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, is used to treat a wide range of conditions, and has been one of the most frequently prescribed medications in the world since its launch in 1963.
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 IVmagnesium 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 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)
Dosages should be determined on an individual basis, depending upon the condition being treated, severity of symptoms, patient body weight, and any comorbid conditions the patient may have.
Diazepam is marketed in over 500 brands throughout the world. It is supplied in oral, injectable, inhalation, and rectal forms.
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:
Benzodiazepine abuse and misuse should be checked if used in the alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders .
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:
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.
Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation), leading to respiratory arrest and death.
Diazepam in doses of 5 mg or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness.
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.
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.
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.
Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.
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.
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.
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.
10 mg Valium.
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.
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.
The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.
Diazepam can be administered orally, intravenously (needs to be diluted, as it is painful and damaging to veins), intramuscularly (IM), or as a suppository.
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.
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.
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. "List of Controlled Drugs".
Germany: classified as a prescription drug, or in high dosage as a restricted drug (Betäubungsmittelgesetz, Anhang III).
^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.
^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 Societies12 (8): 575–81. doi:10.1111/j.1468-1331.2005.01247.x. PMID16053464.
^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. PMID10030438.
^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. PMID15045617.
^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 Iaş̧i106 (4): 806–811. PMID14974234.
^Kozená L, Frantik E, Horváth M (May 1995). "Vigilance impairment after a single dose of benzodiazepines". Psychopharmacology119 (1): 39–45. doi:10.1007/BF02246052. PMID7675948.
^MacKinnon GL, Parker WA (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation". The American Journal of Drug and Alcohol Abuse9 (1): 19–33. doi:10.3109/00952998209002608. PMID6133446.
^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 Psychiatry7 (4–6): 669–73. doi:10.1016/0278-5846(83)90043-X. PMID6141609.
^Lader M (December 1987). "Long-term anxiolytic therapy: the issue of drug withdrawal". The Journal of Clinical Psychiatry48: 12–6. PMID2891684.
^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 Science154 (4): 529–34. doi:10.1192/bjp.154.4.529. PMID2686797.
^Loiseau P (1983). "[Benzodiazepines in the treatment of epilepsy]". L'Encéphale9 (4 Suppl 2): 287B–292B. PMID6373234.
^ abcBarondes SH (2003). Better Than Prozac. New York: Oxford University Press. pp. 47–59. ISBN0-19-515130-5.
^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 Association240 (17): 1872–4. doi:10.1001/jama.240.17.1872. PMID357765.
^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 Polska14 (1): 39–45. PMID7374896.
^Bateman DN (1986). "The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam". European Journal of Clinical Pharmacology30 (2): 205–8. doi:10.1007/BF00614304. PMID3709647.
^Mattila MJ, Nuotto E (1983). "Caffeine and theophylline counteract diazepam effects in man". Medical Biology61 (6): 337–43. PMID6374311.
^Braestrup C, Squires RF (1 April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". European Journal of Pharmacology48 (3): 263–70. doi:10.1016/0014-2999(78)90085-7. PMID639854.
^Chweh AY, Swinyard EA, Wolf HH, Kupferberg HJ (February 25, 1985). "Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines". Life Sciences36 (8): 737–44. doi:10.1016/0024-3205(85)90193-6. PMID2983169.
^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 Research9 (2): 225–31. doi:10.1007/BF00964170. PMID6429560.
^Oishi R, Nishibori M, Itoh Y, Saeki K (May 27, 1986). "Diazepam-induced decrease in histamine turnover in mouse brain". European Journal of Pharmacology124 (3): 337–42. doi:10.1016/0014-2999(86)90236-0. PMID3089825.
^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 Thérapie229 (2): 313–26. PMID23084.
^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 Therapeutics244 (2): 789–95. PMID2450203.
^Date SK, Hemavathi KG, Gulati OD (November 1984). "Investigation of the muscle relaxant activity of nitrazepam". Archives Internationales De Pharmacodynamie Et De Thérapie272 (1): 129–39. PMID6517646.
^Olive G, Dreux C (January 1977). "Pharmacologic bases of use of benzodiazepines in peréinatal medicine". Archives Françaises De Pédiatrie34 (1): 74–89. PMID851373.
^Vozeh S (November 21, 1981). "[Pharmacokinetic of benzodiazepines in old age]". Schweizerische Medizinische Wochenschrift111 (47): 1789–93. PMID6118950.
^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 Monitoring29 (2): 248–60. doi:10.1097/FTD.0b013e31803d3c04. PMID17417081.
^Fraser AD, Bryan W (1991). "Evaluation of the Abbott ADx and TDx serum benzodiazepine immunoassays for analysis of alprazolam". Journal of Analytical Toxicology15 (2): 63–5. doi:10.1093/jat/15.2.63. PMID1675703.
^Baselt R (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 471–473. ISBN978-0-9626523-8-7.
^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 Chemistry26 (12): 4936–4941. doi:10.1021/jo01070a038.
^Gates, M. (1980). "New synthesis of diazepam". The Journal of Organic Chemistry45 (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 Chemistry47 (12): 2456–2461. doi:10.1021/jo00133a042.
^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 : RSAP5 (2): 94–107. doi:10.1016/j.sapharm.2008.06.005. PMID19524858.
^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 Health17 (4): 345–9. doi:10.1111/j.1753-6405.1993.tb00167.x. PMID7911332.
^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 Drugs14 (5): 601–18. doi:10.1517/13543718.104.22.1681. PMID15926867.
^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 Pharmacology20 (3): 235–8. doi:10.1111/j.1472-8206.2006.00400.x. PMID16671957.
^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 Japonica83 (1): 39–67. doi:10.1254/fpj.83.39. PMID6538866.
^Thiébot MH, Le Bihan C, Soubrié P, Simon P (1985). "Benzodiazepines reduce the tolerance to reward delay in rats". Psychopharmacology86 (1–2): 147–52. doi:10.1007/BF00431700. PMID2862657.
^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". Psychopharmacology122 (3): 230–6. doi:10.1007/BF02246544. PMID8748392.
^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. PMID16336040.
^Bergman U, Dahl-Puustinen ML (1989). "Use of prescription forgeries in a drug abuse surveillance network". European Journal of Clinical Pharmacology36 (6): 621–3. doi:10.1007/BF00637747. PMID2776820.
^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 Monitoring29 (2): 248–60. doi:10.1097/FTD.0b013e31803d3c04. PMID17417081.
^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 Science61 (4): 351–5. doi:10.1292/jvms.61.351. PMID10342284.