Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that typically produces a calming effect.[5] It is commonly used to treat a range of conditions including anxiety, alcohol withdrawal syndrome, benzodiazepine withdrawal syndrome, muscle spasms, seizures, trouble sleeping, and restless legs syndrome.[5] It may also be used to cause memory loss during certain medical procedures.[6][7] It can be taken by mouth, inserted into the rectum, injected into muscle, or injected into a vein.[7] When given into a vein, effects begin in one to five minutes and last up to an hour.[7] By mouth, effects may take 40 minutes to begin.[8]
Common side effects include sleepiness and trouble with coordination.[7] Serious side effects are rare.[5] They include suicide, decreased breathing, and an increased risk of seizures if used too frequently in those with epilepsy.[5][7][9] Occasionally excitement or agitation may occur.[10][11] Long term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction.[5] Abrupt stopping after long-term use can be potentially dangerous.[5] After stopping, cognitive problems may persist for six months or longer.[10] It is not recommended during pregnancy or breastfeeding.[7] Its mechanism of action is by increasing the effect of the neurotransmitter gamma-aminobutyric acid(GABA).[10]
Diazepam was patented in 1959 by Hoffmann-La Roche.[5][12] It has been one of the most frequently prescribed medications in the world since its launch in 1963.[5] In the United States it was the highest selling medication between 1968 and 1982, selling more than two billion tablets in 1978 alone.[5] In 2016 it was the 112th most prescribed medication in the United States with more than 6 million prescriptions.[13] In 1985 the patent ended, and there are now more than 500 brands available on the market.[5] Diazepam is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[14] The wholesale cost in the developing world is about US$0.01 per dose as of 2014.[15] In the United States, it is about US$0.40 per dose.[7]
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).[16][17] Diazepam is the drug of choice for treating benzodiazepine dependence with its long half-life allowing easier dose reduction. Benzodiazepines have a relatively low toxicity in overdose.[10]
Diazepam has a number of uses including:
§ Treatment of anxiety, panic attacks, and states of agitation[16]
§ Treatment of neurovegetative symptoms associated with vertigo[18]
§ Treatment of the symptoms of alcohol, opiate, and benzodiazepine withdrawal[16][19]
§ Short-term treatment of insomnia[16]
§ Treatment of muscle spasms
§ Treatment of tetanus, together with other measures of intensive treatment[20]
§ 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)[21]
§ Palliative treatment of stiff person syndrome[22]
§ Pre- or postoperative sedation, anxiolysis or amnesia (e.g., before endoscopic or surgical procedures)[21]
§ Treatment of complications with a hallucinogen crisis and stimulant overdoses and psychosis, such as LSD, cocaine, or methamphetamine[23]
§ Preventative treatment of oxygen toxicity during hyperbaric oxygen therapy[24]
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.[23]
Seizures
Intravenous diazepam or lorazepam are first-line treatments for status epilepticus.[10][25]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.[26]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.[23][27]
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.[23][28]
Diazepam is sometimes used intermittently for the prevention of febrile seizures that may occur in children under five years of age.[10] Recurrence rates are reduced, but side effects are common.[29] 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.[10]
Other
Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfateand blood-pressure control measures have failed.[30][31] Benzodiazepines do not have any pain-relieving properties themselves, and are generally recommended to avoid in individuals with pain.[32] 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.[33][34] Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam.[35] Baclofen[36] or tizanidine is sometimes used as an alternative to diazepam.
Availability
Diazepam is marketed in over 500 brands throughout the world.[37] It is supplied in oral, injectable, inhalation, and rectal forms.[23][38][39]
The United States military employs a specialized diazepam preparation known asConvulsive 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.[40]
Contraindications
Use of diazepam should be avoided, when possible, in individuals with:[41]
§ Ataxia
§ Severe hypoventilation
§ Acute narrow-angle glaucoma
§ Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of two)
§ Severe renal deficiencies (for example, patients on dialysis)
§ Liver disorders
§ Severe sleep apnea
§ Severe depression, particularly when accompanied by suicidal tendencies
§ Psychosis
§ Pregnancy or breast feeding
§ Caution required in elderly or debilitated patients
§ Coma or shock
§ Abrupt discontinuation of therapy
§ Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the exception of some hallucinogens or stimulants, where it is occasionally used as a treatment for overdose)
§ History of alcohol or drug dependence
§ Myasthenia gravis, an autoimmune disorder causing marked fatiguability
§ Hypersensitivity or allergy to any drug in the benzodiazepine class
Caution
§ Benzodiazepine abuse and misuse should be guarded against when prescribed to those with alcohol or drug dependencies or who have psychiatric disorders.[42]
§ Pediatric patients
· Less than 18 years of age, this 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.[43]
· Under 6 months of age, safety and effectiveness have not been established; diazepam should not be given to those in this age group.[22][43]
§ Elderly and very ill patients can possibly suffer apnea 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 people.[43][44] 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 people, and treatment limited to a maximum of two weeks. Long-acting benzodiazepines such as diazepam are not recommended for the elderly.[10] Diazepam can also be dangerous in geriatric patients owing to a significant increased risk of falls.[45]
§ Intravenous or intramuscular injections in hypotensive people or those in shock should be administered carefully and vital signs should be monitored.[44]
§ 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, can result in floppy infant syndrome.[46] 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 metabolicresponses 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.[47]
Adverse effects
Adverse effects of benzodiazepines such as diazepam include anterograde amnesia, 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.[10] 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.[48] 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.[10] 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.[10] Adverse effects such as sedation, benzodiazepine dependence, and abuse potential limit the use of benzodiazepines.[49] Sedatives and sleeping pills, including diazepam, have been associated with an increased risk of death.[50]
Diazepam has a range of side effects common to most benzodiazepines, including:
§ Suppression of REM sleep and Slow wave sleep
§ Impaired motor function
· Impaired coordination
· Impaired balance
· Dizziness
§ Depression[51]
§ Reflex tachycardia[52]
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.[10][53][54][55] Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts.[56] Very rarely dystonia can occur.[57]
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.[22]
During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.[58]
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.[59]
Tolerance and dependence
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.
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.[10][60] 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.[10]
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%.[61]
Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines.[62] 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.[63] 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.[64] In humans, tolerance to the anticonvulsant effects of diazepam occurs frequently.[65]
Dependence
Improper or excessive use of diazepam can lead to dependence.[66] At a particularly high risk for diazepam misuse, abuse or dependence are:
§ People with a history of alcohol or drug abuse or dependence[22][67] Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers.[68]
§ People with severe personality disorders, such as borderline personality disorder[69]
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.[22][67]
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.
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:[22][70]
§ Drowsiness
§ Mental confusion
§ Hypotension
§ Impaired motor functions
· Impaired reflexes
· Impaired coordination
· Impaired balance
· Dizziness
§ Coma
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.[22][23][70][71]
The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats.[22] 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 desmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up.[72]
Overdoses of diazepam with alcohol, opiates or other depressants may be fatal.[71][73]
Mechanism of action
Benzodiazepines are positive allosteric modulators of the GABA type A receptors (GABAA). The GABAA receptors are ligand-gated chloride-selective ion channels that are activated by GABA, the major inhibitory neurotransmitter in the brain. Binding of benzodiazepines to this receptor complex promotes binding of GABA, which in turn increases the total conduction of chloride ions across the neuronal cell membrane. This increased chloride ion influx hyperpolarizes the neuron's membrane potential. As a result, the difference between resting potential and threshold potential is increased and firing is less likely. As a result, the arousal of the cortical and limbic systems in the central nervous system is reduced.[3]
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 GABAAreceptors comprising the α5 subunit were shown to modulate the temporal and spatial memory effects of benzodiazepines.[90] Diazepam is not the only drug to target these GABAA receptors. Drugs such as flumazenil also bind to GABAA to induce their effects.[91]
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.[92]
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.[93]
The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.[94]
