can be thought of as an adaptation of the functional (physiological) systems of the body to opiates. During chronic use of an opiate, physical dependence also develops when the physiological systems have adapted to the point that they actually require the opiate just to maintain physiological equilibrium.

Virtually all physiological systems are affected in opiate addiction. A reproducible syndrome occurs when an opiate addict goes through withdrawal. This syndrome includes yawning, lacrimation, piloerection, perspiration, mydriasis, tremor, gooseflesh, restlessness, myalgia, anorexia, nausea, vomiting, abdominal cramps, diarrhea, fever, hyperpnea, and hypertension. When prolonged, the syndrome includes weight loss and, even after acute withdrawal, symptoms subside, persistent symptoms such as sleep disturbances, irritability, restlessness, and poor concentration which can be present for months or years. Both acute and chronic tolerance are physiological phenomena subserved by the central nervous system. However, both acute and chronic tolerance may also be influenced by environmental variables, such as setting, conditioning, and learning.

The pharmacological approach to long-term treatment of heroin addiction, first undertaken in early 1964, was rooted in what was then a hypothesis that opiate addiction is a metabolic disease, caused by either intrinsic or drug-induced alterations in physiology. The original researchers in the field, Drs. Vincent Dole, the late Marie Nyswander and Mary Jeanne Kreek, hypothesized that in some or most cases of heroin addiction the addicted individuals had a intrinsic metabolic disorder, possibly with an underlying genetic predisposition, which expressed itself clinically after initial exposure to specific types of drugs or other chemical agents of abuse; and that in other cases, individuals who developed addiction were experiencing drug-induced metabolic disruptions in otherwise normal physiology. They speculated that in the latter cases, heroin-induced changes in specific neurobiological systems persist over long periods and possibly become permanent.

The researchers observed that gradual removal of physical dependence upon morphine or heroin (detoxification) followed solely by psychiatric or other behavioral treatment frequently failed to help addicts sustain abstinence. Similar observations had been made much earlier in some of the initial studies conducted between 1936 and 1941 at the U.S. Public Health Service (USPHS) Hospital in Lexington, Kentucky, which showed that less than ten percent of "hard-core" addicts were able to stay free from opiates after discharge from long stays in drug-free treatment programs that only offered counseling and psychiatric care.

Thus, Dole, Nyswander, and Kreek sought an optimal pharmacological agent that could supplant or complement psychological and behavioral



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