Concepts Of Drug Addiction

The initiating event leading to drug addiction is the administration of an agent, such as heroin or cocaine, to obtain a pleasurable effect. Repeated administration can result in addiction defined by compulsive drug-seeking behavior, loss of control over drug use, return to drug use despite repeated efforts to stop, interference with social functioning, and often, impairments to health. Addiction can be associated with the presence of tolerance or sensitization to the effects of the drug and/or dependence, as evidenced by withdrawal symptoms if the drug is abruptly stopped. The two most important psychiatric diagnostic classification schemes, Diagnostic and Statistical Manual (APA, 1987) and International Classification of Diseases (ICD-10 draft; WHO, 1990), emphasize compulsive drug-seeking and drug-taking behavior, rather than tolerance, dependence, and withdrawal (see Appendix C for diagnostic criteria). However, pharmacological definitions used in the scientific literature require the latter symptoms to be present, and most opiate-addicted patients (although not cocaine-addicted patients) seeking treatment, in fact, exhibit these symptoms.

Drug addiction involves a complex interplay of psychological, physiological, and social mechanisms, and various models have been put forward to account for these mechanisms (Jaffe, 1992). Figure 2.1 presents the schematic model of drug dependence developed by the World Health Organization (WHO), which emphasizes individual and social antecedents and consequences. Such a model is extremely useful, in that it offers numerous points at which interventions can be made to prevent the establishment or break the cycle of drug dependence through both individual and social means. Jaffe (1992) found it useful to modify this scheme in two ways to emphasize more clearly aspects that might affect the urge to engage in use of addictive drugs and aspects that might underlie successful treatment or cessation of drug addiction (Figures 2.2 and 2.3).

FIGURE 2.1

World Health Organization schematic model of drug use and dependence (Edwards et al., 1981). Figures 2.2 and 2.3 represent modifications and elaborations of Figure 2.1 Reproduced, by permission of WHO.

FIGURE 2.2

Modification of the WHO model. This figure is a modification of Figure 2.1 that emphasizes that processes that subserve the urge to use drugs can be distinct from processes that subserve cognitive risk-benefit analysis and that both can be influenced (more...)

FIGURE 2.3

Model of drug use and dependence including amelioration influences. This figure is a modification of Figure 2.2 that deletes (for visual clarity) some relationships shown in Figures 2.1 and 2.2 and introduces some of the multiple influences (including (more...)

Although development of effective anti-addiction medications is only one component of the multifaceted approach needed to develop an effective national strategy for drug-addiction treatment, this report focuses on the development of pharmacological interventions, so the models emphasizing biological factors are presented here. An established working model to account for drug addiction is the "brain-reward hypothesis"—i.e., a neural network is responsible for the subjective experience of pleasure (Koob, 1992; Wise and Hoffman, 1992), and drugs are abused after initial exposure because they activate the brain's reward system. The neurons in the brain, particularly those in the regions comprising the mesolimbic dopamine system (so called because it uses the neurotransmitter dopamine) are thought to be prominent in the rewarding actions of drugs (Koob, 1992). It is likely that only a small subset of dopamine neurons are specialized for carrying reward-relevant information. Different classes of abusable substances appear to act on this dopamine reward system at different anatomical levels and via different sites of action on or near the dopamine neurons. Activation of the reward system by addictive drugs induces an immediate sense of euphoria or pleasure similar to that obtained through activities that naturally produce rewards such as sexual pleasure. This reward effect, termed positive reinforcement, leads to compulsive drug use.

In support of this hypothesis, basic research has shown that addictive drugs reinforce voluntary drug-taking behavior in humans and laboratory animals (Deneau et al., 1969). The development of techniques for studying the reinforcing effects of cocaine and opiates has allowed researchers to establish and validate laboratory models of critical features of drug addiction—the chronic relapsing behaviors of drug-seeking and drug-taking (Griffiths et al., 1980; Brady and Lukas, 1984). Basic research in laboratory animals has shown that drug-reinforced behaviors are influenced by multiple factors including the pharmacological properties of a drug and its specific neuronal receptors and effector systems, the learned behaviors and cognitions established during repeated episodes of drug use, and the environmental cues that accompany drug-seeking and drug-taking (Griffiths et al., 1980; Young and Herling, 1986; Katz, 1989). Furthermore, evidence is accumulating that the reinforcing effects of cocaine and opiates can be reduced by medications that alter their ability to activate the brain's reward system (e.g., Bergman et al., 1990; Woolverton and Kleven, 1992). In the case of opiates, preclinical studies of methadone, levo-alpha-acetylmethadol (LAAM), naltrexone, and buprenorphine in the reinforcement model have yielded results consistent with those from clinical studies demonstrating the potential effectiveness of these medications as treatment approaches (reviewed by Mello, 1991, 1992). In the case of cocaine, preliminary data suggest a good concordance between results of animal studies in the reinforcement model and preliminary human trials of potential medications (e.g., Fischman et al., 1990; Kosten et al., 1992a). As our understanding of the mechanism of drug addiction continues to improve, development of medications to treat drug addiction will be enhanced.

Compulsive drug use is a chronic relapsing disorder, focusing attention on how the behavioral and physiological effects of drugs change over long periods of repeated use. Depending on the particular drug involved and its specific effects, tolerance might develop and be marked (e.g., Fischman et al., 1985). Thus, the user might require increasingly large doses of the drug to obtain the same effects; indeed the initial euphoric effects of a person's first experience with the drug are difficult to reproduce and in some cases are never achieved again. Sensitization can also occur; that is, the person might experience greater effects of the drug at a constant dose. The same drug can produce tolerance to some of its effects and sensitization to others.

Psychological and physical dependence implies that a definable, reproducible, and undesirable withdrawal syndrome will occur if the drug is abruptly stopped. For many addictive drugs, there is a definable acute-abstinence syndrome that is qualitatively and quantitatively different from protracted-abstinence syndrome. Acute abstinence, usually lasting for several days or weeks, is more intense and uncomfortable than protracted abstinence. Protracted abstinence is associated with more subtle symptoms, such as nervousness, insomnia, depression, craving, and vague feelings of discomfort and dysphoria. Symptoms of protracted abstinence can last for months to years and can increase the probability of relapse, a return to the addictive substance. The biological basis of protracted symptoms and craving is virtually unknown. Nevertheless, after extended drug use, withdrawal discomfort or "craving" contributes to sustained, compulsive drug use.

The final stage in the cycle of addiction is relapse. Relapse can occur even after medical treatment of acute withdrawal symptoms and psychosocial treatment for psychological and social problems associated with the addictive disorder. Relapse can be triggered by some of the same factors that initially led to drug use, but it often seems unrelated to the original cause of the drug use. Intelligence, motivation, and high socioeconomic class do not necessarily prevent relapse. Athletes have terminated careers involving millions of dollars in salaries by relapsing to cocaine use.

After a person has become addicted to a drug, relapse appears at times to take on an involuntary aspect; this problem has been extensively reviewed (O'Brien et al., 1992). Several categories of variables can contribute to relapse. One factor involves the presence of protracted withdrawal symptoms, most extensively studied in opiate-addicted patients and alcoholics (Martin and Jasinski, 1969). There is some evidence that long-term brain changes occur after chronic cocaine use, and these might be associated with protracted withdrawal symptoms in cocaine addicted individuals (Volkow et al., 1990). Relapse is also associated with the presence of psychiatric disorders in addition to the drug addiction (McLellan et al., 1979; Rounsaville et al., 1982; Khantzian, 1985).

Another class of variables that has been linked to relapse is conditioning factors, that is, environmental factors and physiological states that become associated with each other over time (Wikler, 1973; O'Brien, 1975). Extensive reports show that the rewarding effects of drug use can become associated with particular settings or environments; when formerly addicted patients have been detoxified and treated in a drugfree program, there is an increased probability of relapse to drug use if they are returned to the environment in which they had used drugs (Pratt, 1991). Laboratory studies have demonstrated autonomic nervous system and subjective changes in formerly addicted patients presented with videotaped cues specific to the drugs that they had used (Ehrman et al., 1992). Even highly motivated patients report that these cues produce strong craving for the drug. Accordingly, the use of medications that are effective in reducing the symptoms of protracted abstinence will need to be coupled with behavioral techniques to address conditioned responses.

Addiction is characterized by compulsive drug use, tolerance, dependence, craving, and relapse. Key problems in addiction are: how to prevent the onset of compulsive drug use and how to prevent relapse and the craving that leads to relapse. In the past, much medical attention has been given to treatment (detoxification) for the symptoms of acute abstinence. Acute abstinence syndromes related to a wide array of abused substances can be treated reasonably well with available medications; treatment usually does not even require hospitalization (Hayashida et al., 1989). However, the most difficult problem is preventing relapse to drug use, and relapse prevention is the focal point of much current addiction research, and it is the proper focus of the MDD program. Yet, important challenge to development of anti-addiction medications.

Biological Correlates And Psychopharmacology Of Addiction

MDD And Strategies For The Discovery Of A Cocaine Medication: Description And Critical Analysis

Medication Preclinical Screening

Given the absence of a mechanism of action or a "lead" compound for the treatment of cocaine addiction, MDD established the Cocaine Treatment Discovery Program (CTDP) (Chapter 3). Chemicals are accepted into CTDP screening if they have CNS activity and are likely to have direct or indirect biochemical interactions with dopamine or serotonin. Once a chemical has been identified and accepted for preclinical screening, the protocol used depends on what is known about it. CTDP has developed a tiered strategy that can use both in vitro biochemical assays and in vivo behavioral tests (Figure 2.4). Screening of chemicals that are known to affect the dopamine system and have CNS activity can begin with in vivo behavioral testing rather than in vitro testing. Ultimately, the CTDP hopes to identify promising candidates for further toxicological and human clinical testing.

FIGURE 2.4

Cocaine treatment screening flowchart. MDD's CTDP screening program analyzes compounds from industry, academia, or other sources through a series of assays including in vitro biochemical assays or in vivo behavioral assays. Compounds found serendipitously (more...)

This section examines MDD's CTDP and assesses this program according to established methods of chemical identification and behavioral pharmacology. As noted, once a chemical is identified as a potential drug candidate, it undergoes in vitro or in vivo screening.

In Vitro Screen—Receptors and Mechanisms of Action

One strategy used by MDD to find chemicals that bind to a cocaine receptor is mechanism-based (Figure 2.4). Chemicals are subjected to a battery of in vitro biochemical assays to see whether they prevent cocaine from binding without producing effects of their own on the transporter's function. That approach could provide acute cocaine blocking agents analogous to naltrexone. The recent cloning and expression of the relevant transporter proteins make it possible to determine readily whether a so-called cocaine blocker is feasible. This could be accomplished in a more targeted way by combining the knowledge of the structures of chemicals with yet to be obtained information on the structures of the transporter proteins, as opposed to experimental screening of large numbers of potential drug candidates.

The mechanism-based approach, however, has potential flaws: not all of cocaine's immediate stimulatory effects on the brain are mediated by dopaminergic mechanisms. In addition, other drugs that produce behavioral effects similar to those of cocaine, such as amphetamines, have different mechanisms of action, such as increased release of monoamines from nerve terminals (Cooper et al., 1991). A cocaine-blocker would be expected to have no effect on the action of such other stimulants so that treated patients might simply abuse other stimulants while using a cocaine-blocker. That possibility is supported by the fact that polydrug abuse and substituting and experimenting with available drugs are the rule, rather than the exception, for drug users. In addition, it is not known whether the blockade of the dopamine transporter can be achieved without affecting its functioning with regard to dopamine, which is critical in normal neurotransmission.

To overcome such obstacles, MDD has emphasized the development of potential antagonists that interact with the dopamine receptor itself, because the antagonists would be expected to block many of the acute effects of cocaine and other stimulants. There is, however, considerable clinical evidence of the lack of utility of current nonselective dopamine antagonists in the treatment of cocaine addition. Accordingly, MDD is now trying to develop drugs with increasing specificity (i.e., selective for each of the known dopamine-receptor subtypes). This approach is based on the assumption that increased selectivity will be associated with increased effectiveness—an assumption that is largely untested. Indeed, some of the most widely used and effective drugs (e.g., aspirin, lithium, and benzodiazepines) have the least-specific mechanisms of action.

The obstacles outlined above underscore the complexity of the issues involved in developing medications for cocaine addiction. The effects on the dopamine system will have to be characterized for any compound eventually used to treat cocaine addiction, and compounds that act on the dopamine system may actually be found to be effective when administered in combination with compounds with activity in non-dopamine systems. Although the focus on the dopamine system presents problems, no other neurotransmitter system seems a more attractive target. Unlike drug design for opiate addiction, there is no current medication that is effective in treating cocaine addiction. If such a medication existed, its mechanism of action would provide a tremendously useful basis for development of new screening strategies.

In Vivo Screen—Behavioral Tests

The other component of CTDP consists of a sequence of animal behavioral tests for studying potential cocaine-treatment medications. Three assays are used in this order: the locomotor-activity (LMA) test, the drug-discrimination (DD) test, and the self-administration (SA) test. Each initially uses rodents (mice or rats); promising compounds are then tested in monkeys. The goal of the behavioral component of the screening program—which, like the physiological tests, draws on NIDA-sponsored basic research—is to identify compounds with the potential to interfere with or mimic the rewarding effects of cocaine but without abusive, toxic, or rewarding effects of their own. Compounds that mimic some of cocaine's actions might serve as replacement or substitution therapies, whereas compounds that antagonize cocaine might be used to block the effects of cocaine after a relapse to use.

The LMA test is based on the knowledge that cocaine increases locomotor activity in mice. A compound that increases such activity when administered alone might substitute for cocaine (agonist effects). A compound that does not increase this activity, might have no useful effect or might actually block cocaine's actions (antagonist effects). On the basis of results of the LMA test, potential antagonist compounds are tested with cocaine to see whether they block cocaine-induced increases in locomotor activity. Potential agonists are tested with cocaine to see if they have partial agonist effects that will block those of cocaine.

Results of LMA tests constitute the major decision point regarding further screening of a chemical (Figure 2.4). The next step is to assess whether the chemical can substitute for cocaine in (DD) tests or block cocaine's discriminative properties.¹ Discriminative stimulus effects of drugs in laboratory animals are pharmacologically specific and are often predictive of subjective effects in humans (Johanson, 1992; Preston and Bigelow, 1991). Moreover, the high correlation of discriminative effects with neuropharmacological actions of drugs allows exploration of the neuropharmacological mechanisms that underlie the subjective effects of cocaine.

The SA test is a direct test of the rewarding effects of drugs. It has been noted that animals will consistently self-administer cocaine, often to the exclusion of food or other reinforcers. Thus, a test chemical that blocks cocaine self-administration might be useful in treating cocaine addiction. That chemical, however, might also be avidly self-administered and thus have abuse potential; such chemicals are tested further without cocaine to assess that possibility. Eventually, promising chemicals are tested in all the tests outlined above, and the resulting information is used as baseline data for further development.

MDD moved rapidly to select and implement three behavioral models for initial screening of candidate chemicals. On the basis of available scientific knowledge about the behavioral and neuropharmacological effects of cocaine, those models were reasonable first choices. In particular, the models selected have been well characterized pharmacologically and behaviorally (Griffiths et al., 1980; Colpaert and Balster, 1988; Spealman et al., 1992).

Specific Conclusions and Recommendations for the MDD

At this early date, it is difficult to assess the progress of the screening protocols. The effectiveness of the protocols and their predictive value in humans might be seriously limited, however, because of

• The lack of knowledge on the mechanism of cocaine addiction.
• The lack of animal models for addiction, craving, and relapse.
• The lack of successful treatments in humans against which animal models could be validated.
• The lack of potentially useful chemicals from industry, academe, etc.
• The acute administration of candidate chemicals during screening, whereas anti-addiction medications will be clinically administered over time.

The committee recommends that MDD critically evaluate the usefulness of its preclinical screen for discovery of medications to treat cocaine addiction, inasmuch as current methods may not be predictive for humans.

MDD should provide clear guidance to researchers based on results of molecular, cellular and behavioral studies.

MDD should evaluate alternative biochemical targets, such as nondopaminergic mechanisms and the growing number of postreceptor proteins implicated in cocaine's actions.

MDD should explore new ways to seek continuing scientific guidance from intramural and extramural researchers regarding management and refinement of its preclinical screening procedures (as the committee is aware of budgetary and hiring constraints placed on NIDA).

Conclusions And Recommendations

The initiation and maintenance of drug addiction are complex, involving psychologic, physiologic, interpersonal, and social variables. Of particular focus in the MDD program is development of refined medications to treat opiate-addicted patients and the discovery of compounds that will be effective in treating cocaine-addicted patients. The concept of using medications to help to treat drug-addicted individuals is based on the physiological correlates of drug addiction, and the strategy has been shown to be extremely useful as part of the treatment of opiate addiction. Development of effective medications, however, depends heavily on an adequate knowledge base derived from basic scientific studies. Although the science base for opiates is rich, there are large gaps in knowledge about cocaine. In addition, patterns of cocaine use differ greatly from patterns of opiate use and the differences must be taken into account in understanding the physiological underpinnings of the use of these drugs. The largest gaps are related to craving, which likely represents the most important factor in relapse to drug use once an addict is detoxified and enters treatment.

Emerging evidence suggests that chronic administration of both opiates and cocaine produces adaptive responses in numerous behavioral and physiological systems. Research on tolerance and sensitization suggests that chronic drug use can change the neuronal systems with which addictive drugs interact, but only rudimentary information is available on the cellular and molecular bases of these changes for either opiates or cocaine. Moreover, treatment medications themselves can have different effects in acute or repeated administration, and relatively little is known about how chronic treatment with a medication can alter the subjective or voluntary components of addiction. For those reasons, the committee believes that it is imperative to foster NIDA's basic research efforts in the mechanism of cocaine addiction and in the molecular, cellular, and behavioral bases of chronic drug effects. Basic research to develop laboratory models of critical behavioral characteristics of the addictive process is also needed.

Current clinical understanding of the addictive process suggests that models of drug-craving and relapse can be particularly important for medication development. Animal studies exploring such processes as conditioned-stimulus control of drug taking, incentive and motivational effects, and priming effects have begun to identify potential targets for treatment medications. Identification of such behavioral models must be followed by extensive pharmacological and behavioral characterization to provide benchmarks for evaluation of potential medications. A basic understanding of ''craving" is also needed at both the clinical and preclinical levels. Therefore, the committee strongly believes that unless basic research is supported at an appropriate funding level, it will be difficult to make important progress in the scientific knowledge base. The lack of such knowledge would continue to hamper the private sector and MDD in the development of a medication.

In relation specifically to MDD, the committee recommends two mechanisms to address the critical issue of supporting basic science:

The committee recommends that MDD be given a high priority for funding. Although MDD was authorized at $95 million in FY 1994, its appropriation of $40 million has fallen far short of this mark and is far below what is needed for research and development.

The committee is aware, however, of the budget constraints on the institutes of the National Institutes of Health (NIH); as a possible mechanism for increased support, the committee suggests the use of funds from the Special Forfeiture Fund in the Office of National Drug Control Policy (ONDCP).² Utilizing a portion of those funds for basic research not only would provide additional money to MDD, but would demonstrate executive-branch support.

The committee recommends that NIDA designate national drug abuse research centers, subject to congressional appropriations, as described in the ADAMHA Reorganization Act [Public Law 102-321, Section 464N (a)], "for the purpose of interdisciplinary research relating to drug abuse and other biomedical, behavioral, and social issues related to drug abuse." These centers would be engaged in and would coordinate all aspects of drug-abuse research, treatment, and education.

The committee intends that the designation of such centers would serve as focal points for all aspects of drug-abuse research and would have the added benefit of encouraging new investigators to enter the field; they would also serve as sites for clinical trials and for training clinicians (see Chapter 6 for additional text and recommendations on comprehensive centers). The characteristics of the centers should include the conduct of basic research, clinical research, high-priority clinical trial research, and other applied research, drug abuse prevention, training, information, and community service and outreach. One possible mechanism for funding the centers could be through the use of core grants (similar to those used by the National Cancer Institute) because they are designed to bring together an institution's research efforts into a single administrative structure. The grant provides funds for the operation of a centralized administrative staff, resources, and services. It may also provide funding for newly recruited investigators or investigators who have not previously been supported by grants (Chapter 6). By using the core grant mechanism the centers would have the flexibility to explore new research leads. The core grants are not directly designed to support laboratory and clinical research, but they do so indirectly. Alternative funding mechanisms might include the use of contracts, CRADAs, or cooperative agreements between NIDA and the designated center. It should be noted that NIDA does have a number of specialized research centers, but they are more narrowly focused and lack the flexibility of the centers suggested here.

With the designation of such centers, the committee believes that progress will be made in basic, clinical, and other applied research in and treatment of drug addiction. Furthermore, the paucity of basic knowledge in this field is best approached through the coordinated effort that the centers are likely to achieve.

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Footnotes

1

Discriminative properties of a drug encompass all possible perceived and physiological effects of the drug. To be effective, a "substitute" drug, even if it may not produce all the effects of the drug of interest, will produce a sufficient number to reduce or eliminate use of the original drug. Buprenorphine is a good example of such a substitute in the opioid system.

2

The ONDCP Special Forfeiture Fund results from the transfer of money from the Federal Asset Forfeiture Fund (described below). In FY 1990, the Federal Assets Forfeiture Fund transferred $117 million to federal law-enforcement agencies. Deposits of $17 million were also made to the Special Forfeiture Fund to supplement ONDCP program resources and of $115 million to support Federal prison construction. The use of the Special Forfeiture Fund is at the discretion of the director of ONDCP.

The Federal Asset Forfeiture Fund is a sum of money resulting from the sale of assets used in criminal activity that have been seized by the government. In 1990 DEA seized assets valued at more than $1 billion. About two-fifths of the assets seized by DEA was currency valued at almost $364 million. In addition, DEA seized $346 million worth of real property, 5,674 vehicles worth over $60 million, 187 vessels valued at over $16 million, and 51 airplanes worth over $25 million. Almost two-thirds of DEA's seizures during 1990 resulted from cocaine investigations. DEA seizures that were ultimately forfeited are valued at more than $427 million in 1990 (BJS, 1992).