Benzodiazepines: abuse of benzodiazepines

Benzodiazepines are among the most widely used medications worldwide. They are primarily used to treat anxiety disorders and insomnia. Despite their widespread use, intentional abuse of benzodiazepines is relatively rare. There are currently conflicting data on the development of tolerance to the therapeutic effect of benzodiazepines and the occurrence of withdrawal symptoms when they are suddenly stopped. If benzodiazepines are taken for several weeks, tolerance develops in only a small proportion of patients, so there is no problem with stopping the drug if the need for its use has disappeared. When the drug is taken for several months, the proportion of patients who have developed tolerance increases, and withdrawal symptoms may occur when the dose is reduced or the drug is discontinued. At the same time, it is difficult to distinguish withdrawal symptoms from the recurrence of anxiety symptoms for which benzodiazepines were prescribed. Some patients increase their dose of the drug over time because they develop tolerance to its sedative effects. Many patients and their physicians, however, believe that the anxiolytic effects of the drugs persist even after tolerance to the sedative effect has developed. Moreover, these patients continue to take the drug for many years as directed by their physicians, without needing to increase their dose, and they are able to function effectively as long as they continue taking the benzodiazepine. Thus, it remains unclear whether tolerance to the anxiolytic effects of benzodiazepines develops. Some data suggest that marked tolerance does not develop to all effects of benzodiazepines, since the adverse effects on memory that occur with acute administration of the drug are reproduced in patients who have been taking benzodiazepines for years.

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Withdrawal symptoms when stopping benzodiazepines

• Anxiety, excitement
• Sleep disorders
• Dizziness
• Epileptic seizures
• Increased sensitivity to light and sounds
• Paresthesia, unusual sensations
• Muscle spasms
• Myoclonic jerks
• Delirium

The American Psychiatric Association has formed an expert committee to develop recommendations for the appropriate use of benzodiazepines. Intermittent use—use only when symptoms occur—prevents tolerance and is therefore preferable to daily use. Because patients with a history of alcohol or other dependence are at higher risk for benzodiazepine abuse, chronic use of benzodiazepines should be avoided in these patients.

Only a small proportion of patients taking benzodiazepines for medical reasons begin to abuse these drugs. However, there are people who deliberately take benzodiazepines to get a "high." Among people who abuse benzodiazepines, the most popular are drugs with a rapid onset of action (for example, diazepam or alprazolam). These people sometimes simulate illnesses and force doctors to prescribe the drug or obtain it through illegal channels. In most large cities, benzodiazepines can be purchased from illegal distributors for $1-2 per tablet. When taken without supervision, the dose of the drugs can reach very significant amounts, which is accompanied by the development of tolerance to their sedative effect. Thus, diazepam is usually prescribed to patients in a dose of 5-20 mg/day, while people who abuse the drug take it in a dose of up to 1000 mg/day and do not experience a significant sedative effect.

Benzodiazepine abusers may combine them with other drugs to achieve the desired effect. For example, they often take diazepam 30 minutes after taking methadone; as a result, they experience a "high" that is not possible with either drug alone. Although there are cases in which an illicit benzodiazepine is the primary drug, it is most often used by addicts to reduce the side effects of their main drug or the withdrawal symptoms when it is stopped. For example, cocaine addicts often take diazepam to relieve the irritability and excitement caused by cocaine, and opioid addicts use diazepam and other benzodiazepines to relieve withdrawal symptoms if they cannot obtain their preferred drug in time.

Barbiturates and other nonbenzodiazepine sedatives

The use of barbiturates and other nonbenzodiazepine sedatives has decreased significantly in recent years because new generation drugs have proven to be more effective and safe. Barbiturate abuse causes many of the same problems as benzodiazepine abuse, and is treated in a similar manner.

Since drugs of this group are often prescribed as hypnotics to patients with insomnia, physicians should be aware of the potential dangers of such treatment. Insomnia is rarely primary in nature, except when it is associated with a short-term stressful situation. Sleep disorders are often a symptom of a chronic disease (for example, depression) or represent a natural age-related change in the need for sleep. Taking sedatives can adversely affect the structure of sleep, and subsequently lead to the development of tolerance to this effect. When sedatives are discontinued, rebound insomnia may occur, which is more severe than before treatment. Such drug-induced insomnia requires detoxification with a gradual reduction in the dose of the drug.

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Drug intervention

If patients who have been taking benzodiazepines for a long time as prescribed by their doctor wish to discontinue treatment, the process of tapering the dose may take several months. Detoxification can be done on an outpatient basis; symptoms may occur, but in most cases they are mild. If anxiety symptoms recur, nonbenzodiazepine agents such as buspirone may be used, but they are usually less effective than benzodiazepines in this category of patients. Some experts recommend switching the patient to a long-acting benzodiazepine such as clonazepam during detoxification. Other drugs, such as the anticonvulsants carbamazepine and phenobarbital, are also recommended in this situation. Controlled studies comparing the effectiveness of different treatments have not been conducted. Because patients who have been taking low doses of benzodiazepines for many years usually do not experience side effects, the doctor and patient should decide together whether detoxification or switching to another anxiolytic is worthwhile.

In case of overdose or to stop the action of long-acting benzodiazepines used in general anesthesia, the specific benzodiazepine receptor antagonist flumazenil can be used. It is also used to relieve persistent withdrawal symptoms when stopping long-acting benzodiazepines. Flumazenil is believed to be able to restore the functional state of receptors that have been stimulated by benzodiazepine for a long time, but this assumption is not supported by research data.

In patients with a history of deliberate benzodiazepine abuse, detoxification should usually be performed in an inpatient setting. Benzodiazepine abuse is often part of a combined dependence on alcohol, opioids, or cocaine. Detoxification can be a complex clinical-pharmacologic problem, requiring knowledge of the pharmacologic and pharmacokinetic characteristics of each substance. A reliable anamnestic data may be lacking, sometimes not so much because the patient is dishonest with the physician as because he genuinely does not know what substance he obtained from a street vendor. Detoxification drugs should not be prescribed on a "cookbook" basis; their dosage should be determined by careful titration and observation. For example, withdrawal symptoms on discontinuation of a benzodiazepine may not become apparent until the second week of hospitalization, when the patient has an epileptic seizure.

Combined dependence

In performing the complex process of detoxification in patients dependent on opioids and sedatives, the general rule is to initially stabilize the patient with respect to opioids with methadone and then concentrate on the more dangerous aspects of sedative withdrawal. The dose of methadone depends on the degree of opioid dependence. A trial dose of 20 mg is usually given and then adjusted as needed. Opioid detoxification may be initiated after the more dangerous substances have been addressed. A long-acting benzodiazepine (eg, diazepam, clonazepam, or clorazepate) or a long-acting barbiturate (eg, phenobarbital) may be used to treat sedative withdrawal. The dose is individualized by giving a series of trial doses and monitoring their effect to determine the level of tolerance. In most cases, the combined detoxification procedure can be completed in 3 weeks, but some patients who abuse large doses of psychoactive substances or have concomitant mental disorders require longer treatment. After detoxification, prevention of relapse requires a long-term outpatient rehabilitation program, as in the treatment of alcoholism. No specific means have been found that would be useful in the rehabilitation of persons dependent on sedatives. At the same time, it is obvious that specific mental disorders, such as depression or schizophrenia, require appropriate treatment.