Long-term effects of benzodiazepines

The long-term effects of benzodiazepines include drug dependence as well as the possibility of adverse effects on cognitive function, physical, and mental health. There is evidence that reduction or withdrawal from benzodiazepines can lead to a reduction in anxiety symptoms. There are a number of side effects associated with addiction to benzodiazepines such as depression and flu like symptoms. Due to these increasing physical and mental symptoms from long-term use of benzodiazepines withdrawal from benzodiazepines is recommended for many long-term users.

Some of the symptoms which may occur as a result of long term use of benzodiazepines include emotional clouding nausea, headaches, dizziness, irritability, lethargy, sleep problems, memory impairment, personality changes, aggression, depression, agoraphobia, anxiety and panic attacks, social deterioration as well as employment difficulties. Many of these adverse effects of long term use of benzodiazepines begin to show improvements three to six months after withdrawal of benzodiazepines.

Other concerns about the long-term effects of benzodiazepines include dose escalation, benzodiazepine abuse, tolerance and benzodiazepine dependence and benzodiazepine withdrawal problems. Both physiological tolerance and dependence can lead to a worsening of the adverse effects of 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 research has been conducted in prescribed users of benzodiazepines; even less is known about the mortality risk of illicit benzodiazepine users.

Background
Benzodiazepines when introduced in 1961 were widely believed to be safe drugs but as the decades went by increased awareness of adverse effects connected their to long term use became known. The majority of the problems of benzodiazepines are related to their long-term use rather than their short-term use. There is growing evidence of the harm of long-term use of benzodiazepines, especially at higher doses. The Department of Health recommends that individuals on long-term benzodiazepines are monitored at least every 3 months and also recommends against long-term substitution therapy in benzodiazepine drug misusers due to a lack of evidence base for effectiveness and due to the risks of long-term use. The long-term effects of benzodiazepines are very similar to the long-term effects of alcohol (apart from organ toxicity) and other sedative-hypnotics. Withdrawal effects and dependence are almost identical. A report in 1987 by the Royal College of Psychiatrists in Great Britain reported that any benefits of long-term use of benzodiazepines are likely to be far outweighed by the risks of long-term use. Despite this benzodiazepines are still widely prescribed. The socioeconomic costs of the continued widespread prescribing of benzodiazepines is high.

Long term effects of benzodiazepines may include disinhibition, impaired concentration and memory, depression. as well as sexual dysfunction The long term effects of benzodiazepines may differ from the adverse effects seen after acute administration of benzodiazepines. Concerns regarding the long term effects of benzodiazepines have been raised since 1980. These concerns are still not fully answered. A review of the literature on use of benzodiazepine and nonbenzodiazepine hypnotics concluded that more research is needed to evaluate the long-term effects of hypnotic drugs. An analysis of cancer patients found that those who took tranquillisers or sleeping tablets had a substantial poorer quality of life on all measurements conducted as well as a worse clinical picture of symptomatology. Worsening of symptoms such as fatigue, insomnia, pain, dyspnea and constipation was found when compared against those who did not take tranquillisers or sleeping tablets. 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. A recent British Government parliamentary inquiry recommended that research into the long term effects of benzodiazepines needs to be carried out.

Cognitive status
Long-term benzodiazepine use can lead to a generalised impairment of cognition, including sustained attention, verbal learning and memory and psychomotor, visuo-motor and visuo-conceptual abilities. These effects on cognition exist, although their impact on patient's daily functioning is in most but not all cases insignificant. 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. 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. In the elderly, long term benzodiazepine therapy is a risk factor for amplifying cognitive decline, although gradual withdrawal is associated with improved cognitive status. A study of alprazolam found that 8 weeks administration of alprazolam resulted in persisting deficits still detectable several weeks later.

Elderly
Significant toxicity from benzodiazepines can occur in the elderly as a result of long term use. Benzodiazepines, along with antihypertensives and drugs effecting the cholinergic system are the most common cause of drug induced dementia effecting over 10 percent of patients attending memory clinics. Long term use of benzodiazepines in the elderly can lead to a pharmacological syndrome with symptoms including drowsiness, ataxia, fatigue, confusion, weakness, dizziness, vertigo, syncope, reversible dementia, depression, impairment of intellect, psychomotor and sexual dysfunction, agitation, auditory and visual hallucinations, paranoid ideation, panic, delirium, depersonalisation, sleepwalking, aggressivity, orthostatic hypotension and insomnia. Depletion of certain neurotransmitters and cortisol levels and alterations in immune function and biological markers can also occur.

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. Long-term use of benzodiazepines has been associated with an increased risk of dementia and it is recommended that benzodiazepines are avoided in the elderly.

Mental and physical health
Long term benzodiazepine use may lead to the creation or exacerbation of physical and mental health conditions which improve after 6 or more months of abstinence. After a period of about 3 to 6 months of abstinence after completion of a gradual reduction regime marked improvements in mental and physical wellbeing become apparent. For example one study of hypnotic users who were gradually withdrawn from their hypnotic medication reported after 6 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. A study found that individuals who had withdrawn from benzodiazepines showed a marked reduction in use of medical and mental health services.

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. Sometimes anxiety disorders pre-existed alcohol or benzodiazepine dependence but the alcohol or benzodiazepine dependence often act to keep the anxiety disorders going and often progressively making them worse. Many people who are addicted to alcohol or prescribed benzodiazepines when it is explained to them they have a choice between ongoing ill mental health or quitting and recovering from their symptoms decide on quitting alcohol and or their benzodiazepines. It was noted that every individual has an individual sensitivity level to alcohol or sedative hypnotic drugs and what one person can tolerate without ill health another will suffer very ill health and that even moderate drinking can cause rebound anxiety syndromes and sleep disorders. A person who is suffering 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. Recovery from benzodiazepine dependence tends to take a lot longer than recovery from alcohol but people can regain their previous good health. A review of the literature regarding benzodiazepine hypnotic drugs concluded that these drugs caused 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.

Chronic long term use of benzodiazepines is associated with an increased risk of impulsive, aggressive and violent behaviour. A study showed that 53% of long term benzodiazepine users showed violent characteristics where as only 5.3% of patients receiving psychotherapy developed violent or aggressive behavioural patterns. Daily users of benzodiazepines are also at a higher risk of experiencing psychotic symptomatology such as delusions and hallucinations. A medical paper published findings that of 42 patients treated with alprazolam, up to a third of long term users of the benzodiazepine drug alprazolam (Xanax) develop depression. Studies have shown that long term use of benzodiazepines and the benzodiazepine receptor agonist nonbenzodiazepine Z drugs are associated with causing depression as well as a markedly raised suicide risk as well as an overall increased mortality risk.

A study of 50 patients who attended a benzodiazepine withdrawal clinic found that long term use of benzodiazepines causes a wide range of psychological and physiological disorders. It was found that after several years of chronic benzodiazepine use that a large portion of patients developed various mental and physical health problems including agoraphobia, irritable bowel syndrome, paraesthesiae, increasing anxiety and panic attacks which were not preexisting. The mental health and physical health symptoms induced by long term benzodiazepine use gradually improved significantly over a period of a year following completion of a slow withdrawal. Three of the 50 patients had wrongly been given a preliminary diagnosis of multiple sclerosis when the symptoms were actually due to chronic benzodiazepine use. Ten of the patients had taken drug overdoses whilst on benzodiazepines despite only two of the patients having had any prior history of depressive symptomatology. After withdrawal no patients took any further overdoses after 1 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 stable prescribed doses being taken. Another theory is that chronic benzodiazepine use causes subtle increasing toxicity which in turn leads to increasing psychopathology in long term users of benzodiazepines. Chronic use of benzodiazepines is a risk factor for blepharospasm. Long term use of benzodiazepines can induce perceptual disturbances and depersonalisation in some people even in those who are taking a stable daily dosage and it can also become a protracted withdrawal feature of the benzodiazepine withdrawal syndrome. Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department. Drug induced symptoms which resemble withdrawal like effects can occur on a set dosage as a result of prolonged use have also been documented with barbiturate like substances as well as alcohol and benzodiazepines. This demonstrates that the effects from chronic use of benzodiazepine drugs is not unique but occurs with other GABAergic sedative hypnotic drugs ie alcohol and barbiturates.

Benzodiazepine use is highly associated with suicide. Care should be taken when prescribing especially to at risk patients. Depressed adolescents who were taking benzodiazepines were found to have a greatly increased risk of self harm or suicide, although the sample size was small. The effects of benzodiazepines in individuals under the age of 18 requires further research. Additional caution is required in using benzodiazepines in depressed adolescents. Benzodiazepine dependence often results in an increasingly deteriorating clinical picture which includes social deterioration leading to comorbid alcoholism and drug abuse. Suicide is a common outcome of chronic benzodiazepine dependence. Benzodiazepine misuse or misuse of other CNS depressants increases the risk of suicide in drug misusers. 11% of males and 23% of females with a sedative hypnotic misuse habit commit suicide.

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 American Cancer Society conducted a survey of over 1.1 million participents. A marked increased risk of cancer was found in the users of sleeping pills, mainly benzodiazepines. There have been 15 epidemiologic studies which have suggested that benzodiazepine or nonbenzodiazepine hypnotic drug use is associated with increased mortality, mainly due to increased cancer deaths in humans. The cancers included cancer of the brain, lung, bowel, breast and bladder and other neoplasms. It has been hypothesised that either depressed immune function or the viral infections themselves were the cause of the increased rates of cancer. While initially U.S. Food and Drug Administration reviewers expressed concerns about approving the nonbenzodiazepine Z drugs due to concerns of cancer, ultimately they changed their minds and approved the drugs. A recent case-control study, however, found no link between use of benzodiazepines and cancers of the breast, lung, large bowel, lung, uterine lining, ovaries, testes, thyroid, liver, nor Hodgkin's Disease, melanoma, nor non-Hodgkin's lymphoma. More specific case-control studies since 2000 have shown no link between benzodiazepine use and breast cancer. One study found an association between benzodiazepine use and development of ovarian cancer, whereas another study found no relationship.

Brain damage controversy
Several clinical studies have tried to establish if benzodiazepines cause structural brain damage and have come to different findings. Evidence of structural brain damage is strongest but still not definitive for high dose prescribed users and high dose benzodiazepine drug abusers, although evidence exists from clinical studies of a degree of brain shrinkage even in chronic low dose benzodiazepine users but this has been disputed in other clinical studies. While some of the studies controlled for factors such as alcohol use, others didn't. Some studies were too small or in one case was only a single case report. Medical opinion on whether long term prescribed benzodiazepines cause structural brain damage differs.

High dose abusers of benzodiazepines have shown enlarged cerebrospinal fluid spaces with associated brain shrinkage. Neuropsychological function can be permanently affected in chronic high dose abusers of benzodiazepines, with brain damage similar to alcoholic brain damage, as was shown in a 4 to 6 year follow-up study of benzodiazepine abusers by Borg and others of the Karolinska Institute. The CT scan abnormalities showed dilatation of the ventricular system. However, unlike alcoholics, sedative hypnotic abusers showed no evidence of widened cortical sulci. The study concluded that, when cerebral disorder is diagnosed in sedative hypnotic benzodiazepine abusers, it is often permanent. An earlier study by Borg et al. found evidence of cerebral disorder in those that exclusively abused benzodiazepines, suggesting that cerebral disorder was not the result of other substances of abuse. Withdrawal from high dose abuse of nitrazepam have caused severe hypoperfusion of the whole brain with diffuse slow activity on EEG. After withdrawal, abnormalities in hypofrontal brain wave patterns persist beyond the withdrawal syndrome which suggested organic brain damage occurs from chronic high dose abuse of benzodiazepines. Some studies have demonstrated brain damage in therapeutic dose users whereas other studies have refuted that benzodiazepines caused structural brain damage. The evidence seems to suggest some form of brain damage but whether the long term effects of benzodiazepines are due to structural brain damage or functional brain damage remains to be determined conclusively. Two publications have suggested that lorazepam is more toxic than diazepam. Permanent brain damage may result from chronic use of benzodiazepines similar to alcohol related brain damage. The brain damage reported is similar to but less severe than that seen in chronic alcoholics. Brain damage reportedly appeared to be dose dependent with low dose users having less brain shrinkage than higher dose users. However, two studies found no evidence of brain shrinkage in prescribed benzodiazepine users.

Professor Ashton, a leading expert on benzodiazepines from Newcastle University Institute of Neuroscience, has been cautious in jumping to any firm conclusions and is an advocate for further research into long lasting or possibly permanent symptoms of long term use of benzodiazepines. She has stated that she believes that the most likely explanation for lasting symptoms is persisting but slowly resolving functional changes at the GABAA benzodiazepine receptor level. Newer and more detailed brain scanning technologies such as PET scans and MRI scans have never been used to investigate the question of whether benzodiazepines cause functional or structural brain damage. Professor Ashton tried to acquire funding to perform scans using more detailed scanning technologies such as PET scans and MRI scans but was turned down for research funding. At present the question of whether benzodiazepines cause structural or functional brain damage remains unanswered definitively.

Neonatal effects
Benzodiazepines have been found to cause teratogenic malformations. The literature concerning the safety of benzodiazepines in pregnancy is unclear and controversial. Initial concerns regarding benzodiazepines in pregnancy began with alarming findings in animals but these do not necessarily cross over to humans. Conflicting findings have been found in babies exposed to benzodiazepines. A recent analysis of the Swedish Medical Birth Register found an association with preterm births, low birth weight and a moderate increased risk for congental malformations. An increase in pylorostenosis or alimentary tract atresia was seen. An increase in orofacial clefts was not demonstrated however and it was concluded that benzodiazepines are not major teratogens.

Neurodevelopmental disorders and clinical symptoms are commonly found in babies exposed to benzodiazepines in utero. Benzodiazepine exposed babies have a low birth weight but catch up to normal babies at an early age but smaller head circumferences found in benzo babies persists. Other adverse effects of benzodiazepines taken during pregnancy are deviating neurodevelopmental and clinical symptoms including craniofacial anomalies, delayed development of pincer grasp, deviations in muscle tone and pattern of movements. Motor impairments in the babies are impeded for up to 1 year after birth. Gross motor development impairments take 18 months to return to normal but fine motor function impairments persist. In addition to the smaller head circumference found in benzodiazepine exposed babies mental retardation, functional deficits, long-lasting behavioural anomalies and lower intelligence occurs.

Benzodiazepines, like many other sedative hypnotic drugs causes apoptotic neuronal cell death. However, benzodiazepines do not cause as severe apoptosis to the developing brain as alcohol does. The prenatal toxicity of benzodiazepines is most likely due to their effects on neurotransmitter systems, cell membranes and protein synthesis. This however, is complicated in that neuropsychological or neuropsychiatric effects of benzodiazepines, if they occur, may not become apparent until later childhood or even adolescence. A review of the literature found data on long term follow-up regarding neurobehavioural outcomes is very limited. A study was conducted however, which followed up benzodiazepine exposed 550 children which found 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 were a small number 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. .

Concerns regarding whether benzodiazepines during pregnancy cause major malformations, particularly cleft palet have been hotly debated in the literature. A meta analysis of the data from cohort studies found no link but meta analysis of case control studies did find a significant increase in major malformations (however, it must be noted that the cohort studies were homogenous and the case control studies were heterogeneous, thus reducing the strength of the case control results). There have also been several reports which suggest benzodiazepines have the potential to cause a syndrome similar to fetal alcohol syndrome but this has been disputed by a number of studies. As a result of conflicting findings use of benzodiazepines during pregnancy is controversial. The best available evidence suggests that benzodiazepines are not a major cause of birth defects, i.e. major malformations or cleft lip or cleft palet.