Index
They are a class of psychoactive drugs whose central chemical structure is fusing a benzene ring and a diazepine ring.
Benzodiazepines are also known as BZD, BZ, and sometimes called “benzos.”
The first drug of this type, chlordiazepoxide (Librium), was accidentally discovered by Leo Sternbach in 1955 and made available in 1960 by Hoffmann-La Roche, which, since 1963, has also marketed the benzodiazepine diazepam (Valium).
In 1977, benzodiazepines were the most widely prescribed medications worldwide. They are in the family of drugs commonly known as minor tranquilizers.
Benzodiazepines potentiate the effect of the neurotransmitter gamma-aminobutyric acid (GABA) on the gamma-aminobutyric acid receptor, producing sedative, hypnotic (sleep-inducing), anxiolytic, anticonvulsant, and muscle relaxant properties.
High doses of many shorter-acting benzodiazepines can also cause amnesia and anterograde dissociation.
These properties make benzodiazepines helpful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal, and as a premedication for medical or dental procedures.
Benzodiazepines are generally considered safe and effective for short-term use, although cognitive disturbances and paradoxical effects such as aggression or disinhibition of behavior sometimes occur.
A minority of people may have paradoxical reactions such as agitation or worsened panic. Benzodiazepines are also associated with an increased risk of suicide.
Long-term use is controversial due to concerns about adverse psychological and physical effects, decreased effectiveness, and physical dependence and withdrawal.
As a result of the adverse effects associated with long-term use of benzodiazepines, withdrawal of benzodiazepines often leads to better physical and mental health.
The elderly are at increased risk for both short-term and long-term adverse effects. As a result, all benzodiazepines are included on the Beers List of Inappropriate Medicines for Older Adults. There is controversy about the safety of benzodiazepines in pregnancy.
Although they are not essential teratogens, uncertainty remains about whether they cause a cleft palate in a small number of infants and whether neurobehavioral effects occur due to prenatal exposure; They are known to cause withdrawal symptoms in newborns.
Benzodiazepines can be taken in case of overdose and can cause dangerous deep unconsciousness. However, they are less toxic than their predecessors, barbiturates, and death rarely occurs when a benzodiazepine is the only drug taken.
When combined with another central nervous system (CNS) depressants such as alcoholic beverages and opiates, it increases the possibility of toxicity and fatal overdose. Benzodiazepines are commonly misused and taken in combination with other drugs of abuse.
Medical use
Benzodiazepines possess sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnesic actions, which are helpful in a variety of indications such as alcohol dependence, seizures, anxiety disorders, panic, agitation, and insomnia.
In general, benzodiazepines are well-tolerated and are safe and effective short-term medications for a wide range of conditions. Tolerance can develop its effects, and there is also the risk of dependence, and after discontinuation, a withdrawal syndrome can occur.
These factors, combined with other possible side effects after prolonged use, such as psychomotor, cognitive, or memory deficits, limit its long-term applicability.
Long-term use or misuse effects include the tendency to cause or worsen cognitive deficits, depression, and anxiety. The British Columbia College of Physicians and Surgeons recommends discontinuing benzodiazepine use in those who take opioids and those who have used them long-term.
Benzodiazepines can have serious adverse health effects, and these findings support clinical and regulatory efforts to reduce use, especially in combination with benzodiazepine receptor agonists.
Panic disorder
Points of view range from those who argue that benzodiazepines are not effective in the long term and should be reserved for refractory cases to those who say that they are as effective in the long term as selective serotonin reuptake inhibitors.
The American Psychiatric Association (APA) guidelines state that benzodiazepines are generally well-tolerated, and their use for the initial treatment of the panic disorder is strongly supported by numerous controlled trials.
The American Psychiatric Association states insufficient evidence to recommend any regular panic disorder treatments over another.
The choice of treatment among benzodiazepines, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and psychotherapy should be based on the patient’s history, preference, and other individual characteristics.
Selective serotonin reuptake inhibitors are likely the best drug therapy option for many patients with panic disorder.
But benzodiazepines are also used frequently, and some studies suggest that these drugs are still used more regularly than selective serotonin reuptake inhibitors.
An advantage of benzodiazepines is that they relieve 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 a benzodiazepine dependence. The American Psychiatric Association does not recommend benzodiazepines for people with depressive symptoms or a recent history of substance abuse.
American Psychiatric Association guidelines state that, in general, drug therapy for panic disorder should be continued for at least one year and that clinical experience supports the continuation of benzodiazepine therapy to prevent a recurrence.
Although essential concerns have been raised about tolerance to benzodiazepines and withdrawal syndrome, there is no evidence of a significant increase in dose in patients using long-term benzodiazepines.
For many of these patients, stable doses of benzodiazepines remain effective for several years.
Guidelines issued by the UK-based National Institute for Health and Clinical Excellence (NICE) carried out a systematic review using a different methodology and reached a different conclusion. They questioned the accuracy of studies that were not placebo-controlled.
And based on findings from placebo-controlled studies, they do not recommend benzodiazepine use beyond two to four weeks, as tolerance and physical dependence develop rapidly, with withdrawal symptoms including rebound anxiety after six weeks or more of use.
However, benzodiazepines are still prescribed for the long-term treatment of anxiety disorders.
Although specific antidepressants and psychological therapies are recommended as first-line treatment options, the anticonvulsant drug pregabalin is indicated as second or third-line treatment and is suitable for long-term use.
The National Institute for Health and Clinical Excellence stated that long-term use of benzodiazepines for panic disorder with or without agoraphobia is an unlicensed indication, has no long-term efficacy, and is therefore not recommended in clinical guidelines.
Psychological therapies such as cognitive behavioral therapy are recommended as first-line therapy for panic disorder. The use of benzodiazepines has been found to interfere with the therapeutic benefits of these therapies.
Benzodiazepines are generally administered orally; however, very occasionally, lorazepam or diazepam may be given intravenously to treat panic attacks.
Generalized anxiety disorder
According to the National Institute of Health and Clinical Excellence, benzodiazepines can treat generalized anxiety disorder, if necessary, immediately.
However, they should not be given for more than 2-4 weeks. The only medications that the National Institute of Health and Clinical Excellence recommends for the long-term treatment of generalized anxiety disorder are antidepressants.
Also, the Canadian Psychiatric Association (CPA) recommends the benzodiazepines alprazolam, bromazepam, lorazepam, and diazepam only as a second-line option if treatment with two different antidepressants is unsuccessful.
Although they are second-line agents, benzodiazepines can be used for a limited time to relieve severe anxiety and agitation.
Canadian Psychiatric Association Guidelines state that after 4-6 weeks, the effect of benzodiazepines may decrease to the placebo level and that benzodiazepines are less effective than antidepressants in relieving ruminant worry, the main symptom of generalized anxiety disorder.
However, prolonged treatment with benzodiazepines as an adjunct to an antidepressant may be justified in some cases. A 2015 review found a more significant effect with medications than talk therapy.
Medications with benefits include serotonin-norepinephrine reuptake inhibitors, benzodiazepines, and selective serotonin reuptake inhibitors.
Insomnia
The Committee on Drug Safety report recommended that when long-term use of benzodiazepines is indicated for insomnia, treatment should be intermittent whenever possible. Benzodiazepines are preferred to be taken intermittently and at the lowest effective dose.
Disadvantages of hypnotics, including benzodiazepines, are possible tolerance to their effects, rebound insomnia and decreased slow-wave sleep, and a withdrawal period characterized by rebound insomnia and prolonged anxiety and agitation.
The list of approved benzodiazepines for the treatment of insomnia is quite similar in most countries. Still, the benzodiazepines officially designated as first-line hypnotics for the treatment of insomnia vary between countries.
Longer-acting benzodiazepines such as nitrazepam and diazepam have residual effects that persist overnight and are generally not recommended.
Since the release of nonbenzodiazepines in 1992 in response to safety concerns, individuals with insomnia and other sleep disorders are increasingly being prescribed nonbenzodiazepines (2.3% in 1993 to 13.7% of Americans in 2010), with fewer Benzodiazepines are frequently prescribed (23.5% in 1993 to 10.8% in 2010).
It is not clear whether the newer nonbenzodiazepine hypnotics (Z-drugs) are better than the short-acting benzodiazepines. Some experts suggest using nonbenzodiazepines preferentially as a long-term first-line treatment of insomnia.
However, the UK National Institute for Health and Clinical Excellence found no convincing evidence favoring hypnotics other than benzodiazepines.
The National Institute for Health and Clinical Excellence Review noted that short-acting nonbenzodiazepine hypnotics were inappropriately compared in long-acting benzodiazepine clinical trials.
Based on this, the national health and clinical excellence institute recommended choosing the hypnotic based on cost and patient preference. Older adults should not use benzodiazepines to treat insomnia unless other treatments have failed.
When using benzodiazepines, patients, their caregivers, and physicians should analyze the increased risk of harm, including evidence showing a two-fold incidence of traffic collisions among patients who drive and falls and hip fractures in older patients.
Seizures
Prolonged convulsive epileptic seizures are a medical emergency that can generally be effectively treated by administering rapid-acting benzodiazepines, which are potent anticonvulsants. In a hospital setting, intravenous clonazepam, lorazepam, and diazepam are first-line options.
In the community, intravenous administration is not practical, so rectal diazepam or oral midazolam is used, with a preference for midazolam since its administration is more accessible and socially acceptable. Clobazam was approved for use in the United States in 2011.
In the UK, both clobazam and clonazepam are second-line options for treating many forms of epilepsy. Clobazam also has a valuable role in short-term seizure prophylaxis and catamenial epilepsy.
Discontinuation after long-term use in epilepsy requires extra caution due to the risks of rebound seizures. Therefore, the dose is gradually reduced over six months or more.
Alcohol withdrawal
Chlordiazepoxide is the most commonly used benzodiazepine for alcohol detoxification, but diazepam can be used as an alternative.
Both are used to detoxify people motivated to stop drinking and are prescribed for a short period to reduce the risks of developing tolerance and dependence on the benzodiazepine medications themselves.
Benzodiazepines with a longer half-life make detoxification more tolerable, and dangerous (and potentially fatal) alcohol withdrawal effects are less likely.
On the other hand, short-acting benzodiazepines can lead to endless seizures and are not recommended for detoxification in an outpatient setting.
Oxazepam and lorazepam are often used in patients at risk of drug accumulation, particularly the elderly and those with cirrhosis, as they are metabolized differently from other benzodiazepines through conjugation.
Benzodiazepines are the preferred option in the treatment of alcohol withdrawal syndrome, particularly for the prevention and treatment of the dangerous complication of seizures and in the suppression of severe delirium.
Lorazepam is the only benzodiazepine with predictable intramuscular absorption and is the most effective in preventing and controlling acute seizures.
Anxiety
Benzodiazepines are sometimes used to treat acute anxiety, as they cause rapid, marked, or moderate relief of symptoms in most people. However, they are not recommended beyond 2-4 weeks of use due to the risks of tolerance and dependence and lack of long-term effectiveness.
As for insomnia, they can also be used irregularly / “as needed,” as in cases where such anxiety is worse. Compared with other drug treatments, benzodiazepines are twice as likely to cause a relapse of the underlying condition after discontinuation.
Psychological and other drug therapies are recommended for the long-term treatment of generalized anxiety disorder. Antidepressants have higher remission rates and are generally safe and effective in the short and long term.
Other indications
Benzodiazepines are often prescribed for a wide range of conditions:
They can be instrumental in intensive care to sedate mechanically ventilated patients or those in extreme distress.
Caution should be exercised in this situation due to the occasional occurrence of respiratory depression, and it is recommended that facilities for the treatment of benzodiazepine overdose are available.
Benzodiazepines are effective as medications given a couple of hours before surgery to relieve anxiety. They also produce amnesia, which can be helpful as patients may not remember the unpleasantness of the procedure.
They are also used in patients with dental phobia and some ophthalmic procedures such as refractive surgery. However, such use is controversial and is only recommended for those who are very anxious.
Midazolam is the most prescribed for this use due to its decisive sedative actions and fast recovery time, as well as its solubility in water, which reduces pain at the time of injection.
Diazepam and lorazepam are sometimes used. Lorazepam has particularly marked amnesic properties that can make it more effective when amnesia is the desired effect.
Benzodiazepines are well known for their strong muscle relaxant properties and can help treat muscle spasms, although tolerance often develops for their muscle-relaxing 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 acute panic caused by hallucinogen poisoning. Benzodiazepines are also used to calm acutely agitated people and can be given through intramuscular injection if necessary.
They can sometimes be effective in the short-term treatment of psychiatric emergencies such as acute psychosis such as schizophrenia, or mania, producing rapid reassurance and sedation until the effects of lithium or neuroleptics (antipsychotics) take effect.
Lorazepam is used most often, but clonazepam is sometimes prescribed for psychosis or acute mania; Long-term use is not recommended due to dependency risks.
Further research is needed to investigate benzodiazepines alone and in combination with antipsychotic medications to treat acute psychosis.
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 with clonazepam as a third-line treatment option as clonazepam is still under investigation.
Benzodiazepines are sometimes used for obsessive-compulsive disorder (OCD), although they are generally believed to be ineffective. However, effectiveness was found in a small study. Benzodiazepines can be considered a treatment option in refractory cases.
Antipsychotics are generally the first-line treatment for delirium; however, when fever is caused by alcohol or hypnotic withdrawal from the sedative, benzodiazepines are a first-line treatment.
There is some evidence that low doses of benzodiazepines reduce the adverse effects of electroconvulsive therapy.
Contraindications
Due to their muscle relaxant action, benzodiazepines can cause respiratory depression in susceptible individuals. For that reason, they are contraindicated in people with myasthenia gravis, sleep apnea, bronchitis, and chronic obstructive pulmonary disease (COPD).
Caution should be exercised when benzodiazepines are used in people with personality disorders or intellectual disabilities due to frequent paradoxical reactions. In major depression, they can precipitate suicidal tendencies and are sometimes used for suicidal overdoses.
People with a history of alcohol, opiate, and barbiturate abuse should avoid benzodiazepines, as there is a risk of life-threatening interactions with these drugs.
The pregnancy
In the United States, the Food and Drug Administration has categorized benzodiazepines into categories D or X, which means that the potential for harm to the fetus has been demonstrated.
Exposure to benzodiazepines during pregnancy has been associated with a slightly increased risk (0.06 to 0.07%) of a cleft palate in newborns, a controversial conclusion as some studies find no association between benzodiazepines and a cleft palate.
Its use by pregnant women shortly before delivery can result in floppy baby syndrome, with newborns suffering from hypotonia, hypothermia, lethargy, and difficulty breathing and feeding.
Cases of neonatal withdrawal syndrome have been described in children chronically exposed to benzodiazepines in utero. This syndrome can be challenging to recognize since it begins several days after delivery, for example, as late as 21 days for chlordiazepoxide.
Symptoms include tremors, hypertonia, hyperreflexia, hyperactivity, and vomiting and can last three to six months. Lowering the dose during pregnancy can lessen its severity.
If used during pregnancy, benzodiazepines with a longer and better safety record, such as diazepam or chlordiazepoxide, are recommended over the potentially more harmful benzodiazepines, such as temazepam or triazolam.
Using the lowest effective dose for the shortest period minimizes risks to the fetus.
Old people
The benefits of benzodiazepines are lower, and the risks are higher in the elderly.
The elderly are at increased risk of dependency and are more sensitive to adverse effects such as memory problems, daytime sedation, impaired motor coordination, increased risk of motor vehicle accidents and falls, and 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 worsen over time.
Adverse effects on cognition can be confused with the results of old age. The benefits of abstinence include improved awareness, alertness, mobility, reduced risk of incontinence, and a reduced risk of falls and fractures.
The success of taper benzodiazepines is as great in the elderly as it is in younger people. Benzodiazepines should be prescribed to the elderly only with caution and only for a short period at low doses.
Short- to medium-acting benzodiazepines are preferred in the elderly, as oxazepam and temazepam. The high-potency benzodiazepines alprazolam and triazolam and the long-acting benzodiazepines are not recommended in the elderly due to increased adverse effects.
Non-benzodiazepines such as zaleplon and zolpidem and low-dose sedating antidepressants are sometimes used as alternatives to benzodiazepines. Long-term use of benzodiazepines has been associated with an increased risk of cognitive decline, but their relationship with dementia remains inconclusive.
The association between a history of benzodiazepine use and cognitive impairment is unclear, with some studies reporting a lower risk of cognitive impairment in former users, some finding no association, and others indicating an increased risk of cognitive impairment.
Benzodiazepines are sometimes prescribed to treat the behavioral symptoms of dementia. However, like antidepressants, they have little evidence of effectiveness, although antipsychotics have shown some benefits.
The cognitively detrimental effects of benzodiazepines that frequently occur in the elderly can also make dementia worse.
Adverse effects
The most common side effects of benzodiazepines are related to their sedative and muscle relaxant action. They include drowsiness, dizziness, and decreased alertness and concentration.
Lack of coordination can lead to falls and injuries, particularly in the elderly. Another result is the deterioration of driving skills and the increased probability of traffic accidents.
Low libido and erection problems are common side effects. Depression and disinhibition can arise. Hypotension and suppressed breathing ( hypoventilation ) can be found 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.
Long-term effects of benzodiazepine use can include cognitive decline, as well as practical and behavioral problems.
Feelings of confusion, difficulty thinking constructively, loss of sexual desire, agoraphobia, social phobia, increased anxiety and depression, loss of interest in leisure activities and attractions, and inability to experience or express feelings can also occur.
Not everyone, however, experiences problems with long-term use. In addition, there may be an altered perception of self, environment, and relationships.
Compared with other sedative hypnotics, hospital visits with benzodiazepines were 66% more likely to have a serious adverse health outcome.
This included hospitalization, patient transfer or death, and visits that included a combination of benzodiazepines and nonbenzodiazepine receptor agonists were nearly four times more likely to have a serious health outcome.
Cognitive effects
Short-term benzodiazepine use adversely affects multiple areas of cognition. Most notably, it interferes with the formation and consolidation of memories of new material and can induce complete anterograde amnesia.
However, researchers have conflicting views regarding the effects of long-term administration. One idea is that many short-term products continue in the long term and may even worsen and do not resolve after benzodiazepine use is discontinued.
Another opinion holds that cognitive deficits in chronic benzodiazepine users occur only for a short period after dosing or that anxiety disorder is the cause of these deficits.
Although definitive studies are lacking, the first opinion was supported by a 2004 meta-analysis of 13 small studies.
This meta-analysis found that long-term use of benzodiazepines was associated with moderate to significant adverse effects in all areas of cognition, with visuospatial memory being the most commonly detected impairment.
The other deficiencies reported were decreased intelligence quotient (IQ), visual-motor coordination, information processing, verbal learning, and concentration.
The authors of the meta-analysis and a subsequent reviewer noted that the applicability of this meta-analysis is limited because the subjects were primarily recruited from withdrawal clinics.
The coexisting drug, alcohol use, and psychiatric disorders were not defined, and several of the included studies performed cognitive measurements during the withdrawal period.
Paradoxical effects
Sometimes paradoxical reactions occur, such as increased seizures, aggression, violence, impulsivity, irritability, and suicidal behavior.
These reactions have been explained as the consequences of disinhibition and subsequent loss of control over socially unacceptable behavior.
Paradoxical reactions are rare in the general population, with an incidence rate of less than 1% and similar to placebo. However, they occur more frequently in recreational abusers, individuals with borderline personality disorder, children, and patients on high-dose regimens.
In these groups, impulse control problems are perhaps the most critical 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 can also appear after chronic use of benzodiazepines.
A long-term decline in psychiatric symptoms
While benzodiazepines may have short-term benefits for anxiety, sleep, and agitation in some patients, long-term use (i.e., more than 2-4 weeks) can worsen symptoms that the medications should treat.
Possible explanations include cognitive problems that are already common in anxiety disorders:
- They cause or worsen depression and suicidal tendencies.
- They alter the architecture of sleep by inhibiting deep sleep.
- Withdrawal symptoms or rebound symptoms between doses that mimic or exacerbate underlying anxiety or sleep disturbances.
- Inhibiting the benefits of psychotherapy by inhibiting memory consolidation and reducing the extinction of fear.
- Reduce coping with trauma/stress and increase vulnerability to future stress.
Anxiety, insomnia, and irritability may be temporarily exacerbated during withdrawal, but psychiatric symptoms after discontinuation are generally less than when taking benzodiazepines.
Fortunately, functioning improves significantly within one year of discontinuation for those with benzodiazepine-induced problems.
Reinforcement disorders
Tolerance
The main problem with chronic benzodiazepines is the development of tolerance and dependence. Tolerance manifests as a decreased pharmacological effect and develops relatively rapidly to the sedative, hypnotic, anticonvulsant, and muscle relaxant actions of benzodiazepines.
Tolerance to anxiolytic effects develops more slowly with little evidence of continued effectiveness beyond four to six months of continuous use. In general, tolerance to amnesic impacts does not occur.
However, there is controversy regarding tolerance to anxiolytic effects, with some evidence that benzodiazepines retain efficacy and is opposed to the evidence from a systematic review of the literature that tolerance occurs frequently and some evidence that anxiety it may get worse with long-term use.
The question of tolerance to the amnesic effects of benzodiazepines is also unclear. Some evidence suggests that partial tolerance develops and that “memory impairment is limited to a narrow window within 90 minutes after each dose.”
A significant disadvantage of benzodiazepines is that tolerance to therapeutic effects develops relatively quickly while many adverse effects persist.
Tolerance develops to hypnotic and my-reflexive effects in days or weeks and anticonvulsant and anxiolytic effects in weeks or months. Therefore, benzodiazepines are unlikely to be effective long-term treatments for sleep and anxiety.
While the therapeutic effects of benzodiazepines wear off with tolerance, depression, and impulsivity, high suicide risks 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 increase doses over time, with many eventually taking more than one type of benzodiazepine after the first one loses effectiveness.
In addition, because tolerance to the sedative effects of benzodiazepines develops more rapidly than tolerance to the depressant effects of the brainstem, those who take more benzodiazepines to achieve the desired results may experience sudden respiratory depression, hypotension, or death.
Most patients with anxiety disorders and post-traumatic stress disorder (PTSD) have symptoms that persist for several months.
Which makes tolerance to therapeutic effects a specific problem and requires more effective long-term treatment (such as psychotherapy and serotonergic antidepressants).
Withdrawal symptoms and management
Discontinuation of benzodiazepines or abrupt dose reduction, even after a relatively short course of treatment (three to four weeks), can lead to two groups of symptoms: rebound and withdrawal.
Rebound symptoms are the return of symptoms for which the patient was treated but worse than before. Withdrawal symptoms are the new symptoms that occur when a benzodiazepine is stopped. They are the main sign of physical dependence.
The most common withdrawal symptoms from benzodiazepines are insomnia, gastric problems, tremors, agitation, fears, and muscle spasms.
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 too rapid or abrupt withdrawal. Abrupt withdrawal can be dangerous. Therefore a gradual taper regimen is recommended.
Symptoms can also occur during a gradual dose reduction but are generally less severe and can persist as part of a prolonged withdrawal syndrome for months after benzodiazepines are cessation.
Approximately 10% of patients experience a remarkably prolonged withdrawal syndrome, which can persist for many months or, in some cases, for a year or more.
Benzodiazepines have a reputation among patients and physicians for causing severe and traumatic withdrawal; however, this is mainly due to poor management of the withdrawal process.
Excessive withdrawal of benzodiazepines increases the severity of the withdrawal syndrome and increases the failure rate. A slow and gradual withdrawal personalized for the individual and, if indicated, psychological support is the most effective way to manage withdrawal.
Opinion on the time required to complete the retreat ranges from four weeks to several years.
A goal of fewer than six months has been suggested. Still, due to factors such as the dose and type of benzodiazepine, the reasons for the prescription, lifestyle, personality, environmental stresses, and the amount of support available, it may take a year or more to withdraw.
Withdrawal is best managed by transferring the physically dependent patient to an equivalent dose of diazepam because it has the most extended half-life of all benzodiazepines.
It is metabolized to long-acting active metabolites and is available in low-potency tablets, which can be quartered for smaller doses.
Another advantage is that it is available in liquid form, allowing for even smaller reductions. Chlordiazepoxide, which 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 tolerant of tolerance to benzodiazepines and can induce dependence.
Alcohol is also tolerant of benzodiazepines and more toxic, so caution is needed to avoid replacing one dependency with another.
During withdrawal, it is best to avoid fluoroquinolone antibiotics if possible; they displace benzodiazepines from their binding site and reduce the function of gamma-aminobutyric acid and thus may aggravate withdrawal symptoms.
Antipsychotics are not recommended for benzodiazepine withdrawal (or other depressive central nervous system depressive states), especially clozapine, olanzapine, or low potency phenothiazines, e.g., chlorpromazine.
Since they lower the seizure threshold and can worsen withdrawal effects, if used, extreme caution is required. Long-term withdrawal from benzodiazepines is beneficial for most people.
Withdrawal of benzodiazepines from long-term users generally leads to improved physical and mental health, especially in the elderly; Although some long-term users report continued benefit from taking benzodiazepines, this may result from the suppression of withdrawal effects.
Controversial associations
Beyond the well-established link between benzodiazepines and psychomotor impairment results in car accidents and falls that lead to fractures.
Research in 2000 and 2010 has raised the association between benzodiazepines (and nonbenzodiazepine hypnotics) and other unproven adverse effects, such as dementia, cancer, infections, pancreatitis, and disease exacerbations respiratory.
Dementia
Several studies have established an association between long-term benzodiazepine use and neurodegenerative diseases, particularly Alzheimer’s disease. However, most of these studies have been retrospective and observational, limiting our confidence in causal inference.
The expert critics of this body of research have consistently speculated that the association may be attributable to protopathic bias or confusion by indication.
So individuals who experience early stages of dementia (or have been previously diagnosed) are given benzodiazepines to control agitation and behavioral disturbance.
More evidence is needed from a large prospective long-term follow-up study in conjunction with neuro-pharmacological research to confirm or refute this association.
Infections
Some observational studies have found significant associations between benzodiazepines and respiratory infections, such as pneumonia, whereas others have not.
A large meta-analysis of pre-marketing randomized controlled trials of pharmacology-related nonbenzodiazepine hypnotics suggests a small increased risk of infection.
An immunodeficiency effect of benzodiazepine action on γ-aminobutyric type A receptors (GABA-A) has been postulated from animal studies.
Cancer
A meta-analysis of observational studies has determined an association between benzodiazepine use and cancer, although the risk between different agents and different types of cancer varied significantly.
Furthermore, most of these studies could not control confounding variables that may have influenced the relationship, such as lifestyle exposures (i.e., tobacco, alcohol).
In terms of essential experimental scientific evidence, an analysis of the carcinogenesis and genotoxicity data for several benzodiazepines has suggested a slight possibility of carcinogenesis for a small number of benzodiazepines.
To confirm these preliminary findings, an extensive, properly designed randomized controlled trial with adequate follow-up is needed, as well as additional pharmacological/toxicological investigation.
Pancreatitis
The evidence suggesting a link between benzodiazepines (and nonbenzodiazepine hypnotics) and pancreatic inflammation is very scant and limited to a few observational studies from Taiwan.
