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Benzodiazepines

A benzodiazepine is a psychoactive drug.Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA), which results in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, muscle relaxant and amnesic action.These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures.Benzodiazepines are categorized as either short-, intermediate- or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety.

In general, benzodiazepines are safe and effective in the short term, although cognitive impairments and paradoxical effects such as aggression or behavioral disinhibition occasionally occur. Long-term use is controversial due to concerns about adverse psychological and physical effects, increased questioning of effectiveness and because benzodiazepines are prone to cause tolerance, physical dependence, and, upon cessation of use after long term use, a withdrawal syndrome. Due to adverse effects associated with the long-term use of benzodiazepines, withdrawal from benzodiazepines, in general, leads to improved physical and mental health. The elderly are at an increased risk of suffering from both short- and long-term adverse effects.

There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not major teratogens, uncertainty remains as to whether they cause cleft palate in a small number of babies and whether neurobehavioural effects occur as a result of prenatal exposure;they are known to cause withdrawal symptoms in the newborn. Benzodiazepines can be taken in overdoses and can cause dangerous deep unconsciousness. However, they are much less toxic than their predecessors, the barbiturates, and death rarely results when a benzodiazepine is the only drug taken. When combined with other central nervous system depressants such as alcohol and opiates, the potential for toxicity increases. Benzodiazepines are commonly misused and taken in combination with other drugs of abuse

Medical uses:

Benzodiazepines possess sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnesic actions,which are useful in a variety of indications such as alcohol dependence, seizures, anxiety, panic, agitation and insomnia. Most are administered orally; however, they can also be given intravenously, intramuscularly or rectally In general, benzodiazepines are well-tolerated and are safe and effective drugs in the short term for a wide range of conditions.Tolerance can develop to their effects and there is also a risk of dependence, and upon discontinuation a withdrawal syndrome may occur. These factors, combined with other possible secondary effects after prolonged use such as psychomotor, cognitive, or memory impairments, limit their long-term applicability. The effects of long-term use or misuse include the tendency to cause or worsen cognitive deficits, depression and anxiety.

Panic disorder:

Due to their effectiveness, tolerability, and rapid onset of anxiolytic action, benzodiazepines are frequently used for the treatment of anxiety associated with panic disorder.However, there is disagreement among expert bodies regarding the long-term use of benzodiazepines for panic disorder. The views range from those that hold that benzodiazepines are not effective long-term and that they should be reserved for treatment-resistant cases to that they are as effective in the long term as selective serotonin reuptake inhibitors.Benzodiazepines are usually administered orally, however, very occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks.

 

Generalized anxiety disorder:

Benzodiazepines have robust efficacy in the short-term management of generalized anxiety disorder (GAD), but were not shown to be effective in producing long-term improvement overall.According to National Institute for Health and Clinical Excellence (NICE), benzodiazepines can be used in the immediate management of GAD, if necessary. However, they should not usually be given for longer than 2–4 weeks. 

Insomnia:

Benzodiazepines can be useful for short-term treatment of insomnia. Their use beyond 2 to 4 weeks is not recommended due to the risk of dependence. It is preferred that benzodiazepines be taken intermittently and at the lowest effective dose. They improve sleep-related problems by shortening the time spent in bed before falling asleep, prolonging the sleep time, and, in general, reducing wakefulness.However, they worsen sleep quality by increasing light sleep and decreasing deep sleep. Other drawbacks of hypnotics, including benzodiazepines, are possible tolerance to their effects, rebound insomnia, and reduced slow-wave sleep and a withdrawal period typified by rebound insomnia and a prolonged period of anxiety and agitation. 

 

Anxiety:

Benzodiazepines are sometimes used in the treatment of acute anxiety, as they bring about rapid and marked or moderate relief of symptoms in most individuals;however, they are not recommended beyond 2–4 weeks of use due to risks of tolerance and dependence and a lack of long-term effectiveness. As for insomnia, they may also be used on an irregular/"as-needed" basis, such as in cases where said anxiety is at its worst. Compared to other pharmacological treatments, benzodiazepines are twice as likely to lead to a relapse of the underlying condition upon discontinuation.  

Other indications:

Benzodiazepines are often prescribed for a wide range of conditions:

  • They can be very useful in intensive care to sedate patients receiving mechanical ventilation or those in extreme distress. Caution is exercised in this situation due to the occasional occurrence of respiratory depression, and it is recommended that benzodiazepine overdose treatment facilities should be available.
  • Benzodiazepines are effective as medication given a couple of hours before surgery to relieve anxiety. They also produce amnesia, which can be useful, as patients will not be able to remember any unpleasantness from the procedure. They are also used in patients with dental phobia as well as some ophthalmic procedures like refractive surgery; although such use is controversial and only recommended for those who are very anxious. Midazolam is the most commonly prescribed for this use because of its strong sedative actions and fast recovery time, as well as its water solubility, which reduces pain upon injection. Diazepam and lorazepam are sometimes used. Lorazepam has particularly marked amnesic properties that may make it more effective when amnesia is the desired effect.
  • Benzodiazepines are well known for their strong muscle-relaxing properties and can be useful in the treatment of muscle spasms, although tolerance often develops to their muscle relaxant effects. Baclofenor tizanidine are sometimes used as an alternative to benzodiazepines. Tizanidine has been found to have superior tolerability compared to diazepam and baclofen.
  • Benzodiazepines are also used to treat the acute panic caused by hallucinogen intoxication.Benzodiazepines are also used to calm the acutely agitated individual and can, if required, be given via an intramuscular injection.They can sometimes be effective in the short-term treatment of psychiatric emergencies such as acute psychosis as in schizophrenia or mania, bringing about rapid tranquillization and sedation until the effects of lithium or neuroleptics (antipsychotics) take effect. Lorazepam is most commonly used but clonazepam is sometimes prescribed for acute psychosis or mania;their long-term use is not recommended due to risks of dependence.
  • Clonazepam, a benzodiazepine is used to treat many forms of parasomnia.Rapid eye movement behavior disorder responds well to low doses of clonazepam.Restless legs syndrome can be treated using clonazepam as a third line treatment option as the use of clonazepam is still investigational.
  • Benzodiazepines are sometimes used for obsessive compulsive disorder, although they are generally believed to be ineffective for this indication; effectiveness was, however, found in one small study. Benzodiazepines can be considered as a treatment option in treatment resistant cases.
  • Antipsychotics are generally a first-line treatment for delirium; however, when delirium is caused by alcohol or sedative hypnotic withdrawal, benzodiazepines are a first-line treatment.

Adverse effects:

The most common side-effects of benzodiazepines are related to their sedating and muscle-relaxing action. They include drowsiness, dizziness, and decreased alertness and concentration. Lack of coordination may result in falls and injuries, in particular, in the elderly. Another result is impairment of driving skills and increased likelihood of road traffic accidents. Decreased libido and erection problems are a common side effect. Depression and disinhibition may emerge. Hypotension and suppressed breathing may be encountered with intravenous use.Less common side effects include nausea and changes in appetite, blurred vision, confusion, euphoria, depersonalization and nightmares. Cases of liver toxicity have been described but are very rare.

Long-term effects:

The long-term adverse effects of benzodiazepines include a general deterioration in physical and mental health and tend to increase with time. Not everyone, however, experiences problems with long-term use. The adverse effects can include cognitive impairment, as well as affective and behavioural problems. Feelings of turmoil, difficulty in thinking constructively, loss of sex-drive, agoraphobia and social phobia, increasing anxiety and depression, loss of interest in leisure pursuits and interests, and an inability to experience or express feelings can also occur. Additionally an altered perception of self, environment and relationships may occur.

Overdose:

Although benzodiazepines are much safer in overdose than their predecessors, the barbiturates, they can still cause problems in overdose. Taken alone, they rarely cause severe complications in overdose; statistics in England showed that benzodiazepines were responsible for 3.8% of all deaths by poisoning from a single drug.However, combining these drugs with alcohol, opiates or tricyclic antidepressants markedly raises the toxicity.The elderly are more sensitive to the side effects of benzodiazepines, and poisoning may even occur from their long-term use. The various benzodiazepines differ in their toxicity; temazepam appears to be most toxic in overdose and when used with other drugs.The symptoms of a benzodiazepine overdose may include; drowsiness, slurred speech, nystagmus, hypotension, ataxia, coma, respiratory depression, and cardiorespiratory arrest.

Interactions:

Individual benzodiazepines may have different interactions with certain drugs. Depending on their metabolism pathway, benzodiazepines can be roughly divided into two groups. The largest group consists of those that are metabolized by cytochrome P450 (CYP450) enzymes and possess significant potential for interactions with other drugs. The other group comprises those that are metabolized through glucuronidation, such as lorazepam, oxazepam, and temazepam, and, in general, have few drug interactions.

Recreational use:

Benzodiazepines are considered to be major drugs of abuse. Benzodiazepine abuse is mostly limited to individuals who abuse other drugs, i.e., poly-drug abusers. The majority of prescribed users do not abuse their medication.