It takes about 18–36 hours for the benzodiazepine to be removed from the body. Withdrawal symptoms include headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, dysphoria, dizziness, derealization, depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, short-term memory loss, and hyperthermia. The ease of addiction to lorazepam, (Ativan brand was particularly cited), and its withdrawal were brought to the attention of the British public during the early 1980s in Esther Rantzen's BBC TV series That's Life!, in a feature on the drug over a number of episodes. Withdrawal symptoms can occur after taking therapeutic doses of Ativan for as little as one week.
Lorazepam may also interact with rifabutin. Lorazepam is not usually fatal in overdose, but may cause fatal respiratory depression if taken in overdose with alcohol. Synergistic adverse effects may also occur when lorazepam is administered with other drugs, such as opioids or other hypnotics. Valproate inhibits the metabolism of lorazepam, whereas carbamazepine, lamotrigine, phenobarbital, phenytoin, and rifampin increase its rate of metabolism. Some experts advise that patients should be warned against drinking alcohol while on lorazepam treatment, but such clear warnings are not universal. Some antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opiates, antipsychotics and alcohol, when taken with lorazepam may result in enhanced sedative effects. The combination also causes synergistic enhancement of the disinhibitory and amnesic effects of both drugs, with potentially embarrassing or criminal consequences.
Signs of overdose range through mental confusion, dysarthria, paradoxical reactions, drowsiness, hypotonia, ataxia, hypotension, hypnotic state, coma, cardiovascular depression, respiratory depression, and death.
The plasma levels of lorazepam are proportional to the dose given. Due to its poor lipid solubility, lorazepam is absorbed relatively slowly by mouth and is unsuitable for rectal administration. This contrasts with the highly lipid-soluble diazepam, which, although rapidly absorbed orally or rectally, soon redistributes from the serum to other parts of the body, in particular, body fat. Lorazepam is highly protein bound and is extensively metabolized into pharmacologically inactive metabolites. However, its poor lipid solubility and high degree of protein binding (85-90% ) mean its volume of distribution is mainly the vascular compartment, causing relatively prolonged peak effects. Lorazepam is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine. This explains why one lorazepam dose, despite its shorter serum half-life, has more prolonged peak effects than an equivalent diazepam dose. There is no evidence of accumulation of lorazepam on administration up to six months. Lorazepam glucuronide has no demonstrable CNS activity in animals. On regular administration, diazepam will accumulate, since it has a longer half-life and active metabolites, these metabolites also have long half-lives.
Also, one must ascertain whether other substances were also ingested. In cases of a suspected lorazepam overdose, it is important to establish whether the patient is a regular user of lorazepam or other benzodiazepines since regular use causes tolerance to develop.
Approximay μg/l is found in victims of acute overdosage. Lorazepam may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence of an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma concentrations are usually in a range of 10-300 μg/l in persons either receiving the drug therapeutically or in those arrested for impaired driving.
The wholesale cost in the developing world of a typical dose by mouth is between US$ 0.02 and US$0.16 as of 2014. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. In the United States in 2011, 28 million prescriptions for lorazepam were filled making it the second most prescribed benzodiazepine after alprazolam. In the United States as of 2015 a typical month supply is less than US$25. It is available as a generic medication. Lorazepam was initially patented in 1963 and went on sale in the United States in 1977.
The mechanism of tolerance to benzodiazepines is complex and involves GABA A receptor downregulation, alterations to subunit configuration of GABA A receptors, uncoupling and internalisation of the benzodiazepine binding site from the GABA A receptor complex as well as changes in gene expression. If regular treatment is continued for longer than four to six months, dose increases may be necessary to maintain effects, but treatment-resistant symptoms may in fact be benzodiazepine withdrawal symptoms. Increasing the dose may overcome tolerance, but tolerance may then develop to the higher dose and adverse effects may persist and worsen. Due to the development of tolerance to the anticonvulsant effects, benzodiazepines are generally not recommended for long-term use for the management of epilepsy.
Tolerance to benzodiazepine effects develops with regular use. Potent benzodiazepines, such as lorazepam, alprazolam, and triazolam, have the highest risk of causing a dependence. Dependence typified by a withdrawal syndrome occurs in about one-third of individuals who are treated for longer than four weeks with a benzodiazepine. Higher doses and longer periods of use increase the risk of developing a benzodiazepine dependence. This is desirable with amnesic and sedative effects but undesirable with anxiolytic, hypnotic, and anticonvulsant effects. After four to six months of regular benzodiazepine use, evidence of continued efficacy declines. Patients at first experience drastic relief from anxiety and sleeplessness, but symptoms gradually return, relatively soon in the case of insomnia, but more slowly in the case of anxiety symptoms.
Lorazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant, and muscle relaxant properties. It is a high-potency and an intermediate-acting benzodiazepine, and its uniqueness, advantages, and disadvantages are largely explained by its pharmacokinetic properties (poor water and lipid solubility, high protein binding and anoxidative metabolism to a pharmacologically inactive glucuronide form) and by its high relative potency (lorazepam 1 mg is equal in effect to diazepam 10 mg). The biological half-life of lorazepam is 10–20 hours.
When given intravenously the person should be closely monitored. Among those who are depressed there may be an increased risk of suicide. Common side effects include weakness, sleepiness, low blood pressure, and a decreased effort to breathe. Due to these concerns, lorazepam use is generally only recommended for up to two to four weeks. Older people more often develop adverse effects. With long-term use larger doses may be required for the same effect. Physical dependence and psychological dependence may also occur. In this age group lorazepam is associated with falls and hip fractures. If stopped suddenly after long-term use, benzodiazepine withdrawal syndrome may occur.
However, adverse effects such as behavioral disinhibition may make benzodiazepines inappropriate for some acuy psychotic patients. Lorazepam is absorbed relatively slowly if given intramuscularly, a common route in restraint situations. Lorazepam is sometimes used as an alternative to haloperidol when there is the need for rapid sedation of violent or agitated individuals, but haloperidol plus promethazine is preferred due to better effectiveness and due to lorazepam's adverse effects on respiratory function. Acute delirium is sometimes treated with lorazepam, but as it can cause paradoxical effects, it is preferably given together with haloperidol.
Lorazepam should be avoided in people with:
Therefore, lorazepam's anticonvulsant effects are more durable, thus reducing the need for repeated doses. The prolonged sedation from lorazepam may, however, be an acceptable trade-off for its reliable duration of effects, particularly if the patient needs to be transferred to another facility. If a patient is known to usually stop convulsing after only one or two diazepam doses, it may be preferable because sedative after effects will be less than if a single dose of lorazepam is given (diazepam anticonvulsant/sedative effects wear off after 15–30 minutes, but lorazepam effects last 12–24 hours). Although lorazepam is not necessarily better than diazepam at initially terminating seizures, lorazepam is, nevertheless, replacing diazepam as the intravenous agent of choice in status epilepticus. Clinical example: Diazepam has long been a drug of choice for status epilepticus ; its high lipid solubility means it gets absorbed with equal speed whether given orally, or rectally (nonintravenous routes are convenient in outside hospital settings), but diazepam's high lipid solubility also means it does not remain in the vascular space, but soon redistributes into other body tissues. Lorazepam is a different case; its low lipid solubility makes it relatively slowly absorbed by any route other than intravenously, but once injected, it will not get significantly redistributed beyond the vascular space. So, it may be necessary to repeat diazepam doses to maintain peak anticonvulsant effects, resulting in excess body accumulation.
It is also used, along with other treatments, for acute coronary syndrome due to cocaine use. While it can be used for severe agitation, midazolam is usually preferred. It can be given by mouth or as an injection into a muscle or vein. When given by injection onset of effects is between one and thirty minutes and effects last for up to a day. It is used to treat anxiety disorders, trouble sleeping, active seizures including status epilepticus, alcohol withdrawal, and chemotherapy induced nausea and vomiting, as well as for surgery to interfere with memory formation and to sedate those who are being mechanically ventilated. Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication.
High-dose or prolonged parenterally administered lorazepam is sometimes associated with propylene glycol poisoning.
Lorazepam's anticonvulsant properties and pharmacokinetic profile, make intravenous use reliable for terminating acute seizures, but induces prolonged sedation. Oral benzodiazepines, including lorazepam are occasionally used as long-term prophylactic treatment of resistant absence seizures ; because of gradual tolerance to their anti-seizure effects, benzodiazepines such as lorazepam are not considered first-line therapies.
It is also used as adjunct therapy for cyclic vomiting syndrome. It is sometimes used in chemotherapy in addition to medications used to treat nausea and vomiting, i.e. nausea and vomiting caused or worsened by psychological sensitization to the thought of being sick.
Patients are ideally nursed in a kind, frustrating environment, since, when given or taken in high doses, benzodiazepines are more likely to cause paradoxical reactions. If shown sympathy, even quite crudely feigned, patients may respond solicitously, but they may respond with disproportionate aggression to frustrating cues. Opportunistic counseling has limited value here, as the patient is unlikely to recall this later, owing to drug-induced anterograde amnesia.
If any benzodiazepine has been used long-term, the recommendation is a gradual dose taper over a period of weeks, months or longer, according to dose and duration of use, the degree of dependence and the individual. Because of its high potency, the smallest lorazepam tablet strength of 0.5 mg is also a significant dose reduction (in the UK, the smallest tablet strength is 1.0 mg, which further accentuates this difficulty). To minimise the risk of physical/psychological dependence, lorazepam is best used only short-term, at the smallest effective dose. The likelihood of dependence is relatively high with lorazepam compared to other benzodiazepines. Lorazepam's relatively short serum half-life, its confinement mainly to the vascular space, and its inactive metabolite can result in interdose withdrawal phenomena and next-dose cravings, that may reinforce psychological dependence.
Withdrawal symptoms, including rebound insomnia and rebound anxiety, may occur after seven days' use of lorazepam.
In this setting, impaired liver function is not a hazard with lorazepam, since lorazepam does not require oxidation, hepatic or otherwise, for its metabolism. Lorazepam's anticonvulsant and CNS depressant properties are useful for the treatment and prevention of alcohol withdrawal syndrome.
The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regimen. Short-acting benzodiazepines such as lorazepam are more likely to cause a more severe withdrawal syndrome compared to longer-acting benzodiazepines. Lorazepam, as with other benzodiazepine drugs, can cause physical dependence, addiction, and benzodiazepine withdrawal syndrome. The risk and severity of withdrawal are increased with long-term use, use of high doses, abrupt or over-rapid reduction, among other factors. On abrupt or overly rapid discontinuation of lorazepam, anxiety, and signs of physical withdrawal have been observed, similar to those seen on withdrawal from alcohol and barbiturates. Withdrawal symptoms can, however, occur from standard dosages and also after short-term use. Withdrawal symptoms can range from mild anxiety and insomnia to more severe symptoms such as seizures and psychosis. Rebound effects often resemble the condition being treated, but typically at a more intense level and may be difficult to diagnose.
Coming off long-term lorazepam use may be more realistically achieved by a gradual switch to an equivalent dose of diazepam and a period of stabilization on this, and only then initiating dose reductions. The advantage of switching to diazepam is that dose reductions are felt less acuy, because of the longer half-lives (20–200 hours) of diazepam and its active metabolites.
As lorazepam can have paradoxical effects, haloperidol is sometimes given at the same time. Catatonia due to abrupt or overly rapid withdrawal from benzodiazepines, as part of the benzodiazepine withdrawal syndrome, should also respond to lorazepam treatment. Symptoms may recur and treatment for some days may be necessary. Catatonia with inability to speak is responsive to lorazepam.
Otherwise, management is by observation, including of vital signs, support and, only if necessary, considering the hazards of doing so, giving intravenous flumazenil. Early management of alert patients includes emetics, gastric lavage, and activated charcoal.
Lorazepam by mouth is given 90 to 120 minutes before procedures, and intravenous lorazepam as late as 10 minutes before procedures. Its relative effectiveness in preventing new memory formation, along with its ability to reduce agitation and anxiety, makes lorazepam useful as premedication. Lorazepam is sometimes used as an alternative to midazolam in palliative sedation. In intensive care units lorazepam is sometimes used to produce anxiolysis, hypnosis, and amnesia. It is given before a general anesthetic to reduce the amount of anesthetic required, or before unpleasant awake procedures, such as in dentistry or endoscopies, to reduce anxiety, to increase compliance, and to induce amnesia for the procedure.
However, in critically ill people, propofol has been found to be superior to lorazepam both in effectiveness and overall cost; as a result, the use of propofol for this indication is now encouraged, whereas the use of lorazepam is discouraged. Lorazepam is sometimes used for individuals receiving mechanical ventilation.
However, phenobarbital has a superior success rate compared to lorazepam and other drugs, at least in the elderly. Intravenous diazepam or lorazepam are first-line treatments for convulsive status epilepticus. Lorazepam is more effective than diazepam in the treatment of status epilepticus.
Cognitive impairment, behavioural disinhibition and respiratory depression as well as hypotension may also occur. Side effects such as sedation and unsteadiness increased with age. Sedation is the side effect people taking lorazepam most frequently report. In a group of around 3,500 patients treated for anxiety, the most common side effects complained of from lorazepam were sedation (15.9%), dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%).
With long-term benzodiazepine use it is unclear whether cognitive impairments fully return to normal after stopping lorazepam use; cognitive deficits persist for at least six months after withdrawal, but longer than six months may be required for recovery of cognitive function. Many beneficial effects of lorazepam (e.g., sedative, muscle relaxant, anti-anxiety, and amnesic effects) may become adverse effects when unwanted. Using the smallest dose needed to achieve desired effects lessens the risk of adverse effects. Lorazepam's effects are dose-dependent, meaning the higher the dose, the stronger the effects (and side effects) will be. Adverse effects can include sedation and low blood pressure ; the effects of lorazepam are increased in combination with other CNS depressant drugs. In the elderly, falls may occur as a result of benzodiazepines. Paradoxical effects can also occur, such as worsening of seizures, or paradoxical excitement; paradoxical excitement is more likely to occur in the elderly, children, those with a history of alcohol abuse, and in people with a history of aggression or anger problems. Other adverse effects include confusion, ataxia, inhibiting the formation of new memories, and hangover effects. Benzodiazepines can cause or worsen depression. Adverse effects are more common in the elderly, and they appear at lower doses than in younger patients. Lorazepam appears to have more profound adverse effects on memory than other benzodiazepines; it impairs both explicit and implicit memory.
Longer-term use, up to six months, does not result in further accumulation. A similar lorazepam dose given intravenously will result in an earlier and higher peak serum level, with a higher relative proportion of unmetabolised (active) lorazepam. Lorazepam is metabolized in the liver by conjugation into inactive lorazepam-glucuronide. This metabolism does not involve hepatic oxidation, so is relatively unaffected by reduced liver function. On discontinuation, lorazepam serum levels become negligible after three days and undetectable after about a week. Giving 2 mg oral lorazepam will result in a peak total serum level of around 20 ng/ml around two hours later, half of which is lorazepam, half its inactive metabolite, lorazepam-glucuronide. Lorazepam-glucuronide is more water-soluble than its precursor, so gets more widely distributed in the body, leading to a longer half-life than lorazepam. Lorazepam-glucuronide is eventually excreted by the kidneys, and, because of its tissue accumulation, it remains detectable, particularly in the urine, for substantially longer than lorazepam. On regular administration, maximum serum levels are attained after three days. Lorazepam serum levels are proportional to the dose administered.
It is fast acting, and useful in treating fast onset panic anxiety. Lorazepam has anxiety-reducing effects and its best-known indication is the short-term management of severe anxiety. In the US, the FDA advises against use of benzodiazepines such as lorazepam for longer than four weeks.
Lorazepam can effectively reduce agitation and induce sleep, and the duration of effects from a single dose makes it an appropriate choice for the short-term treatment of insomnia, especially in the presence of severe anxiety or night terrors. It has a fairly short duration of action.Ativan