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Addictive disease disorders are characterized by the chronic use of a drug (such as heroin, cocaine, or amphetamines), alcohol, or similar substances. These disorders usually result in (1) the development of tolerance for the substance, with the need for increasing amounts to achieve the desired effect; (2) physical dependence, characterized by a sequence of well-defined signs and physiological symptoms, such as the withdrawal or abstinence syndrome on cessation of use of the substance; and (3) compulsive drug-seeking behavior, with chronic, regular, or intermittent use, despite possible harm to self or others. Since the early 1960s, research has been increasing in the biology of addictive diseases, and emphasis has shifted from only psychological, sociological, and epidemiological studies to investigations of the metabolic, neurobiological, and molecular bases of addiction.
The four major addictive diseases are alcoholism, narcotic (or opiate) addiction, cocaine and other stimulant addiction, and nicotine addiction. Drug addiction may also occur after chronic use of other types of agents such as barbiturates, benzodiazepines, and marijuana.
Opiate receptors (cell structures that function as an intermediary between the opioid and the physiological response) were conclusively identified in mammals (including humans) in 1973. Since then, it has been determined that there are at least three different types of opioid receptors—mu receptors, delta receptors, and kappa receptors. The genes encoding each of these were cloned for the first time in 1992, beginning with the delta opioid receptor. Subsequent to the discovery of specific opioid receptors, endogenous ligands which bind to these receptors, the so-called endogenous opioids, were discovered. Opioids include substances that are produced endogenously (such as the enkephalins, endorphins, and dynorphins) and may be produced synthetically. Exogenous synthetic opioids are used extensively in the treatment of pain. See Endorphins
It is not known to what extent the endogenous opioids play a role in addictive diseases. It has been suggested that narcotic addiction may be a disorder characterized by (1) a relative or absolute deficiency of endogenous opioids; (2) an end organ or receptor failure to respond to normal or possibly increased levels of endogenous opioids; (3) genetic or acquired (for example, short-acting opiate or stimulant drug–induced) abnormalities in the feedback control of the synthesis, release, and processing, or degradation of one or more types of the endogenous opioids; or (4) genetic variations in the opioid receptors.
The possible role of endogenous opioids in alcoholism is also not clear. It has been shown that a specific opioid antagonist, naloxone, may reverse or ameliorate some of the signs and symptoms and physical abnormalities of the acute alcohol intoxication syndrome. However, this apparent beneficial effect of an opioid antagonist may not be related to the addictive disease per se, but may be due to the counteracting of the possible acute release of large amounts of endogenous opioids in response to excessive acute alcohol ingestion. Whether there are some common mechanisms with a genetic, metabolic, or purely behavioral basis underlying these two addictive diseases has not yet been defined.
There are three approaches to the management of opiate (primarily heroin) addiction: pharmacological treatment, drug-free treatment following detoxification, and incarceration. Statistical data over the last century reveal that after release from prison, completion of drug-free treatment, or discontinuation of chronic pharmacological treatment with methadone or other mu agonists, partial agonists, or antagonists, fewer than 30% of former long-term heroin addicts are able to stay drug-free. (Long-term addiction is defined as more than 1 year of daily use of several doses of heroin, with tolerance, physical dependence, and drug-seeking behavior.)
Since the 1960s, methadone maintenance treatment has been documented to be medically safe and the most effective available treatment for heroin addiction. Unlike heroin, which has a 3-min half-life in humans, and its major metabolite, morphine, which has a half-life of 4–6 h, methadone has a 24-h half-life. Therefore, when given orally daily, methadone prevents the signs and symptoms of narcotic abstinence and also prevents drug hunger, without causing any narcotic-induced euphoria during the 24 h between doses. Steady moderate to high doses of methadone can be used in the treatment of addiction over long periods of time without tolerance developing to these desired effects. Because of the high degree of cross-tolerance developed for other narcotics, a patient receiving methadone maintenance treatment does not experience any narcotic high or other effects after self-administration of a dose of short-acting narcotic such as heroin. Through this cross-tolerance mechanism, methadone blocks any illicit narcotic effect. 60–90% of heroin addicts who have entered into methadone maintenance treatment will stay in treatment voluntarily for 1 year or more. Illicit opiate abuse drops to less than 15% during such treatment when adequate doses of methadone (usually 60–150 mg per day) are administered. Cocaine or polydrug abuse or alcohol abuse may persist in 20–30% of patients even in excellent methadone programs, since methadone maintenance is specific for treatment of narcotic dependency. Chronic methadone treatment also brings about the normalization of the multiple physiological alterations caused by chronic heroin abuse. Methadone-maintained patients, who are not chronic abusers of other drugs or alcohol, are able to work, to attend school, and to take part in normal socialization, including restoration of family life. However, when maintenance treatment is discontinued, over 70% of all patients will return to opiate abuse within 2 years.
A second type of pharmacological treatment of narcotic addiction is chronic treatment with a specific narcotic antagonist, naltrexone. This drug also prevents any narcotic effect from illicitly administered heroin, but does so by way of direct opioid receptor blocking, with displacement of endogenous or exogenous opioids from receptor binding. Naltrexone treatment has limited acceptance by unselected opiate addicts; only 15–30% of former narcotic addicts entering treatment with this agent remain in treatment for 6 months or more. Therefore, although it may be a worthwhile treatment for some small defined special populations, it does not seem to be an effective treatment for the majority of unselected long-term heroin addicts.
Drug-free treatment involving either long-term institutionalization in a drug-free residence or, less frequently, attendance at an outpatient resource, has resulted in long-term success in approximately 10–30% of all unselected heroin addicts who enter treatment.
Alcoholism has been difficult to treat over a long-term period. There is no specific pharmacological replacement treatment for alcoholism. Disulfiram (Antabuse) is an agent which blocks the metabolism of acetaldehyde, the major metabolite of ethanol. When a person treated with Antabuse drinks alcohol, there is a rapid buildup of acetaldehyde and a severe physiological syndrome ensues, which frequently prevents or modifies further immediate drinking behavior.
The most widely used treatment of alcoholism is self-help groups, such as Alcoholics Anonymous (AA), where mutual support is available on a 24-h basis, along with group recognition of chronic problems with alcohol. However, only around 20–40% of severe chronic alcoholics are able to stay alcohol-free for more than 2 years even under such management. Early studies of the use of an opioid antagonist naltrexone or nalmefene for the treatment of chronic alcoholism have shown that about 50% of the subjects had reduced numbers and magnitudes of relapse events. Ethanol, unlike heroin and other narcotics, has many well-defined severes, specific toxic effects on several organs, including the liver, brain, and reproductive system, so even relatively short drug-free intervals will decrease exposure to this toxin. Therefore, it has been suggested that success in treatment of alcoholism be measured in part by increasing lengths of alcohol-free intervals, and not just by permanent restoration of the alcohol-free state.
Cocaine addiction may also involve disruption of the endogenous opioid system in addition to the well-known primary effect of cocaine in blocking reuptake of dopamine by the synaptic dopamine transporter protein. This effect results in the accumulation of dopamine in the synapse and similar actions at the serotonin and norepinephrine reuptake transporter. Demonstrated changes in the mu and kappa endogenous opioid system increase the complexity of the effect of cocaine and may contribute to its resultant reinforcing properties leading to addiction, as well as to the drug craving and relapse. This may explain in part the resultant difficulties in developing a pharmacotherapeutic approach for the treatment of cocaine addiction.