Temazepam

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]

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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 GABA_A 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 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.[1]

See also

• Benzodiazepines
• Flunitrazepam
• Nitrazepam
• Nimetazepam

References