本品副作用少。可有口干、无力等。
Restoril(Temazepam)
Temazepam (brand names Restoril and Normison, among others) is an intermediate-acting 3-hydroxy hypnotic of the benzodiazepine class of psychoactive drugs. It is the 3-hydroxy analogue of diazepam, and one of diazepam's primary active metabolites. In the US, temazepam is approved for the short-term treatment of insomnia. In addition, temazepam has anxiolytic (antianxiety), anticonvulsant, and skeletal muscle relaxant properties.[1][2][3]
Temazapam was patented in 1962 and came into medical use in 1969.[4] In 2016 it was the 185th most prescribed medication in the United States with more than 3 million prescriptions.[5]
Medical uses
In sleep laboratory studies, temazepam significantly decreased the number of nightly awakenings,[6] but has the drawback of distorting the normal sleep pattern.[7] It 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 a "no-go pill" to help aviators and special-duty personnel sleep in support of mission readiness. "Ground tests" are necessary prior to required authorization being issued to use the medication in an operational situation, and a 12-hour restriction is imposed on subsequent flight operation.[9] The other hypnotics used as "no-go pills" are zaleplon and zolpidem, which have shorter mandatory recovery periods.[9]
Contraindications
Use of temazepam should be avoided, when possible, in individuals with these 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 two)
Severe renal deficiencies (e.g. patients on dialysis)
Sleep apnea[10]
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 six months old. Benzodiazepines also require special caution if used in the elderly, alcohol- or drug-dependent individuals, and individuals with comorbid psychiatric disorders.[11]
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.[12] The smallest possible effective dose should be used in elderly or very ill patients, as a risk of apnea and/or cardiac arrest exists. This risk is increased when temazepam is given concomitantly with other drugs that depress the central nervous system(CNS).[13]
People at a high risk for misuse and dependence
Because benzodiazepines can be abused and lead to dependence, their use should be avoided in people in certain particularly high-risk groups. These groups include people with a history of alcohol or drug dependence, people significantly struggling with their mood or people with longstanding mental health difficulties. If temazepam must be prescribed to people in these groups, they should generally be monitored very closely for signs of misuseand development of dependence.[8]
Adverse effects
Common
Side effects typical of hypnotic benzodiazepines are related to CNS depression, and include somnolence, sedation, drunkenness, dizziness, fatigue, ataxia, headache, lethargy, impairment of memory and learning, longer reaction time and impairment of motor functions (including coordination problems),[14] slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, blurred vision (in higher doses), and inattention. Euphoria was rarely reported with its use. According to the U.S. Food and Drug Administration, temazepam had an incidence of euphoria of 1.5%, much more rarely reported than headaches and diarrhea.[13] Anterograde amnesia may also develop, as may respiratory depression in higher doses.
A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking Temazepam or other hypnotic drugs compared to those taking a placebo.[15]
Less common
Hyperhydrosis, hypotension, burning eyes, increased appetite, 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.
Like all benzodiazepines, 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 occasionally occur. These include sleepiness, impaired psychomotor and cognitive functions which may persist into the next day, impaired driving ability, and possible increased risks of falls and hip fractures, especially in the elderly.[16]
Tolerance
Chronic or excessive use of temazepam may cause drug tolerance, which can develop rapidly,[17] so this drug is not recommended for long-term use.[13][18] 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 three to 14 days.[19] In use longer than one to two weeks, tolerance will rapidly develop towards the ability of temazepam to maintain sleep, resulting in a loss of effectiveness.[20] Some studies have observed tolerance to temazepam after as little as one week's use.[21]Another study examined the short-term effects of the accumulation of temazepam over seven days in elderly inpatients, and found little tolerance developed during the accumulation of the drug.[22] Other studies examined the use of temazepam over six days and saw no evidence of tolerance.[23][24] A study in 11 young male subjects showed significant tolerance occurs to temazepam's thermoregulatory effects and sleep inducing properties after one week of use of 30-mg temazepam. Body temperature is well correlated with the sleep-inducing or insomnia-promoting properties of drugs.[25]
In one study, the drug sensitivity of people who had used temazepam for one to 20 years was no different from that of controls.[26] 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 the drug might become more effective over time.[27][28][29]
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 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 involving toxicity, tolerance and dependence, as well as to controversy over long-term efficacy, wise prescribers should restrict benzodiazepines to a few weeks and avoid continuing prescriptions for months or years.[30] A review of the literature found the nonpharmacological treatment options were a more effective treatment option for insomnia due to their sustained improvements in sleep quality.[31]
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, 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, are recommended to prevent severe withdrawal syndromes from developing. Other hypnotic benzodiazepines are not recommended.[32] A study in rats found temazepam is cross tolerant with barbiturates and is able to effectively substitute for barbiturates and suppress barbiturate withdrawal signs.[33]Rare cases are reported in the medical literature of psychotic states developing after abrupt withdrawal from benzodiazepines, even from therapeutic doses.[34] Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions.[35] Patients who were treated in the hospital with temazepam or nitrazepam have continued taking these after leaving the hospital. Hypnotic uses in the hospital were recommended to be limited to five nights' use only, to avoid the development of withdrawal symptoms such as insomnia.[36]
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, sedation
§ Coma
§ Death
Temazepam had the highest rate of drug intoxication, including overdose, among common benzodiazepines in cases with and without combination with alcohol in a 1985 study.[40] Temazepam and nitrazepam were the two benzodiazepines most commonly detected in overdose-related deaths in an Australian study of drug deaths.[41] 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).[42]
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 than other benzodiazepines (odds ratio 1.86). The authors noted several factors, such as differences in potency, receptor affinity, and rate of absorption between benzodiazepines, could explain this higher toxicity.[40] 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.[43]
