Effects of long-term benzodiazepine use

Source: Wikipedia, the free encyclopedia.

Benzodiazepines
Chemical structure diagram of a benzene ring fused to a diazepine ring. Another benzene ring is attached to the bottom of the diazepine ring via a single line. Attached to the first benzene ring is a side chain labeled R7; to the second, a side chain labeled R2'; and attached to the diazepine ring, two side chains labeled R1 and R2.
The core structure of benzodiazepines. "R" labels denote common locations of side chains, which give different benzodiazepines their unique properties.

The effects of long-term benzodiazepine use include

withdrawal from benzodiazepines can lead in the long run to a reduction of anxiety symptoms.[4][5] Due to these increasing physical and mental symptoms from long-term use of benzodiazepines, slow withdrawal is recommended for long-term users.[6][7][8][9] Not everyone, however, experiences problems with long-term use.[10]

Some of the symptoms that could possibly occur as a result of a withdrawal from benzodiazepines after long-term use include emotional clouding,

depression, social deterioration as well as employment difficulties, while others never have any side effects from long-term benzodiazepine use. Abruptly or rapidly stopping benzodiazepines can be dangerous; when withdrawing, a gradual reduction in dosage is recommended, under professional supervision.[7][12][9]

While benzodiazepines are highly effective in the short term, adverse effects associated with long-term use, including impaired cognitive abilities, memory problems, mood swings, and overdoses when combined with other drugs, may make the risk-benefit ratio unfavourable. In addition, benzodiazepines have reinforcing properties in some individuals and thus are considered to be addictive drugs, especially in individuals that have a "drug-seeking" behavior; further, a physical dependence can develop after a few weeks or months of use.[13] Many of these adverse effects associated with long-term use of benzodiazepines begin to show improvements three to six months after withdrawal.[14][15]

Other concerns about the effects associated with long-term benzodiazepine use, in some, include dose escalation, benzodiazepine use disorder, tolerance and benzodiazepine dependence and benzodiazepine withdrawal problems. Both physiological tolerance and dependence can be associated with worsening the adverse effects associated with benzodiazepines. Increased risk of death has been associated with long-term use of benzodiazepines in several studies; however, other studies have not found increased mortality. Due to conflicting findings in studies regarding benzodiazepines and increased risks of death including from cancer, further research in long-term use of benzodiazepines and mortality risk has been recommended; most of the available research has been conducted in prescribed users, even less is known about illicit misusers.[16][17] The long-term use of benzodiazepines is controversial and has generated significant debate within the medical profession. Views on the nature and severity of problems with long-term use of benzodiazepines differ from expert to expert and even from country to country; some experts even question whether there is any problem with the long-term use of benzodiazepines.[18]

Symptoms

Effects of long-term benzodiazepine use may include

dyspnea and constipation was found when compared against those who did not take tranquillisers or sleeping tablets.[23] Most individuals who successfully discontinue hypnotic therapy after a gradual taper and do not take benzodiazepines for 6 months have less severe sleep and anxiety problems, are less distressed and have a general feeling of improved health at 6-month follow-up.[15] The use of benzodiazepines for the treatment of anxiety has been found to lead to a significant increase in healthcare costs due to accidents and other adverse effects associated with the long-term use of benzodiazepines.[24]

Cognitive status

Long-term benzodiazepine use can lead to a generalised impairment of

visuo-conceptual abilities.[25][26] Transient changes in the brain have been found using neuroimaging studies, but no brain abnormalities have been found in patients treated long term with benzodiazepines.[27] When benzodiazepine users cease long-term benzodiazepine therapy, their cognitive function improves in the first six months, although deficits may be permanent or take longer than six months to return to baseline.[28] In the elderly, long-term benzodiazepine therapy is a risk factor for amplifying cognitive decline,[29] although gradual withdrawal is associated with improved cognitive status.[30] A study of alprazolam found that 8 weeks administration of alprazolam resulted in deficits that were detectable after several weeks but not after 3.5 years.[31]

Effect on sleep

Sleep can be adversely affected by benzodiazepine dependence. Possible adverse effects on sleep include induction or worsening of sleep disordered breathing. Like alcohol,

K complexes and delta activity, and decreased deep slow-wave sleep (i.e., NREM stages 3 and 4, the most restorative part of sleep for both energy and mood).[32][33][34]

Mental and physical health

The long-term use of benzodiazepines may have a similar effect on the brain as alcohol, and is also implicated in depression, anxiety, post-traumatic stress disorder (PTSD), mania, psychosis, sleep disorders, sexual dysfunction, delirium, and neurocognitive disorders.[35][36] However a 2016 study found no association between long-term usage and dementia.[37] As with alcohol, the effects of benzodiazepine on neurochemistry, such as decreased levels of serotonin and norepinephrine, are believed to be responsible for their effects on mood and anxiety.[38][39][40][41][42][43] Additionally, benzodiazepines can indirectly cause or worsen other psychiatric symptoms (e.g., mood, anxiety, psychosis, irritability) by worsening sleep (i.e., benzodiazepine-induced sleep disorder). These effects are paradoxical to the use of benzodiazepines, both clinically and non-medically, in management of mental health conditions.[44][45]

Long-term benzodiazepine use may lead to the creation or exacerbation of physical and mental health conditions, which improve after six or more months of abstinence. After a period of about 3 to 6 months of abstinence after completion of a gradual-reduction regimen, marked improvements in mental and physical wellbeing become apparent. For example, one study of hypnotic users gradually withdrawn from their hypnotic medication reported after six months of abstinence that they had less severe sleep and anxiety problems, were less distressed, and had a general feeling of improved health. Those who remained on hypnotic medication had no improvements in their insomnia, anxiety, or general health ratings.[15] A study found that individuals having withdrawn from benzodiazepines showed a marked reduction in use of medical and mental health services.[46][non-primary source needed]

Approximately half of patients attending mental health services for conditions including

anxiety disorders such as panic disorder or social phobia may be the result of alcohol or benzodiazepine dependence.[47] Sometimes anxiety disorders precede alcohol or benzodiazepine dependence but the alcohol or benzodiazepine dependence often acts to keep the anxiety disorders going and often progressively makes them worse.[47][non-primary source needed] Many people who are addicted to alcohol or prescribed benzodiazepines decide to quit when it is explained to them they have a choice between ongoing ill mental health or quitting and recovering from their symptoms. It was noted that because every individual has an individual sensitivity level to alcohol or sedative hypnotic drugs, what one person can tolerate without ill health will cause another to develop very ill health, and that even moderate drinking in sensitive individuals can cause rebound anxiety syndromes and sleep disorders. A person who experiences the toxic effects of alcohol or benzodiazepines will not benefit from other therapies or medications as they do not address the root cause of the symptoms.[47] Recovery from benzodiazepine dependence tends to take a lot longer than recovery from alcohol,[47][48] but people can regain their previous good health.[47][medical citation needed] A review of the literature regarding benzodiazepine hypnotic drugs concluded that these drugs cause an unjustifiable risk to the individual and to public health. The risks include dependence, accidents and other adverse effects. Gradual discontinuation of hypnotics leads to improved health without worsening of sleep.[49]

Daily users of benzodiazepines are also at a higher risk of experiencing

Z drugs are associated with causing depression as well as a markedly raised suicide risk and an overall increased mortality risk.[51][52]

A study of 50 patients who attended a benzodiazepine withdrawal clinic found that, after several years of chronic benzodiazepine use, a large portion of patients developed health problems including

drug overdoses whilst on benzodiazepines, despite the fact that only two of the patients had any prior history of depressive symptomatology. After withdrawal, no patients took any further overdoses after one year post-withdrawal. The cause of the deteriorating mental and physical health in a significant proportion of patients was hypothesised to be caused by increasing tolerance where withdrawal-type symptoms emerged, despite the administration of stable prescribed doses.[53] Another theory is that chronic benzodiazepine use causes subtle increasing toxicity, which in turn leads to increasing psychopathology in long-term users of benzodiazepines.[54]

Long-term use of benzodiazepines can induce

protracted withdrawal feature of the benzodiazepine withdrawal syndrome.[55]

In addition, chronic use of benzodiazepines is a risk factor for

benzodiazepines. This demonstrates that the effects from chronic use of benzodiazepine drugs are not unique but occur with other GABAergic sedative hypnotic drugs, i.e., alcohol and barbiturates.[57]

Immune system

Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department.

endocrine function and immune function.[59]

Suicide and self-harm

Use of prescribed benzodiazepines is associated with an increased rate of suicide or attempted

CNS depressants increases the risk of suicide in drug misusers.[63][64] Benzodiazepine has several risks based on its biochemical function and symptoms associated with this medication like exacerbation of sleep apnea, sedation, suppression of self-care functions, amnesia and disinhibition are suggested as a possible explanation to the increase in mortality. Studies also demonstrate that an increased mortality associated with benzodiazepine use has been clearly documented among 'drug misusers'.[17]

Carcinogenicity

There has been some controversy around the possible link between benzodiazepine use and development of cancer; early cohort studies in the 1980s suggested a possible link, but follow-up case-control studies have found no link between benzodiazepines and cancer. In the second U.S. national cancer study in 1982, the

Z drugs due to concerns of cancer, ultimately they changed their minds and approved the drugs.[66] A 2017 meta-analysis of multiple observational studies found that benzodiazepine use is associated with increased cancer risk.[67]

Brain damage evidence

In a study in 1980 in a group of 55 consecutively admitted patients having engaged in non-medical use of exclusively sedatives or hypnotics, neuropsychological performance was significantly lower and signs of intellectual impairment significantly more often diagnosed than in a matched control group taken from the general population. These results suggested a relationship between non-medical use of sedatives or hypnotics and cerebral disorder.[68]

A publication asked in 1981 if lorazepam is more toxic than diazepam.[69]

In a study in 1984, 20 patients having taken long-term benzodiazepines were submitted to brain CT scan examinations. Some scans appeared abnormal. The mean ventricular-brain ratio measured by planimetry was increased over mean values in an age- and sex-matched group of control subjects but was less than that in a group of alcoholics. There was no significant relationship between CT scan appearances and the duration of benzodiazepine therapy. The clinical significance of the findings was unclear.[70]

In 1986, it was presumed that permanent brain damage may result from chronic use of benzodiazepines similar to alcohol-related brain damage.[71]

In 1987, 17 inpatient people who used high doses of benzodiazepines non-medically have anecdotally shown enlarged cerebrospinal fluid spaces with associated cerebral atrophy. Cerebral atrophy reportedly appeared to be dose dependent with low-dose users having less atrophy than higher-dose users.[72]

However, a CT study in 1987 found no evidence of cerebral atrophy in prescribed benzodiazepine users.[73]

In 1989, in a 4- to 6-year follow-up study of 30 inpatient people who used benzodiazepines non-medically,

alcoholic brain damage was observed. The CT scan abnormalities showed dilatation of the ventricular system. However, unlike people who consume excessive alcohol, people who use sedative hypnotic agents non-medically showed no evidence of widened cortical sulci. The study concluded that, when cerebral disorder is diagnosed in people who use high doses of sedative hypnotic benzodiazepines, it is often permanent.[74]

A CT study in 1993 investigated brain damage in benzodiazepine users and found no overall differences to a healthy control group.[75]

A study in 2000 found that long-term benzodiazepine therapy does not result in brain abnormalities.[76]

Withdrawal from high-dose use of

EEG in one patient after 25 years of use. After withdrawal, abnormalities in hypofrontal brain wave patterns persisted beyond the withdrawal syndrome, which suggested to the authors that organic brain damage occurred from chronic high-dose use of nitrazepam.[77]

benzodiazepine receptor level. Newer and more detailed brain scanning technologies such as PET scans and MRI scans had as of 2002 to her knowledge never been used to investigate the question of whether benzodiazepines cause functional or structural brain damage.[79]

A 2018 review of the research found a likely causative role between the use of benzodiazepines and an increased risk of dementia,[80] but the exact nature of the relationship is still a matter of debate.[81]

History

Benzodiazepines, when introduced in 1961, were widely believed to be safe drugs but as the decades went by increased awareness of

socioeconomic costs of the continued widespread prescribing of benzodiazepines is high.[89]

Political controversy

In 1980, the

parliamentary inquiry recommended that research into the long-term effects of benzodiazepines must be carried out.[91] The view of the Department of Health is that they have made every effort to make doctors aware of the problems associated with the long-term use of benzodiazepines,[92] as well as the dangers of benzodiazepine drug addiction.[93]

In 1980, the

John Hutton stated in response that the Department of Health took the problems of benzodiazepines extremely seriously and was not sweeping the issue under the carpet.[95] In 2010, the All-Party Parliamentary Group on Involuntary Tranquilliser Addiction filed a complaint with the Equality and Human Rights Commission under the Disability Discrimination Act 1995 against the Department of Health and the Department for Work and Pensions alleging discrimination against people with a benzodiazepine prescription drug dependence as a result of denial of specialised treatment services, exclusion from medical treatment, non-recognition of the protracted benzodiazepine withdrawal syndrome, as well as denial of rehabilitation and back-to-work schemes. Additionally the APPGITA complaint alleged that there is a "virtual prohibition" on the collection of statistical information on benzodiazepines across government departments, whereas with other controlled drugs there are enormous volumes of statistical data. The complaint alleged that the discrimination is deliberate, large scale and that government departments are aware of what they are doing.[96]

Declassified Medical Research Council meeting

The

SHHD) felt that, due to the large numbers of people using benzodiazepines for long periods of time, it was important to determine the effectiveness and toxicity of benzodiazepines before deciding what regulatory action to take.[90]

Controversy resulted in 2010 when the previously secret files came to light over the fact that the Medical Research Council was warned that benzodiazepines prescribed to millions of patients appeared to cause

The Independent on Sunday reported allegations that "scores" of the 1.5 million members of the UK public who use benzodiazepines long-term have symptoms that are consistent with brain damage. It has been described as a "huge scandal" by Jim Dobbin, and legal experts and MPs have predicted a class action lawsuit. A solicitor said she was aware of the past failed litigation against the drug companies and the relevance the documents had to that court case and said it was strange that the documents were kept 'hidden' by the MRC.[97]

Professor Lader, who chaired the MRC meeting, declined to speculate as to why the MRC declined to support his request to set up a unit to further research benzodiazepines and why they did not set up a special safety committee to look into these concerns. Professor Lader stated that he regrets not being more proactive on pursuing the issue, stating that he did not want to be labeled as the guy who pushed only issues with benzos. Professor Ashton also submitted proposals for grant-funded research using MRI, EEG, and cognitive testing in a randomized controlled trial to assess whether benzodiazepines cause permanent damage to the brain, but similarly to Professor Lader was turned down by the MRC.[97]

The MRC spokesperson said they accept the conclusions of Professor Lader's research and said that they fund only research that meets required quality standards of scientific research, and stated that they were and continue to remain receptive to applications for research in this area. No explanation was reported for why the documents were sealed by the Public Records Act.[97]

Jim Dobbin, who chaired the All-Party Parliamentary Group for Involuntary Tranquilliser Addiction, stated that:

Many victims have lasting physical, cognitive and psychological problems even after they have withdrawn. We are seeking legal advice because we believe these documents are the bombshell they have been waiting for. The MRC must justify why there was no proper follow-up to Professor Lader's research, no safety committee, no study, nothing to further explore the results. We are talking about a huge scandal here.[97]

The legal director of Action Against Medical Accidents said urgent research must be carried out and said that, if the results of larger studies confirm Professor Lader's research, the government and MRC could be faced with one of the biggest group actions for damages the courts have ever seen, given the large number of people potentially affected. People who report enduring symptoms post-withdrawal such as neurological pain, headaches, cognitive impairment, and memory loss have been left in the dark as to whether these symptoms are drug-induced damage or not due to the MRC's inaction, it was reported. Professor Lader reported that the results of his research did not surprise his research group given that it was already known that alcohol could cause permanent brain changes.[97]

Class-action lawsuit

Benzodiazepines spurred the largest-ever

British law, making class-action lawsuits more difficult.[99]

Special populations

Neonatal effects

Benzodiazepines have been found to cause teratogenic malformations.

alimentary tract atresia was seen. An increase in orofacial clefts was not demonstrated, however, and it was concluded that benzodiazepines are not major teratogens.[102]

lower intelligence occurs.[104][105]

Benzodiazepines, like many other sedative hypnotic drugs, cause

childhood or even adolescence.[109] A review of the literature found data on long-term follow-up regarding neurobehavioural outcomes is very limited.[110] However, a study was conducted that followed up 550 benzodiazepine-exposed children, which found that, overall, most children developed normally. There was a smaller subset of benzodiazepine-exposed children who were slower to develop, but by four years of age most of this subgroup of children had normalised. There was a small number of benzodiazepine-exposed children who had continuing developmental abnormalities at 4-year follow-up, but it was not possible to conclude whether these deficits were the result of benzodiazepines or whether social and environmental factors explained the continuing deficits.[111]

Concerns regarding whether benzodiazepines during pregnancy cause major malformations, in particular cleft palate, have been hotly debated in the literature. A

cleft palate.[112]

Elderly

Significant toxicity from benzodiazepines can occur in the elderly as a result of long-term use.

aggressivity, orthostatic hypotension and insomnia. Depletion of certain neurotransmitters and cortisol levels and alterations in immune function and biological markers can also occur.[116] Elderly individuals who have been long-term users of benzodiazepines have been found to have a higher incidence of post-operative confusion.[117] Benzodiazepines have been associated with increased body sway in the elderly, which can potentially lead to fatal accidents including falls. Discontinuation of benzodiazepines leads to improvement in the balance of the body and also leads to improvements in cognitive functions in the elderly benzodiazepine hypnotic users without worsening of insomnia.[118]

A review of the evidence has found that whilst long-term use of benzodiazepines impairs memory, its association with causing dementia is not clear and requires further research.[119] A more recent study found that benzodiazepines are associated with an increased risk of dementia and it is recommended that benzodiazepines be avoided in the elderly.[120] A later study, however, found no increase in dementia associated with long-term usage of benzodiazepine.[37]

See also

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