Diazepam Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:443634166
Width:200
Tradename:Valium, others
Dailymedid:Diazepam
Pregnancy Au:C
Dependency Liability:High[1]
Addiction Liability:Moderate[2] [3]
Routes Of Administration:oral, intramuscular, intravenous, rectal, nasal,[4] buccal film
Class:Benzodiazepine
Atc Prefix:N05
Atc Suffix:BA01
Legal Au:S4
Legal Au Comment:[5]
Legal Br:B1
Legal Ca:Schedule IV
Legal De:Rx-only/Anlage III
Legal Nz:Class C
Legal Uk:POM
Legal Uk Comment:[6]
Legal Us:Schedule IV
Legal Us Comment:[7]
Legal Un:Psychotropic schedule IV
Legal Status:Rx-only
Legal Status:SE: Förteckning IV -->
Bioavailability:76% (64–97%) oral, 81% (62–98%) rectal[8]
Metabolism:Liver – CYP2B6 (minor route) to desmethyldiazepam, CYP2C19 (major route) to inactive metabolites, CYP3A4 (major route) to temazepam
Metabolites:
Elimination Half-Life:; (for main active metabolite desmethyldiazepam)[10]
Excretion:Kidney
Cas Number:439-14-5
Pubchem:3016
Iuphar Ligand:3364
Drugbank:DB00829
Chemspiderid:2908
Unii:Q3JTX2Q7TU
Kegg:D00293
Chebi:49575
Chembl:12
Iupac Name:7-Chloro-1,3-dihydro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one
C:16
H:13
Cl:1
N:2
O:1
Smiles:c1ccccc1C2=NCC(=O)N(C)c3ccc(Cl)cc23
Stdinchi:1S/C16H13ClN2O/c1-19-14-8-7-12(17)9-13(14)16(18-10-15(19)20)11-5-3-2-4-6-11/h2-9H,10H2,1H3
Stdinchikey:AAOVKJBEBIDNHE-UHFFFAOYSA-N

Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken orally (by mouth), as a suppository inserted into the rectum, intramuscularly (injected into muscle), intravenously (injection into a vein) or used as a nasal spray.[4] When injected intravenously, effects begin in one to five minutes and last up to an hour.[11] When taken by mouth, effects begin after 15 to 60 minutes.[12]

Common side effects include sleepiness and trouble with coordination.[13] Serious side effects are rare. They include increased risk of suicide, decreased breathing, and an increased risk of seizures if used too frequently in those with epilepsy.[14] Occasionally, excitement or agitation may occur.[15] [16] Long-term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction. Abrupt stopping after long-term use can be potentially dangerous. After stopping, cognitive problems may persist for six months or longer. It is not recommended during pregnancy or breastfeeding. Its mechanism of action works by increasing the effect of the neurotransmitter gamma-aminobutyric acid (GABA).

Diazepam was patented in 1959 by Hoffmann-La Roche.[17] [18] It has been one of the most frequently prescribed medications in the world since its launch in 1963. In the United States it was the best-selling medication between 1968 and 1982, selling more than 2billion tablets in 1978 alone. In 2021, it was the 149th most commonly prescribed medication in the United States, with more than 3million prescriptions.[19] [20] In 1985, the patent ended, and there are more than 500 brands available on the market.[21] It is on the World Health Organization's List of Essential Medicines.[22]

Structure, physical and chemical properties

Diazepam does not possess any chiral centers in its structure, but it does have two conformers. The two conformers mentioned were the 'P'-conformer and 'M'-conformer. Diazepam is an equimolar mixture and it was shown through CD spectra in serum protein solutions, that the 'P'-conformer is preferred by α1-acid glycoprotein binding.

The drug diazepam occurs as a pale yellow-white crystalline powder without distinctive smell and has a low molecular weight (MW = 284,74 g/mol). This classic aryl 1,4-benzodiazepine possesses three acceptors and no hydrogen bond donors. Diazepam is moderately lipophilic with LogP (Octanol-Water Partition Coefficient) value of 2,82 and hydrophilic with a TPSA (Topological Polar Surface Area) value of 32.7 Ų.[23] The LogP value indicates that diazepam has a tendency to dissolve more readily in lipid-based environments, such as chloroform, acetone, ethanol and ether, compared to water. While the TPSA value implies that a segment of the molecule exhibits a degree of polarity or hydrophilicity and represents the collective surface area of polar atoms, like oxygen or nitrogen, along with their connected hydrogen atoms. A TPSA value of 32,7 Ų signifies a moderate level of polarity within the compound. TPSA is especially useful in medical chemistry as it shows the ability of a molecule to permeate cells. Molecules with PSA value smaller than 60-70 Ų has a better ability to permeate cells.[24] The balance between its lipophilic and hydrophilic characteristics can impact various aspects of the molecule’s behavior, including its solubility, absorption, distribution, metabolism, and potential interactions within the biological system.

Diazepam is overall a stable molecule. 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). Due to additives such as benzoic acid/benzoate in the injectable form.[25] 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.[26]

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.

Medical uses

Diazepam is mainly used to treat anxiety, insomnia, panic attacks 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).[27] [28] In 2020, it was approved for use in the United States as a nasal spray to interrupt seizure activity in people with epilepsy.[4] [29] Diazepam is the most commonly used benzodiazepine for "tapering" benzodiazepine dependence due to the drug's comparatively long half-life, allowing for more efficient dose reduction. Benzodiazepines have a relatively low toxicity in overdose.

Diazepam has a number of uses, including:

Used in treatment of organophosphate poisoning and reduces the risk of seizure induced brain and cardiac damage.

Dosages should be determined on an individual basis, depending on the condition being treated, severity of symptoms, patient body weight, and any other conditions the person may have.

Seizures

Intravenous diazepam or lorazepam are first-line treatments for status epilepticus.[15] [36] However, intravenous lorazepam has advantages over intravenous diazepam, including a higher rate of terminating seizures and a more prolonged anticonvulsant effect. Diazepam gel was better than placebo gel in reducing the risk of non-cessation of seizures.[37] Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to its anticonvulsant effects usually develops within six to twelve months of treatment, effectively rendering it useless for that purpose.[38]

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, or soman (or other organophosphate poisons), lindane, chloroquine, physostigmine, or pyrethroids.[39]

Diazepam is sometimes used intermittently for the prevention of febrile seizures that may occur in children under five years of age. Recurrence rates are reduced, but side effects are common so the decision to treat febrile seizures (which are benign in nature) with medication should use this as part of the evaluation.[40] 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.

Alcohol withdrawal

Because of its relatively long duration of action, and evidence of safety and efficacy, diazepam is preferred over other benzodiazepines for treatment of persons experiencing moderate to severe alcohol withdrawal.[41] An exception to this is when a medication is required intramuscular in which case either lorazepam or midazolam is recommended.[41]

Other

Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood-pressure control measures have failed.[42] [43] Benzodiazepines do not have any pain-relieving properties themselves, and are generally recommended to avoid in individuals with pain.[44] 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.[45] [46] Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam.[47] Baclofen is sometimes used as an alternative to diazepam.[48]

Availability

Diazepam is marketed in over 500 brands throughout the world.[49] It is supplied in oral, injectable, inhalation, and rectal forms.[50]

The United States military employs a specialized diazepam preparation known as Convulsive Antidote, Nerve Agent, 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.[51]

Contraindications

Use of diazepam should be avoided, when possible, in individuals with:[52]

Caution

Adverse effects

Benzodiazepines, such as diazepam, can cause anterograde amnesia, confusion, and sedation. The elderly are more prone to diazepam's confusion, amnesia, ataxia, hangover symptoms, and falls. Long-term use of benzodiazepines, such as diazepam, induces tolerance, dependency, and withdrawal syndrome. Like other benzodiazepines, diazepam impairs short-term memory and learning new information. Diazepam and other benzodiazepines can produce anterograde amnesia, but not retrograde amnesia. It means information learned before using benzodiazepines is not impaired. Short-term benzodiazepine use does not lead to tolerance, and the elderly are more sensitive to them.[59] Additionally, after stopping benzodiazepines, cognitive problems may last at least six months; it is unclear if these problems last for longer than six months or 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. Sedatives and sleeping pills, including diazepam, have been associated with an increased risk of death.[60]

In September 2020, the U.S. 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.[61]

Diazepam has a range of side effects common to most benzodiazepines, including:

Less commonly, paradoxical reactions 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 a substance use disorder, such as an alcohol use disorder, or a history of aggressive behavior.[62] [63] [64] In some people, diazepam may increase the propensity toward self-harming behavior and, in extreme cases, may provoke suicidal tendencies or acts.[65] Very rarely dystonia can occur.[66]

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.[67]

Patients with severe attacks of apnea during sleep may experience respiratory depression (hypoventilation), leading to respiratory arrest and death.[68]

Diazepam in doses of or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness.[69]

Tolerance and withdrawal

Diazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, substance use disorder, 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.[70]

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.[41]

Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen.[71] 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 withdrawal syndrome on 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%.[72]

Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines.[73] 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.[74] 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.[75] In humans, tolerance to the anticonvulsant effects of diazepam occurs frequently.[76]

Dependence

Improper or excessive use of diazepam can lead to dependence. At a particularly high risk for diazepam misuse, substance use disorder or dependence are:

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 dependence has developed, therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in such instances is not recommended.

People suspected of being 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.[80]

Diazepam is a good choice for tapering for those using high doses of other benzodiazepines since it has a long half-life thus withdrawal symptoms are tolerable.[81] The process is very slow (usually from 14 to 28 weeks) but is considered safe when done appropriately.[82]

Overdose

See main article: Benzodiazepine overdose. An individual who has consumed too much diazepam typically displays one or more of these symptoms in a period of approximately four hours immediately following a suspected overdose:[83]

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 (lethal dose in 50% of the population) of diazepam is in mice and in rats. D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken and 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 desmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up.[84]

Overdoses of diazepam with alcohol, opiates, or other depressants may be fatal.[85]

Interactions

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, opioids, 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.

Pharmacology

Diazepam is a long-acting "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, flurazepam, bromazepam, and clorazepate.[94] Diazepam has anticonvulsant properties.[95] Benzodiazepines act via micromolar benzodiazepine binding sites as calcium channel blockers and significantly inhibit depolarization-sensitive calcium uptake in rat nerve cell preparations.[96]

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.[97]

Diazepam binds with high affinity to glial cells in animal cell cultures.[98] Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex.[99] Diazepam also decreases prolactin release in rats.[100]

Mechanism of action

See also: Benzodiazepine.

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 the 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. As a result, the arousal of the cortical and limbic systems in the central nervous system is reduced.[101]

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.[102] Diazepam is not the only drug to target these GABAA receptors. Drugs such as flumazenil also bind to GABAA to induce their effects.[103]

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.[104]

The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than GABAA receptors. Sustained repetitive firing seems limited by benzodiazepines' effect of slowing recovery of sodium channels from inactivation.[105]

The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.[106]

Pharmacokinetics

Diazepam can be administered orally, intravenously (must be diluted, as it is painful and damaging to veins), intramuscularly (IM), or as a suppository.[107]

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.[108] The half-life of diazepam in general is 30–56 hours.[101] 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 plasma protein-bound, with 96–99% of the absorbed drug being protein-bound. The distribution half-life of diazepam is two to 13 minutes.

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.[109]

Diazepam undergoes oxidative metabolism by demethylation (CYP2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP3A4 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 metabolized; 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.[110]

Synthesis

The synthesis of Diazepam was first achieved through a reaction pathway developed by Leo Sternbach and his team at Hoffmann-La Roche in the late 1950s.

Sternbach's method commenced with 2-amino-5-chlorobenzophenone, which undergoes cyclocondensation with glycine ethyl ester hydrochloride to construct the benzodiazepine core. This core is subsequently alkylated at the nitrogen in the 1-position using dimethyl sulfate in the presence of sodium methoxide and methanol under reflux conditions. Although the direct transformation from 2-amino-5-chlorobenzophenone to Nordazepam is conceptually straightforward, an alternative approach involving the treatment of 2-amino-5-chlorobenzophenon with chloroacetyl chloride, succeeded by ammoniation and heating, culminates in Nordazepam with enhanced yield and facilitates easier purification processes. [111]

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 in persons receiving the drug therapeutically. Most commercial immunoassays for the benzodiazepine class of drugs cross-react with diazepam, but confirmation and quantitation are usually performed using chromatographic techniques.[112] [113] [114]

Environmental

Diazepam is a common environmental contamination finding near human settlement.[115]

History

Diazepam was the second benzodiazepine invented by Leo Sternbach of Hoffmann-La Roche at the company's Nutley, New Jersey, facility[116] 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.[117]

The benzodiazepines gained popularity among medical professionals as an improvement over 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 opioids).[118] 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.[119]

Marketed by Roche using an advertising campaign conceived by the William Douglas McAdams Agency under the leadership of Arthur Sackler,[120] diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak annual sales in 1978 of 2.3 billion tablets. Diazepam, along with oxazepam, nitrazepam and temazepam, represents 82% of the benzodiazepine market in Australia.[121] 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.[122]

Society and culture

Recreational use

See also: Benzodiazepine drug misuse. Diazepam is a medication with a high risk of misuse and can cause drug dependence. Urgent action by national governments has been recommended to improve prescribing patterns of benzodiazepines such as diazepam.[123] [124] A single dose of diazepam modulates the dopamine system in similar ways to how morphine and alcohol modulate the dopaminergic pathways.[125] Between 50 and 64% of rats will self-administer diazepam.[126] Diazepam has been shown to be able to substitute for the behavioral effects of barbiturates in a primate study.[127] Diazepam has been found as an adulterant in heroin.[128]

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.[129]

Sometimes, it is used by stimulant users to "come down" and sleep and to help control the urge to binge. These users often escalate dosage from 2 to 25 times the therapeutic dose of to .[130]

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, the study found 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 misuse benzodiazepines as commonly as females.[131]

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 potential for misuse for benzodiazepines, zolpidem, and zopiclone.[112] 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.[132]

Legal status

Diazepam is regulated as a prescription medication:

International

Diazepam is a Schedule IV controlled drug under the Convention on Psychotropic Substances.[133]

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.[134]

Germany

Classified as a prescription drug, or in high dosage as a restricted drug (Betäubungsmittelgesetz, Anlage III).[135]

Australia

Diazepam is a Schedule 4 substance under the Poisons Standard (June 2018).[136] A Schedule 4 drug is outlined in the Poisons Act 1964 as, "Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription".

United States

Diazepam is controlled as a Schedule IV substance.

Judicial executions

The states of California and Florida offer diazepam to condemned inmates as a pre-execution sedative as part of their lethal injection program, although the state of California has not executed a prisoner since 2006.[137] [138] In August 2018, Nebraska used diazepam as part of the drug combination used to execute Carey Dean Moore, the first death row inmate executed in Nebraska in over 21 years.[139]

Veterinary uses

Diazepam is used as a short-term sedative and anxiolytic for cats and dogs,[140] sometimes used as an appetite stimulant.[141] It can also be used to stop seizures in dogs and cats.[142]

Further reading

External links

Notes and References

  1. Book: Edmunds M, Mayhew M . 2013 . Pharmacology for the Primary Care Provider . 4th . Mosby . 545 . 978-0-323-08790-2 . 13 July 2020 . 14 January 2023 . https://web.archive.org/web/20230114192427/https://books.google.com/books?id=8FwdEsvnw8oC&pg=PA545 . live .
  2. Book: Clinical Addiction Psychiatry. 2010. Cambridge University Press. 978-1-139-49169-3. 156. live. https://web.archive.org/web/20170908135445/https://books.google.com/books?id=xD-R7Z27UBEC&pg=PA156. 8 September 2017.
  3. Book: Ries RK . Principles of addiction medicine. 2009. Wolters Kluwer/Lippincott Williams & Wilkins. Philadelphia. 978-0-7817-7477-2. 106. 4. live. https://web.archive.org/web/20170908135444/https://books.google.com/books?id=j6GGBud8DXcC&pg=PA106. 8 September 2017.
  4. Web site: Valtoco – diazepam spray . DailyMed . 13 January 2020 . 13 February 2020 . 1 August 2020 . https://web.archive.org/web/20200801111151/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a8bcc90-68fa-474d-832c-0df01e825f39 . live .
  5. Web site: Valium . NPS MedicineWise . 31 January 2020 . 9 January 2023 . 29 July 2020 . https://web.archive.org/web/20200729210249/https://www.nps.org.au/medicine-finder/valium-tablets#full-pi . live .
  6. Web site: Diazepam Injection BP Summary of Product Characteristics (SmPC) . emc . 17 January 2022 . 11 February 2024 . 25 January 2023 . https://web.archive.org/web/20230125104650/https://www.medicines.org.uk/emc/product/6274/smpc . live .
  7. Web site: Libervant- diazepam film . DailyMed . 27 April 2024 . 18 May 2024.
  8. Dhillon S, Oxley J, Richens A . Bioavailability of diazepam after intravenous, oral and rectal administration in adult epileptic patients . British Journal of Clinical Pharmacology . 13 . 3 . 427–32 . March 1982 . 7059446 . 1402110 . 10.1111/j.1365-2125.1982.tb01397.x .
  9. Book: Goodkin HP . 2010 . Diazepam . Panayiotopoulos CP . Atlas of Epilepsies . 1727–1731 . Springer . London . 10.1007/978-1-84882-128-6_263 . 978-1-84882-128-6 .
  10. Web site: Diazepam Tablets BP – Summary of Product Characteristics (SmPC) . (emc) . 16 September 2019 . 25 July 2020 . 25 July 2020 . https://web.archive.org/web/20200725234327/https://www.medicines.org.uk/emc/product/4522/smpc . dead .
  11. Web site: Diazepam. The American Society of Health-System Pharmacists. 5 June 2015. live. https://web.archive.org/web/20150630144220/http://www.drugs.com/monograph/diazepam.html. 30 June 2015.
  12. Book: Dhaliwal JS, Saadabadi A. Diazepam. September 2022. http://www.ncbi.nlm.nih.gov/books/NBK537022/. StatPearls [Internet]. StatPearls Publishing. 30725707. 13 October 2019. 8 March 2021. https://web.archive.org/web/20210308201231/http://www.ncbi.nlm.nih.gov/books/NBK537022/. live.
  13. Web site: Valium – diazepam tablet . DailyMed . 8 November 2019 . 30 December 2019 . 28 June 2019 . https://web.archive.org/web/20190628202244/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=554baee5-b171-4452-a50a-41a0946f956c . live .
  14. Dodds TJ . Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature . The Primary Care Companion for CNS Disorders . 19 . 2 . March 2017 . 28257172 . 10.4088/PCC.16r02037 . free .
  15. Riss J, Cloyd J, Gates J, Collins S . Benzodiazepines in epilepsy: pharmacology and pharmacokinetics . Acta Neurologica Scandinavica . 118 . 2 . 69–86 . August 2008 . 18384456 . 10.1111/j.1600-0404.2008.01004.x . 24453988 . free .
  16. Book: Perkin RM . Pediatric hospital medicine : textbook of inpatient management. 2008. Wolters Kluwer Health/Lippincott Williams & Wilkins. Philadelphia. 978-0-7817-7032-3. 862. 2nd.
  17. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery . 2006 . John Wiley & Sons . 978-3-527-60749-5 . 535 . 5 June 2020 . 14 January 2023 . https://web.archive.org/web/20230114172419/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA535 . live .
  18. US . 3371085 . patent . 5-ARYL-3H-1,4-BENZODIAZEPIN-2(1H)-ONES . 1968-02-27 . 1968-02-27 . 1961-11-20 . 1959-12-10 . Sternbach LH, Reeder E . Hoffmann La Roche AG .
  19. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  20. Web site: Diazepam - Drug Usage Statistics . ClinCalc . 14 January 2024 . 4 January 2024 . https://web.archive.org/web/20240104225507/https://clincalc.com/DrugStats/Drugs/Diazepam . live .
  21. Calcaterra NE, Barrow JC . Classics in chemical neuroscience: diazepam (valium) . ACS Chemical Neuroscience . 5 . 4 . 253–60 . April 2014 . 24552479 . 3990949 . 10.1021/cn5000056 .
  22. Book: ((World Health Organization)) . The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) . 2023 . 10665/371090 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2023.02 . free .
  23. Web site: PubChem . U.S. National Library of Medicine . Diazepam . 2 February 2024 .
  24. Pajouhesh H, Lenz GR . Medicinal chemical properties of successful central nervous system drugs . NeuroRx . 2 . 4 . 541–553 . October 2005 . 16489364 . 1201314 . 10.1602/neurorx.2.4.541 .
  25. Plumb's, 6th edition page 372
  26. Web site: 2005 . Diazepam . dead . https://web.archive.org/web/20050908214617/http://www.elephantcare.org/Drugs/diazepam.htm . 8 September 2005 . The Elephant Formulary . Elephant Care International . Mikota SK, Plumb DC.
  27. Web site: Drug Bank . Diazepam . dead . https://web.archive.org/web/20061224154141/http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00642.txt . 24 December 2006 .
  28. Bråthen G, Ben-Menachem E, Brodtkorb E, Galvin R, Garcia-Monco JC, Halasz P, Hillbom M, Leone MA, Young AB . EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force . European Journal of Neurology . 12 . 8 . 575–81 . August 2005 . 16053464 . 10.1111/j.1468-1331.2005.01247.x . 25904252 . free .
  29. Web site: FDA approves Valtoco . Drugs.com . 18 February 2020 . 13 January 2020 . 18 February 2020 . https://web.archive.org/web/20200218141202/https://www.drugs.com/newdrugs/fda-approves-valtoco-diazepam-nasal-seizure-rescue-5141.html . live .
  30. Web site: Valium Tablets. NPS MedicineWise. 29 August 2019. 29 July 2020. https://web.archive.org/web/20200729210249/https://www.nps.org.au/medicine-finder/valium-tablets. live.
  31. Cesarani A, Alpini D, Monti B, Raponi G . 25105327 . The treatment of acute vertigo . Neurological Sciences . 25 . Suppl 1 . S26-30 . March 2004 . 15045617 . 10.1007/s10072-004-0213-8 .
  32. Lader M, Tylee A, Donoghue J . 113206 . Withdrawing benzodiazepines in primary care . CNS Drugs . 23 . 1 . 19–34 . 2009 . 19062773 . 10.2165/0023210-200923010-00002 .
  33. Okoromah CN, Lesi FE . Diazepam for treating tetanus . The Cochrane Database of Systematic Reviews . 1 . CD003954 . 2004 . 2010 . 14974046 . 10.1002/14651858.CD003954.pub2 . 8759227 . Okoromah CA .
  34. Web site: Thomson Healthcare (Micromedex) . March 2000 . Diazepam . Prescription Drug Information . 11 March 2006 . dead . https://web.archive.org/web/20060619102054/http://www.drugs.com/pdr/DIAZEPAM.html . 19 June 2006 .
  35. Book: Kindwall EP, Whelan HT . 1999 . Hyperbaric Medicine Practice . 2nd . Best Publishing Company . 978-0-941332-78-1 .
  36. Walker M . Status epilepticus: an evidence based guide . BMJ . 331 . 7518 . 673–7 . September 2005 . 16179702 . 1226249 . 10.1136/bmj.331.7518.673 .
  37. Prasad M, Krishnan PR, Sequeira R, Al-Roomi K . Anticonvulsant therapy for status epilepticus . The Cochrane Database of Systematic Reviews . 2014 . 9 . CD003723 . September 2014 . 25207925 . 10.1002/14651858.CD003723.pub3 . 7154380 .
  38. Isojärvi JI, Tokola RA . Benzodiazepines in the treatment of epilepsy in people with intellectual disability . Journal of Intellectual Disability Research . 42 . Suppl 1 . 80–92 . December 1998 . 10030438 .
  39. Book: Bajgar J . Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment . 38 . 151–216 . 2004 . 15521192 . 10.1016/S0065-2423(04)38006-6 . 978-0-12-010338-6 . Advances in Clinical Chemistry .
  40. Offringa M, Newton R, Nevitt SJ, Vraka K . Prophylactic drug management for febrile seizures in children . The Cochrane Database of Systematic Reviews . 2021 . 6 . CD003031 . June 2021 . 34131913 . 8207248 . 10.1002/14651858.CD003031.pub4 .
  41. Weintraub SJ . 42610220 . Diazepam in the Treatment of Moderate to Severe Alcohol Withdrawal . CNS Drugs . 31 . 2 . 87–95 . February 2017 . 28101764 . 10.1007/s40263-016-0403-y .
  42. Kaplan PW . Neurologic aspects of eclampsia . Neurologic Clinics . 22 . 4 . 841–61 . November 2004 . 15474770 . 10.1016/j.ncl.2004.07.005 . free .
  43. Duley L . Evidence and practice: the magnesium sulphate story . Best Practice & Research. Clinical Obstetrics & Gynaecology . 19 . 1 . 57–74 . February 2005 . 15749066 . 10.1016/j.bpobgyn.2004.10.010 .
  44. Zeilhofer HU, Witschi R, Hösl K . 5614111 . Subtype-selective GABAA receptor mimetics—novel antihyperalgesic agents? . Journal of Molecular Medicine . 87 . 5 . 465–9 . May 2009 . 19259638 . 10.1007/s00109-009-0454-3 . 20.500.11850/20278 . free . 13 December 2019 . 29 July 2020 . https://web.archive.org/web/20200729222620/https://www.zora.uzh.ch/id/eprint/17933/10/ZORA_NL_17933.pdf . live .
  45. Mezaki T, Hayashi A, Nakase H, Hasegawa K . [Therapy of dystonia in Japan] . ja . Rinsho Shinkeigaku = Clinical Neurology . 45 . 9 . 634–42 . September 2005 . 16248394 .
  46. Kachi T . [Medical treatment of dystonia] . ja . Rinsho Shinkeigaku = Clinical Neurology . 41 . 12 . 1181–2 . December 2001 . 12235832 .
  47. Ashton H . The diagnosis and management of benzodiazepine dependence . Current Opinion in Psychiatry . 18 . 3 . 249–55 . May 2005 . 16639148 . 10.1097/01.yco.0000165594.60434.84 . 1709063 . 13 May 2010 . 8 August 2017 . https://web.archive.org/web/20170808161930/http://www.benzo.org.uk/amisc/ashdiag.pdf . live .
  48. Mañon-Espaillat R, Mandel S . Diagnostic Algorithms for Neuromuscular Diseases . Clinics in Podiatric Medicine and Surgery . 16 . 1 . 67–79 . January 1999 . 10.1016/S0891-8422(23)00935-7 . 9929772 . 12493035 .
  49. Web site: International AED Database. 16 September 2009. ILAE. dead. https://web.archive.org/web/20080509073033/http://www.ilae.org/Visitors/Centre/AEDs/index.cfm. 9 May 2008.
  50. Web site: Delivery of diazepam through an inhalation route . US Patent 6,805,853 . PharmCast.com . 19 October 2004 . 12 December 2014 . dead . https://web.archive.org/web/20151017131331/http://www.pharmcast.com/Patents100/Yr2004/Oct2004/101904/6805853_Diazepam101904.htm . 17 October 2015 .
  51. [United States Army Medical Research Institute of Chemical Defense|U.S. Army Medical Research Institute of Chemical Defense]
  52. Web site: Diazepam Contraindications and Cautions . 16 December 2008 . Epocrates . Epocrates Online . US . live . https://web.archive.org/web/20110710195415/https://online.epocrates.com/u/103193/diazepam/Contraindications+Cautions . 10 July 2011 .
  53. Aparecido da Silva Junior C, Marques DA, Patrone LG, Biancardi V, Bícego KC, Gargaglioni LH . Intra-uterine diazepam exposure decreases the number of catecholaminergic and serotoninergic neurons of neonate rats . Neuroscience Letters . 137014 . December 2022 . 795 . 36521643 . 10.1016/j.neulet.2022.137014 . 254555032 .
  54. Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A . Benzodiazepine dependence: focus on withdrawal syndrome . Annales Pharmaceutiques Françaises . 67 . 6 . 408–13 . November 2009 . 19900604 . 10.1016/j.pharma.2009.07.001 .
  55. Web site: 24 January 2005. Diazepam: precautions. Rxlist.com. RxList Inc.. 10 March 2006. dead. https://web.archive.org/web/20060407221843/http://www.rxlist.com/cgi/generic/diazepam_wcp.htm. 7 April 2006. mdy-all.
  56. Shats V, Kozacov S . [Falls in the geriatric department: responsibility of the care-giver and the hospital] . he . Harefuah . 128 . 11 . 690–3, 743 . June 1995 . 7557666 .
  57. Kanto JH . 27014006 . Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations . Drugs . 23 . 5 . 354–80 . May 1982 . 6124415 . 10.2165/00003495-198223050-00002 .
  58. McElhatton PR . The effects of benzodiazepine use during pregnancy and lactation . Reproductive Toxicology . 8 . 6 . 461–75 . 1994 . 7881198 . 10.1016/0890-6238(94)90029-9 . 1994RepTx...8..461M .
  59. Book: Yudofsky SC, Hales RE . The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences, Fifth Edition (American Psychiatric Press Textbook of Neuropsychiatry) . 1 December 2007 . American Psychiatric Publishing, Inc. . US . 978-1-58562-239-9 . 583–584 . live . https://web.archive.org/web/20160507062907/https://books.google.com/books?id=f5BEk-6yO_4C&pg=PA583 . 7 May 2016 .
  60. Kripke DF . 7946506 . Mortality Risk of Hypnotics: Strengths and Limits of Evidence . Drug Safety . 39 . 2 . 93–107 . February 2016 . 26563222 . 10.1007/s40264-015-0362-0 . free . 2 September 2019 . 14 March 2020 . https://web.archive.org/web/20200314025805/https://escholarship.org/content/qt08d9f3d5/qt08d9f3d5.pdf?t=nz1gjv . live .
  61. Web site: FDA expands Boxed Warning to improve safe use of benzodiazepine drug . U.S. Food and Drug Administration (FDA) . 23 September 2020 . 23 September 2020 . 24 September 2020 . https://web.archive.org/web/20200924002523/https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class . live .
  62. Marrosu F, Marrosu G, Rachel MG, Biggio G . Paradoxical reactions elicited by diazepam in children with classic autism . Functional Neurology . 2 . 3 . 355–61 . 1987 . 2826308 .
  63. Web site: Diazepam: Side Effects . 26 September 2006 . RxList.com . dead . https://web.archive.org/web/20061022201314/http://www.rxlist.com/cgi/generic/diazepam_ad.htm . 22 October 2006 . mdy-all .
  64. Michel L, Lang JP . [Benzodiazepines and forensic aspects] ]. fr . L'Encéphale . 29 . 6 . 479–85 . 2003 . 15029082 . live . https://web.archive.org/web/20071127111542/http://www.masson.fr/masson/portal/bookmark?Global=1&Page=18&MenuIdSelected=106&MenuItemSelected=0&MenuSupportSelected=0&CodeProduct4=539&CodeRevue4=ENC&Path=REVUE%2FENC%2F2003%2F29%2F6%2FARTICLE11106200473.xml&Locations= . 27 November 2007 .
  65. Berman ME, Jones GD, McCloskey MS . 20629702 . The effects of diazepam on human self-aggressive behavior . Psychopharmacology . 178 . 1 . 100–6 . February 2005 . 15316710 . 10.1007/s00213-004-1966-8 .
  66. Pérez Trullen JM, Modrego Pardo PJ, Vázquez André M, López Lozano JJ . Bromazepam-induced dystonia . Biomedicine & Pharmacotherapy . 46 . 8 . 375–6 . 1992 . 1292648 . 10.1016/0753-3322(92)90306-R .
  67. Hriscu A, Gherase F, Năstasă V, Hriscu E . [An experimental study of tolerance to benzodiazepines] . Revista Medico-Chirurgicala a Societatii de Medici Si Naturalisti Din Iasi . 106 . 4 . 806–11 . October–December 2002 . 14974234 .
  68. McNicholas WT, Hansson D, Schiza S, Grote L . Sleep in chronic respiratory disease: COPD and hypoventilation disorders . European Respiratory Review . 28 . 153 . 190064 . September 2019 . 31554703 . 10.1183/16000617.0064-2019 . 9488904 . 203440265 . free .
  69. Kozená L, Frantik E, Horváth M . 2618084 . Vigilance impairment after a single dose of benzodiazepines . Psychopharmacology . 119 . 1 . 39–45 . May 1995 . 7675948 . 10.1007/BF02246052 .
  70. Best KM, Boullata JI, Curley MA . Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: a systematic review and conceptual model . Pediatric Critical Care Medicine . 16 . 2 . 175–83 . February 2015 . 25560429 . 5304939 . 10.1097/PCC.0000000000000306 .
  71. MacKinnon GL, Parker WA . Benzodiazepine withdrawal syndrome: a literature review and evaluation . The American Journal of Drug and Alcohol Abuse . 9 . 1 . 19–33 . 1982 . 6133446 . 10.3109/00952998209002608 .
  72. Onyett SR . The benzodiazepine withdrawal syndrome and its management . The Journal of the Royal College of General Practitioners . 39 . 321 . 160–3 . April 1989 . 2576073 . 1711840 .
  73. Chouinard G, Labonte A, Fontaine R, Annable L . 32967696 . 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 . 1983 . 6141609 . 10.1016/0278-5846(83)90043-X .
  74. Lader M . Long-term anxiolytic therapy: the issue of drug withdrawal . The Journal of Clinical Psychiatry . 48 . Suppl . 12–6 . December 1987 . 2891684 .
  75. Murphy SM, Owen R, Tyrer P . 5024826 . Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks' treatment with diazepam or buspirone . The British Journal of Psychiatry . 154 . 4 . 529–34 . April 1989 . 2686797 . 10.1192/bjp.154.4.529 .
  76. Loiseau P . [Benzodiazepines in the treatment of epilepsy] . L'Encéphale . 9 . 4 Suppl 2 . 287B–292B . 1983 . 6373234 .
  77. Web site: 24 January 2005. Diazepam: abuse and dependence. Rxlist.com. RxList Inc.. 10 March 2006. dead. https://web.archive.org/web/20060216025301/http://www.rxlist.com/cgi/generic/diazepam_ad.htm#DA. 16 February 2006. mdy-all.
  78. Poulos CX, Zack M . Low-dose diazepam primes motivation for alcohol and alcohol-related semantic networks in problem drinkers . Behavioural Pharmacology . 15 . 7 . 503–12 . November 2004 . 15472572 . 10.1097/00008877-200411000-00006 . 23040302 .
  79. Vorma H, Naukkarinen HH, Sarna SJ, Kuoppasalmi KI . 1366333 . Predictors of benzodiazepine discontinuation in subjects manifesting complicated dependence . Substance Use & Misuse . 40 . 4 . 499–510 . 2005 . 15830732 . 10.1081/JA-200052433 .
  80. Parr JM, Kavanagh DJ, Cahill L, Mitchell G, McD Young R . Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis . Addiction . 104 . 1 . 13–24 . January 2009 . 18983627 . 10.1111/j.1360-0443.2008.02364.x .
  81. Web site: Thirtala T, Kaur K, Karlapati SK, Lippmann S . Consider this slow-taper program for benzodiazepines . Current Psychiatry . July 2013 . 29 August 2019 . 29 July 2020 . https://web.archive.org/web/20200729211831/https://www.mdedge.com/psychiatry/article/77248/addiction-medicine/consider-slow-taper-program-benzodiazepines . live .
  82. Web site: Tapering Benzodiazepines . 29 August 2019 . 13 July 2018 . https://web.archive.org/web/20180713180251/http://www.smchealth.org/sites/main/files/file-attachments/benzodiazepinetaper08-12-13.pdf . live .
  83. Web site: 24 January 2005. Diazepam: overdose. Rxlist.com. RxList Inc.. 10 March 2006. dead. https://web.archive.org/web/20060216025309/http://www.rxlist.com/cgi/generic/diazepam_od.htm. 16 February 2006. mdy-all.
  84. Greenblatt DJ, Woo E, Allen MD, Orsulak PJ, Shader RI . Rapid recovery from massive diazepam overdose . JAMA . 240 . 17 . 1872–4 . October 1978 . 357765 . 10.1001/jama.1978.03290170054026 .
  85. Lai SH, Yao YJ, Lo DS . A survey of buprenorphine related deaths in Singapore . Forensic Science International . 162 . 1–3 . 80–6 . October 2006 . 16879940 . 10.1016/j.forsciint.2006.03.037 .
  86. Web site: 2006. Diazepam. PDRHealth.com. 10 March 2006 . https://web.archive.org/web/20060117065720/http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/val1473.shtml . 17 January 2006.
  87. Book: Holt GA . 1998. Food and Drug Interactions: A Guide for Consumers. 90–91. Chicago . Precept Press. 978-0-944496-59-6 .
  88. Zácková P, Kvĕtina J, Nĕmec J, Nĕmcová J . Cardiovascular effects of diazepam and nitrazepam in combination with ethanol . Die Pharmazie . 37 . 12 . 853–6 . December 1982 . 7163374 .
  89. Back DJ, Orme ML . 32523973 . Pharmacokinetic drug interactions with oral contraceptives . Clinical Pharmacokinetics . 18 . 6 . 472–84 . June 1990 . 2191822 . 10.2165/00003088-199018060-00004 .
  90. Bendarzewska-Nawrocka B, Pietruszewska E, Stepień L, Bidziński J, Bacia T . [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 . January–February 1980 . 7374896 .
  91. Bateman DN . 41495586 . The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam . European Journal of Clinical Pharmacology . 30 . 2 . 205–8 . 1986 . 3709647 . 10.1007/BF00614304 .
  92. Mattila MJ, Nuotto E . Caffeine and theophylline counteract diazepam effects in man . Medical Biology . 61 . 6 . 337–43 . 1983 . 6374311 .
  93. Web site: Possible Interactions with: Valerian . . 13 May 2013 . 12 December 2014 . live . https://web.archive.org/web/20130121185201/http://www.umm.edu/altmed/articles/valerian-000934.htm . 21 January 2013 .
  94. Braestrup C, Squires RF . Pharmacological characterization of benzodiazepine receptors in the brain . European Journal of Pharmacology . 48 . 3 . 263–70 . April 1978 . 639854 . 10.1016/0014-2999(78)90085-7 .
  95. Chweh AY, Swinyard EA, Wolf HH, Kupferberg HJ . Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines . Life Sciences . 36 . 8 . 737–44 . February 1985 . 2983169 . 10.1016/0024-3205(85)90193-6 .
  96. Taft WC, DeLorenzo RJ . Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations . Proceedings of the National Academy of Sciences of the United States of America . 81 . 10 . 3118–22 . May 1984 . 6328498 . 345232 . 10.1073/pnas.81.10.3118 . live . PDF . https://web.archive.org/web/20080625212037/http://www.pnas.org/cgi/reprint/81/10/3118.pdf . 25 June 2008 . 1984PNAS...81.3118T . free .
  97. Miller JA, Richter JA . Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes . British Journal of Pharmacology . 84 . 1 . 19–25 . January 1985 . 3978310 . 1987204 . 10.1111/j.1476-5381.1985.tb17368.x .
  98. Gallager DW, Mallorga P, Oertel W, Henneberry R, Tallman J . [3H]Diazepam binding in mammalian central nervous system: a pharmacological characterization . The Journal of Neuroscience . 1 . 2 . 218–25 . February 1981 . 6267221 . 6564145 . 10.1523/JNEUROSCI.01-02-00218.1981 .
  99. Oishi R, Nishibori M, Itoh Y, Saeki K . Diazepam-induced decrease in histamine turnover in mouse brain . European Journal of Pharmacology . 124 . 3 . 337–42 . May 1986 . 3089825 . 10.1016/0014-2999(86)90236-0 .
  100. Grandison L . Suppression of prolactin secretion by benzodiazepines in vivo . Neuroendocrinology . 34 . 5 . 369–73 . 1982 . 6979001 . 10.1159/000123330 .
  101. Web site: National Highway Traffic Safety Administration Drugs and Human Performance Fact Sheet- Diazepam . 13 November 2017 . https://web.archive.org/web/20170327233605/https://one.nhtsa.gov/people/INJURY/research/job185drugs/diazepam.htm . 27 March 2017 . dead .
  102. Web site: Tan KR, Rudolph U, Lüscher C . Hooked on benzodiazepines: GABAA receptor subtypes and addiction . . 2011 . 12 December 2014 . live . https://web.archive.org/web/20150701230113/http://www.addictionscience.unige.ch/LabPublications-1/TrendsNeurosciKT2011.pdf . 1 July 2015 .
  103. Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE . Pharmacogenomics knowledge for personalized medicine . Clinical Pharmacology and Therapeutics . 92 . 4 . 414–7 . October 2012 . 22992668 . 3660037 . 10.1038/clpt.2012.96 .
  104. Zakusov VV, Ostrovskaya RU, Kozhechkin SN, Markovich VV, Molodavkin GM, Voronina TA . Further evidence for GABA-ergic mechanisms in the action of benzodiazepines . Archives Internationales de Pharmacodynamie et de Thérapie . 229 . 2 . 313–26 . October 1977 . 23084 .
  105. McLean MJ, Macdonald RL . 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 . February 1988 . 2450203 .
  106. Date SK, Hemavathi KG, Gulati OD . Investigation of the muscle relaxant activity of nitrazepam . Archives Internationales de Pharmacodynamie et de Thérapie . 272 . 1 . 129–39 . November 1984 . 6517646 .
  107. Web site: Munne P . Ruse M . 1998 . Diazepam . Inchem.org . 11 March 2006 . live . https://web.archive.org/web/20060227195320/http://www.inchem.org/documents/pims/pharm/pim181.htm . 27 February 2006 .
  108. Web site: Langsam Y . Diazepam (Valium and Others) . Brooklyn College (Eilat.sci.Brooklyn.CUNY.edu) . 23 March 2006 . live . https://web.archive.org/web/20070730114031/http://eilat.sci.brooklyn.cuny.edu/newnyc/DRUGS/Diazepam.htm . 30 July 2007 .
  109. Olive G, Dreux C . [Pharmacologic bases of use of benzodiazepines in peréinatal medicine] . Archives Françaises de Pédiatrie . 34 . 1 . 74–89 . January 1977 . 851373 .
  110. Vozeh S . [Pharmacokinetic of benzodiazepines in old age] . Schweizerische Medizinische Wochenschrift . 111 . 47 . 1789–93 . November 1981 . 6118950 .
  111. Stempel A, Reeder E, Sternbach LH . Quinazolines and 1,4-benzodiazepines. XXVII. Mechanism of ring enlargement of quinazoline 3-oxides with alkali to 1,4-benzodiazepin-2-one 4-oxides . The Journal of Organic Chemistry . 30 . 12 . 4267–4271 . December 1965 . 4158669 . 10.1021/jo01023a063 . 2 February 2024 . live . https://web.archive.org/web/20240203000415/https://pubmed.ncbi.nlm.nih.gov/4158669/ . 3 February 2024 .
  112. Jones AW, Holmgren A, Kugelberg FC . 25511804 . Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results . Therapeutic Drug Monitoring . 29 . 2 . 248–60 . April 2007 . 17417081 . 10.1097/FTD.0b013e31803d3c04 .
  113. Fraser AD, Bryan W . Evaluation of the Abbott ADx and TDx serum benzodiazepine immunoassays for analysis of alprazolam . Journal of Analytical Toxicology . 15 . 2 . 63–5 . 1991 . 1675703 . 10.1093/jat/15.2.63 .
  114. Book: Baselt R . Disposition of Toxic Drugs and Chemicals in Man . 9th . Biomedical Publications . Seal Beach, CA . 2011 . 471–473 . 978-0-9626523-8-7.
  115. Chia MA, Lorenzi AS, Ameh I, Dauda S, Cordeiro-Araújo MK, Agee JT, Okpanachi IY, Adesalu AT . Susceptibility of phytoplankton to the increasing presence of active pharmaceutical ingredients (APIs) in the aquatic environment: A review . Aquatic Toxicology . 234 . 105809 . May 2021 . 33780670 . 10.1016/j.aquatox.2021.105809 . 2021AqTox.23405809C . 232419482 .
  116. News: Roche to Shut Former U.S. Headquarters . New York Times . Pollack A . 26 June 2012 . 10 January 2014 . live . https://web.archive.org/web/20130331200545/http://www.nytimes.com/2012/06/27/business/roche-to-shut-down-former-us-headquarters-after-83-years.html . 31 March 2013 .
  117. News: Sample I. Leo Sternbach's Obituary. 3 October 2005. The Guardian (Guardian Unlimited). 10 March 2006. 28 August 2021. https://web.archive.org/web/20210828061851/https://www.theguardian.com/society/2005/oct/03/health.guardianobituaries. live.
  118. Book: Barondes SH . 2003 . Better Than Prozac . 47–59 . New York . Oxford University Press . 978-0-19-515130-5 . registration .
  119. Marshall KP, Georgievskava Z, Georgievsky I . Social reactions to Valium and Prozac: a cultural lag perspective of drug diffusion and adoption . Research in Social & Administrative Pharmacy . 5 . 2 . 94–107 . June 2009 . 19524858 . 10.1016/j.sapharm.2008.06.005 .
  120. Web site: How the American opiate epidemic was started by one pharmaceutical company. 4 March 2015. Theweek.com. 10 January 2018. 10 January 2018. https://web.archive.org/web/20180110022307/http://theweek.com/articles/541564/how-american-opiate-epidemic-started-by-pharmaceutical-company. live.
  121. Mant A, Whicker SD, McManus P, Birkett DJ, Edmonds D, Dumbrell D . Benzodiazepine utilisation in Australia: report from a new pharmacoepidemiological database . Australian Journal of Public Health . 17 . 4 . 345–9 . December 1993 . 7911332 . 10.1111/j.1753-6405.1993.tb00167.x . free .
  122. Web site: 24 January 2005 . Diazepam: indications . Rxlist.com . RxList Inc. . 11 March 2006 . dead . https://web.archive.org/web/20060216025337/http://www.rxlist.com/cgi/generic/diazepam_ids.htm . 16 February 2006 . mdy-all .
  123. Atack JR . 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 . May 2005 . 15926867 . 10.1517/13543784.14.5.601 . 22793644 .
  124. Dièye AM, Sylla M, Ndiaye A, Ndiaye M, Sy GY, Faye B . Benzodiazepines prescription in Dakar: a study about prescribing habits and knowledge in general practitioners, neurologists and psychiatrists . Fundamental & Clinical Pharmacology . 20 . 3 . 235–8 . June 2006 . 16671957 . 10.1111/j.1472-8206.2006.00400.x . 20619323 .
  125. News: New Evidence on Addiction To Medicines Diazepam Has Effect on Nerve Cells in the Brain Reward System . 25 September 2008 . August 2008 . Medical News Today . live . https://web.archive.org/web/20080912163645/http://www.medicalnewstoday.com/articles/119284.php . 12 September 2008 .
  126. Yoshimura K, Horiuchi M, Inoue Y, Yamamoto K . [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 . January 1984 . 6538866 . 10.1254/fpj.83.39 . free .
  127. Woolverton WL, Nader MA . 24836734 . Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline . Psychopharmacology . 122 . 3 . 230–6 . December 1995 . 8748392 . 10.1007/BF02246544 .
  128. Web site: Report of the International Narcotics Control Board for 1996 . PDF . 12 December 2014 . International Narcotics Control Board . United Nations . 1996 . 27 . Phenobarbital was identified as the psychotropic substance most frequently used as an adulterant in seized heroin; it was followed by diazepam and flunitrazepam. . live . https://web.archive.org/web/20150924034301/http://www.incb.org/documents/Publications/AnnualReports/AR1996/AR_1996_E.pdf#37 . 24 September 2015 .
  129. Griffiths RR, Johnson MW . 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 . 2005 . 16336040 .
  130. Web site: Methamphetamine and Benzodiazepines: Methamphetamine & Benzodiazepines . 26 September 2006 . Overclocker . Erowid Experience Vaults . 18 December 2008 . https://web.archive.org/web/20081218232840/http://de1.erowid.org/experiences/exp.phpquery=ID=9402.html . dead .
  131. Web site: Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits . 20 April 2014 . U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration . Substance Abuse and Mental Health Services Administration . 2011 . https://web.archive.org/web/20140531024002/http://www.samhsa.gov/data/2k13/DAWN2k11ED/DAWN2k11ED.htm#6.1 . 31 May 2014 . dead .
  132. Cosbey SH . Drugs and the impaired driver in Northern Ireland: an analytical survey . Forensic Science International . 32 . 4 . 245–58 . December 1986 . 3804143 . 10.1016/0379-0738(86)90201-X .
  133. Web site: International Narcotics Control Board. 2003. List of psychotropic substances under international control. Green list. 12 December 2014. dead. https://web.archive.org/web/20141213032231/http://infoespai.org/wp-content/uploads/2014/12/green.pdf. 13 December 2014.
  134. Web site: List of controlled Drugs . live . https://web.archive.org/web/20111230153451/http://www.homeoffice.gov.uk/publications/alcohol-drugs/drugs/drug-licences/controlled-drugs-list?view=Binary . 30 December 2011 .
  135. Web site: 2001. Anlage III (zu § 1 Abs. 1) verkehrsfähige und verschreibungsfähige Betäubungsmittel. Betäubungsmittelgesetz. 5 January 2010. dead. https://web.archive.org/web/20100103074308/http://bundesrecht.juris.de/btmg_1981/anlage_iii_61.html. 3 January 2010.
  136. Poisons Standard June 2018 Web site: Poisons Standard June 2018 . 6 January 2016 . live . https://web.archive.org/web/20160119074606/https://www.comlaw.gov.au/Details/F2015L01534/ . 19 January 2016 .
  137. Web site: San Quentin State Prison Operational Procedure 0–770, Execution By Lethal Injection (pp. 44 & 92 . https://web.archive.org/web/20080625212037/http://www.cdcr.ca.gov/News/docs/RevisedProtocol.pdf . 25 June 2008 . 10 January 2014 .
  138. Web site: Execution by lethal injection procedures. Florida Department of Corrections. 25 August 2014. 9 September 2013. live. https://web.archive.org/web/20131108160534/http://www.dc.state.fl.us/oth/deathrow/lethal-injection-procedures-as-of_9-9-2013.pdf. 8 November 2013.
  139. News: Nebraska executes Carey Dean Moore for murders of Omaha cab drivers Maynard Helgeland, Reuel Van Ness Jr. . Lincoln Journal Star . 14 August 2018 . 15 August 2018 . 15 August 2018 . https://web.archive.org/web/20180815024214/https://journalstar.com/news/local/911/nebraska-executes-carey-dean-moore-for-murders-of-omaha-cab/article_c2332b24-145e-51b8-9bd3-d4b13e64b70c.html#1 . live .
  140. Web site: Drugs Affecting Appetite (Monogastric) . The Merck Veterinary Manual . 4 January 2014 . dead . https://web.archive.org/web/20121028205743/http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm%2Fbc%2F190302.htm . 28 October 2012 .
  141. Rahminiwati M, Nishimura M . Effects of delta 9-tetrahydrocannabinol and diazepam on feeding behavior in mice . The Journal of Veterinary Medical Science . 61 . 4 . 351–5 . April 1999 . 10342284 . 10.1292/jvms.61.351 . free .
  142. Web site: Anticonvulsants Used to Stop Ongoing Seizure Activity . 10 January 2014 . Shell L . March 2012 . Dogs and Cats:
    A variety of drugs can be used to stop seizures in dogs and cats.
    Benzodiazepines:
    Diazepam is the most common benzodiazepine used in dogs and cats to reduce motor activity and permit placement of an IV catheter. . live . https://web.archive.org/web/20140110200807/http://www.merckmanuals.com/vet/pharmacology/systemic_pharmacotherapeutics_of_the_nervous_system/anticonvulsants_used_to_stop_ongoing_seizure_activity.html#v3331734 . 10 January 2014 .

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