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Benzodiazepines are sometimes abused intravenously which can lead to medical complications including [[abscess]]', [[cellulitis]], [[thrombophlebitis]], arterial puncture, [[deep vein thrombosis]], [[hepatitis]] B and C, [[HIV]] or [[AIDS]], [[overdose]] and [[gangrene]].
Benzodiazepines are sometimes abused intravenously which can lead to medical complications including [[abscess]]', [[cellulitis]], [[thrombophlebitis]], arterial puncture, [[deep vein thrombosis]], [[hepatitis]] B and C, [[HIV]] or [[AIDS]], [[overdose]] and [[gangrene]].


Benzodiazepine use is widespread amongst amphetamine users and those who used amphetamines and benzodiazepines have greater levels of mental health problems, social deterioration, poorer general health and benzodiazepine injectors are almost 4 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 amongst drug misusers.<ref>{{cite journal |author=Darke S |coauthors=Ross J, Cohen J. |title=The use of benzodiazepines among regular amphetamine users. |journal=Addiction (Abingdon, England). |volume=89 |issue=12 |pages=1683-90 |year=1994 |pmid=7866252 |doi=}}</ref> Those who use stimulants 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 stimulants but not depressant drugs.<ref>{{cite journal |author=Williamson S |coauthors=Gossop M, Powis B, Griffiths P, Fountain J, Strang J. |title=Adverse effects of stimulant drugs in a community sample of drug users. |journal=Drug and alcohol dependence. |volume=44 |issue=2-3 |pages=87-94 |date=14 |year=1997 |month=Mar |pmid=9088780 |doi=}}</ref>
Benzodiazepine use is widespread amongst amphetamine users and those who used amphetamines and benzodiazepines have greater levels of mental health problems, social deterioration, poorer general health and benzodiazepine injectors are almost 4 times more likely to inject using a shared needle than non benzodiazepine using injectors. {{Fact}}It has been concluded in various studies that benzodiazepine use causes greater levels of risk and psycho-social dysfunction amongst drug misusers.<ref>{{cite journal |author=Darke S |coauthors=Ross J, Cohen J. |title=The use of benzodiazepines among regular amphetamine users. |journal=Addiction (Abingdon, England). |volume=89 |issue=12 |pages=1683-90 |year=1994 |pmid=7866252 |doi=}}</ref> Those who use stimulants 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 stimulants but not depressant drugs.<ref>{{cite journal |author=Williamson S |coauthors=Gossop M, Powis B, Griffiths P, Fountain J, Strang J. |title=Adverse effects of stimulant drugs in a community sample of drug users. |journal=Drug and alcohol dependence. |volume=44 |issue=2-3 |pages=87-94 |date=14 |year=1997 |month=Mar |pmid=9088780 |doi=}}</ref>


Once benzodiazepine dependence has been established a clinician should first establish the average daily consumption of benzodiazepines and then convert the patient to an equivalent dose of diazepam before beginning a gradual reduction program, starting initially with 2 mg sized reductions. Additional drugs, such as antidepressants like [[buspirone]], [[Beta|β]] blockers or [[carbamazepine]], should not be added into the withdrawal program unless there is a specific indication for their use.<ref>{{cite journal |author=Gerada C |coauthors=Ashworth M |title=ABC of mental health. Addiction and dependence--I: Illicit drugs |journal=BMJ |volume=315 |issue=7103 |pages=297-300 |year=1997 |pmid=9274553 |doi=}}</ref>
Once benzodiazepine dependence has been established a clinician should first establish the average daily consumption of benzodiazepines and then convert the patient to an equivalent dose of diazepam before beginning a gradual reduction program, starting initially with 2 mg sized reductions. Additional drugs, such as antidepressants like [[buspirone]], [[Beta|β]] blockers or [[carbamazepine]], should not be added into the withdrawal program unless there is a specific indication for their use.<ref>{{cite journal |author=Gerada C |coauthors=Ashworth M |title=ABC of mental health. Addiction and dependence--I: Illicit drugs |journal=BMJ |volume=315 |issue=7103 |pages=297-300 |year=1997 |pmid=9274553 |doi=}}</ref>

Revision as of 23:39, 14 August 2007

Alprazolam 2 mg tablets

The benzodiazepines (pronounced [ˌbenzəʊdaɪˈæzəpiːnz], or "benzos" for short) are a class of psychoactive drugs considered minor tranquilizers with varying hypnotic, sedative, anxiolytic, anticonvulsant, muscle relaxant and amnesic properties, which are mediated by slowing down the central nervous system.[1] 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. Another use is to counteract anxiety-related symptoms upon initial use of SSRIs and other antidepressants, or as an adjunctive treatment. Recreational stimulant users often use benzodiazepines as a means of "coming down" (see: Drug abuse).

All benzodiazepines have an addictive potential. Use of benzodiazepines should only commence after medical consultation, and benzodiazepines should be prescribed the smallest dosage possible to provide an acceptable level of symptom relief. Dependence varies with the benzodiazepine used and with the user, with some reporting alprazolam dependence in as little as three days.

Common benzodiazepines

For various benzodiazepines and their respective generic and non-US brand-names, half-lives, and primary uses, see list of benzodiazepines.

Most benzodiazepines are administered orally; however, administration can also occur intravenously, intramuscularly, or as a suppository. When used as a recreational drug, pills are often crushed and snorted. Well-known benzodiazepines and their primary trade names include alprazolam (Xanax), bromazepam (Lexotanil), diazepam (Valium), lorazepam (Ativan), clonazepam (Klonopin), temazepam (Restoril), oxazepam (Serax), flunitrazepam (Rohypnol), triazolam (Halcion), chlordiazepoxide (Librium), flurazepam (Dalmane), estazolam (ProSom), lormetazepam (Loramet) midazolam (Dormicum) and nitrazepam (Mogadon).

A related class of drugs, the nonbenzodiazepines, which are molecularly distinct from the benzodiazepine molecule, has recently been introduced which also work on benzodiazepine receptors.[2] These drugs have benefits very similar to benzodiazepines, but may have less addictive potential.

Pharmacology

Duration of action

Benzodiazepines are commonly divided into three groups by their half-lives: Short-acting compounds have a half life of less than 12 hours and have few residual effects if taken before bedtime, but rebound insomnia may occur and they might cause wake-time anxiety. Intermediate-acting compounds have a half life of 12-24 hours, may have residual effects in the first half of the day. Rebound insomnia however is more common upon discontinuation of short acting benzodiazepines. Day time withdrawal symptoms is also a problem with prolonged usage of short acting benzodiazepines, including day time anxiety. Long-acting compounds have a half life greater than 24 hours.[3][4] Strong sedative effects typically persist throughout the next day if long acting preparations are used for insomnia. Accumulation of the compounds in the body may occur. The elimination half-life may greatly vary between individuals, especially the elderly. Shorter-acting compounds are usually best for their hypnotic effects, whilst longer-acting compounds are usually better for their anxiolytic effects. Benzodiazepines with shorter half-lives tend to be able to produce tolerance and addiction quicker as the drug does not last in the system for as long, with resultant interdose withdrawal phenomenon and next dose craving. Although short acting drugs are more commonly prescribed for insomnia there are exceptions to the rules, such as alprazolam being prescribed as an anxiolytic more than a hypnotic, despite possessing a short half-life.

Mechanism of action

The core chemical structure of benzodiazepines is a fusion between the benzene and diazepine ring systems. Benzodiazepines produce a range of effects from depressing to stimulating the central nervous system via modulating the GABAA receptor, the most prolific inhibitory receptor within the brain. The GABAA receptor is made up from 6 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain and importantly, different activities in regards to pharmacological and clinical effects.

Classical benzodiazepines show high affinity and bind unselectively to GABAA receptors comprised of α1, α2, α3 and α5 subunits but lack affinity for receptors comprised of α4 and α6 subunits. Benzodiazepines bind only to alpha subunits which contain a histidine amino acid residue, (i.e., α1, α2, α3 and α5 containing GABAA receptors). For this reason benzodiazepines show no affinity for α4 and α6 subunits containing GABAA receptors, which contain an arginine instead of a histidine residue. Other sites on the GABAA receptor also bind neurosteroids, barbiturates and certain anesthetics.[5]

In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, where the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarizing the 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 GABAA receptors made up of different collection of subunits. For instance, benzodiazepines with high activity at the α1 are associated with sedation whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits have good anti-anxiety activity.[6]

Clinically used benzodiazepines are full agonists at the benzodiazepine receptor producing anxiolytic and sedating properties. However, with regular or chronic use the risk of physical dependence increases with demonstratable withdrawal symptoms upon discontinuation or dosage reduction. Benzodiazepines also have abuse potential. The benzodiazepine receptor is a modulatory site for the GABA receptor.

Compounds which bind to the benzodiazepine receptor and enhance the GABA receptor function are termed benzodiazepine receptor agonists and display sedative/hypnotic properties. Compounds which in the absence of agonist have no apparent activity but which competitively inhibit the binding of agonists to the receptor are called benzodiazepine receptor antagonists. Finally ligands which decrease GABA function are termed benzodiazepine receptor inverse agonists. Full inverse agonists have potent convulsant activities.

Some compounds lie somewhere between being full agonists or full antagonists and are termed either partial agonists or partial antagonists. There has been interest in partial agonists for the benzodiazepine receptor 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.[7]

The anticonvulsant properties of benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.[8]

Therapeutic uses

Benzodiazepines have a number of therapeutic uses, are well tolerated and are very safe and effective drugs in the short term for a wide range of conditions.

Use as anticonvulsants

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 persistent seizures.[9] 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 and this results in diazepam having only a 20–30 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.[10]

Use as anxiolytics

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.[1]

Use for insomnia

Benzodiazepines have strong sedative effects and benzodiazepines therefore often prescribed for the management of insomnia. Longer-acting benzodiazepines such as nitrazepam have side effects which may persist into the next day whereas the more intermediate-acting benzodiazepines (for example temazepam) may have less "hangover" effects the next day.[2] Benzodiazepine hypnotics should be reserved for short-term courses to treat acute conditions as tolerance and dependence may occur if benzodiazepines are taken regularly for more than a few weeks.[3]

Use as a premedication before procedures

Benzodiazepines can be very beneficial as premedication before surgery, especially in those who are anxious. Usually administered a couple of hours before surgery, benzodiazepines will bring about anxiety relief and also produce amnesia. Amnesia can be useful in this situation as patients will not be able to remember any unpleasant memories from surgery.[4]. Lorazepam can be utilised in patients who are particularly anxious about dental procedures.[5] Alternatively nitrous oxide can be administered in dental phobia due to its sedative and dissociative effects, fast onset of action and its extremely short duration of action.

Use in 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.[6]

Use in alcohol dependence

In the management of alcohol withdrawal benzodiazepines can have potentially life-saving effects by ameliorating the alcohol withdrawal syndrome. Delirium tremens, which can be potentially fatal, can be effectively treated by benzodiazepines and often prevented from occurring in the first place. The usual benzodiazepines used in the management of alcohol withdrawal are Chlordiazepoxide (Librium) or diazepam (Valium). Chlormethiazole is an alternative but is not as well tolerated as benzodiazepines and may have more risks associated with it and should only generally be used in an inpatient setting.[7]

Use in muscular disorders

Benzodiazepines are well known for their strong muscular relaxing properties and can be useful in the treatment of muscular spasms for example Tetanus or spastic disorders.[8]

Use in acute mania

Mania, a mood disorder, is a state of extreme mood elevation and is a diagnosable serious psychiatric disorder. Benzodiazepines can be very useful in the short term treatment of acute mania, until the effects of Lithium or neuroleptics take effect. Benzodiazepines bring about rapid tranquillisation and sedation of the manic individual, therefore benzodiazepines are a very important tool in the management of mania. Both clonazepam and lorazepam are used for the treatment with some evidence that clonazepam may be superior in the treatment of acute mania.[11][12]

Therapeutic uses in veterinary practice

As in humans benzodiazepines have a wide range of uses in veterinary practice in the treatment of various disorders and scenarios involving animals.

Midazolam and diazepam are utilised for its anesthetic properties in veterinary practice in combination with other general anesthetic drugs such as ketamine.[13][14]

Midazolam or diazepam can also be used as a sedative anxiolytic to quell anxiety and agitation experienced by animals in veterinary practice for example during transport. [15][16] Diazepam has also been found to have tranquillising effects on various animals tested with the following properties; myorelaxation, stress reduction and aggression inhibition.[17]

Benzodiazepines are also commonly used for the control of muscular conditions in animals. Diazepam has been prescribed for the effective treatment and control of tremors by veterinarians in animals. Corticosteroids and or Diazepam have been found to be effective for the control of tremors in veterinarian practice.[18][19] Diazepam has also been used in to control muscle spasms that were the result of tetanus in cats.[20]

Benzodiazepines, such as diazepam, are used in the treatment of various forms of epilepsy in dogs.[21] Benzodiazepines have potent anticonvulsant properties and are very effective in the short term in managing seizure disorders in animals. However with prolonged usage benzodiazepines tend to lose their anticonvulsant properties. Partial benzodiazepine receptor agonists have shown some promise with continued efficacy being demonstrated with benzodiazepine receptor partial agonists and also displaying mild withdrawal symptoms upon discontinuation which may make them superior to benzodiazepines in the long term management of epilepsy in animals.[22] Phenobarbitol is the drug of choice and potassium bromide is the drug of 2nd choice in the treatment of epilepsy in dogs and diazepam is recommended for the treatment at home of cluster seizures.[23]

Lorazepam has been found to be an effective premedication before general anesthesia in bringing about adequate muscular relaxation for veterinary surgery.[24]

The benzodiazepine Zolazepam in combination with Tiletamine has been used in the tranquillisation of wild animals such as gorillas and polar bears and has been found to be in terms of reduced side effects superior to ketamine.[25][26] Midazolam can also be used along with other drugs in the sedation and capture of wild animals.[27]

Side effects

The side effects are predictable as they are intrinsic effects of the drug class of benzodiazepines. Knowing the relative effects of benzodiazepine types will help clinicians prescribe the most appropriate type. For example, lorazepam may not be best treatment choice for the elderly due to its stronger amnesic effects and thus greater potential for aggravating forgetfulness and confusion. But then lorazepam is a good choice for the acute treatment of status epilepticus due to its potent anticonvulsant properties.

Benzodiazepines have largely replaced the barbiturates, mainly because benzodiazepines are much safer in terms of overdose. Prior to the introduction of benzodiazepines, barbiturate overdose was of significant concern to both the medical community and the general public. Still, drowsiness, ataxia, confusion, vertigo, impaired judgement, and a number of other effects are common.

The concern is also that - even though they are relatively non-toxic in themselves - benzodiazepines may facilitate suicide by other drugs or means, through disinhibition. However benzodiazepines when combined with other central nervous system depressants such as opiates or alcohol the risk of overdose and death increases significantly due to synergistic CNS, respiratory and cardiovascular system depression. The elderly, alcoholics and those with underlying medical conditions eg respiratory disease or personality disorder are at increased risk for both acute adverse reactions and problems arising from long term use, including dependence, confusion, memory impairment or overdose.[28] 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.[29]

Benzodiazepines may impair the ability to drive vehicles and to operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. The effects of long-acting benzodiazepines can also linger over to the following day.

Benzodiazepines can cause a wide range of significant behavioural disturbances and cognitive impairment. Cognitive deficits including concentration and memory processing problems is a well known adverse effect of benzodiazepines and occurs at prescribed dose levels. The degree of cognitive impairment will depend on the dose used, individual tolerance level to the drug, with the elderly being more vulnerable to cognitive impairments from benzodiazepines.

Amnesia can be a side effect of benzodiazepines and can be utilised in a therapeutic setting to reduce unpleasant memories from investigatory medical procedures eg. endoscopies. Unfortunately the amnesic and sedating properties have found flavour with criminals as a date rape drug. All benzodiazepines can be used as date rape drugs, but flunitrazepam (Rohypnol), clonazepam (Klonopin), midazolam (Versed) and temazepam (Restoril) are the most commonly used.[30]

For a full list of side effects pertaining to a specific drug, individuals in the United States should read the patient information, prescriber guide, or manufacturers information as published in the PDR or other such manuals.

Paradoxical reactions

Severe behavioural changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity and hypomania.[31] Individuals with borderline personality disorder appear to have a greater risk of experiencing severe behavioural or psychiatric disturbances from benzodiazepines. 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.[32] 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.[33]

When benzodiazepines are used as an adjunct in the treatment of seizures, an increase in dosage of the primary agent may be required. The concomitant administration of benzodiazepines and anti-convulsants may precipitate an increase in certain seizure activity, specifically tonic-clonic seizures.

In a letter to the British Medical Journal it was reported that a high proportion of parents referred for actual or threatened child abuse were taking drugs at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members whilst consuming tranquillisers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquillisers may precipitate a child abuse event.[34]

Paradoxical rage reactions from benzodiazepines are thought to be due to partial deterioration from consciousness, generating automatic behaviors, fixation amnesia and aggressiveness from desinhibition with a possible serotonergic mechanism playing a role.[35]

Tolerance

Tolerance develops to many of the therapeutic effects of benzodiazepines rapidly with daily or frequent use. Generally, tolerance to the hypnotic and sedative effects occurs within days; however, tolerance to the anxiolytic effects of benzodiazepines takes longer to develop. According to a 1988 report published by the Committee on Safety of Medicines, there is little evidence of continued anxiolytic properties from benzodiazepines after four months of continuous use other than the suppression of withdrawal signs and recommended that prescriptions of benzodiazepines be limited to 2 - 4 weeks only.[36][37] There is also evidence that long term use may actually worsen anxiety in some people with or without prior psychiatric history as was found in a study of 50 patients.[38] A possible explanation for increased anxiety from chronic use of benzodiazepines is that it is a side effect of tolerance with increasing doses required to suppress withdrawal effects. However, patients should be aware that this could lead to a cycle of increasing doses and worsening side effects. In addition, as dosage is increased, the potential for addiction becomes greater.

Cross tolerance

Benzodiazepines share a similar mechanism of action to various sedative compounds which act via enhancing the GABAA receptor. Cross tolerance typically means that one drug will alleviate the withdrawal effects of another. It also means that taking of one drug will result in a decreased pharmacological effect of another similar acting drug. Benzodiazepines are often used for this reason to detoxify alcohol dependent patients and can have life saving properties in preventing and/or treating severe life threatening withdrawal syndromes from alcohol such as delirium tremens. However, although benzodiazepines can be very useful in the acute detoxification of alcoholics, benzodiazepines in themselves act as positive reinforcers in alcoholics, by increasing the desire for alcohol. Low doses of benzodiazepines were found to significantly increase the level of alcohol consumed in alcoholics.[39] However, alcoholics dependent on benzodiazepines should not be abruptly withdrawn but be very slowly withdrawn from benzodiazepines as over-rapid withdrawal is likely to produce severe anxiety or panic which is well known for being a relapse risk factor in alcoholics. See (benzodiazepine withdrawal syndrome).

There is also cross tolerance between alcohol, the benzodiazepines, the barbiturates and the nonbenzodiazepine drugs which all also act via enhancing the GABAA receptor's function via modulating the chloride ion channel function of the GABAA receptor.[40][41][42][43]

Dependence

Long-term benzodiazepine usage generally leads to some form of tolerance and/or dependence. Regular use of benzodiazepines at prescribed levels for 6 weeks was found to produce a significant risk of dependence with resultant withdrawal symptoms appearing on abrupt discontinuation in a study assessing diazepam and buspirone, but after abrupt withdrawal after 6 weeks of treatment with buspirone no withdrawal symptoms developed.[44] Various studies have shown between 20-100% of patients prescribed benzodiazepines at therapeutic dosages long term are physically dependent and will experience withdrawal symptoms.[45]

Benzodiazepine dependence is a frequent complication when benzodiazepines are prescribed for or taken for longer than 4 weeks with physical dependence and withdrawal symptoms being the most common problem, but also occasionally drug seeking behaviour. Withdrawal symptoms include, anxiety, perceptual disturbances, distortion of all the senses, dysphoria and in rare cases psychosis and epileptic seizures. The risk factors for benzodiazepine dependence are as follows; long term use beyond 4 weeks, use of high doses, use of potent short acting benzodiazepines or those with certain pre-existing personality characteristics such as dependent personalities and those prone to drug abuse.[46]

Previously physical dependence on benzodiazepines was largely thought to only occur in people on high therapeutic dose ranges and low or normal dose dependence wasn't suspected until the 1970's and it wasn't until the early 1980's that it was confirmed.[47] However, low dose dependence is now a recognised clinical disadvantage of benzodiazepines and severe withdrawal syndromes can occur from these low doses of benzodiazepines even after gradual dose reduction.[48][49] Low dose dependence has now been clearly demonstrated in both animal studies and human studies.[50][51]

In an animal study of 4 baboons on low dose benzodiazepine treatment 3 out of the 4 baboons demonstrated physical dependence and developed flumazenil precipitated withdrawal symptoms after only 2 weeks of low dose benzodiazepine treatment. Furthermore the baboons on low dose therapy did not develop more severe flumazenil precipitated withdrawal symptoms as low dose benzodiazepine therapy was continued over a period of 6 - 10 months suggesting, rapid onset of dependence with benzodiazepines and suggesting that physical dependence was complete after 2 weeks of chronic low dose benzodiazepine treatment.[52] In another animal study, physical dependence was demonstrated with withdrawal signs appearing after only 7 days of low dose benzodiazepine treatment and withdrawal signs appeared after only 3 days after high dose treatment demonstrating the development of tolerance and dependence on benzodiazepines at least in baboons as occurring extremely rapidly. It was also found that previous exposure to benzodiazepines sensitised baboons to the development of physical dependence.[53]

In humans, chronic low therapeutic dose dependence was clearly demonstrated using flumazenil to demonstrate physical dependence and withdrawal signs. Withdrawal symptoms experienced by the chronic low therapeutic dose subjects included: increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch.[54] In another study of 34 low dose benzodiazepine users, physiological dependence was demonstrated by the appearance of withdrawal symptoms in 100% of those who received flumazenil whereas those receiving placebo experienced no withdrawal signs. It was also found that those dependent on low doses of benzodiazepines with a history of panic attacks were at an increased risk of suffering panic attacks due to flumazenil precipitated benzodiazepine withdrawal.[55] It has been estimated that 30-45% of chronic low dose benzodiazepine users are dependent and it has been recommended that benzodiazepines even at low dosage be prescribed for a maximum of 7-14 days maximum to avoid dependence.[56]

Some controversy remains however in the medical literature as to the exact nature of low dose dependence and the difficulty in getting patients to discontinue their benzodiazepines with some papers attributing the problem to predominantly drug seeking behaviour and drug craving whereas other papers have found the opposite attributing the problem to predominantly a problem of physical dependence with drug seeking and craving not being typical of low dose benzodiazepine users.[57][58]

Withdrawal

Main article: Benzodiazepine withdrawal syndrome

Benzodiazepine withdrawal syndrome is the symptoms seen when a patient who has taken the drug for a period of time stops taking the drug. Benzodiazepine withdrawal is best managed by transferring the physically dependent patient onto 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.[59][60] The speed that benzodiazepine reduction regimes should be carried out at vary from person to person but usually is between 10% every 2-4 weeks. A slow withdrawal with the patient in control of dosage reductions coupled with reassurance that withdrawal symptoms are temporary have been found to produce the highest success rates.

There is strong anecdotal evidence that a slow withdrawal rate significantly reduces the risk of a protracted and or severe withdrawal state. About 10 - 15% of people who discontinue benzodiazepines develop protracted withdrawal syndrome. There is no known cure for protracted benzodiazepine withdrawal syndrome except time. Flumazenil in a placebo controlled study seemed to bring about temporary relief of protracted withdrawal symptoms, although the author Lader et. al noted that further research is required in this area.[60][61][62]

Withdrawal symptoms

Withdrawal symptoms can occur when benzodiazepine dosage is reduced. Abrupt or over-rapid dosage reduction can produce severe withdrawal symptoms. Withdrawal symptoms can even occur during a very gradual and slow dosage reduction but are rarely serious. The withdrawal symptoms may include:

An abrupt or over-rapid discontinuation of benzodiazepines may result in a more serious and very unpleasant withdrawal syndrome that may additionally result in:

Hence, every person withdrawing from long-term or high dosage of any benzodiazepine should be slowly and carefully weaned off the drug, preferably under medical supervision by a physician who is knowledgeable about the benzodiazepine withdrawal syndrome. The withdrawal syndrome can usually be avoided or minimized by use of a long half-life benzodiazepine and 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 if it is managed effectively by a physician and patient knowledgable in benzodiazepine withdrawal. People who report severe experiences from benzodiazepine withdrawal have almost invariably withdrawn or been withdrawn too quickly.

Abuse

Benzodiazepines are known drugs of abuse and activate the dopaminergic reward pathways in the central nervous system.[71] Misusers of benzodiazepines develop a high degree of tolerance, coupled with dosage escalation, with misusers often increasing their dosage to very high doses. High dose misusers often develop a high degree of tolerance and dependence and are at risk of severe withdrawal syndromes. Tolerance and dependence on benzodiazepines develops rapidly with users of benzodiazepines demonstrating the benzodiazepine withdrawal syndrome after as little as 3 weeks of continuous use. Benzodiazepines are sometimes abused intravenously which can lead to medical complications including abscess', cellulitis, thrombophlebitis, arterial puncture, deep vein thrombosis, hepatitis B and C, HIV or AIDS, overdose and gangrene.

Benzodiazepine use is widespread amongst amphetamine users and those who used amphetamines and benzodiazepines have greater levels of mental health problems, social deterioration, poorer general health and benzodiazepine injectors are almost 4 times more likely to inject using a shared needle than non benzodiazepine using injectors. [citation needed]It has been concluded in various studies that benzodiazepine use causes greater levels of risk and psycho-social dysfunction amongst drug misusers.[72] Those who use stimulants 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 stimulants but not depressant drugs.[73]

Once benzodiazepine dependence has been established a clinician should first establish the average daily consumption of benzodiazepines and then convert the patient to an equivalent dose of diazepam before beginning a gradual reduction program, starting initially with 2 mg sized reductions. Additional drugs, such as antidepressants like buspirone, β blockers or carbamazepine, should not be added into the withdrawal program unless there is a specific indication for their use.[74]

A six year study on 51 vietnam veterans, who were drug abusers of either, mainly stimulants (11 people), mainly opiates (26 people) or mainly benzodiazepines (14 people), was carried out to assess psychiatric symptoms related to the specific drugs of abuse. At 6 year follow up, opiate abusers had little change in psychiatric symptomatology, 5 of the stimulant users had developed psychosis and 8 of the benzodiazepine users had developed depression. Therefore long term benzodiazepine abuse and dependence seems to carry a negative effect on mental health with a significant risk of causing depression.[75]

Increased mortality was found in drug misusers who also used benzodiazepines against those who did not. Heavy alcohol misuse also found to increase mortality amongst poly drug users.[76]

Neuropsychological function can be permanently affected by abuse of sedative hypnotic drugs with brain damage similar to alcoholic brain damage as was shown in a 4-6 year follow-up study of sedative hypnotic abusers by Borg et al of the Karolinska Institute. The CT scan abnormalities showed dilatation of the ventricular system. However, unlike alcoholics there was no evidence of widened cortical sulci. The study concluded that when cerebral disorder is diagnosed in sedative hypnotic abusers, it is often permanent.[77] An earlier study by Borg et al found evidence of cerebral disorder in those who exclusively abused benzodiazepines suggesting that cerebral disorder was not the result of other substances of abuse.[78]

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. Problem benzodiazepine use can be associated with crime. 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 benzodiazepines but some 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.[79] In the USA several jurisdictions have reported that benzodiazepine abuse by criminal detainees has surpassed that of opiates.[80]

Benzodiazepines have also been used as a tool of murder by serial killers, murderers and as a murder weapon by those with the condition Munchausen syndrome by proxy.[81][82][83] Benzodiazepines have also been used to facilitate rape or robbery crimes and benzodiazepine dependence has been linked to shoplifting due to the fugue state induced by the drug.[84][85] When benzodiazepines are used for criminal purposes against a victim they are often mixed with food or drink.[86] Alprazolam has been abused for the purpose of carrying out acts of incest and for the corruption of adolescent girls.[87] However, alcohol remains the most common drug involved in cases of drug rape.[88] Although benzodiazepines and ethanol are the most frequent drugs used in sexual assaults, GHB is another potential date rape drug which has received increased media focus.[89] Some benzodiazepines are more associated with crime than others especially when abused or taken in combination with alcohol. The potent benzodiazepine flunitrazepam (Rohypnol), which has strong amnesia producing effects can cause abusers to become cold blooded and ruthless and also cause feelings of being invincible. This has led to some acts of extreme violence to others, often leaving abusers with no recollection of what they have done in their drug induced state. It has been proposed that criminal and violent acts brought on by benzodiazepine abuse may be related to lowered serotonin levels via enhanced GABAergic effects.[90] Flunitrazepam has been implicated as the cause of one serial killers violent rampage, triggering off extreme aggression with anterograde amnesia.[91] A study on forensic psychiatric patients who had abused Flunitrazepam at the time of their crimes found that the patients displayed extreme violence, lacked the ability to think clearly and experienced a loss of empathy for their victims whilst under the influence of flunitrazepam and it was found that the abuse of alcohol or other drugs in combination with Flunitrazepam compounded the problem. Their behaviour under the influence of Flunitrazepam was in contrast to their normal psychological state.[92]

Patients reporting to two emergency rooms in Canada with violence related injuries were most often found to be in intoxicated with alcohol and were significantly more likely to test positive for benzodiazepines than other groups of individuals whilst other drugs were found to be insignificant in relation to violent injuries.[93]

Overdose

Overdosage of benzodiazepines, particularly when combined with alcohol or opiates may lead to coma.[94] The antidote for all benzodiazepines is flumazenil (Annexate®), a benzodiazepine antagonist, which is occasionally used empirically in patients presenting with unexplained loss of consciousness in an emergency room setting. As with all overdose situations, the care provider must be aware of the possibility that multiple substances were utilized by the patient. Supportive measures should be put in place prior to administration of any benzodiazepine antagonist in order to protect the patient from both the withdrawal effects and possible complications arising from simultaneous utilization of chemically unrelated pharmaceutical compounds. A determination of possible deliberate overdose should be considered with appropriate scrutiny and precautions taken to prevent any attempt by patient to commit further bodily harm.[95][96]

Flumazenil should only be administered by physicians who are familiar and suitably trained in the use of flumazenil in benzodiazepine overdose. Treating benzodiazepine [[overdose] with flumazenil may reduce the chance of the patient being admitted to intensive care, however, caution should be exercised in the administration of flumazenil. The treating physician should bear in mind the possibility of mixed overdoses, especially mixed overdoses of other drugs or substances as cocktails of drugs are often taken in overdose situations with their own overdose risks. Patients suspected of overdosing on benzodiazepines who are showing significant impairment of consciousness and respiratory depression and who are likely to need endotracheal intubation and be admitted to intensive care should be considered for flumazenil therapeutic treatment to avoid intubation and artificial ventilation. The decision to administer flumazenil to a suspected benzodiazepine overdosed patient should be made after a comprehensive clinical evaluation including a complete clinical and biochemical evaluation of the respiratory status and the patients ability to protect his or her own airway. Flumazenil however should be avoided in patients suspected of taking proconvulsant drugs eg tricyclic antidepressants, patients with a history of epilepsy. Flumazenil should also be avoided in patients who have a physical dependency on benzodiazepines as flumazenil may precipitate an acute withdrawal syndrome due to rapidly displacing benzodiazepines from the benzodiazepine receptor, thus potentially triggering severe seizures. Flumazenil should be administrated gradually and carefully to avoid any potentially serious adverse reactions associated with flumazenil usage. The minimum effective dose should be given to patients to avoid the common unpleasant psychological adverse effects of flumazenil administration and also to avoid potentially serious side effects. Patients may become agitated after awakening from flumazenil and may try to leave the treatment environment. In these cases clinicians should warn the patient that leaving the facility may result in re-sedation. Flumazenil should only be used where full resuscitation equipment is immediately available.[97]

Benzodiazepine overdose can either be intentional, accidental or iatrogenic in nature. Flumazenil can reverse all the effects of benzodiazepines due to its specific competitive benzodiazepine receptor antagonist properties. The initial treatment as well as diagnosis of benzodiazepine overdose can be achieved via incremental intravenous bolus injections of flumazenil in the range of 0.1 to 0.3 mg. These dose ranges are generally well tolerated and effective in the diagnosis and treatment of benzodiazepine overdose. Many benzodiazepines are more long acting than flumazenil and therefore there is a significant risk of relapse into coma or respiratory depression as the flumazenil wears off. Additional boluses of flumazenil or else an infusion (0.3 to 0.5 mg/h) therefore may need to be given depending on the half life of the benzodiazepine. Careful monitoring after flumazenil therapy has been discontinued is warranted to avoid relapse of the clinical condition. In neonates and small children intravenous flumazenil 10 to 20 micrograms/kg is an effective dose range for benzodiazepine overdose. Alternative routes of administration are; intramuscular, oral (20 to 25 mg 3 times daily or as required) and rectal administration may be used as alternatives in long term regimens. Flumazenil can precipitate seizures in patients who have taken mixed overdoses of carbamazepine or tricyclic antidepressants, flumazenil can also precipitated benzodiazepine withdrawal symptoms, however these complications of flumazenil administration can be avoided via a careful flumazenil dose titration. Flumazenil therefore is a relatively safe and very effective treatment of benzodiazepine overdose provided it is carried out by an experienced and knowledgeable physician in a suitable clinical environment.[98]

Legal status

All medically-used benzodiazepines are Schedule IV in the USA under the Federal Controlled Substances Act. In Canada benzodiazepines are also Schedule IV.[99]

Australian law allows qualified medical practitioners to prescribe most benzodiazepines to patients, however repeat prescriptions are normally not allowed. Most are subsidised under Medicare, costing around $10, or $AU4.90 for persons on low-income.

Flunitrazepam (Rohypnol) and Temazepam (Restoril) are treated more severely under Federal law than other benzodiazepines. For example, despite being Schedule IV like any other benzodiazepine, flunitrazepam is not commercially available in the United States. It also carries tougher Federal penalties for trafficking and possession than other Schedule IV drugs. With the exception of cases involving 5 grams or more of cocaine or morphine, flunitrazepam is the only controlled substance in which first-offense simple possession is a federal felony. In Europe, especially in the United Kingdom, temazepam and flunitrazepam also carry tougher penalties for trafficking and possession.[100] Similar laws apply for the trafficking and possession of temazepam in Australia and in some parts of Asia. In the United States, some states require specially coded prescriptions for temazepam.

Various other countries limit the availability of benzodiazepines legally. Even though it is a commonly prescribed class of drugs, the Medicare Prescription Drug, Improvement, and Modernization Act specifically states that insurance companies that provide Medicare Part D plans are not allowed to cover benzodiazepines.

All benzodiazepines are List 2 of the opium law in the Netherlands.

History

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. Initially, he discontinued his work on the 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.

In 1963 approval for use was given to diazepam (Valium)—a "simplified" version of chlordiazepoxide—primarily to counteract anxiety symptoms. Sleep-related problems were treated with nitrazepam (Mogadon), which was introduced in 1965, temazepam (Restoril), which was introduced in 1969, and flurazepam (Dalmane), which was introduced in 1973.[101]

See also

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External links

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