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.
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.
Symptoms typically include difficulty thinking, poor coordination, decreased level of consciousness, and a decreased effort to breathe (respiratory depression). Complications of overdose can include noncardiogenic pulmonary oedema. If death occurs this is typically due to a lack of breathing.
Barbiturate overdose may occur by accident or purposefully in an attempt to cause death. The toxic effects are additive to those of alcohol and benzodiazepines. The lethal dose varies with a person’s tolerance and how the drug is taken. The effects of barbiturates occur via the GABA neurotransmitter. Exposure may be verified by testing the urine or blood.
Treatment involves supporting a person’s breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Haemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful. While once a common cause of overdose, barbiturates are now a rare cause.
Mechanism of Action
Barbiturates increase the time that the chloride pore of the GABAA receptor is opened, thereby increasing the efficacy of GABA. In contrast, benzodiazepines increase the frequency with which the chloride pore is opened, thereby increasing GABA’s potency.
Treatment
Treatment involves supporting a person’s breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Haemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful.
If a person is drowsy but awake and can swallow and breathe without difficulty, the treatment can be as simple as monitoring the person closely. If the person is not breathing, it may involve mechanical ventilation until the drug has worn off. Psychiatric consult is generally recommended.
Notable Cases
People who are known to have committed suicide by barbiturate overdose include, Gillian Bennett, Charles Boyer, Ruan Lingyu, Dalida, Jeannine “The Singing Nun” Deckers, Felix Hausdorff, Abbie Hoffman, Phyllis Hyman, C. P. Ramanujam, George Sanders, Jean Seberg, Lupe Vélez and the members of Heaven’s Gate cult. Others who have died as a result of barbiturate overdose include Pier Angeli, Brian Epstein, Judy Garland, Jimi Hendrix, Marilyn Monroe, Inger Stevens, Dinah Washington, Ellen Wilkinson, and Alan Wilson; in some cases these have been speculated to be suicides as well. Those who died of a combination of barbiturates and other drugs include Rainer Werner Fassbinder, Dorothy Kilgallen, Malcolm Lowry, Edie Sedgwick and Kenneth Williams. Dorothy Dandridge died of either an overdose or an unrelated embolism. Ingeborg Bachmann may have died of the consequences of barbiturate withdrawal (she was hospitalised with burns, the doctors treating her not being aware of her barbiturate addiction). Maurice Chevalier unsuccessfully attempted suicide in March 1971 by swallowing a large amount of barbiturates and slitting his wrists; however, he suffered severe organ damage as a result and died from multiple organ failure nine months later.
Differential Diagnosis
The differential diagnosis should include intoxication by other substances with sedative effects, such as benzodiazepines, anticonvulsants (carbamazepine), alcohols (ethanol, ethylene glycol, methanol), opioids, carbon monoxide, sleep aids, and gamma-Hydroxybutyric acid (GHB – a known date rape drug). Natural disease that can result in disorientation may be in the differential, including hypoglycaemia and myxoedema coma. In the right setting, hypothermia should be ruled out.
Barbiturate dependence develops with regular use of barbiturates. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect.
Barbiturate use can lead to both addiction and physical dependence, and as such they have a high potential for excess or non-medical use, however, it does not affect all users. Management of barbiturate dependence involves considering the affected person’s age, comorbidity and the pharmacological pathways of barbiturates.
Psychological addiction to barbiturates can develop quickly. The patients will then have a strong desire to take any barbiturate-like drug. The chronic use of barbiturates leads to moderate degradation of the personality with narrowing of interests, passivity and loss of volition. The somatic signs include hypomimia, problems articulating, weakening of reflexes, and ataxia.
The GABAA receptor, one of barbiturates’ main sites of action, is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates, as well as the euphoric “high” that results from their use. The mechanism by which barbiturate tolerance develops is believed to be different from that of ethanol or benzodiazepines, even though these drugs have been shown to exhibit cross-tolerance with each other and poly drug administration of barbiturates and alcohol used to be common.
The management of a physical dependence on barbiturates is stabilisation on the long-acting barbiturate phenobarbital followed by a gradual titration down of dose. People who use barbiturates tend to prefer rapid-acting barbiturates (amobarbital, pentobarbital, secobarbital) rather than long-acting barbiturates (barbital, phenobarbital). The slowly eliminated phenobarbital lessens the severity of the withdrawal syndrome and reduces the chances of serious barbiturate withdrawal effects such as seizures. A cold turkey withdrawal can in some cases lead to death. Antipsychotics are not recommended for barbiturate withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines e.g. chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required. The withdrawal symptoms after ending barbiturate consumption are quite severe and last from 4 to 7 days.
In pharmacology, a psycholeptic is a medication which produces a calming effect upon a person.
Refer to Analeptic.
Background
Such medications include barbiturates, benzodiazepines, nonbenzodiazepines, phenothiazines, opiates/opioids, carbamates, ethanol, 2-methyl-2-butanol, cannabinoids (in some classifications), some antidepressants, neuroleptics, and some anticonvulsants.
Many herbal medicines may also be classified as psycholeptics (e.g. kava).
Psycholeptics are classified under N05 in the Anatomical Therapeutic Chemical Classification System.
A barbiturate is a drug that acts as a central nervous system depressant.
Barbiturates are effective as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have largely been replaced by benzodiazepines and nonbenzodiazepines (“Z-drugs”) in routine medical practice, particularly in the treatment of anxiety and insomnia, due to the significantly lower risk of addiction and overdose and the lack of an antidote for barbiturate overdose. Despite this, barbiturates are still in use for various purposes: in general anaesthesia, epilepsy, treatment of acute migraines or cluster headaches, acute tension headaches, euthanasia, capital punishment, and assisted suicide.
The name barbiturate originates from the fact that they are all chemical derivatives of barbituric acid.
Barbituric acid was first synthesized 27 November 1864, by German chemist Adolf von Baeyer. This was done by condensing urea with diethyl malonate. There are several stories about how the substance got its name. The most likely story is that Baeyer and his colleagues went to celebrate their discovery in a tavern where the town’s artillery garrison were also celebrating the feast of Saint Barbara – the patron saint of artillerymen. An artillery officer is said to have christened the new substance by amalgamating Barbara with urea. Another story was barbiturate was invented on the feast day of St. Barbara. Another story holds that Baeyer synthesized the substance from the collected urine of a Munich waitress named Barbara. No substance of medical value was discovered, however, until 1903 when two German scientists working at Bayer, Emil Fischer and Joseph von Mering, discovered that barbital was very effective in putting dogs to sleep. Barbital was then marketed by Bayer under the trade name Veronal. It is said that Mering proposed this name because the most peaceful place he knew was the Italian city of Verona.
It was not until the 1950s that the behavioural disturbances and physical dependence potential of barbiturates became recognised.
Barbituric acid itself does not have any direct effect on the central nervous system and chemists have derived over 2,500 compounds from it that possess pharmacologically active qualities. The broad class of barbiturates is further broken down and classified according to speed of onset and duration of action. Ultrashort-acting barbiturates are commonly used for anaesthesia because their extremely short duration of action allows for greater control. These properties allow doctors to rapidly put a patient “under” in emergency surgery situations. Doctors can also bring a patient out of anaesthesia just as quickly, should complications arise during surgery. The middle two classes of barbiturates are often combined under the title “short/intermediate-acting.” These barbiturates are also employed for anaesthetic purposes, and are also sometimes prescribed for anxiety or insomnia. This is not a common practice anymore, however, owing to the dangers of long-term use of barbiturates; they have been replaced by the benzodiazepines and Z-drugs such as zolpidem, zaleplon and eszopiclone for sleep. The final class of barbiturates are known as long-acting barbiturates (the most notable one being phenobarbital, which has a half-life of roughly 92 hours). This class of barbiturates is used almost exclusively as anticonvulsants, although on rare occasions they are prescribed for daytime sedation. Barbiturates in this class are not used for insomnia, because, owing to their extremely long half-life, patients would awake with a residual “hang-over” effect and feel groggy.
Barbiturates can in most cases be used either as the free acid or as salts of sodium, calcium, potassium, magnesium, lithium, etc. Codeine- and Dionine-based salts of barbituric acid have been developed. In 1912, Bayer introduced another barbituric acid derivative, phenobarbital, under the trade name Luminal, as a sedative-hypnotic.
Uses
Medicine
Barbiturates such as phenobarbital were long used as anxiolytics and hypnotics. Intermediate-acting barbiturates reduce time to fall asleep, increase total sleep time, and reduce REM sleep time. Today they have been largely replaced by benzodiazepines for these purposes because the latter are less toxic in drug overdose. However, barbiturates are still used as anticonvulsants (e.g. phenobarbital and primidone) and general anaesthetics (e.g. sodium thiopental).
Barbiturates in high doses are used for medical aid in dying, and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection. Barbiturates are frequently employed as euthanising agents in small-animal veterinary medicine.
Interrogation
Sodium thiopental is an ultra-short-acting barbiturate that is marketed under the name Sodium Pentothal. It is often mistaken for “truth serum”, or sodium amytal, an intermediate-acting barbiturate that is used for sedation and to treat insomnia, but was also used in so-called sodium amytal “interviews” where the person being questioned would be much more likely to provide the truth whilst under the influence of this drug. When dissolved in water, sodium amytal can be swallowed, or it can be administered by intravenous injection. The drug does not itself force people to tell the truth, but is thought to decrease inhibitions and slow creative thinking, making subjects more likely to be caught off guard when questioned, and increasing the possibility of the subject revealing information through emotional outbursts. Lying is somewhat more complex than telling the truth, especially under the influence of a sedative-hypnotic drug.
The memory-impairing effects and cognitive impairments induced by sodium thiopental are thought to reduce a subject’s ability to invent and remember lies. This practice is no longer considered legally admissible in court due to findings that subjects undergoing such interrogations may form false memories, putting the reliability of all information obtained through such methods into question. Nonetheless, it is still employed in certain circumstances by defence and law enforcement agencies as a “humane” alternative to torture interrogation when the subject is believed to have information critical to the security of the state or agency employing the tactic.
Chemistry
In 1988, the synthesis and binding studies of an artificial receptor binding barbiturates by six complementary hydrogen bonds was published. Since this first article, different kind of receptors were designed, as well as different barbiturates and cyanurates, not for their efficiencies as drugs but for applications in supramolecular chemistry, in the conception of materials and molecular devices.
Sodium barbital and barbital have also been used as pH buffers for biological research, e.g. in immuno-electrophoresis or in fixative solutions.
Side Effects
There are special risks to consider for older adults, and women who are pregnant. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people over the age of sixty-five are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose. When barbiturates are taken during pregnancy, the drug passes through the placenta to the foetus. After the baby is born, it may experience withdrawal symptoms and have trouble breathing. In addition, nursing mothers who take barbiturates may transmit the drug to their babies through breast milk. A rare adverse reaction to barbiturates is Stevens-Johnson syndrome, which primarily affects the mucous membranes.
With regular use, tolerance to the effects of barbiturates develops. Research shows tolerance can develop with even one administration of a barbiturate. As with all GABAergic drugs, barbiturate withdrawal produces potentially fatal effects such as seizures, in a manner reminiscent of delirium tremens and benzodiazepine withdrawal although its more direct mechanism of GABA agonism makes barbiturate withdrawal even more severe than that of alcohol or benzodiazepines (subsequently making it one of the most dangerous withdrawals of any known addictive substance). Similarly to benzodiazepines, the longer acting barbiturates produce a less severe withdrawal syndrome than short acting and ultra-short acting barbiturates. Withdrawal symptoms are dose-dependent with heavier users being more affected than lower-dose addicts.
The pharmacological treatment of barbiturate withdrawal is an extended process often consisting of converting the patient to a long-acting benzodiazepine (i.e. Valium), followed by slowly tapering off the benzodiazepine. Mental cravings for barbiturates can last for months or years in some cases and counselling/support groups are highly encouraged by addiction specialists. Patients should never try to tackle the task of discontinuing barbiturates without consulting a doctor, due to the high lethality and relatively sudden onset of the withdrawal. Attempting to quit “cold turkey” may result in serious neurological damage, severe physical injuries received during convulsions, and even death via glutamatergic excitotoxicity.
Some symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgement, drowsiness, shallow breathing, staggering, and, in severe cases, coma or death. The lethal dosage of barbiturates varies greatly with tolerance and from one individual to another. The lethal dose is highly variable among different members of the class, with superpotent barbiturates such as pentobarbital being potentially fatal in considerably lower doses than the low-potency barbiturates such as butalbital. Even in inpatient settings, the development of tolerance is still a problem, as dangerous and unpleasant withdrawal symptoms can result when the drug is stopped after dependence has developed. Tolerance to the anxiolytic and sedative effects of barbiturates tends to develop faster than tolerance to their effects on smooth muscle, respiration, and heart rate, making them generally unsuitable for a long time psychiatric use. Tolerance to the anticonvulsant effects tends to correlate more with tolerance to physiological effects, however, meaning that they are still a viable option for long-term epilepsy treatment.
Barbiturates in overdose with other CNS (central nervous system) depressants (e.g. alcohol, opiates, benzodiazepines) are even more dangerous due to additive CNS and respiratory depressant effects. In the case of benzodiazepines, not only do they have additive effects, barbiturates also increase the binding affinity of the benzodiazepine binding site, leading to exaggerated benzodiazepine effects. (e.g. If a benzodiazepine increases the frequency of channel opening by 300%, and a barbiturate increases the duration of their opening by 300%, then the combined effects of the drugs increases the channels’ overall function by 900%, not 600%).
The longest-acting barbiturates have half-lives of a day or more, and subsequently result in bioaccumulation of the drug in the system. The therapeutic and recreational effects of long-acting barbiturates wear off significantly faster than the drug can be eliminated, allowing the drug to reach toxic concentrations in the blood following repeated administration (even when taken at the therapeutic or prescribed dose) despite the user feeling little or no effects from the plasma-bound concentrations of the drug. Users who consume alcohol or other sedatives after the drug’s effects have worn off, but before it has cleared the system, may experience a greatly exaggerated effect from the other sedatives which can be incapacitating or even fatal.
Barbiturates induce a number of hepatic CYP enzymes (most notably CYP2C9, CYP2C19, and CYP3A4), leading to exaggerated effects from many prodrugs and decreased effects from drugs which are metabolised by these enzymes to inactive metabolites. This can result in fatal overdoses from drugs such as codeine, tramadol, and carisoprodol, which become considerably more potent after being metabolised by CYP enzymes. Although all known members of the class possess relevant enzyme induction capabilities, the degree of induction overall as well as the impact on each specific enzyme span a broad range, with phenobarbital and secobarbital being the most potent enzyme inducers and butalbital and talbutal being among the weakest enzyme inducers in the class.
People who are known to have committed suicide by barbiturate overdose include Charles Boyer, Ruan Lingyu, Dalida, Jeannine “The Singing Nun” Deckers, Felix Hausdorff, Abbie Hoffman, Phyllis Hyman, C.P. Ramanujam, George Sanders, Jean Seberg, Lupe Vélez and the members of Heaven’s Gate cult. Others who have died as a result of barbiturate overdose include Pier Angeli, Brian Epstein, Judy Garland, Jimi Hendrix, Marilyn Monroe, Inger Stevens, Dinah Washington, Ellen Wilkinson, and Alan Wilson; in some cases these have been speculated to be suicides as well. Those who died of a combination of barbiturates and other drugs include Rainer Werner Fassbinder, Dorothy Kilgallen, Malcolm Lowry, Edie Sedgwick and Kenneth Williams. Dorothy Dandridge died of either an overdose or an unrelated embolism. Ingeborg Bachmann may have died of the consequences of barbiturate withdrawal (she was hospitalised with burns, the doctors treating her not being aware of her barbiturate addiction).
Mechanism of Action
Barbiturates act as positive allosteric modulators and, at higher doses, as agonists of GABAA receptors. GABA is the principal inhibitory neurotransmitter in the mammalian central nervous system (CNS). Barbiturates bind to the GABAA receptor at multiple homologous transmembrane pockets located at subunit interfaces,[19] which are binding sites distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABAergic effect, barbiturates also block AMPA and kainate receptors, subtypes of ionotropic glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABAA receptors and inhibit excitatory AMPA receptors can explain the superior CNS-depressant effects of these agents to alternative GABA potentiating agents such as benzodiazepines and quinazolinones. At higher concentration, they inhibit the Ca2+-dependent release of neurotransmitters such as glutamate via an effect on P/Q-type voltage-dependent calcium channels. Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the potency of GABA). The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in overdose.
Further, barbiturates are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABAA receptor channel is only one of several representatives. This Cys-loop receptor superfamily of ion channels includes the neuronal nACh receptor channel, the 5-HT3 receptor channel, and the glycine receptor channel. However, while GABAA receptor currents are increased by barbiturates (and other general anaesthetics), ligand-gated ion channels that are predominantly permeable for cationic ions are blocked by these compounds. For example, neuronal nAChR channels are blocked by clinically relevant anaesthetic concentrations of both thiopental and pentobarbital. Such findings implicate (non-GABA-ergic) ligand-gated ion channels, e.g. the neuronal nAChR channel, in mediating some of the (side) effects of barbiturates. This is the mechanism responsible for the (mild to moderate) anaesthetic effect of barbiturates in high doses when used in anaesthetic concentration.
Society and Culture
Legal Status
During World War II, military personnel in the Pacific region were given “goofballs” to allow them to tolerate the heat and humidity of daily working conditions. Goofballs were distributed to reduce the demand on the respiratory system, as well as maintaining blood pressure, to combat the extreme conditions. Many soldiers returned with addictions that required several months of rehabilitation before discharge. This led to growing dependency problems, often exacerbated by indifferent doctors prescribing high doses to unknowing patients through the 1950s and 1960s.
In the late 1950s and 1960s, an increasing number of published reports of barbiturate overdoses and dependence problems led physicians to reduce their prescription, particularly for spurious requests. This eventually led to the scheduling of barbiturates as controlled drugs.
In the Netherlands, the Opium Law classifies all barbiturates as List II drugs, with the exception of secobarbital, which is on List I.
There is a small group of List II drugs for which doctors have to write the prescriptions according to the same, tougher guidelines as those for List I drugs (writing the prescription in full in letters, listing the patients name, and have to contain the name and initials, address, city and telephone number of the licensed prescriber issuing the prescriptions, as well as the name and initials, address and city of the person the prescription is issued to). Among that group of drugs are the barbiturates amobarbital, butalbital, cyclobarbital, and pentobarbital.
In the United States, the Controlled Substances Act of 1970 classified most barbiturates as controlled substances – and they remain so as of September 2020. Barbital, methylphenobarbital (also known as mephobarbital), and phenobarbital are designated schedule IV drugs, and “Any substance which contains any quantity of a derivative of barbituric acid, or any salt of a derivative of barbituric acid” (all other barbiturates) were designated as being schedule III. Under the original CSA, no barbiturates were placed in schedule I, II, or V; however, amobarbital, pentobarbital, and secobarbital are schedule II controlled substances unless they are in a suppository dosage form.
In 1971, the Convention on Psychotropic Substances was signed in Vienna. Designed to regulate amphetamines, barbiturates, and other synthetics, the 34th version of the treaty, as of 25 January 2014, regulates secobarbital as schedule II, amobarbital, butalbital, cyclobarbital, and pentobarbital as schedule III, and allobarbital, barbital, butobarbital, mephobarbital, phenobarbital, butabarbital, and vinylbital as schedule IV on its “Green List”. The combination medication Fioricet, consisting of butalbital, caffeine, and paracetamol (acetaminophen), however, is specifically exempted from controlled substance status, while its sibling Fiorinal, which contains aspirin instead of paracetamol and may contain codeine phosphate, remains a schedule III drug.
Recreational Use
Recreational users report that a barbiturate high gives them feelings of relaxed contentment and euphoria. Physical and psychological dependence may also develop with repeated use. Chronic misuse of barbiturates is associated with significant morbidity. One study found that 11% of males and 23% of females with a sedative-hypnotic misuse die by suicide. Other effects of barbiturate intoxication include drowsiness, lateral and vertical nystagmus, slurred speech and ataxia, decreased anxiety, and loss of inhibitions. Barbiturates are also used to alleviate the adverse or withdrawal effects of illicit drug use, in a manner similar to long-acting benzodiazepines such as diazepam and clonazepam. Often polysubstance use occurs and barbiturates are consumed with or substituted by other available substances, most commonly alcohol.
People who use substances tend to prefer short-acting and intermediate-acting barbiturates. The most commonly used are amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). A combination of amobarbital and secobarbital (called Tuinal) is also highly used. Short-acting and intermediate-acting barbiturates are usually prescribed as sedatives and sleeping pills. These pills begin acting fifteen to forty minutes after they are swallowed, and their effects last from five to six hours.
Slang terms for barbiturates include barbs, barbies, bluebirds, dolls, wallbangers, yellows, downers, goofballs, sleepers, ‘reds & blues’, and tooties.
The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage.
In the case of re-emergence, the severity of the symptoms is often worse than pre-treatment levels.
Examples
Sedative Hypnotics
Rebound Insomnia
Rebound insomnia is insomnia that occurs following discontinuation of sedative substances taken to relieve primary insomnia. Regular use of these substances can cause a person to become dependent on its effects in order to fall asleep. Therefore, when a person has stopped taking the medication and is ‘rebounding’ from its effects, he or she may experience insomnia as a symptom of withdrawal. Occasionally, this insomnia may be worse than the insomnia the drug was intended to treat.
Common medicines known to cause this problem are eszopiclone, zolpidem, and anxiolytics such as benzodiazepines and which are prescribed to people having difficulties falling or staying asleep.
Rebound Depression
Depressive symptoms may appear to arise in patients previously free of such an illness.
Daytime Rebound
Rebound phenomena do not necessarily only occur on discontinuation of a prescribed dosage. For example, daytime rebound effects of anxiety, metallic taste, perceptual disturbances which are typical benzodiazepine withdrawal symptoms can occur the next day after a short-acting benzodiazepine hypnotic wears off. Another example is early morning rebound insomnia which may occur when a rapidly eliminated hypnotic wears off which leads to rebounding awakeness forcing the person to become wide awake before he or she has had a full night’s sleep. One drug which seems to be commonly associated with these problems is triazolam, due to its high potency and ultra short half life, but these effects can occur with other short-acting hypnotic drugs. Quazepam, due to its selectivity for type1 benzodiazepine receptors and long half-life, does not cause daytime anxiety rebound effects during treatment, showing that half-life is very important for determining whether a night-time hypnotic will cause next-day rebound withdrawal effects or not. Daytime rebound effects are not necessarily mild but can sometimes produce quite marked psychiatric and psychological disturbances.
Stimulants
Rebound effects from stimulants such as methylphenidate or dextroamphetamine include stimulant psychosis, depression and a return of ADHD symptoms but in a temporarily exaggerated form. Up to a third of ADHD children experience a rebound effect when methylphenidate is withdrawn.
Antidepressants
Many antidepressants, including SSRIs, can cause rebound depression, panic attacks, anxiety, and insomnia when discontinued.
Antipsychotics
Sudden and severe emergence or re-emergence of psychosis may appear when antipsychotics are switched or discontinued too rapidly.
Alpha-2 Adrenergic Agents
Rebound hypertension, above pre-treatment level, was observed after clonidine, and guanfacine discontinuation.
Others
Other Rebound Effects
An example is the use of highly potent corticosteroids, such as clobetasol for psoriasis. Abrupt withdrawal can cause a much more severe case of the psoriasis to develop. Therefore, withdrawal should be gradual, diluting the medication with lotion perhaps, until very little actual medication is being applied.
Another example of pharmaceutical rebound is a rebound headache from painkillers when the dose is lowered, the medication wears off, or the drug is abruptly discontinued.
Continuous usage of topical decongestants (nasal sprays) can lead to constant nasal congestion, known as rhinitis medicamentosa.
A paradoxical reaction or paradoxical effect is an effect of a chemical substance, typically a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.
Paradoxical reactions are more commonly observed in people with attention deficit hyperactivity disorder (ADHD).
Substances
Amphetamines
Amphetamines are a class of psychoactive drugs that are stimulants. Paradoxical drowsiness can sometimes occur in adults.
Antibiotics
The paradoxical effect or Eagle effect (named after H. Eagle who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an antimicrobial agent. Initially when an antibiotic agent is added to a culture media, the number of bacteria that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases.
Antidepressants
In rare cases antidepressants can make users obsessively violent or have suicidal compulsions, which is in marked contrast to their intended effect. This can be regarded as a paradoxical reaction but, especially in the case of suicide, may in at least some cases be merely due to differing rates of effect with respect to different symptoms of depression: If generalised overinhibition of a patient’s actions enters remission before that patient’s dysphoria does and if the patient was already suicidal but too depressed to act on their inclinations, the patient may find themselves in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so. Children and adolescents are more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking antidepressants but cases are still very rare.
Antipsychotics
Chlorpromazine, an antipsychotic and antiemetic drug, which is classed as a “major” tranquilizer may cause paradoxical effects such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states.
Barbiturates
Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days. Prerequisity for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital.
Benzodiazepines
Benzodiazepines, a class of psychoactive drugs called the “minor” tranquilisers, have varying hypnotic, sedative, anxiolytic, anticonvulsant, and muscle relaxing properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase in anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behaviour, and even convulsions. Paradoxical adverse effects may even lead to criminal behaviour. Severe behavioural changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania.
Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generates automatic behaviours, anterograde amnesia and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting serotonergic mechanism.
Paradoxical effects of benzodiazepines appear to be dose related, that is, likelier to occur with higher doses.
In a letter to the British Medical Journal, it was reported that a high proportion of parents referred for actual or threatened child abuse were taking medication at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilisers may precipitate a child abuse event.
Self aggression has been reported and also demonstrated in laboratory conditions in a clinical study. Diazepam was found to increase people’s willingness to harm themselves.
Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders.
Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients’ behaviour to baseline levels.
Causes
The mechanism of a paradoxical reaction has as yet (2019) not been fully clarified, in no small part due to the fact that signal transfer of single neurons in subcortical areas of the human brain is usually not accessible.
There are, however, multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates, inhalational anaesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA receptors. The combination of the five subunits of the receptor (see image) can be altered in such a way that for example the receptor’s response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.
There are estimates that about 2-3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.
Quazepam (marketed under brand names Doral, Dormalin) is a relatively long-acting benzodiazepine derivative drug developed by the Schering Corporation in the 1970s.
Quazepam is indicated for the treatment of insomnia including sleep induction and sleep maintenance. Quazepam induces impairment of motor function and has relatively (and uniquely) selective hypnotic and anticonvulsant properties with considerably less overdose potential than other benzodiazepines (due to its novel receptor-subtype selectively). Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture.
Brief History
It was patented in 1970 and came into medical use in 1985.
Medical Uses
Quazepam is used for short-term treatment of insomnia related to sleep induction or sleep maintenance problems and has demonstrated superiority over other benzodiazepines such as temazepam. It had a fewer incidence of side effects than temazepam, including less sedation, amnesia, and less motor-impairment. Usual dosage is 7.5 to 15 mg orally at bedtime.
Quazepam is effective as a premedication prior to surgery.
Side Effects
Quazepam has fewer side effects than other benzodiazepines and less potential to induce tolerance and rebound effects. There is significantly less potential for quazepam to induce respiratory depression or to adversely affect motor coordination than other benzodiazepines. The different side effect profile of quazepam may be due to its more selective binding profile to type 1 benzodiazepine receptors.
Ataxia.
Daytime somnolence.
Hypokinesia.
Cognitive and performance impairments.
In September 2020, the US Food and Drug Administration (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.
Tolerance and Dependence
Tolerance may occur to quazepam but more slowly than seen with other benzodiazepines such as triazolam. Quazepam causes significantly less drug tolerance and less withdrawal symptoms including less rebound insomnia upon discontinuation compared to other benzodiazepines. Quazepam may cause less rebound effects than other type1 benzodiazepine receptor selective nonbenzodiazepine drugs due to its longer half-life. Short-acting hypnotics often cause next day rebound anxiety. Quazepam due to its pharmacological profile does not cause next day rebound withdrawal effects during treatment.
No firm conclusions can be drawn, however, whether long-term use of quazepam does not produce tolerance as few, if any, long-term clinical trials extending beyond 4 weeks of chronic use have been conducted. Quazepam should be withdrawn gradually if used beyond 4 weeks of use to avoid the risk of a severe benzodiazepine withdrawal syndrome developing. Very high dosage administration over prolonged periods of time, up to 52 weeks, of quazepam in animal studies provoked severe withdrawal symptoms upon abrupt discontinuation, including excitability, hyperactivity, convulsions and the death of two of the monkeys due to withdrawal-related convulsions. More monkeys died, however, in the diazepam-treated monkeys. In addition it has now been documented in the medical literature that one of the major metabolites of quazepam, N-desalkyl-2-oxoquazepam (N-desalkylflurazepam), which is long-acting and prone to accumulation, binds unselectively to benzodiazepine receptors, thus quazepam may not differ all that much pharmacologically from other benzodiazepines.
Special Precautions
Benzodiazepines require special precaution if used in the during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.
Quazepam and its active metabolites are excreted into breast milk.
Accumulation of one of the active metabolites of quazepam, N-desalkylflurazepam, may occur in the elderly. A lower dose may be required in the elderly.
Elderly
Quazepam is more tolerable for elderly patients compared to flurazepam due to its reduced next day impairments. However, another study showed marked next day impairments after repeated administration due to accumulation of quazepam and its long-acting metabolites. Thus the medical literature shows conflicts on quazepam’s side effect profile. A further study showed significant balance impairments combined with an unstable posture after administration of quazepam in test subjects. An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilised. Compared with the benzodiazepines including quazepam, the nonbenzodiazepine sedative/hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative/hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.
Interactions
The absorption rate is likely to be significantly reduced if quazepam is taken in the fasted state reducing the hypnotic effect of quazepam. If 3 or more hours have passed since eating food then some food should be eaten before taking quazepam.
Pharmacology
Quazepam is a trifluoroalkyl type of benzodiazepine. Quazepam is unique amongst benzodiazepines in that it selectively targets the GABAA α1 subunit receptors which are responsible for inducing sleep. Its mechanism of action is very similar to zolpidem and zaleplon in its pharmacology and can successfully substitute for zolpidem and zaleplon in animal studies.
Quazepam is selective for type I benzodiazepine receptors containing the α1 subunit, similar to other drugs such as zaleplon and zolpidem. As a result, quazepam has little or no muscle relaxant properties. Most other benzodiazepines are unselective and bind to type1 GABAA receptors and type2 GABAA receptors. Type1 GABAA receptors include the α1 subunit containing GABAA receptors which are responsible for hypnotic properties of the drug. Type 2 receptors include the α2, α3 and α5 subunits which are responsible for anxiolytic action, amnesia and muscle relaxant properties. Thus quazepam may have less side effects than other benzodiazepines but, it has a very long half-life of 25 hours which reduces its benefits as a hypnotic due to likely next day sedation. It also has two active metabolites with half-lives of 28 and 79 hours. Quazepam may also cause less drug tolerance than other benzodiazepines such as temazepam and triazolam perhaps due to its subtype selectivity. The longer half-life of quazepam may have the advantage however, of causing less rebound insomnia than shorter acting subtype selective nonbenzodiazepines. However, one of the major metabolites of quazepam, the N-desmethyl-2-oxoquazepam (aka N-desalkylflurazepam), binds unselectively to both type1 and type2 GABAA receptors. The N-desmethyl-2-oxoquazepam metabolite also has a very long half-life and likely contributes to the pharmacological effects of quazepam.
Pharmacokinetics
Quazepam has an absorption half-life of 0.4 hours with a peak in plasma levels after 1.75 hours. It is eliminated both renally and through faeces. The active metabolites of quazepam are 2-oxoquazepam and N-desalkyl-2-oxoquazepam. The N-desalkyl-2-oxoquazepam metabolite has only limited pharmacological activity compared to the parent compound quazepam and the active metabolite 2-oxoquazepam. Quazepam and its major active metabolite 2-oxoquazepam both show high selectivity for the type1 GABAA receptors. The elimination half-life range of quazepam is between 27 and 41 hours.
Mechanism of Action
Quazepam modulates specific GABAA receptors via the benzodiazepine site on the GABAA receptor. This modulation enhances the actions of GABA, causing an increase in opening frequency of the chloride ion channel which results in an increased influx of chloride ions into the GABAA receptors. Quazepam, unique amongst benzodiazepine drugs selectively targets type1 benzodiazepine receptors which results reduced sleep latency in promotion of sleep. Quazepam also has some anticonvulsant properties.
EEG and Sleep
Quazepam has potent sleep inducing and sleep maintaining properties. Studies in both animals and humans have demonstrated that EEG changes induced by quazepam resemble normal sleep patterns whereas other benzodiazepines disrupt normal sleep. Quazepam promotes slow wave sleep. This positive effect of quazepam on sleep architecture may be due to its high selectivity for type1 benzodiazepine receptors as demonstrated in animal and human studies. This makes quazepam unique in the benzodiazepine family of drugs.
Quazepam is a drug with the potential for misuse. Two types of drug misuse can occur, either recreational misuse where the drug is taken to achieve a high, or when the drug is continued long term against medical advice.
Midazolam, sold under the brand name Versed, among others, is a benzodiazepine medication used for anaesthesia, procedural sedation, trouble sleeping, and severe agitation.
It works by inducing sleepiness, decreasing anxiety, and causing a loss of ability to create new memories. It is also useful for the treatment of seizures. Midazolam can be given by mouth, intravenously, or injection into a muscle, by spraying into the nose, or through the cheek. When given intravenously, it typically begins working within five minutes; when injected into a muscle, it can take fifteen minutes to begin working. Effects last for between one and six hours.
Side effects can include a decrease in efforts to breathe, low blood pressure, and sleepiness. Tolerance to its effects and withdrawal syndrome may occur following long-term use. Paradoxical effects, such as increased activity, can occur especially in children and older people. There is evidence of risk when used during pregnancy but no evidence of harm with a single dose during breastfeeding. It belongs to the benzodiazepine class of drugs and works by increasing the activity of the GABA neurotransmitter in the brain.
Midazolam was patented in 1974 and came into medical use in 1982. It is on the World Health Organisation’s List of Essential Medicines. Midazolam is available as a generic medication. In many countries, it is a controlled substance.
Brief History
Midazolam is among about 35 benzodiazepines currently used medically, and was synthesized in 1975 by Walser and Fryer at Hoffmann-LaRoche, Inc in the United States. Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs. The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus. As of 2010, it is the most commonly used benzodiazepine in anaesthetic medicine. In acute medicine, midazolam has become more popular than other benzodiazepines, such as lorazepam and diazepam, because it is shorter lasting, is more potent, and causes less pain at the injection site. Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility. In 2018 it was revealed the CIA considered using Midazolam as a “truth serum” on terrorist suspects in project “Medication”.
Medical Uses
Seizures
Midazolam is sometimes used for the acute management of seizures. Long-term use for the management of epilepsy is not recommended due to the significant risk of tolerance (which renders midazolam and other benzodiazepines ineffective) and the significant side effect of sedation. A benefit of midazolam is that in children it can be given in the cheek or in the nose for acute seizures, including status epilepticus. Midazolam is effective for status epilepticus that has not improved following other treatments or when intravenous access cannot be obtained, and has advantages of being water-soluble, having a rapid onset of action and not causing metabolic acidosis from the propylene glycol vehicle (which is not required due to its solubility in water), which occurs with other benzodiazepines.
Drawbacks include a high degree of breakthrough seizures – due to the short half-life of midazolam – in over 50% of people treated, as well as treatment failure in 14-18% of people with refractory status epilepticus. Tolerance develops rapidly to the anticonvulsant effect, and the dose may need to be increased by several times to maintain anticonvulsant therapeutic effects. With prolonged use, tolerance and tachyphylaxis can occur and the elimination half-life may increase, up to days. There is evidence buccal and intranasal midazolam is easier to administer and more effective than rectally administered diazepam in the emergency control of seizures.
Procedural Sedation
Intravenous midazolam is indicated for procedural sedation (often in combination with an opioid, such as fentanyl), for preoperative sedation, for the induction of general anaesthesia, and for sedation of people who are ventilated in critical care units. Midazolam is superior to diazepam in impairing memory of endoscopy procedures, but propofol has a quicker recovery time and a better memory-impairing effect. It is the most popular benzodiazepine in the intensive care unit (ICU) because of its short elimination half-life, combined with its water solubility and its suitability for continuous infusion. However, for long-term sedation, lorazepam is preferred due to its long duration of action, and propofol has advantages over midazolam when used in the ICU for sedation, such as shorter weaning time and earlier tracheal extubation.
Midazolam is sometimes used in neonatal intensive care units. When used, additional caution is required in newborns; midazolam should not be used for longer than 72 hours due to risks of tachyphylaxis, and the possibility of development of a benzodiazepine withdrawal syndrome, as well as neurological complications. Bolus injections should be avoided due to the increased risk of cardiovascular depression, as well as neurological complications. Midazolam is also sometimes used in newborns who are receiving mechanical ventilation, although morphine is preferred, owing to its better safety profile for this indication.
Sedation using midazolam can be used to relieve anxiety and manage behaviour in children undergoing dental treatment.
Agitation
Midazolam, in combination with an antipsychotic drug, is indicated for the acute management of schizophrenia when it is associated with aggressive or out-of-control behaviour.
End of Life Care
In the final stages of end-of-life care, midazolam is routinely used at low doses via subcutaneous injection to help with agitation, myoclonus, restlessness or anxiety in the last hours or days of life. At higher doses during the last weeks of life, midazolam is considered a first line agent in palliative continuous deep sedation therapy when it is necessary to alleviate intolerable suffering not responsive to other treatments, but the need for this is rare.
Contraindications
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, in alcohol- or other drug-dependent individuals or those with comorbid psychiatric disorders.[31] Additional caution is required in critically ill patients, as accumulation of midazolam and its active metabolites may occur.[32] Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects.[33][34] Contraindications include hypersensitivity, acute narrow-angle glaucoma, shock, hypotension, or head injury. Most are relative contraindications.
Side effects of midazolam in the elderly are listed above. People experiencing amnesia as a side effect of midazolam are generally unaware their memory is impaired, unless they had previously known it as a side effect.
Long-term use of benzodiazepines has been associated with long-lasting deficits of memory, and show only partial recovery six months after stopping benzodiazepines. It is unclear whether full recovery occurs after longer periods of abstinence. Benzodiazepines can cause or worsen depression. Paradoxical excitement occasionally occurs with benzodiazepines, including a worsening of seizures. Children and elderly individuals or those with a history of excessive alcohol use and individuals with a history of aggressive behaviour or anger are at increased risk of paradoxical effects. Paradoxical reactions are particularly associated with intravenous administration. After night-time administration of midazolam, residual ‘hangover’ effects, such as sleepiness and impaired psychomotor and cognitive functions, may persist into the next day. This may impair the ability of users to drive safely and may increase the risk of falls and hip fractures. Sedation, respiratory depression and hypotension due to a reduction in systematic vascular resistance, and an increase in heart rate can occur. If intravenous midazolam is given too quickly, hypotension may occur. A “midazolam infusion syndrome” may result from high doses, and is characterised by delayed arousal hours to days after discontinuation of midazolam, and may lead to an increase in the length of ventilatory support needed.
In susceptible individuals, midazolam has been known to cause a paradoxical reaction, a well-documented complication with benzodiazepines. When this occurs, the individual may experience anxiety, involuntary movements, aggressive or violent behaviour, uncontrollable crying or verbalisation, and other similar effects. This seems to be related to the altered state of consciousness or disinhibition produced by the drug. Paradoxical behaviour is often not recalled by the patient due to the amnesia-producing properties of the drug. In extreme situations, flumazenil can be administered to inhibit or reverse the effects of midazolam. Antipsychotic medications, such as haloperidol, have also been used for this purpose.
Midazolam is known to cause respiratory depression. In healthy humans, 0.15 mg/kg of midazolam may cause respiratory depression, which is postulated to be a central nervous system (CNS) effect. When midazolam is administered in combination with fentanyl, the incidence of hypoxemia or apnoea becomes more likely.
Although the incidence of respiratory depression/arrest is low (0.1-0.5%) when midazolam is administered alone at normal doses, the concomitant use with CNS acting drugs, mainly analgesic opiates, may increase the possibility of hypotension, respiratory depression, respiratory arrest, and death, even at therapeutic doses. Potential drug interactions involving at least one CNS depressant were observed for 84% of midazolam users who were subsequently required to receive the benzodiazepine antagonist flumazenil. Therefore, efforts directed toward monitoring drug interactions and preventing injuries from midazolam administration are expected to have a substantial impact on the safe use of this drug
Pregnancy and Breastfeeding
Midazolam, when taken during the third trimester of pregnancy, may cause risk to the neonate, including benzodiazepine withdrawal syndrome, with possible symptoms including hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of hypotonia and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Other neonatal withdrawal symptoms include hyperexcitability, tremor, and gastrointestinal upset (diarrhoea or vomiting). Breastfeeding by mothers using midazolam is not recommended.
Elderly
Additional caution is required in the elderly, as they are more sensitive to the pharmacological effects of benzodiazepines, metabolise them more slowly, and are more prone to adverse effects, including drowsiness, amnesia (especially anterograde amnesia), ataxia, hangover effects, confusion, and falls.
Tolerance, Dependence, and Withdrawal
A benzodiazepine dependence occurs in about one-third of individuals who are treated with benzodiazepines for longer than 4 weeks, which typically results in tolerance and benzodiazepine withdrawal syndrome when the dose is reduced too rapidly. Midazolam infusions may induce tolerance and a withdrawal syndrome in a matter of days. The risk factors for dependence include dependent personality, use of a benzodiazepine that is short-acting, high potency and long-term use of benzodiazepines. Withdrawal symptoms from midazolam can range from insomnia and anxiety to seizures and psychosis. Withdrawal symptoms can sometimes resemble a person’s underlying condition. Gradual reduction of midazolam after regular use can minimise withdrawal and rebound effects. Tolerance and the resultant withdrawal syndrome may be due to receptor down-regulation and GABAA receptor alterations in gene expression, which causes long-term changes in the function of the GABAergic neuronal system.
Chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines. Prolonged infusions with midazolam results in the development of tolerance; if midazolam is given for a few days or more a withdrawal syndrome can occur. Therefore, preventing a withdrawal syndrome requires that a prolonged infusion be gradually withdrawn, and sometimes, continued tapering of dose with an oral long-acting benzodiazepine such as clorazepate dipotassium. When signs of tolerance to midazolam occur during intensive care unit sedation the addition of an opioid or propofol is recommended. Withdrawal symptoms can include irritability, abnormal reflexes, tremors, clonus, hypertonicity, delirium and seizures, nausea, vomiting, diarrhoea, tachycardia, hypertension, and tachypnoea. In those with significant dependence, sudden discontinuation may result in withdrawal symptoms such as status epilepticus that may be fatal.
A midazolam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. Benzodiazepine overdose in healthy individuals is rarely life-threatening with proper medical support; however, the toxicity of benzodiazepines increases when they are combined with other CNS depressants such as alcohol, opioids, or tricyclic antidepressants. The toxicity of benzodiazepine overdose and risk of death is also increased in the elderly and those with obstructive pulmonary disease or when used intravenously. Treatment is supportive; activated charcoal can be used within an hour of the overdose. The antidote for an overdose of midazolam (or any other benzodiazepine) is flumazenil. While effective in reversing the effects of benzodiazepines it is not used in most cases as it may trigger seizures in mixed overdoses and benzodiazepine dependent individuals.
Symptoms of midazolam overdose can include:
Ataxia.
Dysarthria.
Nystagmus.
Slurred speech.
Somnolence (difficulty staying awake).
Mental confusion.
Hypotension.
Respiratory arrest.
Vasomotor collapse.
Impaired motor functions.
Impaired reflexes.
Impaired coordination.
Impaired balance.
Dizziness.
Coma.
Death.
Detection in Body Fluids
Concentrations of midazolam or its major metabolite, 1-hydroxymidazolam glucuronide, may be measured in plasma, serum, or whole blood to monitor for safety in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalised patients, or to assist in a forensic investigation of a case of fatal overdosage. Patients with renal dysfunction may exhibit prolongation of elimination half-life for both the parent drug and its active metabolite, with accumulation of these two substances in the bloodstream and the appearance of adverse depressant effects.
Interactions
Protease inhibitors, nefazodone, sertraline, grapefruit, fluoxetine, erythromycin, diltiazem, clarithromycin inhibit the metabolism of midazolam, leading to a prolonged action. St John’s wort, rifapentine, rifampin, rifabutin, phenytoin enhance the metabolism of midazolam leading to a reduced action. Sedating antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opioids, antipsychotics and alcohol enhance the sedative effects of midazolam. Midazolam is metabolised almost completely by cytochrome P450-3A4. Atorvastatin administration along with midazolam results in a reduced elimination rate of midazolam. St John’s wort decreases the blood levels of midazolam. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations.
Pharmacology
Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of 1.5-2.5 hours. In the elderly, as well as young children and adolescents, the elimination half-life is longer. Midazolam is metabolised into an active metabolite alpha1-hydroxymidazolam. Age-related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite. However, the active metabolite of midazolam is minor and contributes to only 10% of biological activity of midazolam. Midazolam is poorly absorbed orally, with only 50% of the drug reaching the bloodstream. Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. The therapeutic as well as adverse effects of midazolam are due to its effects on the GABAA receptors; midazolam does not activate GABAA receptors directly but, as with other benzodiazepines, it enhances the effect of the neurotransmitter GABA on the GABAA receptors (↑ frequency of Cl− channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benzodiazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, induction of sleep, reduction in anxiety, anterograde amnesia, muscle relaxation and anticonvulsant effects.
Society and Culture
Cost
Midazolam is available as a generic medication.
Availability
Midazolam is available in the United States as a syrup or as an injectable solution.
Dormicum brand midazolam is marketed by Roche as white, oval, 7.5-mg tablets in boxes of two or three blister strips of 10 tablets, and as blue, oval, 15-mg tablets in boxes of two (Dormonid 3x) blister strips of 10 tablets. The tablets are imprinted with “Roche” on one side and the dose of the tablet on the other side. Dormicum is also available as 1-, 3-, and 10-ml ampoules at a concentration of 5 mg/ml. Another manufacturer, Novell Pharmaceutical Laboratories, makes it available as Miloz in 3- and 5-ml ampoules. Midazolam is the only water-soluble benzodiazepine available. Another maker is Roxane Laboratories; the product in an oral solution, Midazolam HCl Syrup, 2 mg/ml clear, in a red to purplish-red syrup, cherry in flavour. It becomes soluble when the injectable solution is buffered to a pH of 2.9-3.7. Midazolam is also available in liquid form. It can be administered intramuscularly, intravenously, intrathecally, intranasally, buccally, or orally.
Legal Status
In the Netherlands, midazolam is a List II drug of the Opium Law. Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances. In the United Kingdom, midazolam is a Schedule 3/Class C controlled drug. In the United States, midazolam (DEA number 2884) is on the Schedule IV list of the Controlled Substances Act as a non-narcotic agent with low potential for abuse.
Marketing Authorisation
In 2011, the European Medicines Agency (EMA) granted a marketing authorisation for a buccal application form of midazolam, sold under the trade name Buccolam. Buccolam was approved for the treatment of prolonged, acute, convulsive seizures in people from three months to less than 18 years of age. This was the first application of a paediatric-use marketing authorisation.
Use in Executions
The drug has been introduced for use in executions by lethal injection in certain jurisdictions in the United States in combination with other drugs. It was introduced to replace pentobarbital after the latter’s manufacturer disallowed that drug’s use for executions. Midazolam acts as a sedative to render the condemned prisoner unconscious, at which time vecuronium bromide and potassium chloride are administered, stopping the prisoner’s breathing and heart, respectively.
Midazolam has been used as part of a three-drug cocktail, with vecuronium bromide and potassium chloride in Florida and Oklahoma prisons. Midazolam has also been used along with hydromorphone in a two-drug protocol in Ohio and Arizona.
The usage of midazolam in executions became controversial after condemned inmate Clayton Lockett apparently regained consciousness and started speaking midway through his 2014 execution when the state of Oklahoma attempted to execute him with an untested three-drug lethal injection combination using 100 mg of midazolam. Prison officials reportedly discussed taking him to a hospital before he was pronounced dead of a heart attack 40 minutes after the execution began. An observing doctor stated that Lockett’s vein had ruptured. It is not clear which drug or drugs caused his death or what quantities of vecuronium bromide and potassium chloride were released before the execution was cancelled.
Notable Incidents
The state of Florida used midazolam to execute William Frederick Happ in October 2013.
The state of Ohio used midazolam in the execution of Dennis McGuire in January 2014; it took McGuire 24 minutes to die after the procedure started, and he gasped and appeared to be choking during that time, leading to questions about the dosing and timing of the drug administration, as well as the choice of drugs.
The execution of Ronald Bert Smith in the state of Alabama on 08 December 2016, “went awry soon after (midazolam) was administered” again putting the effectiveness of the drug in question.
In October 2016, the state of Ohio announced that it would resume executions in January 2017, using a formulation of midazolam, vecuronium bromide, potassium chloride, but this was blocked by a Federal judge. On 26 July 2017, Ronald Phillips was executed with a three-drug cocktail including midazolam after the Supreme Court refused to grant a stay.[86] Prior to this, the last execution in Ohio had been that of Dennis McGuire. Murderer Gary Otte’s lawyers unsuccessfully challenged his Ohio execution, arguing that midazolam might not protect him from serious pain when the other drugs are administered. He died without incident in about 14 minutes on 13 September 2017.
On 24 April 2017, the state of Arkansas carried out a double-execution of Jack Harold Jones, 52, and Marcel Williams, 46. The state of Arkansas attempted to execute eight people before its supply of midazolam expired on 30 April 2017. Two of them were granted a stay of execution, and another, Ledell T. Lee, 51, was executed on 20 April 2017.
Legal Challenges
In Glossip v. Gross, attorneys for three Oklahoma inmates argued that midazolam could not achieve the level of unconsciousness required for surgery, meaning severe pain and suffering was likely. They argued that midazolam was cruel and unusual punishment and thus contrary to the Eighth Amendment to the United States Constitution. In June 2015, the US Supreme Court ruled that they had failed to prove that midazolam was cruel and unusual when compared to known, available alternatives.
The state of Nevada is also known to use midazolam in execution procedures. In July 2018, one of the manufacturers accused state officials of obtaining the medication under false pretences. This incident was the first time a drug company successfully, though temporarily, halted an execution. A previous attempt in 2017, to halt an execution in the state of Arizona by another drug manufacturer was not successful.
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