Template:Short description Template:Redirect Template:Good article Template:Use dmy dates Template:Cs1 config Template:Infobox drug class Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) 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.<ref name="isbn0-19-517668-5"/> 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.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref>
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.<ref name=ip2002/> 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.<ref name=pmid18175099/> 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.<ref name=sddat/>
Benzodiazepines are generally viewed as safe and effective for short-term use of two to four weeks,<ref>Template:Cite journal</ref> although cognitive impairment and paradoxical effects such as aggression or behavioral disinhibition can occur.<ref name=pmid18922233/> 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."<ref name="Better Health Channel 2000 i441">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A minority of people have paradoxical reactions after taking benzodiazepines such as worsened agitation or panic.<ref name=pmid18922233/> Benzodiazepines are often prescribed for as-needed use, which is under-studied, but probably safe and effective to the extent that it involves intermittent short-term use.<ref>Template:Cite journal</ref>
Benzodiazepines are associated with an increased risk of suicide due to aggression, impulsivity, and negative withdrawal effects.<ref name="Dodds_2017">Template:Cite journal</ref> Long-term use is controversial because of concerns about decreasing effectiveness, physical dependence, benzodiazepine withdrawal syndrome, and an increased risk of dementia and cancer.<ref name=pmid18671662/><ref name=pmid19062773/><ref name="pmid29926372"/><ref name="Use of benzodiazepine and risk of c">Template:Cite journal</ref> The elderly are at an increased risk of both short- and long-term adverse effects,<ref name=tdamobd2004/><ref name=ohop/> and as a result, all benzodiazepines are listed in the Beers List of inappropriate medications for older adults.<ref name=agsubc2015>Template:Cite journal</ref> 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;<ref name=ACOG /> 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.<ref name=pmid9780123/><ref>Template:Cite press release</ref> Benzodiazepines are commonly used recreationally and also often taken in combination with other addictive substances, and are controlled in most countries.<ref name=Charlson_2009/><ref name=pmid10707430/><ref name=pmid10622686/> Template:TOC limit
Medical usesEdit
Benzodiazepines possess psycholeptic, sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnesic actions,<ref name=ip2002>Template:Cite book</ref><ref name=pmid18175099>Template:Cite book</ref> 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.<ref name="BNF_2009">Template:Cite book</ref>Template:Rp In general, benzodiazepines are well tolerated and are safe and effective drugs in the short term for a wide range of conditions.<ref name=Perugi>Template:Cite journal</ref><ref name=Tesar>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The effects of long-term use or misuse include the tendency to cause or worsen cognitive deficits, depression, and anxiety.<ref name=tdamobd2004>Template:Cite journal</ref><ref name=ohop/> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name=":0" />
Panic disorderEdit
Benzodiazepines are usually administered orally; however, very occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks.<ref name="BNF_2009"/>
Because of their effectiveness, tolerability, and rapid onset of anxiolytic action, benzodiazepines are frequently used for the treatment of anxiety associated with panic disorder.<ref name="pmid15762816">Template:Cite journal</ref> 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<ref name=cgftmamoa2004/> and should be reserved for treatment-resistant cases<ref>Template:Cite journal</ref> to those holding they are as effective in the long term as selective serotonin reuptake inhibitors (SSRIs).<ref name=APA/>
American Psychiatric Association (APA) guidelines, published in January 2009,<ref name="APA">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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 more quickly 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.<ref name=APA/>
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.<ref name=cgftmamoa2004>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite journal</ref> 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.<ref name=cgftmamoa2004 />
Generalized anxiety disorderEdit
Benzodiazepines have robust efficacy in the short-term management of generalized anxiety disorder (GAD) when standardized measures of anxiety are used as the outcome variable,<ref>Template:Cite journal</ref> but did not demonstrate a favorable dropout rate compared to placebo in one meta-analysis.<ref name="pmid17881433">Template:Cite journal</ref> A newer meta-analysis showed that benzodiazepines are significantly more effective than serotonergic agents, regardless of treatment length.<ref name="pmid29806492">Template:Cite journal</ref> More research is needed, but unfortunately, newer randomized controlled trials are scarce for the off patent benzodiazepines. 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.<ref name=NICECG022>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref name="pmid16933543">Template:Cite journal</ref> Although they are second-line agents, benzodiazepines can be used for a limited time to relieve severe anxiety and agitation. CPA guidelines state that after 4–6 weeks the effect of benzodiazepines may decrease to the level of placebo,<ref name="pmid16933543" /> and that benzodiazepines are less effective than antidepressants in alleviating ruminative worry, the core symptom of GAD, but that in some cases, a prolonged treatment with benzodiazepines as the add-on to an antidepressant may be justified. Evidence from reviews of benzodiazepine tolerance mechanisms<ref name=":2" /> and clonazepam use in psychiatric disorders<ref name="pmid16528135" /> is strongly discordant with the claim that benzodiazepines lose anxiolytic efficacy over a period of weeks, as these reviews present RCT evidence of continued anxiolytic efficacy at up to 22 weeks<ref name=":3" /> and observational (open-label) evidence of continued efficacy at up to 3 years.<ref name=":4" />
A 2015 review found a larger effect with medications than talk therapy.<ref name=Band2015>Template:Cite journal</ref> Medications with benefit include serotonin-noradrenaline reuptake inhibitors, benzodiazepines, and selective serotonin reuptake inhibitors.<ref name=Band2015/>
InsomniaEdit
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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="nice-hypnotics">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid17853625">Template:Cite journal</ref> 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.<ref name="handbook_of_integrative">Template:Cite book</ref><ref name="ahrq"/>
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.<ref name="pmid17853625"/> Longer-acting benzodiazepines such as nitrazepam and diazepam have residual effects that may persist into the next day and are, in general, not recommended.<ref name="nice-hypnotics"/>
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).<ref name="Kaufmann_2016">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="nice-hypnotics"/><ref name="ahrq"/> 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.<ref name="ahrq">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia.<ref name="pmid17853625"/> 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.<ref name="nice-hypnotics"/>
Older adults should not use benzodiazepines to treat insomnia unless other treatments have failed.<ref name="AGSfive"/> 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.<ref name="AGSfive">Template:Cite journal, which cites</ref><ref name="pmid16156679"/><ref>Template:Cite journal</ref>
SeizuresEdit
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.<ref name=SIGN70>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=NICECG020>Template:Cite book</ref>
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.<ref name="pmid19298435">Template:Cite journal</ref> Clobazam is widely used by specialist epilepsy clinics worldwide and clonazepam is popular in the Netherlands, Belgium and France.<ref name="pmid19298435"/> 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.<ref name=NICECG020b>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Clobazam also has a useful role for very short-term seizure prophylaxis and in catamenial epilepsy.<ref name="pmid19298435"/> 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.<ref name=NICECG020/>
Alcohol withdrawalEdit
Chlordiazepoxide is the most commonly used benzodiazepine for alcohol detoxification,<ref name="pmid9270461">Template:Cite journal</ref> 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.<ref name="BNF_2009"/>Template:Rp 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
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.<ref>Template:Cite journal</ref> Lorazepam is the only benzodiazepine with predictable intramuscular absorption and it is the most effective in preventing and controlling acute seizures.<ref>Template:Cite journal</ref>
Other indicationsEdit
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.<ref>Template:Cite journal</ref> They have also been found to increase the likelihood of later PTSD after people have been removed from ventilators.<ref>Template:Cite journal</ref>
- 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.<ref>Template:Cite journal</ref>
- 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.<ref name="Broscheit-2008">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref name="BNF_2009"/>Template:Rp
- Benzodiazepines are well known for their strong muscle-relaxing properties and can be useful in the treatment of muscle spasms,<ref name="BNF_2009"/>Template:Rp although tolerance often develops to their muscle relaxant effects.<ref name=tdamobd2004 /> Baclofen<ref>Template:Cite journal</ref> or tizanidine are sometimes used as an alternative to benzodiazepines. Tizanidine has been found to have superior tolerability compared to diazepam and baclofen.<ref name="Kamen-2008">Template:Cite journal</ref>
- Benzodiazepines are also used to treat the acute panic caused by hallucinogen intoxication.<ref>Template:Cite book</ref> Benzodiazepines are also used to calm the acutely agitated individual and can, if required, be given via an intramuscular injection.<ref>Template:Cite journal</ref> 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;<ref>Template:Cite journal</ref> their long-term use is not recommended due to risks of dependence.<ref name="BNF_2009"/>Template:Rp Further research investigating the use of benzodiazepines alone and in combination with antipsychotic medications for treating acute psychosis is warranted.<ref>Template:Cite journal</ref>
- Clonazepam, a benzodiazepine is used to treat many forms of parasomnia.<ref>Template:Cite journal</ref> Rapid eye movement behavior disorder responds well to low doses of clonazepam.<ref name="pmid10996567">Template:Cite journal</ref><ref>Template:Cite journal</ref> Restless legs syndrome can be treated using clonazepam as a third line treatment option as the use of clonazepam is still investigational.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
- 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.<ref>Template:Cite book</ref> Benzodiazepines can be considered as a treatment option in treatment resistant cases.<ref>Template:Cite journal</ref>
- 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.<ref name="Attard-2008">Template:Cite journal</ref>
- There is some evidence that low doses of benzodiazepines reduce adverse effects of electroconvulsive therapy.<ref name="pmid22531198">Template:Cite journal</ref>
ContraindicationsEdit
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.<ref>Template:Cite journal</ref>
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.<ref name="isbn0-683-30128-4"/><ref name="isbn0-444-50998-4"/> Caution is required when benzodiazepines are used in people with personality disorders or intellectual disability because of frequent paradoxical reactions.<ref name="isbn0-683-30128-4"/><ref name="isbn0-444-50998-4"/> In major depression, they may precipitate suicidal tendencies<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and are sometimes used for suicidal overdoses.<ref name="isbn0-444-50998-4"/> 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.<ref name="isbn1-58829-211-8"/>
PregnancyEdit
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.<ref>Template:Cite book</ref>
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.<ref name=ACOG>Template:Cite journal</ref><ref name=pmid9748174>Template:Cite journal</ref> 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.<ref name=ACOG/><ref name=pmid9614425>Template:Cite journal</ref> 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<ref>Temazepam-Rxlist Pregnancy Category@</ref> or triazolam. Using the lowest effective dose for the shortest period of time minimizes the risks to the unborn child.<ref>Template:Cite journal</ref>
ElderlyEdit
The benefits of benzodiazepines are least and the risks are greatest in the elderly.<ref name=pmid18035234>Template:Cite journal</ref><ref>Template:Cite journal</ref> They are listed as a potentially inappropriate medication for older adults by the American Geriatrics Society.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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,<ref name=pmid16156679>Template:Cite journal</ref> and an increased risk of hip fractures.<ref name="pmid22566242">Template:Cite journal</ref> 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 of 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.<ref name="pmid15001721">Template:Cite journal</ref><ref name="prescribing_for_elderly_patients"/> 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.<ref name="prescribing_for_elderly_patients">Template:Cite book</ref><ref>Template:Cite book</ref>
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.<ref name="pmid29926372">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>
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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Cognitive impairing effects of benzodiazepines that occur frequently in the elderly can also worsen dementia.<ref name="pmid10779253">Template:Cite journal</ref>
Adverse effectsEdit
Template:See also 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.<ref name="isbn0-683-30128-4">Template:Cite book</ref><ref name="isbn0-470-02821-1">Template:Cite book</ref><ref name="pmid18929314">Template:Cite journal</ref> Another result is impairment of driving skills and increased likelihood of road traffic accidents.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name="isbn0-683-30128-4"/><ref name="isbn0-470-02821-1"/> 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.<ref name="BNF_2009"/>Template:Rp<ref>Template:Medicinenet</ref>
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.<ref name="asapdacg">Template:Cite book</ref><ref>Template:Cite book</ref> Additionally, an altered perception of self, environment and relationships may occur.<ref name="pmid15762814" /> 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.<ref>Template:Cite journal</ref>
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.<ref name=":0">Template:Cite journal</ref>
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.<ref>Template:Citation-attribution</ref>
Cognitive effectsEdit
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.<ref name="isbn0-683-30128-4" /> 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.<ref name="pmid15762814">Template:Cite journal</ref><ref name="pmid14731058">Template:Cite journal</ref> 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<ref name="pmid14731058" /> and a later reviewer<ref name="pmid15762814" /> 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 effectsEdit
Paradoxical reactions, such as increased seizures in epileptics,<ref name="Riss-2008">Template:Cite journal</ref> aggression, violence, impulsivity, irritability and suicidal behavior sometimes occur.<ref name="Dodds_2017" /> 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.<ref name=pmid18922233>Template:Cite journal</ref><ref name=badar2002>Template:Cite journal</ref> However, they occur with greater frequency in recreational abusers, individuals with borderline personality disorder, children, and patients on high-dosage regimes.<ref name="Bond_1998">Template:Cite journal</ref><ref name="Drummer_2002">Template:Cite journal</ref> 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.<ref name=badar2002 /> Paradoxical effects may also appear after chronic use of benzodiazepines.<ref name=cbpham>Template:Cite book</ref>
Long-term worsening of psychiatric symptomsEdit
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,<ref name="Michelini_1996" /><ref name="Lydiard_1996">Template:Cite journal</ref> disrupting sleep architecture by inhibiting deep stage sleep,<ref name="Psychiatry_2008" /> withdrawal symptoms or rebound symptoms in between doses mimicking or exacerbating underlying anxiety or sleep disorders,<ref name="Michelini_1996" /><ref name="Lydiard_1996" /> inhibiting the benefits of psychotherapy by inhibiting memory consolidation and reducing fear extinction,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and reducing coping with trauma/stress and increasing vulnerability to future stress.<ref>Template:Cite journal</ref> The latter two explanations may be why benzodiazepines are ineffective and/or potentially harmful in PTSD and phobias.<ref>Template:Cite book</ref> Anxiety, insomnia and irritability may be temporarily exacerbated during withdrawal, but psychiatric symptoms after discontinuation are usually less than even while taking benzodiazepines.<ref name="Michelini_1996" /><ref>Template:Cite journal</ref> Functioning significantly improves within 1 year of discontinuation.<ref name="Michelini_1996" /><ref>Template:Cite journal</ref>
Physical dependence, withdrawal and post-withdrawal syndromesEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}
ToleranceEdit
Tolerance and dependence are risks of chronic benzodiazepine use, and can result in doses within the therapeutic range ceasing to offer meaningful symptomatic relief after prolonged use. Tolerance develops at different rates and to different degrees to the sedative, hypnotic, anticonvulsant, muscle relaxant and anxiolytic effects of benzodiazpines. A review<ref name=":2">Template:Cite journal</ref> of benzodiazepine tolerance concluded that it "appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all", although the included randomized controlled trial evidence<ref>Template:Cite journal</ref><ref name=":3">Template:Cite journal</ref> is limited to 22 weeks. A review of clonazepam in the treatment of psychiatric disorders concluded that there is longitudinal data supporting anxiolytic benefit without tolerance during long-term use,<ref name="pmid16528135">Template:Cite journal</ref> including an open-label study finding continued benefit at 3 years.<ref name=":4">Template:Cite journal</ref> However, the review concludes that long-term RCT evidence is scant. A study of benzodiazepine sensitivity found that patients treated chronically with alprazolam did not differ from untreated patients in terms of anxiolytic response to diazepam, suggesting a lack of anxiolytic tolerance.<ref>Template:Cite journal</ref>
However, controversy remains regarding tolerance to anxiolytic effects, with some publications reporting that there is little evidence of continued efficacy beyond 4–6 months<ref name="pmid10779253" /> or that dependence phenomena are common.<ref name="Perugi" /><ref name="cgftmamoa2004" /> However, some of these references were published prior to the in-depth scoping reviews of benzodiazepine tolerance, and lack citations of RCT evidence of tolerance. Studies reporting on voluntary benzodiazepine cessation and withdrawal include patient reports of tolerance and worsening anxiety.<ref name="tdamobd2004" />
The question of tolerance to the amnesic effects of benzodiazepines is, likewise, unclear.<ref name="pmid15762818">Template:Cite journal</ref> Some evidence suggests that partial tolerance does develop, and that, "memory impairment is limited to a narrow window within 90 minutes after each dose".<ref name="pmid15078112">Template:Cite journal</ref>
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 effects within weeks to months.<ref name="Michelini_1996">Template:Cite journal</ref> Therefore, benzodiazepines are unlikely to be effective long-term treatments for sleep. While BZD therapeutic effects may disappear with tolerance, depression and impulsivity with high suicidal risk commonly persist.<ref name="Michelini_1996" /> Several studies have confirmed that long-term benzodiazepines are not significantly different from placebo for sleep,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and question their use for anxiety disorders such as PTSD and OCD.<ref name="Michelini_1996" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name="Psychiatry_2008">Template:Cite book</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name="DSM-5">Template:Cite book</ref> Most patients with anxiety disorders and PTSD have symptoms that persist for at least several months,<ref name="DSM-5" /> 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).<ref>Template:Cite journal</ref>
Withdrawal symptoms and managementEdit
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.<ref name="pmid15078112" />
The most frequent symptoms of withdrawal from benzodiazepines are insomnia, gastric problems, tremors, agitation, fearfulness, and muscle spasms.<ref name="pmid15078112" /> The less frequent effects are irritability, sweating, depersonalization, derealization, hypersensitivity to stimuli, depression, suicidal behavior, psychosis, seizures, and delirium tremens.<ref name="isbn0-19-856667-0">Template:Cite book</ref> 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.<ref name="gaba-glutamate-adapt">Template:Cite journal</ref><ref name="gabaa-dependence">Template:Cite journal</ref> Therefore, a gradual reduction regimen is recommended.<ref name="pmid19062773">Template:Cite journal</ref>
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.<ref name="isbn0-19-852518-4">Template:Cite book</ref> 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.<ref name=pmid1675688>Template:Cite journal</ref>
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,<ref name=pmid19062773 /> 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.<ref name=tdamobd2004 /><ref name="BNF_2009"/>Template:Rp
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.<ref name="manual" /> A further benefit is that it is available in liquid form, which allows for even smaller reductions.<ref name=pmid19062773/> Chlordiazepoxide, which also has a long half-life and long-acting active metabolites, can be used as an alternative.<ref name="manual">Template:Cite book</ref><ref>Template:Cite book</ref>
Nonbenzodiazepines are contraindicated during benzodiazepine withdrawal as they are cross tolerant with benzodiazepines and can induce dependence.<ref name=tdamobd2004 /> Alcohol is also cross tolerant with benzodiazepines and more toxic and thus caution is needed to avoid replacing one dependence with another.<ref name="manual" /> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite book</ref>
Withdrawal from long term benzodiazepines is beneficial for most individuals.<ref name=cbpham /> 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.<ref name=tdamobd2004 /><ref name=asapdacg/>
Controversial associationsEdit
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.<ref>Template:Cite journal</ref>
DementiaEdit
A number of studies have drawn an association between long-term benzodiazepine use and neuro-degenerative disease, particularly Alzheimer's disease.<ref>Template:Cite journal</ref> It has been determined that long-term use of benzodiazepines is associated with increased dementia risk, even after controlling for protopathic bias.<ref name="pmid29926372"/>
InfectionsEdit
Some observational studies have detected significant associations between benzodiazepines and respiratory infections such as pneumonia<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> where others have not.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> An immunodeficiency effect from the action of benzodiazepines on GABA-A receptors has been postulated from animal studies.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
CancerEdit
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.<ref name="Use of benzodiazepine and risk of c"/> 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.<ref>Template:Cite journal</ref>
PancreatitisEdit
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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.
OverdoseEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Although benzodiazepines are much safer in overdose than their predecessors, the barbiturates, they can still cause problems in overdose.<ref name=pmid9780123>Template:Cite journal</ref> Taken alone, they rarely cause severe complications in overdose;<ref>Template:Cite journal</ref> statistics in England showed that benzodiazepines were responsible for 3.8% of all deaths by poisoning from a single drug.<ref name=Charlson_2009/> However, combining these drugs with alcohol, opiates or tricyclic antidepressants markedly raises the toxicity.<ref name=pmid10707430>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=ohoam>Template:Cite book</ref> The elderly are more sensitive to the side effects of benzodiazepines, and poisoning may even occur from their long-term use.<ref>Template:Cite journal</ref> The various benzodiazepines differ in their toxicity; temazepam appears most toxic in overdose and when used with other drugs.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The symptoms of a benzodiazepine overdose may include; drowsiness, slurred speech, nystagmus, hypotension, ataxia, coma, respiratory depression, and cardiorespiratory arrest.<ref name=ohoam />
A reversal agent for benzodiazepines exists, flumazenil (Anexate), itself belonging to the chemical class of benzodiazepines. Its use as an antidote is not routinely recommended because of the high risk of resedation and seizures.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> One study found that only 10% of the people presenting with a benzodiazepine overdose are suitable candidates for treatment with flumazenil.<ref name="isbn0-07-136001-8">Template:Cite book</ref>
InteractionsEdit
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.<ref name="isbn0-444-50998-4">Template:Cite book</ref>
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.<ref name="isbn1-58829-211-8"/><ref name="biadmtad">Template:Cite journal</ref> 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.<ref name="isbn1-58829-211-8">Template:Cite book</ref><ref name=biadmtad/> Antacids can slow down absorption of some benzodiazepines; however, this effect is marginal and inconsistent.<ref name="isbn1-58829-211-8"/>
PharmacologyEdit
PharmacodynamicsEdit
Benzodiazepines work by increasing the effectiveness of the endogenous chemical, GABA, to decrease the excitability of neurons.<ref name="isbn0-12-088397-X">Template:Cite book</ref> 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.<ref name="isbn0-12-088397-X"/> 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.<ref name="pmid16376150">Template:Cite journal</ref> 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.<ref>Template:Cite book</ref>
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.<ref name="pmid8783370">Template:Cite journal</ref> 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.<ref name="pmid15157182">Template:Cite journal</ref> 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.<ref name="pmid9824848">Template:Cite journal</ref>
GABAA receptors participate in the regulation of synaptic pruning by prompting microglial spine engulfment.<ref>Template:Cite journal</ref> Benzodiazepines have been shown to upregulate microglial spine engulfment and prompt overzealous eradication of synaptic connections.<ref>Template:Cite journal</ref> This mechanism may help explain the increased risk of dementia associated with long-term benzodiazepine treatment.<ref>Template:Cite journal</ref>
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.<ref name="pmid12240908">Template:Cite journal</ref> 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.<ref name="pmid9504140">Template:Cite journal</ref><ref name="pmid9378234">Template:Cite journal</ref> 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.<ref name="pmid16780077">Template:Cite journal</ref> 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.<ref name="pmid18922233" />
PharmacokineticsEdit
| Benzodiazepine | Half-life (range, hours) |
Speed of onset |
|---|---|---|
| Alprazolam | 6–15<ref name=OBrien>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation | CitationClass=web
}}</ref>|| Intermediate<ref name=OBrien /> |
| Chlordiazepoxide | Template:Nts–30<ref name=OBrien /> | Intermediate<ref name=OBrien /> |
| Clonazepam | Template:Nts–60<ref name=OBrien /> | Slow<ref name=OBrien /> |
| Diazepam | Template:Nts–80<ref name=OBrien /> | Fast<ref name=OBrien /> |
| Flunitrazepam | Template:Nts–26 | Fast |
| Lorazepam | Template:Nts–20<ref name=OBrien /> | Intermediate<ref name=OBrien /> |
| Midazolam | Template:Nts–2.5<ref name=medsafe2012>{{#invoke:citation/CS1|citation | CitationClass=web
}}</ref> || Fast |
| Oxazepam | Template:Nts–10<ref name=OBrien /> | Slow<ref name=OBrien /> |
| Prazepam | Template:Nts–200<ref name=OBrien /> | Slow<ref name=OBrien /> |
| Triazolam | Template:Nts | Fast |
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.<ref name="Cardinali_2006">Template:Cite book</ref> 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.<ref name=sddat>Template:Cite book</ref><ref name="manual" />
- 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.
ChemistryEdit
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.<ref name="isbn0-12-088397-X"/> Other less important modes of action are also known.<ref name="pmid9504140"/><ref name="pmid16780077"/>
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.<ref name=IUPAC>Template:BlueBook1993; Template:Cite journal</ref> 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.<ref name="IUPAC" />
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.<ref name="isbn0-12-088397-X"/> 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).<ref name=CAS>CAS registry number:Template:CAS; other names: Ro 05-2921, dechlorodemethyldiazepam.</ref> Benzodiazepines have been found to mimic protein reverse turns structurally, which enable them with their biological activity in many cases.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
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.<ref name="isbn0-471-21384-5">Template:Cite book</ref>
Not all benzodiazepines increase the conductance of the GABAA receptor. Flumazenil, an imidazobenzodiazepine, is an antidote for some benzodiazepine overdoses.<ref>Template:Cite journal</ref> The structual scaffold can even be used to target receptors other than GABAA.<ref>Template:Cite journal</ref>
TypesEdit
- 2-keto compounds:
- clorazepate, diazepam, flurazepam, halazepam, prazepam, and others<ref name=ub>{{#invoke:citation/CS1|citation
|CitationClass=web }}</ref><ref name=PC89>Template:Cite journal</ref>
- 3-hydroxy compounds:
- lorazepam, lormetazepam, oxazepam, temazepam<ref name=ub/><ref name=PC89/>
- 7-nitro compounds:
- clonazepam, flunitrazepam, nimetazepam, nitrazepam<ref name=ub/><ref name=PC89/>
- Triazolo compounds:
- adinazolam, alprazolam, estazolam, triazolam<ref name=ub/><ref name=PC89/>
- Imidazo compounds:
- climazolam, loprazolam, midazolam<ref name=ub/><ref name=PC89/>
- 1,5-benzodiazepines:
HistoryEdit
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.<ref name="pmid34039">Template:Cite journal</ref><ref name="Miller-Gold">Template:Cite journal</ref> 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.<ref name="isbn0-19-517668-5">Template:Cite book</ref>
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.<ref>Template:Cite journal</ref> 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.<ref name="urlHouse of Commons">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=":1">Template:Cite journal</ref> The court case fell through, at a cost of £30 million, and led to more cautious funding through legal aid for future cases.<ref>Template:Cite journal</ref> 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.<ref name=":1" />
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.<ref name=pmid18671662>Template:Cite journal</ref> For treatment of insomnia, benzodiazepines are now less popular than nonbenzodiazepines, which include zolpidem, zaleplon and eszopiclone.<ref>Template:Cite journal</ref> Nonbenzodiazepines are molecularly distinct, but nonetheless, they work on the same benzodiazepine receptors and produce similar sedative effects.<ref name=wake>Template:Cite journal</ref>
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.<ref>Template:Cite journal</ref>
Society and cultureEdit
Legal statusEdit
In the United States, benzodiazepines are Schedule IV drugs under the Federal Controlled Substances Act, even when not on the market (for example, flunitrazepam<ref name="deaRohypnol">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>), with the exception of flualprazolam, etizolam, clonazolam, flubromazolam, and diclazepam which are placed in Schedule I.<ref name="deaDiversion">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref name="urlControlled Drugs and Substances Act">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref name="urlwww.blackpool.nhs.uk">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref name="urlwww.cannabisbureau.nl">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Previously only brotizolam, flunitrazepam and triazolam were classed as dangerous drugs.<ref>Template:Cite journal</ref>
Internationally, benzodiazepines are categorized as Schedule IV controlled drugs, apart from flunitrazepam, which is a Schedule III drug under the Convention on Psychotropic Substances.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Recreational useEdit
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Benzodiazepines are considered major addictive substances.<ref name=pmid10622686>Template:Cite journal</ref> Non-medical benzodiazepine use is mostly limited to individuals who use other substances, i.e., people who engage in polysubstance use.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Some variation in drug scheduling exists in individual countries; for example, in the United Kingdom, midazolam and temazepam are Schedule III controlled drugs.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}(Note: The British National Formulary is only accessible in the UK. A cached copy is available from Google.)</ref>
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).<ref>Home Office (2005). Explanatory memorandum to the misuse of drugs and the misuse of drugs Template:Webarchive (supply to addicts) (amendment) regulations 2005. No. 2864. Accessed 20–10–03</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Benzodiazepine use ranges from occasional binges on large doses, to chronic and compulsive drug use of high doses.<ref>Template:Cite book</ref>
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.<ref name="Charlson_2009">Template:Cite journal</ref> Polydrug use involving benzodiazepines and alcohol can result in an increased risk of blackouts, risk-taking behaviours, seizures, and overdose.<ref>Template:Cite journal</ref> 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.<ref name=ohop>Template:Cite book</ref> 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.<ref name="pmid9274553">Template:Cite journal</ref>
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.<ref>Template:Cite journal</ref> Benzodiazepines are sometimes used for criminal purposes; they serve to incapacitate a victim in cases of drug assisted rape or robbery.<ref>Template:Cite journal</ref>
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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="pmid1786493">Template:Cite journal</ref><ref>Template:Cite journal</ref>
Veterinary useEdit
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).<ref name = MVM>Template:Cite book</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name = MVM/><ref name=Adams>Template:Cite book</ref>
ReferencesEdit
External linksEdit
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