Nimetazepam (marketed under brand name Erimin and Lavol) is an intermediate-acting hypnotic drug which is a benzodiazepine derivative. It was first synthesized by a team at Hoffmann-La Roche in 1964. It possesses powerful hypnotic, anxiolytic, sedative, and skeletal muscle relaxant properties. Nimetazepam is also a particularly potent anticonvulsant. It is marketed in 5 mg tablets known as Erimin, which is the brand name manufactured and marketed by the large Japanese corporation Sumitomo. Japan is the sole manufacturer of nimetazepam in the world. Outside of Japan, Erimin is available in much of East and Southeast Asia and was widely prescribed for the short-term treatment of severe insomnia in patients who have difficulty falling asleep or maintaining sleep. Sumitomo has ceased manufacturing Erimin since November 2015. It is still available as a generic drug or as Lavol.
Nimetazepam was widely prescribed in the 1980s and 1990s, particularly in Japan, Malaysia, Brunei, the Philippines, Thailand, Indonesia, Hong Kong and Singapore. Prescriptions for the drug have decreased dramatically since 2005 due to rampant misuse and addiction. It is primarily used as an anticonvulsant in . It is also still used in the most severe and debilitating cases of insomnia in an inpatient setting or in short term outpatient treatment. Hypnotic benzodiazepines estazolam and nitrazepam are used more frequently than nimetazepam for this purpose. Antidepressants such as trazodone and mirtazapine or Z-drugs like zopiclone and zolpidem are first line treatment for insomnia.
Although prescriptions for nimetazepam have decreased, abuse of the drug is still significant in Brunei, Singapore, Malaysia, and the Philippines. It is commonly used in combination with methamphetamine and MDMA (Ecstasy) and opiates (especially heroin or morphine). The strict legal restrictions nimetazepam is subject to in Malaysia has made the drug scarce, but many pills sold as nimetazepam in the black market are counterfeit. Diazepam and nitrazepam are among the most commonly prescribed benzodiazepines in the region, and as a result, they are commonly diverted and sold on the black market, often as nimetazepam.
Illicit manufacturing of nimetazepam (sold as Erimin-5) is prevalent in the region. Abuse of nimetazepam continued to rise throughout the 2010s. Seizures of illicitly manufactured Erimin-5 tablets paralleled the seizures of methamphetamine seizures in Malaysia. A small seizure of 46 illicit Erimin-5 tablets were tested for their physical and chemical characteristics. The active ingredient, adulterant, major diluent, and dyes make up the chemical characteristics of a tablet. The results indicated that nimetazepam was the most common active ingredient in the vast majority of the tablets seized. Lactose was detected as a major diluent in the majority of the samples, followed by mannitol and then calcium phosphate dibasic dihydrate. Sunset yellow was found in most of the tablet samples either alone or in combination with other dyes such as tartrazine and ponceau 4R to give the tablets a peach/orange colour. Green tablets in the samples contained brilliant blue and tartrazine dyes. Diazepam, which is primarily an anxiolytic, was the active ingredient in only one tablet out of the 46. Nitrazepam, a powerful sedative-hypnotic, which is also nimetazepams parent drug, was found to be a minor compound together with a caffeine as a major compound in three of the tablets.
In 2003, 94,200 Erimin-5 tablets were seized in Singapore. The Central Narcotics Bureau’s (CNB) laboratory tested the tablets with results that confirmed the tablets were indeed nimetazepam.
Pharmacokinetics
Taken orally, Nimetazepam has very good bioavailability with nearly 100% being absorbed from the gut. It is among the most rapidly absorbed and quickest acting oral benzodiazepines, and hypnotic effects are typically felt within 15-30 minutes after oral ingestion. The blood level decline of the parent drug was biphasic with the short half-life ranging from 0.5-0.7 hours and the terminal half-life from 8 to 26.5 hours (mean 17.25 hours). It is the N-methylated analogue of nitrazepam (Mogadon, Alodorm), to which it is partially metabolised. nitrazepam has a long elimination half-life, so effects of repeated dosage tend to be cumulative.
There is a risk of misuse and dependence in both patients and non-medical users of Nimetazepam. The pharmacological properties of Nimetazepam such as high affinity binding, high potency, being short to intermediate – acting and having a rapid onset of action increase the abuse potential of Nimetazepam. The physical dependence and withdrawal syndrome of Nimetazepam also adds to the addictive nature of Nimetazepam.
Nimetazepam has a particular reputation in South East Asia for recreational use, at around US$ 7 per tab, and is particularly popular among persons addicted to amphetamines or opioids. In addition, Nimetazepam has an anti-depressant and muscle relaxant effect. Nimetazepam also has withdrawal suppression effect and lower drug seeking versus nitrazepam in rhesus monkey (Macaca Mulatta). which might help stimulant addicts to overcome withdrawal symptoms.
Drug Misuse
Nimetazepam has a reputation for being particularly subject to abuse (known as ‘Happy 5’, sold as an ecstasy replacement without a hangover). Although is still a significant drug of abuse in some Asian countries such as Japan and Malaysia, Nimetazepam is subject to legal restrictions in Malaysia, and due to its scarcity, many tablets sold on the black market are in fact counterfeits containing other benzodiazepines such as diazepam or nitrazepam instead.
Legal Status
In the United States, Nimetazepam is categorized Schedule IV FDA and DEA.
Nimetazepam is currently a Schedule IV drug under the international Convention on Psychotropic Substances of 1971.
In Singapore, Nimetazepam is a physician prescribed drug, and is regulated under the Misuse of Drugs Act. The illegal possession or consumption of Nimetazepam is punishable by up to 10 years of imprisonment, a fine of 20,000 Singapore dollars, or both. Importing or exporting nimetazepam is punishable by up to 20 years of imprisonment and/or caning.
In Hong Kong, Nimetazepam is regulated under Schedule 1 of Hong Kong’s Chapter 134 Dangerous Drugs Ordinance. Nimetazepam can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.
Similarly in Taiwan and Indonesia Nimetazepam is also regulated as a controlled prescribed substance.
In Victoria Australia, nimetazepam is regulated under Schedule 11 of “Drugs, Poisons and Controlled substances act 1981”. It is deemed to fall under the category of “7-NITRO-1,4-BENZODIAZEPINES not included elsewhere in this Part”
Toxicity
In a rat study Nimetazepam showed greater damage to the foetus, as did nitrazepam when compared against other benzodiazepines, all at a dosage of 100 mg/kg. Diazepam however showed relatively weak foetal toxicities. The same fetotoxicity of nitrazepam could not be observed in mice and is likely due to the particular metabolism of the drug in the rat.
In a rat study nimetazepam showed slight enlargement of the liver and adrenals and atrophy of the testes and ovaries were found in high dose groups of both drugs at the 4th and 12th week, however, in histopathological examination, there were no change in the liver, adrenals and ovaries. Degenerative changes of seminiferous epithelium in the testes were observed, but these atrophic change returned to normal by withdrawal of the drugs for 12 weeks.
1929 – John E. Mack, American psychiatrist and author (d. 2004).
John E. Mack
John Edward Mack (04 October 1929 to 27 September 2004) was an American psychiatrist, writer, and professor and the head of the department of psychiatry at Harvard Medical School. In 1977, Mack won the Pulitzer Prize for his book A Prince of Our Disorder on T.E. Lawrence.
As the head of psychiatry at Harvard Medical School, Mack’s clinical expertise was in child psychology, adolescent psychology, and the psychology of religion. He was also known as a leading researcher on the psychology of teenage suicide and drug addiction, and he later became a researcher in the psychology of alien abduction experiences.
2014 – Benedict Groeschel, American priest, psychologist, and talk show host (b. 1933).
Benedict Groeschel
Benedict Joseph Groeschel, C.F.R. (23 July 1933 to 03 October 2014) was an American Franciscan friar, Catholic priest, retreat master, author, psychologist, activist, and television host. He hosted the television talk program Sunday Night Prime (originally Sunday Night Live) broadcast on the Eternal Word Television Network, as well as several serial religious specials.
He founded the Office for Spiritual Development for the Roman Catholic Archdiocese of New York. He was Associate Director of the Trinity Retreat House for clergy and executive director of St. Francis House. He was professor of pastoral psychology at St. Joseph’s Seminary in New York and an adjunct professor at the Institute for Psychological Sciences in Arlington, Virginia. He was one of the founders of the Franciscan Friars of the Renewal and among his close friends were Mother Teresa, Mother Angelica and Alice von Hildebrand.
2012 – J. Philippe Rushton, English-Canadian psychologist, theorist, academic (b. 1943).
J. Philippe Rushton
John Philippe Rushton (03 December 1943 to 02 October 2012) was a Canadian psychologist and author. He taught at the University of Western Ontario and became known to the general public during the 1980s and 1990s for research on race and intelligence, race and crime, and other purported racial correlations.
Rushton’s work was heavily criticised by the scientific community for the questionable quality of his research, with many academics arguing that it was conducted under a racist agenda. From 2002 until his death, he served as the head of the Pioneer Fund, an organisation that was founded in 1937 to promote eugenics and that in its early years supported Nazi ideology, for example, by funding the distribution in US churches and schools of a Nazi propaganda film about eugenics. The Pioneer Fund has been described as a white supremacist organization and designated as a hate group by the Southern Poverty Law Centre.
Rushton was a Fellow of the Canadian Psychological Association and a onetime Fellow of the John Simon Guggenheim Memorial Foundation. In 2020 the Department of Psychology of the University of Western Ontario released a statement stating that “much of his research was racist” and his work was “deeply flawed from a scientific standpoint”. As of 2021, Rushton has had six research publications retracted.
Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression.
It may alternatively be classified as a tricyclic antidepressant (TCA), specifically a secondary amine. In terms of its chemistry and pharmacology, maprotiline is closely related to other secondary amine TCAs like nortriptyline and protriptyline, and has similar effects to them.
Brief History
Maprotiline was developed by Ciba (now operated by Novartis). It was patented in 1966 and was first described in the literature in 1969. The drug was introduced for medical use in 1974. Generics are now widely available. It was introduced after most of the other TCAs but was the first TeCA to be developed and marketed, with the TeCAs mianserin and amoxapine following shortly thereafter and mirtazapine being introduced later on.
Medical Uses
Maprotiline is used in the treatment of depression, such as depression associated with agitation or anxiety and has similar efficacy to the antidepressant drug moclobemide.
Treatment of depression of all forms and severities (endogenous, psychotic, involutional, and neurotic) especially for depression associated with agitation or anxiety.
Panic disorder.
Neuropathic pain.
Treatment of the depressive phase in bipolar depression.
For the symptomatic relief of anxiety, tension or insomnia.
The use of maprotiline in the treatment of enuresis in paediatric patients has so far not been systematically explored and its use is not recommended. Safety and effectiveness in the paediatric population in general have not been established. Anyone considering the use of maprotiline in a child or adolescent must balance the potential risks with the clinical need. In general, lower dosages are recommended for patients over 60 years of age. Dosages of 50 mg to 75 mg daily are usually satisfactory as maintenance therapy for elderly patients who do not tolerate higher amounts.[8][9]
Available Forms
Coated Tablets, 10 mg, 25 mg, 50 mg, and 75 mg.
Injectable concentrate, 25 mg.
Contraindications
Maprotiline may worsen psychotic conditions like schizophrenia and should be given with caution. The antipsychotic treatment should be continued. Patients with bipolar affective disorder should not receive antidepressants whilst in a manic phase, as antidepressants can worsen mania.
Absolute
Hypersensitivity to maprotiline or to other TCAs and TeCAs.
Hypertrophy of the prostate gland with urine hesitancy.
Closed angle glaucoma.
Special Caution Needed
Concomitant treatment with a MAO inhibitor.
Serious impairment of liver and kidney function.
Epilepsy and other conditions that lower the seizure threshold (active brain tumours, alcohol withdrawal, other medications).
Serious cardiovascular conditions (arrhythmias, heart insufficience, state after myocardial infarction etc.).
Treatment of patients under age 18.
Suicidal Patients
Same as other antidepressants, maprotiline increased the risk compared to placebo of suicidal thinking and behaviour (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of maprotiline or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behaviour. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Maprotiline is not approved for use in paediatric patients.
Pregnancy and Lactation
Reproduction studies have been performed in female laboratory rabbits, mice, and rats at doses up to 1.3, 7, and 9 times the maximum daily human dose respectively and have revealed no evidence of impaired fertility or harm to the foetus due to maprotiline. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Maprotiline is excreted in breast milk. At steady-state, the concentrations in milk correspond closely to the concentrations in whole blood. Caution should be exercised when maprotiline hydrochloride is administered to a nursing woman.
Side Effects
The side-effect profile is comparable to other TCAs and TeCAS and many of the following are due to anticholinergic (which are less prominent than those of most TCAs) and antihistamine effects. Most often seen are:
Dizziness.
Drowsiness.
Somnolence.
Fatigue.
Dry mouth (and complications of long-term uncontrolled dry mouth such as dental caries).
Constipation.
Vertigo.
Nausea (rare, incidence of ~2%) and vomiting.
Increased appetite and weight gain.
Orthostatic hypotension, hypertension, sinus tachycardia, heart-block, arrhythmias and other cardiac effects.
Sexual dysfunction in men: impotence, priapism, delayed ejaculation, anejaculation, decreased libido.
Sexual dysfunction in women: decreased libido, vaginal dryness, painful sexual intercourse, anorgasmia.
Allergic skin reactions such as rash or urticaria (more often than with other antidepressants).
Rarely, severe skin reactions such as erythema multiforme can occur.
Photosensitivity.
Agitation, confusion.
Induction of hypomania or mania in patients suffering from underlying bipolar affective disorder.
Psychotic symptoms.
Tremor.
Extrapyramidal symptoms.
Headache.
Seizures (at high doses).
Rare haematological complications: leukopenia and agranulocytosis (dangerous fall in white blood cells).
Fever.
Urinary retention.
Maprotiline causes a strong initial sedation (first 2 to 3 weeks of therapy) and is therefore indicated to treat agitated patients or those with suicidal risks. It causes anticholinergic side effects (dry mouth, constipation, confusion, tachycardia) with a lower incidence than amitriptyline. Originally, the manufacturer claimed that maprotiline is better tolerated than other TCAs and TeCAs. However, seizures, leukopenia and skin reactions occur more often with maprotiline than with comparable drugs like amitriptyline.
Maprotiline has no known potential for abuse and psychological dependence.
Withdrawal
Withdrawal symptoms frequently seen when treatment with maprotiline is stopped abruptly (agitation, anxiety, insomnia, sometimes activation of mania or rebound depression) are not indicative of addiction and can be avoided by reducing the daily dose of maprotiline gradually by approximately 25% each week. If treatment has to be stopped at once due to medical reasons, the use of a benzodiazepine (e.g. lorazepam, clonazepam, or alprazolam) for a maximum of 4 weeks as needed will usually suppress withdrawal symptoms.
Interactions
Maprotiline has a wide range of possible interactions. Some are typical for TCAs and TeCAs, others are caused by specific metabolic effects (e.g. high plasma-protein-binding) of maprotiline:
Irreversible MAO-inhibitors: agitation, delirium, coma, hyperpyrexia (high fever), seizures and severe changes in blood pressure.
Treatment-resistant and hospitalised patients may be treated concomitantly with an MAO-inhibitor, if they are closely monitored and if the initial dose of the MAO-Inhibitor is low.
Increased Drug Actions
Other antidepressants, barbiturates, narcotics, sedating antihistamines, anticonvulsive drugs, alcohol, resulting in increased central depression.
Anticholinergics (antiparkinsonian agents, TCAs and TeCAs) – resulting in increased anticholinergic action (dry mouth, constipation etc.).
Sympathomimetics (also those used in local anaesthetics like noradrenaline):
Clonidine: antihypertensive effects decreased and risk of (massive) rebound hypertension.
Other Types of Interaction
Drugs, which induce certain enzymes in the liver, e.g. barbiturates, phenytoin, carbamazepine and oral anti-conceptive drugs, enhance the elimination of maprotiline and decrease its antidepressant effects.
Additionally the blood-concentrations of phenytoin or carbamazepine may be increased, leading to a higher incidents of side effects.
The concomitant use of maprotiline and neuroleptics can lead to increased maprotiline blood-levels and to seizures.
Combining maprotiline and thioridazine could induce severe arrhythmias.
Additionally, increased blood-levels of Maprotiline are possible, if certain beta-blocking agents (e.g. Propranolol) are given concomitantly.
Maprotiline may amplify the actions of coumarin-type anticoagulants (e.g. warfarin, phenprocoumon).
The plasma-prothrombin-activity must be assessed closely in order to avoid overt bleedings.
Maprotiline can increase the actions of oral antidiabetic drugs (sulfonylureas) and Insulin.
Diabetic patients should have regular assessments of their blood-glucose-levels.
The concomitant application with fluoxetine or fluvoxamine may lead to significantly increased plasma-levels of maprotiline with a high incidence of maprotiline side effects.
Due to the long half-lives of fluoxetine and fluvoxamine this effect may persist.
Pharmacology
Pharmacodynamics
Maprotiline exhibits strong effects as a norepinephrine reuptake inhibitor with only weak actions the reuptake of serotonin and dopamine. It is also a strong antagonist of the H1 receptor, a moderate antagonist of the 5-HT2 and α1-adrenergic receptors, and a weak antagonist of the D2 and muscarinic acetylcholine receptors. Maprotiline has also more recently been identified as a potent antagonist of the 5-HT7 receptor, with this action potentially playing an important role in its antidepressant effectiveness. The drug is a strong antihistamine, but unlike most TCAs, has minimal anticholinergic effects.
The pharmacological profile of maprotiline explains its antidepressant, sedative, anxiolytic, and sympathomimetic activities. In accordance to the pharmacological characteristics it is used in the treatment of depression, such as depression associated with agitation or anxiety. Additionally, it shows strong antagonism against reserpine-induced effects in animal studies, as do the other ‘classical’ antidepressants. Although maprotiline behaves in most regards as a ‘first-generation antidepressant’ it is commonly referred to as ‘second-generation antidepressant’.
The postulated mechanism of maprotiline is that it acts primarily by potentiation of central adrenergic synapses by blocking reuptake of norepinephrine at nerve endings. This pharmacological action is thought to be primarily responsible for the drug’s antidepressant and anxiolytic effects. It is a strong norepinephrine reuptake inhibitor with only weak effects on serotonin and dopamine reuptake. At higher doses however, maprotiline increases serotonergic transmission and increases the level of serotonin available.
Pharmacokinetics
After oral use absorption is good. It binds to plasma proteins 80-90%. Maximal plasma concentration is reached 6 hours after use. The mean time to peak is 12 hours. The terminal half-life of averages 51 hours.
Chemistry
Maprotiline is a tetracyclic compound and is grouped with the TeCAs. Its chemical name is N-methyl-9,10-ethanoanthracen-9(10H)-propylamine. The drug has a dibenzobicyclo[2.2.2]octadiene (9,10-dihydro-9,10-ethanoanthracene) ring system; that is, a tricyclic anthracene ring system with an ethylene bridge across the central ring. This results in it having a unique three-dimensional central ring (a bicyclo[2.2.2]octane or 1,4-endoethylenecyclohexane ring) and being a tetracyclic rather than a tricyclic compound. However, it could also or alternatively be considered to be a tricyclic and hence a TCA. In addition to its heterocyclic ring system, maprotiline has an alkylamine side chain attached similarly to other TCAs (but notably unlike other TeCAs). In terms of the side chain, it is a secondary amine, and its chemical structure, aside from the ethylene link in the central ring, is similar to that of secondary amine TCAs like nortriptyline and protriptyline. In accordance, the pharmacology of maprotiline is very similar to that of secondary amine TCAs.
Maprotiline is very similar in structure to the anxiolytic, sedative, and muscle relaxant drug benzoctamine (Tacitin). The only structural difference between the two compounds is in the length of their side chain. However, this modification results in considerable differences in their pharmacological and therapeutic effects.
Society and Culture
Generic Names
Maprotiline is the English and French generic name of the drug and its INN, USAN, BAN, and DCF, while maprotiline hydrochloride is its USAN, USP, BANM and JAN. Its generic name in Spanish and Italian and its DCIT are maprotilina, in German is maprotilin, and in Latin is maprotilinum. The methanesulfonate (mesylate) salt is known unofficially as maprotiline methanesulfonate.
Brand Names
Maprotiline is marketed throughout the world mainly under the brand name Ludiomil. It is also available under a variety of other brand names including Deprilept, Maprolu, and Psymion among others.
1915 – Jerome Bruner, American psychologist and author (d. 2016).
1940 – Phyllis Chesler, American feminist psychologist, who wrote Women and Madness (1972).
Jerome Bruner
Jerome Seymour Bruner (01 October 1915 to 05 June 2016) was an American psychologist who made significant contributions to human cognitive psychology and cognitive learning theory in educational psychology.
Bruner was a senior research fellow at the New York University School of Law. He received a B.A. in 1937 from Duke University and a Ph.D. from Harvard University in 1941. He taught and did research at Harvard University, the University of Oxford, and New York University. A Review of General Psychology survey, published in 2002, ranked Bruner as the 28th most cited psychologist of the 20th century.
Phyllis Chesler
Phyllis Chesler (born 01 October 1940) is an American writer, psychotherapist, and professor emerita of psychology and women’s studies at the College of Staten Island (CUNY).
She is known as a feminist psychologist, and is the author of 18 books, including the best-seller Women and Madness (1972), With Child: A Story of Motherhood (1979) and An American Bride in Kabul: A Memoir (2013). Chesler has written on topics such as gender, mental illness, divorce and child custody, surrogacy, second-wave feminism, pornography, prostitution, incest, and violence against women.
In more recent years, Chesler has written several works on such subjects as anti-Semitism, Islam, and honour killings. Chesler argues that many western intellectuals, including leftists and feminists, have abandoned Western values in the name of multicultural relativism, and that this has led to an alliance with Islamists, an increase in anti-Semitism, and to the abandonment of Muslim women and religious minorities in Muslim-majority countries.
This show examines how the digital world is impacting the mental health of America’s youth. Hosted by OZY’s Carlos Watson, this special will tell first-person stories of teens and young adults grappling with the obsessive use of social media, computers, mobile devices, and video games, and ask the question: how do these digital technologies impact their stress levels, social interactions, self-esteem, and overall mental health? This special will pinpoint how addiction to the digital world is impacting the brains of our youth and will shed light on things we as a society can do to help.
Magnified Voices
A&E Network has premiered two new specials under the Voices Magnified banner focusing on mental health in America in partnership with OZY. Voices Magnified is a cross-platform campaign spotlighting and amplifying the voices of those making changes in their communities for the greater good. Representing the collective voice of the A+E Networks portfolio, the initiative creates thought-provoking specials and a robust series of short-form videos that give a national spotlight to timely and important conversations on equality and social reform which are occurring across America today.
This one-hour special showcases honest and personal stories of Americans from across the country highlighting the critical issue of mental health in America. Hosted by OZY’s Carlos Watson, the special includes insights with mental health experts and focuses on actionable steps we can take as a country. Using impactful first-person stories, the special strives to end the stigma associated with conversations around mental health and will help viewers understand signs and symptoms, give tools for coping, and educate on different ways people can get help.
Magnified Voices
A&E Network has premiered two new specials under the Voices Magnified banner focusing on mental health in America in partnership with OZY. Voices Magnified is a cross-platform campaign spotlighting and amplifying the voices of those making changes in their communities for the greater good. Representing the collective voice of the A+E Networks portfolio, the initiative creates thought-provoking specials and a robust series of short-form videos that give a national spotlight to timely and important conversations on equality and social reform which are occurring across America today.
Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety disorders, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and chemotherapy-induced nausea and vomiting. It is also used during surgery to interfere with memory formation and to sedate those who are being mechanically ventilated. It is also used, along with other treatments, for acute coronary syndrome due to cocaine use. 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.
Common side effects include weakness, sleepiness, low blood pressure, and a decreased effort to breathe. When given intravenously the person should be closely monitored. Among those who are depressed there may be an increased risk of suicide. With long-term use, larger doses may be required for the same effect. Physical dependence and psychological dependence may also occur (refer to benzodiazepine dependence). If stopped suddenly after long-term use, benzodiazepine withdrawal syndrome may occur. Older people more often develop adverse effects. In this age group lorazepam is associated with falls and hip fractures. Due to these concerns, lorazepam use is generally only recommended for up to two to four weeks.
Lorazepam was initially patented in 1963 and went on sale in the United States in 1977. It is on the World Health Organisation’s (WHO) List of Essential Medicines. It is available as a generic medication. In 2018, it was the 58th most commonly prescribed medication in the United States, with more than 13 million prescriptions.
Brief History
Historically, lorazepam is one of the “classical” benzodiazepines. Others include diazepam, clonazepam, oxazepam, nitrazepam, flurazepam, bromazepam, and clorazepate. Lorazepam was first introduced by Wyeth Pharmaceuticals in 1977 under the brand names Ativan and Temesta. The drug was developed by D.J. Richards, president of research. Wyeth’s original patent on lorazepam is expired in the United States.
Medical Uses
Anxiety
Lorazepam is used in the short-term management of severe anxiety. In the US, the Food and Drug Administration (FDA) advises against use of benzodiazepines such as lorazepam for longer than four weeks. It is fast acting, and useful in treating fast onset panic anxiety.
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.
Withdrawal symptoms, including rebound insomnia and rebound anxiety, may occur after seven days’ use of lorazepam.
Seizures
Intravenous diazepam or lorazepam are first-line treatments for convulsive status epilepticus. Lorazepam is more effective than diazepam and intravenous phenytoin in the treatment of status epilepticus and has a lower risk of continuing seizures that might require additional medication. However, phenobarbital has a superior success rate compared to lorazepam and other drugs, at least in the elderly.
Lorazepam’s anticonvulsant properties and pharmacokinetic profile make intravenous use reliable for terminating acute seizures, but induce 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.
Lorazepam’s anticonvulsant and CNS depressant properties are useful for the treatment and prevention of alcohol withdrawal syndrome. In this setting, impaired liver function is not a hazard with lorazepam, since lorazepam does not require oxidation, in the liver or otherwise, for its metabolism.
Sedation
Lorazepam is sometimes used for individuals receiving mechanical ventilation. 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.
Its relative effectiveness in preventing new memory formation, along with its ability to reduce agitation and anxiety, makes lorazepam useful as premedication. It is given before a general anaesthetic to reduce the amount of anaesthetic 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. Lorazepam by mouth is given 90 to 120 minutes before procedures, and intravenous lorazepam as late as 10 minutes before procedures. 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.
Agitation
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. However, adverse effects such as behavioural disinhibition may make benzodiazepines inappropriate for some people who are acutely psychotic. Acute delirium is sometimes treated with lorazepam, but as it can cause paradoxical effects, it is preferably given together with haloperidol. Lorazepam is absorbed relatively slowly if given intramuscularly, a common route in restraint situations.
Other
Catatonia with inability to speak is responsive to lorazepam. Symptoms may recur and treatment for some days may be necessary. Catatonia due to abrupt or overly rapid withdrawal from benzodiazepines, as part of the benzodiazepine withdrawal syndrome, should also respond to lorazepam treatment. As lorazepam can have paradoxical effects, haloperidol is sometimes given at the same time.
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 sensitisation to the thought of being sick.
Adverse Effects
Many beneficial effects of lorazepam (e.g. sedative, muscle relaxant, anti-anxiety, and amnesic effects) may become adverse effects when unwanted. Adverse effects can include sedation and low blood pressure; the effects of lorazepam are increased in combination with other CNS depressant drugs. Other adverse effects include confusion, ataxia, inhibiting the formation of new memories, and hangover effects. 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. Lorazepam appears to have more profound adverse effects on memory than other benzodiazepines; it impairs both explicit and implicit memory. In the elderly, falls may occur as a result of benzodiazepines. Adverse effects are more common in the elderly, and they appear at lower doses than in younger people. Benzodiazepines can cause or worsen depression. 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. Lorazepam’s effects are dose-dependent, meaning the higher the dose, the stronger the effects (and side effects) will be. Using the smallest dose needed to achieve desired effects lessens the risk of adverse effects. Sedative drugs and sleeping pills, including lorazepam, have been associated with an increased risk of death.
Sedation is the side effect people taking lorazepam most frequently report. In a group of around 3,500 people 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%). Side effects such as sedation and unsteadiness increased with age.[46] Cognitive impairment, behavioural disinhibition and respiratory depression as well as hypotension may also occur.
Effect
Description
Paradoxical Effects
In some cases, paradoxical effects can occur with benzodiazepines, such as increased hostility, aggression, angry outbursts, and psychomotor agitation. These effects are seen more commonly with lorazepam than with other benzodiazepines. Paradoxical effects are more likely to occur with higher doses, in people with pre-existing personality disorders and those with a psychiatric illness. Frustrating stimuli may trigger such reactions, though the drug may have been prescribed to help the person cope with such stress and frustration in the first place. As paradoxical effects appear to be dose-related, they usually subside on dose reduction or on complete withdrawal of lorazepam.
Suicidality
Benzodiazepines are associated with increased risk of suicide, possibly due to disinhibition. Higher dosages appear to confer greater risk.
Amnesic Effects
Among benzodiazepines, lorazepam has relatively strong amnesic effects, but people soon develop tolerance to this with regular use. To avoid amnesia (or excess sedation) being a problem, the initial total daily lorazepam dose should not exceed 2 mg. This also applies to use for night sedation. Five participants in a sleep study were prescribed lorazepam 4 mg at night, and the next evening, three subjects unexpectedly volunteered memory gaps for parts of that day, an effect that subsided completely after two to three days’ use. Amnesic effects cannot be estimated from the degree of sedation present, since the two effects are unrelated.
High/Prolonged Dose
High-dose or prolonged parenterally administered lorazepam is sometimes associated with propylene glycol poisoning.
In September 2020, the FDA required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.
Contraindications
Lorazepam should be avoided in people with:
Allergy or Hypersensitivity
Past hypersensitivity or allergy to lorazepam, to any benzodiazepine, or to any of the ingredients in lorazepam tablets or injections.
Respiratory Failure
Benzodiazepines, including lorazepam, may depress central nervous system respiratory drive and are contraindicated in severe respiratory failure. An example would be the inappropriate use to relieve anxiety associated with acute severe asthma. The anxiolytic effects may also be detrimental to a person’s willingness and ability to fight for breath. However, if mechanical ventilation becomes necessary, lorazepam may be used to facilitate deep sedation.
Acute Intoxication
Lorazepam may interact synergistically with the effects of alcohol, narcotics, or other psychoactive substances. It should, therefore, not be administered to a drunk or intoxicated person.
Ataxia
This is a neurological clinical sign, consisting of unsteady and clumsy motion of the limbs and torso, due to the failure of gross muscle movement coordination, most evident on standing and walking. It is the classic way in which acute alcohol intoxication may affect a person. Benzodiazepines should not be administered to people already-ataxic.
Acute Narrow-Angle Glaucoma
Lorazepam has pupil-dilating effects, which may further interfere with the drainage of aqueous humour from the anterior chamber of the eye, thus worsening narrow-angle glaucoma.
Sleep Apnoea
Sleep apnoea may be worsened by lorazepam’s central nervous system depressant effects. It may further reduce the person’s ability to protect his or her airway during sleep.
Myasthenia Gravis
This condition is characterised by muscle weakness, so a muscle relaxant such as lorazepam may exacerbate symptoms.
Pregnancy and Breastfeeding
Lorazepam belongs to the FDA pregnancy category D, which means it is likely to cause harm to the developing baby if taken during the first trimester of pregnancy. The evidence is inconclusive whether lorazepam if taken early in pregnancy results in reduced intelligence, neurodevelopmental problems, physical malformations in cardiac or facial structure, or other malformations in some newborns. Lorazepam given to pregnant women antenatally may cause floppy infant syndrome in the neonate, or respiratory depression necessitating ventilation. Regular lorazepam use during late pregnancy (the third trimester), carries a definite risk of benzodiazepine withdrawal syndrome in the neonate. Neonatal benzodiazepine withdrawal may include hypotonia, reluctance to suck, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Lorazepam may also inhibit foetal liver bilirubin glucuronidation, leading to neonatal jaundice. Lorazepam is present in breast milk, so caution must be exercised about breastfeeding.
Specific Groups
Children and the Elderly
The safety and effectiveness of lorazepam is not well determined in children under 18 years of age, but it is used to treat acute seizures. Dose requirements have to be individualised, especially in people who are elderly and debilitated in whom the risk of oversedation is greater. Long-term therapy may lead to cognitive deficits, especially in the elderly, which may only be partially reversible. The elderly metabolise benzodiazepines more slowly than younger people and are more sensitive to the adverse effects of benzodiazepines compared to younger individuals even at similar plasma levels. Additionally, the elderly tend to take more drugs which may interact or enhance the effects of benzodiazepines. Benzodiazepines, including lorazepam, have been found to increase the risk of falls and fractures in the elderly. As a result, dosage recommendations for the elderly are about half of those used in younger individuals and used for no longer than two weeks. Lorazepam may also be slower to clear in the elderly, leading potentially to accumulation and enhanced effects. Lorazepam, similar to other benzodiazepines and nonbenzodiazepines, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete, tolerance develops to these impairments.
Liver or Kidney Failure
Lorazepam may be safer than most benzodiazepines in people with impaired liver function. Like oxazepam, it does not require liver oxidation, but only liver glucuronidation into lorazepam-glucuronide. Therefore, impaired liver function is unlikely to result in lorazepam accumulation to an extent causing adverse reactions. Similarly kidney disease has minimal effects on lorazepam levels.
Surgical Premedication
Informed consent given only after receiving lorazepam premedication could have its validity challenged later. Staff must use chaperones to guard against allegations of abuse during treatment. Such allegations may arise because of incomplete amnesia, disinhibition, and impaired ability to process cues. Because of its relatively long duration of residual effects (sedation, ataxia, hypotension, and amnesia), lorazepam premedication is best suited for hospital inpatient use. People should not be discharged from the hospital within 24 hours of receiving lorazepam premedication unless accompanied by a caregiver. They should also not drive, operate machinery, or use alcohol within this period.
Drug and Alcohol Dependence
The risk of abuse of lorazepam is increased in dependent people.
Comorbidity
Comorbid psychiatric disorders also increase the risk of dependence and paradoxical adverse effects.
Tolerance and 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. Potent benzodiazepines with a relatively short half life, such as lorazepam, alprazolam, and triazolam, have the highest risk of causing a dependence. Tolerance to benzodiazepine effects develops with regular use. This is desirable with amnesic and sedative effects but undesirable with anxiolytic, hypnotic, and anticonvulsant effects. People initially 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. After four to six months of regular benzodiazepine use, evidence of continued efficacy declines.
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. Due to the development of tolerance to the anticonvulsant effects, benzodiazepines are generally not recommended for long-term use for the management of epilepsy. Increasing the dose may overcome tolerance, but tolerance may then develop to the higher dose and adverse effects may persist and worsen. The mechanism of tolerance to benzodiazepines is complex and involves GABAA receptor downregulation, alterations to subunit configuration of GABAA receptors, uncoupling and internalisation of the benzodiazepine binding site from the GABAA receptor complex as well as changes in gene expression.
The likelihood of dependence is relatively high with lorazepam compared to other benzodiazepines. Lorazepam’s relatively short serum half-life, its confinement mainly to blood, and its inactive metabolite can result in interdose withdrawal phenomena and next-dose cravings, that may reinforce psychological dependence. Because of its high potency, the smallest lorazepam tablet strength of 0.5 mg is also a significant dose. To minimise the risk of physical/psychological dependence, lorazepam is best used only short-term, at the smallest effective dose. 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.
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 stabilisation on this, and only then initiating dose reductions. The advantage of switching to diazepam is that dose reductions are felt less acutely, because of the longer half-lives (20-200 hours) of diazepam and its active metabolites.
Withdrawal
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. Lorazepam, as with other benzodiazepine drugs, can cause physical dependence, addiction, and benzodiazepine withdrawal syndrome. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can, however, occur from standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regimen. Rebound effects often resemble the condition being treated, but typically at a more intense level and may be difficult to diagnose. Withdrawal symptoms can range from mild anxiety and insomnia to more severe symptoms such as seizures and psychosis. The risk and severity of withdrawal are increased with long-term use, use of high doses, abrupt or over-rapid reduction, among other factors. Short-acting benzodiazepines such as lorazepam are more likely to cause a more severe withdrawal syndrome compared to longer-acting benzodiazepines.
Withdrawal symptoms can occur after taking therapeutic doses of lorazepam for as little as one week. Withdrawal symptoms include headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, dysphoria, dizziness, derealisation, depersonalisation, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhoea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, short-term memory loss, and hyperthermia. It takes about 18-36 hours for the benzodiazepine to be removed from the body. 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.
Interactions
Lorazepam is not usually fatal in overdose, but may cause respiratory depression if taken in overdose with alcohol. The combination also causes greater enhancement of the disinhibitory and amnesic effects of both drugs, with potentially embarrassing or criminal consequences. Some experts advise that people should be warned against drinking alcohol while on lorazepam treatment, but such clear warnings are not universal.
Greater adverse effects may also occur when lorazepam is used with other drugs, such as opioids or other hypnotics. Lorazepam may also interact with rifabutin. Valproate inhibits the metabolism of lorazepam, whereas carbamazepine, lamotrigine, phenobarbital, phenytoin, and rifampin increase its rate of metabolism. 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.
In cases of a suspected lorazepam overdose, it is important to establish whether the person is a regular user of lorazepam or other benzodiazepines since regular use causes tolerance to develop. Also, one must ascertain whether other substances were also ingested.
Signs of overdose range through mental confusion, dysarthria, paradoxical reactions, drowsiness, hypotonia, ataxia, hypotension, hypnotic state, coma, cardiovascular depression, respiratory depression, and death. However, fatal overdoses on benzodiazepines alone are rare and less common than with barbiturates. Such a difference is largely due to benzodiazepine activity as a neuroreceptor modulator, and not as an activator per se. Lorazepam and similar medication do however act in synergy with alcohol, which increases the risk of overdose.
Early management of people under alert includes emetics, gastric lavage, and activated charcoal. Otherwise, management is by observation, including of vital signs, support and, only if necessary, considering the hazards of doing so, giving intravenous flumazenil.
People are ideally nursed in a kind, frustration-free environment, since, when given or taken in high doses, benzodiazepines are more likely to cause paradoxical reactions. If shown sympathy, even quite crudely feigned, people may respond solicitously, but they may respond with disproportionate aggression to frustrating cues. Opportunistic counselling has limited value here, as the person is unlikely to recall this later, owing to drug-induced anterograde amnesia.
Detection in Body Fluids
Lorazepam may be quantitated in blood or plasma to confirm poisoning in hospitalised people, 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. Approximately 300-1000 μg/l is found in people after acute overdosage. Lorazepam may not be detected by commonly used urine drug screenings for benzodiazepines.
Pharmacology
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.
Pharmacokinetics
Lorazepam is highly protein bound and is extensively metabolised into pharmacologically inactive metabolites. Due to its poor lipid solubility, lorazepam is absorbed relatively slowly by mouth and is unsuitable for rectal administration. 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. 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. This explains why one lorazepam dose, despite its shorter serum half-life, has more prolonged peak effects than an equivalent diazepam dose. Lorazepam is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine. Lorazepam glucuronide has no demonstrable CNS activity in animals. The plasma levels of lorazepam are proportional to the dose given. There is no evidence of accumulation of lorazepam on administration up to six months. On regular administration, diazepam will accumulate, since it has a longer half-life and active metabolites, these metabolites also have long half-lives.
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 (non-intravenous 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. So, it may be necessary to repeat diazepam doses to maintain peak anticonvulsant effects, resulting in excess body accumulation. 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. Therefore, lorazepam’s anticonvulsant effects are more durable, thus reducing the need for repeated doses. If a person 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). The prolonged sedation from lorazepam may, however, be an acceptable trade-off for its reliable duration of effects, particularly if the person needs to be transferred to another facility. 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.
Lorazepam serum levels are proportional to the dose administered. 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. A similar lorazepam dose given intravenously will result in an earlier and higher peak serum level, with a higher relative proportion of un-metabolised (active) lorazepam. On regular administration, maximum serum levels are attained after three days. Longer-term use, up to six months, does not result in further accumulation. On discontinuation, lorazepam serum levels become negligible after three days and undetectable after about a week. Lorazepam is metabolised in the liver by conjugation into inactive lorazepam-glucuronide. This metabolism does not involve liver oxidation, so is relatively unaffected by reduced liver function. 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.
Pharmacodynamics
Relative to other benzodiazepines, lorazepam is thought to have high affinity for GABA receptors, which may also explain its marked amnesic effects. Its main pharmacological effects are the enhancement of the effects of the neurotransmitter GABA at the GABAA receptor. Benzodiazepines, such as lorazepam, enhance the effects of GABA at the GABAA receptor via increasing the frequency of opening of the chloride ion channel on the GABAA receptors; which results in the therapeutic actions of benzodiazepines. They, however, do not on their own activate the GABAA receptors, but require the neurotransmitter GABA to be present. Thus, the effect of benzodiazepines is to enhance the effects of the neurotransmitter GABA.
The magnitude and duration of lorazepam effects are dose-related, meaning larger doses have stronger and longer-lasting effects, because the brain has spare benzodiazepine drug receptor capacity, with single, clinical doses leading only to an occupancy of some 3% of the available receptors.
The anticonvulsant properties of lorazepam and other benzodiazepines may be, in part or entirely, due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to get limited, by the benzodiazepine effect of slowing recovery of sodium channels from inactivation to deactivation in mouse spinal cord cell cultures, hence prolonging the refractory period.
Physical Properties and Formulations
Pure lorazepam is an almost white powder that is nearly insoluble in water and oil. In medicinal form, it is mainly available as tablets and a solution for injection, but, in some locations, it is also available as a skin patch, an oral solution, and a sublingual tablet.
Lorazepam tablets and syrups are administered by mouth only. Lorazepam tablets of the Ativan brand also contain lactose, microcrystalline cellulose, polacrilin, magnesium stearate, and coloring agents (indigo carmine in blue tablets and tartrazine in yellow tablets). Lorazepam for injection formulated with polyethylene glycol 400 in propylene glycol with 2.0% benzyl alcohol as preservative.
Lorazepam injectable solution is administered either by deep intramuscular injection or by intravenous injection. The injectable solution comes in 1 ml ampoules containing 2 or 4 mg of lorazepam. The solvents used are polyethylene glycol 400 and propylene glycol. As a preservative, the injectable solution contains benzyl alcohol. Toxicity from propylene glycol has been reported in the case of a person receiving a continuous lorazepam infusion. Intravenous injections should be given slowly and they should be closely monitored for side effects, such as respiratory depression, hypotension, or loss of airway control.
Peak effects roughly coincide with peak serum levels, which occur 10 minutes after intravenous injection, up to 60 minutes after intramuscular injection, and 90 to 120 minutes after oral administration, but initial effects will be noted before this. A clinically relevant lorazepam dose will normally be effective for six to 12 hours, making it unsuitable for regular once-daily administration, so it is usually prescribed as two to four daily doses when taken regularly, but this may be extended to five or six, especially in the case of elderly people who could not handle large doses at once.
Topical formulations of lorazepam, while used as treatment for nausea especially in people in hospice, ought not be used in this form and for this purpose as they have not been proven effective.
Lorazepam is also used for other purposes, such as recreational use, wherein the drug is taken to achieve a high, or when the drug is continued long-term against medical advice.
A large-scale, nationwide, US government study of pharmaceutical-related emergency department (ED) visits by SAMHSA found sedative-hypnotics are the pharmaceuticals most frequently used outside of their prescribed medical purpose in the United States, with 35% of drug-related emergency department visits involving sedative-hypnotics. In this category, benzodiazepines are most commonly used. Males and females use benzodiazepines for nonmedical purposes equally. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceutical drugs, with 26% of attempted suicides involving them. Lorazepam was the third-most-common benzodiazepine used outside of prescription in these ED visit statistics.
Legal Status
Lorazepam is a Schedule IV drug under the Controlled Substances Act in the US and internationally under the United Nations Convention on Psychotropic Substances. It is a Schedule IV drug under the Controlled Drugs and Substances Act in Canada. In the United Kingdom, it is a Class C, Schedule 4 Controlled Drug under the Misuse of Drugs Regulations 2001.
Pricing
In 2000, the US drug company Mylan agreed to pay $147 million to settle accusations by the FTC that they had raised the price of generic lorazepam by 2600% and generic clorazepate by 3200% in 1998 after having obtained exclusive licensing agreements for certain ingredients.
1911 – Gustave Gilbert, American psychologist (d. 1977).
Gustave Gilbert
Gustave Mark Gilbert (30 September 1911 to 06 February 1977) was an American psychologist best known for his writings containing observations of high-ranking Nazi leaders during the Nuremberg trials.
His 1950 book The Psychology of Dictatorship was an attempt to profile the Nazi German dictator Adolf Hitler using as reference the testimonials of Hitler’s closest generals and commanders. Gilbert’s published work is still a subject of study in many universities and colleges, especially in the field of psychology.
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