicit trafficking: manufacture and distribution
In the United Kingdom, temazepam is the most widely-abused legal, prescription drug. It's also the most commonly abused benzodiazepine in Finland, Ireland, the Netherlands, Poland, Czech Republic, Hungary, India, Russia, China, New Zealand, Australia and some parts of Southeast Asia. Surveys in many countries showed that temazepam, heroin, cocaine, MDMA, cannabis, nimetazepam, and amphetamines rank among the top drugs most frequently abused. Misuse of temazepam has led to hundreds of deaths and amputations, according to an unpublished survey. The study of nearly 1,000 people also found that most are unaware of the potential dangers of abusing the drug, temazepam, by injecting the capsules and tablets or swallowing large numbers of them. It discovered more than two-thirds of the randomly selected group from Edinburgh had taken some type of illegal drug in the past six months. Abuse of it has somewhat decreased since the mid-1990s when the drug was placed under a more restrictive schedule, a decision which was welcomed by many pharmacists who have been robbed by drug seekers looking for temazepam all across the country. Despite this, however, temazepam remains to be the most abused and sought after prescription drug in the UK. Temazepam still remains to be one of the most targeted of drugs in most pharmacy robberies. Illicit temazepam is also being trafficked from Eastern Europe to the United Kingdom and other Western European countries to meet the high demands for the hypnotic drug. Drug barons are manufacturing the banned capsules known as 'red jellies' and smuggling them into the UK and other western European countries via west coast ports. Intelligence gathered by police chiefs has revealed a massive increase in the availability of illicit temazepam on the streets. The new capsules were first uncovered in a police raid on a drug dealer in Greenock. Police in Strathclyde have said that the illicit temazepam that has been flooding the UK and other western European countries has caused a surge in drug-fuelled crime. Temazepam today is the most widely abused benzodiazepine worldwide, and is quickly turning into a primary drug of abuse, a fact that distinguishes it from all other benzodiazepines, which are typically used only to enhance the effects of opiates such heroin or morphine, or to ameliorate the adverse effects of cocaine or amphetamines. The use of benzodiazepines by street drug abusers is part of a polydrug abuse pattern. However, unlike other benzodiazepines, temazepam abuse has turned into an epidemic, with many of those entering treatment facilities are declaring temazepam as their main drug of abuse. Temazepam is the only benzodiazepine that is illegally manufactured and distributed by international organized crime syndicates and drug barons, though nimetazepam distribution is also criminally organized, but it is not illicitly manufactured. Primary drugs of abuse are defined as drugs with the ability to induce euphoria with psychic dependence and active drug-seeking behavior. Examples of primary drugs of abuse are cocaine, heroin, methamphetamine, and ethanol.

Border Problem
Temazepam based capsules and tablets are commonly detected by Customs at different ports and airports. Most are coming from countries where they are being illicitly manufactured in clandestine labs. Organized crime syndicates and drug barons in Eastern Europe and China are responsible for the illicit manufacture and distribution of temazepam. Clandestine "jellie labs" have been identified and shutdown in Russia, Ukraine, Greece, Czech Republic, Latvia and Belarus. Temazepam is also found occasionally in the baggage of air passengers. Customs detected 544 unauthorised importations of temazepam-based capsules in 2003–04. Most detections were of small or medium quantities of temazpeam (up to 200–300 tablets/capsules) brought to Australia for personal use. A number of importations, predominantly from China, involved quantities of over 1000 capsules. Most of the temazepam detected originated from the United Kingdom, Russia, China, France, and several Eastern Europe countries. The increase in illicit importation of temazepam in Australia to meet the high demands for the drug are likely due to two reasons: the fact that intravenous drug user-friendly temazepam capsules have been taken off the legal market, and because of a dramatic decrease in prescriptions for temazepam in Australia over the past five years. Customs detected 447 illicit importations of temazepam-based capsules in 2005–06, an increase from 341 in 2004–05, and a decrease from 544 detection in 2003–04. Quantities detected varied from 100 to 2,000 capsules per detection. Eastern European countries, China, Russia, India, United Kingdom, Sri Lanka, Philippines, Thailand, Singapore, New Zealand, Germany, France, South Africa, and even the United States, Peru, and Argentina. This is the first time that the US, Peru, Argentina, and Germany have been mentioned in Australian Illicit Drug Data Report (IDDR) for the importation of illicit temazepam. This may suggest a trend in the growth of an international temazepam epidemic. There were two detections of over 1,000 capsules—one from Sri Lanka and one from Peru—both of temazepam. Additionally, there were 12 detections of over 300 capsules and 10 detections of 100 to 300 capsules.

Domestic Market Indicators
The Australian Institute of Criminology conducts analysis on voluntarily provided urine samples from detainees at police watch houses at selected sites around Australia. In 2003, 24% of males and 40% of females tested positive for temazepam. As temazepam is available under prescription, however, the result does not necessarily translate to illegal use. Reflective of this, 24% of females and 12% of males reported they had taken prescription temazepam in the last fortnight while 31% of respondents reported using temazepam illegally in the previous thirty days.

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. Unpleasant dreams and rebound insomnia have also been reported. High levels of confusion, clumsiness also occurs after administration of temazepam. Increased reaction time, co-ordination problems and impaired learning and memory.


 * Somnolence
 * Impaired motor function
 * Impaired coordination.
 * Impaired balance
 * Impaired learning and memory
 * Euphoria (temazepam had one of the highest incidence of euphoria among the few that reported euphoria from any benzodiazepines according to the FDA)
 * 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.

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.

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).

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.

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. 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. 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.

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.

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.

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.

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.

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).

The oral LD50 of temazepam was 1963 mg/kg in mice, 1833 mg/kg in rats, and >2400 mg/kg in rabbits.

Temazepam has the highest rate of drug intoxication, including overdose, among the common benzodiazepines. 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 and nitrazepam were the two 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.

In the United Kingdom, especially in Scotland, death due to acute temazepam intoxication and overdose is a frequent occurrence. In 1999, temazepam was implicated in about a third of all drug deaths, either alone or in combination with another CNS depressant, most often alcohol or heroin. The frequency of deaths occurring with the ingestion of temazepam alone is of major concern, mainly because a majority of drug users believe that benzodiazepines are not lethal when ingested alone, even in massive quantities. Although most benzodiazepines are considered to have a relatively high therapeutic index and overdose is a rarity, temazepam has consistently been shown to be far more lethal in overdose than other benzodiazepines. In the UK and Ireland, death due to temazepam overdose trumps all other benzodiazepine-related deaths combined. Even outside the United Kingdom, temazepam has the highest number of deaths per million prescriptions in the United States, Canada, Russia, Finland, Australia, and New Zealand.

In 2003 and 2004, temazepam was the most frequently encountered benzodiazepine in drug-related deaths according to reports from US poison control centers. In 2005, a total of 67,593 benzodiazepine exposures were reported to US poison control centers, of which 3018 (0.04%) resulted in major toxicity and 243 (0.003%) resulted in death. Temazepam was once again the most frequently encountered benzodiazepine in the vast majority of the cases which resulted in death. Temazepam was also one of two benzodiazepines most frequently encountered in the cases which resulted in major toxicity. Triazolam (Halcion) was the other.

Temazepam is the benzodiazepine that is by far the most commonly targeted in pharmacy burglaries and prescription forgeries. Seized diverted pharmaceutical and illicitly manufactured temazepam tablets and/or capsules account for nearly half of all police seizures of benzodiazepines, outpacing nimetazepam, which accounts for almost a quarter of benzodiazepines seized by police.

Legal status
In the United Kingdom, temazepam is a Class C controlled drug, is available only via a special controlled drug prescription form, 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. Specially coded prescriptions may be required 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.

In Singapore, temazepam is a Class A-Schedule I controlled drug, along with one other benzodiazepine: Nimetazepam. The clandestine manufacture and illegal distribution of temazepam may be punishable by death. Possession of the drug without a valid prescription from a registered medical doctor is illegal and punishable by extremely long prison terms.

In Australia, temazepam is only available in tablet form and is designated a Schedule 4 drug, requiring a prescription.

In South Africa, temazepam is a Schedule 6 drug, requiring a prescription, and restricted to 10-20 mg doses.

In Hong Kong, temazepam is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. All other benzodiazepines (excluding nimetazepam) 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.

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 and nimetazepam, which are treated in the same manner as temazepam is. Temazepam and nimetazepam continue to be the most widely abused benzodiazepines internationally, and unlike other benzodiazepines, are increasingly being considered primary drugs of abuse. In Singapore, trafficking of nimetazepam and temazepam can be punishable by death.

Street terms
Street terms for temazepam include king kong pills (formerly referred to barbiturates, now more commonly refers to temazepam), jellies, jelly, tams, terms, mazzies, temazies, temmies, beans, eggs, green eggs, wobbly eggs, knockouts, hardball, norries, oranges (common term in Australia and New Zealand), rugby balls, ruggers, terminators, red and blue, no-gos, blackout, green devils, drunk pills, brainwash, mind erasers, tem-tem's (combined with buprenorphine), mommy's big helper, vitamin T, big T, TZ, on the nod (under the influence of heroin and temazepam together), and others.