Diazepam is an anxiolytic benzodiazepine, first patented and marketed in the United States in 1963. It is a fast-acting, long-lasting benzodiazepine commonly used in the treatment of anxiety disorders, as well as alcohol detoxification, acute recurrent seizures, severe muscle spasm, and spasticity associated with neurologic disorders. In the setting of acute alcohol withdrawal, diazepam is useful for symptomatic relief of agitation, tremor, alcoholic hallucinosis, and acute delirium tremens.[1]

When administered intravenously, diazepam actS within 1 to 3 minutes, while oral dosing onset ranges between 15 to 60 minutes. Diazepam is long-lasting with a duration of action of more than 12 hours.

Benzodiazepines have largely replaced barbiturates in the treatment of anxiety and sleep disorders because of their improved safety profile, fewer side effects, and the availability of the antagonist flumazenil to reverse oversedation and benzodiazepine intoxication. 

Diazepam HAs FDA approvAL for the management of anxiety disorders, short-term relief of anxiety symptoms, spasticity associated with upper motor neuron disorders, adjunct therapy for muscle spasms, preoperative anxiety relief, management of certain refractory epilepsy patients and adjunct in severe recurrent convulsive seizures, and an adjunct in status epilepticus. Off label (non-FDA approved) use for diazepam includes sedation in the ICU and short-term treatment of spasticity in children with cerebral palsy.[2]

Benzodiazepines exert their effects by facilitating the activity of GABA at various sites. Specifically, benzodiazepines bind at an allosteric site at the interface between the alpha and gamma subunits on GABA-A receptor chloride ion channels. The allosteric binding of diazepam at the GABA-A receptor leads to an increase in the frequency at which the chloride channel opens, leading to an increased conductance of chloride ions. This shift in charge leads to a hyperpolarization of the neuronal membrane and reduced excitability of the neuron.[3]

Specifically, the allosteric binding within the limbic system leads to the anxiolytic effects seen with diazepam. Allosteric binding within the spinal cord and motor neurons is the primary mediator of the myorelaxant effects seen with diazepam. Mediation of the sedative, amnestic, and anticonvulsant effects of diazepam is through receptor binding within the cortex, thalamus, and cerebellum.[4]

Once in the body, diazepam is mostly broken down by the CYP2C19 and CYP3A4 enzymes to several active metabolites, mainly desmethyldiazepam. Other minor active metabolites include oxazepam and temazepam. The average half-life of oral diazepam and desmethyldiazepam are about 46 hours and 100 hours, respectively. Potent inhibition of the 2C19 enzyme by certain drugs (fluoxetine and chloramphenicol) and 3A4 enzymes by certain medications (ketoconazole, protease inhibitors, erythromycin) may cause increased levels of diazepam, while inducers of 2C19 (rifampicin and prednisone) and 3A4 (carbamazepine, topiramate, phenytoin, St. John's wort, rifampin, or barbiturates) may cause lower levels. Metabolites of diazepam are conjugated with glucuronide and excreted almost entirely in the urine.[5][6][7]

Diazepam is available in multiple formulations, including oral tablets, intramuscular injections (IM), intravenous injection (IV), or rectal gel. Of note, oral tablets have a more reliable absorption and controlled release when compared to IM.

Treatment of acute ethanol withdrawal: Initial dosing should be 10 mg IM or IV. If needed, a follow-up dose of 5 to 10 mg is permissible 3 to 4 hours later. If using the oral tablet, dosing is 10 mg every 6 to 8 hours within the first 24 hours, then 5mg every 6 to 8 hours thereafter as needed.

Treatment of anxiety: 2 to 10 mg can be given orally 2 to 4 times daily. If given parentally, dosing can be 2 to 10 mg and repeated in 3 to 4 hours, if needed.

Treatment of muscle spasm: 2 to 10 mg can be given orally 3 to 4 times daily. If given parentally, an initial dose of 5 to 10 mg can be followed by another 5-10mg dose in 3 to 4 hours, if necessary.

Treatment of preoperative anxiety: Dosing is 10 mg IM prior to surgery

For sedation in the ICU: Loading dose of 5 to 10 mg for initial administration, followed by a maintenance dose of 0.03 to 0.10 mg/kg every 0.5 to 6 hours (Barr 2013)

Treatment of seizures: 2 to 10 mg orally dosed 2 to 4 times daily as adjunctive maintenance therapy. For intermittent management of seizures, rectal gel 0.2mg/kg is an option. It may be repeated in 4 to 12 hours if needed. Do not exceed five uses per month or more than one dose every five days.

Treatment of status epilepticus: 0.15 to 0.20 mg/kg IV per dose,  and may be repeated once if needed. Do not exceed 10 mg per single dose. Rectal administration of 0.2 to 0.5 mg/kg administered one time. Do not exceed 20 mg per dose.

Skeletal muscle relaxant: 2 to 10 mg, dosed 3 to 4 times daily as an adjunct therapy

Like most benzodiazepines, the adverse reactions of diazepam include CNS and respiratory depression, dependence, and benzodiazepine withdrawal syndrome.

Serious adverse effects of diazepam include:

• Respiratory depression
• Seizures
• Suicidality
• Dependency and abuse
• Withdrawal symptoms
• Cardiovascular collapse
• Bradycardia
• Hypotension
• Syncope
• Paradoxical CNS stimulation

Common adverse effects of diazepam include:

• Sedation
• Fatigue
• Confusion
• Anterograde amnesia
• Depression
• Ataxia
• Irritability
• Disinhibition
• Local injection site reaction
• Headache
• Tremor
• Dystonia
• Urinary retention
• Incontinence
• Nausea
• Constipation
• Diplopia
• Libido changes
• Rash
• Menstrual irregularities
• ALT and/or AST elevation

Contraindications to diazepam include patients with a known hypersensitivity to diazepam and, due to a lack of sufficient clinical evidence, diazepam is also contraindicated in patients under 6 months of age. Other contraindications to diazepam include patients with severe respiratory insufficiency, myasthenia gravis,  sleep apnea syndrome, and severe hepatic insufficiency. It is permissible in patients with open-angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow-angle glaucoma.

Use in Special Populations:

Pregnant Patients

Diazepam classifies as FDA pregnancy category D, which means that there is positive evidence of human fetal risk. Still, the benefits from use in pregnant women may be acceptable despite the risk. The use of diazepam and other benzodiazepines in pregnancy correlates with an increased risk of congenital malformations, premature birth, low birth weight, and other neurodevelopmental abnormalities. However, additional studies are needed to confirm.

Diazepam readily crosses the placental barrier, and use during pregnancy may result in neonatal withdrawal soon after birth. Symptoms of neonatal withdrawal include high-pitched cry, hypertonia, tremor, irritability, feeding difficulties, sleep/wake disturbances, gastrointestinal and autonomic disturbances, respiratory problems, and failure to thrive. The onset of withdrawal in a neonate whose mother has taken diazepam during the pregnancy could be anywhere from the first days of life to the first few weeks. Diazepam use during the last trimester of pregnancy can result in “floppy infant syndrome,” characterized by hypotonia, hypothermia, lethargy, respiratory distress, and suckling difficulties.[8][9]

Breastfeeding women

Diazepam and its metabolites are excreted in breast milk and may produce effects in the nursing infant. Some studies have shown the relative infant dose (RID) of diazepam to be approximately 9%. Relative infant dose (RID) is the dose received via breast milk relative to the mother’s dose. A relative dose below 10% is within an acceptable range regarded as reasonably safe in the short term. However, due to diazepam’s long half-life, metabolites may accumulate in a breastfed infant. Therefore, an infant breastfed by a mother receiving diazepam should undergo monitoring for drowsiness, decreased feeding, lethargy, and failure to thrive. Discontinue breastfeeding in cases with high doses of diazepam, or when repeated administration will be necessary.[10]

Elderly

One should exercise caution when prescribing diazepam to the elderly population. Elderly patients tend to have decreased renal function and clearing capability; therefore, this population is at an increased risk for accumulation of diazepam and its major metabolites. The recommendation is to limit the dosage to the smallest effective amount.

Paradoxical reactions of CNS hyperactivity have also been reported with the use of benzodiazepines in the elderly, manifesting as hyperactivity, aggressive behavior, irritability, anxiety, and hallucinations. Should this occur, discontinuation is the recommendation.[11][12]