Complications may include trauma, inhalation of vomitus, delirium, coma, convulsions, and other medical complications. The nature of these complications depends on the pharmacological class of substance and mode of administration. A cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance , and sometimes a physical withdrawal state.
The dependence syndrome may be present for a specific psychoactive substance e. The ICD diagnostic criteria for opioid dependence are:. Narrowing of the personal repertoire of patterns of opioid use has also been described as a characteristic feature of dependence. Opioid dependence does not develop without a period of regular use, although regular use alone is not sufficient to induce dependence. A definite diagnosis of dependence should usually be made only if three or more of the diagnostic criteria have been experienced or exhibited concurrently at some time during the previous 12 months.
A group of symptoms of variable clustering and severity occurring on absolute or relative withdrawal of a psychoactive substance after persistent use of that substance. The onset and course of the withdrawal state are time-limited and are related to the type of psychoactive substance and dose being used immediately before cessation or reduction of use. The withdrawal state may be complicated by convulsions.
Requests for permission to reproduce or translate WHO publications — whether for sale or for noncommercial distribution — should be addressed to WHO Press, at the above address fax: Turn recording back on. National Center for Biotechnology Information , U. World Health Organization ; 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led to statistical significant improvements in memory function and performance related skills in those having withdrawn successfully from benzodiazepines, whereas those having remained on benzodiazepines experienced worsening symptoms. People having withdrawn from benzodiazepines also felt their sleep was more refreshing, making statements such as " I feel sharper when I wake up " or " I feel better, more awake ",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.
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. Tolerance to the anxiolytic effect of benzodiazepines has been clearly demonstrated in rats. 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. 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.
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. Tolerance develops rapidly to the sleep-inducing effects of benzodiazepines. 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 NMDA 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 downregulation 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.
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.
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 glutamate subreceptors, e. NMDA receptors are upregulated in the brain as a result of benzodiazepine tolerance. AMPA receptors are also involved in benzodiazepine tolerance and withdrawal. Benzodiazepines share a similar mechanism of action with various sedative compounds that act by enhancing the GABA A 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 or treating severe life-threatening withdrawal syndromes from alcohol, such as delirium tremens. 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. There is cross tolerance between alcohol , the benzodiazepines , the barbiturates , the nonbenzodiazepine drugs, and corticosteroids , which all act by enhancing the GABA A receptor's function via modulating the chloride ion channel function of the GABA A receptor. Neuroactive steroids , e. Abrupt withdrawal from any of these compounds, e.
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. 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. GABA 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. Benzodiazepines cause a decrease in norepinephrine noradrenaline , serotonin , acetylcholine , and dopamine [ citation needed ].
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. During withdrawal from full or partial agonists, changes occur in benzodiazepine receptor with upregulation of some receptor subtypes and downregulation of other receptor subtypes. Long-term use of benzodiazepines leads to increasing physical and mental health problems, and as a result, discontinuation 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 can lead 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 withdrawal 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 neuroadaptations. For a diagnosis of benzodiazepine dependence to be made, the ICD 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 month period.
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 tranquilizer self-help group. 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? Due to the risk of developing tolerance, dependence, and adverse health effects,  such as cognitive impairment,  benzodiazepines are indicated for short-term use only - a few weeks, followed by a gradual dose reduction. 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 and published the results in the British Medical Journal in March The committee found that benzodiazepines do not have any antidepressant 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 , tremors , 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.
The committee also made a mistake concluding: The number dependent on the benzodiazepines in the UK from to has been estimated to be 28 persons. This is equivalent to a dependence rate of cases per million patient months. Benzodiazepines are regarded as a highly addictive drug class. Patients wanting to withdraw from benzodiazepines typically receive little advice or support, and such withdrawal should be by small increments over a period of months.
Benzodiazepines are usually prescribed only short-term, as there is little justification for their prescribing long-term. 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. 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 intermittent use, which can result in interdose withdrawal and rebound effects.
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. 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 month follow-ups were found in those receiving CBT.
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. 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. 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 having 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 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 Disputed. 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. The results of the Dutch study reported