Understanding Lorazepam: Uses, Mechanism, and Considerations

The US Food and Drug Administration (FDA) has authorised the benzodiazepine drug lorazepam for several ailments. This medication is often compared to other benzodiazepines and is utilised in various clinical settings. DJ Richards created lorazepam, which was first sold in the US in 1977. Due to its quick onset of action (1-3 minutes) when given intravenously (IV), lorazepam is preferred as the drug of choice for sedative and anxiolytic medication in inpatient settings.

FDA-Recommended Uses

Lorazepam is recommended for several conditions, including:

• Reduction of anxiety symptoms linked to anxiety disorders for a brief period of four months

• Sleeplessness linked to anxiety

• Premedication for anaesthesia in adults to reduce anxiety or induce amnesia or sedation

• Managing status epilepticus

  
  

Off-Label Uses

In addition to its FDA-approved uses, lorazepam has several off-label applications:

• Quickly calming down the restless patient

• Delirium and syndrome associated with alcohol withdrawal

• Sleeplessness

• Anxiety disorders

• Delirium

• Anticipatory nausea and vomiting linked to chemotherapy (adjunct or breakthrough)

• Catatonia caused by psychogenic factors

• Dizziness

  
  

The Action Mechanism

Lorazepam binds to benzodiazepine receptors on postsynaptic γ-aminobutyric acid (GABA)-A ligand-gated chloride channel neurons in the central nervous system (CNS). This drug enhances GABA's inhibitory effects, increasing the cell's chloride ion conductance. As a result, the cellular plasma membrane becomes hyperpolarised and stabilised. The cerebral cortex's inhibitory activity is beneficial in seizure disorders, while the amygdala's inhibitory action helps in anxiety disorders.

Pharmacokinetics

Absorption

When taken orally, lorazepam is well absorbed. After oral treatment, peak concentrations are reached two hours later. Approximately 90% of lorazepam is bioavailable. Additionally, lorazepam passively diffuses across the blood-brain barrier without restriction.

Distribution

Lorazepam binds to around 90% of plasma proteins and has a volume of distribution of 1.3 L/kg. The medication utilises passive diffusion to cross the blood-brain barrier.

Metabolism

Lorazepam undergoes enterohepatic recirculation and conjugation in the liver. The metabolite lorazepam glucuronide is inactive. The drug is directly glucuronidated without first undergoing cytochrome P450 metabolism. As a result, lorazepam's pharmacokinetics are not significantly affected when given to individuals with liver disease.

Excretion

The half-life of lorazepam is 14±5 hours, and its clearance is 1.1±0.4 mL/min/kg. Urine is the primary way the medication is excreted.

Strengths and Dosage Forms for Administration

Vial of Lorazepam injection 2 mg/mL labelled for clinical use—commonly prescribed for anxiety, sedation, and seizures.

Normon lorazepam 5mg tablet

Lorazepam is available in various pharmaceutical forms, including oral tablets, oral concentrate solutions, extended-release capsules, and solutions. The available strengths include 0.5 mg, 1 mg, and 2 mg tablets, as well as a 2 mg/mL oral concentrate solution. There are also 1 mg, 2 mg, and 3 mg varieties of extended-release capsules. Furthermore, lorazepam can be administered intramuscularly (IM) or intravenously (IV) using solutions at concentrations of 2 and 4 mg/mL. Usually, the onset of effect occurs 1–3 minutes after IV administration and 15–30 minutes after IM administration.

Doses for Adults

Anxiety Disorder

For anxiety disorder, the recommended starting dose is 2 to 3 mg of lorazepam taken orally, two to three times a day. A daily intake of no more than 10 mg is advised.

Anxiety or Stress-Related Insomnia

Patients aged 65 years or younger should take 0.5 to 2 mg of lorazepam orally before bedtime. Those aged 65 years or older should take 0.5 to 1 mg.

Premedication for Anaesthesia

Lorazepam should be administered intramuscularly (IM) at a maximum dose of 4 mg, with a suggested dosage of 0.05 mg/kg two hours before the operation. If administered IV, the recommended dosage is 0.044 mg/kg given 15 to 20 minutes before surgery, with a maximum dose of 4 mg. However, in individuals aged 50 or above, the maximum dose should not exceed 2 mg.

Status Epilepticus

Lorazepam is usually infused intravenously (IV) at a maximum dose of 4 mg and a maximum infusion rate of 2 mg/min, with a typical dosage of 0.1 mg/kg. If necessary, this dosage can be repeated every five to ten minutes. A 1:1 dilution of the medication requires an equal amount of saline. Parenteral lorazepam is one of the first-line therapies for convulsive status epilepticus, according to the American Epilepsy Society recommendations.

Intensive Care Unit Patient Agitation

For agitation in ICU patients, lorazepam IV loading doses range from 0.02 to 0.04 mg/kg, with a maximum single dosage of 2 mg. Lorazepam can be administered as a continuous infusion of 0.01 to 0.1 mg/kg/h, with a maximum dose limit of less than 10 mg/h, or as a maintenance dosage of 0.02 to 0.06 mg/kg every 2 to 6 hours as needed.

Alcohol Withdrawal Delirium

For alcohol withdrawal delirium, 1–4 mg of lorazepam should be administered intravenously every 5–15 minutes until the patient is comfortable. If necessary, the dose can be repeated every hour. One to four milligrams of lorazepam should be administered intramuscularly (IM) every thirty to sixty minutes until the patient is at ease. The dose can be repeated every hour if needed.

Alcohol Withdrawal Syndrome

Lorazepam is one of the most commonly prescribed medications for treating alcohol withdrawal, according to the clinical practice recommendations of the American Society of Addiction Medicine. A severity evaluation scale can be used to calculate the appropriate dosage for the symptom-triggered regimen, which can be given orally, intramuscularly, or by injection at a rate of 2 to 4 mg/h as needed. A fixed-dose regimen may involve two milligrams every six hours for four doses, followed by one milligram every six hours for eight more. Notably, symptom-triggered regimens, which require lower dosages and shorter treatment periods, are preferable to fixed-dose regimens. For patients with cirrhosis, lorazepam is recommended.

Chemotherapy-Related Nausea and Vomiting

Lorazepam is used as a supplement to conventional antiemetics or for breakthrough nausea or vomiting. A dose of 0.5 to 2 mg can be administered orally, intravenously, or sublingually every 6 hours.

Psychogenic Catatonia

For psychogenic catatonia, 1 to 2 mg of lorazepam should be administered intramuscularly (IM). If the first dose is not successful, it can be repeated after 3 hours, and if necessary, after another 3 hours. A first dose of 1 mg of lorazepam can be given orally, intramuscularly, or intravenously. If required, this dose can be repeated after 5 minutes. The dosage may be raised to 4 to 8 mg per day if the first challenge proves ineffective, and therapy may last for up to five days.

Vertigo

When a rapid onset of action is needed to alleviate vertigo in Meniere's disease, lorazepam at a dose of 1 to 2 mg every 8 hours is recommended by the American Academy of Otolaryngology-Head & Neck Surgery. However, it is not advised to treat benign paroxysmal positional vertigo with benzodiazepines.

Severe Agitation

To treat severe agitation in out-of-hospital or emergency department patients quickly, the American College of Emergency Physicians (ACEP) recommends using either an atypical antipsychotic with midazolam or a combination of droperidol and midazolam. ACEP suggests droperidol or an atypical antipsychotic if only one agent is used. For successful treatment, haloperidol—either by itself or in combination with lorazepam—is also advised.

Pregnancy Considerations

Lorazepam is categorised as a category D medication. Using lorazepam and other benzodiazepines during the first trimester may raise the likelihood of developing cleft palate and cleft lip, according to documented case reports and case-control studies. There is a higher chance of newborn withdrawal symptoms when lorazepam and benzodiazepines are used during the third trimester. If lorazepam must be used during pregnancy, it should be done very carefully, ensuring that the benefits outweigh the risks.

Breastfeeding Considerations

Low levels of lorazepam have been found in breast milk. Research shows that when mothers take regular doses of lorazepam, their breastfed infants do not experience any side effects. Furthermore, lorazepam appears to be safer than other benzodiazepines during nursing, according to a safety ranking methodology that assesses psychotropic medications used in nursing mothers.

Potentially Inappropriate Medication in Older Adults

Lorazepam is categorised as a potentially inappropriate medication for older adults based on the American Geriatric Society's Beers Criteria. Reduced clearance rates and increased susceptibility to benzodiazepines are standard in the elderly population. As a result, when using lorazepam, they are more likely to experience cognitive impairment, falls, and fractures. However, in cases like severe generalised anxiety disorder, alcohol withdrawal, seizure disorders, and periprocedural sedation, its usage could be justified. It is recommended to utilise the lowest effective dosage when indicated.

Considerations for Children

IV lorazepam and IV diazepam are considered successful in stopping seizures in children (level A) according to the American Epilepsy Society standards, but buccal midazolam or rectal diazepam (IM or intranasal) are regarded as probably effective (level B).

Adverse Consequences

Like most benzodiazepines, lorazepam can cause dose-dependent side effects, including respiratory and central nervous system depression. Higher dosages of the medication are associated with additional adverse effects.

Severe Side Effects of Lorazepam

• Depression and respiratory failure

• Seizures

• Suicidal thoughts

• Abuse and dependency

• Heart palpitations

• Low blood pressure

• Syncope

• Blood dyscrasias

• Jaundice

• Paradoxical response (aggressive and hyperactive conduct)

• Intra-arterial gangrene

• Signs of withdrawal if long-term usage is suddenly stopped

• Cognitive deficits

• Behavioural changes

• Paradoxical agitation

• Hyponatremia and metabolic acidosis from large dosages of the parenteral formulation of propylene glycol

  
  

Typical Side Effects of Lorazepam

• Sedation

• Lightheadedness

• Asthenia

• Ataxia

• Local injection site reactions

• Respiratory depression

• Hypoventilation while using an IV

• Low blood pressure

• Fatigue

• Amnesia

• Confusion

• Disinhibition

• Irritability

• Libido changes

• Irregular menstruation

• Diplopia

• Dysarthria

• Changes in appetite

• Constipation

• Urinary retention

• Dystonia

• Elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

• Rarely, lorazepam may result in cholestatic pattern or acute liver damage

  
  

Drug-Drug Interactions

CNS depression can result from lorazepam's interactions with other medications. The adverse effects of lorazepam can be exacerbated by concurrent use of sedatives, hypnotics, opioids, cough and cold medications, antiepileptics, muscle relaxants, and alcohol. It's best to taper down lorazepam gradually when starting treatment with UDP-glucuronosyltransferase (UGT) inhibitors to minimise the risk of withdrawal.

Propylene glycol products found in parenteral lorazepam formulations should not be administered with metronidazole because they may cause a disulfiram-like reaction. In the US, kratom, a plant that has effects similar to those of partial opioid agonists, is often abused. It is essential to avoid taking benzodiazepines and kratom together since doing so can significantly increase the chance of developing severe central nervous system depression.

Contraindications

Alerts and Safety Measures

Patients who have experienced anaphylactic responses to lorazepam, any of the formulation's ingredients, or other benzodiazepines in the past should not use lorazepam (cross-sensitivity with other benzodiazepines may occur). Additionally, the medication should not be used in newborns or premature babies, in patients with acute narrow-angle glaucoma, sleep apnea, severe respiratory insufficiency, severe respiratory impairment (except while on artificial ventilation), or when given intra-arterially.

It is not advised to use lorazepam or other benzodiazepines as first-line treatments for anxiety or other symptoms of mental disorders in the first or third trimesters of pregnancy. There is a higher chance of abuse, misuse, and dependency with benzodiazepines like lorazepam. As a result, they should not be administered to patients who are already abusing narcotics or illegal substances. People with a history of alcohol abuse or dependency who are not in remission should not use lorazepam or other benzodiazepines unless they are detoxing from alcohol use disorder. There is a higher chance of death when alcohol and lorazepam are used together in an overdose.

Hypersensitivity to polyethylene glycol, propylene glycol, or benzyl alcohol is a contraindication for the injectable formulation of lorazepam. Patients with a history of allergic reactions should not use extended-release capsules because they contain tartrazine.

Warning Box

Sedation, severe respiratory depression, coma, and even death can occur when benzodiazepines and opioids are used together. Therefore, it is crucial to avoid combining these medications.

Monitoring

As a schedule IV medication, lorazepam can cause tolerance and dependency in users over time. Therefore, it is recommended to use the lowest effective dose of lorazepam for the shortest possible duration. When stopping lorazepam, a tapering programme of 0.5 mg every 3 days is advised to reduce withdrawal symptoms. According to the Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) procedure, the dosage of lorazepam should be tracked and modified. A validated scoring system, like the Hamilton Anxiety Scale, should be used to track improvements in anxiety.

Overdose Symptoms and Toxicity Indications

When used in excess, lorazepam can produce respiratory and central nervous system depression, which can result in hypotension, ataxia, disorientation, coma, excessive sleepiness, muscular weakness, and even death. When benzodiazepines and opioids are used together, it can cause severe drowsiness, respiratory depression, coma, and even death. Therefore, individuals with insufficient other treatment choices should be the only ones prescribed benzodiazepines and opioids combined. Patients need to be monitored for respiratory depression symptoms, and the dosage and duration of lorazepam must be restricted according to the indication. Like other benzodiazepines, lorazepam is rarely linked to elevated serum ALT; however, it is uncommon for lorazepam to cause clinically noticeable liver damage. Cholestatic is the usual clinical picture of acute benzodiazepine-induced liver damage.

In general, lorazepam dosages and durations should be carefully considered, particularly for patients who have a history of substance use disorders or who are currently taking opioid prescriptions. To handle such patients, a multidisciplinary healthcare team of nurses, pharmacists, and other specialised physicians is required. Signs of misuse, diversion, or concurrent usage with other prescription or over-the-counter sedative drugs should be closely watched by this team. Prescribers and pharmacists who prescribe benzodiazepines, including lorazepam, must be vigilant, provide patient information, and continuously monitor medication. The prescription medication monitoring programme can also assist in spotting any lorazepam abuse.

To your health,

Nwabekee

REFERENCE

• Ghiasi, N., Bhansali, R.K. and Marwaha, R. (2024). Lorazepam, PubMed. Treasure Island (FL): StatPearls Publishing. Available at: https://www.ncbi.nlm.nih.gov/books/NBK532890/.

• Science photo library

• Normon lorazepam