Lorazepam

• 1. Introduction

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  Lorazepam ranked 100th among the most commonly prescribed medications in the United States in 2023, with more than 6 million prescriptions. That is a striking figure for a drug meant for short stretches of use. Lorazepam is a benzodiazepine, a class of medicine that slows activity in the central nervous system. Yet it appears in settings as different as emergency care, surgery and palliative medicine. How can one compound halt a convulsing patient, settle a panic attack and erase the memory of an unpleasant procedure? Why is it considered gentler on a damaged liver than most of its relatives? And why do the same doctors who rely on it handle it with such care?

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• 2. Origins and Forms

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  Wyeth Pharmaceuticals introduced lorazepam in 1977 under the brand names Ativan and Temesta. The compound had first been patented in 1963, and it went on sale in the United States in 1977. Wyeth's president of research, D.J. Richards, developed the drug. Lorazepam is counted among the classical benzodiazepines, alongside diazepam, clonazepam, oxazepam, nitrazepam, flurazepam, bromazepam and clorazepate. Wyeth's original patent has expired in the United States, and generic versions are available. The World Health Organization lists lorazepam on its List of Essential Medicines.

  In its pure form, lorazepam is an almost white powder that barely dissolves in water or oil. Medicines made from it are mainly tablets and a solution for injection. In some places it also comes as a skin patch, an oral solution or a sublingual tablet. Doctors can give it by mouth, through the skin as a patch or topical gel, into a vein or into a muscle.

  Injectable lorazepam is sold in 1 mL ampoules holding either 2 or 4 mg. The solvents are polyethylene glycol 400 and propylene glycol, and benzyl alcohol acts as the preservative. Toxicity from propylene glycol has been reported in one person receiving a continuous lorazepam infusion. After an injection, effects begin within one to thirty minutes and can last up to a day, a profile that suits emergencies.

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• 3. Seizure Emergencies

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  Intravenous diazepam or lorazepam is the first-line treatment for convulsive status epilepticus, where seizures are still under way. Lorazepam is more effective than diazepam and than intravenous phenytoin. It also carries a lower risk of seizures continuing and calling for additional medication. One exception appears in the elderly, where phenobarbital has a better success rate than lorazepam and the other drugs.

  Given into a vein, lorazepam reliably ends acute seizures, though it leaves the person sedated for a long time. By mouth it plays a smaller role. Oral benzodiazepines, lorazepam included, are occasionally used long term to prevent resistant absence seizures. Because tolerance to their anti-seizure effect builds gradually, they are not first-line therapies. Seizures themselves complicate swallowing a tablet, since hypersalivation, jaw-clenching and involuntary swallowing are common.

  Alcohol withdrawal syndrome is another target, because lorazepam's anticonvulsant and depressant properties help both treat and prevent it. Here the liver is not a hazard, since lorazepam needs no oxidation, in the liver or anywhere else, to be metabolized. It is noted as the most tolerable benzodiazepine for people with advanced-stage liver disease. Kidney disease likewise has minimal effects on lorazepam levels. Oxazepam shares this trait, relying on the same single glucuronidation step in the liver.

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• 4. Anxiety and Sleep

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  The United States Food and Drug Administration advises against using benzodiazepines such as lorazepam for longer than four weeks. Within that limit, lorazepam is used in the short-term management of severe anxiety. It acts quickly, which makes it useful for anxiety that comes on suddenly and for panic attacks.

  A single dose can reduce agitation and induce sleep. Because its action is fairly short, lorazepam is an appropriate choice for short-term insomnia. This is especially so when severe anxiety or night terrors are present.

  Rebound insomnia and rebound anxiety can appear after only seven days of use, an early hint of the dependence problems discussed later.

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• 5. Sedation and Agitation

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  Ninety to 120 minutes before a procedure, a patient may be given lorazepam by mouth; by vein, the dose goes in up to 10 minutes beforehand. Doctors use it as premedication before a general anesthetic, where it reduces the amount of anesthetic needed. It is also given before unpleasant procedures done while the patient is awake, such as dental work or endoscopies. There it lowers anxiety, improves cooperation and induces anterograde amnesia, so the procedure is not remembered.

  Among benzodiazepines, lorazepam has relatively strong amnesic effects, though people soon develop tolerance to them with regular use. In one sleep study, five participants were prescribed 4 mg at night. The next evening, three unexpectedly volunteered memory gaps for parts of the day, and the effect faded completely after two to three days of use. An initial total daily dose that does not exceed 2 mg may help avoid amnesia or excess sedation. Amnesia cannot be judged from how sedated a person is, because the two effects are unrelated.

  In intensive care units, lorazepam is sometimes used to produce anxiolysis, hypnosis and amnesia. In palliative sedation it is sometimes an alternative to midazolam. For critically ill people on mechanical ventilation, however, propofol has proved superior in both effectiveness and cost. Its use is now encouraged, and lorazepam's is discouraged.

  For rapid sedation of violent or agitated people, haloperidol plus promethazine is preferred over lorazepam. The reasons are better effectiveness and lorazepam's adverse effects on breathing. Behavioral disinhibition may make benzodiazepines unsuitable for some people who are acutely psychotic. Acute delirium is sometimes treated with lorazepam, but because it can cause paradoxical effects it is preferably given with haloperidol. Injected into a muscle, a common route in restraint situations, lorazepam is absorbed relatively slowly.

  Catatonia with an inability to speak responds to lorazepam, although symptoms may recur and treatment for some days may be necessary. Catatonia caused by abrupt or overly rapid withdrawal from benzodiazepines also responds. Along with other treatments, lorazepam is used for acute coronary syndrome due to cocaine use. In chemotherapy it is sometimes added to antiemetics, for nausea and vomiting caused or worsened by a psychological sensitization to the thought of being sick.

  A topical product called ABH gel combines lorazepam with diphenhydramine and haloperidol. It is widely used in hospice and palliative care for nausea and vomiting, even though absorption through the skin is poor and evidence of benefit is limited. The American Academy of Hospice and Palliative Medicine has advised against topical lorazepam for this purpose because it has not been proven effective.

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• 6. Body and Brain

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  One milligram of lorazepam equals 10 mg of diazepam in effect, which marks it as a high-potency benzodiazepine. Its biological half-life is 10-20 hours. Its properties are anxiolytic, sedative, hypnotic, amnesic, anticonvulsant and muscle relaxant.

  Poor solubility in both water and fat shapes much of how lorazepam behaves. It is 85-90% bound to proteins, so it stays mostly within the blood vessels, which gives it relatively prolonged peak effects. By mouth it is absorbed slowly, and it is unsuitable for rectal use. Diazepam is the contrast. Highly fat-soluble, it is absorbed quickly by mouth or rectum, then redistributes into body fat. That is why one lorazepam dose has longer peak effects than an equivalent diazepam dose, despite a shorter serum half-life.

  In status epilepticus, diazepam's anticonvulsant and sedative effects wear off in 15-30 minutes, while lorazepam's last 12-24 hours. Repeated diazepam doses can lead to excess accumulation in the body. Lorazepam's prolonged sedation may be an acceptable trade-off, particularly if the person must be transferred to another facility. It is not necessarily better at first ending a seizure, yet it is replacing diazepam as the intravenous agent of choice.

  A 2 mg oral dose produces a peak total serum level of around 20 ng/mL about two hours later. Half of that is lorazepam and half is its inactive metabolite. A similar intravenous dose peaks earlier and higher, with more unmetabolised drug. With regular dosing, maximum levels arrive after three days, and use for up to six months causes no further accumulation. After stopping, levels become negligible after three days and undetectable after about a week.

  The liver rapidly conjugates lorazepam at its 3-hydroxy group into lorazepam glucuronide, which showed no demonstrable activity in the central nervous system of animals. This metabolite dissolves more readily in water, so it spreads more widely and has a longer half-life than lorazepam. The kidneys eventually excrete it, and it stays detectable in urine for substantially longer than the parent drug.

  In the brain, lorazepam strengthens the effect of the neurotransmitter GABA at the GABAA receptor by increasing how often the chloride ion channel opens. It cannot activate these receptors alone, because GABA must be present. Lorazepam is thought to have a high affinity for them, which may also explain its marked amnesic effects. The brain has spare receptor capacity, and a single clinical dose occupies only some 3% of the available receptors. That is why larger doses produce stronger and longer-lasting effects.

  Part or all of the anticonvulsant action may instead come from binding to voltage-dependent sodium channels. In mouse spinal cord cell cultures, benzodiazepines slowed the recovery of these channels from inactivation, which prolongs the refractory period. The same receptors change with prolonged use, which sets up the problem of tolerance.

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• 7. Risks and Cautions

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  Among around 3,500 people treated for anxiety, sedation was the most common complaint at 15.9%. Dizziness followed at 6.9%, weakness at 4.2% and unsteadiness at 3.4%. Sedation and unsteadiness grew more frequent with age. Confusion, ataxia, hangover effects, low blood pressure, respiratory depression and behavioral disinhibition may also occur. The effects are dose-dependent, so the smallest dose that works lowers the risk.

  Six months is the minimum span over which cognitive deficits persist after long-term benzodiazepine use ends, and recovery may take longer. Whether function fully returns is unclear. Lorazepam appears to harm memory more profoundly than other benzodiazepines, impairing both explicit and implicit memory.

  Paradoxical effects are a stranger hazard. They include increased hostility, aggression, angry outbursts and psychomotor agitation, and they are seen more often with lorazepam than with other benzodiazepines. Higher doses, pre-existing personality disorders and psychiatric illness make them more likely. Frustrating stimuli may trigger them, even though the drug may have been prescribed to help the person cope with that very frustration. Paradoxical excitement is also more likely in the elderly, in children, and in people with a history of alcohol abuse, aggression or anger problems. These reactions usually subside when the dose is reduced or the drug is stopped.

  Benzodiazepines can cause or worsen depression and are associated with an increased risk of suicide, possibly through disinhibition. Higher dosages appear to carry greater risk. Sedative drugs and sleeping pills, including lorazepam, have been associated with an increased risk of death. In September 2020, the FDA required the boxed warning on all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence and withdrawal reactions consistently across the class.

  Dosage recommendations for the elderly are about half those for younger people, and use should last no longer than two weeks. Older people metabolize benzodiazepines more slowly, are more sensitive to them even at similar plasma levels, and often take other interacting drugs. Falls and hip fractures are frequently reported, and alcohol worsens the impairments of balance. In children under 18, safety and effectiveness are not well determined, although lorazepam is used to treat acute seizures.

  Several conditions argue against lorazepam. These include past allergy to it or to any other benzodiazepine, and ataxia, the unsteady and clumsy movement that acute alcohol intoxication classically produces. It may worsen narrow-angle glaucoma by interfering with drainage of fluid from the eye. Sleep apnea can worsen because the drug depresses the central nervous system. Myasthenia gravis, marked by muscle weakness, may be aggravated by muscle relaxants such as lorazepam.

  The FDA places lorazepam in pregnancy category D, meaning it is likely to harm the developing baby if taken in the first trimester. Evidence is inconclusive on whether early use causes reduced intelligence, neurodevelopmental problems or malformations of the heart or face. Given before birth, it may cause floppy infant syndrome or respiratory depression requiring ventilation. Regular use in the third trimester carries a definite risk of benzodiazepine withdrawal syndrome in the newborn, with hypotonia, reluctance to suck, apneic spells and cyanosis. These symptoms have been reported to persist from hours to months after birth. Lorazepam may also inhibit fetal liver bilirubin glucuronidation, leading to neonatal jaundice, and it is present in breast milk.

  Alcohol is the interaction experts worry about most. Together they can cause respiratory depression in overdose and amplify disinhibition and amnesia, with potentially embarrassing or criminal consequences. Opioids and other hypnotics also add to the effects. Valproate inhibits lorazepam's metabolism, whereas carbamazepine, lamotrigine, phenobarbital, phenytoin and rifampin speed it up.

  Lorazepam is not usually fatal in overdose, and fatal overdoses on benzodiazepines alone are rare and less common than with barbiturates. Signs range from confusion and drowsiness to coma. Management is mainly observation and support, with intravenous flumazenil if necessary.

  In blood or plasma, concentrations of 10-300 micrograms per litre are usual in people taking the drug therapeutically or arrested for impaired driving. Roughly 300-1000 micrograms per litre is found after acute overdose. Common urine screens may miss lorazepam, because most detect only benzodiazepines that pass through oxazepam glucuronide metabolism.

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• 8. Dependence and Withdrawal

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  About one-third of people treated with a benzodiazepine for longer than four weeks develop dependence marked by a withdrawal syndrome. Higher doses and longer use raise the risk. Potent, short half-life benzodiazepines such as lorazepam, alprazolam and triazolam carry the highest risk of causing dependence.

  After four to six months of regular treatment, dose increases may become necessary to keep the same effect. Symptoms that resist treatment at that stage may actually be withdrawal symptoms. Tolerance to the anticonvulsant effect is the reason benzodiazepines are generally not recommended for long-term epilepsy management. The mechanism is complex, involving GABAA receptor downregulation, altered receptor subunit configuration, uncoupling and internalization of the benzodiazepine binding site, and changes in gene expression.

  Stopping abruptly or too quickly brings anxiety and signs of physical withdrawal like those seen with alcohol and barbiturates. Symptoms can range from mild anxiety and insomnia to seizures and psychosis. Rebound effects often resemble the condition being treated, but more intensely, which makes them hard to diagnose. Short-acting drugs such as lorazepam are more likely to cause a severe syndrome than longer-acting ones. The long list of possible symptoms includes headaches, sweating, tremor, numbness and tingling in the limbs, hypersensitivity to light, sound and smell, derealization, depersonalization, hallucinations, delirium, palpitations and hyperthermia. It takes about 18-36 hours for lorazepam to leave the body.

  The recommended way off long-term lorazepam is a gradual switch to an equivalent dose of diazepam, a period of stabilization, and only then dose reductions. Diazepam and its active metabolites have half-lives of 20-200 hours, so reductions are felt less acutely.

  Some people take lorazepam to achieve a high, or keep taking it long term against medical advice. A 2006 nationwide US government study by SAMHSA of pharmaceutical-related emergency department visits found that sedative-hypnotics were the pharmaceuticals most often used outside their prescribed purpose. They accounted for 35% of drug-related visits, and benzodiazepines were the most common in that category. Males and females used them for nonmedical purposes equally. Benzodiazepines were involved in 25% of attempted suicides, with lorazepam specifically used in 3.6% of attempts. It was the third-most-common benzodiazepine used outside of prescription in those statistics.

  Law treats lorazepam as a controlled drug in several countries. It is a Schedule IV drug under the Controlled Substances Act in the US and under the United Nations Convention on Psychotropic Substances. Canada also lists it as Schedule IV, under the Controlled Drugs and Substances Act. In the United Kingdom, it is a Class C, Schedule 4 Controlled Drug under the Misuse of Drugs Regulations 2001.

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