Diazepam

Diazepam is a long-acting benzodiazepine used for short-term anxiety, alcohol withdrawal, seizures including status epilepticus, muscle spasm, and sedation. It acts rapidly, accumulates with repeated dosing because of active metabolites, and causes dependence, so long-term use is avoided.

Classification. Benzodiazepine, long-acting.

Mechanism. Positive allosteric modulation of GABA-A receptors, which increases chloride channel opening and neuronal inhibition.

Pharmacokinetics. Rapid oral absorption; peak in 30 to 90 minutes. Intramuscular absorption is slow and erratic. Rectal absorption is rapid in 5 to 15 minutes. Metabolised by CYP2C19 and CYP3A4 to desmethyldiazepam (active). Half-life 20 to 100 hours (desmethyldiazepam up to 200 hours), and longer in older adults and liver disease.

Short-term anxiety, adults (oral). 2 mg three times daily; increase if needed to a maximum of 30 mg daily in divided doses. Use for the shortest time, no longer than 2 to 4 weeks.

Insomnia, short term. 5 to 15 mg at night for no more than 2 to 4 weeks.

Alcohol withdrawal, adults.

• Fixed reducing regimen: 10 to 20 mg four times daily on day 1, reducing by about 20% daily and stopping over 7 days; or symptom-triggered 10 to 20 mg orally every 1 to 4 hours based on withdrawal severity.
• Reassess severity before each dose and withhold if the patient is drowsy. Give thiamine to all patients.

Status epilepticus or prolonged seizure, adults (intravenous). 10 mg (0.15 to 0.25 mg/kg) at a rate not over 5 mg/min; repeat once after 10 to 15 minutes. Maximum 30 mg. Give undiluted into a large vein; do not mix in infusion bags.

Status epilepticus, children. Intravenous 0.2 to 0.3 mg/kg (maximum 10 mg); rectal gel or solution by weight (about 0.5 mg/kg aged 2 to 5 years, 0.3 mg/kg aged 6 to 11 years, 0.2 mg/kg aged 12 years and over); repeat once after 10 to 15 minutes.

Muscle spasm. 2 to 15 mg daily in divided doses. Tetanus spasm: higher doses under specialist care.

Dose limits. Older adults and liver impairment: half the usual dose (start 2 mg). Kidney impairment: start low. Respiratory disease: use lower doses.

Contraindications. Respiratory depression, severe sleep apnoea, acute pulmonary insufficiency, myasthenia gravis, severe liver impairment, phobic or obsessional states, unmanaged psychosis, hypersensitivity. Boxed-warning-level risk of profound sedation, respiratory depression and death with opioids; abuse, misuse and dependence.

Serious adverse effects. Respiratory depression, apnoea, hypotension (rapid intravenous), thrombophlebitis, paradoxical agitation, dependence and withdrawal seizures, delirium in older adults, falls and fractures, anterograde amnesia.

Common adverse effects. Drowsiness, ataxia, dizziness, confusion, memory impairment, muscle weakness, dependence.

Interactions. Opioids, alcohol, other sedatives and gabapentinoids add respiratory depression. Omeprazole, cimetidine, fluconazole, erythromycin and fluvoxamine raise levels. Clozapine with benzodiazepines can cause collapse. Rifampicin and carbamazepine lower levels. Flumazenil reverses the effect but can precipitate seizures in dependent patients.

Common prescribing errors. Long-term prescribing; giving intramuscularly for seizures; mixing with infusion fluids; combining with opioids; giving rapid intravenous boluses; no taper after prolonged use.

Special groups.

• Pregnancy: avoid regular use; floppy infant syndrome and neonatal withdrawal with late exposure; use for seizures if needed.
• Breastfeeding: single doses acceptable; avoid repeated dosing because of infant sedation.
• Children: used for seizures and procedural sedation; not for routine anxiety.
• Older adults: halve the dose; high risk of falls, confusion and respiratory depression; avoid where possible.
• Kidney impairment: start low.
• Liver impairment: halve the dose; avoid in severe impairment.

Formulations. Tablets 2 mg, 5 mg and 10 mg; oral solution 2 mg/5 mL; injection 5 mg/mL (propylene glycol based); rectal solution or gel 2.5 mg, 5 mg and 10 mg. Inject slowly into a large vein; avoid small veins.

Baseline. Respiratory status, alcohol and other sedative use, liver function, pregnancy status, history of dependence, medicines list.

Monitoring. After intravenous dosing, monitor respiratory rate, oxygen saturation, blood pressure and level of consciousness continuously until recovered; have airway equipment and oxygen ready. Review anxiety or insomnia treatment at 2 weeks. In alcohol withdrawal, assess withdrawal severity every 1 to 4 hours.

Stopping. After more than 2 to 4 weeks of use, reduce the dose by 5 to 10% every 1 to 2 weeks (or by 2 mg every 1 to 2 weeks), more slowly at the lowest doses. Abrupt stopping can cause seizures and delirium.

Referral and escalation. Refer to addiction or psychiatric services for dependence or withdrawal. A seizure lasting more than 5 minutes, respiratory depression, or oxygen saturation under 92% needs emergency care.