Tolerance Dependence And Abuse

Repeated administration of any number of drugs results in eventual compensatory changes in the body. These changes are usually in the opposite direction of those initially produced by the drug such that more and more drug is needed to achieve the initial desired effect. This process is called TOLERANCE. There are two basic mechanisms for tolerance development: tissue tolerance and metabolic or pharmacokinetic tolerance. Tissue tolerance refers to the changes that occur on the tissue or cell that is affected by the drug. Metabolic tolerance refers to the increase in the processes that metabolize or break down the drug. This process generally occurs in the liver. Barbiturates are subject to both types of tolerance development.

Tolerance does not develop equally in all effects produced by barbiturates. Barbiturate-induced respiratory depression is one example. Barbiturates reduce the drive to breathe and the processes necessary for maintaining a normal breathing rhythm. Thus, while tolerance is quickly developing to the desired sedative effects, the toxic doses change to a lesser extent. As a result, when the dose is increased to achieve the desired effects (e.g., sleep), the margin of safety actually decreases as the dose comes closer to producing toxicity. A complete cessation of breathing is often the cause of death in barbiturate poisoning (Rall, 1990).

If tolerance develops and the amount of drug taken continues to increase, then PHYSICAL DEPENDENCE can develop. This means that if the drug is suddenly stopped, the tissues' compensatory effects become unbalanced and withdrawal signs appear. In the case of barbiturates, mild signs of withdrawal include apprehension, insomnia, excitability, mild tremors, and loss of appetite. If the dose was very high, more severe signs of withdrawal can occur, such as weakness, vomiting, decrease in blood pressure regulatory mechanisms (so that pressure drops when a person rises from a lying position, called orthostatic hypotension), increased pulse and respiratory rates, and grand mal (epileptic) seizures or convulsions. DELIRIUM with fever, disorientation, and HALLUCINATIONS may also occur. Unlike withdrawal from the opioids, withdrawal from central nervous system depressants such as barbiturates can be life threatening. The proper treatment of a barbiturate-dependent individual always includes a slow reduction in the dose to avoid the dangers of rapid detoxification.

Few, if any, illegal laboratories manufacture barbiturates. Diversion of licit production from pharmaceutical companies is the primary source for the illicit market. Almost all barbiturate users take it by mouth. Some try to dissolve the capsules and inject the liquid under their skin (called skin-popping) but the toxic effects of the alcohols used to dissolve the drug and the strong alkaline nature of the solutions can cause lesions of the skin. Intravenous administration is a rare practice among barbiturate abusers.

Many barbiturate users become dependent to some degree during the course of treatment for insomnia. This type of problem is called iatrogenic, because it is initiated by a physician. In some instances the problem will be limited to continued use at gradually increasing doses at night, to prevent insomnia that is in turn due to withdrawal. However, some individuals who are susceptible to the euphoric effects of barbiturates may develop a pattern of taking increasingly larger doses to become intoxicated, rather than for the intended therapeutic effects (for example, to promote sleepiness). To achieve these aims, the person may obtain prescriptions from a number of physicians and take them to a number of pharmacists—or secure their needs from illicit distributors (dealers). If the supply is sufficient, the barbiturate abuser can rapidly increase the dose within a matter of weeks. The upper daily limit is about 1,500 to 3,000 milligrams; however, many can titrate their daily dose to the 800 to 1,000 milligram range such that the degree of impairment is not obvious to others. The pattern of abuse resembles that of ethyl (drinking) ALCOHOL, in that it can be daily or during binges that last from a day to many weeks at a time. This pattern of using barbiturates for intoxification is more typically seen in those who, from the beginning, obtain barbiturates from illicit sources rather than those who began by seeking help for insomnia.

Barbiturates are sometimes used along with other drugs. Often, the barbiturate is used to potentiate, or boost, the effects of another drug upon which a person is physically dependent. Alcohol and HEROIN are commonly taken together in this way. Since barbiturates are ''downers,'' they also are used to counteract the unwanted overstimulation associated with stimulant-induced intoxication. It is not uncommon for stimulant abusers (on

COCAINE or amphetamines) to use barbiturates to combat the continued "high" and the associated motor disturbances associated with heavy and continued cocaine use. Also, barbiturates are used to ward off the early signs of withdrawal from alcohol.

Treatment for barbiturate dependence is often conducted under carefully controlled conditions, because of the potential for severe developments, such as seizures. Under all conditions, a program of supervised withdrawal is needed. Many years ago, pentobarbital was used for this purpose and the dose was gradually decreased until no drug was given. More recently, phenobarbital or the benzodiazepines—CHLORDIAZEPOXIDE and diazepam— have been used for their greater margin of safety. The reason that the benzodiazepines sometimes work is because the general central nervous system depressants—barbiturates, alcohol, and benzodiazepines—develop cross-dependence to one another. Thus a patient s barbiturate or alcohol withdrawal signs are reduced or even eliminated by diazepam.

(SEE ALSO: Addiction: Concepts and Definitions; Withdrawal)

BIBLIOGRAPHY

CsAky, T. Z. (1979). Cutting's handbook of pharmacology: The actions and uses of drugs, 6th ed. New York: Appleton-Century Crofts. Henningfield, J. E., & AtOR, N. A. (1986). Barbiturates: Sleeping potion or intoxicant? In The encyclopedia of psychoactive drugs. New York: Chelsea House.

MeNDELSON, J. H., & Mello, N. K. (1992). Medical diagnosis and treatment of alcoholism. New York: McGraw-Hill.

Rall, T. W. (1990). Hypnotics and sedatives: Ethanol. In A. G. Gilman et al. (Eds.), Goodman and Gilman's the pharmacological basis of therapeutics, 8th ed. New York: Pergamon. Winger, G., Hoffman, F. G., & Woods, J. H. (1992). A handbook ofdrugs and alcohol abuse: the biomedical aspects, 3rd ed. New York: Oxford University Press.

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