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Benzodiazepine dependence

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Benzodiazepine dependence or benzodiazepine addiction is the condition when a person is dependent on benzodiazepine drugs. Dependence can either be a psychological dependence (addiction) or a physical dependence or a combination of the two. Physical dependence occurs when a person becomes tolerant to benzodiazepines and as a result of the physiological tolerance they develop a physical dependence which can manifest itself upon dosage reduction or withdrawal as the benzodiazepine withdrawal syndrome. Addiction or what it is sometimes referred to as psychological dependence includes people who misuse and/or crave the drug not to relieve withdrawal symptoms but to experience its euphoric and or intoxicating effects. Addiction to benzodiazepines can also include people who are not abusing benzodiazepines but take them as prescribed who psychologically can't stop taking benzodiazepines despite the drug causing harm. 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 addiction does not typically occur in prescribed users.[1] 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 survery 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 insistance of the patient, presumably because physical dependence and/or addiction had developed.[2][3][4]

Tolerance and physical dependence

Main article: Benzodiazepine withdrawal syndrome

Physical dependence

Regular use of benzodiazepines at prescribed levels for six weeks was found to produce a significant risk of dependence, with resultant withdrawal symptoms appearing on abrupt discontinuation in a study assessing diazepam and buspirone. However, with abrupt withdrawal after six weeks of treatment with buspirone, no withdrawal symptoms developed.[5] Various studies have shown between 20–100% of patients prescribed benzodiazepines at therapeutic dosages long term are physically dependent and will experience withdrawal symptoms.[6]

Benzodiazepine dependence is a frequent complication when they are prescribed for or taken 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. The risk factors for benzodiazepine dependence are long-term use beyond four weeks, use of high doses and use of potent short-acting benzodiazepines among those with certain pre-existing personality characteristics such as dependent personalities and those prone to drug abuse.[7]

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 wasn't until the early 1980s that it was confirmed.[8][9] However, low-dose dependence is now a recognized clinical disadvantage of benzodiazepines and severe withdrawal syndromes can occur from these low doses of benzodiazepines even after gradual dose reduction.[10][11] Low dose dependence has now been clearly demonstrated in both animal studies and human studies.[12][13]

In an animal study of four baboons on low-dose benzodiazepine treatment, three out of the four baboons demonstrated physical dependence and developed flumazenil-precipitated withdrawal symptoms after only two weeks of low-dose benzodiazepine treatment. Furthermore, the baboons on low-dose therapy did not develop more severe flumazenil-precipitated withdrawal symptoms when low-dose benzodiazepine therapy was continued over a period of 6–10 months, suggesting rapid onset of tolerance and dependence with benzodiazepines and suggesting that physical dependence was complete after two weeks of chronic, low-dose benzodiazepine treatment.[14] In another animal study, physical dependence was demonstrated with withdrawal signs appearing after only seven days of low-dose benzodiazepine treatment and withdrawal signs appeared after only three days after high-dose treatment, which demonstrated the extremely rapid development of tolerance and dependence on benzodiazepines, at least in baboons. It was also found that previous exposure to benzodiazepines sensitized baboons to the development of physical dependence.[15]

In humans, chronic, low-therapeutic-dose dependence was demonstrated in experimentally precipitated withdrawal using flumazenil to show physical dependence and withdrawal signs. Withdrawal symptoms experienced by the chronic therapeutic low-dose subjects included increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch. Healthy control subjects who were not dependent on benzodiazepines exhibited no benzodiazepine withdrawal like effects or notable side effects.[16] In another study of 34 low-dose benzodiazepine users, physiological dependence was demonstrated by the appearance of withdrawal symptoms in 100% of those who received flumazenil whereas those receiving placebo experienced no withdrawal signs. It was also found that those dependent on low doses of benzodiazepines with a history of panic attacks were at an increased risk of suffering panic attacks due to flumazenil precipitated benzodiazepine withdrawal.[17] It has been estimated that 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.[18]

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 have 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.[19][20]

Tolerance

Tolerance in humans to the anxiolytic effects of benzodiazepines develops over a period of 3 months. Tolerance to the anxiolytic effect of benzodiazepines also occurs in animals. The study found that tolerance does not occur at the GABA binding site on the GABAA receptor but that tolerance occurs at the benzodiazepine site on the GABAA receptor.[21][22]Glutamate receptors and especially NMDA receptors also appear to play an important role in benzodiazepine tolerance, dependence and withdrawal.[23][24][25] Tolerance to the anticonvulsant effect of benzodiazepines also develops in both humans and animals.[26][27] A decrease in benzodiazepine binding sites in the brain may also occur as part of benzodiazepine tolerance.[28]

Patients taking daily benzodiazepine drugs have a reduced sensitivity to further additional doses of benzodiazepines.[29]

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 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.[30] However, 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.[31]

There is also cross tolerance between alcohol, the benzodiazepines, the barbiturates and the nonbenzodiazepine drugs, corticosteroids which all act by enhancing the GABAA receptor's function via modulating the chloride ion channel function of the GABAA receptor.[32][33][34][35][36]

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 and benzodiazepine withdrawal problems and other adverse effects. 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 dysmenorrhoea. Benzodiazepines are also not beneficial in the treatment of psychosis. The committee also recommended against benzodiazepines being used 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 was little evidence that long term use of benzodiazepine hypnotics were beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended 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 retained efficacy in the treatment of anxiety after 4 months continuous use due to the development of tolerance. The committee found that the regular use of benzodiazepines caused the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal symptoms tended to develop within 24 hours upon cessation of short acting; 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 tended to occur with habitual use beyond 2 weeks and were 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. In the neonate 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. Benzodiazepines should be avoided in lactation. Withdrawal from benzodiazepines should 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.[37]

Drug misuse and addiction

Benzodiazepines can cause serious addiction problems. Organic brain syndrome occurs in approximately 30% of benzodiazepine misusers causing an induction or a worsening of somatic symptomatology such as anxiety and depression. After withdrawal and a period of abstinence symptomatology improved in 80% of patients.[38] A survey in Senegal of doctors found that many doctors feel that their training and knowledge of benzodiazepines is generally poor. 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.[39] Drug misusers addicted to benzodiazepines develop a high degree of tolerance, coupled with dosage escalation, often increasing their dosage to very high levels. Long-term use of benzodiazepines has the potential to cause both physical and psychological dependence, and are at risk of severe withdrawal symptoms. Tolerance and dependence to benzodiazepines develop rapidly with users of benzodiazepines, demonstrating benzodiazepine withdrawal syndrome after as little as 3 weeks of continuous use. Benzodiazepines, and in particular temazepam, are sometimes used intravenously, which if done incorrectly, or in an unsterile manner, or by using shared syringes & needles can lead to medical complications including abscesses, cellulitis, thrombophlebitis, arterial puncture, deep vein thrombosis, hepatitis B and C, HIV or AIDS, overdose and gangrene. Benzodiazepines are also sometimes abused intranasally which may have additional health consequences. Once benzodiazepine dependence has been established a clinician should first establish the average daily consumption of benzodiazepines and then convert the patient to an equivalent dose of diazepam before beginning a gradual reduction program. Additional drugs, such as antianxiety drugs like buspirone or β blockers, and carbamazepine, should not be added into the withdrawal program unless there is a specific indication for their use.[40][41]

A 2004 US government study of nationwide ED visits conducted by SAMHSA found that sedative-hypnotics in the USA are the most frequently misused pharmaceutical drug with 35% of drug related visits to the Emergency Department involving sedative hypnotics. Benzodiazepines accounted for the majority of these. Benzodiazepines are more commonly misused than opiate pharmaceuticals which accounted for 32% of visits to the emergency department. Males and females misuse benzodiazepines equally. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceutical drug with 26% of attempted suicides involving benzodiazepines. Alprazolam is the most commonly misused benzodiazepine, followed clonazepam, lorazepam and diazepam as the 4th most commonly misused benzodiazepine in the USA.[42]

See also

References

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