Temazepam

Temazepam

Systematic (IUPAC) name
7-Chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-1,4-benzodiazepin-2-one
Clinical data
Trade names	Restoril
AHFS/Drugs.com	monograph
MedlinePlus	a684003
Pregnancy cat.	C(AU) X(US)
Legal status	Prescription Only (S4) (AU) Schedule IV (CA) CD No Reg POM (UK) Schedule IV (US) IV (International)
Routes	Oral
Pharmacokinetic data
Bioavailability	96%
Metabolism	Hepatic
Half-life	8–20 hours
Excretion	Renal
Identifiers
CAS number	846-50-4 Y
ATC code	N05CD07
PubChem	CID 5391
DrugBank	DB00231
ChemSpider	5198 Y
UNII	CHB1QD2QSS Y
KEGG	D00370 Y
ChEMBL	CHEMBL967 Y
Chemical data
Formula	C16H13ClN2O2
Mol. mass	300.7 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C16H13ClN2O2/c1-19-13-8-7-11(17)9-12(13)14(18-15(20)16(19)21)10-5-3-2-4-6-10/h2-9,15,20H,1H3 Y Key:SEQDDYPDSLOBDC-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Temazepam^[1] (trade name Restoril, among others) is an intermediate-acting 3-hydroxy benzodiazepine. It is mostly prescribed for the short-term treatment of sleeplessness in patients who have difficulty maintaining sleep. In addition, temazepam has anxiolytic (anti-anxiety), anticonvulsant, and skeletal muscle relaxant properties.^[2][3][4]

History

Temazepam was first synthesized in 1964, but it first came into use in 1969 when its ability to counter insomnia was realized.^[5] By the late 1980s, temazepam was one of the most popular and widely prescribed hypnotics on the market and it became one of the most widely prescribed drugs.

Indications

Temazepam is a hypnotic agent. In sleep laboratory studies, temazepam significantly decreased the number of nightly awakenings^[6] but has the drawback of distorting the normal sleep pattern.^[7]

Temazepam is officially indicated for severe insomnia and other severe or disabling sleep disorders. The prescribing guidelines in the UK limit the prescribing of hypnotics to two-to-four weeks due to concerns of tolerance and dependence.^[8]

The United States Air Force uses temazepam as one of the hypnotics approved as "no-go pills" to help aviators and special duty personnel sleep in support of mission readiness. "Ground tests" are required prior to authorization being issued to use the medication in an operational situation.

Contraindications

Use of temazepam should be avoided, when possible, in individuals with the following conditions:

• Ataxia (gross lack of coordination of muscle movements)
• 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)
• Sleep apnea^[9]
• Severe depression, particularly when accompanied by suicidal tendencies
• Acute intoxication with alcohol, narcotics, or other psychoactive substances
• Myasthenia gravis (autoimmune disorder causing muscle weakness)
• Hypersensitivity or allergy to any drug in the benzodiazepine class

Special caution needed

Temazepam should not be used in pregnancy, as it may cause harm to the fetus. The safety and effectiveness of temazepam has not been established in children; therefore temazepam should generally not be given to individuals under 18 years of age, and should not be used at all in children under 6 months old. Benzodiazepines also require special caution if used in the elderly, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.^[10]

Temazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.^[11] The smallest possible effective dose should be used in elderly or very ill patients, as there is a risk of apnea and/or cardiac arrest. This risk is increased when temazepam is given concomitantly with other drugs that depress the central nervous system.^[12]

Patients at a high risk for abuse and dependence

Because benzodiazepines can be abused and lead to dependence, their use should be avoided in people in certain particularly high risk groups. High risk groups include people with a history of alcohol or drug abuse or dependence, emotionally unstable patients, people with severe personality disorders (such as Borderline Personality Disorder). If temazepam is indeed prescribed to people in these groups, they should generally be monitored very closely for signs of abuse and development of dependence.^[8]

Adverse effects

Common

Side effects typical of hypnotic benzodiazepines are related to CNS depression, and include somnolence, dizziness, fatigue, ataxia, headache, lethargy, impairment of memory and learning, longer reaction time and impairment of motor functions (including coordination problems),^[13] slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, blurred vision (in higher doses), and inattention. Euphoria was rarely reported with the use of temazepam. According to the FDA, temazepam had an incidence of euphoria of 1.5%, much more rarely reported than headaches and diarrhea.^[12] Anterograde amnesia may also develop, as may respiratory depression in higher doses.

Less common

Hyperhydrosis, hypotension, burning eyes, changes in libido, hallucinations, faintness, nystagmus, vomiting, pruritus, gastrointestinal disturbances, nightmares, palpitation and paradoxical reactions including restlessness, aggression, violence, overstimulation 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.

The use of this drug in combination with alcohol potentiates the side effects, and can lead to toxicity and death.

Though rare, residual "hangover" effects after nighttime 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.^[14]

Tolerance and physical dependence

See also: benzodiazepine withdrawal syndrome

Tolerance

Chronic or excessive use of temazepam may cause drug tolerance, which can develop rapidly,^[15] so this drug is therefore not recommended for long-term use.^[12][16] In 1979 the Institute of Medicine (USA) and the National Institute on Drug Abuse stated that most hypnotics lose their sleep-inducing properties after about 3 to 14 days.^[17] In use longer than 1–2 weeks, tolerance will frequently develop towards the ability of temazepam to maintain sleep, so that the drug loses effectiveness.^[18] Some studies have observed tolerance to temazepam after as little as one week's use.^[19] Another study examined the short-term effects of the accumulation of temazepam over 7 days in elderly inpatients, and found that little tolerance developed during the accumulation of the drug.^[20] Other studies examined the use of temazepam over six days and saw no evidence of tolerance.^[21][22] A study in 11 young male subjects showed that significant tolerance occurs to temazepam's thermoregulatory effects and sleep inducing properties after 1 week of use of 30 mg temazepam. Body temperature is well correlated with the sleep inducing or insomnia promoting properties of drugs.^[23]

In one study the drug sensitivity of people who had used temazepam for 1–20 years was no different from that of controls.^[24] An additional study, in which at least one of the authors is employed by multiple drug companies, examined the efficacy of temazepam treatment on chronic insomnia over three months and saw no drug tolerance, with the authors even suggesting that the drug might become more effective over time.^[25][26][27]

Establishing continued efficacy beyond a few weeks can be complicated by the difficulty in distinguishing between the return of the original insomnia complaint and withdrawal or rebound related insomnia. Sleep EEG studies on hypnotic benzodiazepines show that tolerance tends to occur completely after one to four weeks with sleep EEG returning to pretreatment levels. The paper concluded that due to concerns about long term use both toxicity and tolerance and dependence as well as controversy over long term efficacy that wise prescribers should restrict benzodiazepines to a few weeks and avoid continuing prescriptions for months or years.^[28] A review of the literature found that non-pharmacological treatment options were a more effective treatment option for insomnia due to their sustained improvements in sleep quality.^[29]

Physical dependence

Temazepam like other benzodiazepine drugs can cause physical dependence and addiction. Withdrawal from temazepam or other benzodiazepines after regular use often leads to a benzodiazepine withdrawal syndrome, which resembles symptoms 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 also occur from standard dosages and after short term use. Abrupt withdrawal from therapeutic doses of temazepam after long term use may result in a severe benzodiazepine withdrawal syndrome. Gradual and careful reduction of the dosage, preferably with a long-acting benzodiazepine with long half-life active metabolites such as chlordiazepoxide or diazepam is recommended, to prevent severe withdrawal syndromes from developing. Other hypnotic benzodiazepines are not recommended.^[30] A study in rats found that temazepam is cross tolerant with barbiturates and is able to effectively substitute for barbiturates and suppress barbiturate withdrawal signs.^[31] There are rare reports in the medical literature of psychotic states developing after abrupt withdrawal from benzodiazepines, even from therapeutic doses.^[32] Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions.^[33] Patients who were treated in the hospital with temazepam or nitrazepam have continued taking these after leaving the hospital. It was recommended that hypnotics in the hospital be limited to 5 nights use only, to avoid the development of withdrawal symptoms like insomnia.^[34]

Medical research issues

The Journal of Clinical Sleep Medicine published a paper expressing concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs that are used as hypnotics in humans. The paper cites a systematic review of the medical literature concerning insomnia medications and states that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry while this is not the case in general medicine or psychiatry. It cites another study that "found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times as high as in non–industry-sponsored studies". Issues discussed regarding industry-sponsored studies include: comparison of a drug to a placebo, but not to an alternative treatment; unpublished studies with unfavorable outcomes; and trials organized around a placebo baseline followed by drug treatment, but not counterbalanced with parallel-placebo-controlled studies. Quoting a 1979 report that there was then, too, little research into hypnotics that was independent of the drug manufacturers, the authors conclude that "the public desperately needs an equipoised assessment of hypnotic benefits and risks" and that the NIH and VA should provide leadership to that end.^[35]

Pharmacology

It is a white, crystalline substance, is very slightly soluble in water and sparingly soluble in alcohol. The main pharmacological action of temazepam is to increase the effect of the neurotransmitter GABA (gamma-aminobutyric acid) at the GABA_A receptor. This causes sedation, motor-impairment, ataxia, anxiolysis, anticonvulsant effect, muscle relaxation and reinforcing effect.^[36] As a premedication before surgery, temazepam decreased cortisol in elderly patients.^[37] In rats, temazepam triggered the release of vasopressin into paraventricular nucleus of the hypothalamus and decreased the release of ACTH under stress.^[38]

Pharmacokinetics

Oral administration of 15 to 45 mg temazepam in man resulted in rapid absorption with significant blood levels achieved in less than 30 minutes and peak levels at 2 to 3 hours.^[39] 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 drug 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.^[40]

Temazepam has very good bioavailability with almost 100% being absorbed from the gut. The drug is metabolized through conjugation and demethylation prior to excretion. Most of the drug is excreted in the urine, with about 20% appearing in the feces. The major metabolite was the O-conjugate of temazepam (90%); the O-conjugate of N-desmethyl temazepam was a minor metabolite (7%).^[41]

Interactions

As other benzodiazepines, temazepam produces additive CNS depressant effects when co-administered with other medications which themselves produce CNS depression, such as barbiturates, alcohol,^[42] opiates, tricyclic antidepressants, non-selective MAO inhibitors, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines and anaesthetics. Administration of theophylline or aminophylline has been shown to reduce the sedative effects of temazepam and other benzodiazepines.

Unlike many benzodiazepines, pharmacokinetic interactions involving the P450 system have not been observed with temazepam. Temazepam shows no significant interaction with CYP3A4 inhibitors (e.g. itraconazole, erythromycin).^[43] Oral contraceptives may decrease the effectiveness of temazepam and speed up its elimination half-life.^[44]

Overdose

Generic temazepam 10 mg tablets (UK)

Main article: Benzodiazepine overdose

Overdosage of temazepam results in increasing CNS effects, including:

• Somnolence (difficulty staying awake)
• Mental confusion
• Respiratory depression
• Hypotension
• Impaired motor functions
• Impaired or absent reflexes
• Impaired coordination
• Impaired balance
• Dizziness
• Coma
• Death

Temazepam had the highest rate of drug intoxication, including overdose, among the common benzodiazepines in cases with and without combination with alcohol in a 1985 study.^[45] Temazepam and nitrazepam were the two benzodiazepines most commonly detected in overdose-related deaths in an Australian study of drug deaths.^[46] A 1993 British study found temazepam to have the highest number of deaths per million prescriptions among medications commonly prescribed in the 1980s (11.9, versus 5.9 for benzodiazepines overall, taken with or without alcohol).^[47]

A 1995 Australian study of patients admitted to hospital after benzodiazepine overdose corroborated these results, and found temazepam overdose much more likely to lead to coma in comparison to other benzodiazepines (odds ratio 1.86). The authors note that several factors, such as differences in potency, receptor affinity, and rate of absorption between benzodiazepines could explain this higher toxicity.^[45]

Although benzodiazepines have a high therapeutic index, temazepam is one of the more dangerous of this class of drugs.

The combination of alcohol and temazepam makes death by alcohol poisoning more likely.^[48]

Recreational use

See also: Benzodiazepine drug misuse

Temazepam is a drug with the potential for misuse.^[49]

North America

In North America, temazepam misuse is not widespread. Other benzodiazepines are more commonly prescribed for insomnia. In the United States, temazepam is the fifth most prescribed benzodiazepine. Individuals abusing benzodiazepines obtain the drug by getting prescriptions from several doctors, forging prescriptions, or buying diverted pharmaceutical products on the illicit market.^[50] North America never had a serious problem with temazepam misuse, but is becoming increasingly vulnerable to the illicit trade of temazepam.^[51]

Australia

Temazepam accounts for most benzodiazepine sought by forgery of prescriptions and through pharmacy burglary in Victoria.^[52] Due to intravenous abuse, the Australian government decided to put it under a more restrictive schedule than it previously was,^[53] and since March 2004 temazepam capsules have been withdrawn from the Australian market.^[54][55] Benzodiazepines are commonly detected by Customs at different ports and airports, arriving by mail, also found occasionally in the baggage of air passengers, mostly small or medium quantities (up to 200–300 tablets) for personal use. From 2003 to 2006 customs detected approximately 500 illegal importations of benzodiazepines per year, most frequently diazepam. Quantities varied from single tablets to 2,000 tablets.^[56][57]

United Kingdom

In 1987, Temazepam was the most widely-abused legal prescription drug in the United Kingdom. The use of benzodiazepines by street drug abusers was part of a polydrug abuse pattern, but many of those entering treatment facilities were declaring temazepam as their main drug of abuse. Temazepam was the most commonly used benzodiazepine in a study, published 1994, of injecting drug users in seven cities and had been injected from preparations of capsules, tablets and syrup.^[58] The increase in use of heroin, often mixed with other drugs, which most often included temazepam, diazepam and alcohol, was a major factor in the increase in drug related deaths in Glasgow and Edinburgh 1990-1992.^[59] Temazepam use was particularly associated with violent or disorderly behaviours and contact with the police in a 1997 study of young single homeless people in Scotland.^[60]

Street terms

Street terms for temazepam include king kong pills (formerly referred to barbiturates, now more commonly refers to temazepam), jellies, jelly, Edinburgh eccies, tams, terms, mazzies, temazies, tammies, 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, and others.^[61][62]

Availability

Normison (temazepam) 10 mg tablets (AU)

Temazepam is available in English-speaking countries under the following brand names:

• Euhypnos
• Normison
• Norkotral
• Nortem
• Remestan
• Restoril
• Temaze
• Temtabs
• Tenox

Legal status

Temazepam is currently a Schedule IV drug under the international Convention on Psychotropic Substances of 1971.^[63]

In Australia, prescription is restricted as a Schedule 4 controlled drug.^[64] It is used primarily for the treatment of severe insomnia that has not responded to other treatments.

In Canada, temazepam is a Schedule IV controlled substance requiring a registered doctors prescription.

In Hong Kong, temazepam is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. 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 $10,000 (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.^[65]

In Ireland, temazepam is a Schedule 3 controlled substance with strict restrictions.^[66]

In the Netherlands, temazepam is available for prescription as 10–20 mg tablets and capsules. Formulations of temazepam containing less than 20 mg are included in List 2 of the Opium Law, while formulations containing 20 mg or more of the drug (along with the gel-capsules) are a List 1 substance of the Opium Law and thus subject to more stringent regulation.

In Norway, temazepam is not available as a prescription drug. It is regulated as a Class A substance under Norway's Narcotics Act.

In Portugal, temazepam is a Schedule IV controlled drug under Decree-Law 15/93.^[67]

In Singapore, temazepam is a Class A controlled drug (Schedule I), making it illegal to possess and requiring a private prescription from a licensed physician in order to be dispensed.

In Slovenia, it is regulated as a Group II (Schedule 2) controlled substance under The Production and Trade in Illicit Drugs Act.^[68][69]

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

In Sweden, temazepam is classed as a "narcotic" drug listed as both a List II (Schedule II) which denotes that it is a drug with limited medicinal use and a high risk of addiction, and it's also listed as a List V (Schedule V) substance which denotes that the drug is prohibited in Sweden under the Narcotics Drugs Act (1968).^[70] Temazepam is banned in Sweden and possession and distribution of even small amounts is punishable by a prison sentence and a fine.

In Switzerland, temazepam is a Class B controlled substance, like all other benzodiazepines. This means it is presciption only.^[71]

In Thailand, temazepam is a Schedule II controlled drug under the Psychotropic Substances Act. Possession and distribution of the drug is illegal.

In the United Kingdom, temazepam is a Class C controlled drug under the Misuse of Drugs Act 1971 (Schedule 3 under the Misuse of Drugs Regulations 2001).^[72][73] If prescribed privately (not on the NHS), temazepam is available only by a special controlled drug prescription form (FP10PCD) and pharmacies are obligated to follow special procedures for storage and dispensing.^[74] Additionally, all manufacturers in the UK have replaced the gel-capsules with solid tablets.

In the USA, temazepam is a Schedule IV drug and is only available by prescription. Specially coded prescriptions may be required in certain States.

See also

• Long term effects of benzodiazepines
• Benzodiazepine withdrawal syndrome
• Benzodiazepine dependence
• Benzodiazepines
• Flunitrazepam
• Nitrazepam
• Nimetazepam

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External links

• Professor Heather Ashton, Benzodiazepines; How they work and How to Withdraw
• Rx-List - Temazepam
• Inchem - Temazepam
• Medline Plus (US Government supported website) entry for Temazepam
• Active Ingredients information