Benzodiazepine

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 (Template:Pron-en, often abbreviated to "benzos") are a commonly prescribed class of psychoactive drugs with varying sedative, hypnotic, anxiolytic (antianxiety), anticonvulsant, muscle relaxant and amnesic properties. Benzodiazepines are useful in treating anxiety, insomnia, agitation, seizures and muscle spasms, as well as alcohol withdrawal. They can also be used before certain medical procedures such as endoscopies or dental work where tension and anxiety are present and prior to some unpleasant medical procedures in order to induce sedation and amnesia for the procedure. Benzodiazepines are an important therapeutic tool and can be life saving in certain conditions such as status epilepticus. Benzodiazepines vary in their elimination half life with some being short acting, intermediate acting or long acting. Short acting and intermediate acting benzodiazepines are prefered for the treatment of insomnia or those at risk of drug accumulation, eg the elderly or those with severe liver disorders. Some benzodiazepines also have active metabolites which can contribute to drug accumulation. Longer acting benzodiazepines are prefered for the treatment of anxiety.

The first benzodiazepine, chlordiazepoxide (Librium) which was discovered by accident by Leo Sternbach, was introduced to the market in 1960 and was quickly followed by diazepam (Valium). The therapeutic properties of benzodiazepines are mediated via benzodiazepines modulating the GABA_A receptors which results in a depressant or slowing down effect of the central nervous system. The benzodiazepines largely replaced the barbiturates as sedative hypnotics which prior to the introduction of benzodiazepines were a commonly prescribed sedative hypnotic drug class. However, the benzodiazepines are now beginning to be replaced by the nonbenzodiazepines especially in the treatment of insomnia.

Benzodiazepines are generally safe and effective in the short term although cognitive impairments or paradoxical effects occasionally occur such as aggression or behavioural disinhibition. However, longer term use of benzodiazepines 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. The elderly are at an increased risk of suffering from the adverse effects of benzodiazepines.

There is controversy concerning the safety of benzodiazepines in pregnancy. Much of this controversy surrounds whether or not benzodiazepines are associated with major malformations. Benzodiazepines are not however, considered to be major teratogens but they can cause neonatal withdrawal effects. Benzodiazepines are often taken in overdoses but are considered to be much less toxic in overdose compared to their predecessors the barbiturates. When benzodiazepines are mixed with other CNS depressants for example alcohol or opiates their overdose potential is greatly increased. This is particularly problematic in the drug misusing community.

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. Chlordiazepoxide was synthesised by accident while trying to synthesise a chemical dye. The chemical class synthesised was initially believed to be heptoxdiazines but on further investigation Leo Sternbach soon discovered the new compound was in fact quinazolone-3-oxides. Leo Sternbach had synthesised 40 derivatives of the quinazolone-3-oxides and tested 39 of them with disappointing results. Leo Sternbach 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. Tests revealed that the compound had 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, in 1963 diazepam hit the market 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.

Dr. Carl F. Essig of the Addiction Research Center of the National Institute of Mental Health spoke at a symposium on drug abuse at an annual meeting of the American Association for the Advancement of Science, in December 1963. He named meprobamate, glutethimide, ethinamate, ethchlorvynol, methyprylon and chlordiazepoxide as drugs whose usefulness can hardly be questioned. However, Essig labeled these newer products as drugs of addiction, like barbiturates, whose habit-forming qualities were more widely known. He mentioned a 90-day study of chlordiazepoxide, which concluded that the automobile accident rate among 68 users was 10 times higher than normal. Participants' daily dosage ranged from 5 to 100 milligrams.

Prior to benzodiazepines coming onto the market the barbiturates were the most commonly prescribed sedative hypnotic. The introduction of benzodiazepines sedative hypnotics largely replaced the barbiturates after their introduction. 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 also work on the benzodiazepine receptors. Nonbenzodiazepines are molecularly distinct from benzodiazepines 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.

Benzodiazepines and their therapeutic uses

Main article: List of benzodiazepines

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 (see figure to the above right). Benzodiazepines are molecularly similar to several groups of drugs, some of which share similar pharmacological properties, including the quinazolinones, hydantoines, succinimides, oxazolidinediones, barbiturates and glutarimides. Most benzodiazepines are administered orally; however, administration can also occur intravenously, intramuscularly or as a suppository. 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.

Anticonvulsants

Main anticonvulsant benzodiazepines
clobazam clonazepam clorazepate diazepam lorazepam midazolam

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 meta-analysis of 11 clinical trials concluded that lorazepam was superior to diazepam in treating status epilepticus. 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. Long term prophylactic use of benzodiazepines for seizure disorders is limited due to a high risk of tolerance to the anticonvulsant effects of benzodiazepines.

Anxiolytics

Main anxiolytic benzodiazepines
alprazolam bromazepam chlordiazepoxide clonazepam clorazepate diazepam lorazepam medazepam nordazepam 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, occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks. Benzodiazepines are also used to treat the acute panic that can be caused by hallucinogen intoxication.

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. 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. 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. Treatment patterns for psychotropic drugs appear to have remained stable over the past decade, with benzodiazepines being the most commonly used medication for panic disorder.

Insomnia

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

Hypnotic benzodiazepines are prescribed for the short-term management of and severe or debilitating insomnia. Hypnotic 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. The risks of tolerance and dependence with long term use of benzodiazepines for insomnia limits their use long term. Long term use of benzodiazepine hypnotics as well as 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.

Premedication before procedures

Benzodiazepines are effective as premedication before surgery, especially in those that are anxious. Usually 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. Diazepam or temazepam can be utilized in patients who are particularly anxious about dental procedures. Alternatively nitrous oxide can be administered in dental phobia due to its sedative and dissociative effects, its fast onset of action and its extremely short duration of action.

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.

Alcohol dependence

Benzodiazepines have been shown to be safe and effective, particularly for preventing or treating seizures and delirium and are the preferred agents for treating the symptoms of alcohol withdrawal syndrome. 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 make withdrawal smoother and rebound withdrawal symptoms are less likely to occur. The two intermediate-acting agents have excellent records of efficacy. Chlordiazepoxide is the benzodiazepine of choice in uncomplicated alcohol withdrawal. Oxazepam or lorazepam is often used in patients at risk of drug accumulation, particularly the elderly and those with cirrhosis because of its shorter half life. Lorazepam, also a short acting benzodiazepine 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. However, the shorter acting benzodiazepines eg lorazepam or oxazepam may be less effective than longer acting benzodiazepines eg chlordiazepoxide or diazepam in reducing alcohol withdrawal symptoms eg risk of break through seizures and thus are not recommended for outpatient detoxification. They are also more prone to rebound if not tapered after alcohol detoxification.

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 and restless legs syndrome.

Psychiatry

Benzodiazepines can be very useful in the short-term treatment of acute psychosis such as schizophrenia or mania, 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. Benzodiazepines bring about rapid tranquillisation and sedation of the psychotic individual, therefore benzodiazepines are a very important tool in the management of acute psychosis. Lorazepam is the benzodiazepine most commonly used but clonazepam is also sometimes used.

Veterinary practice

Benzodiazepines have a wide range of uses in veterinary practice in the treatment of various disorders and scenarios involving animals. As in humans, their usefulness comes from their tranquilizing, muscle relaxing, aggression inhibiting and anxiolytic properties.

Benzodiazepines are used before surgery as premedication for muscular relaxation, and during surgery in combination with other general anesthetic drugs such as ketamine. They are effective in controlling tremors, seizures and epilepsy. Midazolam can also be used along with other drugs in the sedation and capture of wild animals.

Contraindications, interactions and side effects

Contraindications

The following are some important contraindications or situations where extreme caution should be exercised when prescribing benzodiazepines.

• Myasthenia gravis
• Respiratory disorders
• Severe hepatic insufficiency
• Sleep apnoea syndrome
• Pregnancy, labour and lactation
• Breast feeding
• 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. Benzodiazepines increase craving for alcohol in problem alcohol consumers. Benzodiazepines also increase the volume of alcohol consumed by problem drinkers.
• Driving a motor vehicle, increased risk of road traffic accidents

Interactions

Individual benzodiazepines may have their own additional interactions which will vary from benzodiazepine to benzodiazepine. The interactions of benzodiazepines as a drug class with other drugs are as follows;

• Alcohol and other CNS depressants - cause synergistic adverse effects, with possible increase in depression and suicide.
• 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 half-life 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

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 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.

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 with borderline personality disorder are at a greater risk of experiencing severe behavioral or psychiatric disturbances from benzodiazepines with up to 58% of borderline personality disorder patients experiencing behavioural disinhibition. Aggression and violent outbursts can also occur with benzodiazepines, particularly when they are combined with alcohol. Recreational abusers and patients on high-dosage regimes may be at an even greater risk of experiencing paradoxical reactions to benzodiazepines. 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. Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders.

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 disinhibiting a serotonergic mechanism.

Physical dependence and withdrawal

Diazepam 2 mg and 5 mg diazepam tablets, which are commonly used in the treatment of benzodiazepine withdrawal.

See also: Benzodiazepine dependence

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 is also associated with impaired concentration and memory and depression. Use of high doses (or high potency benzodiazepines) and those with a shorter half life increases the severity of 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. Withdrawal from chronic benzodiazepine use is usually beneficial due to improved health such as cognition and improved functioning with possible improved 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. 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 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 individual needs.

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, delirium tremens. Benzodiazepine dependence often occurs as a result of medical use but may also occur as a result of illict misuse. Withdrawal effects may linger for many months or sometimes for a year or more after cessation of benzodiazepines. Approximately 10% of patients will experience 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 compared to the symptoms seen during the first 2 or 3 months of withdrawal. 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 lessen as the months and years go by eventually disappearing altogether.

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.

Main article: Benzodiazepine withdrawal syndrome

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.

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 low-potency, 2-mg tablets, which can be quartered for small dose reductions. 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. The speed of benzodiazepine reduction regimes varies from person to person, but is usually done in 10% sized 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 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.

Pregnancy

See also: Long term effects of benzodiazepines § Neonatal effects

International statistics show that 3.5% of women consume psychotropic drugs during pregnancy and of that 3.5% up to 85% report using benzodiazepines during pregnancy making benzodiazepines the most commonly prescribed psychotropic drug consumed during pregnancy. Approximately 0.4% of all pregnancies are to women who have used benzodiazepines chronically throughout their pregnancy. Chronic use of benzodiazepines during pregnancy or breast feeding is contraindicated. In the United States the FDA has categorised benzodiazepines into either category D or category X benzodiazepines.

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. 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 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 benzodiazepines are used in pregnancy benzodiazepines with 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.

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 suicidal ideation as well as 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 reported they 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.

Elderly

Benzodiazepines are generally not recommended for the elderly due to a range of adverse effects. 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. 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. Still, a law introduced in New York State reducing benzodiazepine use by 60% did not result in a measurable decrease in hip fractures. 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 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.

Benzodiazepines cause an increased morbidity in the elderly which results in an increased use of healthcare services due to the adverse effects of benzodiazepines on the elderly. 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 longer-term 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.

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 such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination and increased risk of motor vehicle accidents and falls. In addition, 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 persons with 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 and found that 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.

Pharmacology

Mechanism of action

Benzodiazepines produce a range of effects due to depressing of the central nervous system via modulation the GABA_A receptor, the most prevalent inhibitory receptor within the brain. The subset of GABA_A receptors that also bind benzodiazepines are referred to as benzodiazepine receptors (BzR). The GABA_A receptor is composed of five subunits, most commonly two α's, two β's and one γ (α₂β₂γ). For each subunit, multiple subtypes exist (α_1-6, β_1-3 and γ_1-3). GABA_A receptors that are made up of different combinations of subunit subtypes have different properties, different distributions within the brain and different activities relative to pharmacological and clinical effects.

Benzodiazepines bind at the interface of the α and γ subunits on the GABA_A receptor. Benzodiazepine binding also requires that alpha subunits contain a histidine amino acid residue, (i.e., α₁, α₂, α₃ and α₅ containing GABA_A receptors). For this reason, benzodiazepines show no affinity for GABA_A receptors containing α₄ and α₆ subunits, which contain an arginine instead of a histidine residue. Other sites on the GABA_A receptor also bind neurosteroids, barbiturates and certain anesthetics. 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.

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 than otherwise. This 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 GABA_A receptors containing α₂ and/or α₃ subunits (diazepam, clonazepam, bromazepam, etc) have good anti-anxiety activity.

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 with chronic use, with partial agonists demonstrating continued anxiolytic properties with reduced sedation, dependence and withdrawal problems.

Peripheral benzodiazepine receptors (PBRs) also appear peripheral nervous system tissues, glial cells and to a lesser extent the central nervous system. The benzodiazepine class of drug interact with peripheral benzodiazepine receptors. These peripheral benzodiazepine receptors are not coupled (or "attached") to GABA_A receptors. They modulate the immune system and are involved in the response of the body to injury.

Duration of action

Benzodiazepines are commonly divided into three groups by their half-lives:

Type	Half-life	Notes	Examples
Short-acting compounds	a half-life of less than 12 hours	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.	Alprazolam, Midazolam, Oxazepam, Triazolam
Intermediate-acting compounds	a half-life of 12–24 hours	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.)	Lorazepam, Bromazepam, Estazolam, Temazepam
Long-acting compounds	a half-life greater than 24 hours	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.	Clonazepam, Diazepam, Flurazepam, Chlordiazepoxide

Overdose

Main article: Benzodiazepine overdose

Benzodiazepines taken alone rarely cause severe complications in overdose, and deaths after hospital admission are rare. However, combination of these drugs with alcohol or opiates is particularly dangerous and may lead to coma and death. 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.

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 population presenting with a benzodiazepine overdose.

Benzodiazepine drug misuse

Main article: Benzodiazepine addiction

Drug misuse

Benzodiazepines are used/abused recreationally. Benzodiazepine use is widespread among amphetamine abusers, 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 non-benzodiazepine-using injectors. It has been concluded in various studies that benzodiazepine use causes greater levels of risk and psycho-social dysfunction among drug abusers. 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. Increased mortality was found in drug misusers that also used benzodiazepines against those that did not. Heavy alcohol misuse was also found to increase mortality among multiple-drug misusers.

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 are at risk of severe withdrawal symptoms. Tolerance and dependence to benzodiazepines develop rapidly with users of benzodiazepines, demonstrating 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 abused intranasally which may have additional health consequences. Once benzodiazepine dependence has been established a clinician usually convert the patient to an equivalent dose of diazepam before beginning a gradual 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.

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 abused 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.

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. Temazepam misuse was particularly associated with violent or disorderly behaviours and contact with the police in a 1997 study of young single homeless people in Scotland.

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 of temazepam. A total of 2.75 million temazepam capsules were seized in the Netherlands by authorities between 1996 and 1999.

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 are heavily addicted to Benzodiazepine at the moment. spiegel.de (german)

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 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’.

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.

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. Together with temazepam abusers, they accounted for 47% of the abusers arrested in 2005. 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.

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.

In the United Kingdom the benzodiazepines flunitrazepam, temazepam and midazolam are Schedule III controlled drugs and carry stronger penalties for trafficking and possession.

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.

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.

Internationally, flunitrazepam is a Schedule III drug under the Convention on Psychotropic Substances.

See also

• Long term effects of benzodiazepines
• Z drugs

External links

• Ashton CH (2002-08-01). "Benzodiazepines How They Work & How to Withdraw". benzo.org.uk. Retrieved 2008-06-19. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
• Ashton CH (2007-04-01). "Benzodiazepine Equivalence Table". benzo.org.uk. Retrieved 2008-06-19.
• Fruchtengarten L, (1998-04-01). "Benzodiazepines". PIM G008. International Programme on Chemical Safety (IPCS) INCHEM. Retrieved 2008-06-19. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)CS1 maint: extra punctuation (link)
• Longo LP, Johnson B (2000-04-01). "Benzodiazepines Side Effects, Abuse Risk and Alternatives". Addiction: Part I. American Academy of Family Physicians. Retrieved 2008-06-19.
• "An Overview of the History, Chemistry, and Pharmacodynamics of Benzodiazepines". The Eaton T. Fores Research Center. 2002-01-01. Retrieved 2008-06-19.
• "Benzodiazepines advanced consumer information". drugs.com. 2005-02-24. Retrieved 2008-06-19. {{cite web}}: Text "Drugs.com" ignored (help)