|Systematic (IUPAC) name|
|Trade names||Diastat, Valium|
|Routes||Oral, IM, IV, suppository|
|Metabolism||Hepatic – CYP2B6 (minor route) to desmethyldiazepam - CYP2C19 (major route) to inactive metabolites – CYP3A4 (major route) to desmethyldiazepam|
|Half-life||20–100 hours (36–200 hours for main active metabolite desmethyldiazepam)|
|Mol. mass||284.7 g/mol|
|(what is this?)|
It is commonly used to treat a wide range of conditions, including anxiety, panic attacks, insomnia, seizures (including status epilepticus), muscle spasms (such as in tetanus cases), restless legs syndrome, alcohol withdrawal, benzodiazepine withdrawal, opiate withdrawal syndrome and Ménière's disease. It may also be used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia (it may be used to hasten the onset of intravenous (IV) anesthesia while reducing dose requirements or as the sole agent when IV anesthesia is not available or is contraindicated).
It possesses anxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant, and amnestic properties. The pharmacological action of diazepam enhances the effect of the neurotransmitter GABA by binding to the benzodiazepine site on the GABAA receptor (via the constituent chlorine atom) leading to central nervous system depression.
Adverse effects of diazepam include anterograde amnesia (especially at higher doses) and sedation, as well as paradoxical effects such as excitement, rage, or worsening of seizures in epileptics. Benzodiazepines also can cause or worsen depression, particularly after extended periods of use. Long-term effects of benzodiazepines such as diazepam include tolerance, benzodiazepine dependence, and benzodiazepine withdrawal syndrome upon dose reduction. After cessation of benzodiazepines, cognitive deficits may persist for at least six months and longer than six months may be needed for recovery from some deficits. Diazepam also has physical dependence potential and can cause serious problems of physical dependence with long-term use. Compared to other benzodiazepines, though, physical withdrawal from diazepam following long-term use is usually far more mild due to its long elimination half-life. Diazepam is the drug of choice for treating benzodiazepine dependence, with its low potency, long duration of action, and availability of low-dose tablets, making it ideal for gradual dose reduction and the circumvention of withdrawal symptoms. Diazepam can also be used to treat depression, but newer drugs are generally favored as more effective.
Advantages of diazepam are a rapid onset of action and high efficacy rates, which are important for managing acute seizures, anxiety attacks, and panic attacks; benzodiazepines also have a relatively low toxicity in overdose. Diazepam is a core medicine in the World Health Organization's Essential Drugs List, which list minimum medical needs for a basic health-care system. Diazepam, first synthesized by Leo Sternbach, has been one of the most frequently prescribed medications in the world since its launch in 1963.
- 1 Medical uses
- 2 Contraindications
- 3 Adverse effects
- 4 Pharmacology
- 5 History
- 6 Society and culture
- 7 Veterinary uses
- 8 References
- 9 External links
Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol withdrawal. It is also used as a premedication for inducing sedation, anxiolysis, or amnesia before certain medical procedures (e.g., endoscopy).
Intravenous diazepam or lorazepam are first-line treatments for status epilepticus; However, lorazepam has advantages over diazepam, including a higher rate of terminating seizures and a more prolonged anticonvulsant effect. Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to its anticonvulsant effects usually develops within six to 12 months of treatment, effectively rendering it useless for that purpose. Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood-pressure control measures have failed. Benzodiazepines do not have any pain-relieving properties themselves, and are generally recommended to avoid in individuals with pain. However, benzodiazepines such as diazepam can be used for their muscle-relaxant properties to alleviate pain caused by muscle spasms and various dystonias, including blepharospasm. Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam. Baclofen or tizanidine is sometimes used as an alternative to diazepam.
The anticonvulsant effects of diazepam can help in the treatment of seizures due to a drug overdose or chemical toxicity as a result of exposure to sarin, VX, soman (or other organophosphate poisons; see #CANA), lindane, chloroquine, physostigmine, or pyrethroids. It is sometimes used intermittently for the prophylaxis of febrile seizures caused by high fever in children and children under five years of age. Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup of individuals with treatment-resistant epilepsy benefit from long-term benzodiazepines, and for such individuals, clorazepate has been recommended due to its slower onset of tolerance to the anticonvulsant effects.
Diazepam has a broad spectrum of indications (most of which are off-label), including:
- Treatment of anxiety, panic attacks, and states of agitation
- Treatment of neurovegetative symptoms associated with vertigo
- Treatment of the symptoms of alcohol, opiate, and benzodiazepine withdrawal
- Short-term treatment of insomnia
- Treatment of tetanus, together with other measures of intensive treatment
- Adjunctive treatment of spastic muscular paresis (paraplegia/tetraplegia) caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, or spinal cord injury (long-term treatment is coupled with other rehabilitative measures)
- Palliative treatment of stiff person syndrome
- Pre- or postoperative sedation, anxiolysis and/or amnesia (e.g., before endoscopic or surgical procedures)
- Treatment of complications with a hallucinogen crisis and stimulant overdoses and psychosis, such as LSD, cocaine, or methamphetamine
- Prophylactic treatment of oxygen toxicity during hyperbaric oxygen therapy
The United States military employs a specialized diazepam preparation known as Convulsive Antidote, Nerve Agent (CANA), which contains diazepam. One CANA kit is typically issued to service members, along with three Mark I NAAK kits, when operating in circumstances where chemical weapons in the form of nerve agents are considered a potential hazard. Both of these kits deliver drugs using autoinjectors. They are intended for use in "buddy aid" or "self aid" administration of the drugs in the field prior to decontamination and delivery of the patient to definitive medical care.
Use of diazepam should be avoided, when possible, in individuals with these conditions:
- Severe hypoventilation
- Acute narrow-angle glaucoma
- Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of two)
- Severe renal deficiencies (for example, patients on dialysis)
- Liver disorders
- Severe sleep apnea
- Severe depression, particularly when accompanied by suicidal tendencies
- Pregnancy or breast feeding
- Caution required in elderly or debilitated patients
- Coma or shock
- Abrupt discontinuation of therapy
- Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the exception of some hallucinogens and/or stimulants, where it is occasionally used as a treatment for overdose)
- History of alcohol or drug dependence
- Myasthenia gravis, an autoimmune disorder causing marked fatiguability
- Hypersensitivity or allergy to any drug in the benzodiazepine class
Special caution needed
- Benzodiazepine abuse and misuse should be checked if used in the alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders .
- Pediatric patients
- Less than 18 years of age, treatment is usually not indicated, except for treatment of epilepsy, and pre- or postoperative treatment. The smallest possible effective dose should be used for this group of patients.
- Under 6 months of age, safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.
- Elderly and very ill patients may possibly suffer apnea and/or cardiac arrest. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of patients. The elderly metabolise benzodiazepines much more slowly than younger adults, and are also more sensitive to the effects of benzodiazepines even at similar blood plasma levels. Doses of diazepam are recommended to be about half of those given to younger individuals, and treatment limited to a maximum of two weeks. Long-acting benzodiazepines such as diazepam are not recommended for the elderly. Diazepam may also be dangerous in geriatric patients owing to a significant increased risk of falls.
- Intravenous or intramuscular injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.
- Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes, so rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, may result in floppy infant syndrome. Diazepam when taken late in pregnancy, during the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.
Adverse effects of benzodiazepines such as diazepam include anterograde amnesia and confusion (especially pronounced in higher doses) and sedation. The elderly are more prone to adverse effects of diazepam, such as confusion, amnesia, ataxia, and hangover effects, as well as falls. Long-term use of benzodiazepines such as diazepam is associated with drug tolerance, benzodiazepine dependence, and benzodiazepine withdrawal syndrome. Like other benzodiazepines, diazepam can impair short-term memory and learning of new information. While benzodiazepine drugs such as diazepam can cause anterograde amnesia, they do not cause retrograde amnesia; information learned before using benzodiazepines is not impaired. Tolerance to the cognitive-impairing effects of benzodiazepines does not tend to develop with long-term use, and the elderly are more sensitive to them. Additionally, after cessation of benzodiazepines, cognitive deficits may persist for at least six months; it is unclear whether these impairments take longer than six months to abate or if they are permanent. Benzodiazepines may also cause or worsen depression. Infusions or repeated intravenous injections of diazepam when managing seizures, for example, may lead to drug toxicity, including respiratory depression, sedation and hypotension. Drug tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours. Adverse effects such as sedation, benzodiazepine dependence, and abuse potential limit the use of benzodiazepines.
Diazepam has a range of side effects common to most benzodiazepines, including:
- Suppression of REM sleep
- Impaired motor function
- Impaired coordination
- Impaired balance
- Reflex tachycardia
Less commonly, paradoxical side effects can occur, including nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in libido, and in some cases, rage and violence. These adverse reactions are more likely to occur in children, the elderly, and individuals with a history of drug or alcohol abuse and or aggression. Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts. Very rarely dystonia can occur.
Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.
During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.
Tolerance and dependence
Diazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, addiction, and benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms similar to those seen during barbiturate or alcohol withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms.
Withdrawal symptoms can occur from standard dosages and also after short-term use, and can range from insomnia and anxiety to more serious symptoms, including seizures and psychosis. Withdrawal symptoms can sometimes resemble pre-existing conditions and be misdiagnosed. Diazepam may produce less intense withdrawal symptoms due to its long elimination half-life.
Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen. Tolerance develops to the therapeutic effects of benzodiazepines; for example tolerance occurs to the anticonvulsant effects and as a result benzodiazepines are not generally recommended for the long-term management of epilepsy. Dose increases may overcome the effects of tolerance, but tolerance may then develop to the higher dose and adverse effects may increase. The mechanism of tolerance to benzodiazepines includes uncoupling of receptor sites, alterations in gene expression, down-regulation of receptor sites, and desensitisation of receptor sites to the effect of GABA. About one-third of individuals who take benzodiazepines for longer than four weeks become dependent and experience a withdrawal syndrome upon cessation.
Differences in rates of withdrawal (50–100%) vary depending on the patient sample. For example, a random sample of long-term benzodiazepine users typically finds around 50% experience few or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups show a higher rate of notable withdrawal symptoms, up to 100%.
Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines. Diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction. The risk of pharmacological dependence on diazepam is significant, and patients experience symptoms of benzodiazepine withdrawal syndrome if it is taken for six weeks or longer. In humans, tolerance to the anticonvulsant effects of diazepam occurs frequently.
- People with a history of alcohol or drug abuse or dependence Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers.
- People with severe personality disorders, such as borderline personality disorder
Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Therapy should be discontinued if any of these signs are noted, although if physical dependence has developed, therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in these people is not recommended.
People suspected of being physiologically dependent on benzodiazepine drugs should be very gradually tapered off the drug. Withdrawals can be life-threatening, particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether dependence has occurred in therapeutic or recreational contexts.
- Mental confusion
- Impaired motor functions
- Impaired reflexes
- Impaired coordination
- Impaired balance
Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug, and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary. Though not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated. Dialysis is minimally effective. Hypotension may be treated with levarterenol or metaraminol.
The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats. D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately deep comas, and were discharged within 48 hours without having experienced any important complications, in spite of having high concentrations of diazepam and its metabolites esmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up.
If diazepam is administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that potentiate the effects of diazepam, such as barbiturates, phenothiazines, narcotics, and antidepressants.
Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. No evidence would suggest diazepam alters its own metabolism with chronic administration.
Agents with an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable.
- Diazepam increases the central depressive effects of alcohol, other hypnotics/sedatives (e.g., barbiturates), narcotics, other muscle relaxants, certain antidepressants, sedative antihistamines, opiates, and antipsychotics, as well as anticonvulsants such as phenobarbital, phenytoin, and carbamazepine. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.
- Cimetidine, omeprazole, oxcarbazepine, ticlopidine, topiramate, ketoconazole, itraconazole, disulfiram, fluvoxamine, isoniazid, erythromycin, probenecid, propranolol, imipramine, ciprofloxacin, fluoxetine, and valproic acid prolong the action of diazepam by inhibiting its elimination.
- Alcohol (ethanol]) in combination with diazepam may cause a synergistic enhancement of the hypotensive properties of benzodiazepines and alcohol.
- Oral contraceptives significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.
- Rifampin, phenytoin, carbamazepine, and phenobarbital increase the metabolism of diazepam, thus decreasing drug levels and effects. Dexamethasone and St John's wort also increase the metabolism of diazepam.
- Diazepam increases the serum levels of phenobarbital.
- Nefazodone can cause increased blood levels of benzodiazepines.
- Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.
- Small doses of theophylline may inhibit the action of diazepam.
- Diazepam may block the action of levodopa (used in the treatment of Parkinson's disease).
- Diazepam may alter digoxin serum concentrations.
- Other drugs that may have interactions with diazepam include antipsychotics (e.g. chlorpromazine), MAO inhibitors, and ranitidine.
- Because it acts on the GABA receptor, the herb valerian may produce an adverse effect.
- Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.
- Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.
- Reports conflict as to whether food in general has any effects on the absorption and activity of orally administered diazepam.
Diazepam is a long-acting "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, flurazepam, bromazepam, and clorazepate. Diazepam has anticonvulsant properties. Diazepam has no effect on GABA levels and no effect on glutamate decarboxylase activity, but has a slight effect on gamma-aminobutyric acid transaminase activity. It differs from some other anticonvulsive drugs with which it was compared. Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations.
Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. This has been found by measuring sodium-dependent high-affinity choline uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo. This may play a role in explaining diazepam's anticonvulsant properties.
Diazepam binds with high affinity to glial cells in animal cell cultures. Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex. Diazepam also decreases prolactin release in rats.
Mechanism of action
Benzodiazepines are positive allosteric modulators of the GABA type A receptors (GABAA). The GABAA receptors are ligand-gated chloride-selective ion channels that are activated by GABA, the major inhibitory neurotransmitter in the brain. Binding of benzodiazepines to this receptor complex promotes binding of GABA, which in turn increases the total conduction of chloride ions across the neuronal cell membrane. This increased chloride ion influx hyperpolarizes the neuron's membrane potential. As a result, the difference between resting potential and threshold potential is increased and firing is less likely.
The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). GABAA receptors containing the α1 subunit mediate the sedative, the anterograde amnesic, and partly the anticonvulsive effects of diazepam. GABAA receptors containing α2 mediate the anxiolytic actions and to a large degree the myorelaxant effects. GABAA receptors containing α3 and α5 also contribute to benzodiazepines myorelaxant actions, whereas GABAA receptors comprising the α5 subunit were shown to modulate the temporal and spatial memory effects of benzodiazepines.
Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.
The anticonvulsant properties of diazepam 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 limited by benzodiazepines' effect of slowing recovery of sodium channels from inactivation.
When administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is one to five minutes for IV administration and 15–30 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to one hour for both routes of administration. The bioavailability after oral administration is 100%, and 90% after rectal administration. Peak plasma levels occur between 30 and 90 minutes after oral administration and between 30 and 60 minutes after intramuscular administration; after rectal administration, peak plasma levels occur after 10 to 45 minutes. Diazepam is highly protein-bound, with 96 to 99% of the absorbed drug being protein-bound. The distribution half-life of diazepam is two to 13 minutes.
When diazepam is administered IM, absorption is slow, erratic, and incomplete.
Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood–brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam quickly build to a high concentration in the body (mainly in adipose tissue), far in excess of the actual dose for any given day.
Diazepam is stored preferentially in some organs, including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate, and withdrawal of diazepam during pregnancy and breast feeding is clinically justified.
Diazepam undergoes oxidative metabolism by demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19) and glucuronidation in the liver as part of the cytochrome P450 enzyme system. It has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Its other active metabolites include the minor active metabolites temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug. Diazepam has a biphasic half-life of about one to three days, and two to seven days for the active metabolite desmethyldiazepam. Most of the drug is metabolised; very little diazepam is excreted unchanged. The elimination half-life of diazepam and also the active metabolite desmethyldiazepam increases significantly in the elderly, which may result in prolonged action, as well as accumulation of the drug during repeated administration.
Detection in body fluids
Diazepam may be quantified in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma diazepam concentrations are usually in a range of 0.1–1.0 mg/l in persons receiving the drug therapeutically, 1–5 mg/l in those arrested for impaired driving, and 2–20 mg/l in victims of acute overdose. Most commercial immunoassays for the benzodiazepine class of drugs cross-react with diazepam, but confirmation and quantitation are usually performed using chromatographic techniques.
Diazepam occurs as solid white or yellow crystals with a melting point of 131.5 to 134.5°C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists it as being very slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 ethyl alcohol, 1 in 2 of chloroform, 1 in 39 ether, and practically insoluble in water. The pH of diazepam is neutral (i.e., pH = 7). Diazepam has a shelf life of five years for oral tablets and three years for IV/IM solutions. Diazepam should be stored at room temperature (15–30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.
Diazepam can absorb into plastics, so liquid preparations should not be kept in plastic bottles or syringes, etc. As such, it can leach into the plastic bags and tubing used for intravenous infusions. Absorption appears to depend on several factors, such as temperature, concentration, flow rates, and tube length. Diazepam should not be administered if a precipitate has formed and does not dissolve.
From a chemical point of view, diazepam, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, is the most simple of all of the examined derivatives of 1,4-benzodiazepin-2-ones. Various ways for the synthesis of diazepam from 2-amino-5-chlorobenzophenone have been proposed. The first two ways consist of the direct cyclocondensation of 2-amino-5-chlorobenzophenone or 2-methylamino-5-chlorobenzophenone with the ethyl ester of glycine hydrochloride. The amide nitrogen atom of the obtained 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, is methylated by dimethylsulfate, which leads to the formation of diazepam.
The second way differs from the first in that the methylation of nitrogen is accomplished before the cyclocondensation reaction. To do this, the initial 2-amino-5-chlorobenzophenone is first tosylated by p-toluenesulfonylchloride and the obtained tosylate transformed into the N-sodium salt, which is then alkylated by dimethylsulfate. The resulting 2-N-tosyl-N-methyl-5-chlorobenzophenone is hydrolyzed in an acidic medium, giving 2-methylamino-5-chlorobenzophenone, which undergoes cyclocondensation by reaction with ethyl ester of glycine hydrochloride, forming the desired diazepam.
Diazepam was the second benzodiazepine invented by Dr. Leo Sternbach of Hoffmann-La Roche at the company's Nutley, New Jersey, facility following chlordiazepoxide (Librium), which was approved for use in 1960. Released in 1963 as an improved version of Librium, diazepam became incredibly popular, helping Roche to become a pharmaceutical industry giant. It is 2.5 times more potent than its predecessor, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.
The benzodiazepines gained popularity among medical professionals as an improvement upon barbiturates, which have a comparatively narrow therapeutic index, and are far more sedative at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or other sedatives). Benzodiazepine drugs such as diazepam initially had widespread public support, but with time the view changed to one of growing criticism and calls for restrictions on their prescription.
Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets. Diazepam, along with oxazepam, nitrazepam and temazepam, represents 82% of the benzodiazepine market in Australia. While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, for example, forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome.
Society and culture
Diazepam is a drug of potential abuse and can cause serious problems of addiction and is regulated. Urgent action by national governments has been recommended to improve prescribing patterns of benzodiazepines such as diazepam. A single dose of diazepam modulates the dopamine system in similar ways to how morphine and alcohol modulate the dopaminergic pathways. Between 50 and 64% of rats will self-administer diazepam. Benzodiazepines including diazepam in animal studies have been shown to increase reward-seeking behaviours by increasing impulsivity, which may suggest an increased risk of addictive behavioural patterns with usage of diazepam or other benzodiazepines. In addition, diazepam has been shown to be able to substitute for the behavioural effects of barbiturates in a primate study. Diazepam has been found as an adulterant in heroin.
Diazepam drug misuse can occur either through recreational misuse where the drug is taken to achieve a high or when the drug is continued long term against medical advice.
Sometimes, it is used by stimulant users to "come down" and sleep and to help control the urge to binge.
A large-scale study in the US, conducted by SAMHSA, using data from 2011, determined benzodiazepines were present in 28.7% of emergency department visits involving nonmedical use of pharmaceuticals. In this regard, benzodiazepines are second only to opiates which were detected in 39.2% of visits. About 29.3% of drug-related suicide attempts involve benzodiazepines, making them the most frequently represented class in drug-related suicide attempts. Males abuse benzodiazepines as commonly as females.
Benzodiazepines, including diazepam, nitrazepam, and flunitrazepam, account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.
Diazepam was detected in 26% of cases of people suspected of driving under the influence of drugs in Sweden, and its active metabolite nordazepam was detected in 28% of cases. Other benzodiazepines and zolpidem and zopiclone also were found in high numbers. Many drivers had blood levels far exceeding the therapeutic dose range, suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone. In Northern Ireland in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found in 87% of cases. Diazepam was the most commonly detected benzodiazepine.
Diazepam is regulated in most countries as a prescription drug:
- International: diazepam is a schedule IV controlled drug under the Convention on Psychotropic Substances.
- UK: classified as a controlled drug, listed under Schedule IV, Part I (CD Benz POM) of the Misuse of Drugs Regulations 2001, allowing possession with a valid prescription. The Misuse of Drugs Act 1971 makes it illegal to possess the drug without a prescription, and for such purposes it is classified as a Class C drug.
- Germany: classified as a prescription drug, or in high dosage as a restricted drug (Betäubungsmittelgesetz, Anhang III).
- "Diazepam". PubChem. National Institute of Health: National Library of Medicine. 2006. Retrieved 2006-03-11.
- "Diazepam". Medical Subject Headings (MeSH). National Library of Medicine. 2006. Retrieved 2006-03-10.
- Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614.
- Riss J, Cloyd J, Gates J, Collins S (August 2008). "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics". Acta Neurologica Scandinavica 118 (2): 69–86. doi:10.1111/j.1600-0404.2008.01004.x. PMID 18384456.
- Ashton, R.L. "Benzodiazepine Withdrawal".
- Mehdi T (2012). "Benzodiazepines Revisited". British Journal of Medical Practitioners.
- "WHO Model List of Essential Medicines" (PDF). World Health Organization. March 2005. Retrieved 2006-03-12.
- Sternbach LH, Reeder E, Keller O, Metlesics W (1961). "Quinazolines and 1,4-benzodiazepines III substituted 2-amino-5-phenyl-3H-1,4-benzodiazepine 4-oxides". J. Org. Chem. 26 (11): 4488–4497. doi:10.1021/jo01069a069.
- "Drug Bank – Diazepam".[dead link]
- Bråthen G, Ben-Menachem E, Brodtkorb E, Galvin R, Garcia-Monco JC, Halasz P, Hillbom M, Leone MA, Young AB (August 2005). "EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force". European Journal of Neurology : The Official Journal of the European Federation of Neurological Societies 12 (8): 575–81. doi:10.1111/j.1468-1331.2005.01247.x. PMID 16053464.
- Walker M (September 2005). "Status epilepticus: an evidence based guide". BMJ (Clinical Research Ed.) 331 (7518): 673–7. doi:10.1136/bmj.331.7518.673. PMC 1226249. PMID 16179702.
- Prasad K, Al-Roomi K, Krishnan PR, Sequeira R (2005). "Anticonvulsant therapy for status epilepticus". The Cochrane Database of Systematic Reviews (4): CD003723. doi:10.1002/14651858.CD003723.pub2. PMID 16235337.
- Pere Munne (1998). M. Ruse, ed. "Diazepam". Inchem.org. Inchem.org. Retrieved 2006-03-11.
- Isojärvi JI, Tokola RA (December 1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability". Journal of Intellectual Disability Research : JIDR. 42 Suppl 1: 80–92. PMID 10030438.
- Kaplan PW (November 2004). "Neurologic aspects of eclampsia". Neurologic Clinics 22 (4): 841–61. doi:10.1016/j.ncl.2004.07.005. PMID 15474770.
- Duley L (February 2005). "Evidence and practice: the magnesium sulphate story". Best Practice & Research. Clinical Obstetrics & Gynaecology 19 (1): 57–74. doi:10.1016/j.bpobgyn.2004.10.010. PMID 15749066.
- Zeilhofer HU, Witschi R, Hösl K (May 2009). "Subtype-selective GABAA receptor mimetics—novel antihyperalgesic agents?". Journal of Molecular Medicine (Berlin, Germany) 87 (5): 465–9. doi:10.1007/s00109-009-0454-3. PMID 19259638.
- Mezaki T, Hayashi A, Nakase H, Hasegawa K (September 2005). "[Therapy of dystonia in Japan]". Rinshō Shinkeigaku = Clinical Neurology (in Japanese) 45 (9): 634–42. PMID 16248394.
- Kachi T (December 2001). "[Medical treatment of dystonia]". Rinshō Shinkeigaku = Clinical Neurology (in Japanese) 41 (12): 1181–2. PMID 12235832.
- Ashton H (2005). "The diagnosis and management of benzodiazepine dependence" (PDF). Current Opinion in Psychiatry 18 (3): 249–55. doi:10.1097/01.yco.0000165594.60434.84. PMID 16639148.
- Mañon-Espaillat R, Mandel S (1999). "Diagnostic algorithms for neuromuscular diseases". Clinics in Podiatric Medicine and Surgery 16 (1): 67–79. PMID 9929772.
- Bajgar J (2004). "Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment". Advances in Clinical Chemistry. Advances in Clinical Chemistry 38: 151–216. doi:10.1016/S0065-2423(04)38006-6. ISBN 978-0-12-010338-6. PMID 15521192.
- Karande S (March 2007). "Febrile seizures: a review for family physicians". Indian Journal of Medical Sciences 61 (3): 161–72. doi:10.4103/0019-5359.30753. PMID 17337819.
- Cesarani A, Alpini D, Monti B, Raponi G (March 2004). "The treatment of acute vertigo". Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 25 Suppl 1: S26–30. doi:10.1007/s10072-004-0213-8. PMID 15045617.
- Lader M, Tylee A, Donoghue J (2009). "Withdrawing benzodiazepines in primary care". CNS Drugs 23 (1): 19–34. doi:10.2165/0023210-200923010-00002. PMID 19062773.
- Okoromah CN, Lesi FE (2004). Okoromah, Christy AN, ed. "Diazepam for treating tetanus". The Cochrane Database of Systematic Reviews (1): CD003954. doi:10.1002/14651858.CD003954.pub2. PMID 14974046.
- "Diazepam: indications". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-11.
- Thomson Healthcare (Micromedex) (March 2000). "Diazepam". Prescription Drug Information. Drugs.com. Retrieved 2006-03-11.
- Eric P.; Whelan, Harry T., eds. (1999). Hyperbaric Medicine Practice, Second Edition. Best Publishing Company. ISBN 0-941332-78-0.
|last1=in Authors list (help)
- "International AED Database". ILAE. Retrieved 2009-09-16.
- Mikota, Susan K. and Plumb, Donald C. (2005). "Diazepam". The Elephant Formulary. Elephant Care International.
- Pharmaceutical Patents. http://www.pharmcast.com/Patents100/Yr2004/Oct2004/101904/6805853_Diazepam101904.htm
- U.S. Army Medical Research Institute of Chemical Defense, Medical Management of Chemical Casualties Handbook, Third Edition (June 2000), Aberdeen Proving Ground, MD, pp. 118–126.
- Epocrates. "Diazepam Contraindications and Cautions". US: Epocrates Online. Retrieved 16 December 2008.
- Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Annales Pharmaceutiques Françaises 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.
- "Diazepam". PDRHealth.com. PDRHealth.com. 2006. Archived from the original on 2006-01-17. Retrieved 2006-03-10.
- "Diazepam: precautions". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-10.
- Shats V, Kozacov S (June 1995). "[Falls in the geriatric department: responsibility of the care-giver and the hospital]". Harefuah (in Hebrew) 128 (11): 690–3, 743. PMID 7557666.
- Kanto JH (May 1982). "Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations". Drugs 23 (5): 354–80. doi:10.2165/00003495-198223050-00002. PMID 6124415.
- McElhatton PR (1994). "The effects of benzodiazepine use during pregnancy and lactation". Reproductive Toxicology (Elmsford, N.Y.) 8 (6): 461–75. doi:10.1016/0890-6238(94)90029-9. PMID 7881198.
- Yudofsky SC, Hales RE (1 December 2007). The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences, Fifth Edition (American Psychiatric Press Textbook of Neuropsychiatry). US: American Psychiatric Publishing, Inc. pp. 583–584. ISBN 978-1-58562-239-9.
- Whiting PJ (February 2006). "GABA-A receptors: a viable target for novel anxiolytics?". Current Opinion in Pharmacology 6 (1): 24–9. doi:10.1016/j.coph.2005.08.005. PMID 16359919.
- Kay DW, Fahy T, Garside RF (December 1970). "A seven-month double-blind trial of amitriptyline and diazepam in ECT-treated depressed patients". The British Journal of Psychiatry : The Journal of Mental Science 117 (541): 667–71. doi:10.1192/bjp.117.541.667. PMID 4923720.
- Langsam, Yedidyah. "DIAZEPAM (VALIUM AND OTHERS)". Brooklyn College (Eilat.sci.Brooklyn.CUNY.edu). Retrieved 2006-03-23.
- Marrosu F, Marrosu G, Rachel MG, Biggio G (1987). "Paradoxical reactions elicited by diazepam in children with classic autism". Functional Neurology 2 (3): 355–61. PMID 2826308.
- "Diazepam: Side Effects". RxList.com. Retrieved September 26, 2006.
- Michel L, Lang JP (2003). "[Benzodiazepines and forensic aspects]". L'Encéphale (in French) 29 (6): 479–85. PMID 15029082.
- Berman ME, Jones GD, McCloskey MS (February 2005). "The effects of diazepam on human self-aggressive behavior". Psychopharmacology 178 (1): 100–6. doi:10.1007/s00213-004-1966-8. PMID 15316710.
- Pérez Trullen JM, Modrego Pardo PJ, Vázquez André M, López Lozano JJ (1992). "Bromazepam-induced dystonia". Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie 46 (8): 375–6. doi:10.1016/0753-3322(92)90306-R. PMID 1292648.
- Hriscu A, Gherase F, Năstasă V, Hriscu E (October–December 2002). "[An experimental study of tolerance to benzodiazepines]". Revista Medico-Chirurgicală̆ a Societă̆ţ̜ii De Medici ş̧i Naturaliş̧ti Din Iaş̧i 106 (4): 806–811. PMID 14974234.
- Kozená L, Frantik E, Horváth M (May 1995). "Vigilance impairment after a single dose of benzodiazepines". Psychopharmacology 119 (1): 39–45. doi:10.1007/BF02246052. PMID 7675948.
- MacKinnon GL, Parker WA (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation". The American Journal of Drug and Alcohol Abuse 9 (1): 19–33. doi:10.3109/00952998209002608. PMID 6133446.
- Onyett SR (April 1989). "The benzodiazepine withdrawal syndrome and its management". The Journal of the Royal College of General Practitioners 39 (321): 160–3. PMC 1711840. PMID 2576073.
- Chouinard G, Labonte A, Fontaine R, Annable L (1983). "New concepts in benzodiazepine therapy: rebound anxiety and new indications for the more potent benzodiazepines". Progress in Neuro-Psychopharmacology & Biological Psychiatry 7 (4–6): 669–73. doi:10.1016/0278-5846(83)90043-X. PMID 6141609.
- Lader M (December 1987). "Long-term anxiolytic therapy: the issue of drug withdrawal". The Journal of Clinical Psychiatry 48: 12–6. PMID 2891684.
- Murphy SM, Owen R, Tyrer P (1989). "Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks' treatment with diazepam or buspirone". The British Journal of Psychiatry : The Journal of Mental Science 154 (4): 529–34. doi:10.1192/bjp.154.4.529. PMID 2686797.
- Loiseau P (1983). "[Benzodiazepines in the treatment of epilepsy]". L'Encéphale 9 (4 Suppl 2): 287B–292B. PMID 6373234.
- "Treating Anxiety – Avoiding Dependence on Xanax, Klonopin, Valium, and Other Antianxiety Drugs". johnshopkinshealthalerts.com. Johnshopkinshealthalerts.com. 2005. Retrieved 2007-12-23.
- "Diazepam: abuse and dependence". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-10.
- Poulos CX, Zack M (November 2004). "Low-dose diazepam primes motivation for alcohol and alcohol-related semantic networks in problem drinkers". Behavioural Pharmacology 15 (7): 503–12. doi:10.1097/00008877-200411000-00006. PMID 15472572.
- Vorma H, Naukkarinen HH, Sarna SJ, Kuoppasalmi KI (2005). "Predictors of benzodiazepine discontinuation in subjects manifesting complicated dependence". Substance Use & Misuse 40 (4): 499–510. doi:10.1081/JA-200052433. PMID 15830732.
- "Diazepam: overdose". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-10.
- Barondes SH (2003). Better Than Prozac. New York: Oxford University Press. pp. 47–59. ISBN 0-19-515130-5.
- Greenblatt DJ, Woo E, Allen MD, Orsulak PJ, Shader RI (October 1978). "Rapid recovery from massive diazepam overdose". JAMA : The Journal of the American Medical Association 240 (17): 1872–4. doi:10.1001/jama.240.17.1872. PMID 357765.
- Lai SH, Yao YJ, Lo DS (October 2006). "A survey of buprenorphine related deaths in Singapore". Forensic Science International 162 (1–3): 80–6. doi:10.1016/j.forsciint.2006.03.037. PMID 16879940.
- Holt, Gary A. (1998). Food and Drug Interactions: A Guide for Consumers. Chicago: Precept Press. pp. 90–91. ISBN 0-944496-59-8.
- Zácková P, Kvĕtina J, Nĕmec J, Nĕmcová J (December 1982). "Cardiovascular effects of diazepam and nitrazepam in combination with ethanol". Die Pharmazie 37 (12): 853–6. PMID 7163374.
- Back DJ, Orme ML (June 1990). "Pharmacokinetic drug interactions with oral contraceptives". Clinical Pharmacokinetics 18 (6): 472–84. doi:10.2165/00003088-199018060-00004. PMID 2191822.
- Bendarzewska-Nawrocka B, Pietruszewska E, Stepień L, Bidziński J, Bacia T (January–February 1980). "[Relationship between blood serum luminal and diphenylhydantoin level and the results of treatment and other clinical data in drug-resistant epilepsy]". Neurologia I Neurochirurgia Polska 14 (1): 39–45. PMID 7374896.
- Bateman DN (1986). "The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam". European Journal of Clinical Pharmacology 30 (2): 205–8. doi:10.1007/BF00614304. PMID 3709647.
- Mattila MJ, Nuotto E (1983). "Caffeine and theophylline counteract diazepam effects in man". Medical Biology 61 (6): 337–43. PMID 6374311.
- Possible Interactions with: Valerian, University of Maryland Medical Center, http://www.umm.edu/altmed/articles/valerian-000934.htm
- Braestrup C, Squires RF (1 April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". European Journal of Pharmacology 48 (3): 263–70. doi:10.1016/0014-2999(78)90085-7. PMID 639854.
- Chweh AY, Swinyard EA, Wolf HH, Kupferberg HJ (February 25, 1985). "Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines". Life Sciences 36 (8): 737–44. doi:10.1016/0024-3205(85)90193-6. PMID 2983169.
- Battistin L, Varotto M, Berlese G, Roman G (February 1984). "Effects of some anticonvulsant drugs on brain GABA level and GAD and GABA-T activities". Neurochemical Research 9 (2): 225–31. doi:10.1007/BF00964170. PMID 6429560.
- Taft WC, DeLorenzo RJ (May 1984). "Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations" (PDF). Proceedings of the National Academy of Sciences of the United States of America (PDF) 81 (10): 3118–22. doi:10.1073/pnas.81.10.3118. PMC 345232. PMID 6328498.
- Miller JA, Richter JA (January 1985). "Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes". British Journal of Pharmacology 84 (1): 19–25. PMC 1987204. PMID 3978310.
- Gallager DW, Mallorga P, Oertel W, Henneberry R, Tallman J (February 1981). "[3H]Diazepam binding in mammalian central nervous system: a pharmacological characterization". The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 1 (2): 218–25. PMID 6267221.
- Oishi R, Nishibori M, Itoh Y, Saeki K (May 27, 1986). "Diazepam-induced decrease in histamine turnover in mouse brain". European Journal of Pharmacology 124 (3): 337–42. doi:10.1016/0014-2999(86)90236-0. PMID 3089825.
- Grandison L (1982). "Suppression of prolactin secretion by benzodiazepines in vivo". Neuroendocrinology 34 (5): 369–73. doi:10.1159/000123330. PMID 6979001.
- Zakusov VV, Ostrovskaya RU, Kozhechkin SN, Markovich VV, Molodavkin GM, Voronina TA (October 1977). "Further evidence for GABA-ergic mechanisms in the action of benzodiazepines". Archives Internationales De Pharmacodynamie Et De Thérapie 229 (2): 313–26. PMID 23084.
- McLean MJ, Macdonald RL (February 1988). "Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture". The Journal of Pharmacology and Experimental Therapeutics 244 (2): 789–95. PMID 2450203.
- Date SK, Hemavathi KG, Gulati OD (November 1984). "Investigation of the muscle relaxant activity of nitrazepam". Archives Internationales De Pharmacodynamie Et De Thérapie 272 (1): 129–39. PMID 6517646.
- Olive G, Dreux C (January 1977). "Pharmacologic bases of use of benzodiazepines in peréinatal medicine". Archives Françaises De Pédiatrie 34 (1): 74–89. PMID 851373.
- Vozeh S (November 21, 1981). "[Pharmacokinetic of benzodiazepines in old age]". Schweizerische Medizinische Wochenschrift 111 (47): 1789–93. PMID 6118950.
- Jones AW, Holmgren A, Kugelberg FC (April 2007). "Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results". Therapeutic Drug Monitoring 29 (2): 248–60. doi:10.1097/FTD.0b013e31803d3c04. PMID 17417081.
- Fraser AD, Bryan W (1991). "Evaluation of the Abbott ADx and TDx serum benzodiazepine immunoassays for analysis of alprazolam". Journal of Analytical Toxicology 15 (2): 63–5. doi:10.1093/jat/15.2.63. PMID 1675703.
- Baselt R (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 471–473. ISBN 978-0-9626523-8-7.
- Sternbach, L. H.; Reeder, E. (1961). "Quinazolines and 1,4-Benzodiazepines. IV.1,2 Transformations of 7-Chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-Oxide3". The Journal of Organic Chemistry 26 (12): 4936–4941. doi:10.1021/jo01070a038.
- K.B. Nutley, L.H. Sternbach, U.S. Patent 3,109,843 (1963).
- E. Reeder, L.H. Sternbach, U.S. Patent 3,371,085 (1968).
- Gates, M. (1980). "New synthesis of diazepam". The Journal of Organic Chemistry 45 (9): 1675–1681. doi:10.1021/jo01297a030.
- Ishikura, M. .; Mori, M. .; Ikeda, T. .; Terashima, M. .; Ban, Y. . (1982). "New synthesis of diazepam and the related 1,4-benzodiazepines by means of palladium-catalyzed carbonylation". The Journal of Organic Chemistry 47 (12): 2456–2461. doi:10.1021/jo00133a042.
- Pollack, Andrew (June 26, 2012). "Roche to Shut Former U.S. Headquarters". New York Times. Retrieved January 10, 2014.
- Sample I (October 3, 2005). "Leo Sternbach's Obituary". The Guardian (Guardian Unlimited). Retrieved 2006-03-10.
- Marshall KP, Georgievskava Z, Georgievsky I (June 2009). "Social reactions to Valium and Prozac: a cultural lag perspective of drug diffusion and adoption". Research in Social & Administrative Pharmacy : RSAP 5 (2): 94–107. doi:10.1016/j.sapharm.2008.06.005. PMID 19524858.
- Mant A, Whicker SD, McManus P, Birkett DJ, Edmonds D, Dumbrell D (December 1993). "Benzodiazepine utilisation in Australia: report from a new pharmacoepidemiological database". Australian Journal of Public Health 17 (4): 345–9. doi:10.1111/j.1753-6405.1993.tb00167.x. PMID 7911332.
- Atack JR (May 2005). "The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics". Expert Opinion on Investigational Drugs 14 (5): 601–18. doi:10.1517/135437188.8.131.521. PMID 15926867.
- Dièye AM, Sylla M, Ndiaye A, Ndiaye M, Sy GY, Faye B (June 2006). "Benzodiazepines prescription in Dakar: a study about prescribing habits and knowledge in general practitioners, neurologists and psychiatrists". Fundamental & Clinical Pharmacology 20 (3): 235–8. doi:10.1111/j.1472-8206.2006.00400.x. PMID 16671957.
- "New Evidence on Addiction To Medicines Diazepam Has Effect on Nerve Cells in the Brain Reward System". Medical News Today. August 2008. Retrieved September 25, 2008.
- Yoshimura K, Horiuchi M, Inoue Y, Yamamoto K (January 1984). "[Pharmacological studies on drug dependence. (III): Intravenous self-administration of some CNS-affecting drugs and a new sleep-inducer, 1H-1, 2, 4-triazolyl benzophenone derivative (450191-S), in rats]". Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica 83 (1): 39–67. doi:10.1254/fpj.83.39. PMID 6538866.
- Thiébot MH, Le Bihan C, Soubrié P, Simon P (1985). "Benzodiazepines reduce the tolerance to reward delay in rats". Psychopharmacology 86 (1–2): 147–52. doi:10.1007/BF00431700. PMID 2862657.
- Woolverton WL, Nader MA (December 1995). "Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline". Psychopharmacology 122 (3): 230–6. doi:10.1007/BF02246544. PMID 8748392.
- "Chapter II. operation of the international drug control system – B. Psychotropic substances – 10. Survey on the use of psychotropic substances as heroin adulterants". "Report of the International Narcotics Control Board for 1996". United Nations. International Narcotics Control Board. 1996. p. 27. Retrieved January 10, 2014. "Phenobarbital was identified as the psychotropic substance most frequently used as an adulterant in seized heroin; it was followed by diazepam and flunitrazepam."
- Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". The Journal of Clinical Psychiatry. 66 Suppl 9: 31–41. PMID 16336040.
- Overclocker. "Methamphetamine and Benzodiazepines: Methamphetamine & Benzodiazepines". Erowid Experience Vaults. Retrieved September 26, 2006.
- United States Government; U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (2011). "Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits". Substance Abuse and Mental Health Services Administration. Archived from the original on 31 March 2008. Retrieved 20 Apr 2014.
- Bergman U, Dahl-Puustinen ML (1989). "Use of prescription forgeries in a drug abuse surveillance network". European Journal of Clinical Pharmacology 36 (6): 621–3. doi:10.1007/BF00637747. PMID 2776820.
- Jones AW, Holmgren A, Kugelberg FC (April 2007). "Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results". Therapeutic Drug Monitoring 29 (2): 248–60. doi:10.1097/FTD.0b013e31803d3c04. PMID 17417081.
- Cosbey SH (December 1986). "Drugs and the impaired driver in Northern Ireland: an analytical survey". Forensic Science International 32 (4): 245–58. doi:10.1016/0379-0738(86)90201-X. PMID 3804143.
- International Narcotics Control Board (2003). "List of psychotropic substances under international control" (PDF). Green list. Retrieved 2006-03-11.[dead link]
- "List of Controlled Drugs".
- "Anlage III (zu § 1 Abs. 1) verkehrsfähige und verschreibungsfähige Betäubungsmittel". Betäubungsmittelgesetz. 2001. Retrieved 2010-01-05.
- San Quentin State Prison Operational Procedure 0–770, Execution By Lethal Injection (pp. 44 & 92). Accessed January 10, 2014.
- "Execution by lethal injection procedures". Florida Department of Corrections. 9 September 2013. Retrieved 25 August 2014.
- "Drugs Affecting Appetite (Monogastric)". The Merck Veterinary Manual. Retrieved 2014-01-04.
- Rahminiwati M, Nishimura M (April 1999). "Effects of delta 9-tetrahydrocannabinol and diazepam on feeding behavior in mice". The Journal of Veterinary Medical Science / the Japanese Society of Veterinary Science 61 (4): 351–5. doi:10.1292/jvms.61.351. PMID 10342284.
- Linda Shell (March 2012). "Anticonvulsants Used to Stop Ongoing Seizure Activity". Retrieved 10 January 2014. "Dogs and Cats:
A variety of drugs can be used to stop seizures in dogs and cats.
Diazepam is the most common benzodiazepine used in dogs and cats to reduce motor activity and permit placement of an IV catheter."
- Hines, Ron DVM PhD (2006-01-14). "Epilepsy in Your Dog Or Cat". Second Chance Sanctuary Pet Health Center. Retrieved May 18, 2006.
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