Temazepam

Temazepam (marketed under brand names Restoril, Euhypnos, Normison, Remestan, Tenox and Norkotral) is an intermediate-acting 3-hydroxy benzodiazepine. It is generally prescribed for the short-term treatment of severe or debilitating sleeplessness in patients who have difficulty falling asleep or maintaining sleep. In addition, temazepam has anxiolytic, anticonvulsant, and skeletal muscle relaxant properties.

History

Temazepam was first synthesized in 1964, but it first came into use in 1969 when its ability to counter insomnia was realized. 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.

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. As a premedication before surgery, temazepam decreased cortisol in elderly patients. In rats, temazepam triggered the release of vasopressin into paraventricular nucleus of the hypothalamus and decreased the release of ACTH under stress.

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 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.

Temazepam has very good bioavailability with 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%).

Indications

Temazepam is a hypnotic agent. In sleep laboratory studies, temazepam significantly decreased the number of nightly awakenings.

Temazepam is officially indicated for severe insomnia and other severe or disabling sleep disorders. The prescribing guidelines limit prescribing of hypnotics to two-four weeks due to concerns of tolerance and physical dependence.

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

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; temazepam should therefore generally not be given to individuals under 18 years of age, and should not be used at all in children under 6 months old.

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.

Patients at a high risk for abuse and dependence

Since benzodiazepines can be abused and lead to psychological 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 psychological dependence.

Adverse effects

Common

The typical side effects of typical of hypnotic benzodiazepines are related to CNS depression, and include somnolence, dizziness, fatigue, ataxia, headache, lethargy, impairment of memory and learning, increased reaction time and impairment of motor functions (including coordination problems), 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 incidences of euphoria of 1.5%, much more rarely reported than headaches and diarrhea. Anterograde amnesia may also develop, as may respiratory depression in higher doses.

Less common

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.

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 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

As other benzodiazepines, temazepam produces additive CNS depressant effects when co-administered with other medications which themselves produce CNS depression, such as barbiturates, alcohol, 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).

Tolerance and physical dependence

Tolerance

Chronic or excessive use of temazepam may cause drug tolerance, which can develop rapidly, so this drug is therefore not recommended for long-term use. 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. 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. Some studies have observed tolerance to temazepam after as little as one week's use. 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. Other studies examined the use of temazepam over six days and saw no evidence of tolerance. 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. In one study the drug sensitivity of people who had used temazepam for 1–20 years was no different from that of controls. In 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. The Journal of Clinical Sleep Medicine published a paper which had carried out a systematic review of the medical literature concerning insomnia medications and raised concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs that are used as hypnotics in humans. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies and that 24% of authors did not disclose being funded by the drug companies in their published paper when they were funded by the drug companies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. 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.

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. There are rare reports in the medical literature of psychotic states developing after abrupt withdrawal from benzodiazepines, even from therapeutic doses. Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions. 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.

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 has the highest rate of drug intoxication, including overdose, among the common benzodiazepines. Temazepam and nitrazepam were the two benzodiazepines most commonly detected in overdose-related 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. 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). 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 relatively higher toxicity.

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

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 (4.46%) resulted in major toxicity and 243 (0.35%) resulted in death. Temazepam was the most frequently encountered benzodiazepine in the cases which resulted in death. Temazepam was also one of two benzodiazepines most frequently encountered in the cases which resulted in major toxicity.

Abuse

North America

Temazepam abuse 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. North America never had a serious problem with temazepam abuse, but is becoming increasingly vulnerable to the illicit trade of temazepam.

Australia

Temazepam accounts for most benzodiazepine sought by forgery of prescriptions and through pharmacy burglary in Victoria. Due to intravenous abuse, the Australian government decided to put it under a more restrictive schedule than it previously was, and since March 2004 temazepam capsules have been withdrawn from the Australian market. 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.

United Kingdom

Temazepam was the most widely-abused legal prescription drug, stated 1987. 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 abusers in seven cities and had been injected from preparations of capsules, tablets and syrup. 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.

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.

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 Norway, temazepam is a "narcotic" drug (According to the norwegian narcotics list), all benzodiazepine derivates and analogues are considered narcotic and temazepam is not available by prescription. Small amounts are punishable with a fine.

In Sweden, temazepam is a "narcotic" drug under the Narcotics Drugs Act (1968). Temazepam is banned in Sweden and possession and distribution of even small amounts is punishable by a prison sentence and a fine.

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 8 controlled drug, requiring a medical doctor's 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. 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. Penalties for its possession and/or trafficking in some countries are more severe than for most other benzodiazepines.