Benzodiazepines Information, Use, Testing and Treatment

Extensive List of Benzodiazepines By Trade Name, Uses and Doses

The benzodiazepines (pronounced /ˌbɛnzəʊdaɪˈæzəˌpiːn/, often abbreviated to "benzos") are a class of psychoactive drugs with varying hypnotic, sedative, anxiolytic (anti-anxiety), anticonvulsant, muscle relaxant and amnesic properties, which are mediated by slowing down the central nervous system. 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". Benzodiazepines are also used to treat the panic that can be caused by hallucinogen intoxication.

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Benzodiazepines can cause a physical dependence and a benzodiazepine addiction to develop and upon cessation of long term use a benzodiazepine withdrawal syndrome can occur.

History

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The first benzodiazepine, chlordiazepoxide (Librium) was discovered serendipitously in 1954 by the Austrian scientist Leo Sternbach (1908–2005), working for the pharmaceutical company Hoffmann–La Roche. Chlordiazepoxide was synthesised from work on a chemical dye, quinazolone-3-oxides. 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. Tests revealed that the compound had hypnotic, anxiolytic and muscle relaxant effects. Three years later chlordiazepoxide was marketed as a therapeutic benzodiazepine medication under the brand name Librium. Following chlordiazepoxide, in 1963 diazepam hit the market under the brand name Valium, followed by many further benzodiazepine compounds which were introduced over the subsequent years and decades.

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.

A related class of drugs that also work on the benzodiazepine receptors, the nonbenzodiazepines, has recently been introduced. Nonbenzodiazepines are molecularly distinct from benzodiazepines and have similar risks and benefits to those of benzodiazepines. There have been suggestions that they may have a better side effect profile with less dependence potential. However, this is controversial and disputed by bodies such as the National Institute for Clinical Excellence.

Benzodiazepines and their therapeutic uses

The core chemical structure of "classical" benzodiazepine drugs is a fusion between the benzene and diazepine ring systems. Many of these drugs contain the 5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one substructure (see figure to the above right). Benzodiazepines are molecularly similar to several groups of drugs, some of which share similar pharmacological properties, including the quinazolinones, hydantoines, succinimides, oxazolidinediones, barbiturates and glutarimides. Most benzodiazepines are administered orally; however, administration can also occur intravenously, intramuscularly, sublingually or as a suppository. 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.

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. 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.

Anxiolytics

Benzodiazepines possess anti-anxiety properties and can be useful for the short-term treatment of severe anxiety. Like the anticonvulsants, they tend to be mild, well tolerated, and extremely safe. 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.

A panel of over 50 peer-nominated internationally recognized experts in the pharmacotherapy of anxiety and depression judged the benzodiazepines, especially combined with an antidepressant, as the mainstays of pharmacotherapy for anxiety disorders.

Despite increasing focus on the use of antidepressants and other agents for the treatment of anxiety, benzodiazepines have remained a mainstay of anxiolytic pharmacotherapy due to their robust efficacy, rapid onset of therapeutic effect, and generally favorable side effect profile. Treatment patterns for psychotropic drugs appear to have remained stable over the past decade, with benzodiazepines being the most commonly used medication for panic disorder.

Insomnia

Certain benzodiazepines are strictly prescribed for the short-term management of mild (flurazepam, quazepam, estazolam), moderate (lormetazepam, midazolam, loprazolam, brotizolam, nitrazepam), and severe or debilitating (triazolam, nimetazepam, temazepam, flunitrazepam, flutoprazepam) insomnia. Hypnotic benzodiazepines have strong sedative effects, are typically the most rapid-acting benzodiazepines, and have strong receptor affinity. In addition, many of the hypnotics are powerful anticonvulsants (midazolam, nitrazepam, nimetazepam, temazepam, and flutoprazepam) and all are very strong anxiolytics and amnesic agents. Longer-acting benzodiazepines, such as nitrazepam or quazepam, have side-effects that may persist into the next day, whereas the more intermediate-acting benzodiazepines (for example, temazepam or loprazolam) may have less "hangover" effects the next day. 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.

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. Diazepam or temazepam can be utilized in patients who are particularly anxious about dental procedures. Alternatively nitrous oxide can be administered in dental phobia due to its sedative and dissociative effects, its fast onset of action, and its extremely short duration of action.

Intensive care

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

Alcohol dependence

Benzodiazepines have been shown to be safe and effective, particularly for preventing or treating seizures and delirium, and are the preferred agents for treating the symptoms of alcohol withdrawal syndrome. The choice of agent is based on pharmacokinetics. The most commonly used benzodiazepines in the management of alcohol withdrawal are diazepam (Valium) and chlordiazepoxide (Librium), two long-acting agents, and lorazepam (Ativan) and oxazepam (Serax), two intermediate-acting agents. The long half-life of diazepam and chlordiazepoxide make withdrawal smoother, and rebound withdrawal symptoms are less likely to occur. The two intermediate-acting agents have excellent records of efficacy. Chlordiazepoxide is the benzodiazepine of choice in uncomplicated alcohol withdrawal. Oxazepam is the most commonly used benzodiazepine in managing alcohol withdrawal symptoms. It is the benzodiazepine of choice in treating severe alcohol withdrawal symptoms, and it is often used in patients that metabolize medications less effectively, particularly the elderly and those with cirrhosis. Lorazepam is the only benzodiazepine with predictable intramuscular absorption (if intramuscular administration is necessary) and it is the most effective in preventing and controlling seizures. Phenazepam is another benzodiazepine that has been used to treat alcohol withdrawal with excellent efficacy. In Russia, it is preferred over diazepam in the management of alcohol withdrawal.

Muscular disorders

Benzodiazepines are well known for their strong muscle-relaxing properties, and can be useful in the treatment of muscle spasms, for example, Tetanus or spastic disorders and Restless legs syndrome. Clonazepam has been used with efficacy in the treatment of some forms of Tourette's syndrome (with symptoms more on the side of motor tics, as opposed to vocal tics, although almost any tic can be preceded by, and intensify with stress; therapy for Tourette's syndrome is highly individualized.) Many people experiencing tremors may be helped with benzodiazepines.

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 (antipsychotics) 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.

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Interactions and side effects

Interactions

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

• Alcohol and other CNS depressants - cause synergistic adverse effects, with possible increase in depression and suicide.
• Antacids and anticholinergics - may slow down absortion which may slow down acute therapeutic effects.
• Oral contraceptives, isoniazid - reduces the rate of elimination and thus the half-life increases leading to possibly excessive drug accumulation.
• Cimetidine Inhibition of metabolism of benzodiazepines, causing accumulation which especially with long half life benzodiazepines such as diazepam may cause toxic effects.
• Rifampicin - increases rate of metabolism, thus shortening the elimination half-life of benzodiazepines
• Digoxin - protein binding of diazepam altered causing increased digoxin levels
• L-dopa - worsening of parkinsonian symptoms
• Disulfiram - slows down the rate of metabolism leading to increased effects of benzodiazepines

Side-effects

The following list summarizes the side effects which may occur from use of benzodiazepines.

• Drowsiness
• Dizziness
• Upset stomach
• Blurred vision
• Headache
• Confusion
• Depression
• Euphoria
• Impaired coordination
• Changes in heart rate
• Trembling
• Weakness
• Amnesia
• Hangover effect (grogginess)
• Dreaming or nightmares
• Chest pain
• Vision changes
• Jaundice
• Dissociation or depersonalization
• Paradoxical reactions

Physical dependence and withdrawal

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See also: Benzodiazepine dependence

Long-term benzodiazepine usage, in general, leads to some form of tolerance and/or drug dependence with the appearance of a benzodiazepine withdrawal syndrome when the benzodiazepines are stopped or the dose is reduced. Withdrawal from chronic benzodiazepine use is usually beneficial due to improved health such as cognition and improved functioning with possible improved employment status. Abrupt withdrawal can be hazardous therefore a gradual withdrawal is recommended. The time needed to complete withdrawal differs from expert to expert but ranges from 4 weeks to several years, with aiming for 6 months suggested by one leading expert.

Approximately half of patients attending mental health services for conditions including anxiety disorders such as panic disorder or social phobia may be the result of alcohol or benzodiazepine dependence. Sometimes anxiety disorders pre-existed alcohol or benzodiazepine dependence but the alcohol or benzodiazepine dependence often act to keep the anxiety disorders going and often progressively making them worse. Many people who are addicted to alcohol or prescribed benzodiazepines when it is explained to them they have a choice between ongoing ill mental health or quitting and recovering from their symptoms decide on quitting alcohol and or their benzodiazepines. It was noted that every individual has an individual sensitivity level to alcohol or sedative hypnotic drugs and what one person can tolerate without ill health another will suffer very ill health and that even moderate drinking can cause rebound anxiety syndromes and sleep disorders. A person who is suffering the toxic effects of alcohol or benzodiazepines will not benefit from other therapies or medications as they do not address the root cause of the symptoms. Recovery from benzodiazepine dependence tends to take a lot longer than recovery from alcohol but people can regain their previous good health.

Benzodiazepine drug misuse

Benzodiazepines are used/abused recreationally and activate the dopaminergic reward pathways in the central nervous system.

Benzodiazepine use is widespread among amphetamine abusers, those that use amphetamines and benzodiazepines have greater levels of mental health problems and social deterioration. Benzodiazepine injectors are almost four times more likely to inject using a shared needle than non-benzodiazepine-using injectors. It has been concluded in various studies that benzodiazepine use causes greater levels of risk and psycho-social dysfunction among drug abusers. Those who use stimulant and depressant drugs are more likely to report adverse reactions from stimulant use, more likely to be injecting stimulants, and more likely to have been treated for a drug problem than those using stimulant but not depressant drugs. Increased mortality was found in drug misusers that also used benzodiazepines against those that did not. Heavy alcohol misuse was also found to increase mortality among multiple-drug misusers.

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.

Drug related crime

Problem benzodiazepine use can be associated with drug related crime. In a survey of police detainees carried out by the Australian Government, both legal and illegal users of benzodiazepines were found to be more likely to have lived on the streets, less likely to have been in full time work, and more likely to have used heroin or methamphetamines in the past 30 days from the date of taking part in the survey. Benzodiazepine users were also more likely to be receiving illegal incomes and more likely to have been arrested or imprisoned in the previous year. Benzodiazepines were sometimes reported to be abused alone, but most often formed part of a poly drug-using problem. Female users of benzodiazepines were more likely than men to be using heroin, whereas male users of benzodiazepines were more likely to report amphetamine use. Benzodiazepine users were more likely than non-users to claim government financial benefits, and benzodiazepine users who were also poly-drug users were the most likely to be claiming government financial benefits. Those who reported using benzodiazepines alone were found to be in the mid range when compared to other drug using patterns in terms of property crimes and criminal breaches. Of the detainees reporting benzodiazepine use, one in five reported injection use, mostly of illicit temazepam, 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. Benzodiazepines are also sometimes used for criminal purposes such as to rob a victim or to incapacitate a victim in cases of drug assisted rape.