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Benzodiazepine

Benzodiazepine
Benzodiazepines Benzodiazepine List of benzodiazepines Benzodiazepine overdose Benzodiazepine dependence Benzodiazepine withdrawal syndrome Long term effects of benzodiazepines intermediate acting benzodiazepines are preferred for the treatment of insomnia or those at risk of drug accumulation, for example the elderly or those with severe liver disorders. Longer acting benzodiazepines are preferred for the treatment of anxiety. Some benzodiazepines also have active metabolites which can contribute to drug accumulation.[4] The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach; it was introduced to the market in 1960 and quickly followed by diazepam (Valium). The therapeutic properties are mediated via the modulation of GABAA receptors, which results in a depressant or slowing down effect of the central nervous system.[5] The benzodiazepines largely replaced the barbiturates as the most commonly prescribed sedative hypnotics. However, the benzodiazepines are now beginning to be replaced by the nonbenzodiazepines especially in the treatment of insomnia.[6] Benzodiazepines are generally safe and effective in the short term, although cognitive impairments or paradoxical effects such as aggression or behavioural disinhibition occasionally occur. Their use in the longer term is not recommended due to their propensity to cause tolerance, physical dependence, addiction and a benzodiazepine withdrawal syndrome upon cessation of use. Benzodiazepines are also major drugs of abuse.[7][8][9] The elderly are at an increased risk of suffering from the adverse effects of benzodiazepines.[10][11] There is controversy concerning the safety of benzodiazepines in pregnancy. Much of this surrounds whether or not they are associated with major malformations. Benzodiazepines are not however, considered to be major teratogens but they can cause neonatal withdrawal effects.[12][13] Benzodiazepines are often taken in overdoses but are considered to be much less toxic in overdose than their predecessors the barbiturates.[14] When benzodiazepines are mixed with other CNS depressants such as alcohol or opiates, their overdose potential is greatly increased.

5-Phenyl-1,4-benzodiazepin-2(3H)-one forms the skeleton on many of the most common benzodiazepine pharmaceuticals, such as diazepam (chloro-substituted). The benzodiazepines (pronounced /ˌbɛnzoʊdaɪˈæzɨpiːn/, often abbreviated to "benzos") are a commonly prescribed class of sedative hypnotic psychoactive drugs with varying sedative, hypnotic, anxiolytic (antianxiety), anticonvulsant, muscle relaxant and amnesic properties.[1] These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms and alcohol withdrawal and for medical or dental proceedures.[2][3] Benzodiazepines vary in their elimination half life being categorised as either short acting, intermediate acting or long acting. Short acting and

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This is particularly problematic in the drug misusing community.[15][16]

Benzodiazepine
realised in the 1980s leading them to be regarded unpopularly. Benzodiazepines have a unique history, at least in the UK, in that they were responsible for the largest ever class action lawsuit involving 14,000 patients and 18,000 law firms against the drugs manufacturers, alleging that they knew of the dependence potential of benzodiazepines but intentionally withheld this information from doctors. At the same time there were 117 general practitioners and 50 health authorities also being sued by patients to recover damages they incurred as a result of benzodiazepine dependence and withdrawal. This led to some doctors requiring a signed consent form from their patients and recommendations that all patients are adequately warned of the dependence and withdrawal problems before starting benzodiazepines.[18] The court case against the drug manufacturers never reached conclusion, collapsing due to legal aid being withdrawn and allegations of conflicts of interest of consultant psychiatrists who were case experts. The benzodiazepine litigation led to changes in the British law making class action law suits more difficult.[19] Before benzodiazepines entered the market, the barbiturates were the most commonly prescribed sedative hypnotic. The introduction of benzodiazepine sedative hypnotics led to a fall in barbiturate prescriptions and by the 1970s benzodiazepines had largely replaced the older drugs. A newer class of drugs called the nonbenzodiazepines are now beginning to replace the benzodiazepines, particularly in the treatment of insomnia. The nonbenzodiazepine class of drugs are molecularly distinct from benzodiazepines but they work on benzodiazepine receptors[6][20][21] and have similar risks and benefits to those of benzodiazepines. There have been suggestions that they may have a better side effect profile with less dependence potential. However, this is controversial and disputed by bodies such as the National Institute for Clinical Excellence.[22][23] Some research demonstrating the effectiveness of anticonvulsants as anxiolytics has been conducted lately and thus they are a potential rival to the benzodiazepines in the treatment of anxiety.[20]

History

Alprazolam "Bars" 2 mg tablets See also: Chlordiazepoxide The first benzodiazepine, chlordiazepoxide (Librium), was discovered serendipitously in 1954 by the Austrian scientist Leo Sternbach (1908–2005), working for the pharmaceutical company Hoffmann–La Roche, being discovered by accident while trying to synthesise a chemical dye. The chemical class synthesised was initially believed to be heptoxdiazines but determined to be quinazolone-3-oxides on further investigation. Sternbach had synthesised 40 derivatives of the quinazolone-3-oxides and tested 39 of them with disappointing results. He discontinued his work on the remaining compound Ro-5-0690, but he "rediscovered" it in 1957 when an assistant was cleaning up the laboratory. Although initially discouraged by his employer, Sternbach conducted further research that revealed the compound was a very effective tranquilizer, with hypnotic, anxiolytic, anticonvulsant and muscle relaxant effects. Three years later, chlordiazepoxide was marketed as a therapeutic benzodiazepine medication under the brand name Librium. Following chlordiazepoxide, diazepam hit the market in 1963 under the brand name Valium, followed by oxazepam (Serax) and nitrazepam (Mogadon) in 1965, clorazepate (Tranxene) in 1968, lorazepam (Ativan) in 1973, bromazepam (Lexotan) in 1974, clobazam (Frisium) in 1975 and flunitrazepam (Rohypnol) in 1978.[17] The benzodiazepines were initially greeted with hope and optimism by the medical profession but gradually concerns emerged, in particular the risk of dependence came to be

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Benzodiazepine
detoxification. They are also more prone to rebound effects if not tapered after alcohol detoxification.[32][33]

Therapeutic uses
The core chemical structure of "classical" benzodiazepine drugs is a fusion between the benzene and diazepine ring systems. Many of these drugs contain the 5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one substructure (Figure, above right). Benzodiazepines are structurally similar to several groups of drugs, some of which share similar pharmacological properties, including the quinazolinones, hydantoins, succinimides, oxazolidinediones, barbiturates and glutarimides.[24][25] Most benzodiazepines are administered orally; however, administration can also be given intravenously, intramuscularly or as a suppository.[26] Benzodiazepines have a number of therapeutic uses, are well-tolerated and are generally safe and effective drugs in the short term for a wide range of conditions.[27][28]

Anticonvulsants
Main anticonvulsant benzodiazepines • • • • • • clobazam clonazepam clorazepate diazepam lorazepam midazolam

Alcohol dependence
Benzodiazepines have been shown to be safe and effective and are the preferred choice in the management of alcohol withdrawal syndrome, particularly for preventing or treating seizures and delirium.[29] The choice of agent is based on pharmacokinetics. The most commonly used benzodiazepines in the management of alcohol withdrawal are diazepam (Valium) and chlordiazepoxide (Librium), two long-acting agents and lorazepam (Ativan) and oxazepam (Serax), two short-acting agents. The long half-life of diazepam and chlordiazepoxide makes withdrawal smoother and rebound withdrawal symptoms less likely to occur. The two intermediate-acting agents also have good efficacy in managing alcohol withdrawal. Chlordiazepoxide is the benzodiazepine of choice in uncomplicated alcohol withdrawal.[30] Oxazepam or lorazepam are often used in patients at risk of drug accumulation, particularly the elderly and those with cirrhosis because of their shorter half life. Lorazepam, is the only benzodiazepine with predictable intramuscular absorption (if intramuscular administration is necessary) and it is the most effective in preventing and controlling acute seizures.[31] However, the shorter acting benzodiazepines may be less effective than longer acting benzodiazepines in reducing alcohol withdrawal symptoms and may lead to break through seizures and thus are not recommended for outpatient

Benzodiazepines are potent anticonvulsants and have life-saving properties in the acute management of status epilepticus. The most commonly-used benzodiazepines for seizure control are lorazepam and diazepam. A metaanalysis of 11 clinical trials concluded that lorazepam was superior to diazepam in treating status epilepticus.[34] Although diazepam is much longer-acting than lorazepam, lorazepam has a more prolonged anticonvulsant effect. This is because diazepam is very lipid-soluble and highly protein-bound and has a very large distribution of unbound drug, resulting in diazepam’s having only a 20– to 30-minute duration of action against status epilepticus. Lorazepam, however, has a much smaller volume of distribution of unbound drug, which results in a more prolonged duration of action against status epilepticus. Lorazepam can therefore be considered superior to diazepam, at least in the initial stages of treatment of status epilepticus.[35] Long term prophylactic use of benzodiazepines for seizure disorders is limited due to a high risk of tolerance to the anticonvulsant effects of benzodiazepines.[36][37][38]

Anxiolytics
Main anxiolytic benzodiazepines • • • • • • • • • alprazolam bromazepam chlordiazepoxide clonazepam clorazepate diazepam lorazepam medazepam nordazepam

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• oxazepam • prazepam Benzodiazepines possess anti-anxiety properties and can be useful for the short-term treatment of severe anxiety. Benzodiazepines are usually administered orally for the treatment of anxiety; however, very occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks.[39] Benzodiazepines are also used to treat the acute panic caused by hallucinogen intoxication.[40] Tolerance can develop to the anxiolytic effects of benzodiazepines and there is also a risk of dependence. These factors limit the long term use of benzodiazepines in the treatment of anxiety disorders.[38][41] The World Council of Anxiety does not recommend benzodiazepines for the long term treatment of anxiety due to a range of problems associated with long term use of benzodiazepines including tolerance, psychomotor impairment, cognitive and memory impairments, physical dependence and a benzodiazepine withdrawal syndrome upon discontinuation of benzodiazepines.[42] Despite increasing focus on the use of antidepressants and other agents for the treatment of anxiety, benzodiazepines have remained a mainstay of anxiolytic pharmacotherapy due to their robust efficacy, rapid onset of therapeutic effect and generally favorable side effect profile.[43]

Benzodiazepine
benzodiazepines have strong sedative effects, are typically the most rapid-acting benzodiazepines and have strong receptor affinity. Longer-acting benzodiazepines, such as nitrazepam or quazepam, have side-effects that may persist into the next day, whereas the more intermediate-acting benzodiazepines (for example, temazepam or loprazolam) may have less "hangover" effects the next day.[44] The risks of tolerance and dependence with long term use of benzodiazepines for insomnia limits their use long term.[38] Long term use of benzodiazepine hypnotics and Z drugs coupled with over prescribing of these drugs represents an unjustifiable risk to the individual and to public health. The risks include dependence, accidents and other adverse effects. Gradual discontinuation of hypnotics leads to improved health without worsening of sleep. Preferably they should be prescribed for only a few days at the lowest effective dose and avoided altogether wherever possible in the elderly.[45]

Intensive care
Benzodiazepines can be very useful in intensive care to sedate patients receiving mechanical ventilation, or those in extreme distress or severe pain. Caution should be exercised in this situation due to the occasional scenario of respiratory depression and benzodiazepine overdose treatment facilities should be available.[46]

Insomnia
Main hypnotic benzodiazepines • • • • • • • • • • • • brotizolam estazolam flunitrazepam flurazepam flutoprazepam loprazolam lormetazepam midazolam nimetazepam nitrazepam temazepam triazolam

Muscular disorders
Benzodiazepines are well known for their strong muscle-relaxing properties and can be useful in the treatment of muscle spasms, for example, tetanus or spastic disorders[47] and restless legs syndrome.[48]

Premedication before procedures
Benzodiazepines are effective as premedication before surgery, administered a couple of hours before surgery, benzodiazepines bring about anxiety relief and also produce amnesia. Amnesia can be useful in this situation, as patients will not be able to remember any unpleasantness from surgery.[46] Diazepam or temazepam can be utilized in patients who are particularly anxious about dental procedures for example those with dental phobia.[46]

Hypnotic benzodiazepines are prescribed for the short-term management of severe or debilitating insomnia. Hypnotic

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Benzodiazepine
• Phobic or obsessional states • Chronic psychosis • Risk of worsening depression in mood disorders such as major depression and thus precipitating suicidal tendencies • Abrupt or over rapid withdrawal after long term use is contraindicated - risk of a severe benzodiazepine withdrawal syndrome developing with symptoms such as toxic psychosis, convulsions or a condition resembling delirium tremens. • History of physical dependence on benzodiazepines or other cross tolerant drugs such as other GABAergic sedative hypnotic drugs including alcohol - risk of rapid reinstatement of dependency.[67] Benzodiazepines increase craving for alcohol in problem alcohol consumers. Benzodiazepines also increase the volume of alcohol consumed by problem drinkers.[68] • Driving a motor vehicle, increased risk of road traffic accidents[69]

Psychiatry
Benzodiazepines can be very useful in the short-term treatment of acute psychosis such as schizophrenia or mania, bringing about rapid tranquillisation and sedation until the effects of lithium or neuroleptics (antipsychotics) take effect. They are also used to calm the acutely agitated individual in a psychiatric emergency and may if required be given via an intramuscular injection. Lorazepam is the benzodiazepine most commonly used but clonazepam is also sometimes used.[49][50][51][52] Benzodiazepines are occasionally prescribed off-label long term for panic disorder. There are no controlled clinical trials to demonstrate whether efficacy is maintained and not lost due to tolerance. Limited data from longitudinal studies have suggested benefit from long term benzodiazepines in panic disorder.[53]

Veterinary practice
Benzodiazepines are used in veterinary practice in the treatment of various disorders and conditions involving animals. As in humans, their usefulness comes from their tranquilizing, muscle relaxing, aggression inhibiting and anxiolytic properties.[54][55] Benzodiazepines are used before surgery as premedication for muscular relaxation[56] and during surgery in combination with other general anesthetic drugs such as ketamine.[57][58][59] They are effective in controlling tremors, seizures and epilepsy.[60][61][62] Midazolam can also be used along with other drugs in the sedation and capture of wild animals.[63]

Interactions
Individual benzodiazepines may have their own additional interactions which will vary from benzodiazepine to benzodiazepine.[70] The interactions of benzodiazepines as a drug class with other drugs are as follows;[64] • Alcohol and other CNS depressants synergistic adverse effects, with possible increase in depression and suicide.[71] • Antacids and anticholinergics - may slow down absorption which may slow down acute therapeutic effects. • Oral contraceptives, isoniazid - reduces the rate of elimination and thus the halflife increases leading to possibly excessive drug accumulation. • Rifampicin - increases rate of metabolism, thus shortening the elimination half-life of benzodiazepines • Digoxin - protein binding of diazepam altered causing increased digoxin levels • L-dopa - worsening of parkinsonian symptoms • Disulfiram - slows down the rate of metabolism leading to increased effects of benzodiazepines

Contraindications, interactions and side effects
Contraindications
The following are some important contraindications or situations where extreme caution should be exercised when prescribing benzodiazepines.[64][65][66] • Myasthenia gravis • Respiratory disorders • Severe hepatic insufficiency • Sleep apnoea syndrome • Pregnancy, labour and lactation • Breast feeding

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Benzodiazepine

Side-effects
The following list summarizes the side effects which may occur from use of benzodiazepines. Drowsiness, hypotension, dizziness, upset stomach, blurred vision, hangover effect (grogginess), headache, impaired alertness, confusion, falls or ataxia (particularly in the elderly), depression, impaired coordination, changes in heart rate, weakness. Floppy infant syndrome or neonatal withdrawal reactions are common if taken during third trimester of pregnancy. Less common side effects include; euphoria, amnesia, dissociation or depersonalisation, dreaming or nightmares, chest pain, paradoxical reactions, vision changes and very rarely jaundice.[65][72][73][74]

Physical dependence and withdrawal

Paradoxical reactions
See also: Paradoxical reaction#Benzodiazepines Severe paradoxical reactions such as physical aggression, criminal acts, impulsivity, violence and suicide can occur but are considered rare occurring in less than 1% of treated patients. However, a meta-analysis has shown that benzodiazepines are more likely to cause aggression than to alleviate it. Individuals who have a borderline personality disorder are at a greater risk of experiencing severe behavioral or psychiatric disturbances from benzodiazepines with up to 58% experiencing behavioural disinhibition.[75] Aggression and violent outbursts can also occur with benzodiazepines, particularly when they are combined with alcohol. Recreational abusers and patients on high-dosage regimes are at an even greater risk of experiencing paradoxical reactions to benzodiazepines.[76] Paradoxical reactions may occur in any individual on commencement of therapy and initial monitoring should take into account the risk of increase in anxiety or suicidal thoughts.[74] Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders.[77] The core element of a paradoxical rage reaction due to benzodiazepines is a partial deterioration from consciousness, which generates automatic behaviours, anterograde amnesia and uninhibited aggression and might occur from a disinhibiting serotonergic mechanism.[78]

Diazepam 2 mg and 5 mg diazepam tablets, which are commonly used in the treatment of benzodiazepine withdrawal. See also: Long term effects of benzodiazepines Long-term benzodiazepine usage, in general, leads to some form of tolerance and/or drug dependence with the appearance of a benzodiazepine withdrawal syndrome when the benzodiazepines are stopped or the dose is reduced. Long term use of benzodiazepines can cause a range of health problems in a proportion of people. The long term effects of benzodiazepines include impaired concentration and memory, sleep problems, depression, anxiety and panic attacks as well as agoraphobia.[11][79][80] Use of high doses (or high potency benzodiazepines) and those with a shorter half life increases the severity of the withdrawal syndrome. Use of other cross tolerant sedative hypnotics, eg barbiturates or alcohol are additive and thus also contribute to the severity of the withdrawal syndrome.[81] Withdrawal from chronic benzodiazepine use is usually beneficial due to improved health such as cognition and functioning with possible benefits in employment status. Abrupt withdrawal can be hazardous, therefore a gradual withdrawal is recommended. The opinion on the time needed to complete withdrawal differs but ranges from 4 weeks to several years. Aiming for within 6 months has been suggested.[9] However, due to individual variability some people may require longer than 6 months to complete withdrawal with some people requiring a year or more to complete withdrawal. Factors

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effecting the rate of withdrawal include severity of physical dependence, dose and length of use, type of benzodiazepine used, social and environmental factors as well as psychological and possibly genetic factors. Thus the rate of withdrawal can vary quite significantly and needs to be customised to the needs of the individual person.[82] Benzodiazepine dependence often occurs as a result of medical use but may also occur as a result of illicit misuse. Withdrawal effects may linger for many months or sometimes for a year or more after cessation of benzodiazepines. The withdrawal symptoms may include anxiety, irritability, sweating, tremor, sleep disorders, depersonalisation, derealisation, hypersensitivity to stimuli, abnormal sensation of movement and less commonly depression, suicidal behaviour, psychosis, seizures and delirium tremens.[83] Approximately 10% of patients will experience a notable protracted withdrawal syndrome. Protracted withdrawal symptoms tend to resemble those seen during the first couple of months of withdrawal but usually are of a sub acute level of severity. It is not known definitively whether such symptoms persisting long after withdrawal are related to true pharmacological withdrawal or whether they are due to structural neuronal damage as result of chronic use of benzodiazepines or withdrawal. Nevertheless such symptoms do typically gradually lessen as the months and years go by eventually disappearing altogether.[84]

Benzodiazepine
Benzodiazepine withdrawal symptoms occur when benzodiazepine dosage is reduced in people who are physically dependent on benzodiazepines. Abrupt or over-rapid dosage reduction can produce severe withdrawal symptoms. Withdrawal symptoms may also occur during a very gradual and slow dosage reduction but are typically less severe. Withdrawal symptoms may persist as part of a protracted withdrawal syndrome for many months after cessation of benzodiazepines.[85] Benzodiazepine withdrawal is best managed by transferring the physically-dependent patient to an equivalent dose of diazepam because it has the longest half-life of all of the benzodiazepines and is available in lowpotency, 2-mg tablets, which can be quartered for small dose reductions.[86] A further benefit of diazepam is that it is available in liquid form which allows for even smaller reductions if problems occur getting off the last few mgs.[9] The speed of benzodiazepine reduction regimes varies from person to person, but is usually done in 10% (of daily dose) stepped reductions. A slow withdrawal, under medical supervision by a physician that is knowledgeable about the benzodiazepine withdrawal syndrome, with the patient in control of dosage reductions coupled with reassurance that withdrawal symptoms are temporary, has been found to produce the highest success rates. The withdrawal syndrome can usually be avoided or minimized by use of a long half-life benzodiazepine such as diazepam (Valium) or chlordiazepoxide (Librium) and a very gradually tapering off the drug over a period of months, or even up to a year or more, depending on the dosage and degree of dependency of the individual. A slower withdrawal rate significantly reduces the intensity of withdrawal symptoms. In fact, some people feel better and more clear-headed as the dose gradually gets lower, so withdrawal from benzodiazepines is not necessarily an unpleasant event. People that report severe experiences from benzodiazepine withdrawal have almost invariably withdrawn or been withdrawn too quickly.[82]

Withdrawal management

Chlordiazepoxide 5 mg capsules which are sometimes used as an alternative to diazepam for benzodiazepine withdrawal. Like diazepam it has a long elimination half life and long acting active metabolites.

Pregnancy
See also: Long term effects of benzodiazepines#Neonatal effects International statistics show that 3.5% of women consume psychotropic drugs during

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pregnancy and of that 3.5% up to 85% report using benzodiazepines making benzodiazepines the most commonly prescribed psychotropic drug consumed during pregnancy. Around 0.4% of all pregnancies are to women who have used benzodiazepines chronically throughout their pregnancy.[87] Long term use of benzodiazepines during pregnancy or breast feeding is contraindicated.[88] In the United States the Food and Drug Administration has categorised benzodiazepines into either category D or category X benzodiazepines.[89] Use of benzodiazepines during pregnancy may result in a neonatal withdrawal syndrome including irritability, hyperactivity, disturbed sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, weight loss and failure to gain weight.[90] Other neonatal withdrawal symptoms include; hypertonia, hyperreflexia, restlessness, abnormal sleep patterns, jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnea, risk of aspiration of feeds and growth retardation. The neonatal withdrawal syndrome may last from a few days to several months. Tapering down the dose of the benzodiazepine during pregnancy may lessen the severity of the neonatal withdrawal syndrome. Acute doses of benzodiazepines during labour may additionally lead to floppy infant syndrome. A small study linked benzodiazepines to a number of adverse effects in the new born including causing low birth weight, which normalised by 10 months and small head circumference which was still present at 18 months. Possible but uncertain teratrogenic effects of benzodiazepines include, abortion, malformation, intrauterine growth retardation, functional deficits, carcinogenesis and mutagenesis. If used in pregnancy benzodiazepines which have a better and longer safety record such as diazepam or chlordiazepoxide should be preferred over potentially more harmful benzodiazepines such as alprazolam or triazolam. Using the lowest effective dose for the shortest period of time should minimise the risks to the unborn child.[91] Discontinuing benzodiazepines or antidepressants abruptly due to concerns of teratogenic effects of the medications has a high risk of causing serious complications and therefore is not recommended. For example abrupt withdrawal of benzodiazepines or antidepressants has a high risk of causing extreme withdrawal symptoms including

Benzodiazepine
suicidal ideation and a severe rebound effect of the underlying mental health disorder if present. This can lead to hospitalisation of the pregnant mother and may potentially lead to suicide attempts and thus potentially the death of the mother and unborn child. One study reported that one third of mothers who suddenly discontinued or very rapidly tapered their medications became acutely suicidal due to ’unbearable symptoms’. One woman had a medical abortion as she felt that she could no longer cope and another woman used alcohol in a bid to combat the withdrawal symptoms from benzodiazepines. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications including benzodiazepines. The study reported that physicians in general are not aware of the severe consequences of abrupt withdrawal of psychotropic medications such as benzodiazepines or antidepressants.[92]

Elderly
Benzodiazepines are generally not recommended for the elderly due to a range of adverse effects. Long term use of benzodiazepines in the elderly can induce a pharmacological syndrome which includes a wide range of physiological and neuropsychological symptoms which can be mistaken for the effects of old age.[93] A large cohort study found that benzodiazepine use is associated with a significantly higher incidence of hip fracture. Benzodiazepines of a short half-life are as likely to be associated with hip fracture as long-acting benzodiazepines. Because hip fractures are a frequent cause of disability and death in the elderly, efforts have been underway to reduce benzodiazepine prescribing in the elderly.[94] A review of the literature from between 1975 and 2005 found that medical papers consistently report increased risk of falls and fractures in the elderly. Benzodiazepine hypnotics produce also the most significant effects on body sway. Newer hypnotics (eg zaleplon and zolpidem) do not seem to cause such profound effects as benzodiazepines on the elderly.[95] Still, a law introduced in New York State reducing benzodiazepine use by 60% did not result in a measurable decrease in hip fractures.[96] This suggests that any effect of benzodiazepines on fracture rate may be non-significant and more important factors predict fracture rate such as osteoporosis rather

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than benzodiazepine induced falls. Use of other psychotropic drugs which are often prescribed in combination with benzodiazepines particularly SSRI antidepressants may also effect fracture rate.[97][98][99] Benzodiazepines cause an increased morbidity in the elderly which results in an increased use of healthcare services due to the adverse effects of benzodiazepines.[100] The elderly are more sensitive to benzodiazepines and are at an increased risk of dependence. Up to 10% of hospital admissions of the elderly are because of benzodiazepines. The elderly are more sensitive to the intellectual and cognitive impairing effects of benzodiazepines including amnesia, diminished short-term recall and increased forgetfulness. Chronic use of benzodiazepines and benzodiazepine dependence in the elderly can resemble dementia, depression or anxiety syndromes, which worsens with longerterm use of benzodiazepines. The success of gradual-tapering benzodiazepines is as great in the elderly as in younger people. Benzodiazepines should be prescribed to the elderly only with caution and only for a short period at low doses.[101] Benzodiazepines are sometimes prescribed to treat behavioural symptoms in dementia but there is little evidence demonstrating their effectiveness and limited information on their safety.[102][103][104] Benzodiazepines are one of the most common causes of drug induced dementia effecting up to 10 percent of patients attending memory clinics. Other drugs commonly associated with drug induced dementia include antihypertensives and anticholinergic drugs.[105] A past history of benzodiazepine use and withdrawal may also predict dementia but the literature is conflicting and inconclusive.[106] The long term use of benzodiazepines or the nonbenzodiazepines in management of insomnia in the elderly lacks an evidence base and has been historically discouraged for reasons that include concerns about potential adverse drug effects for example cognitive impairment including anterograde amnesia, daytime sedation, motor incoordination, increased risk of motor vehicle accidents and falls. The long term effectiveness is unproven and the safety of long-term use of these agents is unknown. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly people who have

Benzodiazepine
chronic insomnia. There is however, significant evidence of the effectiveness and long term effectiveness of non-drug treatments for insomnia in adults, including the elderly but these interventions are underused. Nonbenzodiazepine sedative-hypnotics compared with benzodiazepines offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. Melatonin agonists, such as ramelteon are more suitable for the management of chronic insomnia in elderly people.[107]

Pharmacology
Mechanism of action
Benzodiazepines produce a range of effects due to depressing of the central nervous system via modulation the GABAA receptor, the most prevalent inhibitory receptor in the brain. The subset of GABAA receptors that also bind benzodiazepines are referred to as benzodiazepine receptors (BzR). The GABAA receptor is composed of five subunits, most commonly two α’s, two β’s and one γ (α2β2γ). For each subunit, many subtypes exist (α1-6, β1-3 and γ1-3). GABAA receptors that are made up of different combinations of subunit subtypes have different properties, different distributions in the brain and different activities relative to pharmacological and clinical effects.[108] Benzodiazepines bind at the interface of the α and γ subunits on the GABAA receptor. Benzodiazepine binding also requires that alpha subunits contain a histidine amino acid residue, (i.e., α1, α2, α3 and α5 containing GABAA receptors). For this reason, benzodiazepines show no affinity for GABAA receptors containing α4 and α6 subunits, which contain an arginine instead of a histidine residue.[109] Other sites on the GABAA receptor also bind neurosteroids, barbiturates and certain anesthetics.[110] Individual types of subunits are expressed more densely in certain brain regions and thus modulation of certain subunits produces certain therapeutic as well as adverse effects of benzodiazepines. The α4 and α6 are expressed in very low numbers in the brain.[111] Benzodiazepines once bound to the benzodiazepine receptor the benzodiazepine ligand locks the benzodiazepine receptor into a conformation in which it has a much higher affinity for the GABA neurotransmitter. This

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Type Short-acting compounds Halflife a halflife of less than 12 hours Notes They have few residual effects if taken before bedtime, but rebound insomnia may occur and they might cause wake-time anxiety. Daytime withdrawal symptoms are also a problem with prolonged usage of short-acting benzodiazepines, including daytime anxiety. They may have some residual effects in the first half of the day if used as a hypnotic. (Rebound insomnia, however, is more common upon discontinuation of intermediate-acting benzodiazepines than longer acting benzodiazepines.) They have a risk of accumulation in the elderly and in individuals with severely impaired liver function, but they have a reduced severity of rebound effects and withdrawal.

Benzodiazepine
Examples Alprazolam, Midazolam, Oxazepam, Triazolam

Intermediate- a halfacting life of compounds 12–24 hours Long-acting compounds a halflife greater than 24 hours

Lorazepam, Bromazepam, Estazolam, Temazepam Clonazepam, Diazepam, Flurazepam, Chlordiazepoxide

increases the frequency of opening of the associated chloride ion channel and hyperpolarizes the membrane of the associated neuron. This potentiates the inhibitory effect of the available GABA, leading to sedatory and anxiolytic effects. As mentioned above, different benzodiazepines can have different affinities for BzRs made up of different collection of subunits. For instance, benzodiazepines with high activity at the α1 (temazepam, triazolam, nitrazepam, etc) are associated with stronger hypnotic effects, whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits (diazepam, clonazepam, bromazepam, etc) have good anti-anxiety activity.[112] Some compounds lie somewhere between being full agonists and neutral antagonists and are termed either partial agonists or partial antagonists. There has been interest in partial agonists for the BzR, with evidence that complete tolerance may not occur during chronic use, with continued anxiolytic properties, reduced sedation, dependence and withdrawal problems.[113] The benzodiazepine class of drug interact with peripheral benzodiazepine receptors. Peripheral benzodiazepine receptors (PBRs) are present in peripheral nervous system tissues, glial cells and to a lesser extent the central nervous system. These peripheral benzodiazepine receptors are not coupled (or "attached") to GABAA receptors. They modulate the immune system and are involved in

the response of the jury.[114][115][116][117]

body

to

in-

Duration of action
Benzodiazepines are commonly divided into three groups by their half-lives:[118][119]

Overdose
Benzodiazepines taken alone rarely cause severe complications in overdose,[120] and deaths after hospital admission are rare.[121] However, combination of these drugs with alcohol or opiates is particularly dangerous and may lead to coma and death.[122][123] The various benzodiazepines differ in their toxicity since they produce varying levels of sedation in overdose, with oxazepam being least toxic and least sedative and temazepam most toxic and most sedative in overdose. Temazepam is more frequently involved in drug-related deaths causing more deaths per million than other benzodiazepines in an Australian study.[124] A reversal agent for benzodiazepines exists, flumazenil (Anexate). Its use as an antidote in an overdose however is controversial. Numerous contraindications to its use exist. It is contraindicated in patients who are on long term benzodiazepines, those who have ingested a substance that lowers the seizure threshold or may cause an arrhythmia and in those with abnormal vital signs. One study found that this is about 10% of the patient

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population presenting with a benzodiazepine overdose.[125]

Benzodiazepine
reduction program. Additional drugs, such as antianxiety drugs like buspirone or β blockers and carbamazepine, should not be added into the withdrawal program unless there is a specific indication for their use.[129]

Benzodiazepine drug misuse
Drug misuse
Benzodiazepines are used recreationally. Benzodiazepine use is widespread among amphetamine users, with those that use amphetamines and benzodiazepines having greater levels of mental health problems and social deterioration. Benzodiazepine injectors are almost four times more likely to inject using a shared needle than nonbenzodiazepine-using injectors. It has been concluded in various studies that benzodiazepine use causes greater levels of risk and psycho-social dysfunction among drug misusers.[126] Those who use stimulant and depressant drugs are more likely to report adverse reactions from stimulant use, more likely to be injecting stimulants and more likely to have been treated for a drug problem than those using stimulant but not depressant drugs.[127] Mortality is higher among poly-drug misusers that also use benzodiazepines. Heavy alcohol use also increases mortality among poly-drug users.[128] Drug misusers addicted to benzodiazepines develop a high degree of tolerance, coupled with dosage escalation, often increasing their dosage to very high levels. Long-term use of benzodiazepines has the potential to cause both physical and psychological dependence and severe withdrawal symptoms. Tolerance and dependence to benzodiazepines develops rapidly, with a benzodiazepine withdrawal syndrome after as little as 3 weeks of continuous use. Benzodiazepines and in particular temazepam, are sometimes used intravenously, which if done incorrectly, or in an unsterile manner, or by using shared syringes & needles can lead to medical complications including abscesses, cellulitis, thrombophlebitis, arterial puncture, deep vein thrombosis, hepatitis B and C, HIV or AIDS, overdose and gangrene. Benzodiazepines are also sometimes misused intranasally which may have additional health consequences. Once benzodiazepine dependence has been established a clinician usually converts the patient to an equivalent dose of diazepam before beginning a gradual

Drug related crime
See also: Drug-related crime Problem benzodiazepine use can be associated with drug related crime. In a survey of police detainees carried out by the Australian Government, both legal and illegal users of benzodiazepines were found to be more likely to have lived on the streets, less likely to have been in full time work and more likely to have used heroin or methamphetamines in the past 30 days from the date of taking part in the survey. Benzodiazepine users were also more likely to be receiving illegal incomes and more likely to have been arrested or imprisoned in the previous year. Benzodiazepines were sometimes reported to be used alone, but most often formed part of a poly drug-using problem. Female users of benzodiazepines were more likely than men to be using heroin, whereas male users of benzodiazepines were more likely to report amphetamine use. Benzodiazepine users were more likely than non-users to claim government financial benefits and benzodiazepine users who were also poly-drug users were the most likely to be claiming government financial benefits. Those who reported using benzodiazepines alone were found to be in the mid range when compared to other drug using patterns in terms of property crimes and criminal breaches. Of the detainees reporting benzodiazepine use, one in five reported injection use, mostly of illicit temazepam, with some who reported injecting prescribed benzodiazepines. Injection was a concern in this survey due to increased health risks. The main problems highlighted in this survey were concerns of dependence, the potential for overdose of benzodiazepines in combination with opiates and the health problems associated with injection of benzodiazepines.[130] Benzodiazepines are also sometimes used for criminal purposes such as to rob a victim or to incapacitate a victim in cases of drug assisted rape. However, alcohol is more commonly involved than benzodiazepines in such cases.[131] Temazepam use was particularly associated with violent or disorderly

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behaviours and contact with the police in a 1997 study of young single homeless people in Scotland.[132]

Benzodiazepine
benzodiazepines have different abuse potential. The more rapid the increase in the plasma level following ingestion, the greater the intoxicating effect and the more open to abuse the drug becomes. The speed of onset of action of a particular benzodiazepine correlates well with the ‘popularity’ of that drug for abuse. Darke, Ross & Hall found that temazepam rated significantly higher than the next most liked drug, nimetazepam. The two most common reasons for this preference were that it was the ‘strongest’ and that it gave a good ‘high’.[135]

Drug regulation and enforcement
Europe
In 2006/2007, seizures of benzodiazepines had trebled from the previous 2 years in the United Kingdom. Temazepam abuse and seizures have been falling in the UK probably due to its reclassification as Schedule III controlled drug with tighter prescribing restrictions and the resultant reduction in availability.[133] A total of 2.75 million temazepam capsules were seized in the Netherlands by authorities between 1996 and 1999.[134] A new yet to be fully released study by the Hamburg, Germany, based institute for interdisciplinary drug and dependency studies, reveals that at least 1.5 million patients in Germany receive benzodiazepine prescriptions longer than needed, making 800,000 patients dependent and 130,000 patients heavily addicted to Benzodiazepine at the moment.spiegel.de (german)

North America
Abuse of benzodiazepine drugs is a serious problem in North America. The most frequently abused of the benzodiazepines in both the United States and Canada are alprazolam, clonazepam, lorazepam and diazepam.[136]

East and Southeast Asia
Abuse of benzodiazepines is a serious problem throughout East and Southeast Asia. The Central Narcotics Bureau of Singapore seized 94,200 nimetazepam tablets in 2003. This is the largest nimetazepam seizure recorded since nimetazepam became a controlled drug under the Misuse of Drugs Act in 1992.[137] Together with temazepam abusers, they accounted for 47% of the abusers arrested in 2005.[138] In Singapore, both temazepam and nimetazepam are Class A Schedule I controlled drugs. Similar strict laws apply to both of these benzodiazepines all across Asia. In Hong Kong, for example, they’re both regulated under Schedule 1 of Hong Kong’s Chapter 134 Dangerous Drugs Ordinance.[139]

Oceania
Benzodiazepines are common drugs of abuse in Australia and New Zealand, particularly among those who may also be using other illicit drugs. The intravenous use of temazepam poses the greatest threat to those who misuse benzodiazepines. Simultaneous consumption of temazepam with heroin is a potential risk factor of overdose. An Australian study of non-fatal heroin overdoses, noted that 26% of heroin users had consumed temazepam at the time of their overdose. This is consistent with a NSW investigation of coronial files from 1992. Temazepam was found in 26% of heroin-related deaths. Temazepam, including tablet formulations, are used intravenously. In an Australian study of 210 heroin users who used temazepam, 48% had injected it. Although abuse of benzodiazepines has decreased over the past few years, temazepam continues to be a major drug of abuse in Australia. In certain states like Victoria and Queensland, temazepam accounts for most benzodiazepine sought by forgery of prescriptions and through pharmacy burglary. Darke, Ross & Hall found that different

Legal status
Benzodiazepines are Schedule IV in the USA under the Federal Controlled Substances Act, even when not on the market (for example, nitrazepam and bromazepam). Flunitrazepam is subject to more stringent regulations in certain states and temazepam prescriptions require specially coded pads in certain states. In Canada all benzodiazepines are Schedule IV.[140] In the United Kingdom the benzodiazepines are Schedule IV controlled drugs apart from flunitrazepam, temazepam and

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midazolam which are Schedule III controlled drugs and carry stronger penalties for trafficking and possession.[141][142] In the Netherlands, since October 1993, benzodiazepines are all placed on List 2 of the Opium Law. A prescription is needed for possession of all benzodiazepines.[143] In East Asia and Southeast Asia, temazepam and nimetazepam are often heavily controlled and restricted. In certain countries, triazolam, flunitrazepam, flutoprazepam and midazolam are also restricted or controlled to certain degrees. In Hong Kong all benzodiazepines were reclassified as dangerous drugs and are regulated under Schedule 1 of Hong Kong’s Chapter 134 Dangerous Drugs Ordinance. Previously only brotizolam, flunitrazepam and triazolam were classed as dangerous drugs.[144] Internationally, flunitrazepam is a Schedule III drug under the Convention on Psychotropic Substances.[145]

Benzodiazepine

See also
• Z drugs

References
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