Continuing Education Activity

Lorazepam is FDA-approved for short-term (4 months) relief of anxiety symptoms related to anxiety disorders, anxiety-associated insomnia, anesthesia premedication in adults to relieve anxiety or to produce sedation/amnesia, and treatment of status epilepticus. Off-label (non-FDA-approved) uses for lorazepam include rapid tranquilization of the agitated patient, alcohol withdrawal delirium, alcohol withdrawal syndrome, insomnia, panic disorder, delirium, chemotherapy-associated anticipatory nausea, and vomiting (adjunct or breakthrough), as well as psychogenic catatonia. This activity covers lorazepam, including mechanism of action, pharmacology, adverse event profiles, eligible patient populations, and monitoring. It also highlights the interprofessional team's role in managing lorazepam therapy.

Objectives:

• Identify the mechanism of action of lorazepam.
• Summarize the various indications for initiating therapy with lorazepam.
• Describe the adverse events of lorazepam.
• Review interprofessional team strategies for improving care coordination and communication to properly use lorazepam to improve patient outcomes in the varied scenarios where lorazepam is effective.

Indications

Lorazepam is a benzodiazepine medication developed by DJ Richards. It went on the market in the United States in 1977. Lorazepam has common use as the sedative and anxiolytic of choice in the inpatient setting owing to its fast (1 to 3 minutes) onset of action when administered intravenously.[1] Lorazepam is also one of the few sedative-hypnotics with a relatively clean side effect profile.

FDA-approved Indications

• Short-term (4 months) relief of anxiety symptoms related to anxiety disorders
• Anxiety-associated insomnia
• Anesthesia premedication in adults to relieve anxiety or to produce sedation/amnesia
• Treatment of status epilepticus[2] 

Off-label (non-FDA-approved) Indications

• Rapid tranquilization of the agitated patient[3]
• Alcohol withdrawal delirium
• Alcohol withdrawal syndrome
• Insomnia
• Panic disorder
• Delirium
• Chemotherapy-associated anticipatory nausea and vomiting (adjunct or breakthrough)
• Psychogenic catatonia
• Vertigo[4]

Mechanism of Action

Lorazepam binds to benzodiazepine receptors on the postsynaptic GABA-A ligand-gated chloride channel neuron at several sites within the central nervous system (CNS). It enhances the inhibitory effects of GABA, which increases the conductance of chloride ions in the cell. This shift in chloride ions results in hyperpolarization and stabilization of the cellular plasma membrane.[5] Its inhibitory action in the amygdala is beneficial in anxiety disorders, while its inhibitory activity in the cerebral cortex is beneficial in seizure disorders.

Pharmacokinetics

Absorption: lorazepam is well absorbed after oral administration. Peak concentrations are attained two hours following oral administration. The bioavailability of lorazepam is approximately 90%. Lorazepam crosses the blood/brain barrier freely by passive diffusion.

Distribution: The volume of distribution is 1.3 L/kg. Lorazepam has approximately 90% plasma protein binding. Lorazepam crosses the blood/brain barrier freely by passive diffusion.

Metabolism: Lorazepam is metabolized by conjugation in the liver and undergoes enterohepatic recirculation. Lorazepam glucuronide is an inactive metabolite. Lorazepam undergoes direct glucuronidation without prior cytochrome p450 metabolism; consequently, lorazepam can be used in patients with hepatic dysfunction with insignificant effects on the pharmacokinetics.[6]

Excretion: The elimination half-life is 14±5 hours, and clearance is 1.1±0.4 mL/min/kg. Lorazepam is excreted primarily in the urine.[7]

Administration

Lorazepam can be administered orally (0.5 mg tablet, 1 mg tablet, 2 mg tablet, oral concentrate solution 2 mg/mL, 1 mg extended-release capsule, 2 mg extended-release capsule, and 3 mg extended-release capsule). In addition, it can be administered via intravenous(IV) or intramuscular(IM) injection (2 mg/mL solution and 4 mg/mL solution). The onset of its action is 1 to 3 minutes if administered IV and 15 to 30 minutes if administered IM.

Anxiety Disorder

The initial starting dose is 2 to 3 mg orally; repeat the dose 2 to 3 times per day; the maximum recommended dosage is 10 mg daily.[8]

Insomnia Due to Anxiety or Stress

In patients under 65 years of age, the dose is 0.5 to 2 mg orally at bedtime, and in patients over 65 years of age, the dose is reduced to 0.5 to 1 mg at bedtime.

Premedication for Anesthesia

If given IM, the dose is 0.05 mg/kg administered 2 hours before surgery (maximum dose 4 mg). If administered IV, the dose is 0.044 mg/kg, administered 15 to 20 minutes before surgery (maximum dose 4 mg). In patients older than 50 years of age, the maximum dosage is 2 mg.[9]

Status Epilepticus

Administered IV, the dose is 0.1 mg/kg (maximum dose 4 mg), at a maximum rate of 2 mg per minute; may repeat in 5 to 10 minutes. Note: Must dilute dose with 1:1 saline.        According to American Epilepsy Society guidelines, parenteral lorazepam is one of the first-line treatments for convulsive status epilepticus.[10]

Agitation in the Intensive Care Unit (ICU) Patient (off-label use)

An IV Loading dose is 0.02 to 0.04 mg/kg (maximum single dose 2 mg); the Maintenance dose is 0.02 to 0.06 mg/kg every 2 to 6 hours as needed or 0.01 to 0.1 mg/kg per hour with a maximum dosing of less than 10 mg per hour.

Alcohol Withdrawal Delirium (off-label use)

IV dose is 1 to 4 mg every 5 to 15 minutes until the patient is calm; can repeat every hour as needed. IM dose is 1 to 4 mg every 30 to 60 minutes until the patient is calm; can repeat every hour as needed.[11]

Alcohol Withdrawal Syndrome (off-label use)

According to ASAM (American Society of Addiction Medicine) clinical practice guidelines, lorazepam is one of the most frequently used drugs for managing alcohol withdrawal. The symptom-triggered regimen can be administered orally, intramuscularly, or intravenously at 2 mg to 4 mg per hour as needed; the severity assessment scale must determine the dose. The fixed-dose regimen can be administered orally, intramuscularly, or intravenously at 2 mg every 6 hours for four doses, followed by 1 mg every 6 hours for eight additional doses. Note: Symptom-triggered regimen is preferable to the fixed-dose regimens; lower doses and shorter treatment duration are in order. Lorazepam is preferred in patients with cirrhosis.[12][13]

Chemotherapy-associated Nausea and Vomiting (off-label use)

Lorazepam is used for breakthrough nausea/vomiting or adjunct to standard antiemetics. It can be given orally, intravenously, or sublingually at 0.5 to 2 mg every 6 hours as needed.

Psychogenic Catatonia (off-label use)

IM dose is 1 mg to 2 mg; clinicians can repeat the dose in 3 hours and then again in another 3 hours if the initial and subsequent doses are ineffective. It can be administered orally, intramuscularly, or intravenously; initially, 1 mg and may be repeated in 5 minutes if necessary. If the initial challenge is unsuccessful, one may increase the dose to 4 to 8 mg daily and continue treatment for up to 5 days.[14]

Vertigo (off-label use)

According to the American Academy of Otolaryngology-Head and Neck Surgery((AAO-HNS), lorazepam (1-2 mg every 8 hours) is preferred when a rapid onset of action is required to relieve vertigo in Meniere's disease.[15] However (AAO-HNS) doesn't endorse the use of benzodiazepines for the relief of vertigo in benign paroxysmal positional vertigo (BPPV).[16]

Use in Specific Population

Pregnancy Considerations: It is pregnancy category D medicine. There are documented case reports and case-control studies showing an increased risk for cleft palate and cleft lip using lorazepam and other benzodiazepines in the first trimester. Third-trimester use of lorazepam and benzodiazepine is associated with an increased risk of causing neonatal withdrawal symptoms. If lorazepam needs to be used during pregnancy, it should be used with extreme caution, and the benefit has to outweigh the risk.[17]

Breastfeeding Considerations: Lorazepam is found in low levels of breast milk. Studies report that it does not cause adverse reactions in breastfed babies with standard maternal dosages.[18] A safety scoring system of psychotropic drugs used in lactating women found lorazepam safer than other benzodiazepines during breastfeeding.[19]

Hepatic Impairment: Product labeling does not have information on using lorazepam in patients with hepatic impairment. As discussed above, lorazepam can be used cautiously in patients with hepatic impairment.[6]

Renal Impairment: Manufacturers recommend precautions in case of using frequent doses of lorazepam over relatively short periods in patients with renal disease. According to a review, if benzodiazepines are required, lorazepam is a reasonable first-line choice for patients with ESRD.[20]

Potentially Inappropriate Medication (PIM) in Older Adults: According to the American Geriatric Society Beers Criteria, lorazepam is identified as a potentially inappropriate medication for older adults. Older patients have increased sensitivity to benzodiazepines and decreased clearance. Patients have an increased risk of cognitive impairment, falls, and fractures. However, using lorazepam may be reasonable for patients with seizure disorders, alcohol withdrawal, severe generalized anxiety disorder, and periprocedural sedation.[21]

Adverse Effects

Like most benzodiazepines, adverse reactions to lorazepam include CNS and respiratory depression, which are dose-dependent. More severe effects occur with high doses.[22][17][22]

Serious adverse effects of lorazepam include:

• Respiratory depression
• Respiratory failure
• Seizures
• Suicidality
• Dependency and abuse
• Tachycardia
• Hypotension
• Syncope
• Blood dyscrasias
• Jaundice
• Paradoxical reaction; hyperactive and aggressive behavior
• Gangrene (intra-arterial)
• Withdrawal symptoms if abruptly discontinued after long-term use.
• Cognitive deficits
• Behavioral changes
• Paradoxical agitation[23]
• Propylene glycol toxicity when using the parenteral formulation in high doses (hyponatremia and metabolic acidosis).[12]

Common adverse effects of lorazepam include:

• Sedation
• Dizziness
• Asthenia
• Ataxia
• Local injection site reaction
• Respiratory depression
• Hypoventilation with IV use
• Hypotension
• Fatigue
• Amnesia
• Confusion
• Disinhibition
• Irritability
• Libido changes
• Menstrual irregularities
• Diplopia
• Dysarthria
• Appetite changes
• Constipation
• Incontinence
• Urinary retention
• Dystonia
• AST and ALT elevation
• In rare instances, lorazepam can cause acute liver injury(cholestatic pattern)[24]

Drug-Drug Interactions

• Lorazepam has drug interaction with other drugs, which causes CNS depression. Concomitant use of sedatives, hypnotics, opioids, cough and cold medicines, antiepileptics, muscle relaxers, and alcohol can worsen adverse reactions caused by lorazepam. If a patient starts treatment with UDP-glucuronosyltransferase (UGT) inhibitors, then taper off lorazepam to discontinue.[17]
• Metronidazole should not be used with products containing propylene glycol(present in parenteral lorazepam formulation). A disulfiram-like reaction may occur.[25]
• Kratom is a plant with partial opioid agonist effects, and its misuse has become widespread in the US.[26] The use of kratom, along with benzodiazepines, can increase the risk of severe CNS depression. Avoid combination.[27][26]

Contraindications

Lorazepam is contraindicated in patients with an anaphylactic reaction to lorazepam, any component of the formulation, or other benzodiazepines (cross-sensitivity with other benzodiazepines may exist).

It is contraindicated to use in neonates or premature infants, in patients with severe respiratory impairment (except during mechanical ventilation), acute narrow-angle glaucoma, sleep apnea, severe respiratory insufficiency, and intra-arterial administration route.[28] 

Lorazepam and other benzodiazepines should not be first-line agents for anxiety and other psychiatric disorder symptoms in the first and third trimesters of pregnancy.[17]

Lorazepam and other benzodiazepines have an increased risk of abuse, misuse, and dependence; these medications are contraindicated in patients actively using illicit substances and drugs. Except for use in Alcohol withdrawal disorder symptoms and detoxification, lorazepam and other benzodiazepine are contraindicated in patients with a history of alcohol dependence and abuse and not in remission. Increased risk of fatality with the combined use of alcohol and lorazepam in overdose, including death.[17]

Injection formulation contains polyethylene glycol, propylene glycol, or benzyl alcohol, so contraindications include hypersensitivity to these excipients.[29] Extended-release capsules contain tartrazine; therefore, patients with a history of allergic reactions should avoid capsules.

Box Warning: Concomitant use of benzodiazepines with opioids can lead to sedation, severe respiratory depression, coma, and death. Avoid this combination.[30]

Monitoring

Monitor respiratory and cardiovascular status, blood pressure, and heart rate.

With Long-term therapy, monitor CBC, liver function tests, and LDH. With high-dose or continuous IV use or IV use in patients with renal impairment, monitor clinical signs of propylene glycol toxicity, serum creatinine, BUN, serum lactate, and osmolality gap.[31] With critically ill patients, monitor the depth of sedation.

Lorazepam is a Schedule IV drug, and patients may develop dependence and tolerance with long-term use. The recommendation is to use the lowest possible effective dose for the shortest period. When stopping lorazepam, it should be tapered by 0.5 mg every three days to avoid withdrawal symptoms.[32]

Monitor and adjust the dose of lorazepam according to the Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) protocol.[33]

Monitor for improvement in anxiety by using a validated scoring system like Hamilton Anxiety Scale.[34]

Toxicity

Lorazepam can cause CNS and respiratory depression in overdose. It can lead to hypotension, ataxia, confusion, coma, extreme drowsiness, muscle weakness, and death.[17] Concurrent use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.[35] Concomitant prescribing of benzodiazepines and opioids must be reserved for patients with inadequate alternative treatment options. The dosage and duration of lorazepam must be limited to the minimum required. Patients require surveillance for signs and symptoms of respiratory depression. Lorazepam, as with other benzodiazepines, is rarely associated with elevated serum ALT, and clinically apparent liver injury from lorazepam is extremely rare.[36] 

The clinical pattern of acute liver injury from benzodiazepines is typically cholestatic. Flumazenil is an antidote for benzodiazepine toxicity.[37] Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine receptor complex. Abrupt awakening can cause dysphoria, agitation, and increased adverse effects.[38] If administered to patients on chronic benzodiazepine therapy, the sudden interruption of benzodiazepine antagonism by flumazenil can induce benzodiazepine withdrawal, including seizures. Flumazenil has minimal effects on benzodiazepine-induced respiratory depression, and suitable ventilatory support should be available in treating acute benzodiazepine overdose.[39] A Recent case report described a severe overdose of lorazepam associated with absent corneal, oculocephalic, and oculovestibular reflexes; the patient recovered after administration of 0.25 mg IV flumazenil.[40]

Enhancing Healthcare Team Outcomes

Lorazepam, like other benzodiazepine medications, can be a highly addictive medication. As a result, an interprofessional team approach to prescribing and managing these medications is necessary. This team includes the prescribers (MDs, DOs, NPs, PAs), psychiatrists, nursing staff, and pharmacists, each of whom must be vigilant for signs of misuse or adverse effects. This approach will prevent misuse and unintended adverse events and optimize therapy. [Level 5]

Great care is necessary when prescribing lorazepam at high doses or prolonged durations, particularly in patients with a history of substance use disorder or concurrent opioid prescriptions. Managing such patients requires an interprofessional team that includes nurses, pharmacists, and several specialist clinicians, to monitor for signs of abuse, diversion, or concomitant use with other prescription or non-prescription sedative medications. Prescribers and pharmacists must monitor treatment, provide patient education, and be vigilant in prescribing benzodiazepines such as lorazepam. The prescription drug monitoring program (PDMP) can identify potential misuse of lorazepam.[41]

The interprofessional healthcare team should use state and federal controlled substance monitoring and diversion databases to identify high-risk patients with multiple and frequent prescriptions for benzodiazepines, opioids, muscle relaxants, and other sedative-hypnotics. Safe prescribing is only achievable with interprofessional treatment monitored by both the clinician and pharmacist. [Level 5]