Lorazepam

Indications

• FDA-approved orally for anxiety disorders, short-term relief of anxiety symptoms, and anxiety associated with depressive symptoms in adults.
• FDA-approved as an injection for status epilepticus and as a preanesthetic agent providing sedation and anterograde amnesia before procedures.
• Off-label but standard of care for catatonia, where a diagnostic lorazepam challenge often produces rapid and dramatic symptomatic response.
• Off-label as the benzodiazepine backbone of symptom-triggered alcohol withdrawal protocols, particularly when liver disease is present.
• Off-label for acute agitation, alone or with an antipsychotic, and for chemotherapy-induced anticipatory nausea and vomiting.
• Guidelines reserve benzodiazepines for short-term anxiety use, with SSRIs or SNRIs carrying the maintenance treatment of anxiety disorders.

Mechanism of action

• Positive allosteric modulator at the GABA-A benzodiazepine site, increasing chloride channel opening frequency and dampening neuronal excitability.
• Intermediate lipophilicity gives slower brain entry than diazepam but longer CNS residence, which is why it outperforms diazepam in status epilepticus.
• Non-selective across alpha subunits, producing anxiolysis, sedation, amnesia, muscle relaxation and anticonvulsant effect as one package.
• Presumed correction of GABA-A hypofunction underlies its dramatic effect in catatonia and its suppression of alcohol withdrawal hyperexcitability.
• Repeated dosing downregulates GABA-A receptors, producing tolerance to sedation and the physiologic dependence that drives withdrawal.

Pharmacokinetics

• Oral bioavailability is about 90 percent with peak levels near 2 hours; intramuscular absorption is reliable, unlike chlordiazepoxide or diazepam.
• Elimination half-life is roughly 12 hours, so oral dosing is typically two or three times daily with little day-to-day accumulation.
• Cleared solely by UGT2B15 glucuronidation to an inactive glucuronide, bypassing hepatic oxidation entirely and producing no active metabolites.
• Along with oxazepam and temazepam, this glucuronidation-only route makes lorazepam the preferred benzodiazepine in cirrhosis and in older adults.
• Kinetics are essentially unaffected by CYP inhibitors or inducers, so it is the safer choice when a patient is on ritonavir or carbamazepine.

Dosing

• Anxiety: start 0.5-1 mg PO two or three times daily, usual range 2-6 mg/day, labeled maximum 10 mg/day in divided doses.
• Insomnia due to anxiety or situational stress: 2-4 mg PO at bedtime, intended for a few nights rather than as continuing hypnotic therapy.
• Status epilepticus: 4 mg IV given at no more than 2 mg/min, repeated once after 10-15 minutes if seizures continue; pediatric dose 0.1 mg/kg up to 4 mg.
• Catatonia: 1-2 mg IV, IM or PO every 4-12 hours, titrating as high as 8-24 mg/day; failure to respond should prompt consideration of ECT.
• Older adults or debilitated patients start at 0.5-1 mg/day in divided doses; no renal or hepatic dose reduction is formally required.
• Taper by about 10 percent of the current dose every 1-2 weeks after chronic use, slowing near the end, since abrupt stop can cause seizures and death.

Adverse effects

• Sedation is the most common effect at roughly 16 percent, followed by dizziness 7 percent, weakness 4 percent and unsteadiness 3 percent.
• Anterograde amnesia is dose-dependent and pronounced after intravenous use, which is useful before procedures but problematic in ward settings.
• Falls, hip fracture and delirium in older adults; benzodiazepine exposure is a common reversible contributor to hospital-acquired confusion.
• Paradoxical agitation, disinhibition and aggression, seen most often in children, older adults, dementia and traumatic brain injury.
• Rapid intravenous administration can cause apnea, hypotension and airway compromise, so push slowly with monitoring and resuscitation available.
• Withdrawal after chronic use brings rebound anxiety, insomnia, tremor, hallucinations and seizures, and can be fatal without a managed taper.

Monitoring

• Assess sedation level, respiratory rate and oxygen saturation after parenteral doses, especially when an opioid or antipsychotic is co-administered.
• Screen for substance use history and check the prescription monitoring program before initiating and periodically during outpatient therapy.
• Track falls, gait, cognition and driving safety at every visit in older adults, and revisit whether ongoing benzodiazepine use is still warranted.
• In alcohol withdrawal use a validated scale such as CIWA-Ar to drive symptom-triggered dosing rather than fixed standing orders.
• No routine laboratory monitoring is needed; propylene glycol toxicity is a concern only with prolonged high-dose continuous infusions.

Interactions

• Additive respiratory depression and death with opioids, the basis of the boxed warning; avoid the combination or use the lowest doses with naloxone available.
• Alcohol, gabapentinoids, sedating antihistamines, clozapine and other hypnotics all compound sedation and psychomotor impairment.
• Intramuscular olanzapine plus parenteral lorazepam has been linked to excess sedation and cardiorespiratory depression; separate doses by at least an hour.
• Valproate and probenecid inhibit glucuronidation and raise lorazepam levels, so reduce the dose by roughly half when either is added.
• Contraindicated in acute narrow-angle glaucoma, benzodiazepine hypersensitivity and, for the injection, in severe respiratory insufficiency.

Special populations

• Pregnancy: crosses the placenta; late exposure causes neonatal sedation, hypotonia and withdrawal, so limit use and alert the delivery team.
• Lactation: low milk transfer and it is often considered acceptable, but monitor the nursing infant for sedation and poor feeding.
• Pediatrics: oral use is not established under age 12, though the injection is used for pediatric status epilepticus at 0.1 mg/kg.
• Older adults: the AGS Beers Criteria advise avoiding benzodiazepines, but when one is unavoidable lorazepam is preferred over oxidized agents.
• Hepatic and renal impairment: glucuronidation is relatively preserved in cirrhosis, making lorazepam the class choice in liver failure.

Clinical pearls

• Lorazepam, oxazepam and temazepam skip hepatic oxidation, so they are safest in liver disease.
• A lorazepam challenge is both a diagnostic test and the first treatment for suspected catatonia.
• The only oral benzodiazepine here with reliable IM absorption and a widely stocked IV form.