Diazepam


Diazepam, sold under the brand name Valium among others, is a medication of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken orally, as a suppository inserted into the rectum, intramuscularly, intravenously or used as a nasal spray. When injected intravenously, effects begin in one to five minutes and last up to an hour. When taken by mouth, effects begin after 15 to 60 minutes.
Common side effects include sleepiness and trouble with coordination. Serious side effects are rare. They include increased risk of suicide, decreased breathing, and a paradoxical increased risk of seizures if used too frequently in those with epilepsy. Occasionally, excitement or agitation may occur. Long-term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction. Abrupt stopping after long-term use can be potentially dangerous. After stopping, cognitive problems may persist for six months or longer. It is not recommended during pregnancy or breastfeeding. Its mechanism of action works by increasing the effect of the neurotransmitter gamma-aminobutyric acid.
Diazepam was patented in 1959 by Hoffmann-La Roche. It has been one of the most frequently prescribed medications in the world since its launch in 1963. In the United States it was the best-selling medication between 1968 and 1982, selling more than 2billion tablets in 1978 alone. In 2023, it was the 183rd most commonly prescribed medication in the United States, with more than 2million prescriptions. In 1985, the patent ended, and there are more than 500 brands available on the market. It is on the World Health Organization's List of Essential Medicines.

Medical uses

Diazepam is mainly used to treat anxiety, insomnia, panic attacks, and symptoms of acute alcohol withdrawal. It is also used as a premedication for inducing sedation, anxiolysis, or amnesia before certain medical procedures. In 2020, it was approved for use in the United States as a nasal spray to interrupt seizure activity in people with epilepsy. Diazepam is the most commonly used benzodiazepine for "tapering" benzodiazepine dependence due to the drug's comparatively long half-life, allowing for more efficient dose reduction. Benzodiazepines have a relatively low toxicity in overdose.
Diazepam has several uses, including:
Dosages are typically determined on an individual basis, depending on the condition being treated, the severity of symptoms, the patient's body weight, and any other conditions the person may have.

Seizures

Intravenous diazepam and lorazepam are first-line treatments for status epilepticus. However, intravenous lorazepam has advantages over intravenous diazepam, including a higher rate of terminating seizures and a more prolonged anticonvulsant effect. Diazepam gel was better than placebo gel in reducing the risk of non-cessation of seizures. Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to its anticonvulsant effects usually develops within six to twelve months of treatment, effectively rendering it useless for that purpose.
The anticonvulsant effects of diazepam can help in the treatment of seizures due to a drug overdose or chemical toxicity as a result of exposure to sarin, VX, or soman, lindane, chloroquine, physostigmine, or pyrethroids.
Diazepam is sometimes used intermittently for the prevention of febrile seizures that may occur in children under five years of age. Recurrence rates are reduced, but side effects are common, and the decision to treat febrile seizures with medication uses these factors as part of the evaluation. Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup of individuals with treatment-resistant epilepsy benefit from long-term benzodiazepines, and for such individuals, clorazepate has been recommended due to its slower onset of tolerance to the anticonvulsant effects.

Alcohol withdrawal

Because of its relatively long duration of action and evidence of safety and efficacy, diazepam is preferred over other benzodiazepines for the treatment of persons experiencing moderate to severe alcohol withdrawal. An exception to this is when a medication is required intramuscular in which case either lorazepam or midazolam is recommended.

Other

Diazepam is used for the emergency treatment of eclampsia when IV magnesium sulfate and blood-pressure control measures have failed. Benzodiazepines do not have any pain-relieving properties themselves and are generally recommended to be avoided in individuals with pain. However, benzodiazepines such as diazepam can be used for their muscle-relaxant properties to alleviate pain caused by muscle spasms and various dystonias, including blepharospasm. Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam. Baclofen is sometimes used as an alternative to diazepam.

Availability

Diazepam is marketed in over 500 brands throughout the world. It is supplied in oral, injectable, inhalation, and rectal forms.
The United States military employs a specialized diazepam preparation known as Convulsive Antidote, Nerve Agent, which contains diazepam. One CANA kit is typically issued to service members, along with three Mark I NAAK kits, when operating in circumstances where deployment of nerve agents is considered a potential hazard. Both of these kits deliver drugs using autoinjectors. They are intended for use in "buddy aid" or "self-aid" administration of the drugs in the field before decontamination and delivery of the patient to definitive medical care.

Contraindications

Use of diazepam is avoided, when possible, in individuals with:
  • Ataxia
  • Severe hypoventilation
  • Acute narrow-angle glaucoma
  • Severe hepatic deficiencies
  • Severe renal deficiencies
  • Liver disorders
  • Severe sleep apnea
  • Severe depression, particularly when accompanied by suicidal tendencies
  • Psychosis
  • Pregnancy or breastfeeding
  • Caution required in elderly or debilitated patients
  • Coma or shock
  • Abrupt discontinuation of therapy
  • Acute intoxication with alcohol, narcotics, or other psychoactive substances
  • History of alcohol or drug dependence
  • Myasthenia gravis, an autoimmune disorder causing marked fatiguability
  • Hypersensitivity or allergy to any drug in the benzodiazepine class

    Abuse and special populations

  • Benzodiazepine abuse and misuse are guarded against when prescribed to those with alcohol or drug dependencies or who have psychiatric disorders.
  • Pediatric patients
  • * For those less than 18 years of age, this treatment is usually not indicated, except for treatment of epilepsy, and pre-or postoperative treatment. The smallest possible effective dose is typically used for this group of patients.
  • * Under 6 months of age, safety and effectiveness have not been established; diazepam is not given to those in this age group.
  • Elderly and very ill patients can experience apnea or cardiac arrest. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose is generally used for this group of people. The elderly metabolise benzodiazepines much more slowly than younger adults, and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels. Doses of diazepam are recommended to be about half of those given to younger people, and treatment is limited to a maximum of two weeks. Long-acting benzodiazepines such as diazepam are not recommended for the elderly. Diazepam can also be dangerous in geriatric patients owing to a significantly increased risk of falls.
  • Intravenous or intramuscular injections in hypotensive people or those in shock are administered carefully, and vital signs are closely monitored.
  • Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes, thus rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines, including diazepam in late pregnancy, especially high doses, can result in floppy infant syndrome. Diazepam when taken late in pregnancy, during the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.

    Adverse effects

Benzodiazepines, such as diazepam, can cause anterograde amnesia, confusion, and sedation. The elderly are more prone to diazepam's confusion, amnesia, ataxia, hangover symptoms, and falls. Long-term use of benzodiazepines, such as diazepam, induces tolerance, dependency, and withdrawal syndrome. Like other benzodiazepines, diazepam impairs short-term memory and learning new information. Diazepam and other benzodiazepines can produce anterograde amnesia, but not retrograde amnesia, which means information learned before using benzodiazepines is not impaired. Short-term benzodiazepine use does not lead to tolerance, and the elderly are more sensitive to them. Additionally, after stopping benzodiazepines, cognitive problems may last at least six months; it is unclear if these problems last for longer than six months or are permanent. Benzodiazepines may also cause or worsen depression. Infusions or repeated intravenous injections of diazepam when managing seizures, for example, may lead to drug toxicity, including respiratory depression, sedation, and hypotension. Drug tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours. Sedatives and sleeping pills, including diazepam, have been associated with an increased risk of death.
In September 2020, the U.S. Food and Drug Administration required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.
Diazepam has a range of side effects common to most benzodiazepines, including:
Less commonly, paradoxical reactions can occur, including nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in libido, and in some cases, rage and violence. These adverse reactions are more likely to occur in children, the elderly, and individuals with a history of a substance use disorder, such as an alcohol use disorder, or a history of aggressive behavior. In some people, diazepam may increase the propensity toward self-harming behavior and, in extreme cases, may provoke suicidal tendencies or acts. Very rarely dystonia can occur.
Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by the consumption of alcohol because both act as central nervous system depressants.
During therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.
Patients with severe attacks of apnea during sleep may experience respiratory depression, leading to respiratory arrest and death.
Diazepam in doses of or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness.