Lorazepam

Lorazepam is a prescription-only benzodiazepine medication indicated for the treatment of anxiety disorder, anxiety-associated insomnia, and status epilepticus.
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Common Trade Names: Ativan

Other Names: benzos, downers, nerve pills, tranks, roofies, roches, R2, goofballs, stupefy, 7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one

It is available in tablet form, as oral concentrate or as an injectable solution. It is frequently misused and often induces both physical and psychological dependency in long-term users, eventually leading them to substance use disorder. To learn more about how it happens, what you can expect, and how to treat it, read on.

A Brief History of Lorazepam

Lorazepam was developed by DJ Richards. It was patented in 1963 and was first marketed by Wyeth Pharmaceuticals in the United States in 1977. Lorazepam received its first FDA-approval in 1985 by the Mutual Pharm company.

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In 2018, lorazepam ranked 58th in the list of most commonly prescribed medications in the United States, with over 13 million documented prescriptions.

How Does Lorazepam Work in the Human Body?

Lorazepam is an anxiolytic and sedative medication. Lorazepam works by binding to benzodiazepine receptors on post-synaptic GABA-A ligand-gated chloride ion channels within the central nervous system. GABA is the primary inhibitory neurotransmitter in the nervous system. By binding to a site distinct from the GABA binding site, lorazepam augments the inhibitory effects of GABA, leading to an influx of chloride ions into the neurons. This cascade of events results in the hyperpolarization of the cellular membrane and inhibition of neuronal transmission, ultimately causing a decrease in nervous excitation.

Lorazepam is FDA-approved for the treatment of anxiety disorder, anxiety-associated insomnia, relief of pre-operative anxiety, and status epilepticus. It is also FDA-approved as a sedative or amnesic drug. Off-label uses of lorazepam include chronic insomnia, panic disorder, delirium (including alcohol withdrawal delirium), control of agitation, alcohol withdrawal syndrome, chemotherapy-induced nausea and vomiting, and psychogenic catatonia. Catatonia is a behavioral syndrome typically characterized by abnormal or uncoordinated body movements and lack of communication.

Presently, lorazepam is only indicated for short-term use (e.g. 2 to 4 weeks). The effectiveness of lorazepam in long-term use (i.e. longer than 4 months) has not been adequately studied and is thus not recommended.

Contraindications to lorazepam use include documented hypersensitivity to the drug or any of its components, severe respiratory illness, and acute narrow-angle glaucoma. Patients in the first and third trimester of pregnancy, neonates, and infants must also not take lorazepam as first-line agents for anxiety.

How is Lorazepam Taken or Administered?

Lorazepam comes in tablets, oral concentrates or injectable solutions. Lorazepam tablets are available in 0.5mg, 1mg, and 2mg formulations. Oral concentrate is available in 2mg/mL formulations, while injectable solutions are available in 2mg/mL and 4mg/mL formulations.

The following are the recommended doses for lorazepam:

Anxiety Disorder

Initial: 2 to 3mg orally every 8 to 12 hours as needed; not to exceed 10mg per day

Maintenance: 2 to 6 mg orally per day every 8 to 12 hours

Insomnia

2 to 4mg orally before bedtime

Status Epilepticus

4mg per dose slow IV at 2mg per minute

Preoperative sedation

0.05mg/kg IM for one dose, 2 hours before surgery; not to exceed 4mg (2mg per dose in the elderly)

Chemotherapy-induced nausea and vomiting (Off-label)

0.5 to 2 mg orally or IV every 6 hours; as needed thereafter

Anxiolytic/Sedation in the ICU (Off-label)

In mechanically ventilated patients: 0.02 to 0.04mg/kg loading dose IV

What Are the Immediate and Long-Term Effects of Lorazepam Use?

The adverse effects associated with lorazepam use are typically dose-dependent. Some of the common adverse effects of lorazepam are:

  • Dizziness
  • Double vision
  • Urinary retention or incontinence
  • Fatigue
  • Confusion
  • Amnesia
  • Irritability
  • Menstrual irregularities
  • Inflammation at the injection site
  • Respiratory depression
  • Decreased blood pressure

Abrupt cessation of lorazepam use may also cause development of withdrawal symptoms, including:

  • Headache
  • Tension
  • Depression
  • Anxiety
  • Restlessness or irritability
  • Tremor
  • Seizures
  • Confusion
  • Insomnia
  • Increased sweating, heart rate, and temperature
  • Dizziness
  • Numbness of extremities
  • Nausea and vomiting
  • Diarrhea
  • Involuntary movements
  • Panic attacks

There are also several paradoxical reactions linked to lorazepam use (i.e. any effect of a drug or substance that is opposite of what might be expected). Some of these are:

  • Anxiety
  • Excitation
  • Agitation
  • Hostility
  • Aggression or rage
  • Sleep disturbances (including insomnia)
  • Sexual arousal
  • Hallucinations

It is also noteworthy that use of lorazepam in combination with other benzodiazepines or opioids is potentially fatal as it can result in severe respiratory depression and coma. Concomitant prescribing of these drugs must be reserved for situations where alternative treatments have been fully explored and deemed inadequate.

Benzodiazepines may also exacerbate pre-existing depression and are associated with increased suicidal ideation. Patients clinically diagnosed with primary depressive disorder or psychosis are advised against taking lorazepam without concomitant adequate antidepressant therapy.

Signs of Lorazepam Use Disorder

In general, long-term use of benzodiazepines like lorazepam can lead to both physical and psychological dependence. The risk for dependence increases with increasing dose and longer period of use. In addition, patients with a history of substance or alcohol abuse or those with personality disorders are at an increased risk for benzodiazepine dependence.

The 5th Edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM5)  has listed four major categories of pathologic behavioral patterns manifested in substance abuse:

  1. Impaired control
  2. Social impairment
  3. Risky use
  4. Pharmacological indicators (tolerance and withdrawal)

These categories cover all 11 criteria for the diagnosis of SUDs:

Impaired control

  1. Taking the substance in greater amounts or for longer than prescribed
  2. Being unsuccessful in reducing or stopping the use of substance
  3. Spending a significant of time to get, use or recover from use of the substance
  4. Feeling intense urges to use or cravings for the substance

Social impairment

  1. Use of the substance leads to inability to fulfill school, work or family obligations
  2. Continued use of the substance despite having it cause interpersonal or relationship problems
  3. Letting go of important social, occupational, or recreational activities because of substance use

Risky Use

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  1. Use of substance in risky or dangerous situations such as while driving a car or operating machinery
  2. Continuing to use the substance despite exacerbation of physical and psychological problems

Physical tolerance

  1. Increasing the amount of the substance to achieve the desired effect (tolerance)
  2. Development of negative withdrawal symptoms (withdrawal)

Rehab and Treatment for Lorazepam Use Disorder

Cases of benzodiazepine abuse, including abuse of lorazepam, have continuously risen over the past few decades. The abuse potential of benzodiazepines can be attributed to its mood-altering properties, rapid onset of action, high potency, and brief duration of action. Benzodiazepines that have these properties, such as lorazepam, have been shown to have the strongest association with addiction.

Research has shown that abuse of lorazepam is more common among polydrug users, particularly those who are concomitantly using opioids, as it can enhance the opioid’s euphoric effects. Individuals who struggle with alcohol use disorder also seem to be at a greater risk for lorazepam abuse as lorazepam acts synergistically with alcohol.

At present, no medication has been approved for the treatment of lorazepam abuse. However, most healthcare professionals agree that the most effective way to reverse lorazepam use disorder is by gradual discontinuation of the drug over a period of several weeks, in a process called tapering. The aim of tapering is to control the development of withdrawal symptoms and prevent seizures. The recommended rate of discontinuation is based on the individual’s capacity to tolerate withdrawal symptoms. Withdrawal can be done in an outpatient setting, but hospitalization may be required for patients who have already reached very high doses.

Flumazenil, a benzodiazepine antagonist, has shown efficacy as an adjunct therapy for acute lorazepam overdose among hospitalized patients. It must be noted that flumazenil therapy may cause seizures particularly in long-term lorazepam abusers, and thus must be prescribed with great caution.

Symptoms-based pharmacotherapy can also be initiated to manage the withdrawal symptoms. Antidepressants, mood stabilizers, non-benzodiazepine anxiolytics, and beta-blockers can be considered to treat possible sleep disorders and depression.

Psychosocial and behavioral interventions may also be instituted to help the patient achieve complete abstinence. Various forms of psychotherapy such as cognitive-behavioral therapy (CBT), counselling, motivational interviewing, and relapse prevention are some strategies that can facilitate rehab for lorazepam abusers.

Cognitive-Behavioral Therapy (CBT). In CBT, patients are professionally guided to explore and recognize their maladaptive behaviors that predispose them to substance abuse. The aim of CBT is to correct these behavioral patterns to decrease the risk of relapse episodes and help the patient achieve a drug-free state.

Counselling. Much like CBT, counselling aims to help the patient achieve lifetime abstinence from drugs by teaching them healthy ways to cope with relapse triggers. Counsellors also help patients identify possible difficulties in their treatment journey and come up with acceptable resolutions.

Motivational Interviewing. Motivational interviewing is a client-centered approach that focuses on resolving the patient’s ambivalent feelings that would lead to a positive behavioral change.

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