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Prolonged convulsive [[epileptic seizure]]s are a [[medical emergency]] that can usually be dealt with effectively by administering fast-acting benzodiazepines, which are potent [[anticonvulsants]]. In a hospital environment, [[intravenous]] [[lorazepam]] and [[diazepam]] are first-line choices, with a preference for lorazepam due to its longer duration of action. In the community, intravenous administration is not practical and so [[rectal]] diazepam or (more recently) [[buccal mucosa|buccal]] [[midazolam]] are used, with a preference for midazolam as its administration is easier and more socially acceptable.<ref name=SIGN70>{{cite web | url = http://www.sign.ac.uk/guidelines/fulltext/70/index.html | title = Guideline No. 70: Diagnosis and management of epilepsy in adults | accessdate = 2009-06-02 | author = Scottish Intercollegiate Guidelines Network | year = 2003 | month = April | publisher = Royal College of Physicians, Edinburgh | pages = 17–19}}</ref><ref name=NICECG020>{{cite web | url = http://www.nice.org.uk/nicemedia/pdf/CG020fullguideline.pdf | format = PDF | title = Clinical Guidelines and Evidence Review for the Epilepsies: diagnosis and management in adults and children in primary and secondary care | accessdate = 2009-06-02 | author = Stokes T, Shaw EJ, Juarez-Garcia A, Camosso-Stefinovic J, Baker R | year = 2004 | publisher = Royal College of General Practitioners, London | pages = 61,64–65}}</ref>
Prolonged convulsive [[epileptic seizure]]s are a [[medical emergency]] that can usually be dealt with effectively by administering fast-acting benzodiazepines, which are potent [[anticonvulsants]]. In a hospital environment, [[intravenous]] [[lorazepam]] and [[diazepam]] are first-line choices, with a preference for lorazepam due to its longer duration of action. In the community, intravenous administration is not practical and so [[rectal]] diazepam or (more recently) [[buccal mucosa|buccal]] [[midazolam]] are used, with a preference for midazolam as its administration is easier and more socially acceptable.<ref name=SIGN70>{{cite web | url = http://www.sign.ac.uk/guidelines/fulltext/70/index.html | title = Guideline No. 70: Diagnosis and management of epilepsy in adults | accessdate = 2009-06-02 | author = Scottish Intercollegiate Guidelines Network | year = 2003 | month = April | publisher = Royal College of Physicians, Edinburgh | pages = 17–19}}</ref><ref name=NICECG020>{{cite web | url = http://www.nice.org.uk/nicemedia/pdf/CG020fullguideline.pdf | format = PDF | title = Clinical Guidelines and Evidence Review for the Epilepsies: diagnosis and management in adults and children in primary and secondary care | accessdate = 2009-06-02 | author = Stokes T, Shaw EJ, Juarez-Garcia A, Camosso-Stefinovic J, Baker R | year = 2004 | publisher = Royal College of General Practitioners, London | pages = 61,64–65}}</ref>


When the benzodiazepines were first introduced they were enthusiastically adopted for treating all forms of [[epilepsy]]. However, drowsiness and [[drug tolerance|tolerance]] become problems with continued use and none are now considered [[first-line treatment|first-line]] choices for long-term epilepsy therapy.<ref name="pmid19298435">{{cite journal |author=Shorvon SD |title=Drug treatment of epilepsy in the century of the ILAE: the second 50 years, 1959–2009 |journal=Epilepsia |volume=50 Suppl 3 |issue= |pages=93–130 |year=2009 |month=March |pmid=19298435 |doi=10.1111/j.1528-1167.2009.02042.x |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/122250225/HTMLSTART}}</ref> Clobazam is widely used by specialist epilepsy clinics worldwide (but is unavailable in the US), and clonazepam is popular in France.<ref name="pmid19298435"/> In the UK, both clobazam and clonazepam are second-line choices for treating many forms of epilepsy.<ref name=NICECG020b>{{cite web | url = http://www.nice.org.uk/nicemedia/pdf/CG020fullguideline_appendixB.pdf | format = PDF | title = Clinical Guidelines and Evidence Review for the Epilepsies: diagnosis and management in adults and children in primary and secondary care (Appendix B) | accessdate = 2009-06-02 | author = Stokes T, Shaw EJ, Juarez-Garcia A, Camosso-Stefinovic J, Baker R | year = 2004 | publisher = Royal College of General Practitioners, London | pages = 432}}</ref> Clobazam also has a useful role for very short-term seizure [[prophylaxis]] and in [[menstrual cycle|catamenial]] epilepsy.<ref name="pmid19298435"/> Discontinuation of benzodiazepines after long term use in epilepsy requires additional caution because of the risks of [[rebound effect|rebound]] seizures as well as a [[benzodiazepine withdrawal syndrome]]. Therefore, the dose is slowly tapered over a period of several months.<ref name=NICECG020/>
When the benzodiazepines were first introduced they were enthusiastically adopted for treating all forms of [[epilepsy]]. However, drowsiness and [[drug tolerance|tolerance]] become problems with continued use and none are now considered [[first-line treatment|first-line]] choices for long-term epilepsy therapy.<ref name="pmid19298435">{{cite journal |author=Shorvon SD |title=Drug treatment of epilepsy in the century of the ILAE: the second 50 years, 1959–2009 |journal=Epilepsia |volume=50 Suppl 3 |issue= |pages=93–130 |year=2009 |month=March |pmid=19298435 |doi=10.1111/j.1528-1167.2009.02042.x |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/122250225/HTMLSTART}}</ref> Clobazam is widely used by specialist epilepsy clinics worldwide (but is unavailable in the US), and clonazepam is popular in France.<ref name="pmid19298435"/> In the UK, both clobazam and clonazepam are second-line choices for treating many forms of epilepsy.<ref name=NICECG020b>{{cite web | url = http://www.nice.org.uk/nicemedia/pdf/CG020fullguideline_appendixB.pdf | format = PDF | title = Clinical Guidelines and Evidence Review for the Epilepsies: diagnosis and management in adults and children in primary and secondary care (Appendix B) | accessdate = 2009-06-02 | author = Stokes T, Shaw EJ, Juarez-Garcia A, Camosso-Stefinovic J, Baker R | year = 2004 | publisher = Royal College of General Practitioners, London | pages = 432}}</ref> Clobazam also has a useful role for very short-term seizure [[prophylaxis]] and in [[menstrual cycle|catamenial]] epilepsy.<ref name="pmid19298435"/> Discontinuation of benzodiazepines after long term use in epilepsy requires additional caution because of the risks of [[rebound effect|rebound]] seizures as well as a [[benzodiazepine withdrawal syndrome]]. Therefore, the dose is slowly tapered over a period of up to six months or longer.<ref name=NICECG020/>


===Anxiety, panic and agitation===
===Anxiety, panic and agitation===

Revision as of 00:51, 3 June 2009

Benzodiazepines
Chemical structure diagram of a benzene ring fused to a diazepine ring. Another benzene ring is attached to the bottom of the diazepine ring via a single line. Attached to the first benzene ring is a side chain labeled R7; to the second, a side chain labeled R2'; and attached to the diazepine ring, two side chains labeled R1 and R2.
The core structure of benzodiazepines. "R" labels denote common locations of side chains, which give different benzodiazepines their unique properties.

The benzodiazepine (Template:Pron-en) class of psychoactive drugs have varying sedative, hypnotic (sleep inducing), anxiolytic (antianxiety), anticonvulsant, muscle relaxant and amnesic properties.[1] These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal, and for medical or dental procedures.[2][3] Benzodiazepines vary in their elimination half-life, being categorized as either short-acting, intermediate-acting or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia. Longer-acting benzodiazepines are preferred for the treatment of anxiety.[4]

The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach; it was introduced to the market in 1960 and was quickly followed by diazepam (Valium). The therapeutic properties are mediated via the enhancing the effect of neurotransmitter GABA at GABAA receptors, which results in a depressant or calming effect of the central nervous system.[5] The benzodiazepines 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 behavioral 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. They are are also major drugs of abuse.[7][8][9] Other drawbacks from long term use of benzodiazepines include their propensity to cause or worsen sleep problems, cognitive deficits, depression, anxiety and panic attacks as well as agoraphobia.[10][11][12] The elderly are at an increased risk of suffering from the adverse effects.[13][10]

There is controversy concerning their safety of benzodiazepines in pregnancy; whilst they are not major teratogens, uncertainty remains whether they cause major malformations in a small number of babies. Taken during pregnancy can however, cause neonatal withdrawal effects.[14][15] Benzodiazepines are often taken in overdoses, but are considered to be much less toxic in overdose than their predecessors, the barbiturates.[16] When combined with other central nervous system depressants such as alcohol or opiates, the potential for overdose greatly increases. This is particularly problematic in the drug misusing community.[17][18]

History

See also: Chlordiazepoxide
The molecular structure of chlordiazepoxide, discovered by Leo Sternbach which gave birth to the benzodiazepine drug class

The first benzodiazepine, chlordiazepoxide (Librium), was synthesized in 1955 by Leo Sternbach while working at Hoffmann–La Roche on the development of tranquilizers. Pharmacological properties of many compounds prepared initially were disappointing, and Sternbach abandoned the project. Two years later, in April 1957 during a spring cleaning in the lab, his co-worker, Earl Reeder noticed a "nicely crystalline" compound left over from the discontinued project. This compound, which later was named chlordiazepoxide, had not been tested in 1955 because of Sternbach's "involvement with other problems". Expecting the pharmacology results to be negative and then hoping to publish the chemistry part of their work, researchers submitted it for a standard battery of animal tests. Unexpectedly, the compound showed very strong sedative, anticonvulsant and muscle relaxant effects. The impressive clinical results led to the speedy introduction of chlordiazepoxide in 1960 throughout the world under the brand name Librium.[19][20] Following chlordiazepoxide, diazepam hit the market in 1963 under the brand name Valium, and for a while Librium and Valium were the two most commercially successful drugs. The introduction of benzodiazepine sedative hypnotics led to a fall in barbiturate prescriptions and by the 1970s they had largely replaced the older drugs. It is estimated that in 1977 the United States consumers took about 8000 tons of benzodiazepines.[21]

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 realized in the 1980s leading them to be regarded unpopularly. Benzodiazepines have a unique history, in that they were responsible for the largest ever class action lawsuit in the United Kingdom, involving 14,000 patients and 1800 law firms against the drugs manufacturers, alleging that they knew of the dependence potential 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.[22] 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 litigation led to changes in the British law making class action law suits more difficult.[23]

A newer class of drugs called the nonbenzodiazepines (also sometimes referred to as Z-drugs) are now beginning to replace the benzodiazepines, particularly in the treatment of insomnia. Although they are molecularly distinct, nonbenzodiazepines work on benzodiazepine receptors[6][24][25] and have similar risks and benefits to those of their predecessors.[26]

Therapeutic uses

See also: List of benzodiazepines
Injectable midazolam in 1mg /ml and 5 mg / ml strengths.

Benzodiazepines possess sedative, hypnotic, anxiolytic (antianxiety), anticonvulsant, muscle relaxant and amnesic actions,[1] which are useful in a variety of indications such as alcohol dependence, seizures, anxiety, panic, agitation and insomnia. Most are administered orally; however, administration can also be given intravenously, intramuscularly or rectally.[27] 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.[28][29]

Benzodiazepines are commonly divided into three groups by their half-lives:[30][31]

Type Half-life Notes Examples
Short-acting compounds 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 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 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

Alcohol dependence

Benzodiazepines are the preferred choice in the management of alcohol withdrawal syndrome, particularly for preventing or treating seizures and delirium.[32] The most commonly used in the management of alcohol withdrawal are diazepam (Valium) and chlordiazepoxide (Librium). Their long half-life makes withdrawal smoother and rebound withdrawal symptoms less likely to occur. 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, and it is the most effective in preventing and controlling acute seizures.[33] However, the shorter acting benzodiazepines may be less effective than longer acting ones in reducing alcohol withdrawal symptoms, and may lead to break through seizures. They are thus not recommended for outpatient detoxification. The patient is also more prone to rebound effects if they are not tapered after alcohol detoxification.[34][35]

Seizures

Main anticonvulsant
benzodiazepines

Prolonged convulsive epileptic seizures are a medical emergency that can usually be dealt with effectively by administering fast-acting benzodiazepines, which are potent anticonvulsants. In a hospital environment, intravenous lorazepam and diazepam are first-line choices, with a preference for lorazepam due to its longer duration of action. In the community, intravenous administration is not practical and so rectal diazepam or (more recently) buccal midazolam are used, with a preference for midazolam as its administration is easier and more socially acceptable.[36][37]

When the benzodiazepines were first introduced they were enthusiastically adopted for treating all forms of epilepsy. However, drowsiness and tolerance become problems with continued use and none are now considered first-line choices for long-term epilepsy therapy.[38] Clobazam is widely used by specialist epilepsy clinics worldwide (but is unavailable in the US), and clonazepam is popular in France.[38] In the UK, both clobazam and clonazepam are second-line choices for treating many forms of epilepsy.[39] Clobazam also has a useful role for very short-term seizure prophylaxis and in catamenial epilepsy.[38] Discontinuation of benzodiazepines after long term use in epilepsy requires additional caution because of the risks of rebound seizures as well as a benzodiazepine withdrawal syndrome. Therefore, the dose is slowly tapered over a period of up to six months or longer.[37]

Anxiety, panic and agitation

Main anxiolytic
benzodiazepines

As they possess anti-anxiety properties, benzodiazepines can be useful for the short-term treatment of severe anxiety.[40] Tolerance can develop to their anxiolytic effects, and there is also a risk of dependence. These factors limit their long term use in the treatment of anxiety disorders.[41][42] Other problems associated with long term use include psychomotor impairment, cognitive and memory impairments, and a benzodiazepine withdrawal syndrome upon discontinuation.[43]

Benzodiazepines are often prescribed long term for anxiety disorders, despite certain antidepressants and the anticonvulsant drug pregabalin being recommended as first line treatment options. Their effectiveness is questioned for this indication and is not recommended by current guidelines.[44] They 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.[45] Benzodiazepines are also used to treat the acute panic caused by hallucinogen intoxication.[46] Benzodiazepines are occasionally prescribed for panic disorder.[47][48] 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 use in panic disorder.[49]

Benzodiazepines can be very useful in the short-term treatment of acute psychosis such as schizophrenia or mania, bringing about rapid tranquillization 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 most commonly used but clonazepam is also sometimes prescribed.[50][51][52][53]

Insomnia

Main hypnotic
benzodiazepines

Hypnotic benzodiazepines are prescribed for the short-term management of severe or debilitating insomnia. Hypnotic benzodiazepines have strong sedative effects, are typically the most rapid-acting 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 ones (for example, temazepam or loprazolam) may have less "hangover" effects.[54] The risks of tolerance and dependence limits their use long term.[41] Preferably they should be prescribed for only a few days at the lowest effective dose and avoided altogether wherever possible in the elderly. It has been argued that long term use of hypnotics and overprescribing of these drugs represents an unjustifiable risk to the individual and to public health.[55]

Other indications

Benzodiazepines are often used for a wide range of conditions. Some of the most notable indications are summarised below.

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.[56]

Benzodiazepines are effective as premedication before surgery. Administered a couple of hours before surgery, they 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.[56] Diazepam or temazepam can be utilized in patients who are particularly anxious about dental procedures for example those with dental phobia.[56]

Benzodiazepines are well known for their strong muscle-relaxing properties and can be useful in the treatment of muscle spasms caused by tetanus.[57] Stiff person syndrome which is a neurological disorder characterized by severe muscle stiffness can be treated with benzodiazepines.[58][59] Eclampsia is also responsive to benzodiazepines but is not as effective as intravenous magnesium.[60]

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.[61][62] Benzodiazepines are used before surgery as premedication for muscular relaxation[63] and during surgery in combination with other general anesthetic drugs such as ketamine.[64][65][66] They are effective in controlling tremors, seizures and epilepsy.[67][68][69] Midazolam can also be used along with other drugs in the sedation and capture of wild animals.[70]

Contraindications and interactions

Contraindications

The use of benzodiazepines in certain groups of people may cause significant adverse effects or worsening of a medical condition. Therefore they are either not recommended or special caution is required in the following groups of people; benzodiazepines are contraindicated in those with neuromuscular respiratory weakness including myasthenia gravis or respiratory depression, pregnancy, breast feeding,[71] acute pulmonary insufficiency, sleep apnoea syndrome or severe liver impairment. Benzodiazepines should not be used for chronic psychosis, phobic or obsessional states. Caution is required in individuals with a history of drug or alcohol abuse, personality disorders, porphyria, elderly and debilitated, renal impairment or in depressive mood disorders such as major depression risk of precipitating suicidal tendencies. If used they should not be used alone to treat major depression. Prolonged use should be avoided and abrupt withdrawal thereafter.[72][73] Individuals with a history of physical dependence on benzodiazepines or other cross tolerant drugs such as other GABAergic sedative hypnotic drugs including alcohol should generally avoid them as there is a risk of rapid reinstatement of dependency.[74]

Interactions

Individual benzodiazepines may have different interactions with certain drugs and depending on their metabolism pathway they can be roughly divided into two groups. The largest group consists of benzodiazepines that are metabolized by cytochrome enzymes and possess significant potential for interactions with other drugs. The other group includes lorazepam, oxazepam and temazepam that are metabolized through glucoronidation generally have few drug interactions.[75] Taking benzodiazepines with alcohol, opioids and other central nervous system depressants potentiates their action. This often results in increased sedation, impaired motor coordination, suppressed breathing and other adverse effects and may potentially be lethal.[76][71][77] Antacids may slow down absorption of some benzodiazepines; however, this effect is marginal and inconsistent.[76] Oral contraceptives, some antibiotics, antidepressants, antifungal agents and other drugs inhibit cytochrome enzymes in the liver. They reduce the rate of elimination of many benzodiazepines leading to possibly excessive drug accumulation and increased side effects. St John's wort, antibiotic rifampicin and anticonvulsants carbamazepine and phenytoin induce cytochrome enzymes, accelerate elimination of many benzodiazepines and decrease their action. [71][76]

Side effects

The most common side effects are related to their sedating and muscle-relaxing action. They include drowsiness, dizziness, decreased alertness, concentration and coordination. This may result in ataxia, falls and injuries, particularly in the elderly. Benzodiazepines adversely affect cognition; they interfere with the formation and consolidation of memories of the new material and may induce complete anterograde amnesia. Decreased libido and erection problems are a common side effect. An emergence of depression and paradoxical side reactions of disinhibition have been observed.[78][79] Impairment driving skills and increase the risk of road traffic accidents.[80][81] Less common side effects include nausea and changes in appetite, blurred vision, headache, confusion, changes in heart rate, euphoria, hypotension, dissociation or depersonalization, nightmares, chest pain, vision changes and very rarely jaundice.[72][82][83][84][85]

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 the general population. These reactions are explained as consequences of disinhibition. Disinhibition often occurs when benzodiazepines are taken by individuals who have a borderline personality disorder or consumed with alcohol or in high doses.[86] Aggression and violent outbursts can also occur, 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.[87][88] It is possible that oxazepam has a lower rate of disinhibition reactions than other benzodiazepines. In controlled trials, the disinhibition reactions were monitored only in clinical trials of alprazolam and were observed in 10–20% of the treated patients.[88] Paradoxical reactions may occur in any individual on commencement of therapy but may be more common in certain groups of patients e.g., alcoholics, children and individuals with certain psychiatric disorders.[84]

Physical dependence and withdrawal

Main article: Benzodiazepine dependence
See also: Long-term effects of benzodiazepines
Diazepam 2 mg and 5 mg diazepam tablets, which are commonly used in the treatment of benzodiazepine withdrawal.

Long-term 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. The long-term effects of benzodiazepines include impaired concentration and memory, sleep problems, depression, anxiety and panic attacks as well as agoraphobia.[10][11][12] Use of high doses (or high potency benzodiazepines) and those with a shorter half life increases the severity of the withdrawal syndrome. Effects of other cross tolerant sedative hypnotics, e.g., barbiturates or alcohol are additive and thus also contribute to the severity of the withdrawal syndrome.[89] Withdrawal from chronic 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 reduction regime is recommended. The opinion on the time needed to complete it 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 times 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 reduction can vary quite significantly and needs to be customized to the needs of the individual person.[90]

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, depersonalization, derealization, hypersensitivity to stimuli, abnormal sensation of movement and less commonly depression, suicidal behavior, psychosis, seizures and delirium tremens.[91] Approximately 10% of patients will experience a notable protracted withdrawal syndrome. Protracted 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 or withdrawal. Nevertheless such symptoms do typically gradually lessen as the months and years go by eventually disappearing altogether.[12]

Withdrawal management

Main article: Benzodiazepine withdrawal syndrome
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.

Benzodiazepine withdrawal symptoms occur when the dosage is reduced in people who are physically dependent on benzodiazepines. Abrupt or over-rapid dosage reduction can produce severe symptoms. Withdrawal symptoms may also occur during a very gradual and slow dosage reduction but are typically less severe. Symptoms may persist as part of a protracted withdrawal syndrome for many months after cessation of benzodiazepines.[92]

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.[90] 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] Chlordiazepoxide which also has a long half life and long acting active metabolites can be used as an alternative to diazepam.[93][90]

The speed of 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 rate of reduction 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 have almost invariably withdrawn or been withdrawn too quickly.[90]

Use in special populations

Pregnancy

See also: Long term effects of benzodiazepines § Neonatal effects
Benzodiazepines taken during pregnancy has adverse effects on the baby. Abrupt withdrawal in benzodiazepine dependent pregnant women may result in spontaneous abortions and provoke suicidal ideation.

International statistics show that 3.5% of women consume psychotropic drugs during 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.[94] Long term use of benzodiazepines during pregnancy or breast feeding is contraindicated.[95] In the United States, the Food and Drug Administration has categorized benzodiazepines into either category D or category X meaning potential for harm in humans has been demonstrated.[96]

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.[97] 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 during pregnancy may lessen the severity. Acute doses of benzodiazepines during labor may additionally lead to floppy infant syndrome. A small study linked benzodiazepines to a number of adverse effects in the newborn including low birth weight, which normalized by 10 months and small head circumference which was still present at 18 months. Possible but uncertain teratogenic effects 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 are recommended over potentially more harmful benzodiazepines such as alprazolam or triazolam. Using the lowest effective dose for the shortest period of time minimizes the risks to the unborn child.[98]

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. Sudden withdrawal has a high risk of causing extreme withdrawal symptoms including suicidal ideation and a severe rebound effect of the underlying mental health disorder, if present. One study reported that one third of mothers who suddenly discontinued or very rapidly tapered their medications became acutely suicidal due to "unbearable symptoms". 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.[99]

Elderly

Adverse effects of benzodiazepines are increased in the elderly. These adverse effects are often mistaken for the effects of old age.

Benzodiazepines are generally not recommended for the elderly due to a range of adverse effects.[4] The toxicity is increased with the coadministration of other central nervous system depressants or from long term use of benzodiazepines.[100] 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.[101] 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 ones. 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.[102] 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 (e.g., zaleplon and zolpidem) do not seem to cause such profound adverse effects on the elderly.[103] Still, a law introduced in New York State reducing benzodiazepine use by 60% did not result in a measurable decrease in hip fractures.[104] 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.[105][106][107]

The adverse effects of benzodiazepines cause an increased morbidity in the elderly which results in an increased use of healthcare services.[108] The elderly are more sensitive to the adverse effects 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 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 over time. 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.[109] Whilst sometimes prescribed to treat behavioral symptoms in dementia there is little evidence demonstrating their effectiveness and limited information on their safety.[110][111][112] 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.[113] A past history of benzodiazepine use and withdrawal may also predict dementia but the literature is conflicting and inconclusive.[114]

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 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.[115]

Pharmacology

Chemistry

5-phenyl-1H-benzo[e]
[1,4]diazepin-2(3H)-one forms the skeleton on many of the most common benzodiazepine pharmaceuticals, such as diazepam (7-chloro-1-methyl substituted).

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-1H-benzo[e][1,4]diazepin-2(3H)-one substructure (see figure to the right).[116] 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.[117][118][119][120]

Mechanism of action

GABAA receptor activation

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 a heteromer 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.[121]

Benzodiazepines bind at the interface of the α and γ subunits on the GABAA receptor. 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.[122] Other sites on the GABAA receptor also bind neurosteroids, barbiturates and certain anesthetics.[123] 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.[124]

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 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, those 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.[125]

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.[126]

PBR modulation

The benzodiazepine class of drugs also 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 body to injury.[127][128][129]

Adenosine reuptake inhibition

Finally, benzodiazepines also function as weak adenosine reuptake inhibitors. It has been suggested that some of their anticonvulsant, anxiolytic, and muscle relaxant effects may be in part mediated by this action.[130][131]

Overdose

Main article: Benzodiazepine overdose
The use of Flumazenil is controversial following benzodiazepine overdose.

Taken alone, benzodiazepines rarely cause severe complications in overdose,[132] and deaths after hospital admission are rare.[133] However, combining these drugs with alcohol or opiates is particularly dangerous and may lead to coma and death.[134][135] 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.[136]

A reversal agent for benzodiazepines exists, flumazenil (Anexate). Its use as an antidote in an overdose however is controversial.[137] 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.[138] One study found that only 10% of the patient population presenting with a benzodiazepine overdose are suitable candidates for treatment with flumazenil.[139]

Drug misuse

Main article: Benzodiazepine drug misuse
Alprazolam "Bars" 2 mg tablets

Benzodiazepines are used recreationally. 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 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 misusers.[140] 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.[141] Mortality is higher among poly-drug misusers that also use benzodiazepines. Heavy alcohol use also increases mortality among poly-drug users.[142]

Drug misusers addicted to benzodiazepines develop a high degree of tolerance, coupled with dosage escalation, often increasing their dosage to very high levels. Tolerance and dependence to benzodiazepines develops rapidly, with a benzodiazepine withdrawal syndrome after as little as 3 weeks of continuous use. Long-term use of benzodiazepines has the potential to cause both physical and psychological dependence and severe withdrawal symptoms. Benzodiazepines and in particular temazepam, are sometimes used intravenously, which if done incorrectly, or in an unsterile manner, or by using shared syringes and 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 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.[143]

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 were more likely than men to be using heroin, whereas male users 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.[144]

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.[145] Temazepam use was particularly associated with violent or disorderly behaviours and contact with the police in a 1997 study of young single homeless people in Scotland.[146]

See also: Benzodiazepine_drug_misuse § Legal_status

Internationally, benzodiazepines are categorized as Schedule IV controlled drugs, apart from flunitrazepam which is a Schedule III drug under the Convention on Psychotropic Substances.[147] Some variation in drug scheduling exists in individual countries, for example in the United Kingdom midazolam and temazepam are Schedule III controlled drugs.[148][149]

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Further reading

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