Benzodiazepine dependence
Encyclopedia
Benzodiazepine dependence or benzodiazepine addiction is a condition during which a person is dependent on benzodiazepine
drugs. Dependence can be either a psychological dependence
, physical dependence
, or a combination of the two. Physical dependence occurs when a person becomes tolerant to benzodiazepines and, as a result of both physiological tolerance and withdrawal symptoms
, they develop a physical dependence
, which can manifest itself upon dosage reduction or cessation as the benzodiazepine withdrawal syndrome
. Addiction, or what it is sometimes referred to as psychological dependence, includes people misusing and/or craving the drug not to relieve withdrawal symptoms but to experience its euphoric and/or intoxicating effects. Addiction to benzodiazepines can also include people who take them normally as prescribed but find themselves unable to stop taking benzodiazepines despite any harmful effects. It is important to distinguish between addiction
and drug abuse
of benzodiazepines and normal physical dependence
on benzodiazepines. Physical dependence typically occurs from long-term prescribed use, but drug abuse and/or behavioral addiction does not typically occur in prescribed users. The increased GABAA inhibition caused by benzodiazepines is counteracted by the body's development of tolerance to the drug's effects; the development of tolerance occurs as a result of neuroadaptations, which result in decreased GABA inhibition and increased excitability of the glutamate system; these adaptations occur as a result of the body trying to overcome the central nervous system depressant effects of the drug to restore homeostasis
. When benzodiazepines are stopped, these neuroadaptations are "unmasked" leading to hyper-excitability of the nervous system and the appearance of withdrawal symptoms.
Therapeutic dose dependence is the largest category of people dependent on benzodiazepines. These individuals typically do not escalate their doses to high levels or abuse their medication. Smaller groups include patients escalating their dosage to higher levels and drug misusers as well. It is unclear exactly how many people illicitly abuse benzodiazepines. Tolerance develops within days or weeks to the anticonvulsant, hypnotic muscle relaxant and after 4 months there is little evidence that benzodiazepines retain their anxiolytic properties. Some authors, however, disagree and feel that benzodiazepines retain their anxiolytic properties. Long-term benzodiazepine treatment may remain necessary in certain clinical conditions.
Dependence and misuse of benzodiazepines have been of concern in 2002. Based on findings in the US from the Treatment Episode Data Set (TEDS), an annual compilation of patient characteristics in substance abuse treatment facilities in the United States, admissions due to "primary tranquilizer" (including, but not limited to, benzodiazepine-type) drug use increased 79% from 1992 to 2002. Thus, the DAWN and TEDS data sets demonstrate clearly that the misuse of these sedative/hypnotics is on the rise, and cause for concern (^ Licata, SC; Rowlett, JK (January 12, 2008). "Abuse and dependence liability of benzodiazepine-type drugs: GABA(A) receptor modulation and beyond". Pharmacology Biochemistry and Behavior 90 (1): 74–89. PMID 18295321.
Numbers of benzodiazepine prescriptions have been declining, due primarily to concerns of dependence. In the short term, benzodiazepines can be effective drugs for acute anxiety or insomnia. With longer-term use, other therapies, both pharmacological and psychotherapeutic, become more effective. This is in part due to the greater effectiveness over time of other forms of therapy, and also due to the eventual development of pharmacological benzodiazepine tolerance.
as well as a psychological dependence
and is typified by a withdrawal syndrome upon a fall in blood plasma levels of benzodiazepines, e.g., during dose reduction or abrupt withdrawal.
attempts to cut down or stop benzodiazepine use, tolerance to the effects of benzodiazepines, and withdrawal symptoms when not taking the drug. Some withdrawal symptoms that may appear include anxiety
, depressed mood, depersonalisation, derealisation, sleep disturbance, hypersensitivity to touch and pain, tremor
, shakiness, muscular aches, pains, twitches, and headache. Benzodiazepine dependence and withdrawal have been associated with suicide and self-harming behaviors, especially in young people. The Department of Health
substance misuse guidelines recommend monitoring for mood disorder in those dependent on or withdrawing from benzodiazepines.
Benzodiazepine dependence is a frequent complication for those prescribed for or using for longer than four weeks, with physical dependence and withdrawal symptoms being the most common problem, but also occasionally drug-seeking behavior. Withdrawal symptoms include anxiety, perceptual disturbances, distortion of all the senses, dysphoria, and, in rare cases, psychosis and epileptic seizures.
(Xanax) than with lower potency benzodiazepines such as chlordiazepoxide
(Librium).
Symptom severity is worse with the use of high doses, or with benzodiazepines of high potency or short half-life. Other cross-tolerant sedative hypnotics, such as barbiturates or alcohol
. increase the risk of benzodiazepine dependence. Similar to opioids' use for pain, therapeutic use of benzodiazepines rarely leads to substance abuse.
glutamate receptors. These changes occur as a result of the body trying to overcome the drug's effects. Other changes that occur are the reduction of the number of GABA receptors (internalization
) as well as possibly long term changes in gene transcription coding of brain cells. The differing speed at which tolerance occurs to the therapeutic effects of benzodiazepines can be explained by the speed of changes in the range of neurotransmitter systems and subsystems that are altered by chronic benzodiazepine use. The various neurotransmitter systems and subsystems may reverse tolerance at different speeds, thus explaining the prolonged nature of some withdrawal symptoms. As a result of a physical dependence
that develops due to tolerance, a characteristic benzodiazepine withdrawal syndrome
often occurs after removal of the drug or a reduction in dosage. Changes in the expression of neuropeptides such as corticotropin-releasing hormone
and neuropeptide Y
may play a role in benzodiazepine dependence. Individuals taking daily benzodiazepine drugs have a reduced sensitivity to further additional doses of benzodiazepines. Tolerance to benzodiazepines can be demonstrated by injecting diazepam into long-term users. In normal subjects, increases in growth hormone occurs, whereas, in benzodiazepine-tolerant individuals, this effect is blunted.
Animal studies have shown that repeated withdrawal from benzodiazepines leads to increasingly severe withdrawal symptoms, including an increased risk of seizures; this phenomenon is known as kindling
. Kindling phenomena are well established for repeated ethanol (alcohol) withdrawal; alcohol has a very similar mechanism of tolerance and withdrawal to benzodiazepines, involving the GABAa, NMDA, and AMPA receptors.
The shift of benzodiazepine receptors to an inverse agonist state after chronic treatment leads the brain to be more sensitive to excitatory drugs or stimuli. Excessive glutamate activity can result in excitotoxicity
, which may result in neurodegeneration
. The glutamate receptor subtype NMDA is well known for its role in causing excito-neurotoxicity. The glutamate receptor subtype AMPA is believed to play an important role in neuronal kindling as well as excitotoxicity during withdrawal from alcohol as well as benzodiazepines. It is highly possible that NMDA receptors are involved in the tolerance to some effects of benzodiazepines.
Animal studies have found that glutamergic changes as a result of benzodiazepine use are responsible for a delayed withdrawal syndrome, which in mice peaks 3 days after cessation of benzodiazepines. This was demonstrated by the ability to avoid the withdrawal syndrome by the administration of AMPA antagonists. It is believed that different different glutamate subreceptors, e.g., NMDA and AMPA, are responsible for different stages/time points of the withdrawal syndrome. NMDA receptors are upregulated in the brain as a result of benzodiazepine tolerance. AMPA receptors are also involved in benzodiazepine tolerance and withdrawal. A decrease in benzodiazepine binding sites in the brain may also occur as part of benzodiazepine tolerance.
. However, although benzodiazepines can be very useful in the acute detoxification of alcoholics, benzodiazepines in themselves act as positive reinforcers in alcoholics, by increasing the desire for alcohol. Low doses of benzodiazepines were found to significantly increase the level of alcohol consumed in alcoholics. Alcoholics dependent on benzodiazepines should not be abruptly withdrawn but be very slowly withdrawn from benzodiazepines, as over-rapid withdrawal is likely to produce severe anxiety or panic, which is well known for being a relapse risk factor in recovering alcoholics.
There is cross tolerance between alcohol
, the benzodiazepines, the barbiturate
s, the nonbenzodiazepine
drugs, and corticosteroids, which all act by enhancing the GABAA receptor's function via modulating the chloride ion channel function of the GABAA receptor.
Neuroactive steroids, e.g., progesterone
and its active metabolite allopregnanolone
, are positive modulators of the GABAA receptor and are cross tolerant with benzodiazepines. The active metabolite
of progesterone has been found to enhance the binding of benzodiazepines to the benzodiazepine binding sites on the GABAA receptor. The cross-tolerance between GABAA receptor positive modulators occurs because of the similar mechanism of action and the subunit changes that occur from chronic use from one or more of these compounds in expressed receptor isoforms. Abrupt withdrawal from any of these compounds, e.g., barbiturates, benzodiazepines, alcohol, corticosteroids, neuroactive steroids, and nonbenzodiazepines, precipitate similar withdrawal effects characterized by central nervous system hyper-excitability, resulting in symptoms such as increased seizure susceptibility and anxiety. While many of the neuroactive steroids do not produce full tolerance to their therapeutic effects, cross-tolerance to benzodiazepines still occurs as had been demonstrated between the neuroactive steroid ganaxolone
and diazepam
. Alterations of levels of neuroactive steroids in the body during the menstrual cycle, menopause
, pregnancy, and stressful circumstances can lead to a reduction in the effectiveness of benzodiazepines and a reduced therapeutic effect. During withdrawal of neuroactive steroids, benzodiazepines become less effective.
is the second-most-common neurotransmitter in the central nervous system
(the most common being glutamate) and by far the most abundant inhibitory neurotransmitter; roughly one-quarter to one-third of synapses use GABA. The use of benzodiazepines has a profound effect on almost every aspect of brain
and body function, either directly or indirectly.
Benzodiazepines cause a decrease in norepinephrine
(noradrenaline), serotonin
, acetylcholine
, and dopamine
. These neurotransmitters are needed for normal memory, mood, muscle tone
and coordination, emotional responses, endocrine gland secretions, heart rate, and blood pressure control. With chronic benzodiazepine use, tolerance develops rapidly to most of its effects, so that, when benzodiazepines are withdrawn, various neurotransmitter
systems go into overdrive due to the lack of inhibitory GABA
-ergic activity. Withdrawal symptoms then emerge as a result, and persist until the nervous system physically reverses the adaptions (physical dependence) that have occurred in the CNS.
Withdrawal symptoms typically consist of a mirror image of the drug's effects: Sedative effects and suppression of REM and SWS
stages of sleep can be replaced by insomnia
, nightmares, and hypnogogic hallucinations; its antianxiety effects are replaced with anxiety and panic; muscle-relaxant effects are replaced with muscular spasms or cramps; and anticonvulsant
effects are replaced with seizures, especially in cold turkey
or overly-rapid withdrawal.
Benzodiazepine withdrawal represents in part excitotoxicity
to brain neurons. Rebound activity of the hypothalamic-pituitary-adrenocortical axis also plays an important role in the severity of benzodiazepine withdrawal. Tolerance and the resultant withdrawal syndrome may be due to alterations in gene expression, which results in long-term changes in the function of the GABAergic neuronal system.
During withdrawal from full or partial agonists, changes occur in benzodiazepine receptor with upregulation of some receptor subtypes and downregulation of other receptor subtypes.
Withdrawal symptoms can emerge despite slow reduction but can be reduced by a slower rate of withdrawal. As a result, withdrawal rates have been recommended to be customized to each individual patient. The time needed to withdraw can vary from a couple of months to a year or more and often depends on length of use, dosage taken, lifestyle, health, and social and environmental stress factors.
Diazepam
is often recommended due to its long elimination half-life and also because of its availability in low potency doses. The non-benzodiazepine Z drugs such as zolpidem, zaleplon, and zopiclone should not be used as a replacement for benzodiazepines, as they have a similar mechanism of action and can induce a similar dependence. The pharmacological mechanism of benzodiazepine tolerance and dependence is the internalization (removal) of receptor site in the brain and changes in gene transcription codes in the brain.
With long-term use and during withdrawal of benzodiazepines, treatment-emergent depression and emotional blunting may emerge and sometimes also suicidal ideation. There is evidence that the higher the dose used the more likely it is benzodiazepine use will induce these feelings. Reducing the dose or discontinuing benzodiazepines may be indicated in such cases. Withdrawal symptoms can persist for quite some time after discontinuing benzodiazepines. Some common protracted withdrawal symptoms include anxiety
, depression
, insomnia
, and physical symptoms such as gastrointestinal, neurologic, and musculoskeletal effects. The protracted withdrawal state may still occur despite slow titration of dosage. It is believed that the protracted withdrawal effects are due to persisting neuroadapations.
or analgesic
properties and are, therefore, unsuitable treatments for conditions such as depression, tension headaches, and dysmenorrhea
. Benzodiazepines are also not beneficial in the treatment of psychosis
. The committee also recommended against benzodiazepines for use in the treatment of anxiety
or insomnia
in children.
The committee was in agreement with the Institute of Medicine
(USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse
(USA) that there is little evidence that long-term use of benzodiazepine hypnotics are beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tend to lose their sleep-promoting properties within 3–14 days of continuous use, and, in the treatment of anxiety, the committee found that there was little convincing evidence that benzodiazepines retains efficacy in the treatment of anxiety after 4 months of continuous use due to the development of tolerance.
The committee found that the regular use of benzodiazepines causes the development of dependence characterized by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety
, apprehension, tremor
s, insomnia
, nausea
, and vomiting
upon cessation of benzodiazepine use. Withdrawal symptoms tend to develop within 24 hours upon cessation of short-acting benzodiazepines, and 3–10 days after cessation of longer-acting benzodiazepines. Withdrawal effects could occur after treatment, lasting only 2 weeks at therapeutic dose levels, however withdrawal effects tend to occur with habitual use beyond 2 weeks and are more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition.
The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short-term use only. It was noted in the review that alcohol can potentiate the central nervous system
-depressant effects of benzodiazepines and should be avoided. The central nervous system-depressant effects of benzodiazepines may make driving or operating machinery dangerous, and the elderly are more prone to these adverse effects. High single doses or repeated low doses have been reported to produce hypotonia
, poor sucking, and hypothermia
in the neonate, and irregularities in the fetal heart. The committee recommended that benzodiazepines be avoided in lactation
.
The committee recommended that withdrawal from benzodiazepines be gradual, as abrupt withdrawal from high doses of benzodiazepines may cause confusion
, toxic psychosis, convulsions, or a condition resembling delirium tremens
. Abrupt withdrawal from lower doses may cause depression, nervousness
, rebound insomnia, irritability
, sweating
, and diarrhea
.
These diagnostic criteria are good for research purposes, but, in everyday clinical practice, they should be interpreted according to clinical judgement. In clinical practice, benzodiazepine dependence should be suspected in those having used benzodiazepines for longer than a month, in particular, if they are from a high-risk group. The main factors associated with an increased incidence of benzodiazepine dependence include:
Benzodiazepine dependence should be suspected also in individuals having substance use disorders including alcohol, and should be suspected in individuals obtaining their own supplies of benzodiazepines. Benzodiazepine dependence is almost certain in individuals who are members of a tranquillizer self-help groups.
Research has found that about 40 percent of people with a diagnosis of benzodiazepine dependence are not aware that they are dependent on benzodiazepines, whereas about 11 percent of people judged not to be dependent believe that they are.
When assessing a person for benzodiazepine dependence, asking specific questions rather than questions based on concepts is recommended by experts as the best approach of getting a more accurate diagnosis. For example, asking persons if they "think about the medication at times of the day other than when they take the drug" would provide a more meaningful answer than asking "do you think you are psychologically dependent?". The Benzodiazepine Dependence Self Report Questionnaire is one questionnaire used to assess and diagnose benzodiazepine dependence.
and are more sensitive to the short (e.g., in between dose withdrawal) and protracted withdrawal effects of benzodiazepines, as well as the side-effects both from short-term and long-term use. This can lead to excessive contact with their doctor. Research has found that withdrawing elderly people from benzodiazepines leads to a significant reduction in doctor visits per year, it is presumed, due to an elimination of drug side-effects and withdrawal effects.
Tobacco
and alcohol
are the most common substances that elderly people get a dependence
on or misuse. The next-most-common substance that elderly people develop a drug dependence to and/or misuse is benzodiazepines. Drug-induced cognitive problems can have serious consequences for elderly people and can lead to confusional states and "pseudo-dementia". About 10% of elderly patients referred to memory clinics actually have a drug-induced cause that most often is benzodiazepines. Benzodiazepines have also been linked to an increased risk of road traffic accidents and falls
in the elderly. The long-term effects of benzodiazepines are still not fully understood in the elderly or any age group. Long-term benzodiazepine use is associated with attentional and visuospatial functional impairments. Withdrawal from benzodiazepines can lead to improved alertness
and decreased forgetfulness in the elderly. Withdrawal led to statistical significant improvements in memory function and performance related skills in those having withdrawn successfully from benzodiazepines, whereas those having remained on benzodiazepines experienced worsening symptoms. People having withdrawn from benzodiazepines also felt their sleep was more refreshing, making statements such as "I feel sharper when I wake up" or "I feel better, more awake", or "It used to take me an hour to fully wake up." This suggests that benzodiazepines may actually make insomnia worse in the elderly.
can develop in as short as a few weeks but may take years to develop in other individuals. Patients wanting to withdraw from benzodiazepines typically receive little advice or support.
Benzodiazepines are usually prescribed only short-term, as there is little justification for their prescribing long-term. Some doctors however, disagree and believe long-term use beyond 4 weeks is sometimes justified, although there is little data to support this viewpoint. Such viewpoints are a minority in the medical literature.
There is no evidence that "drug holidays" or periods of abstinence reduced the risk of dependence; there is evidence from animal studies that such an approach does not prevent dependence from happening. Use of short-acting benzodiazepines is associated with interdose withdrawal symptoms, which may increase the risk of kindling
; kindling has clinical relevance with regard to benzodiazepines; for example, there is an increasing shift to use of benzodiazepines with a shorter half-life and intermitant use, which can result in interdose withdrawal and rebound effects.
is the most frequently prescribed hypnotic in the UK, followed by nitrazepam
, and then temazepam
. Hypnotic drugs are of poor value for the management of chronic insomnia. Hypnotic drug consumption has been shown to reduce work performance, increase absenteeism, increase road traffic accidents, increase morbidity, and increase mortality, and is associated with an increased incidence of deliberate self harm. In the elderly, increases in falls and fractures associated with sedative hypnotic drug use has been found. It is widely accepted that hypnotic drug usage beyond 4 weeks is undesirable for all age groups of patients. Many continuous hypnotic users exhibit disturbed sleep as a consequence of tolerance but experience worsening rebound or withdrawal insomnia when the dose is reduced too quickly, which compounds the problem of chronic hypnotic drug use. Cognitive behavioral therapy has been found to be more effective for the long term management of insomnia than sedative hypnotic drugs. No formal withdrawal programs for benzodiazepines exists with local providers in the UK. Meta-analysis of published data on psychological treatments for insomnia show a success rate between 70 and 80%. A largescale trial utilizing cognitive behavioral therapy in chronic users of sedative hypnotics including nitrazepam, temazepam, and zopiclone found CBT to be a significantly more effective long-term treatment for chronic insomnia than sedative hypnotic drugs. Persisting improvements in sleep quality, sleep onset latency, increased total sleep, improvements in sleep efficiency, significant improvements in vitality, physical and mental health at 3-, 6-, and 12-month follow-ups was found in those receiving CBT. A marked reduction in total sedative hypnotic drug use was found in those receiving CBT, with 33% reporting zero hypnotic drug use. Age has been found not to be a barrier to successful outcome of CBT. It was concluded that CBT for the management of chronic insomnia is a flexible, practical, and cost-effective treatment, and it was also concluded that CBT leads to a reduction of benzodiazepine drug intake in a significant number of patients. Chronic use of hypnotic medications is not recommended due to their adverse effects on health and the risk of dependence. A gradual taper is usual clinical course in getting people off of benzodiazepines, but, even with gradual reduction, a large proportion of people fail to stop taking benzodiazepines. The elderly are particularly sensitive to the adverse effects of hypnotic
medications. A clinical trial in elderly people dependent on benzodiazepine
hypnotics showed that the addition of CBT to a gradual benzodiazepine reduction program increased the success rate of discontinuing benzodiazepine hypnotic
drugs from 38% to 77% and at the 12-month follow-up from 24% to 70%. The paper concluded that CBT is an effective tool for reducing hypnotic
use in the elderly and reducing the adverse health effects that are associated with hypnotics such as drug dependence, cognitive impairments, and increased road traffic accidents.
A study of patients undergoing benzodiazepine withdrawal who had a diagnosis of generalized anxiety disorder showed that those hainvg received CBT had a very high success rate of discontinuing benzodiazepines compared to those not having receive CBT. This success rate was maintained at the 12-month follow-up. Furthermore it was found that, in patients having discontinued benzodiazepines, they no longer met the diagnosis of general anxiety disorder
, and that the number of patients no longer meeting the diagnosis of general anxiety disorder was higher in the group having received CBT. Thus, CBT can be an effective tool to add to a gradual benzodiazepine dosage reduction program leading to improved and sustained mental health
benefits.
in the UK, for example, for stopping sleeping tablets abruptly or reducing anxiolytics too quickly, failure to initiate replacement therapy (e.g., equivalent dose of diazepam), failure to increase dosage to alleviate severe withdrawal effects, and failure to warn the patient of the possibility of withdrawal symptoms, having led to a finding by the GMC of negligence against one doctor.
Benzodiazepines can be addictive and induce dependence even at low doses, with 23% becoming addicted within 3 months of use. Benzodiazepine addiction is considered a public health problem. Approximately 68.5% of prescriptions of benzodiazepines originate from local health centers, with psychiatry and general hospitals accounting for 10% each. A survey of general practitioners reported that the reason for initiating benzodiazepines was due to an empathy for the patients suffering and a lack of other therapeutic options rather than patients demanding them. However, long-term use was more commonly at the insistence of the patient, it is presumed, because physical dependence
and/or addiction had developed.
Approximately twice as many women as men are prescribed benzodiazepines. It is believed that this is largely because men typically turned to alcohol to cope with stress and women to prescription drugs. Biased perception of women by male doctors may also play a role in increased prescribing rates to women; however, increased anxiety features in women does not account for the wide gap alone between men and women.
disadvantage of benzodiazepines. Severe withdrawal syndromes can occur from these low doses of benzodiazepines even after gradual dose reduction. An estimated 30–45% of chronic low-dose benzodiazepine users are dependent and it has been recommended that benzodiazepines even at low dosage be prescribed for a maximum of 7–14 days to avoid dependence.
Some controversy
remains, however, in the medical literature as to the exact nature of low-dose dependence and the difficulty in getting patients to discontinue their benzodiazepines, with some papers attributing the problem to predominantly drug-seeking behavior and drug craving, whereas other papers having found the opposite, attributing the problem to a problem of physical dependence with drug-seeking and craving not being typical of low-dose benzodiazepine users.
Benzodiazepines are one of the largest classes of abused drugs; they are classed as schedule IV controlled drugs because of their recognized medical uses.
Benzodiazepines can cause serious addiction problems. A survey in Senegal
of doctors found that many doctors feel that their training and knowledge of benzodiazepines is, in general, poor; a study in Dakar
found that almost one-fifth of doctors ignored prescribing guidelines regarding short-term use of benzodiazepines, and almost three-quarters of doctors regarded their training and knowledge of benzodiazepines to be inadequate. More training regarding benzodiazepines has been recommended for doctors. Due to the serious concerns of addiction, national governments were recommended to urgently seek to raise knowledge via training about the addictive nature of benzodiazepines and appropriate prescribing of benzodiazepines.
A six-year study on 51 Vietnam veteran
s who were drug abusers of either mainly stimulants (11 people), mainly opiates (26 people), or mainly benzodiazepines (14 people) was carried out to assess psychiatric symptoms related to the specific drugs of abuse. After six years, opiate
abusers had little change in psychiatric symptomatology; five of the stimulant users had developed psychosis
, and eight of the benzodiazepine users had developed depression. Therefore, long-term benzodiazepine abuse and dependence seems to carry a negative effect on mental health
, with a significant risk of causing depression. Benzodiazepines are also sometimes abused intra-nasally.
In the elderly, alcohol
and benzodiazepines are the most commonly abused substances, and the elderly population is more susceptible to benzodiazepine withdrawal syndrome
and delirium
than are younger patients.
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
drugs. Dependence can be either a psychological dependence
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
, physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
, or a combination of the two. Physical dependence occurs when a person becomes tolerant to benzodiazepines and, as a result of both physiological tolerance and withdrawal symptoms
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
, they develop a physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
, which can manifest itself upon dosage reduction or cessation as the benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
. Addiction, or what it is sometimes referred to as psychological dependence, includes people misusing and/or craving the drug not to relieve withdrawal symptoms but to experience its euphoric and/or intoxicating effects. Addiction to benzodiazepines can also include people who take them normally as prescribed but find themselves unable to stop taking benzodiazepines despite any harmful effects. It is important to distinguish between addiction
Substance use disorder
Substance use disorders include substance abuse and substance dependence. In DSM-IV, the conditions are formally diagnosed as one or the other, but it has been proposed that DSM-5 combine the two into a single condition called "Substance-use disorder"....
and drug abuse
Drug abuse
Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...
of benzodiazepines and normal physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
on benzodiazepines. Physical dependence typically occurs from long-term prescribed use, but drug abuse and/or behavioral addiction does not typically occur in prescribed users. The increased GABAA inhibition caused by benzodiazepines is counteracted by the body's development of tolerance to the drug's effects; the development of tolerance occurs as a result of neuroadaptations, which result in decreased GABA inhibition and increased excitability of the glutamate system; these adaptations occur as a result of the body trying to overcome the central nervous system depressant effects of the drug to restore homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
. When benzodiazepines are stopped, these neuroadaptations are "unmasked" leading to hyper-excitability of the nervous system and the appearance of withdrawal symptoms.
Therapeutic dose dependence is the largest category of people dependent on benzodiazepines. These individuals typically do not escalate their doses to high levels or abuse their medication. Smaller groups include patients escalating their dosage to higher levels and drug misusers as well. It is unclear exactly how many people illicitly abuse benzodiazepines. Tolerance develops within days or weeks to the anticonvulsant, hypnotic muscle relaxant and after 4 months there is little evidence that benzodiazepines retain their anxiolytic properties. Some authors, however, disagree and feel that benzodiazepines retain their anxiolytic properties. Long-term benzodiazepine treatment may remain necessary in certain clinical conditions.
Dependence and misuse of benzodiazepines have been of concern in 2002. Based on findings in the US from the Treatment Episode Data Set (TEDS), an annual compilation of patient characteristics in substance abuse treatment facilities in the United States, admissions due to "primary tranquilizer" (including, but not limited to, benzodiazepine-type) drug use increased 79% from 1992 to 2002. Thus, the DAWN and TEDS data sets demonstrate clearly that the misuse of these sedative/hypnotics is on the rise, and cause for concern (^ Licata, SC; Rowlett, JK (January 12, 2008). "Abuse and dependence liability of benzodiazepine-type drugs: GABA(A) receptor modulation and beyond". Pharmacology Biochemistry and Behavior 90 (1): 74–89. PMID 18295321.
Numbers of benzodiazepine prescriptions have been declining, due primarily to concerns of dependence. In the short term, benzodiazepines can be effective drugs for acute anxiety or insomnia. With longer-term use, other therapies, both pharmacological and psychotherapeutic, become more effective. This is in part due to the greater effectiveness over time of other forms of therapy, and also due to the eventual development of pharmacological benzodiazepine tolerance.
Definition
Benzodiazepine dependence is the condition resulting from repeated use of benzodiazepine drugs. It can include both a physical dependencePhysical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
as well as a psychological dependence
Psychological dependence
In the APA Dictionary of Psychology, psychological dependence is defined as "dependence on a psychoactive substance for the reinforcement it provides." Most times psychological dependence is classified under addiction...
and is typified by a withdrawal syndrome upon a fall in blood plasma levels of benzodiazepines, e.g., during dose reduction or abrupt withdrawal.
Signs and symptoms
The signs and symptoms of benzodiazepine dependence include feeling unable to cope without the drug, unsuccessfulattempts to cut down or stop benzodiazepine use, tolerance to the effects of benzodiazepines, and withdrawal symptoms when not taking the drug. Some withdrawal symptoms that may appear include anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, depressed mood, depersonalisation, derealisation, sleep disturbance, hypersensitivity to touch and pain, tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, shakiness, muscular aches, pains, twitches, and headache. Benzodiazepine dependence and withdrawal have been associated with suicide and self-harming behaviors, especially in young people. The Department of Health
Department of Health (United Kingdom)
The Department of Health is a department of the United Kingdom government with responsibility for government policy for health and social care matters and for the National Health Service in England along with a few elements of the same matters which are not otherwise devolved to the Scottish,...
substance misuse guidelines recommend monitoring for mood disorder in those dependent on or withdrawing from benzodiazepines.
Benzodiazepine dependence is a frequent complication for those prescribed for or using for longer than four weeks, with physical dependence and withdrawal symptoms being the most common problem, but also occasionally drug-seeking behavior. Withdrawal symptoms include anxiety, perceptual disturbances, distortion of all the senses, dysphoria, and, in rare cases, psychosis and epileptic seizures.
Cause
Tolerance occurs to the muscle-relaxant, anticonvulsant, and sleep-inducing effects of benzodiazepines, and upon cessation a benzodiazepine withdrawal syndrome occurs. This can lead to benzodiazepines' being taken for longer than originally intended, as people continue to take the drugs over a long period of time to suppress withdrawal symptoms. Some people abuse benzodiazepines at very high doses and devote a lot of time to doing so, satisfying the diagnostic criteria in DSM IV for substance abuse and dependence. Another group of people include those on low to moderate therapeutic doses of benzodiazepines who do not abuse their benzodiazepines but develop a tolerance and benzodiazepine dependence. A considerable number of individuals using benzodiazepines for insomnia escalate their dosage, sometimes above therapeutically-prescribed dose levels. Tolerance to the anxiolytic effect of benzodiazepines has been clearly demonstrated in rats. In humans, there is little evidence that benzodiazepines retain their anti-anxiety effects beyond four months of continuous treatment; there is evidence that suggests that long-term use of benzodiazepines may actually worsen anxiety, which in turn may lead to dosage escalation, with one study finding 25% of patients escalated their dosage. Some authors, however, consider benzodiazepines to be effective long-term; however, it is more likely that the drugs are acting to prevent rebound anxiety withdrawal effects. Tolerance to the anticonvulsant and muscle-relaxing effects of benzodiazepines occurs within a few weeks in most patients.Risk factors
The risk factors for benzodiazepine dependence are long-term use beyond four weeks, use of high doses, use of potent short-acting benzodiazepines, dependent personalities, and proclivity for drug abuse. Use of short-acting benzodiazepines leads to repeated withdrawal effects that are alleviated by the next dose, which reinforce in the individual the dependence. A physical dependence develops more quickly with higher potency benzodiazepines such as alprazolamAlprazolam
Alprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor...
(Xanax) than with lower potency benzodiazepines such as chlordiazepoxide
Chlordiazepoxide
Chlordiazepoxide, is a sedative/hypnotic drug and benzodiazepine. It is marketed under the trade names Angirex, Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen and Tropium.Chlordiazepoxide was the first benzodiazepine to be synthesised and...
(Librium).
Symptom severity is worse with the use of high doses, or with benzodiazepines of high potency or short half-life. Other cross-tolerant sedative hypnotics, such as barbiturates or alcohol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
. increase the risk of benzodiazepine dependence. Similar to opioids' use for pain, therapeutic use of benzodiazepines rarely leads to substance abuse.
Tolerance and physical dependence
Tolerance develops rapidly to the sleep-inducing effects of benzodiazepines but takes several months to develop to the anxiolytic effects. The anticonvulsant and muscle-relaxant effects last for a few weeks before tolerance develops in most individuals. Tolerance results in a desensitization of GABA receptors and an increased sensitization of the excitatory neurotransmitter system, glutamate such as NMDANMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
glutamate receptors. These changes occur as a result of the body trying to overcome the drug's effects. Other changes that occur are the reduction of the number of GABA receptors (internalization
Internalization
Internalization has different definitions depending on the field that the term is used in. Internalization is the opposite of externalization.- General :...
) as well as possibly long term changes in gene transcription coding of brain cells. The differing speed at which tolerance occurs to the therapeutic effects of benzodiazepines can be explained by the speed of changes in the range of neurotransmitter systems and subsystems that are altered by chronic benzodiazepine use. The various neurotransmitter systems and subsystems may reverse tolerance at different speeds, thus explaining the prolonged nature of some withdrawal symptoms. As a result of a physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
that develops due to tolerance, a characteristic benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
often occurs after removal of the drug or a reduction in dosage. Changes in the expression of neuropeptides such as corticotropin-releasing hormone
Corticotropin-releasing hormone
Corticotropin-releasing hormone , originally named corticotropin-releasing factor , and also called corticoliberin, is a polypeptide hormone and neurotransmitter involved in the stress response...
and neuropeptide Y
Neuropeptide Y
Neuropeptide Y is a 36-amino acid peptide neurotransmitter found in the brain and autonomic nervous system."NPY has been associated with a number of physiologic processes in the brain, including the regulation of energy balance, memory and learning, and epilepsy." The main effect is increased food...
may play a role in benzodiazepine dependence. Individuals taking daily benzodiazepine drugs have a reduced sensitivity to further additional doses of benzodiazepines. Tolerance to benzodiazepines can be demonstrated by injecting diazepam into long-term users. In normal subjects, increases in growth hormone occurs, whereas, in benzodiazepine-tolerant individuals, this effect is blunted.
Animal studies have shown that repeated withdrawal from benzodiazepines leads to increasingly severe withdrawal symptoms, including an increased risk of seizures; this phenomenon is known as kindling
Kindling (substance withdrawal)
Kindling due to substance withdrawal, refers to the neurological condition which results from repeated withdrawal episodes from sedative-hypnotic drugs such as alcohol or benzodiazepines. Each withdrawal leads to more severe withdrawal symptoms than the first withdrawal syndrome...
. Kindling phenomena are well established for repeated ethanol (alcohol) withdrawal; alcohol has a very similar mechanism of tolerance and withdrawal to benzodiazepines, involving the GABAa, NMDA, and AMPA receptors.
The shift of benzodiazepine receptors to an inverse agonist state after chronic treatment leads the brain to be more sensitive to excitatory drugs or stimuli. Excessive glutamate activity can result in excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
, which may result in neurodegeneration
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
. The glutamate receptor subtype NMDA is well known for its role in causing excito-neurotoxicity. The glutamate receptor subtype AMPA is believed to play an important role in neuronal kindling as well as excitotoxicity during withdrawal from alcohol as well as benzodiazepines. It is highly possible that NMDA receptors are involved in the tolerance to some effects of benzodiazepines.
Animal studies have found that glutamergic changes as a result of benzodiazepine use are responsible for a delayed withdrawal syndrome, which in mice peaks 3 days after cessation of benzodiazepines. This was demonstrated by the ability to avoid the withdrawal syndrome by the administration of AMPA antagonists. It is believed that different different glutamate subreceptors, e.g., NMDA and AMPA, are responsible for different stages/time points of the withdrawal syndrome. NMDA receptors are upregulated in the brain as a result of benzodiazepine tolerance. AMPA receptors are also involved in benzodiazepine tolerance and withdrawal. A decrease in benzodiazepine binding sites in the brain may also occur as part of benzodiazepine tolerance.
Cross tolerance
Benzodiazepines share a similar mechanism of action with various sedative compounds that act by enhancing the GABAA receptor. Cross tolerance means that one drug will alleviate the withdrawal effects of another. It also means that tolerance of one drug will result in tolerance of another similarly-acting drug. Benzodiazepines are often used for this reason to detoxify alcohol-dependent patients and can have life-saving properties in preventing and/or treating severe life-threatening withdrawal syndromes from alcohol, such as delirium tremensDelirium tremens
Delirium tremens is an acute episode of delirium that is usually caused by withdrawal from alcohol, first described in 1813...
. However, although benzodiazepines can be very useful in the acute detoxification of alcoholics, benzodiazepines in themselves act as positive reinforcers in alcoholics, by increasing the desire for alcohol. Low doses of benzodiazepines were found to significantly increase the level of alcohol consumed in alcoholics. Alcoholics dependent on benzodiazepines should not be abruptly withdrawn but be very slowly withdrawn from benzodiazepines, as over-rapid withdrawal is likely to produce severe anxiety or panic, which is well known for being a relapse risk factor in recovering alcoholics.
There is cross tolerance between alcohol
Alcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
, the benzodiazepines, the barbiturate
Barbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
s, the nonbenzodiazepine
Nonbenzodiazepine
The nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.-Classes:There are currently three...
drugs, and corticosteroids, which all act by enhancing the GABAA receptor's function via modulating the chloride ion channel function of the GABAA receptor.
Neuroactive steroids, e.g., progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
and its active metabolite allopregnanolone
Allopregnanolone
Allopregnanolone is a prototypic neurosteroid present in the blood and also the brain. It is a metabolite of progesterone and potent modulator of GABAA receptors...
, are positive modulators of the GABAA receptor and are cross tolerant with benzodiazepines. The active metabolite
Active metabolite
- Prodrugs :Sometimes drugs are formulated deliberately so they will break down inside the body to form the active drug, these are called prodrugs. The reason for this may be because the drug is more stable during manufacture and storage as the prodrug form, or because the prodrug is better...
of progesterone has been found to enhance the binding of benzodiazepines to the benzodiazepine binding sites on the GABAA receptor. The cross-tolerance between GABAA receptor positive modulators occurs because of the similar mechanism of action and the subunit changes that occur from chronic use from one or more of these compounds in expressed receptor isoforms. Abrupt withdrawal from any of these compounds, e.g., barbiturates, benzodiazepines, alcohol, corticosteroids, neuroactive steroids, and nonbenzodiazepines, precipitate similar withdrawal effects characterized by central nervous system hyper-excitability, resulting in symptoms such as increased seizure susceptibility and anxiety. While many of the neuroactive steroids do not produce full tolerance to their therapeutic effects, cross-tolerance to benzodiazepines still occurs as had been demonstrated between the neuroactive steroid ganaxolone
Ganaxolone
Ganaxolone is a steroid drug, with the molecular formula C22H36O2, related to allopregnanolone that has sedative, anxiolytic, and anticonvulsant effects. It is a potent and selective positive allosteric modulator of GABAA receptors. Ganaxolone protects against seizures in diverse animal models,...
and diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
. Alterations of levels of neuroactive steroids in the body during the menstrual cycle, menopause
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
, pregnancy, and stressful circumstances can lead to a reduction in the effectiveness of benzodiazepines and a reduced therapeutic effect. During withdrawal of neuroactive steroids, benzodiazepines become less effective.
Physiology of withdrawal
Withdrawal symptoms are a normal response in individuals having chronically used benzodiazepines, and an adverse effect and result of drug tolerance. Symptoms typically emerge when dosage of the drug is reduced. GABAGabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
is the second-most-common neurotransmitter in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(the most common being glutamate) and by far the most abundant inhibitory neurotransmitter; roughly one-quarter to one-third of synapses use GABA. The use of benzodiazepines has a profound effect on almost every aspect of brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and body function, either directly or indirectly.
Benzodiazepines cause a decrease in norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(noradrenaline), serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
. These neurotransmitters are needed for normal memory, mood, muscle tone
Muscle tone
In physiology, medicine, and anatomy, muscle tone is the continuous and passive partial contraction of the muscles, or the muscle’s resistance to passive stretch during resting state. It helps maintain posture, and it declines during REM sleep.-Purpose:Unconscious nerve impulses maintain the...
and coordination, emotional responses, endocrine gland secretions, heart rate, and blood pressure control. With chronic benzodiazepine use, tolerance develops rapidly to most of its effects, so that, when benzodiazepines are withdrawn, various neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
systems go into overdrive due to the lack of inhibitory GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
-ergic activity. Withdrawal symptoms then emerge as a result, and persist until the nervous system physically reverses the adaptions (physical dependence) that have occurred in the CNS.
Withdrawal symptoms typically consist of a mirror image of the drug's effects: Sedative effects and suppression of REM and SWS
Slow-wave sleep
Slow-wave sleep , often referred to as deep sleep, consists of stages 3 and 4 of non-rapid eye movement sleep, according to the Rechtschaffen & Kales standard of 1968. As of 2008, the American Academy of Sleep Medicine has discontinued the use of stage 4, such that the previous stages 3 and 4 now...
stages of sleep can be replaced by insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, nightmares, and hypnogogic hallucinations; its antianxiety effects are replaced with anxiety and panic; muscle-relaxant effects are replaced with muscular spasms or cramps; and anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
effects are replaced with seizures, especially in cold turkey
Cold turkey
"Cold turkey" describes the actions of a person who abruptly gives up a habit or addiction rather than gradually easing the process through gradual reduction or by using replacement medication....
or overly-rapid withdrawal.
Benzodiazepine withdrawal represents in part excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
to brain neurons. Rebound activity of the hypothalamic-pituitary-adrenocortical axis also plays an important role in the severity of benzodiazepine withdrawal. Tolerance and the resultant withdrawal syndrome may be due to alterations in gene expression, which results in long-term changes in the function of the GABAergic neuronal system.
During withdrawal from full or partial agonists, changes occur in benzodiazepine receptor with upregulation of some receptor subtypes and downregulation of other receptor subtypes.
Withdrawal
Long-term use of benzodiazepines leads to increasing physical and mental health problems, and as a result, withdrawal is recommended for many long-term users. The withdrawal syndrome from benzodiazepines can range from a mild and short-lasting syndrome to a prolonged and severe syndrome. Withdrawal symptoms leads to continued use of benzodiazepines for many years, long after the original reason for taking benzodiazepines has passed. Many patients know that the benzodiazepines no longer work for them but are unable to discontinue benzodiazepines because of withdrawal symptoms.Withdrawal symptoms can emerge despite slow reduction but can be reduced by a slower rate of withdrawal. As a result, withdrawal rates have been recommended to be customized to each individual patient. The time needed to withdraw can vary from a couple of months to a year or more and often depends on length of use, dosage taken, lifestyle, health, and social and environmental stress factors.
Diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
is often recommended due to its long elimination half-life and also because of its availability in low potency doses. The non-benzodiazepine Z drugs such as zolpidem, zaleplon, and zopiclone should not be used as a replacement for benzodiazepines, as they have a similar mechanism of action and can induce a similar dependence. The pharmacological mechanism of benzodiazepine tolerance and dependence is the internalization (removal) of receptor site in the brain and changes in gene transcription codes in the brain.
With long-term use and during withdrawal of benzodiazepines, treatment-emergent depression and emotional blunting may emerge and sometimes also suicidal ideation. There is evidence that the higher the dose used the more likely it is benzodiazepine use will induce these feelings. Reducing the dose or discontinuing benzodiazepines may be indicated in such cases. Withdrawal symptoms can persist for quite some time after discontinuing benzodiazepines. Some common protracted withdrawal symptoms include anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, and physical symptoms such as gastrointestinal, neurologic, and musculoskeletal effects. The protracted withdrawal state may still occur despite slow titration of dosage. It is believed that the protracted withdrawal effects are due to persisting neuroadapations.
The Committee on the Review of Medicines (UK)
The Committee on the Review of Medicines carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence, benzodiazepine withdrawal problems, and other adverse effects. The committee found that benzodiazepines do not have any antidepressantAntidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
or analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
properties and are, therefore, unsuitable treatments for conditions such as depression, tension headaches, and dysmenorrhea
Dysmenorrhea
Dysmenorrhea is a gynecological medical condition of pain during menstruation that interferes with daily activities, as defined by ACOG and others. Still, dysmenorrhea is often defined simply as menstrual pain, or at least menstrual pain that is excessive...
. Benzodiazepines are also not beneficial in the treatment of psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
. The committee also recommended against benzodiazepines for use in the treatment of anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
or insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
in children.
The committee was in agreement with the Institute of Medicine
Institute of Medicine
The Institute of Medicine is a not-for-profit, non-governmental American organization founded in 1970, under the congressional charter of the National Academy of Sciences...
(USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse
National Institute on Drug Abuse
The National Institute on Drug Abuse is a United States federal-government research institute whose mission is to "lead the Nation in bringing the power of science to bear on drug abuse and addiction."-History:...
(USA) that there is little evidence that long-term use of benzodiazepine hypnotics are beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tend to lose their sleep-promoting properties within 3–14 days of continuous use, and, in the treatment of anxiety, the committee found that there was little convincing evidence that benzodiazepines retains efficacy in the treatment of anxiety after 4 months of continuous use due to the development of tolerance.
The committee found that the regular use of benzodiazepines causes the development of dependence characterized by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, apprehension, tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
s, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
upon cessation of benzodiazepine use. Withdrawal symptoms tend to develop within 24 hours upon cessation of short-acting benzodiazepines, and 3–10 days after cessation of longer-acting benzodiazepines. Withdrawal effects could occur after treatment, lasting only 2 weeks at therapeutic dose levels, however withdrawal effects tend to occur with habitual use beyond 2 weeks and are more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition.
The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short-term use only. It was noted in the review that alcohol can potentiate the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
-depressant effects of benzodiazepines and should be avoided. The central nervous system-depressant effects of benzodiazepines may make driving or operating machinery dangerous, and the elderly are more prone to these adverse effects. High single doses or repeated low doses have been reported to produce hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, poor sucking, and hypothermia
Hypothermia
Hypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...
in the neonate, and irregularities in the fetal heart. The committee recommended that benzodiazepines be avoided in lactation
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
.
The committee recommended that withdrawal from benzodiazepines be gradual, as abrupt withdrawal from high doses of benzodiazepines may cause confusion
ConFusion
ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
, toxic psychosis, convulsions, or a condition resembling delirium tremens
Delirium tremens
Delirium tremens is an acute episode of delirium that is usually caused by withdrawal from alcohol, first described in 1813...
. Abrupt withdrawal from lower doses may cause depression, nervousness
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, rebound insomnia, irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
, sweating
Sweating
Perspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
, and diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
.
Diagnosis
For a diagnosis of benzodiazepine dependence to be made, the ICD-10 requires that at least 3 of the below criteria are met and that they have been present for at least a month, or, if less than a month, that they appeared repeatedly during a 12-month period.- Behavioral, cognitive, and physiological phenomena that are associated with the repeated use and that typically include a strong desire to take the drug.
- Difficulty controlling use
- Continued use despite harmful consequences
- Preference given to drug use rather than to other activities and obligations
- Increased tolerance to effects of the drug and sometimes a physical withdrawal stateBenzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
.
These diagnostic criteria are good for research purposes, but, in everyday clinical practice, they should be interpreted according to clinical judgement. In clinical practice, benzodiazepine dependence should be suspected in those having used benzodiazepines for longer than a month, in particular, if they are from a high-risk group. The main factors associated with an increased incidence of benzodiazepine dependence include:
- Dose
- Duration
- Concommittant use of antidepressants
Benzodiazepine dependence should be suspected also in individuals having substance use disorders including alcohol, and should be suspected in individuals obtaining their own supplies of benzodiazepines. Benzodiazepine dependence is almost certain in individuals who are members of a tranquillizer self-help groups.
Research has found that about 40 percent of people with a diagnosis of benzodiazepine dependence are not aware that they are dependent on benzodiazepines, whereas about 11 percent of people judged not to be dependent believe that they are.
When assessing a person for benzodiazepine dependence, asking specific questions rather than questions based on concepts is recommended by experts as the best approach of getting a more accurate diagnosis. For example, asking persons if they "think about the medication at times of the day other than when they take the drug" would provide a more meaningful answer than asking "do you think you are psychologically dependent?". The Benzodiazepine Dependence Self Report Questionnaire is one questionnaire used to assess and diagnose benzodiazepine dependence.
In the elderly
Long-term use and benzodiazepine dependence is a serious problem in the elderly. Failure to treat benzodiazepine dependence in the elderly can cause serious medical complications. The elderly have less cognitive reserveCognitive reserve
The term cognitive reserve describes the mind's resilience to neuropathological damage of the brain. The mind's resilience is evaluated behaviorally, whereas the neuropathological damage is evaluated histologically, although damage may be estimated using blood-based markers and imaging methods...
and are more sensitive to the short (e.g., in between dose withdrawal) and protracted withdrawal effects of benzodiazepines, as well as the side-effects both from short-term and long-term use. This can lead to excessive contact with their doctor. Research has found that withdrawing elderly people from benzodiazepines leads to a significant reduction in doctor visits per year, it is presumed, due to an elimination of drug side-effects and withdrawal effects.
Tobacco
Tobacco
Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as a pesticide and, in the form of nicotine tartrate, used in some medicines...
and alcohol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
are the most common substances that elderly people get a dependence
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
on or misuse. The next-most-common substance that elderly people develop a drug dependence to and/or misuse is benzodiazepines. Drug-induced cognitive problems can have serious consequences for elderly people and can lead to confusional states and "pseudo-dementia". About 10% of elderly patients referred to memory clinics actually have a drug-induced cause that most often is benzodiazepines. Benzodiazepines have also been linked to an increased risk of road traffic accidents and falls
Falling (accident)
Falling is a major cause of personal injury, especially for the elderly. Builders, electricians, miners, and painters represent worker categories representing high rates of fall injuries. The WHO estimate that 392,000 people die in falls every year...
in the elderly. The long-term effects of benzodiazepines are still not fully understood in the elderly or any age group. Long-term benzodiazepine use is associated with attentional and visuospatial functional impairments. Withdrawal from benzodiazepines can lead to improved alertness
Alertness
Alertness is the state of paying close and continuous attention, being watchful and prompt to meet danger or emergency, or being quick to perceive and act. It is related to psychology as well as to physiology...
and decreased forgetfulness in the elderly. Withdrawal led to statistical significant improvements in memory function and performance related skills in those having withdrawn successfully from benzodiazepines, whereas those having remained on benzodiazepines experienced worsening symptoms. People having withdrawn from benzodiazepines also felt their sleep was more refreshing, making statements such as "I feel sharper when I wake up" or "I feel better, more awake", or "It used to take me an hour to fully wake up." This suggests that benzodiazepines may actually make insomnia worse in the elderly.
Treatment and prevention
Benzodiazepines are regarded as potentially addictive drugs. A psychological and physical dependencePhysical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
can develop in as short as a few weeks but may take years to develop in other individuals. Patients wanting to withdraw from benzodiazepines typically receive little advice or support.
Benzodiazepines are usually prescribed only short-term, as there is little justification for their prescribing long-term. Some doctors however, disagree and believe long-term use beyond 4 weeks is sometimes justified, although there is little data to support this viewpoint. Such viewpoints are a minority in the medical literature.
There is no evidence that "drug holidays" or periods of abstinence reduced the risk of dependence; there is evidence from animal studies that such an approach does not prevent dependence from happening. Use of short-acting benzodiazepines is associated with interdose withdrawal symptoms, which may increase the risk of kindling
Kindling (substance withdrawal)
Kindling due to substance withdrawal, refers to the neurological condition which results from repeated withdrawal episodes from sedative-hypnotic drugs such as alcohol or benzodiazepines. Each withdrawal leads to more severe withdrawal symptoms than the first withdrawal syndrome...
; kindling has clinical relevance with regard to benzodiazepines; for example, there is an increasing shift to use of benzodiazepines with a shorter half-life and intermitant use, which can result in interdose withdrawal and rebound effects.
Letter to patients
Sending a letter to patients warning of the adverse effects of long-term use of benzodiazepines and recommending dosage reduction has been found to be successful and a cost-effective strategy in reducing benzodiazepine consumption in general practice. Within a year of the letter's going out, there was found to be a 17% fall in the number of benzodiazepines being prescribed, with 5% of patients having totally discontinued benzodiazepines. A study in Holland reported a higher success rate by sending a letter to patients who are benzodiazepine-dependent. The results of the Dutch study reported 11.3% of patients discontinuing benzodiazepines completely within a year.Pharmacist intervention programs
A study found that pharmacists providing educational sessions for medical staff at nursing homes for the elderly combined with medicine audits and feedback cycles combined with an interdisciplinary sedative review resulted in a large reduction in both the number of residents taking benzodiazepines or antipsychotics at all as well as an overall reduction in total dosage.Cognitive behavioral therapy
ZopicloneZopiclone
Zopiclone is a non-benzodiazepine hypnotic agent used in the treatment of insomnia. In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone, is sold under the name Lunesta...
is the most frequently prescribed hypnotic in the UK, followed by nitrazepam
Nitrazepam
Nitrazepam is a type of benzodiazepine drug and is marketed in English-speaking countries under the following brand names: Alodorm, Arem, Insoma, Mogadon, Nitrados, Nitrazadon, Ormodon, Paxadorm, Remnos, and Somnite...
, and then temazepam
Temazepam
Temazepam is an intermediate-acting 3-hydroxy benzodiazepine. It is mostly prescribed for the short-term treatment of sleeplessness in patients who have difficulty maintaining sleep...
. Hypnotic drugs are of poor value for the management of chronic insomnia. Hypnotic drug consumption has been shown to reduce work performance, increase absenteeism, increase road traffic accidents, increase morbidity, and increase mortality, and is associated with an increased incidence of deliberate self harm. In the elderly, increases in falls and fractures associated with sedative hypnotic drug use has been found. It is widely accepted that hypnotic drug usage beyond 4 weeks is undesirable for all age groups of patients. Many continuous hypnotic users exhibit disturbed sleep as a consequence of tolerance but experience worsening rebound or withdrawal insomnia when the dose is reduced too quickly, which compounds the problem of chronic hypnotic drug use. Cognitive behavioral therapy has been found to be more effective for the long term management of insomnia than sedative hypnotic drugs. No formal withdrawal programs for benzodiazepines exists with local providers in the UK. Meta-analysis of published data on psychological treatments for insomnia show a success rate between 70 and 80%. A largescale trial utilizing cognitive behavioral therapy in chronic users of sedative hypnotics including nitrazepam, temazepam, and zopiclone found CBT to be a significantly more effective long-term treatment for chronic insomnia than sedative hypnotic drugs. Persisting improvements in sleep quality, sleep onset latency, increased total sleep, improvements in sleep efficiency, significant improvements in vitality, physical and mental health at 3-, 6-, and 12-month follow-ups was found in those receiving CBT. A marked reduction in total sedative hypnotic drug use was found in those receiving CBT, with 33% reporting zero hypnotic drug use. Age has been found not to be a barrier to successful outcome of CBT. It was concluded that CBT for the management of chronic insomnia is a flexible, practical, and cost-effective treatment, and it was also concluded that CBT leads to a reduction of benzodiazepine drug intake in a significant number of patients. Chronic use of hypnotic medications is not recommended due to their adverse effects on health and the risk of dependence. A gradual taper is usual clinical course in getting people off of benzodiazepines, but, even with gradual reduction, a large proportion of people fail to stop taking benzodiazepines. The elderly are particularly sensitive to the adverse effects of hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
medications. A clinical trial in elderly people dependent on benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
hypnotics showed that the addition of CBT to a gradual benzodiazepine reduction program increased the success rate of discontinuing benzodiazepine hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
drugs from 38% to 77% and at the 12-month follow-up from 24% to 70%. The paper concluded that CBT is an effective tool for reducing hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
use in the elderly and reducing the adverse health effects that are associated with hypnotics such as drug dependence, cognitive impairments, and increased road traffic accidents.
A study of patients undergoing benzodiazepine withdrawal who had a diagnosis of generalized anxiety disorder showed that those hainvg received CBT had a very high success rate of discontinuing benzodiazepines compared to those not having receive CBT. This success rate was maintained at the 12-month follow-up. Furthermore it was found that, in patients having discontinued benzodiazepines, they no longer met the diagnosis of general anxiety disorder
General anxiety disorder
Generalized anxiety disorder is an anxiety disorder that is characterized by excessive, uncontrollable and often irrational worry about everyday things that is disproportionate to the actual source of worry...
, and that the number of patients no longer meeting the diagnosis of general anxiety disorder was higher in the group having received CBT. Thus, CBT can be an effective tool to add to a gradual benzodiazepine dosage reduction program leading to improved and sustained mental health
Mental health
Mental health describes either a level of cognitive or emotional well-being or an absence of a mental disorder. From perspectives of the discipline of positive psychology or holism mental health may include an individual's ability to enjoy life and procure a balance between life activities and...
benefits.
Legal implications
Negligent management of the benzodiazepine withdrawal syndrome has led to some doctors' being brought before the General Medical CouncilGeneral Medical Council
The General Medical Council registers and regulates doctors practising in the United Kingdom. It has the power to revoke or restrict a doctor's registration if it deems them unfit to practise...
in the UK, for example, for stopping sleeping tablets abruptly or reducing anxiolytics too quickly, failure to initiate replacement therapy (e.g., equivalent dose of diazepam), failure to increase dosage to alleviate severe withdrawal effects, and failure to warn the patient of the possibility of withdrawal symptoms, having led to a finding by the GMC of negligence against one doctor.
Epidemiology
Research studies have come to different conclusions on the number of therapeutic dose users who develop a physical dependence and withdrawal syndrome. Estimates by researchers of the number of people affected range 20–100% of patients prescribed benzodiazepines at therapeutic dosages long term are physically dependent and will experience withdrawal symptoms.Benzodiazepines can be addictive and induce dependence even at low doses, with 23% becoming addicted within 3 months of use. Benzodiazepine addiction is considered a public health problem. Approximately 68.5% of prescriptions of benzodiazepines originate from local health centers, with psychiatry and general hospitals accounting for 10% each. A survey of general practitioners reported that the reason for initiating benzodiazepines was due to an empathy for the patients suffering and a lack of other therapeutic options rather than patients demanding them. However, long-term use was more commonly at the insistence of the patient, it is presumed, because physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
and/or addiction had developed.
Approximately twice as many women as men are prescribed benzodiazepines. It is believed that this is largely because men typically turned to alcohol to cope with stress and women to prescription drugs. Biased perception of women by male doctors may also play a role in increased prescribing rates to women; however, increased anxiety features in women does not account for the wide gap alone between men and women.
History
Previously, physical dependence on benzodiazepines was largely thought to occur only in people on high-therapeutic-dose ranges and low- or normal-dose dependence was not suspected until the 1970s; and it was not until the early 1980s that it was confirmed. Low-dose dependence has now been clearly demonstrated in both animal studies and human studies, and is a recognized clinicalIllness
Illness is a state of poor health. Illness is sometimes considered another word for disease. Others maintain that fine distinctions exist...
disadvantage of benzodiazepines. Severe withdrawal syndromes can occur from these low doses of benzodiazepines even after gradual dose reduction. An estimated 30–45% of chronic low-dose benzodiazepine users are dependent and it has been recommended that benzodiazepines even at low dosage be prescribed for a maximum of 7–14 days to avoid dependence.
Some controversy
Controversy
Controversy is a state of prolonged public dispute or debate, usually concerning a matter of opinion. The word was coined from the Latin controversia, as a composite of controversus – "turned in an opposite direction," from contra – "against" – and vertere – to turn, or versus , hence, "to turn...
remains, however, in the medical literature as to the exact nature of low-dose dependence and the difficulty in getting patients to discontinue their benzodiazepines, with some papers attributing the problem to predominantly drug-seeking behavior and drug craving, whereas other papers having found the opposite, attributing the problem to a problem of physical dependence with drug-seeking and craving not being typical of low-dose benzodiazepine users.
Misuse and addiction
Benzodiazepines are one of the largest classes of abused drugs; they are classed as schedule IV controlled drugs because of their recognized medical uses.
Benzodiazepines can cause serious addiction problems. A survey in Senegal
Senegal
Senegal , officially the Republic of Senegal , is a country in western Africa. It owes its name to the Sénégal River that borders it to the east and north...
of doctors found that many doctors feel that their training and knowledge of benzodiazepines is, in general, poor; a study in Dakar
Dakar
Dakar is the capital city and largest city of Senegal. It is located on the Cap-Vert Peninsula on the Atlantic coast and is the westernmost city on the African mainland...
found that almost one-fifth of doctors ignored prescribing guidelines regarding short-term use of benzodiazepines, and almost three-quarters of doctors regarded their training and knowledge of benzodiazepines to be inadequate. More training regarding benzodiazepines has been recommended for doctors. Due to the serious concerns of addiction, national governments were recommended to urgently seek to raise knowledge via training about the addictive nature of benzodiazepines and appropriate prescribing of benzodiazepines.
A six-year study on 51 Vietnam veteran
Vietnam veteran
Vietnam veteran is a phrase used to describe someone who served in the armed forces of participating countries during the Vietnam War.The term has been used to describe veterans who were in the armed forces of South Vietnam, the United States armed forces, and countries allied to them, whether or...
s who were drug abusers of either mainly stimulants (11 people), mainly opiates (26 people), or mainly benzodiazepines (14 people) was carried out to assess psychiatric symptoms related to the specific drugs of abuse. After six years, opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
abusers had little change in psychiatric symptomatology; five of the stimulant users had developed psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
, and eight of the benzodiazepine users had developed depression. Therefore, long-term benzodiazepine abuse and dependence seems to carry a negative effect on mental health
Mental health
Mental health describes either a level of cognitive or emotional well-being or an absence of a mental disorder. From perspectives of the discipline of positive psychology or holism mental health may include an individual's ability to enjoy life and procure a balance between life activities and...
, with a significant risk of causing depression. Benzodiazepines are also sometimes abused intra-nasally.
In the elderly, alcohol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
and benzodiazepines are the most commonly abused substances, and the elderly population is more susceptible to benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
and delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
than are younger patients.
See also
- Long term effects of benzodiazepinesLong term effects of benzodiazepinesThe long-term effects of benzodiazepines include drug dependence as well as the possibility of adverse effects on cognitive function, physical health, and mental health. There are significant risks associated with the long-term use of benzodiazepines. However, not all people experience problems...
- Alcohol withdrawal syndromeAlcohol withdrawal syndrome-Protracted withdrawal:A protracted alcohol withdrawal syndrome occurs in many alcoholics where withdrawal symptoms continue beyond the acute withdrawal stage but usually at a subacute level of intensity and gradually decreasing with severity over time. This syndrome is also sometimes referred to...
- Long term effects of alcohol
- SSRI discontinuation syndromeSSRI discontinuation syndromeSSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a syndrome that can occur following the interruption, dose reduction, or discontinuation of SSRI or SNRI antidepressant medications...
- Drug related crime