Benzodiazepine

The benzodiazepines (pronounced [ˌben-zō-dī-ˈa-zə-ˌpēn], 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).

The long-term use of benzodiazapines can cause physical dependence. The use of benzodiazepines should therefore commence only 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.

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Common benzodiazepines

The core chemical structure of "classical" benzodiazepine drugs is a fusion between the benzene and diazepine ring systems. Many of these drugs contain the 5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one substructure (see figure to the above right).

Most benzodiazepines are administered orally; however, administration can also occur intravenously, intramuscularly, sublingually or as a suppository. Well-known benzodiazepines and their primary trade names include:

• alprazolam (Xanax)
• bromazepam (Lexotanil or Lexotan)
• chlordiazepoxide (Librium)
• clonazepam (Klonopin)
• diazepam (Valium)
• estazolam (ProSom)
• flunitrazepam (Rohypnol)
• flurazepam (Dalmane)
• lorazepam (Ativan)
• lormetazepam (Loramet)
• mexazolam (Sedoxil)
• midazolam (Dormicum)
• nitrazepam (Mogadon)
• oxazepam (Serax)
• temazepam (Restoril)
• triazolam (Halcion)
• clorazepate (Tranxene)

A related class of drugs that also work on the benzodiazepine receptors, the nonbenzodiazepines, has recently been introduced.^[2] Nonbenzodiazepines are molecularly distinct from benzodiazepines and have less addictive potential, while still offering benefits very similar to those of benzodiazepines.

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. Daytime withdrawal symptoms are also a problem with prolonged usage of short-acting benzodiazepines, including daytime 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, whereas 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

Benzodiazepines produce a range of effects from depressing to stimulating the central nervous system via modulating the GABA_A receptor, the most prolific inhibitory receptor within the brain. The GABA_A receptor is made up from 5 subunits out of a possible 19, and GABA_A receptors made up of different combinations of subunits have different properties, different locations within the brain, and different activities relative to pharmacological and clinical effects.

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

In order for GABA_A 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 GABA_A receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABA_A 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 GABA_A 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 GABA_A 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 that bind to the benzodiazepine receptor and enhance the GABA receptor function are termed benzodiazepine receptor agonists and display sedative/hypnotic properties. Compounds that, in the absence of agonist, have no apparent activity but that competitively inhibit the binding of agonists to the receptor are called benzodiazepine receptor antagonists. Ligands that 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, resulting in diazepam's having only a 20– to 30-minute duration of action against status epilepticus. Lorazepam, however, has a much smaller volume of distribution of unbound drug, which results in a more prolonged duration of action against status epilepticus. Lorazepam can therefore be considered superior to diazepam, at least in the initial stages of treatment of status epilepticus.^[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

Hypnotic benzodiazepines have strong sedative effects, and certain benzodiazepines therefore are often prescribed for the management of insomnia. Longer-acting benzodiazepines, such as nitrazepam, have side-effects that 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 these benzodiazepines are taken regularly for more than a few weeks.

Use as a premedication before procedures

Benzodiazepines can be very beneficial as premedication before surgery, especially in those that 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 unpleasantness from surgery.[3] Lorazepam can be utilized in patients who are particularly anxious about dental procedures.[4] Alternatively nitrous oxide can be administered in dental phobia due to its sedative and dissociative effects, its fast onset of action, and its extremely short duration of action.

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.[5]

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, because it may have more risks associated with it, should only be used in an inpatient setting.[6]

Use in muscular disorders

Benzodiazepines are well known for their strong muscle-relaxing properties, and can be useful in the treatment of muscle spasms, for example, Tetanus or spastic disorders [7] and Restless legs syndrome.

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 utilized for their 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] Phenobarbital is the drug of choice and potassium bromide is the drug of second 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 tranquilization 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, 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, e.g., 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 to the following day.

Benzodiazepines can cause a wide range of significant behavioral disturbances and cognitive impairment. Cognitive deficits, including concentration and memory-processing problems, are a well-known adverse effect of benzodiazepines and occur at prescribed dose levels. The degree of cognitive impairment will depend on the dose used and 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 utilized in a therapeutic setting to reduce unpleasant memories from investigatory medical procedures, e.g., endoscopies. In addition, the amnesic and sedating properties have found favor 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, those in the United States should read the patient information, prescriber guide, or manufacturer's information as published in the PDR or other such manuals.

Paradoxical reactions

Severe behavioral 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 behavioral 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 while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilizers 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 disinhibition 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. In general, 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 with various sedative compounds that act by enhancing the GABA_A receptor. Cross tolerance means that one drug will alleviate the withdrawal effects of another. It also means that tolerance of one drug will result in tolerance of another similarly-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 act by enhancing the GABA_A receptor's function via modulating the chloride ion channel function of the GABA_A receptor.^{[40][41][42][43]}

Dependence and withdrawal

Main article: Benzodiazepine withdrawal syndrome

Long-term benzodiazepine usage, in general, leads to some form of tolerance and/or dependence. Regular use of benzodiazepines at prescribed levels for six 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. However, with abrupt withdrawal after six 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 they are prescribed for or taken for longer than four weeks, with physical dependence and withdrawal symptoms being the most common problem, but also occasionally drug-seeking behavior. 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 long-term use beyond four weeks, use of high doses, and use of potent short-acting benzodiazepines among 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 occur only in people on high-therapeutic-dose ranges, and low- or normal-dose dependence was not suspected until the 1970s; and it wasn't until the early 1980s that it was confirmed.^[47] However, low-dose dependence is now a recognized 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 four baboons on low-dose benzodiazepine treatment, three out of the four baboons demonstrated physical dependence and developed flumazenil-precipitated withdrawal symptoms after only two weeks of low-dose benzodiazepine treatment. Furthermore, the baboons on low-dose therapy did not develop more severe flumazenil-precipitated withdrawal symptoms because 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 two weeks of chronic, low-dose benzodiazepine treatment.^[52] In another animal study, physical dependence was demonstrated with withdrawal signs appearing after only seven days of low-dose benzodiazepine treatment, and withdrawal signs appeared after only three days after high-dose treatment, which demonstrated the extremely rapid development of tolerance and dependence on benzodiazepines, at least in baboons. It was also found that previous exposure to benzodiazepines sensitized baboons to the development of physical dependence.^[53]

In humans, chronic, low-therapeutic-dose dependence was clearly demonstrated using flumazenil to show physical dependence and withdrawal signs. Withdrawal symptoms experienced by the chronic therapeutic low-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 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 behavior and drug craving, whereas other papers have found the opposite, attributing the problem to a problem of physical dependence with drug-seeking and craving not being typical of low-dose benzodiazepine users.^[57][58]

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 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.^[59][60] The speed of benzodiazepine reduction regimes varies from person to person, but is usually 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]

The Committee on the Review of Medicines

The Committee on the Review of Medicines (UK) carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence, and benzodiazepine withdrawal problems and other adverse effects. The committee found that benzodiazepines do not have any antidepressant or analgesic properties, and are therefore unsuitable treatments for conditions such as depression, tension headaches, and dysmenorrhoea. Benzodiazepines are also not beneficial in the treatment of psychosis due to a lack of efficacy. The committee also recommended against benzodiazepines being used in the treatment of anxiety or insomnia in children. The committee was in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA) that there was little evidence that long-term use of benzodiazepine hypnotics are beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep-promoting properties within 3–14 days of continuous use, and, in the treatment of anxiety, the committee found that there was little convincing evidence that benzodiazepines retain efficacy in the treatment of anxiety after 4 months of continuous use due to the development of tolerance.

The committee found that regular use of benzodiazepines may cause dependence characterized by tolerance to the therapeutic effects and the development of benzodiazepine withdrawal syndrome, which includes symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal symptoms tended to develop within 24 hours after the cessation of a short-acting benzodiazepine and within 3–10 days after intermediate-acting benzodiazepines. Withdrawal effects could occur, however, after treatment lasting only 2 weeks at therapeutic-dose levels, but with a higher tendency with habitual use beyond 2 weeks and more likely at higher doses. The withdrawal symptoms may appear to be similar to the original condition before treatment. The committee reported that all benzodiazepine therapy should be withdrawn gradually, that therapy be limited to short-term use only and only in carefully-selected patients.

It was noted in the review that alcohol can potentiate the central nervous system depressant effects of benzodiazepines and should be avoided concomitantly. These effects may affect an individual's ability to drive or operate machinery, with the elderly being more prone to these adverse effects. In the neonate, high single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hypothermia, along with irregularities in the fetal heart. Benzodiazepines should also be avoided during lactation.

Taken together, withdrawal from benzodiazepines should be gradual, as abrupt withdrawal from high doses may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhoea.^[63]

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:

• Insomnia
• Rebound REM (or dreaming) sleep
• Hypnagogia
• Nightmares
• Anxiety, possible panic attacks
• Tachycardia
• Hypertension
• Depression, possible suicidal ideation
• Tremor
• Perspiration
• Loss of appetite
• Dysphoria
• Depersonalization
• Derealisation (Feelings of unreality)
• Tinnitus
• Gastrointestinal problems (Stomach and abdomen)^[64]
• muscular spasms or cramps, fasciculations ^[65]

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

• Convulsions, which may result in death^[66][67]
• Catatonia, which may result in death^[68]
• Delusions
• Homicidal ideation^[69]
• Violence ^[70]
• Psychosis
• Mania ^[71]
• Effects similar to delirium tremens

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 that 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 a patient knowledgable in benzodiazepine withdrawal. People that report severe experiences from benzodiazepine withdrawal have almost invariably withdrawn or been withdrawn too quickly.

Non-medical use

Benzodiazepines are used/abused recreationally and activate the dopaminergic reward pathways in the central nervous system.^[72] Misusers of benzodiazepines develop a high degree of tolerance, coupled with dosage escalation, often increasing their dosage to very high levels. Long-term use of benzodiazepines has the potential to cause both physical and psychological dependence, and are at risk of severe withdrawal symptoms. Tolerance and dependence to benzodiazepines develop rapidly with users of benzodiazepines, demonstrating benzodiazepine withdrawal syndrome after as little as 3 weeks of continuous use. Benzodiazepines, and in particular temazepam, are sometimes used intravenously, which can lead to medical complications including abscesses, cellulitis, thrombophlebitis, arterial puncture, deep vein thrombosis, hepatitis B and C, HIV or AIDS, overdose and gangrene.

Benzodiazepine use is widespread among amphetamine users, and those that have used amphetamines and benzodiazepines have greater levels of mental health problems, social deterioration, and poorer general health. 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 users.^[73] 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.^[74]

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 2mg-size reductions. Additional drugs, such as antidepressants like buspirone, β blockers, and carbamazepine, should not be added into the withdrawal program unless there is a specific indication for their use.^[75]

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. After six years, 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.^[76]

Increased mortality was found in drug misusers that also used benzodiazepines against those that did not. Heavy alcohol misuse was also found to increase mortality among multiple-drug users.^[77]

Neuropsychological function can be permanently affected by abuse of certain hypnotic benzodiazepines (temazepam, nitrazepam, flunitrazepam, and nimetazepam were found to be particularly toxic), with brain damage similar to alcoholic brain damage, as was shown in a 4– to 6-year follow-up study of hypnotic abusers by Borg and others of the Karolinska Institute. The CT scan abnormalities showed dilatation of the ventricular system. However, unlike alcoholics, hypnotic abusers showed no evidence of widened cortical sulci. The study concluded that, when cerebral disorder is diagnosed in hypnotic benzodiazepine abusers, it is often permanent.^[78] An earlier study by Borg et al. found evidence of cerebral disorder in those that exclusively abused hypnotic benzodiazepines, suggesting that cerebral disorder was not the result of other substances of abuse. Anxiolytic benzodiazepines, such as diazepam, clonazepam, alprazolam, bromazepam and lorazepam were not found to have the same toxic properties of most of the hypnotics.^[79]

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 temazepam, but some reported injecting prescribed temazepam or more rarely, other 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. The most consequential, and by far most commonly-abused benzodiazepine, was temazepam.^[80] In the U.S. several jurisdictions have reported that benzodiazepine abuse by criminal detainees has surpassed that of opiates.^[81]

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.^[82][83][84] 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.^[85][86] When benzodiazepines are used for criminal purposes against a victim they are often mixed with food or drink.^[87] Flunitrazepam, temazepam, and midazolam are the most common benzodiazepines used to facilitate date rape.^[88] Alprazolam has been abused for the purpose of carrying out acts of incest and for the corruption of adolescent girls.^[89] However, alcohol remains the most common drug involved in cases of drug rape.^[90] 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.^[91] 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.^[92] Flunitrazepam has been implicated as the cause of one serial killers violent rampage, triggering off extreme aggression with anterograde amnesia.^[93] 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 while 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.^[94]

Patients reporting to two emergency rooms in Canada with violence-related injuries were most often found to be intoxicated with alcohol and were significantly more likely to test positive for benzodiazepines (most commonly temazepam) than other groups of individuals, whereas other drugs were found to be insignificant in relation to violent injuries.^[95]

Overdose

Overdosage of benzodiazepines, particularly when combined with alcohol or opiates, may lead to coma.^[96] The antidote for all benzodiazepines is flumazenil (Anexate®), 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.^[97][98]

Flumazenil should be administered only by physicians that 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 that are showing significant impairment of consciousness and respiratory depression and that 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 patient's ability to protect his or her own airway. Flumazenil, however, should be avoided in patients suspected of taking proconvulsant drugs, e.g., tricyclic antidepressants, and patients with a history of epilepsy. Flumazenil should also be avoided in patients that 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 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 be used only where full resuscitation equipment is immediately available.^[99]

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 longer-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 in order to avoid relapse of the clinical condition. In neonates and small children, intravenous flumazenil of 10 to 20 μg/kg is an effective dose range for benzodiazepine overdose. Alternative routes of administration are intramuscular, oral (20 to 25 mg three times daily or as required), and rectal, which may be used as alternatives in long-term regimens. Flumazenil can precipitate seizures in patients that have taken mixed overdoses of carbamazepine or tricyclic antidepressants; flumazenil can also precipitate 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.^[100]

From a research perspective, there are some data suggesting that temazepam may be more frequently involved in drug-related deaths than are some other benzodiazepines. Temazepam produced more sedation than did other benzodiazepines, in overdose situations. Thus, there is some reason to think that temazepam (once taken in overdose) may have greater toxicity than other benzodiazepines. ^[101]

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.^[102]

In Australia, most benzodiazepines are schedule 4, which means they must be prescribed by a registered doctor. Dentists are also able to prescribe benzos, however they are not able to prescribe repeats. Flunitrazepam is the only benzo that is rated as a schedule 8, which places a number of additional requirements on the prescribing doctor and the dispensing pharmacist. Injectable, liquid preparations of many common bendzodiazepines are also classed as schedule 8, despite their tablet dose forms being only schedule 4.

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 whose 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.^[103] In Ireland, temazepam and flunitrazepam are both Schedule 3 drugs under the Misuse of Drugs (Amendment) Regulations, (1993), while all other benzodiazepines are Schedule 4. Similar laws apply for the trafficking and possession of temazepam in Australia and Asia. In the United States, temazepam is the only benzodiazepine that requires specially-coded prescriptions in some states. In Hong Kong, temazepam and nimetazepam are regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. All other benzodiazepines are regulated under a much less restrictive Schedule category.

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.

The generic chemical name of chlordiazepoxide is methaminodiazepoxide. It was marketed under the trade name Librium, derived from the final syllables of equilibrium. In 1959 it was used by over 2,000 physicians and more than 20,000 patients. It was described as "chemically and clinically different from any of the tranquilizers, psychic energizers or other psychotherapeutic drugs now available." During studies, chlordiazepoxide induced muscle relaxation and a quieting effect on laboratory animals like mice, rats, cats, and dogs. Fear and aggression were eliminated in much smaller doses than those necessary to produce hypnosis. Chlordiazepoxide is similar to phenobarbital in its anticonvulsant properties. However, it lacks the hypnotic effects of barbiturates. Animal tests were conducted in the Boston Zoo and the San Diego Zoo. Forty-two hosptial patients admitted for acute and chronic alcoholism, and various psychoses and neuroses were treated with chlordiazepoxide. In a majority of the patients, anxiety, tension, and motor excitement were "effectively reduced." The most positive results were observed among alcoholic patients. It was reported that ulcers and dermatologic problems, both of which involve emotional factors, were reduced by chlordiazepoxide.^[104]

Chlordiazepoxide enabled the treatment of emotional disturbances without a loss of mental acuity or alertness. It assisted persons burdened by compulsive reactions like one that felt compelled to count the slats on venetian blinds upon entering a room.^[105]

Dr. Carl F. Essig of the Addiction Research Center of the National Institute of Mental Health spoke at a symposium on drug abuse at an annual meeting of the American Association for the Advancement of Science, in December 1963. He named meprobamate, glutethimide, ethinamate, ethchlorvynol, methyprylon, and chlordiazepoxide as drugs whose usefulness can hardly be questioned. However, Essig labeled these newer products as drugs of addiction, like barbiturates, whose habit-forming qualities were more widely-known. He mentioned a 90-day study of chlordiazepoxide, which concluded that the automobile accident rate among 68 users was ten times higher than normal. Participants' daily dosage ranged from 5 to 100 milligrams.^[106]

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.^[107]

See also

• Barbiturate
• Nonbenzodiazepine

References