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Abuse of and addiction to alcohol, tobacco, and illegal drugs may represent the most costly public health problem in the world. Drug abuse and addiction are central contributors to serious social ills such as accidents, crime, suicide, homicide, and family violence. Drug use is also a major contributor to the transmission of HIV, not only through the sharing of infected needles but also as a result of individual behaviors related to drug use. For example, in poor, inner-city communities, some smokers of crack cocaine, especially women, have sex in exchange for drugs or the money to buy drugs, promoting transmission of HIV. Drug-related harm is not entirely attributable to drug-dependent persons. Nondependent drug abusers and traffickers in illegal drugs are responsible for many social and health-related problems, most notably accidents and violence. For people who are sus ceptible to drug dependency, the sequelae of drug abuse and addiction are particularly serious because drug use generally begins early in life and seriously compromises personal development and work potential.

Drug abuse can be defined as the use of a drug or other substance by a person to modify a mood or state of mind in a manner that is potentially harmful or illegal. Drug abuse by itself does not imply addiction. For example, ingestion of alcohol, a legal psychoactive substance, even on rare occasions can represent abuse if the individual drinks to get drunk and then drives a car. It follows that not all of the medical and social problems related to drugs are the result of addiction. Indeed, nondependent drug abusers may be responsible for large numbers of accidents, injuries, and criminal activities, including assaults.

Tolerance is a state in which a constant dose of a drug produces a diminishing response over time or a state in which an increasing dose of a drug is required to achieve the same effect. Tolerance may result from either pharmacokinetic adaptations (i. e., increased metabolism or clearance of the drug) or pharmacodynamic adaptations (i. e., diminished responsiveness of the brain to the drug). The most significant aspects of tolerance to psychoactive substances have a pharmacodynamic basis.

Drug dependence is defined as a physiologic state of adaptation to a substance such that pathologic symptoms and signs occur on cessation of use. Pathologic symptoms and signs resulting from adaptations to a drug are often divided clinically into two ove rlapping categories: rebound and withdrawal. Rebound symptoms are defined as an exacerbation of symptoms for which the drug was initially taken. For example, someone who uses alcohol or sedative-hypnotics to sleep may have rebound insomnia after discont inuance; with alcohol, rebound frequently occurs after a single dose (i.e., the user wakes during the middle of the night, is unable to fall back asleep, and is often tachycardic and anxious). A major clinical problem associated with rebound symptoms is the tendency to misinterpret them as an endogenous state rather than as unwanted drug effects. Thus, rebound symptoms may contribute to increasing drug use when cessation would be more likely to provide long-term relief. Rebound symptoms may also occur with drugs that are not psychoactive. For example, beta-adrenergic agonist inhalers for asthma may give rise to rebound bronchospasm, and too-rapid tapering of the antihypertensive drug clonidine may lead to severe rebound hypertension.

Withdrawal symptoms are generally characterized by a drug-specific complex of symptoms and signs after cessation. Withdrawal symptoms may overlap with rebound symptoms, but they often also include new symptoms. For example, opiate withdrawal may produce lacrimation, hypertension, and abdominal cramps. In general, the biologic mechanisms underlying the pharmacodynamic aspects of tolerance and those underlying dependence are related or identical.

Drug addiction has many definitions, but the core features of most modern definitions, including that of the American Psychiatric Association, are compulsive drug use and inability to control use despite negative consequences. The life of the addicted person revolves around obtaining drugs, using drugs, and recovering from the effects of drugs despite medical complications, failures in life roles, and serious interpersonal problems. Although not a defining characteristic, denial of theproblem is an almost universal feature of at least some stages of the addicted person's life.

Because the term addiction has taken on pejorative connotations, the American Psychiatric Association uses the term substance dependence in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The DSM-IV criteria for a diagnosis of substance dependence include drug-taking behavior marked by compulsion (e.g., failure of efforts to cut down or control substance use, continued substance use despite significant distress or life impairment) and symptoms and signs of tolerance and withdrawal.

The DSM-IV terminology has the unfortunate consequence of confusing the status of patients who become dependent on prescribed drugs, especially on psychotropic or narcotic analgesic drugs, but do not exhibit addictive behaviors (i.e., compulsive, out-of-control use). For example, patients requiring long-term use of a high-potency benzodiazepine for panic disorder or high-dose morphine for cancer pain may suffer rebound symptoms if the dosage is decreased or the drug is discontinued. These symptoms of dependence may complicate drug discontinuance but are not indicators of addiction. Indeed, a requirement for long-term treatment may be misinterpreted as addiction by patients even if they are using drugs with little or no potential for causing either dependence or compulsive use, such as antidepressants. Effective practice and patient education require that the physician be clear about these distinctions .

The potential for confusion between some aspects of dependence and addiction is magnified by the fact that until the 1980s it was often taught that the most important characteristic of drug addiction was physical dependence, as manifested by physical withdrawal symptoms. The current understanding is that with some psychoactive drugs, physical dependence contributes to the syndrome of addiction but physical dependence is neither necessary nor sufficient for addiction. Thus, physical dependence does not occur with all addictive drugs; it can be produced by opiates, ethyl alcohol, or sedative-hypnotics but not by other highly addictive compounds, most notably cocaine, amphetamines, or nicotine. Conversely, many drugs that are used in general medicine and are not addictive (e.g., inhaled beta-adrenergic agonists for asthma) may produce physical dependence, as evidenced by rebound symptoms on discontinuance.

An additional confusion that permeates discussion of addiction is the idea that there is some scientific or biomedical distinction between illegal drugs such as heroin and cocaine and legal drugs such as alcohol and tobacco. There is no such distinction. The division into legal and illegal categories has a historical and social basis rather than a medical one. The total morbidity and mortality stemming from tobacco and alcohol far surpass the total from illegal drugs, probably reflecting the far greater availability and acceptability of legal drugs. In terms of direct morbidity and mortality, the drug with the greatest impact on health nationwide is nicotine..

While the overall prevalence of drug use has declined somewhat in recent years, the prevalence of heavy drug use among dependent persons has not changed appreciably. The most widely used psychoactive substance in the world is caffeine. Caffeine may produce a mild withdrawal syndrome on discontinuance of regular use (e.g., drowsiness and, occasionally, headache); however, it does not produce addictive behavior. Among those substances that can produce significant intoxication or addiction, alcohol is the most commonly used. The major classes of drugs that are used illicitly are marijuana, the opiates, the psychostimulants (most commonly, cocaine and amphetamine derivatives), the sedative-hypnotics (most commonly, barbiturate-like drugs or benzodiazepines), hallucinogens, phencyclidine, and anabolic steroids. There is also a substantial worldwide problem with the abuse of solvents and inhalants among young people.

A well-conducted door-to-door survey to provide estimates of the prevalence of drug use and dependence found that males are significantly more likely than females to have such a lifetime history. This dependence was not merely attributed to males being more likely to use drugs than females of those who used drugs, males were more likely than females to become dependent .There was also a consistent trend of higher prevalence of dependence in successively younger age groups.

Among the cocaine abusers, anxiety disorders, antisocial personality disorder, and attention deficit disorder more commonly preceded drug abuse, and mood disorders and alcoholism usually followed the onset of cocaine abuse. The high prevalence of comorbidity has substantial implications for treatment because many drug treatment programs are not well equipped to care for other psychiatric disorders, such as depression, bipolar disorder, anxiety disorders, and schizophrenia. Conversely, when practitioners attempt to treat depression and anxiety without addressing concurrent substance use disorders, failure of treatment is the likely result.

Drugs of abuse (e.g., cocaine, amphetamines, opiates, nicotine, ethyl alcohol) are typically taken because they produce feelings of euphoria or relieve distress. These drugs mimic the actions of the neurotransmitters that activate the brain reward circuitry, which normally functions to motivate positive-stimuli- seeking behavior and record the circumstances under which rewards occur. In vulnerable persons, repeated administration of these drugs with sufficient dose, frequency, and chronicity produces long-lived molecular adaptations that result in compulsive, out-of-control drug use. Some of these changes are thought to reverse, over time, with detoxification. Others may create a lifelong vulnerability to relapse.

The brain reward circuitry, on which drugs of abuse act, is the dopaminergic pathway that extends from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (NAc) in the limbic system . Within this mesoaccumbens pathway, the neurotransmitter dopamine plays a major role in marking the circumstances under which rewarding stimuli occur. Cocaine, nicotine, opiates, and ethyl alcohol are reinforcing because they mimic or enhance the actions of neurotransmitters used in the brain reward pathway. Cocaine inhibits the reuptake and clearance of dopamine from synapses, and amphetamine causes dopamine release. The opiates mimic endogenous opiatelike compounds (e.g., enkephalins), which can act directly on the NAc and can also disinhibit the VTA, leading to dopamine release. Nicotine mimics the action of acetylcholine at its nicotinic receptors. Ethanol is a nonselective agent but at intoxicating doses has powerful facilitative effects on g-aminobutyric acid_A (GABA_A) receptors. Both nicotine and ethyl alcohol have been shown to cause dopamine release in the NAc.

Although all highly addictive drugs activate the mesoaccumbens brain reward pathway, they are quite heterogeneous with respect to their other sites of action in the brain. Specific syndromes of intoxication, dependence, and withdrawal depend on the tota lity of locations in the brain where receptors for each drug are found. In addition, the form of drug delivery is important in drug abuse and addiction. Drugs are most reinforcing when their level in the brain rises very rapidly; thus, drugs that are smo ked or injected produce far more powerful effects than drugs that are taken orally. This explains why smoked cocaine base (e.g., crack) and intravenous use of cocaine have a greater propensity for causing dependence than intranasal use of cocaine.

That certain drugs are rewarding does not fully explain compulsive use. Indeed, with chronic drug use, enjoyment of the substance may diminish or even disappear without diminishing the amount of drug taken. The syndrome of addiction results from adaptati ons that occur in the brain as a result of the overstimulation of specific neural circuits. Because drugs such as cocaine and opiates stimulate the brain reward system with a longevity and power that do not occur with naturally occurring stimuli, their positive motivational effects are extremely powerful. The drug abuser learns, in essence, to short-circuit the processes by which naturally rewarding stimuli produce their effect. At least initially, abusers find that they can reliably produce a sense o f euphoria and well-being. Of course, the efficacy and reliability of addictive drugs turn out to be a two-edged sword. It is precisely the potent ability of these drugs to stimulate cells in the mesoaccumbens dopamine system that drives the powerful hom eostatic mechanisms that lead to tolerance and dependence. Because dopamine also signals the presence of positive stimuli, drugs of abuse are powerful conditioning agents, marking the circumstances (both environmental and interoceptive) surrounding their use as highly significant and predictive of reward. The deeply etched emotional memories that result can form the basis of cue-conditioned craving that may occur years after detoxification. Despite development of tolerance and diminished enjoyment of the drug and despite drug-related medical conditions (e.g., alcoholic gastritis), failures in life roles, and other sources of distress, the addicted person continues to want drugs or alcohol intensely. Specific syndromes of dependence and withdrawal depend on where, in addition to the mesoaccumbens pathway, receptors for each drug are found and which particular brain pathways undergo long-term alterations in response to repeated drug exposure.

The types of long-term changes that addictive drugs produce in the brain can be divided conceptually into three categories: (1) physical dependence; (2) control of motivated behavior (e.g., fear of the discomfort of physical withdrawal); and (3) emotional memories associated with and reinforcing of drug use.

First, opiates and ethyl alcohol, but not cocaine, produce compensatory adaptations in brain regions that control somatic functions, thus producing physical dependence. As a result, discontinuance of opiates or alcohol can produce a physical withdrawal syndrome, such as the well-known alcohol withdrawal syndrome that includes hypertension, tachycardia, tremor, nystagmus, insomnia, and, often, grand mal seizures. The first drug-induced adaptation to be well understood was the substrate of physical dependence on opiates. The noradrenergic locus coeruleus (LC) in the dorsal pons and related noradrenergic nuclei appear to be the final common pathways for this syndrome. LC neurons play a role in the control of autonomic function and other somatic functions related to the fight-or-flight response. LC neurons and some of their afferents have mu opiate receptors that respond to morphinelike drugs. With chronic bombardment of these opiate receptors consequent to use of heroin, morphine, or related drugs, homeostatic adaptations occur within the LC and its inputs, which tend to compensate for the effects of opiates on the brain . Thus, acute administration of opiates markedly inhibits LC firing; with long-term administration of opiates, however, the LC exhibits tolerance (i.e., its firing rate slowly returns toward normal). Dependence is unmasked with cessation of opiate administration; as a compensatory adaptation to opioid administration, the intrinsic excitability of the LC increases but is balanced by ongoing opioid administration. With opioid abstinence, the now adapted LC is hyperexcitable and fires at a very high rate. This high rate of firing has been correlated experimentally with the physical opiate withdrawal syndrome.

All addictive drugs produce changes within the brain reward circuitry itself. These adaptations are quite complex and far from fully understood. A subset of these adaptations result in tolerance, decreasing some of the reinforcing effects of the drug and therefore contributing to increases in dosage. The same types of adaptations that contribute to tolerance also contribute to dependence by putting the brain in a state that will lead to emotional and motivational symptoms of withdrawal (e.g., dysphoria, inability to experience pleasure, drug craving) following drug cessation. Functional magnetic resonance imaging examinations of cocaine-dependent human subjects have found that following cocaine infusion, NAc activation continues well beyond the period of euphoria and into the period of dysphoria and drug craving. Continued noninvasive human investigation and investigation in animal models should help elucidate the types of alterations that occur in neural function, their timing, and how they contribute to the addicted state. In addition to those adaptations that lead to dependence and withdrawal, there is evidence for adaptations that produce sensitization-that is, a subset of the effects of some drugs may actually increase. Some aspects of sensitization might increase the desire for the drug; others, such as the syndrome of cocaine-induced paranoia that may develop with chronic use, represent serious clinical problems for some drug users.

Thus, this second type of adaptation in brain functioning involves the control of motivated behavior. The discomfort of physical withdrawal is feared by opiate addicts and may contribute to maintenance of opiate use. Nonetheless, it is not physical withd rawal that is most crucial in maintaining the addictive state but rather the motivational aspect of withdrawal. The precise symptoms of motivational withdrawal differ from drug to drug, but as users of addictive drugs emerge from an episode of use, they may begin to experience dysphoric mood, anhedonia, and, as time passes, increasingly intense drug craving. Such symptoms have been best documented in cocaine withdrawal. If the user has taken the drug to relieve antecedent feelings of distress, the symptoms may seem magnified (rebound symptoms), markedly increasing craving for the drug as a means of relief.

The third type of long-term alteration in brain function produced by drugs of abuse is the production of emotional memories related to drug use. Well-known examples of cue-induced desire for drugs include the craving for a cigarette produced by a large m eal or the reexperiencing of some withdrawal symptoms by detoxified heroin addicts who return to a site where they had previously used drugs. Although the precise relation of these cue-dependent emotional memories to relapse in previously detoxified persons is currently a matter of study, cue-based behavioral therapies have been developed to help detoxified persons cope with circumstances that elicit drug craving.

These different types of long-term changes in the brain have varied courses of onset and abatement. Somatic withdrawal may last from days to one or two weeks; the motivational aspects of withdrawal may last from several weeks to months; emotional memories related to drug use may last a lifetime.

Initial experimentation with alcohol, tobacco, and other psychoactive substances generally occurs during the teenage years, with onset of dependence lagging by several years. Which persons will go on to become dependent often cannot be determined by patterns of early experimentation. However, early use of drugs that have great dependence liability (e.g., cocaine or opioids) and routes of administration that produce rapid onset and high blood levels (e.g., intravenous use or smoking) are likely to be predictive of serious substance use disorders. Risk factors for addiction are not yet well understood but reveal themselves by causing increased drug use, by increasing the likelihood that the individual will become addicted to the drug, or both. The best-established risk factors for substance dependence are male sex and a history of dependence in a first-degree relative. Although familial risk is clearest for alcoholism, it likely holds for other substance use disorders as well. Preexisting psychiatric disorders that may also predispose to substance use disorders include conduct disorder, antisocial personality disorder, and attention deficit disorder. Other psychiatric disorders that have been hypothesized to increase risk of substance use disorders are bipolar disorder and anxiety disorders.

It has been posited that use of so-called soft drugs (i.e., nicotine, alcohol, and marijuana) may provide a gateway to the use of hard drugs, such as heroin and cocaine. However, this hypothesis has never been proved. It has never been shown convincingly that use of nicotine, alcohol, or marijuana has a significant independent effect on subsequent drug use; however, it may be the case that because these drugs are the most readily available ones in the United States, they are the first substances used by persons already predisposed to experimentation with drugs. Regardless of the status of the gateway hypothesis, soft drugs can produce serious difficulties of their own. Alcohol and nicotine dependence are the most common drug addictions in the United States and contribute a disproportionately large share of morbidity and mortality.

After a period of experimentation, many regular substance abusers identify a drug of choice, but polysubstance abuse has become increasingly frequent. Factors leading to selection of a drug of choice or to the onset of polysubstance abuse are complex. Polysubstance abuse may be related at times to drug availability or fashions of drug use in the user's peer group. It may also develop from attempts to achieve desired drug interactions. For example, cocaine abusers may use heroin, anxiolytics, hypnotics, or alcohol to decrease the anxiety and agitation that frequently characterize cocaine binges.For any drug or combination of drugs, the likelihood of achieving long-term abstinence is markedly improved by treatment. Because substance use disorders are chronic and relapsing in nature, positive outcomes are often directly related to the duration and intensity of treatment.

The identification and assessment of patients with substance use disorders are complicated by both patient and physician attitudes. Addicted patients are often unwilling to face the painful consequences of giving up their chosen substance. In addition, patients who are dependent on drugs, including legal psychoactive substances such as alcohol and tobacco, are frequently ashamed of their inability to control their behavior. As a result, many addicted patients deny significant use or loss of control; often, they become defensive or overtly angry when pressed. With illegal drugs or diverted prescription drugs, an additional obstacle to direct patient requests for help is the risk of the serious legal and social consequences of being identified as a drug addict. Patients may fear criminal prosecution, loss of professional licenses, loss of insurance, and, in many industries, loss of employment. Finally, an implicit or explicit admission to a physician that prior visits to doctors may have represented man ipulative attempts to obtain drugs risks endangering the physician-patient relationship.

Physicians may gloss over the topic of substance abuse because of concern for the dignity of valued patients, the desire to avoid potentially explosive topics, excessive pessimism about the efficacy of treatment, and, if substance abuse is suspected, ang er at what physicians may feel are self-inflicted problems not entirely worthy of treatment. A recognition that addiction is not simple, willful misbehavior and that the pathophysiology of addiction impairs the ability of patients to control their substa nce abuse may help physicians assume the nonmoralizing, nonblaming stance that maximizes the likelihood of honest, effective interactions with patients. The disease of addiction makes resumption of substance abuse the patient's behavioral priority despite the negative consequences. At the same time, it must be recognized that understanding addiction as a brain disease does not absolve addicted patients from responsibility for their actions. To put this in perspective, we do not obtain optimal therapeutic results by blaming patients with strong genetic loading and other risk factors for coronary artery disease, but we do ask them to follow a certain diet, to exercise, and to comply with prescribed medication regimens. So it is with addicted patients: we do not blame them for having the disease, but we obtain the best therapeutic results when we convince them to be responsible for themselves once a diagnosis is made and treatment is recommended. The clinically critical difference between addictive disorders and other medical illnesses, however, is that the disease of addiction markedly diminishes the ability of the patient to follow through on medical advice. Thus, the clinician as well as the patient's family, friends, and employer must be prepared to press on through denial, defensiveness, and relapses to get the patient to enter treatment and to keep the patient engaged in treatment over the long term.

In an initial medical history, questions about current and past substance use can follow naturally from questions about the use of prescribed and over-the-counter medications. Some physicians prefer to inquire about drug use after taking the social history. Questions about drug use should be asked respectfully but without apology. Apologies or excessive preambles before asking drug-related questions will suggest to the patient that an admission of substance use or dependence will not be heard or will be met with disapproval. If the patient's illness or laboratory tests are highly suggestive of a substance use disorder but the patient denies substance use, the physician should discuss his or her concerns frankly toward the end of the consultation, after the history and physical examination. The physician should directly relate information from the history, physical examination, and laboratory tests to the possibility of drug use. Follow-up questions about drug use are more likely to engender a useful dialogue if they are asked in a concerned manner in the context of a differential diagnosis.

When patients admit to substance use, physicians should ask which substances have been used and the approximate amounts, frequency, and settings of the use of each substance. Reported amounts and frequencies are often inaccurate; thus, such questions must be supplemented with inquiries about the effects of substance use on the patient's health, cognitive and emotional functioning, and ability to perform in life roles. It is important to determine whether the patient becomes intoxicated and then drives or engages in other high-risk activities and whether the patient has had any legal difficulties as a result of substance use. Other elements of the history include prior treatments for substance use disorders or psychiatric disorders and the patient's per ception of their outcomes. A family history of substance use disorders and psychiatric disorders should also be obtained.

In addition to a general medical examination and laboratory tests to investigate the possibility of general medical conditions that may exist independently of or in association with substance use, it is useful to obtain blood and urine tests for abused substances. Serum and urine tests are useful when they are positive, but they are of limited utility when they are negative because of the short duration of detectability of cocaine (6 to 8 hours), cocaine metabolites (2 to 4 days), opioids such as heroin (36 to 72 hours), and ethanol (7 to 12 hours). Cannabinoids, resulting from marijuana use, may be observed in urine for long periods, but the test is insensitive for intermittent drug use. Testing of hair samples for substance abuse is still not generally available but may become useful in the future because drug deposition in hair gives an integrated picture of drug use over time. However, a variety of technical problems must be overcome before such testing can be considered reliable for general medical use.

The goals of treatment for persons who are dependent on psychoactive substances can be divided into three major components: the achievement of abstinence, relapse prevention, and rehabilitation. Detoxification from alcohol or opioids is usually effected by temporary substitution of a cross-reactive agent (e.g., benzodiazepines for alcohol and methadone or other long-acting opioids for heroin), followed by gradual tapering. Detoxification from barbiturate-like drugs is usually accomplished with the long-acting barbiturate phenobarbital. Cessation of cigarette smoking may be aided by nicotine chewing gum or transdermal nicotine patches. For other major classes of drugs, such as the psychostimulants, effective cross-reactive agents are not available.

Gamma-vinyl-GABA (vigabatrin), an irreversible inhibitor of an enzyme that inactivates GABA , has been shown to decrease the rewarding properties of cocaine in an animal model and thus appears to be a promising candidate for a human clinical trial. Vigabatrin increases GABA levels in the brain over a prolonged time course. The mechanism by which it acts might be indirect, potentially involving adaptations to elevated GABA levels within brain reward circuits. Compounds such as barbiturates and benzodiazepines, which act rapidly and directly to increase the effect of GABA, can themselves be addictive. Thus, despite the promise of vigabatrin, caution must be exercised pending adequate clinical trials in human addicts.

After the patient achieves stable abstinence, treatment enters the phase of relapse prevention. This requires ongoing involvement in treatment, such as regular attendance at Alcoholics Anonymous-type support groups or individual therapies. Also crucial are the detection and effective treatment of intercurrent physical and comorbid psychiatric disorders such as anxiety and depression. It is particularly important to avoid the administration of potentially abusable drugs, such as benzodiazepines, to former drug abusers whenever possible. Thus, an effort should be made to treat anxiety disorders with antidepressants or buspirone as appropriate. Drug dependence produces long-term alterations in brain function. Because addictive drugs tap into adaptive circuits that evolved in part to produce privileged long-term memories of experiences with positive survival value, there are particular risks of relapse associated with such drugs. Environmental cues previously associated with drug use-a particular neighborhood, drug paraphernalia, or, for the former smoker, even a festive meal-may induce intense drug craving years after cessation of use. Therapies specifically aimed at relapse prevention have been designed to help patients minimize exposure to drug cues and to modify their responses to them. Such therapies are most useful as part of a comprehensive treatment program.

A final critical component of treatment is rehabilitation. The patient's reintegration into family and work, obtainment of new skills, and involvement with persons who are not drug users are all critical if treatment is to be successful in the long term. Animportant exception to the usual goal of cessation of drug use is the case of opioid addicts who cannot achieve or maintain stable abstinence. For these individuals, methadone maintenance is an effective alternative.