Lorazepam


Article Author:
Noman Ghiasi


Article Editor:
Raman Marwaha


Editors In Chief:
Susan Johnson
Alexandra Caley


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
12/23/2018 10:15:34 AM

Indications

Lorazepam is a benzodiazepine medication developed by DJ Richards. It went on the market in the United States in 1977. Lorazepam is commonly used as the sedative and anxiolytic of choice in the inpatient setting owing to its fast (1 to 3 minute) onset of action when administered intravenously.[1] Lorazepam is also one of the few sedative-hypnotics with a relatively clean side effect profile. 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.[2] 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.[3]

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) and enhances the inhibitory effects of GABA, which increases the conductance of chloride ions into the cell. This shift in chloride ions results in hyperpolarization and stabilization of the cellular plasma membrane.[4] Its inhibitory action in the amygdala helps with anxiety disorders while its inhibitory action in the cerebral cortex helps in seizure disorders.

Administration

Lorazepam has an 85% bioavailability when taken by mouth and is metabolized in the liver by glucuronidation using the CYP450 enzymes and has a half-life of 14 hours.[5] Lorazepam can be administered orally, intravenously (IV), or intramuscularly (IM). The onset of its action is 1 to 3 minutes if administered IV and 15 to 30 minutes if administered IM. Lorazepam reaches its peak plasma time in 2 hours if administered orally.

Anxiety disorder: Initial starting dose: 2 mg to 3 mg by mouth,  can repeat dose 2 to 3 times per day Maximum dosage 10 mg per day.[6]

Insomnia due to anxiety or stress: In patients less than 65 years of age: 0.5 to 2 mg at bedtime  In patients over 65 years age: 0.5 to 1 mg at bedtime.

Premedication for anesthesia: IM 0.05 mg/kg administered 2 hours prior to surgery (maximum dose 4 mg); IV 0.044 mg/kg administered 15 to 20 minutes prior to surgery (maximum dose 4 mg). Note: In patients older than 50 years of age, maximum dosage is 2 mg.[7]

Status epilepticus: IV 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.

Agitation in the intensive care unit (ICU) patient (off-label use): IV Loading dose 0.02 to 0.04 mg/kg (maximum single dose 2 mg); Maintenance 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 1 to 4 mg every 5 to 15 minutes until the patient is calm; Can repeat every hour as need; IM 1 to 4 mg every 30 to 60 minutes until the patient is calm; Can repeat every hour as needed.[8]

Alcohol withdrawal syndrome (off-label use):  Symptom-triggered regimen: Oral, IM, IV 2 mg to 4 mg per hour as needed; dose must be determined by the severity assessment scale. Fixed-dose regimen: Oral, IM, IV 2 mg every 6 hours for 4 doses, followed by 1 mg every 6 hours for 8 additional doses. Note: Symptom-triggered regimen is preferred over the fixed-dose regimens; lower doses and shorter duration of treatment are needed.

For chemotherapy-associated nausea and vomiting (off-label use): For breakthrough nausea/vomiting or as an adjunct to standard antiemetics oral, IV, sublingual: 0.5 to 2 mg every 6 hours as needed.

For psychogenic catatonia (off-label use): IM 1 mg to 2 mg; can repeat dose in 3 hours then again in another 3 hours if initial and subsequent doses are ineffective; Oral, IM, IV: Initially 1 mg and may repeat in 5 minutes if necessary. If the initial challenge is unsuccessful, may increase the dose up to 4 to 8 mg per day and may continue treatment for up to 5 days.[9]

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.[10]

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

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

Contraindications

Lorazepam is contraindicated in patients with an anaphylactic reaction to lorazepam, any component of the formulation, other benzodiazepines (cross-sensitivity with other benzodiazepines may exist), intra-arterial administration, use in neonates or infants, severe respiratory impairment (except during mechanical ventilation), pregnancy (third trimester), and acute narrow-angle glaucoma, severe respiratory insufficiency.[11] Additional contraindications include Hypersensitivity to polyethylene glycol, propylene glycol, or benzyl alcohol, and sleep apnea. It can cause “floppy infant syndrome” due to neonatal withdrawal.

Monitoring

Monitor respiratory and cardiovascular status, blood pressure, heart rate, and symptoms of anxiety. 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. 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. It is recommended to use the lowest possible effective dose for the shortest period. When stopping Lorazepam, it should be tapered by 0.5 mg every 3 days to avoid withdrawal symptoms.[12]

Toxicity

Lorazepam can cause CNS and respiratory depression in overdose. It can lead to hypotension, ataxia, confusion, coma and can be fatal. Concurrent use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.[13] Concomitant prescribing of benzodiazepines and opioids must be reserved for patients for whom alternative treatment options are inadequate. Dosages and durations of Lorazepam must be limited to the minimum required. Patients must be followed for signs and symptoms of respiratory depression. Lorazepam, as with other benzodiazepines, is rarely associated with elevations in serum ALT, and clinically apparent liver injury from lorazepam is extremely rare.[14] The clinical pattern of acute liver injury from benzodiazepines is typically cholestatic. Flumazenil is used as an antidote to benzodiazepine toxicity.[15] Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine receptor complex. Abrupt awakening can cause dysphoria, agitation, and increased adverse effects.[16] If it is administered to patients who have received a benzodiazepine chronically, abrupt 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.[17]

Enhancing Healthcare Team Outcomes

Lorazepam, like other benzodiazepine medications, is a highly addictive medication. Great care must be taken 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 inter-professional team of healthcare professionals that include nurses, pharmacists, and a number of specialist physicians to monitor for signs of abuse, diversion or concomitant use with other prescription or non-prescription sedative medications. Prescribing physicians must be vigilant in prescribing benzodiazepine such as lorazepam and make use of 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.


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Lorazepam - Questions

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Which of the following benzodiazepines is not metabolized into an active product?



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Which of the following drugs is FDA approved for the treatment of anxiety disorders?



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Insomnia due to anxiety or stress is treated with which of the following drugs?



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Which form of lorazepam must be stored in a refrigerator?



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Which of the following is a common adverse effect of lorazepam?



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A 47-year-old homeless man is admitted to the psychiatric unit for attempted suicide. On day 5 of the admission, the patient becomes extremely agitated and complains of insomnia and rapid heart rate. On physical exam, the patient has a blood pressure of 155/96 mmHg, heart rate of 110 beats per minute, respirations are 20/minute, and temperature 100.2 F. The patient looks visibly anxious is diaphoretic and has a fine tremor. What’s the next best step?



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What’s the mechanism of action of lorazepam?



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What is the onset of action of intramuscularly administered lorazepam?



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How long does it take for lorazepam to reach its peak plasma concentrations if administered orally?



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Which is a sign of lorazepam toxicity?



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What is an FDA-approved indication of lorazepam?



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A 37-year-old patient who has been taking lorazepam 4 mg at night for the past three months for insomnia due to anxiety comes to the clinic concerned about developing dependence. She states she would like to cut back on lorazepam. What is the next best step?



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Lorazepam - References

References

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Leppik IE, Status epilepticus in the elderly. Epilepsia. 2018 Oct     [PubMed]
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Petrides AK,Melanson SEF,Kantartjis M,Le RD,Demetriou CA,Flood JG, Monitoring opioid and benzodiazepine use and abuse: Is oral fluid or urine the preferred specimen type? Clinica chimica acta; international journal of clinical chemistry. 2018 Jun     [PubMed]
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