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2 Overview of the State of Scientific Knowledge Concerning Drug Addiction This chapter focuses on opiates and cocaine, the two classes of drugs targeted by the National Institute on Drug Abuse (NIDA) Medications Develop- ment Division (MDD), and begins with an overview of the various concepts of addiction that influence not only the current addiction-treatment methods, but also the scientific investigation of current and potential pharmacological approaches to treatment. For each of the two drug classes, an overview of current scientific knowledge is presented. The remainder of the chapter discusses the MDD cocaine-medication screening program and other strategies for the discovery of an anti-cocaine medication. Conclusions and recommendations are presented with reference to the specific activities of MDD. 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 Classif cation of Diseases (ICD-10 draft; WHO, 1990), emphasize 43

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44 DEVELOPMENT OF MEDICATIONS 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, 19921. 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 2.39. 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 re- lapsing behaviors of drug-seeking and drug- taking (Griffiths et al., 1980; Brady and Lukas, 19841. Basic research in laboratory animals has shown that drug

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THE STATE OF SCIENTIFIC KNOWLEDGE 45 reinforced behaviors are influenced by multiple factors including the phannaco- logical properties of a drug and its specific neuronal receptors and effecter systems, the learned behaviors and cognitions established during repeated episodes of drug use, arid 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 arid 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 demonstrat- ing the potential effectiveness of these medications as treatment approaches (reviewed bY Mello, 1991, 19921. In the case of cocaine, preliminary data suggest a good concordance between results of animal studies in the reinforce- ment 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. SOCIAL AND INDIVIDUAL ANTECEDENTS l SOCIAL INDIVIDUAL SOCIAL AND INDIVIDUAL CONSEQUENCES . r 4' ~ ~1 IMMEDIATE T ANTECEDENTS ANTECEDENTS ~ I e e.g. AVOIDANCE peer groups ~ licensing laws LEARNING family interactions social pressures \ ~/ parental drug use ava' a 'ty variables \ / ~ ~ ~ L IDISPOSITION ~;: _ Lit UG ~ r ~ , Few \ ANTECI [A' IMME DIATE / ~ ~\ _ e e.9. / APPR ACH early learning ~ mood states I LEAR NING I drug experience withdrawal states . genet~cen ment i n developmenta expectato s events T 4, ' , AVERSIVE CONSEQUENCES e.g. toxic effects reduced snug effect organic damage psychosoc al dysfunction NEURO ADAPTIVE STATE REINFORCING CONSEQUENCES erg. mood enhancement psyching taalitation avoidanos or relist of withdrawal symptoms . i, ~ 1 l | TOLERANCE | . I Y WrrHDRAWAL I SYMPTOMS I WHO 81023 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.

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46 a' DEVELOPMENT OF MEDICATIONS | Approach L6aming | ~ me_ _. ~ 1 _! _-1 _~ ~ -1 ~. _ _ - ~^ ~ ~ ~ _n Urge Co5,nltlYe I _~_ (Incilnat~on ~ Rlsk/~r - fit ~ ~ _ r ~J AN __ 1~51 ~ T y ~ ~ _ . -- ~. _ . .......... ........ . ~ ........................... ....... .... _ Em_ Fir is; ~=- ~ ~] Jobrance ~ Positive I .. _ I ~ Consequence. no Drug U8O ~ ~ -- I ~ ~aUve _ Consequences _ I Avoidance Learning I ~_ 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 by distinct factors. Note consequences of alternative drug-use or no drug-use decisions and variety of factors shown by recent research to influence mood, urge to use drugs, and ca- pacity (coping skills) to avoid drug use. Reprinted with permission of Raven Press from Jaffe, 1992. 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

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THE STATE OF SCIENTIFIC KNOWLEDGE 47 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. 1 1 r~ 97O~n" I ~_1 ~ _ ~_ Confluence l l l Urge Cogaltive (IncilneVon ~ Rl~ne fou-J 4_rnent ~I - ~_,~ ~ ~ ~ ''"'' ~ _ it_ _ ~ ..... ,. ~. :. _ 1 ............................ ',:::. Hi - :: :: .. , , , , .: . :'::': ::~;o;c - :,:: "': :: :' Coste:': : :: .:: :: :: . .: . :. :: : :. , ~ p-4lw 1 I| Con~qwnc~. | Con~quencee F~ -~f/. .~ in ::: ..... :.,,,;, :~.":2 ,.. - W:;':'..:".2. ::::: :: molt :::: ...................... ................... L TREATMENTS 1 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 treatment) that can ameliorate patterns of harmful drug use (including dependence). Reprinted with permission of Raven Press from Jaffe, 1992.

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48 DEVELOPMENT OF MEDICATIONS 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., 19921. 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, 19691. 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; Rounsavilleet al., 1982; Khantzian, 19851. 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, l991~. 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., 19921. 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., 19891. 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, knowledge about the pathophysiology of the syndromes of protracted abstinence and conditioned withdrawal or relapse is still rudimentary and presents an important challenge to development of anti-addiction medications.

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THE STATE OF SCIENTIFIC KNOWLEDGE BIOLOGICAL CORRELATES AND PSYCHOPHARMACOLOGY OF ADDICTION Opiate Addiction 49 Opiates can be thought of as a category of plant-derived compounds that happen to activate a major biological system in mammals, the endogenous opiate system. This activation produces many important cardiovascular, endocrine, immune, and neurophysiological effects including euphoria, analgesia, and addiction. Heroin is a well-known example of this group of compounds. These compounds in high doses can produce death from respiratory depression. They also produce abnormalities in the endocrine system that are not easily reversible. Since the 1960s, it has become clear that the effects of opiate drugs are mediated through interaction with opioid receptors. Moreover, studies of the binding of various related opiate compounds in the brain and other tissues indicate the existence of a multitude of opioid-receptor types and subtypes (Leslie, 1987; Terenius and O'Brien, 1992~. The brain contains three major categories of receptors (mu, kappa, and delta), each with at least two subtypes. An opiate drug can simultaneously interact with all three types and act as an agonist (a compound that fully activates a receptor) or partial agonist at each. Binding to the mu receptor, however, is generally considered to be the most important with respect to the pathogenesis of opiate addiction. The rewarding and subjective effects of opiates are mediated through actions at mu opioid receptors (Holtzman and Locke, 1988; Woods et al., 1988, 1993), and interference with actions at these receptors presents a rational strategy for developing medications for opiate addiction. Specifically, medications that block activation of mu opioid receptors (e.g., naltrexone and long-lasting partial agonists) might reduce drug-taking by preventing or reversing the reinforcing or subjective effects of opiates, whereas medications that produce long-lasting receptor activation and tolerance (e.g., methadone and LAAM) might reduce compulsive drug use by substituting at the receptor site of action and block euphoria and withdrawal (reviewed by Preston and Bigelow, 1991; Mello and Mendelson, 1992~. Research examining the effects of opiate maintenance or antagonist treatments on voluntary drug-rewarded behaviors in laboratory animals (e.g., Jones and Prada, 1977; Harrigan and Downs, 1978; Mello et al., 1981 ~ has provided the framework for rational development of medications for opiate addiction (Mello and Mendelson, 1992~. Until very recently, attempts to characterize the opioid receptor at the molecular level had been unsuccessful. However, in 1992 the delta receptor was cloned and sequenced (Evans et al., 1992; Kieffer et al., 1992~; the mu and kappa receptors were similarly cloned (Chen et al., 1993a,b; Li et al., 1993; Meng et al., 1993; Wang et al., 1993; Yasuda et al., 1993~. It is now possible to

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so DEVELOPMENT OF MEDICATIONS express the individual types of receptor in isolated cells, making it easier to characterize their specific properties in detail. Such molecular studies will undoubtedly facilitate the unraveling of some of the complexities of opiate drug use and possibly addiction. They will probably also aid in the further identifica- tion and development of agonists and antagonists (compounds that block activation of the receptor) that are specific for an individual type of receptor. In turn, the availability of such selective chemical probes might provide new mechanistic insights that can be applied to the development of medications to treat the various aspects of opiate addiction. As a result of the identification of the opioid receptors in the early 1970s endogenous Jigands (peptides) for the receptor were isolated and characterized. These function as neurotransmitters, neurotransmitter modulators, or neurohor- mones. Three distinct families of peptides have been identified: enkephalins, endorphins, and dynorphins (Simon and Hiller, 1994~. Considerable knowledge has been obtained with respect to the physiological role of the endogenous opiate peptides in normal physiological function. Although the endorphins bind to all three opioid receptor types, they bind preferentially to the mu-receptor, whereas the enkephalins interact with delta and, to a lesser extent, mu receptors, and dynorphins appear to interact with the kappa receptor. Beta-endorphin is present in circulating plasma and appears to function as an endocrine hormone. Its release is therefore coupled with the release of adrenocorticotrophic hormone (ACTH) and melanocyte-stimulating hormone (MSH). The feedback of systemic cortisol and endogenous, as well as exogenous, opiates on the hypothalamus inhibits the release of pro-opiomelanocortin (POMC) peptides. Thus, the function of the hypothalamic-pituitary-adrenal axis is intimately tied to the physiology of the endogenous opiate system. In contrast, the other endogenous opiates seem to have more neurotransmitter or paracrine functions. Despite the accumulation of considerable knowledge about the impact of opioid-receptor activity on physiological and behavioral functioning, including tolerance and dependence, the molecular mechanisms involved remain to be defined. All opioid receptors appear to be coupled to molecular effector systems involving so-called G-proteins. By analogy to similar types of receptors, it is likely that opiates regulate signaling across cell membranes that requires a complex interplay of molecules including adenylyl cyclase, protein kineses, and various ion channels (K+, Ca2+) (North, 1979; Crain et al., 1986; Childers, 1991; Harris and Nestler, 1993; Nestler and Greengard, 1994~. Presumably, opiate inhibition of adenylyl cyclase results in alterations in the structure (via phos- phorylation) of intracellular proteins that change their functioning and account for many of the acute effects of opiates on neuronal function (Nestler, 1992~. It appears that adaptations in some of the same intracellular signaling pathways represent part of the molecular basis of opiate tolerance and dependence. Despite considerable progress in recent years (Guitart and Nestler, 1989; Guitart et al.,

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TlIE STATE OF SCIENTIFIC KNOWLEDGE 51 1990), much more understanding is required at this mechanistic level before it can be applied to the discovery and development of treatment medications. Recent information shows that among the many effects of endogenous opiate peptides and opiates on neurons are changes in gene expression. Such alterations in gene expression are presumed to be important in drug addiction because of its gradual and progressive development and the persistence of many of its features long after discontinuation of drug exposure. Studies have demonstrated that opiates can regulate some transcription factors that are important in neuronal gene expression (Chang et al., 1988; Hayward et al., 1990; Guitart et al., 1992; Nestler et al., 1993~. That could be important in the long-term adaptations induced by opiates in the brain that ultimately lead to addiction. Many other additional, and poorly understood, adaptive changes probably also contribute to opiate reinforcement, tolerance, and dependence (Nestler, 1992; Nestler et al., 1993). Work to date suggests that use of opiate drugs can effect long-term changes in the brain that can be successfully treated with medications. Although mu and delta opioid receptors appear to play important roles in the development of opiate tolerance and dependence, it has been difficult to relate reinforcement, tolerance, or dependence to changes in these receptors themselves (Loin and Smith, 1990; Nestler, 1992~. The acute withdrawal of opiates from humans who are tolerant to and dependent on those drugs produces a reproducible physiological syndrome. The syndrome consists of yawning, lacrimation, rhinorrhea, perspiration, mydriasis, tremor, gooseflesh, restlessness, myalgia, anorexia, nausea, vomiting, abdominal cramps, diarrhea, fever, hyperpnea, hypertension, and, if prolonged, weight loss (Kleber, 1981~. Many of these acute manifestations of opiate withdrawal represent hyperactivity of the noradrenergic system, thought to be mediated by the loss of opiate feedback inhibition to a specific brain region, the locus ceruleus (Gold et al., 1979; Koob, 1992; Nestler, 1992~. The alpha-2-noradre- nergic agonist clonidine reduces noradrenergic activity by autoreceptor activation and can ameliorate many of the signs and symptoms of early withdrawal. However, clonidine has proved to be of limited usefulness in the treatment of opiate craving and in the prevention of relapse to addiction (Kleber et al., 1985; Fraser, 1990~. After acute withdrawal of opiates most drug-free formerly addicted patients will still feel uncomfortable. Discomfort can take the form of quantifiable symptoms such as restlessness, irritability, poor concentration, and sleep disturbances which might persist for months or even years (Pratt, 1991~. Those symptoms are not relieved by clonidine. Subjects on clonidine might also complain of drug craving and engage in drug-seeking behavior and relapse to drug use. However, methadone, a mu-receptor agonist, is capable of blocking the euphoria of simultaneously administered opiates and inhibiting the symptoms of

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52 DEVELOPMENT OF MEDICATIONS acute and chronic abstinence, including craving. Its clinical efficacy has been shown to be dose-dependent and enhanced by the provision of ancillary psychosocial services (McLellan et al., 1993~. About 117,000 heroin-addicted individuals in the United States are being treated with methadone and are able to perform normally in the workplace (see Chapter 4 for discussion of the effectiveness of methadone maintenance treatment). An additional benefit of methadone treatment is that it can give opiate-addicted patients, who typically suffer from multiple medical problems, access to other health-care services. A good methadone program can provide medications for infectious diseases and treatment of psychiatric disorders and other clinical problems that often accompany and aggravate opiate-addicted patients' health status. LAAM, another opiate agonist has recently been approved for use in the treatment of opiate addiction, primarily because of MDD's efforts and those of the Food and Drug Administration (FDA). LAAM is similar to methadone but stays in the body longer and has active metabolites that persist for days, so it can be taken as infrequently as three times per week. For some patients not having to go to a clinic daily for medication removes a major disruption from their lives. Naltrexone, an antagonist, exploits the specificity of opiate binding to the mu opioid receptor. Naltrexone binds preferentially to the mu receptor and so prevents the binding of any opiate agonist. In animal studies, naltrexone acts to block or reverse the rewarding and subjective effects of mu opiates, and in fact its affinity for the mu receptor is 140 times greater than that of morphine (Holtzman and Locke, 1988; Woods et al., 19931. Naltrexone is being used clinically after detoxification and acute withdrawal to help patients stay off opiate agonist by blocking their effects. Thus, patients taking naltrexone cannot achieve euphoria if they take heroin, so the positive reinforcing effects of opiate addiction are reduced or eliminated (Rose and Levin, 1992~. Naltrexone, however, does not relieve all the symptoms of protracted abstinence. In particular, craving, anxiety, and depression are still present, and a person being treated with naltrexone can readily relapse if the naltrexone is stopped. For this reason, naltrexone has proved most valuable in highly motivated addicted patients who have a great socioeconomic risk or other risk associated with relapse, such as medical personnel or parolees. MOD is developing an improved delivery system for naltrexone that would reduce treatment failure due to noncompliance. An implantable "depot" form of naltrexone, for example, that lasts 30~0 days would help a patient who is ambivalent about remaining opiate-free. Buprenorphine is another new medication for the treatment of opiate addic- tion. It is a partial mu agonist; i.e., it can mimic the effects of agonists under some conditions (especially conditions in which low doses of agonists are effective) but antagonize effects of agonists under other conditions.

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THE STATE OF SCIENTIFIC KNOWLEDGE New approaches to medications for opiate addiction might include . 53 More effective forms of the above medications for example, agents that selectively interact with the various opioid-receptor subtypes or novel partial agonists that work at the mu opioid receptors. A completely new category of medications, such as anticraving compounds to reduce relapse in patients who have been detoxified from opiates. . A wealth of scientific information and understanding of opiate effects, ranging from the clinical to the molecular, has been obtained over the last several decades. This information will continue to grow, especially at the molecular level, primarily through NIDA-supported research. MDD should continue to apply new fundamental knowledge to the study and development of potentially more specific medications for opiate addiction. These might include delta receptor agonists and antagonists or novel partial agonists. At the same time, the clinical evaluation of new medications (such as buprenorphine) or delivery systems (e.g., depot naltrexone) should be continued. Finally, a long-term scientific program should be established with the focus of developing a completely new category of medications based on their anticraving effects. Cocaine Addiction Cocaine addiction differs importantly from opiate addiction. Opiates produce an initial calming effect, and dosing takes place two to four times per day. But, cocaine is a stimulant that produces intense, brief euphoria, and dosing typically takes place as often as every 15-30 minutes for hours or even days. Cocaine users tend to use the drug intermittently in binges, rather than in relatively stable daily doses. Cocaine can be taken by several routes; its toxicity depends on its concentrations in the blood and brain. The euphoric effect of cocaine is a function not just of the blood concentration, but of the rapidity and degree of rise of that concentration. The faster the drug reaches the brain, the more euphoric the effect; if the drug is taken intranasally, this takes 90 seconds, intravenously or by smoking 15 seconds (as this involves no dilution with venous blood from the rest of the body). A major pharmacological effect of cocaine associated with its addictive properties is on the dopaminergic system of the brain (Koob, 1992; Wise and Hoffman, 1992~. Specifically, cocaine blocks the reuptake of dopamine in the synaptic cleft by the dopamine transporter. That increases the amount of dopa- mine available to dopamine receptors and leads to activation of dopaminergic pathways. Although the brain contains several neural pathways rich in dopamine,

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THE STATE OF SCIENTIFIC KNOWLEDGE 63 Clinical Trials In the absence of a clear understanding of the complexity of cocaine's effects on the brain and lack of candidate compounds, there is an alternative approach to identifying potentially useful medications for cocaine addiction: evaluation of the efficacy of currently available psychopharmacological agents to treat the various aspects of cocaine addiction. A number of drugs, approved for indications other than treating drug addiction, have been clinically investi- gated over the last several years. Many of these investigations have been investi- gator-initiated and spontaneous (not necessarily funded by NIDA). That strategy was taken with gepirone, a drug that facilitates serotonin neurotransmission in the brain, and bupropion, an antidepressant with stimulant properties. The findings were negative for both compounds. They were tested initially in multiclinic trials, however, if gepirone and bupropion had first been evaluated in more moderate-sized double-blinded trials, resources could have been saved and the multiclinic strategy reserved for more promising medications. Unfortunately, the typical history has been that open clinical trials of potential medications have shown apparent effects but there has been failure to confirm such effects consistently in carefully controlled studies. Even agents that show effectiveness in double blind studies (e.g., desipramine in Gawin et al., 1989) might not be effective for different populations such as cocaine-using methadone patients, unless subpopulations are carefully analyzed; e.g., desipra- mine showed effectiveness in the methadone studies if antisocial-personality patients were removed from the analysis (Arndt et al., 1992; Arndt et al., in press; Kosten et al., 1992b; Leal et al., in press). The committee believes, however, that studies should be designed to take full advantage of serendipity. The study design is critical; nonblinded and uncontrolled studies should be avoided (Fraser, 1990~. Randomized controlled trials with enough patients to ensure adequate statistical power are preferred. The process by which subjects are selected for study should control for confounding variables such as polydrug use; 20 percent of cocaine users self-medicate the cocaine crash with ethanol; 50 percent of opiate users also use cocaine, and psy- chiatric comorbidity must be controlled for because cocaine-addicted patients with other diagnoses especially attention deficit disorder, major depression, and bipolar disorders- respond differently to different medications (Metzger et al., 19891. In addition, studies that include subjective ratings of craving should be confirmed objectively, with a urine screen. The committee believes that candidate compounds should be tested in rigorously controlled, moderate-size trials and in a limited number of sites; promising compounds can then be further evaluated in multi-clinic settings.

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64 DEVELOPMENT OF MEDICATIONS It has been shown that statistically significant results can often be achieved when 20 to 30 individuals participate in a clinical trial in both the test and placebo controlled groups (Alterman et al., 1992~. While the committee acknow- ledges that the power analysis indicates that small effects will be missed, they nonetheless believe that the ability to screen more substances for substantial effects, with the given resources, is worth the risk of missing small effects. Not only would that approach save resources, but moderate-sized studies can often answer the questions being posed by the larger, multiclinic studies more quickly. Finally, selection of compounds based on a systematic analysis of chemical structure would be advantageous before selection of drugs for clinical evaluation. Promising candidates might also be initially evaluated with appropriate laboratory methods (Fischman and Foltin, 19921. MDD's focus on evaluating multiple members of the same classes of compounds might be questionable and could result in nonproductive, resource-intensive efforts for many years. The clinical evaluation of promising medications, whether derived from screening procedures or from the armamentarium of currently approved drugs, is resource-intensive, and the validity of the findings depends heavily on appropriate experimental design. Human Behavioral Models Two test models that have been developed in human subjects are used to screen potential medications for their efficacy in the treatment of cocaine addic- tion (Fischman and Foltin, 1992; Robbins et al., 19921. These tests are conducted in the laboratory and are completed more rapidly than long-term clinical trials. They have not yet been sufficiently validated as to their predictive potential for determining medications that are likely to be effective in clinical trials. In the first model, volunteers are given the opportunity to take repeated doses of cocaine, with doses and patterning approximating those reported in natural settings (Fischman and Foltin, 19921. Separate measures are made of the amount of drug taken, cardiovascular effects, subjective effects, and craving. The results can be compared with the results measured when the volunteers are given potential treatment medications. In addition, volunteers are given the opportunity to choose between cocaine and nondrugs (a similarity to the ordinary setting, where alternative reinforcers are available); this allows the investigator to deter- mine how medications might interact with other behavioral treatment approaches (Fischman and Foltin, 19921. The second model evaluates human subjects' responses to cocaine-related cues (Robbing et al., 19921. It relies on the conditioned effects of long-term cocaine use. It has been noted that after detoxification cocaine-addicted patients

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THE STATE OF SCIENTIFIC KNOWLEDGE 65 with the determination to refrain from further cocaine use, regardless of the form of psychotherapy, are likely to experience involuntary reactions (such as cocaine craving and other psychological changes) when they return to areas in which they previously used cocaine. Those reactions can also be produced by videotape or other stimuli associated with cocaine even when presented to drugfree former cocaine-addicted patients in the laboratory. A medication that dampens these cue- elicited responses might have a protective value in the enhancement of cocaine treatment programs. Theoretically, a large number of compounds could be screened with the two models, and those which seem to dampen drug-taking or the craving response could be studied in clinical trials that are more time-consuming and costly. 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

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66 DEVELOPMENT OF MEDICA TIONS 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 2The 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~.

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THE STATE OF SCIENTIFIC KNOWLEDGE 67 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)l, "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 administra- tive 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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