StatPearls Update, Nov/20: Lorazepam

"Lorazepam"

https://www.ncbi.nlm.nih.gov/books/NBK532890/#article-24422.s1 

Lorazepam

Noman Ghiasi; Rakesh Kumar Bhansali; Raman Marwaha.

Author Information

Authors

Noman Ghiasi1; Rakesh Kumar Bhansali; Raman Marwaha2.

Affiliations

1 American Un of the Caribbean School Med

2 Case Western Reserve Un/MetroHealth MC

Last Update: November 29, 2020.

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 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). It 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, the 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; the severity assessment scale must determine the dose. Fixed-dose regimen: Oral, IM, IV 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 duration of treatment are in order.

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 the dose in 3 hours then again in another 3 hours if the 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, one 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) and acute narrow-angle glaucoma, severe respiratory insufficiency.[11] Lorazepam and other benzodiazepines should not be first-line agents for anxiety and other psychiatric disorder symptoms in the first and third trimester of pregnancy. There are documented case reports and case-control studies showing an increased risk for cleft palate and cleft lip with the use of 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 in pregnancy it should be used with extreme caution and benefit has to outweigh the risk. Lorazepam and other benzodiazepines have increased risk of abuse, misuse, and dependence these medications are contraindicated in the patient who is actively using illicit substances and drugs. Except for use in Alcohol withdrawal disorder symptoms and for detoxifications Lorazepam and other benzodiazepine are contraindicated in patients with h/o alcohol dependence and abuse and not in remission. Increased risk of fatality with the combined use of alcohol and lorazepam in overdose, including death. Additional contraindications include Hypersensitivity to polyethylene glycol, propylene glycol, or benzyl alcohol, and sleep apnea.

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. 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.[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. 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 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 an antidote for 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 administered to patients who 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.[17]

:

Enhancing Healthcare Team Outcomes

Lorazepam, like other benzodiazepine medications, is a highly addictive medication. 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 of healthcare professionals that include nurses, pharmacists, and several specialist physicians to monitor for signs of abuse, diversion, or concomitant use with other prescription or non-prescription sedative medications. Prescribing physicians and pharmacists must monitor treatment and provide patient education, being 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. Safe prescribing is only achievable with interprofessional treatment monitored by both the clinician and pharmacist. [Level 5]

Continuing Education / Review Questions

    Access free multiple choice questions on this topic.

    Earn continuing education credits (CME/CE) on this topic.

    Comment on this article.

Lorazepam chemical structure

Figure

Lorazepam chemical structure. Contributed from the Public Domain

Go to:

References

1.

    Hui D. Benzodiazepines for agitation in patients with delirium: selecting the right patient, right time, and right indication. Curr Opin Support Palliat Care. 2018 Dec;12(4):489-494. [PMC free article] [PubMed]

2.

    Leppik IE. Status epilepticus in the elderly. Epilepsia. 2018 Oct;59 Suppl 2:140-143. [PubMed]

3.

    Berman E, Eyal S, Marom E. Trends in utilization of benzodiazepine and Z-drugs in Israel. Pharmacoepidemiol Drug Saf. 2017 Dec;26(12):1555-1560. [PubMed]

4.

    Vinkers CH, Tijdink JK, Luykx JJ, Vis R. [Choosing the correct benzodiazepine: mechanism of action and pharmacokinetics]. Ned Tijdschr Geneeskd. 2012;155(35):A4900. [PubMed]

5.

    Yeary J, Garavaglia J, McKnight R, Smith M. Change in Management of Status Epilepticus With the Addition of Neurointensivist-Led Neurocritical Care Team at a Rural Academic Medical Center. Hosp Pharm. 2018 Oct;53(5):303-307. [PMC free article] [PubMed]

6.

    Vlastra W, Delewi R, Rohling WJ, Wagenaar TC, Hirsch A, Meesterman MG, Vis MM, Wykrzykowska JJ, Koch KT, de Winter RJ, Baan J, Piek JJ, Sprangers MAG, Henriques JPS. Premedication to reduce anxiety in patients undergoing coronary angiography and percutaneous coronary intervention. Open Heart. 2018;5(2):e000833. [PMC free article] [PubMed]

7.

    Maurice-Szamburski A, Auquier P, Viarre-Oreal V, Cuvillon P, Carles M, Ripart J, Honore S, Triglia T, Loundou A, Leone M, Bruder N., PremedX Study Investigators. Effect of sedative premedication on patient experience after general anesthesia: a randomized clinical trial. JAMA. 2015 Mar 03;313(9):916-25. [PubMed]

8.

        Heavner JJ, Akgün KM, Heavner MS, Eng CC, Drew M, Jackson P, Pritchard D, Honiden S. Implementation of an ICU-Specific Alcohol Withdrawal Syndrome Management Protocol Reduces the Need for Mechanical Ventilation. Pharmacotherapy. 2018 May 25; [PubMed]

9.

    Cevher Binici N, Topal Z, Demir Samurcu N, Cansız MA, Savcı U, Öztürk Y, Özyurt G, Tufan AE. Response of Catatonia to Amisulpride and Lorazepam in an Adolescent with Schizophenia. J Child Adolesc Psychopharmacol. 2018 Mar;28(2):151-152. [PubMed]

10.

    Strand MC, Mørland J, Slørdal L, Riedel B, Innerdal C, Aamo T, Mathisrud G, Vindenes V. Conversion factors for assessment of driving impairment after exposure to multiple benzodiazepines/z-hypnotics or opioids. Forensic Sci Int. 2017 Dec;281:29-36. [PubMed]

11.

    Naso AR. Optimizing patient safety by preventing combined use of intramuscular olanzapine and parenteral benzodiazepines. Am J Health Syst Pharm. 2008 Jun 15;65(12):1180-3. [PubMed]

12.

    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? Clin Chim Acta. 2018 Jun;481:75-82. [PubMed]

13.

    Xiang J, Wu M, Lei J, Fu C, Gu J, Xu G. The fate and risk assessment of psychiatric pharmaceuticals from psychiatric hospital effluent. Ecotoxicol Environ Saf. 2018 Apr 15;150:289-296. [PubMed]

14.

    Arai T, Kogi K, Honda Y, Suzuki T, Kawai K, Okamoto M, Fujioka T, Murata N. Lorazepam as a Cause of Drug-Induced Liver Injury. Case Rep Gastroenterol. 2018 May-Aug;12(2):546-550. [PMC free article] [PubMed]

15.

    Wallace IR, Campbell EC, Trimble M. Use of a flumazenil infusion to treat chlordiazepoxide toxicity. Acute Med. 2017;16(1):30-34. [PubMed]

16.

    Niedrig DF, Hoppe L, Mächler S, Russmann H, Russmann S. Benzodiazepine Use During Hospitalization: Automated Identification of Potential Medication Errors and Systematic Assessment of Preventable Adverse Events. PLoS One. 2016;11(10):e0163224. [PMC free article] [PubMed]

17.

    Rubio González V, Redondo Martín S, Ruíz López Del Prado G, Muñoz Moreno MF, Velázquez Miranda A. [Hospital Emergencies Associated with the Consumption of Hypnotics and Sedatives, 2009-2013,Castilla y León, Spain]. Rev Esp Salud Publica. 2016 Oct 24;90:e1-e12. [PubMed]