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Benzodiazepine

Benzodiazepines (BZD, BDZ, BZs), colloquially called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and was made available in 1960 by Hoffmann–La Roche, which followed with the development of diazepam (Valium) three years later, in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.

Benzodiazepines are depressants that enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties. High doses of many shorter-acting benzodiazepines may also cause anterograde amnesia and dissociation. These properties make benzodiazepines useful in treating anxiety, panic disorder, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures. Benzodiazepines are categorized as short, intermediate, or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety.

Benzodiazepines are generally viewed as safe and effective for short-term use of two to four weeks, although cognitive impairment and paradoxical effects such as aggression or behavioral disinhibition can occur. According to the Government of Victoria's (Australia) Department of Health, long-term use can cause "impaired thinking or memory loss, anxiety and depression, irritability, paranoia, aggression, etc." A minority of people have paradoxical reactions after taking benzodiazepines such as worsened agitation or panic.

Benzodiazepines are associated with an increased risk of suicide due to aggression, impulsivity, and negative withdrawal effects. Long-term use is controversial because of concerns about decreasing effectiveness, physical dependence, benzodiazepine withdrawal syndrome, and an increased risk of dementia and cancer. The elderly are at an increased risk of both short- and long-term adverse effects, and as a result, all benzodiazepines are listed in the Beers List of inappropriate medications for older adults. There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not major teratogens, uncertainty remains as to whether they cause cleft palate in a small number of babies and whether neurobehavioural effects occur as a result of prenatal exposure; they are known to cause withdrawal symptoms in the newborn.

In an overdose, benzodiazepines can cause dangerous deep unconsciousness, but are less toxic than their predecessors, the barbiturates, and death rarely results when a benzodiazepine is the only drug taken. Combined with other central nervous system (CNS) depressants such as alcohol and opioids, the potential for toxicity and fatal overdose increases significantly. Benzodiazepines are commonly used recreationally and also often taken in combination with other addictive substances, and are controlled in most countries.

Medical uses
Benzodiazepines possess psycholeptic, sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnesic actions, which are useful in a variety of indications such as alcohol dependence, seizures, anxiety disorders, panic, agitation, and insomnia. Most are administered orally; however, they can also be given intravenously, intramuscularly, or rectally. In general, benzodiazepines are well tolerated and are safe and effective drugs in the short term for a wide range of conditions. Tolerance can develop to their effects and there is also a risk of dependence, and upon discontinuation a withdrawal syndrome may occur. These factors, combined with other possible secondary effects after prolonged use such as psychomotor, cognitive, or memory impairments, limit their long-term applicability. The effects of long-term use or misuse include the tendency to cause or worsen cognitive deficits, depression, and anxiety. The College of Physicians and Surgeons of British Columbia recommends discontinuing the usage of benzodiazepines in those on opioids and those who have used them long term. Benzodiazepines can have serious adverse health outcomes, and these findings support clinical and regulatory efforts to reduce usage, especially in combination with non-benzodiazepine receptor agonists.

Panic disorder
Because of their effectiveness, tolerability, and rapid onset of anxiolytic action, benzodiazepines are frequently used for the treatment of anxiety associated with panic disorder. However, there is disagreement among expert bodies regarding the long-term use of benzodiazepines for panic disorder. The views range from those holding benzodiazepines are not effective long-term and should be reserved for treatment-resistant cases to those holding they are as effective in the long term as selective serotonin reuptake inhibitors (SSRIs).

American Psychiatric Association (APA) guidelines, published in January 2009, note that, in general, benzodiazepines are well tolerated, and their use for the initial treatment for panic disorder is strongly supported by numerous controlled trials. APA states that there is insufficient evidence to recommend any of the established panic disorder treatments over another. The choice of treatment between benzodiazepines, SSRIs, serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and psychotherapy should be based on the patient's history, preference, and other individual characteristics. Selective serotonin reuptake inhibitors are likely to be the best choice of pharmacotherapy for many patients with panic disorder, but benzodiazepines are also often used, and some studies suggest that these medications are still used with greater frequency than the SSRIs. One advantage of benzodiazepines is that they alleviate the anxiety symptoms much faster than antidepressants, and therefore may be preferred in patients for whom rapid symptom control is critical. However, this advantage is offset by the possibility of developing benzodiazepine dependence. APA does not recommend benzodiazepines for persons with depressive symptoms or a recent history of substance use disorder. APA guidelines state that, in general, pharmacotherapy of panic disorder should be continued for at least a year, and that clinical experience supports continuing benzodiazepine treatment to prevent recurrence. Although major concerns about benzodiazepine tolerance and withdrawal have been raised, there is no evidence for significant dose escalation in patients using benzodiazepines long-term. For many such patients, stable doses of benzodiazepines retain their efficacy over several years.

Guidelines issued by the UK-based National Institute for Health and Clinical Excellence (NICE), carried out a systematic review using different methodology and came to a different conclusion. They questioned the accuracy of studies that were not placebo-controlled. And, based on the findings of placebo-controlled studies, they do not recommend use of benzodiazepines beyond two to four weeks, as tolerance and physical dependence develop rapidly, with withdrawal symptoms including rebound anxiety occurring after six weeks or more of use. Nevertheless, benzodiazepines are still prescribed for long-term treatment of anxiety disorders, although specific antidepressants and psychological therapies are recommended as the first-line treatment options with the anticonvulsant drug pregabalin indicated as a second- or third-line treatment and suitable for long-term use. NICE stated that long-term use of benzodiazepines for panic disorder with or without agoraphobia is an unlicensed indication, does not have long-term efficacy, and is, therefore, not recommended by clinical guidelines. Psychological therapies such as cognitive behavioural therapy are recommended as a first-line therapy for panic disorder; benzodiazepine use has been found to interfere with therapeutic gains from these therapies.

Benzodiazepines are usually administered orally; however, very occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks.

Generalized anxiety disorder
Benzodiazepines have robust efficacy in the short-term management of generalized anxiety disorder (GAD), but were not shown effective in producing long-term improvement overall. According to National Institute for Health and Clinical Excellence (NICE), benzodiazepines can be used in the immediate management of GAD, if necessary. However, they should not usually be given for longer than 2–4 weeks. The only medications NICE recommends for the longer term management of GAD are antidepressants.

Likewise, Canadian Psychiatric Association (CPA) recommends benzodiazepines alprazolam, bromazepam, lorazepam, and diazepam only as a second-line choice, if the treatment with two different antidepressants was unsuccessful. Although they are second-line agents, benzodiazepines can be used for a limited time to relieve severe anxiety and agitation. CPA guidelines note that after 4–6 weeks the effect of benzodiazepines may decrease to the level of placebo, and that benzodiazepines are less effective than antidepressants in alleviating ruminative worry, the core symptom of GAD. However, in some cases, a prolonged treatment with benzodiazepines as the add-on to an antidepressant may be justified.

A 2015 review found a larger effect with medications than talk therapy. Medications with benefit include serotonin-noradrenaline reuptake inhibitors, benzodiazepines, and selective serotonin reuptake inhibitors.

Anxiety
Benzodiazepines are sometimes used in the treatment of acute anxiety, since they result in rapid and marked relief of symptoms in most individuals; however, they are not recommended beyond 2–4 weeks of use due to risks of tolerance and dependence and a lack of long-term effectiveness. As for insomnia, they may also be used on an irregular/"as-needed" basis, such as in cases where said anxiety is at its worst. Compared to other pharmacological treatments, benzodiazepines are twice as likely to lead to a relapse of the underlying condition upon discontinuation. Psychological therapies and other pharmacological therapies are recommended for the long-term treatment of generalized anxiety disorder. Antidepressants have higher remission rates and are, in general, safe and effective in the short and long term.

Insomnia
Benzodiazepines can be useful for short-term treatment of insomnia. Their use beyond 2 to 4 weeks is not recommended due to the risk of dependence. The Committee on Safety of Medicines report recommended that where long-term use of benzodiazepines for insomnia is indicated then treatment should be intermittent wherever possible. It is preferred that benzodiazepines be taken intermittently and at the lowest effective dose. They improve sleep-related problems by shortening the time spent in bed before falling asleep, prolonging the sleep time, and, in general, reducing wakefulness. However, they worsen sleep quality by increasing light sleep and decreasing deep sleep. Other drawbacks of hypnotics, including benzodiazepines, are possible tolerance to their effects, rebound insomnia, and reduced slow-wave sleep and a withdrawal period typified by rebound insomnia and a prolonged period of anxiety and agitation.

The list of benzodiazepines approved for the treatment of insomnia is fairly similar among most countries, but which benzodiazepines are officially designated as first-line hypnotics prescribed for the treatment of insomnia varies between countries. Longer-acting benzodiazepines such as nitrazepam and diazepam have residual effects that may persist into the next day and are, in general, not recommended.

Since the release of nonbenzodiazepines, also known as z-drugs, in 1992 in response to safety concerns, individuals with insomnia and other sleep disorders have increasingly been prescribed nonbenzodiazepines (2.3% in 1993 to 13.7% of Americans in 2010), less often prescribed benzodiazepines (23.5% in 1993 to 10.8% in 2010). It is not clear as to whether the new non benzodiazepine hypnotics (Z-drugs) are better than the short-acting benzodiazepines. The efficacy of these two groups of medications is similar. According to the US Agency for Healthcare Research and Quality, indirect comparison indicates that side-effects from benzodiazepines may be about twice as frequent as from nonbenzodiazepines. Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia. However, the UK National Institute for Health and Clinical Excellence did not find any convincing evidence in favor of Z-drugs. NICE review pointed out that short-acting Z-drugs were inappropriately compared in clinical trials with long-acting benzodiazepines. There have been no trials comparing short-acting Z-drugs with appropriate doses of short-acting benzodiazepines. Based on this, NICE recommended choosing the hypnotic based on cost and the patient's preference.

Older adults should not use benzodiazepines to treat insomnia unless other treatments have failed. When benzodiazepines are used, patients, their caretakers, and their physician should discuss the increased risk of harms, including evidence that shows twice the incidence of traffic collisions among driving patients, and falls and hip fracture for older patients.

Seizures
Prolonged convulsive epileptic seizures are a medical emergency that can usually be dealt with effectively by administering fast-acting benzodiazepines, which are potent anticonvulsants. In a hospital environment, intravenous clonazepam, lorazepam, and diazepam are first-line choices. In the community, intravenous administration is not practical and so rectal diazepam or buccal midazolam are used, with a preference for midazolam as its administration is easier and more socially acceptable.

When benzodiazepines were first introduced, they were enthusiastically adopted for treating all forms of epilepsy. However, drowsiness and tolerance become problems with continued use and none are now considered first-line choices for long-term epilepsy therapy. Clobazam is widely used by specialist epilepsy clinics worldwide and clonazepam is popular in the Netherlands, Belgium and France. Clobazam was approved for use in the United States in 2011. In the UK, both clobazam and clonazepam are second-line choices for treating many forms of epilepsy. Clobazam also has a useful role for very short-term seizure prophylaxis and in catamenial epilepsy. Discontinuation after long-term use in epilepsy requires additional caution because of the risks of rebound seizures. Therefore, the dose is slowly tapered over a period of up to six months or longer.

Alcohol withdrawal
Chlordiazepoxide is the most commonly used benzodiazepine for alcohol detoxification, but diazepam may be used as an alternative. Both are used in the detoxification of individuals who are motivated to stop drinking, and are prescribed for a short period of time to reduce the risks of developing tolerance and dependence to the benzodiazepine medication itself. The benzodiazepines with a longer half-life make detoxification more tolerable, and dangerous (and potentially lethal) alcohol withdrawal effects are less likely to occur. On the other hand, short-acting benzodiazepines may lead to breakthrough seizures, and are, therefore, not recommended for detoxification in an outpatient setting. Oxazepam and lorazepam are often used in patients at risk of drug accumulation, in particular, the elderly and those with cirrhosis, because they are metabolized differently from other benzodiazepines, through conjugation.

Benzodiazepines are the preferred choice in the management of alcohol withdrawal syndrome, in particular, for the prevention and treatment of the dangerous complication of seizures and in subduing severe delirium. Lorazepam is the only benzodiazepine with predictable intramuscular absorption and it is the most effective in preventing and controlling acute seizures.

Other indications
Benzodiazepines are often prescribed for a wide range of conditions:
 * They can sedate patients receiving mechanical ventilation or those in extreme distress. Caution is exercised in this situation due to the risk of respiratory depression, and it is recommended that benzodiazepine overdose treatment facilities should be available. They have also been found to increase the likelihood of later PTSD after people have been removed from ventilators.
 * Benzodiazepines are indicated in the management of breathlessness (shortness of breath) in advanced diseases, in particular where other treatments have failed to adequately control symptoms.
 * Benzodiazepines are effective as medication given a couple of hours before surgery to relieve anxiety. They also produce amnesia, which can be useful, as patients may not remember unpleasantness from the procedure. They are also used in patients with dental phobia as well as some ophthalmic procedures like refractive surgery; although such use is controversial and only recommended for those who are very anxious. Midazolam is the most commonly prescribed for this use because of its strong sedative actions and fast recovery time, as well as its water solubility, which reduces pain upon injection. Diazepam and lorazepam are sometimes used. Lorazepam has particularly marked amnesic properties that may make it more effective when amnesia is the desired effect.
 * Benzodiazepines are well known for their strong muscle-relaxing properties and can be useful in the treatment of muscle spasms, although tolerance often develops to their muscle relaxant effects. Baclofen or tizanidine are sometimes used as an alternative to benzodiazepines. Tizanidine has been found to have superior tolerability compared to diazepam and baclofen.
 * Benzodiazepines are also used to treat the acute panic caused by hallucinogen intoxication. Benzodiazepines are also used to calm the acutely agitated individual and can, if required, be given via an intramuscular injection. They can sometimes be effective in the short-term treatment of psychiatric emergencies such as acute psychosis as in schizophrenia or mania, bringing about rapid tranquillization and sedation until the effects of lithium or neuroleptics (antipsychotics) take effect. Lorazepam is most commonly used but clonazepam is sometimes prescribed for acute psychosis or mania; their long-term use is not recommended due to risks of dependence. Further research investigating the use of benzodiazepines alone and in combination with antipsychotic medications for treating acute psychosis is warranted.
 * Clonazepam, a benzodiazepine is used to treat many forms of parasomnia. Rapid eye movement behavior disorder responds well to low doses of clonazepam. Restless legs syndrome can be treated using clonazepam as a third line treatment option as the use of clonazepam is still investigational.
 * Benzodiazepines are sometimes used for obsessive–compulsive disorder (OCD), although they are generally believed ineffective for this indication. Effectiveness was, however, found in one small study. Benzodiazepines can be considered as a treatment option in treatment resistant cases.
 * Antipsychotics are generally a first-line treatment for delirium; however, when delirium is caused by alcohol or sedative hypnotic withdrawal, benzodiazepines are a first-line treatment.
 * There is some evidence that low doses of benzodiazepines reduce adverse effects of electroconvulsive therapy.

Contraindications
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.

Because of their muscle relaxant action, benzodiazepines may cause respiratory depression in susceptible individuals. For that reason, they are contraindicated in people with myasthenia gravis, sleep apnea, bronchitis, and COPD. Caution is required when benzodiazepines are used in people with personality disorders or intellectual disability because of frequent paradoxical reactions. In major depression, they may precipitate suicidal tendencies and are sometimes used for suicidal overdoses. Individuals with a history of excessive alcohol use or non-medical use of opioids or barbiturates should avoid benzodiazepines, as there is a risk of life-threatening interactions with these drugs.

Pregnancy
In the United States, the Food and Drug Administration has categorized benzodiazepines into either category D or X meaning potential for harm in the unborn has been demonstrated.

Exposure to benzodiazepines during pregnancy has been associated with a slightly increased (from 0.06 to 0.07%) risk of cleft palate in newborns, a controversial conclusion as some studies find no association between benzodiazepines and cleft palate. Their use by expectant mothers shortly before the delivery may result in a floppy infant syndrome. Newborns with this condition tend to have hypotonia, hypothermia, lethargy, and breathing and feeding difficulties. Cases of neonatal withdrawal syndrome have been described in infants chronically exposed to benzodiazepines in utero. This syndrome may be hard to recognize, as it starts several days after delivery, for example, as late as 21 days for chlordiazepoxide. The symptoms include tremors, hypertonia, hyperreflexia, hyperactivity, and vomiting and may last for up to three to six months. Tapering down the dose during pregnancy may lessen its severity. If used in pregnancy, those benzodiazepines with a better and longer safety record, such as diazepam or chlordiazepoxide, are recommended over potentially more harmful benzodiazepines, such as temazepam or triazolam. Using the lowest effective dose for the shortest period of time minimizes the risks to the unborn child.

Elderly
The benefits of benzodiazepines are least and the risks are greatest in the elderly. They are listed as a potentially inappropriate medication for older adults by the American Geriatrics Society. The elderly are at an increased risk of dependence and are more sensitive to the adverse effects such as memory problems, daytime sedation, impaired motor coordination, and increased risk of motor vehicle accidents and falls, and an increased risk of hip fractures. The long-term effects of benzodiazepines and benzodiazepine dependence in the elderly can resemble dementia, depression, or anxiety syndromes, and progressively worsens over time. Adverse effects on cognition can be mistaken for the effects of old age. The benefits of withdrawal include improved cognition, alertness, mobility, reduced risk incontinence, and a reduced risk of falls and fractures. The success of gradual-tapering benzodiazepines is as great in the elderly as in younger people. Benzodiazepines should be prescribed to the elderly only with caution and only for a short period at low doses. Short to intermediate-acting benzodiazepines are preferred in the elderly such as oxazepam and temazepam. The high potency benzodiazepines alprazolam and triazolam and long-acting benzodiazepines are not recommended in the elderly due to increased adverse effects. Nonbenzodiazepines such as zaleplon and zolpidem and low doses of sedating antidepressants are sometimes used as alternatives to benzodiazepines.

Long-term use of benzodiazepines is associated with increased risk of cognitive impairment and dementia, and reduction in prescribing levels is likely to reduce dementia risk. The association of a history of benzodiazepine use and cognitive decline is unclear, with some studies reporting a lower risk of cognitive decline in former users, some finding no association and some indicating an increased risk of cognitive decline.

Benzodiazepines are sometimes prescribed to treat behavioral symptoms of dementia. However, like antidepressants, they have little evidence of effectiveness, although antipsychotics have shown some benefit. Cognitive impairing effects of benzodiazepines that occur frequently in the elderly can also worsen dementia.

Adverse effects

The most common side-effects of benzodiazepines are related to their sedating and muscle-relaxing action. They include drowsiness, dizziness, and decreased alertness and concentration. Lack of coordination may result in falls and injuries particularly in the elderly. Another result is impairment of driving skills and increased likelihood of road traffic accidents. Decreased libido and erection problems are a common side effect. Depression and disinhibition may emerge. Hypotension and suppressed breathing (hypoventilation) may be encountered with intravenous use. Less common side effects include nausea and changes in appetite, blurred vision, confusion, euphoria, depersonalization and nightmares. Cases of liver toxicity have been described but are very rare.

The long-term effects of benzodiazepine use can include cognitive impairment as well as affective and behavioural problems. Feelings of turmoil, difficulty in thinking constructively, loss of sex-drive, agoraphobia and social phobia, increasing anxiety and depression, loss of interest in leisure pursuits and interests, and an inability to experience or express feelings can also occur. Not everyone, however, experiences problems with long-term use. Additionally, an altered perception of self, environment and relationships may occur. A study published in 2020 found that long-term use of prescription benzodiazepines is associated with an increase in all-cause mortality among those age 65 or younger, but not those older than 65. The study also found that all-cause mortality was increased further in cases in which benzodiazepines are co-prescribed with opioids, relative to cases in which benzodiazepines are prescribed without opioids, but again only in those age 65 or younger.

Compared to other sedative-hypnotics, visits to the hospital involving benzodiazepines had a 66% greater odds of a serious adverse health outcome. This included hospitalization, patient transfer, or death, and visits involving a combination of benzodiazepines and non-benzodiapine receptor agonists had almost four-times increased odds of a serious health outcome.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Cognitive effects
The short-term use of benzodiazepines adversely affects multiple areas of cognition, the most notable one being that it interferes with the formation and consolidation of memories of new material and may induce complete anterograde amnesia. However, researchers hold contrary opinions regarding the effects of long-term administration. One view is that many of the short-term effects continue into the long-term and may even worsen, and are not resolved after stopping benzodiazepine usage. Another view maintains that cognitive deficits in chronic benzodiazepine users occur only for a short period after the dose, or that the anxiety disorder is the cause of these deficits.

While the definitive studies are lacking, the former view received support from a 2004 meta-analysis of 13 small studies. This meta-analysis found that long-term use of benzodiazepines was associated with moderate to large adverse effects on all areas of cognition, with visuospatial memory being the most commonly detected impairment. Some of the other impairments reported were decreased IQ, visiomotor coordination, information processing, verbal learning and concentration. The authors of the meta-analysis and a later reviewer noted that the applicability of this meta-analysis is limited because the subjects were taken mostly from withdrawal clinics; the coexisting drug, alcohol use, and psychiatric disorders were not defined; and several of the included studies conducted the cognitive measurements during the withdrawal period.

Paradoxical effects
Paradoxical reactions, such as increased seizures in epileptics, aggression, violence, impulsivity, irritability and suicidal behavior sometimes occur. These reactions have been explained as consequences of disinhibition and the subsequent loss of control over socially unacceptable behavior. Paradoxical reactions are rare in the general population, with an incidence rate below 1% and similar to placebo. However, they occur with greater frequency in recreational abusers, individuals with borderline personality disorder, children, and patients on high-dosage regimes. In these groups, impulse control problems are perhaps the most important risk factor for disinhibition; learning disabilities and neurological disorders are also significant risks. Most reports of disinhibition involve high doses of high-potency benzodiazepines. Paradoxical effects may also appear after chronic use of benzodiazepines.

Long-term worsening of psychiatric symptoms
While benzodiazepines may have short-term benefits for anxiety, sleep and agitation in some patients, long-term (i.e., greater than 2–4 weeks) use can result in a worsening of the very symptoms the medications are meant to treat. Potential explanations include exacerbating cognitive problems that are already common in anxiety disorders, causing or worsening depression and suicidality, disrupting sleep architecture by inhibiting deep stage sleep, withdrawal symptoms or rebound symptoms in between doses mimicking or exacerbating underlying anxiety or sleep disorders, inhibiting the benefits of psychotherapy by inhibiting memory consolidation and reducing fear extinction,   and reducing coping with trauma/stress and increasing vulnerability to future stress. The latter two explanations may be why benzodiazepines are ineffective and/or potentially harmful in PTSD and phobias. Anxiety, insomnia and irritability may be temporarily exacerbated during withdrawal, but psychiatric symptoms after discontinuation are usually less than even while taking benzodiazepines. Functioning significantly improves within 1 year of discontinuation.

Tolerance
The main problem of the chronic use of benzodiazepines is the development of tolerance and dependence. Tolerance manifests itself as diminished pharmacological effect and develops relatively quickly to the sedative, hypnotic, anticonvulsant, and muscle relaxant actions of benzodiazepines. Tolerance to anti-anxiety effects develops more slowly with little evidence of continued effectiveness beyond four to six months of continued use. In general, tolerance to the amnesic effects does not occur. However, controversy exists as to tolerance to the anxiolytic effects with some evidence that benzodiazepines retain efficacy and opposing evidence from a systematic review of the literature that tolerance frequently occurs and some evidence that anxiety may worsen with long-term use. The question of tolerance to the amnesic effects of benzodiazepines is, likewise, unclear. Some evidence suggests that partial tolerance does develop, and that, "memory impairment is limited to a narrow window within 90 minutes after each dose".

A major disadvantage of benzodiazepines is that tolerance to therapeutic effects develops relatively quickly while many adverse effects persist. Tolerance develops to hypnotic and myorelaxant effects within days to weeks, and to anticonvulsant and anxiolytic effects within weeks to months. Therefore, benzodiazepines are unlikely to be effective long-term treatments for sleep and anxiety. While BZD therapeutic effects disappear with tolerance, depression and impulsivity with high suicidal risk commonly persist. Several studies have confirmed that long-term benzodiazepines are not significantly different from placebo for sleep  or anxiety. This may explain why patients commonly increase doses over time and many eventually take more than one type of benzodiazepine after the first loses effectiveness. Additionally, because tolerance to benzodiazepine sedating effects develops more quickly than does tolerance to brainstem depressant effects, those taking more benzodiazepines to achieve desired effects may experience sudden respiratory depression, hypotension or death. Most patients with anxiety disorders and PTSD have symptoms that persist for at least several months, making tolerance to therapeutic effects a distinct problem for them and necessitating the need for more effective long-term treatment (e.g., psychotherapy, serotonergic antidepressants).

Withdrawal symptoms and management

Discontinuation of benzodiazepines or abrupt reduction of the dose, even after a relatively short course of treatment (two to four weeks), may result in two groups of symptoms, rebound and withdrawal. Rebound symptoms are the return of the symptoms for which the patient was treated but worse than before. Withdrawal symptoms are the new symptoms that occur when the benzodiazepine is stopped. They are the main sign of physical dependence.

The most frequent symptoms of withdrawal from benzodiazepines are insomnia, gastric problems, tremors, agitation, fearfulness, and muscle spasms. The less frequent effects are irritability, sweating, depersonalization, derealization, hypersensitivity to stimuli, depression, suicidal behavior, psychosis, seizures, and delirium tremens. Severe symptoms usually occur as a result of abrupt or over-rapid withdrawal. Abrupt withdrawal can be dangerous and lead to excitotoxicity, causing damage and even death to nerve cells as a result of excessive levels of the excitatory neurotransmitter glutamate. Increased glutamatergic activity is thought to be part of a compensatory mechanism to chronic GABAergic inhibition from benzodiazepines. Therefore, a gradual reduction regimen is recommended.

Symptoms may also occur during a gradual dosage reduction, but are typically less severe and may persist as part of a protracted withdrawal syndrome for months after cessation of benzodiazepines. Approximately 10% of patients experience a notable protracted withdrawal syndrome, which can persist for many months or in some cases a year or longer. Protracted symptoms tend to resemble those seen during the first couple of months of withdrawal but usually are of a sub-acute level of severity. Such symptoms do gradually lessen over time, eventually disappearing altogether.

Benzodiazepines have a reputation with patients and doctors for causing a severe and traumatic withdrawal; however, this is in large part due to the withdrawal process being poorly managed. Over-rapid withdrawal from benzodiazepines increases the severity of the withdrawal syndrome and increases the failure rate. A slow and gradual withdrawal customised to the individual and, if indicated, psychological support is the most effective way of managing the withdrawal. Opinion as to the time needed to complete withdrawal ranges from four weeks to several years. A goal of less than six months has been suggested, but due to factors such as dosage and type of benzodiazepine, reasons for prescription, lifestyle, personality, environmental stresses, and amount of available support, a year or more may be needed to withdraw.

Withdrawal is best managed by transferring the physically dependent patient to an equivalent dose of diazepam because it has the longest half-life of all of the benzodiazepines, is metabolised into long-acting active metabolites and is available in low-potency tablets, which can be quartered for smaller doses. A further benefit is that it is available in liquid form, which allows for even smaller reductions. Chlordiazepoxide, which also has a long half-life and long-acting active metabolites, can be used as an alternative.

Nonbenzodiazepines are contraindicated during benzodiazepine withdrawal as they are cross tolerant with benzodiazepines and can induce dependence. Alcohol is also cross tolerant with benzodiazepines and more toxic and thus caution is needed to avoid replacing one dependence with another. During withdrawal, fluoroquinolone-based antibiotics are best avoided if possible; they displace benzodiazepines from their binding site and reduce GABA function and, thus, may aggravate withdrawal symptoms. Antipsychotics are not recommended for benzodiazepine withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines, e.g., chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required.

Withdrawal from long term benzodiazepines is beneficial for most individuals. Withdrawal of benzodiazepines from long-term users, in general, leads to improved physical and mental health particularly in the elderly; although some long term users report continued benefit from taking benzodiazepines, this may be the result of suppression of withdrawal effects.

Controversial associations
Beyond the well established link between benzodiazepines and psychomotor impairment resulting in motor vehicle accidents and falls leading to fracture; research in the 2000s and 2010s has raised the association between benzodiazepines (and Z-drugs) and other, as of yet unproven, adverse effects including dementia, cancer, infections, pancreatitis and respiratory disease exacerbations.

Dementia
A number of studies have drawn an association between long-term benzodiazepine use and neuro-degenerative disease, particularly Alzheimer's disease. It has been determined that long-term use of benzodiazepines is associated with increased dementia risk, even after controlling for protopathic bias.

Infections
Some observational studies have detected significant associations between benzodiazepines and respiratory infections such as pneumonia where others have not. A large meta-analysis of pre-marketing randomized controlled trials on the pharmacologically related Z-Drugs suggest a small increase in infection risk as well. An immunodeficiency effect from the action of benzodiazepines on GABA-A receptors has been postulated from animal studies.

Cancer
A meta-analysis of observational studies has determined an association between benzodiazepine use and cancer, though the risk across different agents and different cancers varied significantly. In terms of experimental basic science evidence, an analysis of carcinogenetic and genotoxicity data for various benzodiazepines has suggested a small possibility of carcinogenesis for a small number of benzodiazepines.

Pancreatitis
The evidence suggesting a link between benzodiazepines (and Z-Drugs) and pancreatic inflammation is very sparse and limited to a few observational studies from Taiwan. A criticism of confounding can be applied to these findings as with the other controversial associations above. Further well-designed research from other populations as well as a biologically plausible mechanism is required to confirm this association.

Overdose
Although benzodiazepines are much safer in overdose than their predecessors, the barbiturates, they can still cause problems in overdose. Taken alone, they rarely cause severe complications in overdose; statistics in England showed that benzodiazepines were responsible for 3.8% of all deaths by poisoning from a single drug. However, combining these drugs with alcohol, opiates or tricyclic antidepressants markedly raises the toxicity. The elderly are more sensitive to the side effects of benzodiazepines, and poisoning may even occur from their long-term use. The various benzodiazepines differ in their toxicity; temazepam appears most toxic in overdose and when used with other drugs. The symptoms of a benzodiazepine overdose may include; drowsiness, slurred speech, nystagmus, hypotension, ataxia, coma, respiratory depression, and cardiorespiratory arrest.

A reversal agent for benzodiazepines exists, flumazenil (Anexate). Its use as an antidote is not routinely recommended because of the high risk of resedation and seizures. In a double-blind, placebo-controlled trial of 326 people, 4 people had serious adverse events and 61% became resedated following the use of flumazenil. Numerous contraindications to its use exist. It is contraindicated in people with a history of long-term use of benzodiazepines, those having ingested a substance that lowers the seizure threshold or may cause an arrhythmia, and in those with abnormal vital signs. One study found that only 10% of the people presenting with a benzodiazepine overdose are suitable candidates for treatment with flumazenil.

Interactions
Individual benzodiazepines may have different interactions with certain drugs. Depending on their metabolism pathway, benzodiazepines can be divided roughly into two groups. The largest group consists of those that are metabolized by cytochrome P450 (CYP450) enzymes and possess significant potential for interactions with other drugs. The other group comprises those that are metabolized through glucuronidation, such as lorazepam, oxazepam, and temazepam, and, in general, have few drug interactions.

Many drugs, including oral contraceptives, some antibiotics, antidepressants, and antifungal agents, inhibit cytochrome enzymes in the liver. They reduce the rate of elimination of the benzodiazepines that are metabolized by CYP450, leading to possibly excessive drug accumulation and increased side-effects. In contrast, drugs that induce cytochrome P450 enzymes, such as St John's wort, the antibiotic rifampicin, and the anticonvulsants carbamazepine and phenytoin, accelerate elimination of many benzodiazepines and decrease their action. Taking benzodiazepines with alcohol, opioids and other central nervous system depressants potentiates their action. This often results in increased sedation, impaired motor coordination, suppressed breathing, and other adverse effects that have potential to be lethal. Antacids can slow down absorption of some benzodiazepines; however, this effect is marginal and inconsistent.

Pharmacodynamics

Benzodiazepines work by increasing the effectiveness of the endogenous chemical, GABA, to decrease the excitability of neurons. This reduces the communication between neurons and, therefore, has a calming effect on many of the functions of the brain.

GABA controls the excitability of neurons by binding to the GABAA receptor. The GABAA receptor is a protein complex located in the synapses between neurons. All GABAA receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for the neurotransmitter gamma-aminobutyric acid (GABA), while a subset of GABAA receptor complexes also contain a single binding site for benzodiazepines. Binding of benzodiazepines to this receptor complex does not alter binding of GABA. Unlike other positive allosteric modulators that increase ligand binding, benzodiazepine binding acts as a positive allosteric modulator by increasing the total conduction of chloride ions across the neuronal cell membrane when GABA is already bound to its receptor. 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. Different GABAA receptor subtypes have varying distributions within different regions of the brain and, therefore, control distinct neuronal circuits. Hence, activation of different GABAA receptor subtypes by benzodiazepines may result in distinct pharmacological actions. In terms of the mechanism of action of benzodiazepines, their similarities are too great to separate them into individual categories such as anxiolytic or hypnotic. For example, a hypnotic administered in low doses produces anxiety-relieving effects, whereas a benzodiazepine marketed as an anti-anxiety drug at higher doses induces sleep.

The subset of GABAA receptors that also bind benzodiazepines are referred to as benzodiazepine receptors (BzR). The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ1). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). GABAA receptors that are made up of different combinations of subunit subtypes have different properties, different distributions in the brain and different activities relative to pharmacological and clinical effects. Benzodiazepines bind at the interface of the α and γ subunits on the GABAA receptor. Binding also requires that alpha subunits contain a histidine amino acid residue, (i.e., α1, α2, α3, and α5 containing GABAA receptors). For this reason, benzodiazepines show no affinity for GABAA receptors containing α4 and α6 subunits with an arginine instead of a histidine residue. Once bound to the benzodiazepine receptor, the benzodiazepine ligand locks the benzodiazepine receptor into a conformation in which it has a greater affinity for the GABA neurotransmitter. This increases the frequency of the opening of the associated chloride ion channel and hyperpolarizes the membrane of the associated neuron. The inhibitory effect of the available GABA is potentiated, leading to sedative and anxiolytic effects. For instance, those ligands with high activity at the α1 are associated with stronger hypnotic effects, whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits have good anti-anxiety activity.

GABAA receptors participate in the regulation of synaptic pruning by prompting microglial spine engulfment. Benzodiazepines have been shown to upregulate microglial spine engulfment and prompt overzealous eradication of synaptic connections. This mechanism may help explain the increased risk of dementia associated with long-term benzodiazepine treatment.

The benzodiazepine class of drugs also interact with peripheral benzodiazepine receptors. Peripheral benzodiazepine receptors are present in peripheral nervous system tissues, glial cells, and to a lesser extent the central nervous system. These peripheral receptors are not structurally related or coupled to GABAA receptors. They modulate the immune system and are involved in the body response to injury. Benzodiazepines also function as weak adenosine reuptake inhibitors. It has been suggested that some of their anticonvulsant, anxiolytic, and muscle relaxant effects may be in part mediated by this action. Benzodiazepines have binding sites in the periphery, however their effects on muscle tone is not mediated through these peripheral receptors. The peripheral binding sites for benzodiazepines are present in immune cells and gastrointestinal tract.

Pharmacokinetics
A benzodiazepine can be placed into one of three groups by its elimination half-life, or time it takes for the body to eliminate half of the dose. Some benzodiazepines have long-acting active metabolites, such as diazepam and chlordiazepoxide, which are metabolised into desmethyldiazepam. Desmethyldiazepam has a half-life of 36–200 hours, and flurazepam, with the main active metabolite of desalkylflurazepam, with a half-life of 40–250 hours. These long-acting metabolites are partial agonists.
 * Short-acting compounds have a median half-life of 1–12 hours. They have few residual effects if taken before bedtime, rebound insomnia may occur upon discontinuation, and they might cause daytime withdrawal symptoms such as next day rebound anxiety with prolonged usage. Examples are brotizolam, midazolam, and triazolam.
 * Intermediate-acting compounds have a median half-life of 12–40 hours. They may have some residual effects in the first half of the day if used as a hypnotic. Rebound insomnia, however, is more common upon discontinuation of intermediate-acting benzodiazepines than longer-acting benzodiazepines. Examples are alprazolam, estazolam, flunitrazepam, clonazepam, lormetazepam, lorazepam, nitrazepam, and temazepam.
 * Long-acting compounds have a half-life of 40–250 hours. They have a risk of accumulation in the elderly and in individuals with severely impaired liver function, but they have a reduced severity of rebound effects and withdrawal. Examples are diazepam, clorazepate, chlordiazepoxide, and flurazepam.

Chemistry
Benzodiazepines share a similar chemical structure, and their effects in humans are mainly produced by the allosteric modification of a specific kind of neurotransmitter receptor, the GABAA receptor, which increases the overall conductance of these inhibitory channels; this results in the various therapeutic effects as well as adverse effects of benzodiazepines. Other less important modes of action are also known.

The term benzodiazepine is the chemical name for the heterocyclic ring system (see figure to the right), which is a fusion between the benzene and diazepine ring systems. Under Hantzsch–Widman nomenclature, a diazepine is a heterocycle with two nitrogen atoms, five carbon atom and the maximum possible number of cumulative double bonds. The "benzo" prefix indicates the benzene ring fused onto the diazepine ring.

Benzodiazepine drugs are substituted 1,4-benzodiazepines, although the chemical term can refer to many other compounds that do not have useful pharmacological properties. Different benzodiazepine drugs have different side groups attached to this central structure. The different side groups affect the binding of the molecule to the GABAA receptor and so modulate the pharmacological properties. Many of the pharmacologically active "classical" benzodiazepine drugs contain the 5-phenyl-1H-benzo[e] [1,4]diazepin-2(3H)-one substructure (see figure to the right). Benzodiazepines have been found to mimic protein reverse turns structurally, which enable them with their biological activity in many cases.

Nonbenzodiazepines also bind to the benzodiazepine binding site on the GABAA receptor and possess similar pharmacological properties. While the nonbenzodiazepines are by definition structurally unrelated to the benzodiazepines, both classes of drugs possess a common pharmacophore (see figure to the lower-right), which explains their binding to a common receptor site.

Types

 * 2-keto compounds:
 * clorazepate, diazepam, flurazepam, halazepam, prazepam, and others

 * 3-hydroxy compounds:
 * lorazepam, lormetazepam, oxazepam, temazepam

 * 7-nitro compounds:
 * clonazepam, flunitrazepam, nimetazepam, nitrazepam

 * Triazolo compounds:
 * adinazolam, alprazolam, estazolam, triazolam

 * Imidazo compounds:
 * climazolam, loprazolam, midazolam

 * 1,5-benzodiazepines:
 * clobazam

History
The first benzodiazepine, chlordiazepoxide (Librium), was synthesized in 1955 by Leo Sternbach while working at Hoffmann–La Roche on the development of tranquilizers. The pharmacological properties of the compounds prepared initially were disappointing, and Sternbach abandoned the project. Two years later, in April 1957, co-worker Earl Reeder noticed a "nicely crystalline" compound left over from the discontinued project while spring-cleaning in the lab. This compound, later named chlordiazepoxide, had not been tested in 1955 because of Sternbach's focus on other issues. Expecting pharmacology results to be negative, and hoping to publish the chemistry-related findings, researchers submitted it for a standard battery of animal tests. The compound showed very strong sedative, anticonvulsant, and muscle relaxant effects. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name Librium. Following chlordiazepoxide, diazepam marketed by Hoffmann–La Roche under the brand name Valium in 1963, and for a while the two were the most commercially successful drugs. The introduction of benzodiazepines led to a decrease in the prescription of barbiturates, and by the 1970s they had largely replaced the older drugs for sedative and hypnotic uses.

The new group of drugs was initially greeted with optimism by the medical profession, but gradually concerns arose; in particular, the risk of dependence became evident in the 1980s. Benzodiazepines have a unique history in that they were responsible for the largest-ever class-action lawsuit against drug manufacturers in the United Kingdom, involving 14,000 patients and 1,800 law firms that alleged the manufacturers knew of the dependence potential but intentionally withheld this information from doctors. At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of dependence and withdrawal. This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines. The court case against the drug manufacturers never reached a verdict; legal aid had been withdrawn and there were allegations that the consultant psychiatrists, the expert witnesses, had a conflict of interest. The court case fell through, at a cost of £30 million, and led to more cautious funding through legal aid for future cases. This made future class action lawsuits less likely to succeed, due to the high cost from financing a smaller number of cases, and increasing charges for losing the case for each person involved.

Although antidepressants with anxiolytic properties have been introduced, and there is increasing awareness of the adverse effects of benzodiazepines, prescriptions for short-term anxiety relief have not significantly dropped. For treatment of insomnia, benzodiazepines are now less popular than nonbenzodiazepines, which include zolpidem, zaleplon and eszopiclone. Nonbenzodiazepines are molecularly distinct, but nonetheless, they work on the same benzodiazepine receptors and produce similar sedative effects.

Benzodiazepines have been detected in plant specimens and brain samples of animals not exposed to synthetic sources, including a human brain from the 1940s. However, it is unclear whether these compounds are biosynthesized by microbes or by plants and animals themselves. A microbial biosynthetic pathway has been proposed.

Legal status
In the United States, benzodiazepines are Schedule IV drugs under the Federal Controlled Substances Act, even when not on the market (for example, nitrazepam and bromazepam). Flunitrazepam is subject to more stringent regulations in certain states and temazepam prescriptions require specially coded pads in certain states.

In Canada, possession of benzodiazepines is legal for personal use. All benzodiazepines are categorized as Schedule IV substances under the Controlled Drugs and Substances Act.

In the United Kingdom, benzodiazepines are Class C controlled drugs, carrying the maximum penalty of 7 years imprisonment, an unlimited fine or both for possession and a maximum penalty of 14 years imprisonment, an unlimited fine or both for supplying benzodiazepines to others.

In the Netherlands, since October 1993, benzodiazepines, including formulations containing less than 20 mg of temazepam, are all placed on List 2 of the Opium Law. A prescription is needed for possession of all benzodiazepines. Temazepam formulations containing 20 mg or greater of the drug are placed on List 1, thus requiring doctors to write prescriptions in the List 1 format.

In East Asia and Southeast Asia, temazepam and nimetazepam are often heavily controlled and restricted. In certain countries, triazolam, flunitrazepam, flutoprazepam and midazolam are also restricted or controlled to certain degrees. In Hong Kong, all benzodiazepines are regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. Previously only brotizolam, flunitrazepam and triazolam were classed as dangerous drugs.

Internationally, benzodiazepines are categorized as Schedule IV controlled drugs, apart from flunitrazepam, which is a Schedule III drug under the Convention on Psychotropic Substances.

Recreational use
Benzodiazepines are considered major addictive substances. Non-medical benzodiazepine use is mostly limited to individuals who use other substances, i.e., people who engage in polysubstance use. On the international scene, benzodiazepines are categorized as Schedule IV controlled drugs by the INCB, apart from flunitrazepam, which is a Schedule III drug under the Convention on Psychotropic Substances. Some variation in drug scheduling exists in individual countries; for example, in the United Kingdom, midazolam and temazepam are Schedule III controlled drugs.

British law requires that temazepam (but not midazolam) be stored in safe custody. Safe custody requirements ensures that pharmacists and doctors holding stock of temazepam must store it in securely fixed double-locked steel safety cabinets and maintain a written register, which must be bound and contain separate entries for temazepam and must be written in ink with no use of correction fluid (although a written register is not required for temazepam in the United Kingdom). Disposal of expired stock must be witnessed by a designated inspector (either a local drug-enforcement police officer or official from health authority). Benzodiazepine use ranges from occasional binges on large doses, to chronic and compulsive drug use of high doses.

Benzodiazepines are commonly used recreationally by poly-drug users. Mortality is higher among poly-drug users that also use benzodiazepines. Heavy alcohol use also increases mortality among poly-drug users. Polydrug use involving benzodiazepines and alcohol can result in an increased risk of blackouts, risk-taking behaviours, seizures, and overdose. Dependence and tolerance, often coupled with dosage escalation, to benzodiazepines can develop rapidly among people who misuse drugs; withdrawal syndrome may appear after as little as three weeks of continuous use. Long-term use has the potential to cause both physical and psychological dependence and severe withdrawal symptoms such as depression, anxiety (often to the point of panic attacks), and agoraphobia. Benzodiazepines and, in particular, temazepam are sometimes used intravenously, which, if done incorrectly or in an unsterile manner, can lead to medical complications including abscesses, cellulitis, thrombophlebitis, arterial puncture, deep vein thrombosis, and gangrene. Sharing syringes and needles for this purpose also brings up the possibility of transmission of hepatitis, HIV, and other diseases. Benzodiazepines are also misused intranasally, which may have additional health consequences. Once benzodiazepine dependence has been established, a clinician usually converts the patient to an equivalent dose of diazepam before beginning a gradual reduction program.

A 1999–2005 Australian police survey of detainees reported preliminary findings that self-reported users of benzodiazepines were less likely than non-user detainees to work full-time and more likely to receive government benefits, use methamphetamine or heroin, and be arrested or imprisoned. Benzodiazepines are sometimes used for criminal purposes; they serve to incapacitate a victim in cases of drug assisted rape or robbery.

Overall, anecdotal evidence suggests that temazepam may be the most psychologically habit-forming (addictive) benzodiazepine. Non-medical temazepam use reached epidemic proportions in some parts of the world, in particular, in Europe and Australia, and is a major addictive substance in many Southeast Asian countries. This led authorities of various countries to place temazepam under a more restrictive legal status. Some countries, such as Sweden, banned the drug outright. Temazepam also has certain pharmacokinetic properties of absorption, distribution, elimination, and clearance that make it more apt to non-medical use compared to many other benzodiazepines.

Veterinary use
Benzodiazepines are used in veterinary practice in the treatment of various disorders and conditions. As in humans, they are used in the first-line management of seizures, status epilepticus, and tetanus, and as maintenance therapy in epilepsy (in particular, in cats). They are widely used in small and large animals (including horses, swine, cattle and exotic and wild animals) for their anxiolytic and sedative effects, as pre-medication before surgery, for induction of anesthesia and as adjuncts to anesthesia.

title: Benzodiazepine


text:
Talk:Benzodiazepine

broken chart
im not sure if its my screen or display but the table at the beginning is "broken", dont want to fix it because im not sure if its my screen only. DANIELTHEDON (talk) 16:21, 26 November 2018 (UTC)

Benzo[e][1,4]diazepine
Why is it benzo[e][1,4]diazepine and not benzo[f][1,4]diazepine? As far as I understand the IUPAC nomeclature (https://www.acdlabs.com/iupac/nomenclature/93/r93_229.htm) it should be named benzo[f][1,4]diazepine. --Esmu Igors (talk) 03:27, 15 September 2019 (UTC)

Legal Status
I am proposing that much of the "regulatory" clutter found in the legal stats section be moved elsewhere. While drugs may have lots of regulations surrounding their use, legal status is a horse of a different colour and this should be reflected in its own relevant section. A drug is either legal to use or it is not; whether its a "target of interest amongst seniors" for example is irrelevant. Daystrom (talk) 05:49, 6 December 2022 (UTC)

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Talk:Benzodiazepine


text:
Bell curve (disambiguation)

The bell curve is typical of the normal distribution.

Bell curve may also refer to:

 * Gaussian function, a specific kind of function whose graph is a bell-shaped curve
 * The Bell Curve, a 1994 book by Richard J. Herrnstein and Charles Murray
 * Bell curve grading, a method of evaluating scholastic performance

title: Bell curve (disambiguation)


text:
Body mass index

Body mass index (BMI) is a value derived from the mass (weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms (kg) and height in metres (m).

The BMI may be determined first by measuring its components by means of a weighing scale and a stadiometer. The multiplication and division may be carried out directly, by hand or using a calculator, or indirectly using a lookup table (or chart). The table displays BMI as a function of mass and height and may show other units of measurement (converted to metric units for the calculation). The table may also show contour lines or colours for different BMI categories.

The BMI is a convenient rule of thumb used to broadly categorize a person as based on tissue mass (muscle, fat, and bone) and height. Major adult BMI classifications are underweight (under 18.5 kg/m2), normal weight (18.5 to 24.9), overweight (25 to 29.9), and obese (30 or more). When used to predict an individual's health, rather than as a statistical measurement for groups, the BMI has limitations that can make it less useful than some of the alternatives, especially when applied to individuals with abdominal obesity, short stature, or high muscle mass.

BMIs under 20 and over 25 have been associated with higher all-cause mortality, with the risk increasing with distance from the 20–25 range.

History
Adolphe Quetelet, a Belgian astronomer, mathematician, statistician, and sociologist, devised the basis of the BMI between 1830 and 1850 as he developed what he called "social physics". Quetelet himself never intended for the index, then called the Quetelet Index, to be used as a means of medical assessment. Instead, it was a component of his study of l'homme moyen, or the average man. Quetelet thought of the average man as a social ideal, and developed the body mass index as a means of discovering the socially ideal human person. According to Lars Grue and Arvid Heiberg in the Scandinavian Journal of Disability Research, Quetelet's idealization of the average man would be elaborated upon by Francis Galton a decade later in the development of Eugenics.

The modern term "body mass index" (BMI) for the ratio of human body weight to squared height was coined in a paper published in the July 1972 edition of the Journal of Chronic Diseases by Ancel Keys and others. In this paper, Keys argued that what he termed the BMI was "if not fully satisfactory, at least as good as any other relative weight index as an indicator of relative obesity".

The interest in an index that measures body fat came with observed increasing obesity in prosperous Western societies. Keys explicitly judged BMI as appropriate for population studies and inappropriate for individual evaluation. Nevertheless, due to its simplicity, it has come to be widely used for preliminary diagnoses. Additional metrics, such as waist circumference, can be more useful.

The BMI is expressed in kg/m2, resulting from mass in kilograms and height in metres. If pounds and inches are used, a conversion factor of 703 (kg/m2)/(lb/in2) is applied. (If pounds and feet are used, a conversion factor of 4.88 is used.) When the term BMI is used informally, the units are usually omitted.

 * $$\mathrm{BMI} = \frac{\text{mass}_\text{kg}}{{\text{height}_\text{m}}^2}

= \frac{\text{mass}_\text{lb}}{{\text{height}_\text{in}}^2}\times 703$$

BMI provides a simple numeric measure of a person's thickness or thinness, allowing health professionals to discuss weight problems more objectively with their patients. BMI was designed to be used as a simple means of classifying average sedentary (physically inactive) populations, with an average body composition. For such individuals, the BMI value recommendations are as follows: 18.5 to 24.9 kg/m2 may indicate optimal weight, lower than 18.5 may indicate underweight, 25 to 29.9 may indicate overweight, and 30 or more may indicate obese. Lean male athletes often have a high muscle-to-fat ratio and therefore a BMI that is misleadingly high relative to their body-fat percentage.

Categories
A common use of the BMI is to assess how far an individual's body weight departs from what is normal for a person's height. The weight excess or deficiency may, in part, be accounted for by body fat (adipose tissue) although other factors such as muscularity also affect BMI significantly (see discussion below and overweight).

The WHO regards an adult BMI of less than 18.5 as underweight and possibly indicative of malnutrition, an eating disorder, or other health problems, while a BMI of 25 or more is considered overweight and 30 or more is considered obese. In addition to the principle, international WHO BMI cut-off points (16, 17, 18.5, 25, 30, 35 and 40), four additional cut-off points for at-risk Asians were identified (23, 27.5, 32.5 and 37.5). These ranges of BMI values are valid only as statistical categories.

Children and youth
BMI is used differently for people aged 2 to 20. It is calculated in the same way as for adults but then compared to typical values for other children or youth of the same age. Instead of comparison against fixed thresholds for underweight and overweight, the BMI is compared against the percentiles for children of the same sex and age.

A BMI that is less than the 5th percentile is considered underweight and above the 95th percentile is considered obese. Children with a BMI between the 85th and 95th percentile are considered to be overweight.

Studies in Britain from 2013 have indicated that females between the ages 12 and 16 had a higher BMI than males of the same age by 1.0 kg/m2 on average.

International variations
These recommended distinctions along the linear scale may vary from time to time and country to country, making global, longitudinal surveys problematic. People from different populations and descent have different associations between BMI, percentage of body fat, and health risks, with a higher risk of type 2 diabetes mellitus and atherosclerotic cardiovascular disease at BMIs lower than the WHO cut-off point for overweight, 25 kg/m2, although the cut-off for observed risk varies among different populations. The cut-off for observed risk varies based on populations and subpopulations in Europe, Asia and Africa.

Hong Kong
The Hospital Authority of Hong Kong recommends the use of the following BMI ranges:

Japan
A 2000 study from the Japan Society for the Study of Obesity (JASSO) presents the following table of BMI categories:

Singapore
In Singapore, the BMI cut-off figures were revised in 2005 by the Health Promotion Board (HPB), motivated by studies showing that many Asian populations, including Singaporeans, have a higher proportion of body fat and increased risk for cardiovascular diseases and diabetes mellitus, compared with general BMI recommendations in other countries. The BMI cut-offs are presented with an emphasis on health risk rather than weight.

United Kingdom
In the UK, NICE guidance recommends prevention of type 2 diabetes should start at a BMI of 30 in White and 27.5 in Black African, African-Caribbean, South Asian, and Chinese populations.

New research based on a large sample of almost 1.5 million people in England found that some ethnic groups would benefit from prevention at or above a BMI of (rounded):
 * 30 in White
 * 28 in Black
 * just below 30 in Black British
 * 29 in Black African
 * 27 in Black Other
 * 26 in Black Caribbean
 * 27 in Arab and Chinese
 * 24 in South Asian
 * 24 in Pakistani, Indian and Nepali
 * 23 in Tamil and Sri Lankan
 * 21 in Bangladeshi

United States
In 1998, the U.S. National Institutes of Health brought U.S. definitions in line with World Health Organization guidelines, lowering the normal/overweight cut-off from a BMI of 27.8 (men) and 27.3 (women) to a BMI of 25. This had the effect of redefining approximately 25 million Americans, previously healthy, to overweight.

This can partially explain the increase in the overweight diagnosis in the past 20 years, and the increase in sales of weight loss products during the same time. WHO also recommends lowering the normal/overweight threshold for southeast Asian body types to around BMI 23, and expects further revisions to emerge from clinical studies of different body types.

A survey in 2007 showed 63% of Americans were then overweight or obese, with 26% in the obese category (a BMI of 30 or more). By 2014, 37.7% of adults in the United States were obese, 35.0% of men and 40.4% of women; class 3 obesity (BMI over 40) values were 7.7% for men and 9.9% for women. The U.S. National Health and Nutrition Examination Survey of 2015-2016 showed that 71.6% of American men and women had BMIs over 25. Obesity—a BMI of 30 or more—was found in 39.8% of the US adults.

Consequences of elevated level in adults
The BMI ranges are based on the relationship between body weight and disease and death. Overweight and obese individuals are at an increased risk for the following diseases:
 * Coronary artery disease
 * Dyslipidemia
 * Type 2 diabetes
 * Gallbladder disease
 * Hypertension
 * Osteoarthritis
 * Sleep apnea
 * Stroke
 * Infertility
 * At least 10 cancers, including endometrial, breast, and colon cancer
 * Epidural lipomatosis

Among people who have never smoked, overweight/obesity is associated with 51% increase in mortality compared with people who have always been a normal weight.

Public health
The BMI is generally used as a means of correlation between groups related by general mass and can serve as a vague means of estimating adiposity. The duality of the BMI is that, while it is easy to use as a general calculation, it is limited as to how accurate and pertinent the data obtained from it can be. Generally, the index is suitable for recognizing trends within sedentary or overweight individuals because there is a smaller margin of error. The BMI has been used by the WHO as the standard for recording obesity statistics since the early 1980s.

This general correlation is particularly useful for consensus data regarding obesity or various other conditions because it can be used to build a semi-accurate representation from which a solution can be stipulated, or the RDA for a group can be calculated. Similarly, this is becoming more and more pertinent to the growth of children, since the majority of children are sedentary. Cross-sectional studies indicated that sedentary people can decrease BMI by becoming more physically active. Smaller effects are seen in prospective cohort studies which lend to support active mobility as a means to prevent a further increase in BMI.

Legislation
In France, Italy, and Spain, legislation has been introduced banning the usage of fashion show models having a BMI below 18. In Israel, a model with BMI below 18.5 is banned. This is done to fight anorexia among models and people interested in fashion.

Relationship to health
A study published by Journal of the American Medical Association (JAMA) in 2005 showed that overweight people had a death rate similar to normal weight people as defined by BMI, while underweight and obese people had a higher death rate.

A study published by The Lancet in 2009 involving 900,000 adults showed that overweight and underweight people both had a mortality rate higher than normal weight people as defined by BMI. The optimal BMI was found to be in the range of 22.5–25. The average BMI of athletes is 22.4 for women and 23.6 for men.

High BMI is associated with type 2 diabetes only in people with high serum gamma-glutamyl transpeptidase.

In an analysis of 40 studies involving 250,000 people, patients with coronary artery disease with normal BMIs were at higher risk of death from cardiovascular disease than people whose BMIs put them in the overweight range (BMI 25–29.9).

One study found that BMI had a good general correlation with body fat percentage, and noted that obesity has overtaken smoking as the world's number one cause of death. But it also notes that in the study 50% of men and 62% of women were obese according to body fat defined obesity, while only 21% of men and 31% of women were obese according to BMI, meaning that BMI was found to underestimate the number of obese subjects.

A 2010 study that followed 11,000 subjects for up to eight years concluded that BMI is not the most appropriate measure for the risk of heart attack, stroke or death. A better measure was found to be the waist-to-height ratio. A 2011 study that followed 60,000 participants for up to 13 years found that waist–hip ratio was a better predictor of ischaemic heart disease mortality.

Limitations
The medical establishment and statistical community have both highlighted the limitations of BMI.

Racial and gender differences
Part of the statistical limitations of the BMI scale is the result of Quetelet's original sampling methods. As noted in his primary work, A Treatise on Man and the Development of His Faculties, the data from which Quetelet derived his formula was taken mostly from Scottish Highland soldiers and French Gendarmerie. The BMI was always designed as a metric for European men. For women, and people of non-European origin, the scale is often biased. As noted by sociologist Sabrina Strings, the BMI is largely inaccurate for black people especially, disproportionately labelling them as overweight even for healthy individuals.

Scaling
The exponent in the denominator of the formula for BMI is arbitrary. The BMI depends upon weight and the square of height. Since mass increases to the third power of linear dimensions, taller individuals with exactly the same body shape and relative composition have a larger BMI. BMI is proportional to the mass and inversely proportional to the square of the height. So, if all body dimensions double, and mass scales naturally with the cube of the height, then BMI doubles instead of remaining the same. This results in taller people having a reported BMI that is uncharacteristically high, compared to their actual body fat levels. In comparison, the Ponderal index is based on the natural scaling of mass with the third power of the height.

However, many taller people are not just "scaled up" short people but tend to have narrower frames in proportion to their height. Carl Lavie has written that "The B.M.I. tables are excellent for identifying obesity and body fat in large populations, but they are far less reliable for determining fatness in individuals."

For US adults, exponent estimates range from 1.92 to 1.96 for males and from 1.45 to 1.95 for females.

Physical characteristics
The BMI overestimates roughly 10% for a large (or tall) frame and underestimates roughly 10% for a smaller frame (short stature). In other words, people with small frames would be carrying more fat than optimal, but their BMI indicates that they are normal. Conversely, large framed (or tall) individuals may be quite healthy, with a fairly low body fat percentage, but be classified as overweight by BMI.

For example, a height/weight chart may say the ideal weight (BMI 21.5) for a 5 ft man is 150 lb. But if that man has a slender build (small frame), he may be overweight at 150 lb and should reduce by 10% to roughly 135 lb (BMI 19.4). In the reverse, the man with a larger frame and more solid build should increase by 10%, to roughly 165 lb (BMI 23.7). If one teeters on the edge of small/medium or medium/large, common sense should be used in calculating one's ideal weight. However, falling into one's ideal weight range for height and build is still not as accurate in determining health risk factors as waist-to-height ratio and actual body fat percentage.

Accurate frame size calculators use several measurements (wrist circumference, elbow width, neck circumference, and others) to determine what category an individual falls into for a given height. The BMI also fails to take into account loss of height through ageing. In this situation, BMI will increase without any corresponding increase in weight.

Muscle versus fat
Assumptions about the distribution between muscle mass and fat mass are inexact. BMI generally overestimates adiposity on those with leaner body mass (e.g., athletes) and underestimates excess adiposity on those with fattier body mass.

A study in June 2008 by Romero-Corral et al. examined 13,601 subjects from the United States' third National Health and Nutrition Examination Survey (NHANES III) and found that BMI-defined obesity (BMI ≥ 30) was present in 21% of men and 31% of women. Body fat-defined obesity was found in 50% of men and 62% of women. While BMI-defined obesity showed high specificity (95% for men and 99% for women), BMI showed poor sensitivity (36% for men and 49% for women). In other words, the BMI will be mostly correct when determining a person to be obese, but can err quite frequently when determining a person not to be. Despite this undercounting of obesity by BMI, BMI values in the intermediate BMI range of 20–30 were found to be associated with a wide range of body fat percentages. For men with a BMI of 25, about 20% have a body fat percentage below 20% and about 10% have body fat percentage above 30%.

Body composition for athletes is often better calculated using measures of body fat, as determined by such techniques as skinfold measurements or underwater weighing and the limitations of manual measurement have also led to new, alternative methods to measure obesity, such as the body volume indicator.

Variation in definitions of categories
It is not clear where on the BMI scale the threshold for overweight and obese should be set. Because of this, the standards have varied over the past few decades. Between 1980 and 2000 the U.S. Dietary Guidelines have defined overweight at a variety of levels ranging from a BMI of 24.9 to 27.1. In 1985 the National Institutes of Health (NIH) consensus conference recommended that overweight BMI be set at a BMI of 27.8 for men and 27.3 for women.

In 1998, an NIH report concluded that a BMI over 25 is overweight and a BMI over 30 is obese. In the 1990s the World Health Organization (WHO) decided that a BMI of 25 to 30 should be considered overweight and a BMI over 30 is obese, the standards the NIH set. This became the definitive guide for determining if someone is overweight.

One study found that the vast majority of people labelled 'overweight' and 'obese' according to current definitions do not in fact face any meaningful increased risk for early death. In a quantitative analysis of several studies, involving more than 600,000 men and women, the lowest mortality rates were found for people with BMIs between 23 and 29; most of the 25–30 range considered 'overweight' was not associated with higher risk.

Corpulence index (exponent of 3)
The corpulence index uses an exponent of 3 rather than 2. The corpulence index yields valid results even for very short and very tall people, which is a problem with BMI. For example, a 152.4 cm tall person at an ideal body weight of 48 kg gives a normal BMI of 20.74 and CI of 13.6, while a 200 cm tall person with a weight of 100 kg gives a BMI of 24.84, very close to an overweight BMI of 25, and a CI of 12.4, very close to a normal CI of 12.

New BMI (exponent of 2.5)
A study found that the best exponent E for predicting the fat percent would be between 2 and 2.5 in $$mass/height^E$$.

An exponent of 5/2 or 2.5 was proposed by Quetelet in the 19$th$ century: "In general, we do not err much when we assume that during development the squares of the weight at different ages are as the fifth powers of the height"

This exponent of 2.5 is used in a revised formula for Body Mass Index, proposed by Nick Trefethen, Professor of numerical analysis at the University of Oxford, which minimizes the distortions for shorter and taller individuals resulting from the use of an exponent of 2 in the traditional BMI formula:
 * $$\mathrm{BMI}_\text{new} = 1.3 \times \frac{\text{mass}_\text{kg}}{\text{height}_\text{m}^{2.5}}$$

The scaling factor of 1.3 was determined to make the proposed new BMI formula align with the traditional BMI formula for adults of average height, while the exponent of 2.5 is a compromise between the exponent of 2 in the traditional formula for BMI and the exponent of 3 that would be expected for the scaling of weight (which at constant density would theoretically scale with volume, i.e., as the cube of the height) with height. In Trefethen's analysis, an exponent of 2.5 was found to fit empirical data more closely with less distortion than either an exponent of 2 or 3.

BMI prime (exponent of 2, normalization factor)
BMI Prime, a modification of the BMI system, is the ratio of actual BMI to upper limit optimal BMI (currently defined at 25 kg/m2), i.e., the actual BMI expressed as a proportion of upper limit optimal. BMI Prime is a dimensionless number independent of units. Individuals with BMI Prime less than 0.74 are underweight; those with between 0.74 and 1.00 have optimal weight; and those at 1.00 or greater are overweight. BMI Prime is useful clinically because it shows by what ratio (e.g. 1.36) or percentage (e.g. 136%, or 36% above) a person deviates from the maximum optimal BMI.

For instance, a person with BMI 34 kg/m2 has a BMI Prime of 34/25 = 1.36, and is 36% over their upper mass limit. In South East Asian and South Chinese populations (see § international variations), BMI Prime should be calculated using an upper limit BMI of 23 in the denominator instead of 25. BMI Prime allows easy comparison between populations whose upper-limit optimal BMI values differ.

Waist circumference
Waist circumference is a good indicator of visceral fat, which poses more health risks than fat elsewhere. According to the U.S. National Institutes of Health (NIH), waist circumference in excess of 1020 mm for men and 880 mm for (non-pregnant) women is considered to imply a high risk for type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease CVD. Waist circumference can be a better indicator of obesity-related disease risk than BMI. For example, this is the case in populations of Asian descent and older people. 940 mm for men and 800 mm for women has been stated to pose "higher risk", with the NIH figures "even higher".

Waist-to-hip circumference ratio has also been used, but has been found to be no better than waist circumference alone, and more complicated to measure.

A related indicator is waist circumference divided by height. A 2013 study identified critical threshold values for waist-to-height ratio according to age, with consequent significant reduction in life expectancy if exceeded. These are: 0.5 for people under 40 years of age, 0.5 to 0.6 for people aged 40–50, and 0.6 for people over 50 years of age.

Surface-based body shape index
The Surface-based Body Shape Index (SBSI) is far more rigorous and is based upon four key measurements: the body surface area (BSA), vertical trunk circumference (VTC), waist circumference (WC) and height (H). Data on 11,808 subjects from the National Health and Human Nutrition Examination Surveys (NHANES) 1999–2004, showed that SBSI outperformed BMI, waist circumference, and A Body Shape Index (ABSI), an alternative to BMI.

 * $$\mathrm{SBSI} = \frac{(\text{H}^{7/4})(\text{WC}^{5/6})}{\text{BSA VTC}}$$

A simplified, dimensionless form of SBSI, known as SBSI*, has also been developed.

 * $$\mathrm{SBSI^\star} = \frac{(\text{H}^2)(\text{WC})}{\text{BSA VTC}}$$

Modified body mass index
Within some medical contexts, such as familial amyloid polyneuropathy, serum albumin is factored in to produce a modified body mass index (mBMI). The mBMI can be obtained by multiplying the BMI by serum albumin, in grams per litre.

title: Body mass index


text:
Behistun Inscription

The Behistun Inscription (also Bisotun, Bisitun or Bisutun;, Old Persian: Bagastana, meaning "the place of god") is a multilingual Achaemenid royal inscription and large rock relief on a cliff at Mount Behistun in the Kermanshah Province of Iran, near the city of Kermanshah in western Iran, established by Darius the Great ((r. 522 – 486)). It was important to the decipherment of cuneiform, as it is the longest known trilingual cuneiform inscription, written in Old Persian, Elamite, and Babylonian (a variety of Akkadian).

Authored by Darius the Great sometime between his coronation as king of the Persian Empire in the summer of 522 BC and his death in autumn of 486 BC, the inscription begins with a brief autobiography of Darius, including his ancestry and lineage. Later in the inscription, Darius provides a lengthy sequence of events following the death of Cambyses II in which he fought nineteen battles in a period of one year (ending in December 521 BC) to put down multiple rebellions throughout the Persian Empire. The inscription states in detail that the rebellions were orchestrated by several impostors and their co-conspirators in various cities throughout the empire, each of whom falsely proclaimed himself king during the upheaval following Cambyses II's death. Darius the Great proclaimed himself victorious in all battles during the period of upheaval, attributing his success to the "grace of Ahura Mazda".

The inscription is approximately 15 m high by 25 m wide and 100 m up a limestone cliff from an ancient road connecting the capitals of Babylonia and Media (Babylon and Ecbatana, respectively). The Old Persian text contains 414 lines in five columns; the Elamite text includes 260 lines in eight columns, and the Babylonian text is in 112 lines. A copy of the text in Aramaic, written during the reign of Darius II, was found in Egypt. The inscription was illustrated by a life-sized bas-relief of Darius I, the Great, holding a bow as a sign of kingship, with his left foot on the chest of a figure lying supine before him. The supine figure is reputed to be the pretender Gaumata. Darius is attended to the left by two servants, and nine one-meter figures stand to the right, with hands tied and rope around their necks, representing conquered peoples. A Faravahar floats above, giving its blessing to the king. One figure appears to have been added after the others were completed, as was Darius's beard, which is a separate block of stone attached with iron pins and lead.

Name
The name Behistun is derived from usage in Ancient Greek and Arabic sources, particularly Diodorus Siculus and Ya'qubi, transliterated into English in the 19th century by Henry Rawlinson. The modern Persian version name is Bisotun.

History
After the fall of the Persian Empire's Achaemenid Dynasty and its successors, and the lapse of Old Persian cuneiform writing into disuse, the nature of the inscription was forgotten, and fanciful explanations became the norm.

In 1598, Englishman Robert Sherley saw the inscription during a diplomatic mission to Safavid Persia on behalf of Austria, and brought it to the attention of Western European scholars. His party incorrectly came to the conclusion that it was Christian in origin. French General Gardanne thought it showed "Christ and his twelve apostles", and Sir Robert Ker Porter thought it represented the Lost Tribes of Israel and Shalmaneser of Assyria. In 1604, Italian explorer Pietro della Valle visited the inscription and made preliminary drawings of the monument.

Translation efforts

German surveyor Carsten Niebuhr visited in around 1764 for Frederick V of Denmark, publishing a copy of the inscription in the account of his journeys in 1778. Niebuhr's transcriptions were used by Georg Friedrich Grotefend and others in their efforts to decipher the Old Persian cuneiform script. Grotefend had deciphered ten of the 37 symbols of Old Persian by 1802, after realizing that unlike the Semitic cuneiform scripts, Old Persian text is alphabetic and each word is separated by a vertical slanted symbol.

In 1835, Sir Henry Rawlinson, an officer of the British East India Company army assigned to the forces of the Shah of Iran, began studying the inscription in earnest. As the town of Bisotun's name was anglicized as "Behistun" at this time, the monument became known as the "Behistun Inscription". Despite its relative inaccessibility, Rawlinson was able to scale the cliff with the help of a local boy and copy the Old Persian inscription. The Elamite was across a chasm, and the Babylonian four meters above; both were beyond easy reach and were left for later. In 1847, he was able to send a full and accurate copy to Europe.

Later research and activity
The site was visited by the American linguist A. V. Williams Jackson in 1903. Later expeditions, in 1904 sponsored by the British Museum and led by Leonard William King and Reginald Campbell Thompson and in 1948 by George G. Cameron of the University of Michigan, obtained photographs, casts and more accurate transcriptions of the texts, including passages that were not copied by Rawlinson. It also became apparent that rainwater had dissolved some areas of the limestone in which the text was inscribed, while leaving new deposits of limestone over other areas, covering the text.

In 1938, the inscription became of interest to the Nazi German think tank Ahnenerbe, although research plans were cancelled due to the onset of World War II.

The monument later suffered some damage from Allied soldiers using it for target practice in World War II, and during the Anglo-Soviet invasion of Iran.

In 1999, Iranian archeologists began the documentation and assessment of damages to the site incurred during the 20th century. Malieh Mehdiabadi, who was project manager for the effort, described a photogrammetric process by which two-dimensional photos were taken of the inscriptions using two cameras and later transmuted into 3-D images.

In recent years, Iranian archaeologists have been undertaking conservation works. The site became a UNESCO World Heritage Site in 2006.

In 2012, the Bisotun Cultural Heritage Center organized an international effort to re-examine the inscription.

Lineage
In the first section of the inscription, Darius the Great declares his ancestry and lineage:

"King Darius says: My father is Hystaspes [Vištâspa]; the father of Hystaspes was Arsames [Aršâma]; the father of Arsames was Ariaramnes [Ariyâramna]; the father of Ariaramnes was Teispes [Cišpiš]; the father of Teispes was Achaemenes [Haxâmaniš]. King Darius says: That is why we are called Achaemenids; from antiquity we have been noble; from antiquity has our dynasty been royal. King Darius says: Eight of my dynasty were kings before me; I am the ninth. Nine in succession we have been kings. King Darius says: By the grace of Ahuramazda am I king; Ahuramazda has granted me the kingdom."

Territories
Darius also lists the territories under his rule:

"King Darius says: These are the countries which are subject unto me, and by the grace of Ahuramazda I became king of them: Persia [Pârsa], Elam [Ûvja], Babylonia [Bâbiruš], Assyria [Athurâ], Arabia [Arabâya], Egypt [Mudrâya], the countries by the Sea [Tyaiy Drayahyâ (Phoenicia)], Lydia [Sparda], the Greeks [Yauna (Ionia)], Media [Mâda], Armenia [Armina], Cappadocia [Katpatuka], Parthia [Parthava], Drangiana [Zraka], Aria [Haraiva], Chorasmia [Uvârazmîy], Bactria [Bâxtriš], Sogdia [Suguda], Gandhara [Gadâra], Scythia [Saka], Sattagydia [Thataguš], Arachosia [Harauvatiš] and Maka [Maka]; twenty-three lands in all."

Conflicts and revolts
Later in the inscription, Darius provides an eye-witness account of battles he successfully fought over a one-year period to put down rebellions which had resulted from the deaths of Cyrus the Great, and his son Cambyses II:

Other historical monuments in the Behistun complex
The site covers an area of 116 hectares. Archeological evidence indicates that this region became a human shelter 40,000 years ago. There are 18 historical monuments other than the inscription of Darius the Great in the Behistun complex that have been registered in the Iranian national list of historical sites. Some of them are:

 * Hunters' cave
 * Farhād Tarāsh
 * Median fortress
 * Parthian town
 * Statue of Hercules in Behistun
 * Parthian site of worship

 * Behistun Palace (said to be Palace of Khosrau II)
 * Ilkhanid caravanserai
 * Median temple
 * Bas relief of Mithridates II of Parthia
 * Bas relief of Gotarzes II of Parthia

 * Sheikh Ali khan Zangeneh text endowment
 * Safavid caravanserai
 * Vologases's relief
 * Carved Sassanian stones
 * Royal Road

Similar reliefs and inspiration

The Anubanini rock relief, also called Sarpol-i Zohab, of the Lullubi king Anubanini, dated to c. 2300 BC, and which is located not far from the Behistun reliefs at Sarpol-e Zahab, is very similar to the reliefs at Behistun. The attitude of the ruler, the trampling of an enemy, the lines of prisoners are all very similar, to such extent that it was said that the sculptors of the Behistun Inscription had probably seen the Anubanini relief beforehand and were inspired by it. The Lullubian reliefs were the model for the Behistun reliefs of Darius the Great.

The inscriptional tradition of the Achaemenids, starting especially with Darius I, is thought to have derived from the traditions of Elam, Lullubi, the Babylonians and the Assyrians.

title: Behistun Inscription