Diazepam

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Note. The following terms have been used as ‘street names’ or slang names for various forms of diazepam: Benzo; Blue; Blues; Drunk pills; La Roche; Ludes; Mother’s little helper; Mother’s little helpers; Pami; Roaches; Roachies; Roche; V V’s blues; Vallies; Vals.

Pharmacopoeias. In China, Europe, International, Japan, US

European Pharmacopoeia, 6th ed. (Diazepam). A white or almost white, crystalline powder. Very slightly soluble in water soluble in alcohol. Protect from light.

The United States Pharmacopeia 31, 2008 (Diazepam). An off-white to yellow, practically odourless, crystalline powder. Soluble 1 in 333 of water, 1 in 16 of alcohol, 1 in 2 of chloroform, and 1 in 39 of ether. Store in airtight containers. Protect from light.

Incompatibility.

Incompatibility has been reported between diazepam and several other drugs. Manufacturers of diazepam injection (Roche and others) have advised against its admixture with other drugs.

Sorption.

Substantial adsorption of diazepam onto some plastics may cause problems when giving the drug by continuous intravenous infusion. More than 50% of diazepam in solution may be adsorbed onto the walls of PVC infusion bags and their use should, therefore, be avoided. Giving sets should contain the minimum amount of PVC tubing and should not contain a cellulose propionate volume-control chamber. Suitable materials for infusion containers, syringes, and giving sets for diazepam include glass, polyolefm, polypropylene, and polyethylene.

Stability.

Care should be observed when diluting diazepam injections for infusion because of problems of precipitation. The manufacturer’s directions should be followed regarding diluent and concentration of diazepam and all solutions should be freshly prepared.

Dependence and Withdrawal

The development of dependence is common after regular use of benzodiazepines, even in therapeutic doses for short periods. Dependence is particularly likely in patients with a history of alcohol or drug abuse and in those with marked personality disorders. Benzodiazepines should therefore be withdrawn by gradual reduction of the dose after regular use for even a few weeks the time needed for withdrawal can vary from about 4 weeks to a year or more. The extent to which tolerance occurs has been debated but appears to involve psychomotor performance more often than anxiolytic effects. Drug-seeking behaviour is uncommon with therapeutic doses of benzodiazepines. High doses of diazepam and other benzodiazepines, injected intravenously, have been abused for their euphoriant effects.

Benzodiazepine withdrawal syndrome.

Development of dependence to benzodiazepines cannot be predicted but risk factors include high dosage, regular continuous use, the use of benzodiazepines with a short half-life, use in patients with dependent personality characteristics or a history of drug or alcohol dependence, and the development of tolerance. The mechanism of dependence is unclear but may involve reduced gamma-aminobutyric acid (GABA) activity resulting from down-regulation of GABA receptors.

Symptoms of benzodiazepine withdrawal include anxiety, depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual, and auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, palpitations, mild systolic hypertension, tachycardia, and orthostatic hypotension. Rare and more serious symptoms include muscle twitching, confusional or paranoid psychosis, convulsions, hallucinations, and a state resembling delirium tre-mens. Broken sleep with vivid dreams and increased REM sleep may persist for some weeks after withdrawal of benzodiazepines.

Symptoms typical of withdrawal have occurred despite continued use of benzodiazepines and have been attributed either to the development of tolerance or, as in the case of very short-acting drugs such as triazolam, to rapid benzodiazepine elimination. Pseudowithdrawal has been reported in patients who believed incorrectly that their dose of benzodiazepine was being reduced. Benzodiazepine withdrawal syndrome can theoretically be distinguished from these reactions and from rebound phenomena (return of original symptoms at greater than pretreatment severity) by the differing time course.

A withdrawal syndrome is characterised by its onset, by the development of new symptoms, and by a peak in intensity followed by resolution. Onset of withdrawal symptoms depends on the half-life of the drug and its active metabolites. Symptoms can begin within a few hours after withdrawal of a short-acting benzodiazepine, but may not develop for up to 3 weeks after stopping a longer-acting benzodiazepine. Resolution of symptoms may take several days or months. The dependence induced by short- and long-acting benzodiazepines appears to be qualitatively similar although withdrawal symptoms may be more severe with short-acting benzodiazepines. Rebound effects are also more likely with short-acting benzodiazepines.

Rebound and withdrawal symptoms develop particularly rapidly with the very short-acting drug triazolam. With increased awareness of the problems of benzodiazepine dependence, emphasis has been placed on prevention by proper use and careful patient selection. For example, the UK CSMhas recommended that benzodiazepines should be reserved for the short-term relief (2 to 4 weeks only) of anxiety that is severe, disabling, or subjecting the individual to unacceptable distress and is occurring alone or in association with insomnia or short-term psychosomatic, organic, or psychotic illness. These recommendations are similar to those of the UK Royal College of Psychiatrists.

Withdrawal from long-term benzodiazepine use should generally be encouraged. Established dependence can be difficult to treat the patient should have professional and family support and behavioural therapy may be helpful. Withdrawal in a specialist centre may be required for some patients. Since abrupt withdrawal of benzodiazepines may result in severe withdrawal symptoms dosage should be tapered.

The BNF considers that benzodiazepines can be withdrawn in steps of about one-eighth of the daily dose every fortnight (range one-tenth to one-quarter). There are no comparative studies of the efficacy of various withdrawal schedules and in practice the protocol should be titrated against the response of the patient. Clinicians often favour transferring the patient to an equivalent dose of diazepam given at night and the following rough dosage equivalents to diazepam 5 mg have been recommended in the United Kingdom:

• chlordiazepoxide 15 mg
• loprazolam 0.5 to 1 mg
• lorazepam 500 micrograms
• lormetazepam 0.5 to 1 mg
• nitrazepam 5 mg
• oxazepam 15 mg
• temazepam 10 mg

The daily dosage of diazepam can then be reduced in steps of 0.5 to 2.5 mg at fortnightly intervals. If troublesome abstinence effects occur the dose should be held level for a longer period before further reduction increased dosage should be avoided if possible. It is better to reduce too slowly than too quickly. Time required for withdrawal can vary from about 4 weeks to a year or longer. In many cases the rate of withdrawal is best decided by the patient.

Adjuvant therapy should generally be avoided. Although a beta blocker may be given for prominent sympathetic overactivity the BNF recommends that this be tried only if other measures fail antidepressants should be used only for clinical depression or panic attacks. Antipsychotic drugs should be avoided as they may aggravate symptoms.

Symptoms gradually improve after withdrawal but postwithdrawal syndromes lasting for several weeks or months have been described. Continued support may be required for the first year after withdrawal to prevent relapse.

Adverse Effects

Drowsiness, sedation, muscle weakness, and ataxia are the most frequent adverse effects of diazepam use. They generally decrease on continued dosage and are a consequence of CNS depression. Less frequent effects include vertigo, headache, confusion, depression (but see Effects on Mental Function, below), slurred speech or dysarthria, changes in libido, tremor, visual disturbances, urinary retention or incontinence, gastrointestinal disturbances, changes in salivation, and amnesia. Some patients may experience a paradoxical excitation which may lead to hostility, aggression, and disinhibi-tion. Jaundice, blood disorders, and hypersensitivity reactions have been reported rarely. Respiratory depression and hypotension occasionally occur with high dosage and parenteral use.

Pain and thrombophlebitis may occur with some intravenous formulations of diazepam raised liver enzyme values have occurred.

Overdosage can produce CNS depression and coma or paradoxical excitation. However, fatalities are rare when taken alone.

Use of diazepam in the first trimester of pregnancy has occasionally been associated with congenital malformations in the infant but no clear relationship has been established. This topic is reviewed under Pregnancy below. Use of diazepam in late pregnancy has been associated with intoxication of the neonate.

Carcinogenicity.

The International Agency for Research on Cancer concluded that there was sufficient evidence from human studies that diazepam did not produce breast cancer, and that there was inadequate data to support its potential carcinogenicity at other sites. For most other benzodiazepines the lack of human studies meant that the carcinogenic risk to humans was not classifiable. However, there appeared to be sufficient evidence of carcinogenicity in animal studies for oxazepam to be classified as possibly carcinogenic in humans.

Effects on body temperature.

Studies in healthy subjects’ indicate that benzodiazepines can reduce body temperature. After a single dose of diazepam 10 mg by mouth in 11 subjects, body temperature on exposure to cold fell to a mean of 36.93° compared with 37.08° on exposure without the drug. An 86-year-old woman developed hypothermia after being given nitrazepam 5 mg. After recovery she was mistakenly given another 5-mg dose of nitrazepam and again developed hypothermia. Midazolam (given as anaesthetic premedication) also produces modest decreases in core body temperature, which can be abolished by atropine, but its effects are negligible compared with other elements of the anaesthetic regimen. Hypothermia has been reported in the neonates of mothers given benzodiazepines during the late stages of pregnancy.

Effects on endocrine function.

Galactorrhoea with normal serum-prolactin concentrations has been noted in 4 women taking benzodiazepines. Gynaecomastia has been reported in a man taking up to 140 mg diazepam daily and in 5 men taking diazepam in doses of up to 30 mg daily. Serumoestradiol concentrations were raised in the latter group. However, raised plasma-testosterone concentrations have also been observed in men taking diazepam 10 to 20 mg daily for 2 weeks.

Effects on the eyes.

Brown opacification of the lens occurred in 2 patients who took diazepam 5 mg or more daily by mouth over several years. Severe visual field loss associated with very high doses (100 mg) of diazepam has also been described.

Effects on the liver.

Cholestatic jaundice and focal hepatic necrosis with intracellular cholestasis have been associated with the use of diazepam.

Effects on mental function.

The effects of benzodiazepines on psychomotor performance in laboratory tests are not easily extrapolated to the clinical situation. For example postoperative cognitive dysfunction in the elderly does not seem to be related to benzodiazepine concentration in the blood. Concern has been expressed over the possible effects of long-term benzodiazepine use on the brain. A detailed study found that performance of tasks involving visual-spatial ability and sustained attention was poor in patients taking high doses of benzodiazepines for long periods of time.

There was no evidence of impairment in global measures of intellectual functioning such as memory, flexibility, and simple reaction time. The authors could draw no conclusions about the effect of benzodiazepine withdrawal on these changes. A study of 17 long-term users of benzodiazepines has indicated a dose-dependent increase in cerebral ventricle size.

Sexual fantasies have been reported in women sedated with intravenous diazepam or midazolam. These appear to be dose-related.

The view that benzodiazepines can cause depression, albeit infrequently, has been queried.

Adverse effects of alprazolam on behaviour have also been reviewed.

Effects on the nervous system.

There are a few isolated reports of extrapyramidal symptoms in patients taking benzodiazepines. Benzodiazepines have been used to treat such symptoms induced by antipsychotics (see Extrapyramidal Disorders under Chlorpromazine).

ENCEPHALOPATHY.

Prolonged use of midazolam with fentanyl has been associated with encephalopathy in infants sedated under intensive care.

Effects on sexual function.

The sedative effects of benzodiazepines may reduce sexual arousal and lead to impotence in some patients. Conversely sexual performance may be improved by therapy if it was previously impaired by anxiety. Increased libido and orgasmic function has been reported in 2 women after withdrawal of long-term benzodiazepine use.

Effects on skeletal muscle.

In a report of 2 patients who developed rhabdomyolysis secondary to hyponatraemia it was suggested that the use of benzodiazepines might have contributed to the rhabdomyolysis. Of 8 reported cases of rhabdomyolysis associated with hyponatraemia, 5 had received benzodiazepines. Rhabdomyolysis associated with intravenous drug abuse of oral temazepam formulations has also been reported.

Effects on the skin.

There have been rare reports of cutaneous reactions to benzodiazepines, including contact dermatitis, fixed drug eruptions, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Analysis by the Boston Collaborative Drug Surveillance Program of data on 15 438 patients hospitalised between 1975 and 1982 detected 2 allergic skin reactions attributed to diazepam among 4707 recipients of the drug. A reaction rate of 0.4 per 1000 recipients was calculated from these figures.

Hypersensitivity.

Hypersensitivity reactions including anaphylaxis are very rare after use of diazepam. Reactions have been attributed to the polyoxyl castor oil vehicle used for some parenteral formulations. There is also a report of a type I hypersensitivity reaction to a lipid emulsion formulation of diazepam. See also under Effects on the Skin, above.

Local reactions.

Ischaemia and gangrene have been reported after accidental intra-arterial injection of diazepam. Clinical signs may not occur until several days after the event. Pain and thrombophlebitis after intravenous use may be similarly delayed. Local reactions after intravenous injection have been attributed to the vehicle, and have been observed more often when diazepam is given as a solution in propylene glycol than in polyethoxylated castor oil. An emulsion of diazepam in soya oil and water has been associated with a lower incidence of local reactions.

Pain and phlebitis may also be caused by precipitation of diazepam at the site of infusion. Arterial spasm experienced by a patient given diazepam intravenously was probably due to pressure from a cuff on the arm being inflated causing extravasation of diazepam out of the vein and into the radial artery. Local irritation has also occurred after rectal use of diazepam. For a report of the exacerbation of diazepam-induced thrombophlebitis by penicillamine.

Overdosage.

Impairment of consciousness is fairly rapid in poisoning by benzodiazepines. Deep coma or other manifestations of severe depression of brainstem vital functions are rare more common is a sleep-like state from which the patient can be temporarily roused by appropriate stimuli. There is usually little or no respiratory depression, and cardiac rate and rhythm remain normal in the absence of anoxia or severe hypotension. Since tolerance to benzodiazepines develops rapidly, consciousness is often regained while concentrations of drug in the blood are higher than those which induced coma.

Anxiety and insomnia can occur during recovery from acute overdosage, while a full-blown withdrawal syndrome, possibly with major convulsions, can occur in patients who have previously been chronic users. During the years 1980 to 1989, 1576 fatal poisonings in Britain were attributed to benzodiazepines.Of these, 891 were linked to overdosage with benzodiazepines alone and another 591 to overdosage combined with alcohol. A comparison of these mortality statistics with prescribing data for the same period, to calculate a toxicity index of deaths per million prescriptions, suggested that there were differences between the relative toxicities of individual benzodiazepines in overdosage. A later study of another 303 cases of benzodiazepine poisoning supported these findings of differences in toxicity as well as pointing to the relative safety of the benzodiazepines in overdosage.

Treatment of Adverse Effects

The treatment of benzodiazepine overdosage is generally symptomatic and supportive. Activated charcoal may be given orally within one hour of ingestion of more than 100 mg of diazepam (or its equivalent) by adults, or 1 mg/kg by children, provided they are not too drowsy. Gastric lavage is generally not advocated in overdoses of benzodiazepines alone. The specific benzodiazepine antagonist, flumazenil, is rarely required and can be hazardous, particularly in mixed overdoses involving tricyclic antidepressants or in benzodiazepine-dependent patients the UK Poisons Information Service, contra-indicates its use in mixed overdoses. The BNFrecommends that flumazenil should be used on expert advice only.

Precautions

Diazepam should be avoided in patients with pre-existing CNS depression or coma, respiratory depression, acute pulmonary insufficiency, myasthenia gravis, or sleep apnoea, and used with care in those with chronic pulmonary insufficiency Diazepam should be given with care to elderly or debilitated patients who may be more prone to adverse effects. Caution is required in patients with muscle weakness, or those with hepatic or renal impairment, who may require reduced doses its use should be avoided in severe hepatic impairment. The sedative effects of diazepam are most marked during the first few days of use affected patients should not drive or operate machinery (see also Driving, below). Monitoring of cardiorespiratory function is generally recommended when benzodiazepines are used for deep sedation.

Diazepam is not appropriate for the treatment of chronic psychosis or for phobic or obsessional states. Di-azepam-induced disinhibition may precipitate suicide or aggressive behaviour and it should not, therefore, be used alone to treat depression or anxiety associated with depression it should also be used with care in patients with personality disorders. Caution is required in patients with organic brain changes particularly arteriosclerosis. In cases of bereavement, psychological adjustment may be inhibited by diazepam. Many manufacturers of diazepam and other benzodiazepines advise against their use in patients with glaucoma, but the rationale for this contra-indication is unclear.

For warnings on benzodiazepines during pregnancy and breast feeding, see below.

Dependence characterised by a withdrawal syndrome may develop after regular use of diazepam, even in therapeutic doses for short periods (see above) because of the risk of dependence, diazepam should be used with caution in patients with a history of alcohol or drug addiction.

Since hypotension and apnoea may occur when benzodiazepines are given intravenously it has been recommended that this route should only be used when facil-ities for reversing respiratory depression with mechanical ventilation are available. Patients should remain supine and under medical supervision for at least one hour after intravenous injection. Intravenous infusion is best undertaken in specialist centres with intensive care facilities where close and constant supervision can be undertaken.

Administration.

INTRAVENOUS.

Prolonged use of high-dose intravenous infusions of diazepam preparations containing benzyl alcohol can result in benzyl alcohol poisoning. (Such preparations should never be used in neonates).

Breast feeding.

The American Academy of Pediatrics considers that benzodiazepine use by nursing mothers for long periods was a cause for concern anxiolytic drugs appear in breast milk and could conceivably alter CNS function in the infant both in the short and long term. Similarly, in the UK the CSM has recommended that benzodiazepines should not be given to breast-feeding mothers. In one reviewer’s opinion the limited distribution into breast milk did not constitute a hazard to the breast-fed infant but the infant should be monitored for sedation and the inability to suckle.

Another group has also reported a low incidence of toxicity and adverse effects in the breast-fed infants of mothers taking psychotropic drugs including benzodiazepines. It has been suggested that if a benzodiazepine must be used during breast feeding it would be preferable to use a short-acting drug with minimal distribution into breast milk and inactive metabolites oxazepam, lorazepam, alprazolam, or midazolam might be suitable.

Cardiovascular disorders.

See under Respiratory System Disorders, below.

Driving.

Most benzodiazepines can adversely affect parameters of driving performance in healthy subjects. It is not entirely clear to what extent benzodiazepines contribute to the risk of driving accidents. A large case-control cohort study in elderly drivers suggested that the risk of accidents was increased in those who took longeracting benzodiazepines. However, younger drivers are more susceptible to the effects of benzodiazepines or zopiclone as a group the risk is increased by alcohol consumption.

Patients affected by drowsiness while taking benzodiazepines should not drive or operate machinery. In the UK, it is an offence to drive while unfit due to the influence of any drug, and benzodiazepines are considered to be the most likely psychotropic medication to impair driving performance, particularly the long-acting compounds. However, it is also noted that drivers with psychiatric illnesses may be safer when well controlled with regular medication than when ill. Drowsiness often becomes less troublesome with continued use of these drugs.

The elderly.

Old age may alter the distribution, elimination, and clearance of benzodiazepines. Metabolic clearance of benzodiazepines metabolised principally by oxidation appears to be reduced but not clearance of those biotransformed by glucuronide conjugation or nitroreduction. Prolonged half-life in the elderly may be a result of such a decrease in clearance or of an increase in the volume of distribution. The clinical consequence of these changes depends on factors such as dosage schedule and extent of first-pass extraction by the liver.

Irrespective of pharmacokinetic changes, the elderly may exhibit increased sensitivity to acute doses of benzodiazepines. Impairment of memory, cognitive function, and psychomotor performance and behaviour disinhibition may be more common than with younger patients. Long-term use commonly exacerbates underlying dementia in elderly patients The upshot of the pharmacokinetic and pharmacodynamic changes of benzodiazepines in the elderly is that adverse effects may be more frequent in these patients and lower doses are commonly required.

An epidemiological study of persons 65 years and older found an increased rate of hip fracture among current users of long-acting benzodiazepines (chlordiazep oxide, clorazepate, diazepam, and fiurazepam), but not among users of short-acting drugs (alprazolam, bromazepam, lorazepam, oxazepam, and triazolam) A case-control study of patients with falls leading to femur fractures suggested that the most important factor in increasing risk was the dose of benzodiazepine.

However, another case-control study found no correlation between hip fracture and benzodiazepines either as a group or according to half-life or to characterisation as an anxiolytic or a hypnotic there might, though, be an increase in risk with lorazepam. There was also an increased risk associated with use of two or more benzodiazepines. Nonetheless, if use of a benzodiazepine is considered necessary in elderly patients, a short-acting drug is to be preferred. It should also be remembered that the elderly are at increased risk of sleep-related breathing disorders, such as sleep apnoea and the use of hypnotics such as benzodiazepines should be avoided in these patients (see Respiratory System Disorders, below).

Hangover effects.

Long-acting benzodiazepines accumulate in the body to a greater extent than ones with a shorter half-life. Although this might be expected to increase the frequency of daytime sedation and impairment of performance (so-called hangover effects) after a hypnotic dose, such a straightforward relationship has not always been observed in practice. Anterograde amnesia is more common with short-acting drugs such as triazolam ‘traveller’s amnesia’ has been used to describe amnesia in persons taking benzodiazepines for sleep disturbances resulting from jet lag.

High-altitude disorders.

Sleep may be impaired at high altitude due to frequent arousals associated with pronounced oxygen desaturation and periodic breathing. Traditional advice has been that sedatives should not be given at high altitude. Caution may also be warranted at moderate altitudes especially in non-acclimatised climbers. It has been argued that since diazepam, and possibly other sedatives, blunt the hypoxic ventilatory response, sleep hypoxaemia might be exacerbated.

A small study has suggested that small doses of a short-acting benzodiazepine, such as temazepam, might actually improve the subjective quality of sleep and reduce episodes of arterial desaturation without changing mean oxygen saturation. However the possibility of an interaction between acetazolamide taken for prophylaxis or treatment of acute mountain sickness and the benzodiazepine should be borne in mind ventilatory depression in a mountain climber with acute mountain sickness was considered to be due to the potentiation of triazolam by acetazolamide.

Neonates.

A retrospective review of records from 63 infants given lorazepam or midazolam in a neonatal intensive-care unit indicated that there were 14 cases of adverse effects associated with benzodiazepine use (seizures in 6 cases, hypotension in 5, and respiratory depression in 3). Seven of these were associated with intravenous bolus doses of lorazepam and the remainder with continuous midazolam infusions. Despite the limitations of the study, the incidence of adverse effects in this group seemed high, and the authors recommended that benzodiazepine use in neonates be accompanied by close monitoring.

Nervous system disorders.

Benzodiazepines can reduce cerebral perfusion pressure and blood oxygenation to an extent that results in irreversible neurological damage in patients with head injuries. Consequently, they should be given with great care to such patients. Their use should be avoided for the control of seizures in patients with head injuries or other acute neurological lesions as these patients can be managed effectively with phenytoin.

Porphyria.

Diazepam has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients. Intravenous diazepam has been used successfully, however, to control status epilepticus occurring after the acute porphyric attack. For a discussion of the management of seizures associated with acute porphyric attacks.

Pregnancy.

Benzodiazepines have been widely used in pregnant patients. Use of benzodiazepines in the third trimester and during labour seems to be associated in some infants with neonatal withdrawal symptoms or the floppy infant syndrome. Also a small number exposed in utero to benzodiazepines have shown slow development in the early years but by 4 years of age most had developed normally, and for those that had not it was not possible to prove a cause-effect relationship with benzodiazepine exposure.

In a meta-analysis of live births after benzodiazepine use during the first trimester of pregnancy, pooled data from cohort studies showed no apparent association between benzodiazepine use and the risk of major malformations or oral cleft alone. There was, however, a small but significantly increased risk of oral cleft according to data from case-control studies. Although benzodiazepines did not appear to be a major human teratogen, use of ultrasonography was advised to rule out visible forms of cleft lip. The UK CSM has recommended that women of child-bearing potential prescribed benzodiazepines should be advised to contact the physician about stopping the drug if they intend to become, or suspect that they are, pregnant.

Respiratory system disorders.

Benzodiazepines may affect the control of ventilation during sleep and may worsen sleep apnoea or other sleep-related breathing disorders especially in patients with chronic obstructive pulmonary disease or cardiac failure. Risk factors for sleep apnoea, which often goes undiagnosed, include old age, obesity, male sex, postmenopausal status in women, and a history of heavy snoring. Although benzodiazepines may reduce sleep fragmentation, their long-term use may result in conversion from partial to complete obstructive sleep apnoea in heavy snorers or in short repetitive central sleep apnoea in patients with recent myocardial infarction.