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1 Introduction Drug addiction' is a highly complex process that involves physiological, behavioral, psychological, and social components. Similarly, its treatment usually takes a multifaceted approach. Methods of treating drug addiction include pharmacotherapy (the use of medications), psychotherapy (group and individual counseling) and social support (such as in the form of employment opportunities and education). Pharmacotherapy has not received broad support from the federal govern- ment, nor has the private sector been active in developing anti-addiction medications. There are many reasons for the apparent lack of support of and activity in this kind of drug development. Clearly, the absence of a large, vocal advocacy group that would voice strong support and lobby for treatment funding and research contributes to the lack of federal leadership and the dearth of anti- addiction medications. But, it should be recognized that drug addiction is a disease thriller, l991:one that is widespread in the United States (there are an estimated 0.5-l million heroin-dependent individuals and 2.1 million cocaine- dependent individuals) and shows no signs of abating according to national surveys (Hunt and Rhodes, 1992; Kreek, 1992; Johnston et al., 1994a,b~and like people with any other medical condition, drug addicted individuals deserve to be considered as candidates for medications. 'Drug addiction is defined as the compulsive use of a drug despite adverse consequences. This report focuses on opiate and cocaine addictions and does not address alcohol and nicotine addictions. 26

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INTRODUCTION 27 In 1990, the Medications Development Division (MDD) of the National Institute on Drug Abuse (NIDA) was established to support research and development and to work with the private sector to secure Food and Drug Administration (FDA) marketing approval for new medications to treat drug addiction (see mission statement in Appendix B). This report of the Institute of Medicine (IOM) Committee to Study Medication Development and Research at the National institute on Drug Anuse focuses on pharmacotherapy for the treatment of drug addiction for several reasons: Phannacotherapy for opiate addiction is successful, and it seems reasonable to assume that effective medications could be useful in treating cocaine addiction. . Pharmacotherapies will expand the range of treatment options available to physicians and treatment programs (U.S. Congress, Senate, 1989). . Pharmacotherapies might enhance other treatment modalities. Pharmacotherapy might permit more cost-effective outpatient approaches. Additionally, Congress has specifically required the committee to determine the current conditions for developing anti-addiction medications. The need for pharmacotherapy is further driven by the public-health, economic, and criminal repercussions of illicit drug use (particularly use of opiates and cocaine). The committee focused its attention on medications to treat opiate and cocaine addictions, although it recognizes that the two addictive drugs that are most important with respect to morbidity, mortality, and economic costs are alcohol and nicotine. This chapter examines the magnitude of the illicit drug-use problem and its effects on society. Chapter 2 examines the state of scientific knowledge concerning the mechanisms of drub addiction and the difficulty of developing A, ., . _ anti-addiction medications. the work of NIDA's MDD is discussed in Chapter 3. Chapters 4-9 focus on the disincentives faced by the pharmaceutical industry in developing anti-addiction medications-treatment financing, physician training and education, federal and state regulation, and market issues- and present policy and legislative solutions. PUBLIC-HEALTH REPERCUSSIONS OF ILLICIT DRUG USE Drug addiction has both individual and societal ramifications. Overall societal trends in drug-addiction policy have ranged from minimal libertarian

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28 DEVELOPMENT OF MEDICATIONS approaches in the middle 1800s to medical and criminal approaches that have alternated in emphasis since the late 1800s (IOM, 1990~. Current government approaches are both medical and criminal, involving federal expenditures for drug enforcement and interdiction and federal, state, and private expenditures for drug treatment and drug-addiction research (IOM, 1990~. Historical analysis has demonstrated that policy trends are driven by various factors, including the social class of drug-users, prevailing perceptions regarding the causes of drug addiction (e.g., personal choice, physiological dependence, moral weakness, and genetic predisposition), the limited availability of effective treatments (e.g., methadone), and the relation of the costs of drug-related violence to the Fublic-health costs of drug addiction. Increasingly violence itself is being viewed as a public-health problem as evidenced by increasing public support of antiviolence initiatives in the agencies of the Department of Health and Human Services (DHHS), such as the Centers for Disease Control and Prevention (CDC). This shin coincides with a well-defined relationship between drug addiction and the acquired immune deficiency syndrome (AIDS) epidemic; mounting data on the role of drug addiction in the alarming rise of tuberculosis (TB), particularly the often intractable and deadly drug-resistant form; and the increase in the number of drug-exposed infants. Thus, the development of anti- addiction medications to treat illicit drug use has ramifications not only for addicted individuals, but also for society at large. Health Consequences: Violence Violence is now accepted as one of the major public-health problems facing the United States2, and the CDC has given the prevention of violence one of its highest priorities (Koop and Lundberg, 1992; Rosenberg et al., 1992; Schneider et al., 1992~. Violence and illicit drug use are inextricably linked through several scenarios: the "turf battles" of drug sale and drug distribution, the criminal and open violent behavior prompted by the need for money to support drug use, and the violence (often domestic) associated with the pharmacological effects of some drugs on the drug-addicted individual (BJS, 1992; Marwick, 1992~. In the illegal drug business, violence is systemic and is the typical interaction used to protect and expand markets and deal with competitors, with buyers or sellers suspected of cheating, and with police or witnesses (BJS, 19921. 2Violence has many causes, including the direct behavioral disinhibiting effects of alcohol. Of state prison inmates surveyed who were convicted of committing homicide, 25 percent reported being under the influence of alcohol at the time of the offense (BJS, 1993~.

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INTRODUCTION 29 In the circular nature of the drug-crime relationship, persons with criminal records are more likely than persons without criminal records to report being drug-users, and drug-users report greater involvement with crime (BJS, 1992~. In a 1991 survey of state-prison inmates, 28 percent of inmates incarcerated for violent crimes reported committing the crimes while under the influence of drugs, and 27 percent reported committing robbery to obtain money to buy drugs (BJS, 1993~. Data from the 1991 Drug Use Forecasting Program (a 24-city program involving interviews and urine-tests of a sample of arrested persons) indicate that 65 percent of males arrested for robbery and 48 percent of males arrested for homicide had evidence of illicit drug use in their urine (NIJ, 1992~. Data on arrested females show even higher percentages 76 percent arrested for robbery, 50 percent arrested for assault, and 65 percent arrested for homicide had evidence of illicit drug use in their urine (NIJ, 1992~. Cocaine was the most prevalent drug, with percentages as high as 62 percent of arrested males in Manhattan and Philadelphia (NIJ, 1992~. Violence and drug use are also connected through drugs' pharmacological activity-especially that of such stimulants as cocaine, crack cocaine, phencyclidine (PCP), and ampheta- mines-which can produce irritability, paranoia, and a"need for action" that increases the likelihood of violence (Miller et al., 1991; BJS, 1992; Marwick, 1992~. The links between violence and drug addiction add to the seriousness of the public-health need for effective treatment of drug addiction. Health Consequences: AIDS Injection of illicit drugs is the second most common risk behavior associated with the spread of AIDS, and in some sections of the U.S. recent data show that heterosexual drug users account for the largest group of new AIDS cases (CDC, 1994; Goldstein, 1994~. More than one-third (37 percent) of AIDS cases reported from June 1993 through June 1994 were related to injection of illicit drugs through the sharing of contaminated injection equipment, through heterosexual contact with an injecting drug-user (IDU), or through maternal injection of drugs (Table 1.1) (CDC, 1994~. In women, the percentages of AIDS cases involving injection of illicit drugs are alarmingly high. Of the 51,235 female AIDS cases reported to CDC through June 1994 almost half (24,660 cases) were attributable to injection of illicit drugs and another 19 percent (9,976 cases) to sex with infected IDU partners (CDC, 1994~. The current prevalence of the human immunodeficiency virus (HIV) in the estimated 1.1-1.8 million IDUs is unknown (OTA, 1990~. However, of those in treatment programs, an estimated 61,000-398,000 IDUs are infected with HIV; the estimates vary in different regions of the United States and reach a high of 65 percent in New York City (OTA, 1990; Hahn et al., 1989~.

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30 DEVELOPMENT OF MEDICATIONS TABLE 1.1 AIDS Cases Related to Injection of Illicit Drugs (Percentage of total cases) Exposure Category Cases Reported Cumulative Total June 1993-June 1994 Reported Injecting drug use: Men Women Heterosexual contact with an injecting drug user: 17,441 (20.5) 6,138 (7) 73,705 (18.3) 24,660 (6) Men959 (1) 4,263 (1) Women2,197 (3) 9,976 (2.5) Men who have sex with men and inject drugs4,165 (5) 25,447 (6) Pediatric cases (<13 years old): Mother who is an injecting drug user Mother who has sex with an injecting drug user Total cases related to injecting drug use 284 (0.3)2,192 (0.5) 1 37 (0.2)969 (0.2) 3 1,321 (37)141,212 (35) Total cases reported 85,260 401,749 SOURCE: CDC, 1994. AIDS and illicit drug use are linked not only by injection drug use, but also through an increase in high-risk sexual behaviors and perinatal transmission of HIV. Such behaviors include exchange of sex for drugs, unprotected sex and multiple partners, and prostitution to gain money to buy drugs (Turner et al., 1989~. Heroin and cocaine alone or in combination are the most common injectable drugs, although some injection of amphetamines has also been reported (OTA, 1990~. Of the 5,734 cases of AIDS in children under 13 years old reported to CDC through June 1994,89 percent are attributable to perinatal HIV transmission (CDC, 1994~. Most (55 percent) of the pediatric AIDS cases are associated with injection of illicit drugs 38 percent with maternal injection of drugs and 17 percent with maternal sexual contact with an IDU (CDC, 1994~.A11 infants bone to HIV-infected mothers carry passively acquired maternal antibodies that make them HIV-seropositive, and an estimated 25-35 percent of these infants are actually infected (Hardy, 1991~.

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INTRODUCTION 31 Health Consequences: Tuberculosis TB was once a major public-health problem in the United States that caused many deaths, but it declined with the discovery of effective medications and with increased public-health screening and intervention programs. TB is an infectious bacterial disease that commonly affects the lungs (pulmonary type) but can also affect other organ systems (systemic type). It is again an immediate threat to the well-being of thousands of Americans who are homeless, live in poverty, take illicit drugs, or are infected with HIV. The very factors that are contributing most greatly to the increase in TB also present severe challenges to stemming its further spread (OTA, 1993~. For example, CDC recently reported that nearly 23 percent of inmates in correctional facilities had positive skin tests for TB (CDC, 1993 a). The closed nature of the prison environment, coupled with overcrowding, makes prisons ideal for transmission of TB. Prisons also have a high concentra- tion of people from environments of poverty, and the inmate population has a high prevalence of drug addiction. Most inmates will re-enter the community, and failures of the prison health system will have impacts outside the prison walls. The emergence of TB strains that are resistant to many of the standard medications exacerbates the threat. From 1985 to 1992, rates of TB increased significantly in people 25~4 years old (54.5 percent increase), Hispanics (74.5 percent increase), and African-Americans (26.8 percent increase) (CDC, 1993b). TB has also increased greatly in children, presumably in part through transmis- sion from older family members (CDC, 1993b). Drug-resistant TB is high among IDUs and those infected with HIV. Positive skin tests for TB have been found in nearly 10 percent of patients in drug-treatment programs (CDC, 1993a). The incidence of TB among those with HIV is almost 500 times that in the non-HIV- infected population (Barnes et al., 1991~. That is an ominous figure because people in the later, more severe stages of AIDS often do not test positive for TB in standard skin tests, even if they have active TB (Barnes et al., 1 99 1; Braun et al., 1993~; thus, simple screening procedures are often inaccurate, and this increases the threat of TB transmission to health-care workers. It is clear from a public-health perspective that illicit drug use and its associated risks of HIV and TB are serious threats to the health of non-drug- addicted populations that justify the investment of federal funds in drug-treatment research and prevention. The burden of HIV and TB on the health-care system is important to consider. For example, the CDC spent about $20 million per year for TB programs in 1967, 1968, and 1969. The expenditure fell dramatically in 1972-1983 but increased to $ 100 million in 1993, mainly because of HIV-related programs (OTA, 1993~. The average cost of medication to treat uncomplicated TB is about $350 per person, but medications for a case of drug resistant TB cost an average of $8,720 and possibly as much as $35,000 (OTA, 1993~.

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32 DEVELOPMENT OF MEDICATIONS Health Consequences: Drug-exposed Infants NIDA's recently released National Pregnancy and Health Survey provides nationally representative data on the extent of drug use during pregnancy (NIDA, 1994~. The survey estimated that 221,000 women (with 220,000 live births) used one or more illicit drugs during pregnancy with estimates of 45,100 women having used cocaine (34,800 of those women used crack cocaine) and 3,600 women having used heroin during pregnancy. Drug-exposed infants have more medical complications and longer hospital stays after birth and possibly suffer from long-term developmental deficits (GAO, 1990~. Fetal effects of maternal illicit drug use are difficult to separate, however, from the many risk factors often present in the lives of drug-using women, such as infrequent or no prenatal care, poor nutrition, low socioeconomic status, low maternal age, and multiple drug use, including cigarette-smoking and alcohol. Frequency of drug use, timing of drug use during pregnancy, drug purity, and dosage are additional confounding variables. Cocaine acts as a vasoconstrictor (possibly constricting blood vessels in the placenta and umbilical cord), and its maternal use during pregnancy has been found to be associated with impaired fetal growth and lower head size at birth (Finnegan and Kandall, 1992~. Studies are ongoing to determine the relationship between prenatal cocaine exposure and birth defects, preterrn birth, and neonatal neurobehavioral dysfunction, including heightened sensitivity and irritability, abnormal sleep patterns, and decreased interactive behavior (Peters and Theorell, 1990; Zuckerman, 1991~. Maternal use of opiates increases the likelihood of low birth weight, prematurity, small fetal head size, and sudden infant death syndrome (Zuckerman, 1991; Finnegan and Kandall, 1992~. Infants of opiate- addicted mothers often are addicted and go through the neonatal abstinence syndrome in withdrawal (Kronstadt, 1991~. Long-term developmental conse- quences of in utero exposure to illicit drugs including language, behavioral, and learning difficulties are being studied (Kronstadt, 1991; Zuckerman, 1991~. ECONOMIC COSTS OF ILLICIT DRUG USE TO SOCIETY Given the extent of the major health consequences associated with illicit drug use, the need for treatment? including effective pharmacotherapy, is urgent. In addition to the public-health imperative for developing these medications, the economic costs associated with use of illicit drugs are staggering. It has been estimated that about $66.9 billion (Table 1.2) was spent in 1990 in dealing with some aspect of illicit drug use (D. Rice, University of California at San Francisco, personal communication). That figure includes costs for health are, for drug-addiction treatment and prevention, for fighting and preventing

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INTRODUCTION ~3 J drug-related crime, and for resources lost because of reduced worker productivity or death (Figure 1.11. These costs have steadily and substantially risen from an estimated $44 billion in 1985 to $58 billion in 1988 and to the 1990 estimates in excess of $66 billion (Rice et al., 1991; Rice, UCSF, personal communica- tion). Although the focus of this report is on heroin and cocaine, economic costs are not available for specific drugs, so the data cited here include all illicit drug use. TABLE 1.2 Estimated Economic Costs of Drug Abuse, 1990 Type of Cost Amount Percent ($ millions) Distribution . Total66,873 100.0 Core Costs14,602 21.8 Direct3,197 4.8 Mental health organizations867 1.3 Short stay hospitals1,889 2.8 Office-based physicians88 0.1 Other professional services32 0.05 Support costs321 0.5 Indirect11,405 17.1 Morbiditya7,997 12.0 Mortality3,408 5.1 Other related costs45,989 68.8 Direct18,043 27.0 Crime18,035 27.0 Social-welfare administration8 0.01 Indirect27,946 41.8 Victims of crime1,042 1.6 Incarceration7,813 11.7 Crime careers19,091 28.5 AIDS6,282 9.4 NOTE: Within each category are direct costs, for which payment is made, and indirect costs, for which resources are lost. 1990 costs based on socioeconomic indexes applied to 1985 estimates. Defined by the author as the value of goods and services lost by individuals unable to perform their usual activities because of drug abuse, or unable to perform them at a level of full effectiveness (Rice et al., 1990~. SOURCE: D. Rice, University of California at San Francisco, personal communication.

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34 DEVELOPMENT OF MEDICATIONS Drug-related crime cost society over $46 billion in 1990 and constitutes the highest percentage of the economic burden placed on society as a result of illicit drug use (Table 1.2~. This figure is a composite of the direct costs of police protection, drug-traffic control, property destruction, and legal adjudication and the indirect costs of lost productivity for victims of crime and for those incarcer- ated in prisons or involved in criminal careers. Direct health-related costs of illicit drug use were estimated to have totaled over $3 billion in 1990, and health-care costs due to the large number of AIDS cases associated with injection drug use were-estimated at $6.3 billion in 1990 (Table 1.2~. Other costs of illicit drug use include morbidity costs (the value of reduced or lost productivity due to drug use) and mortality costs (the value of productivity lost because of premature death resulting from drug addiction); these indirect costs were estimated to total over $11 billion in 1990 in the United States. The social- welfare costs summarized in Table 1.2 (estimated at $8 million in 1990) include costs of public assistance, food stamps, unemployment insurance, and other social-welfare programs. Crime 68.7% AIDS 9.4% Mortality 5.1% Health care 4.8% Morbidity 1 2.0% FIGURE 1.1 Summary of the economic cost of illicit drug use, 1990. Percentage breakdown of $66.9 billion cost of U.S. illicit drug use in 1990. SOURCE: D. Rice, University of California at San Francisco, personal communication. Those estimates include federal expenditures. In 1992, the federal govern- ment spent $11.9 billion on drug control and employed 66,652 persons (full-time equivalents) to work in various agencies on the illicit drug-use problem (ONDCP, 1992~. The Department of Justice handled 36 percent of the 1992 expenditure, DHHS received 17 percent, and the Department of Defense received

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INTRODUCTION 35 11 percent (ONDCP, 1992~. Total drug-control expenditures by the federal government have increased by more than 750 percent from 1981 to 1993 (ONDCP, 1992~. U.S. national drug-control policy has focused primarily on supply reduction; about two-thirds of drug-control expenditure has gone for interdiction, intelli- gence, incarceration, and other law-enforcement activities (ONDCP, 1992~. The remaining one-third of the federal drug-control expenditure has been divided among research and development, treatment, and prevention (Figure 1.2~. The percentage for research and development has remained virtually unchanged since 1981, varying from 3.5 to 5 percent of the total expenditure (ONDCP, 19921. While there have been increases in the amount spent on treatment and preven- tion, the percentage of the total drug-control budget spent for treatment has been halved from 30 percent in 1981 to a low of 16 percent in 1992. 8 7 a, 6 5 o c 4 a ._ = m 3 2 1 - ,, l / 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 + ROD _ Treatment _ Prevention D - Law enforcement l~lGtJRE 1.' Federal drug control budget trends (1981-1993~. NOTE: Figures are in current dollars. SOURCE: ONDCP, 1992. The 1994 national drug-control strategy proposed substantial increases in spending for treatment, and reductions in the percentage spent on law-enforce- ment supply control efforts (Washington Post, 19941. The strategy called for increasing the availability of treatment by providing $355 million in new block grants to states, with the target of treating an additional 140,000 heavy drug users each year. However, the final legislation approved only a $57 million increase for state block grants in the FY95 budget.

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36 DEVELOPMENT OF MEDICATIONS EXTENT OF ILLICIT DRUG USE The widespread presence of illicit drug use in the United States is document- edinsurveys of households, students, and jail end prison inmates (Table 1.3~. National incidence of illicit drug use was highest in the 1970s (although cocaine use peaked in the 1980s) and has steadily declined in the past 20 years. However, a recent survey of junior-high-school and high-school students shows indications that this decline has halted and there may be a small upturn in illicit drug use (Johnston et-al., 1994a). Of 1993 high-school seniors surveyed, 42.9 percent reported ever using illicit drugs, and 18.3 percent reported use in the preceding month, predominantly marijuana use (Johnston et al., 1994a). Similarly, 14.9 percent of young adults reported using any illicit drug in the preceding month (Johnston et al., 1994b). Household, prison and jail, and school surveys result in the following data:3 . An estimated 77 million Americans have used an illicit drug at some time in their life (SAMHSA, 1994c). An estimated 24.4 million Americans have used an illicit drug within the last year (SAMHSA, 1994c). An estimated 11.7 million Americans have used an illicit drug within the last month (SAMHSA, 1994c). Of 1993 high-school seniors surveyed, 18.3 percent reported use of an illicit drug in the last month a substantial increase from the 14.4 percent of 1992 high-school seniors (Johnston et al., 1994a). Marijuana, the most commonly used illicit drug in the United States, has been tried by nearly one-third of all Americans, with highest preceding year use in those 18-25 years old (22.9 percent had used marijuana in 1993~. Of the 18.6 million Americans estimated to have used marijuana in 1993, 5.1 million are estimated to have used it weekly (SAMHSA, 1994c). An estimated 4.5 million Americans used cocaine in 1993 (SAMH- SA, 1994c). The number of heavy cocaine users, using at least once a week, is estimated at 2.1 million (Hunt and Rhodes, 1992~. Crack, a smokable form of cocaine, is estimated to have been used by 996,000 Americans in the last year (SAMHSA, 1994c). Heroin statistics are more difficult to obtain from nationwide surveys because heroin use involves less than 1 percent of the population 3Note that a recent General Accounting Office report warns that use figures, particularly in household and student surveys, are underestimated in that these surveys have high nonresponse rates and do not include high-risk groups, such as high-school dropouts (GAO, 1993~.

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INTRODUCTION 37 and many heroin-users are not part of a traditional household environment. It is estimated that there are 1 million recent or frequent heroin-users, including 0.5 million heroin-addicted individuals (Kreek, 1992~. Drug use was a direct or contributing factor in 7,532 deaths reported in 1992 to the Drug Abuse Warning Network (DAWN) by 137 medical examiner facilities in 38 metropolitan areas. Cocaine was the most frequently reported drug (46 percent), alcohol in combination with other drugs was mentioned in 39 percent of the cases, and heroin or morphine in 39 percent (SAMHSA, 1994b). Morbidity reports from DAWN indicate that there were about 433,493 drug abuse-related hospital emergency-room episodes in 1992 (SAMHSA, 1994a). Alcohol in combination with other drugs was mentioned most frequently, in nearly one-third of all episodes (more than one drug per episode can be mentioned), followed in frequency by cocaine (28 percent), and heroin or morphine (11 percent). Data collection difficulties including changes in sample composition, nonresponse from data collectors, changes in data collectors, and coding errors, place limitations on interpreting the DAWN data. ROLE OF PHARMACOTHERAPY Given the magnitude of the illicit-drug-use problem, and its economic and public-health consequences, addressing this issue requires a dedicated effort not only to develop pharmacotherapies but also to foster prevention, education, and the use of other kinds of treatment. Pharmacotherapy, as an adjunct to other treatment modalities, has not received widespread support, in part because of the lack of patient advocacy and the belief espoused by some that to treat drug addiction with a medication is merely to substitute one drug for another. That belief stems largely from the use of methadone maintenance for opiate-addicted individuals and, although it's a common view, should not be allowed to detract from the proven success of methadone maintenance programs, which have allowed many people to become functional and productive (IOM, 1990; OTA, 1990), or to dominate thinking about the treatment of all types of addictions. Drug addiction is a disease that merits medication for its treatment, like such other chronic diseases as hypertension, diabetes, and cancer (Miller, 1991~. That such treatment might not treat root causes of the illness or offer a permanent cure does not detract from the value of pharmacotherapy in improving both quality of life and mortality in patients with those diseases.

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38 Cat o ._ Cal o Cat ._ o Cat o Is Cat Cd m v) cn Cot o Cal 00 Cd Cal - - .= 0 - a' V] A: ._ Cd o C: V] 4- ._ - - _. o .= ._ a' ;> ~ . _ ;> ~ AS A: ~0 ~ ._ ._ ~ PA ;> _ U) :> can Vet a z z z z z V _ ~ ~ ~ ~_ _ O O _ _- 0 0Z _ ~D ~ v~ O ~ ~ ~ . . . . .. . .. ~. ~ O O _ _ O_ 0 ~ C ~- ' ~) ~ ,o~ ~ ~z vo ~vom ~ ~ w? v~ oo~ ~ ~ vO ~ ~ oo ~O Vo ~(~} d O ~ ~ ~ - ~ ~ ~ ..... ... <,4 0 _ o ~ vO a ~oo =` o c~ ~ ~~ as ~<: - ~- _ ~_, ~ ~ ~ ~, ^ ~- - o d) - ~, ~ ~S V) m ~ ~ ~: . ~ - - 0 ~ d~ ~ O O ~ C~ ~ 3 ~ V) - ~ o . _ d) ~ O d) _ ,.O Ct ~ d) ~ O O I_ d~ ,= ~ ~: .^,S O C~ ~ ~ ^ ~ O _ ._ ~ ~ ~ . ~ S ~ O CL ~ ~ ~s -~: o ~ o ce o .^ .= =` d~ _ ~ C~ ~ d~ _ :5 U) O =0 _ U) - = ._ O -~ ~ . ~ - ~ ~ C~ ~ ~o, m - ^ ) ~ ,.~} Cd ~ ~ = ;> ._ _ ._ Cd O ~ _ .O 11 O ~ ~ z ~ d) C~ ~ V, ~ cn :, d) C: ~ O ~ Cd O C~ ~ d) .= o C~ C~ 3 d) V) o d) ~: d)

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INTRODUCTION 39 Many illnesses combine both biological and behavioral components. Cardio- vascular disease, for example, can be caused by an inherited tendency toward high cholesterol concentrations and be exacerbated by eating habits that increase dietary fat intake. Its treatment often consists of interventions to change the diet and, when necessary, drugs to lower cholesterol concentration. Similarly, the optimal treatment in diabetes might involve a combination of dietary manage- ment and drug therapy; some people do well with dietary management alone, others need a combination of dietary management and oral antidiabetes drugs or insulin. Likewise,-some opiate-addicted individuals do well with supportive therapy after only a short time on methadone; others require methadone therapy for the rest of their life. Whether the methadone model will apply directly to other addictive drugs, such as cocaine, is not clear. Cocaine is a more complex drug pharmacologically, and a good substitute that is less abusable has not yet been found. The important point is that there is no inherent reason why pharmacological therapy cannot play as important a role in the treatment of drug addiction as other medicinal agents do in the treatment of heart disease, diabetes, and a host of other illnesses. The pharmaceutical industry has not responded to this urgent need. Since the 1960s and the acceptance of methadone as the treatment of choice for opiate addiction, no pharmacotherapies for cocaine addiction have been approved, and only in the last 10 years have two medications been approved for opiate addiction (levo-alpha-acetylmethadol [LAAM] and naltrexone). In an effort to determine the status of pharmaceutical industry participation in the development of anti-addiction medications, the committee queried the FDA about the numbers of companies submitting investigational new drug applications (INDs) for anti-addiction medications. FDA's response indicates that there are six pharmaceutical companies with INDs for medications to treat opiate or cocaine addiction (C. Moody, FDA, personal communication). Currently there are 37 INDs for the treatmen' of drug addiction, but only 18 different drugs are represented. The FDA reports that 5 or 6 INDs are entering phase III clinical trials, however only one IND represents a new substance. Three companies have submitted new drug applications (NDAs) for anti-addiction medications. The committee was asked to determine the reasons for the lack of activity in the development of anti-addiction medications. It became evident that many factors contribute, including: an inadequate science base on addiction and the prevention of relapse (especially for cocaine); an uncertain market environment (which includes such issues as: treatment financing, lack of trained specialists for the treatment of drug addiction, federal and state regulations, market size, pricing issues, societal stigma, liability issues, difficulties in conducting clinical research); and a lack of sustained federal leadership. Although for a certain segment of the pharmaceutical industry (e.g., small companies, biotechnology companies, or those companies already involved in the development of central

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40 DEVELOPMENT OF MEDICATIONS nervous system medications) there may be an interest with suitable incentives to proceed with development of arlti-addiction medications. Chapter 2 examines the state of the scientific knowledge concerning opiate arid cocaine addiction, the approaches used by NIDA's Medications Development Division to discover medications for cocaine addiction, and the advantages and limitations of those approaches. In Chapter 3, the background and progress of MDD are addressed. Chapters 4-9 examine the obstacles and disincentives faced by the private sector in the development of anti-addiction medications and policy and legislative solutions are presented. Chapters 4 and 5 address drug-abuse treat- ment the setting, effectiveness, cost-effectiveness, and the impact of treatment financing on drug development. The need for increased training and education of both specialists and primary care physicians in drug-abuse research and treatment is the focus of Chapter 6. The following two chapters examine the extent and impact of federal (Chapter 7) and state (Chapter 8) laws and regulations on anti-addiction medication development, marketing, and treatment. The report concludes in Chapter 9 with a discussion of additional marketing obstacles, leadership issues, and outlines steps necessary for increasing private sector involvement in the development of anti-addiction medications. REFERENCES Barnes PF, Bloch AB, Davidson PT, Snider DE Jr. 1991. Tuberculosis in patients with human immunodeficiency virus infection. New England Journal of Medicine 324:1644-1650. BJS (Bureau of Justice Statistics). 1991. Drugs and Jail Inmates, 1989. Washington, DC: BJS. BJS (Bureau of Justice Statistics). 1992. Drugs, Crime, and the Justice System. Washing- ton, DC: Government Printing Office. NCJ-1335652. BJS (Bureau of Justice Statistics). 1993. Survey of State Prison Inmates, 1991. Washington, DC: BJS. NCJ-136949. Braun MM, Cote TR, Rabkin CS. 1993. Trends in death with tuberculosis during the AIDS era. Journal of the American Medical Association 269:2865-2868. Bray RIM, Kroutil LA, Luckey JW, Wheeless SC, Iannacchione VG, Anderson DW, Marsden ME, Dunteman GH.1992.1992 Worldwide Survey of Substance Abuse and Health Behaviors Among Military Personnel. Research Triangle Park, NC: Research Triangle Institute. RTI/5154/06-16FR. CDC (Centers for Disease Control and Prevention). 1993a. Tuberculosis prevention in drug-treatment centers and correctional facilities: selected U.S. cities, 1990-1991. Morbidity and Mortality Weekly Report 42:210-213. CDC (Centers for Disease Control and Prevention). 1993b. Tuberculosis morbidity: United States, 1992. Morbidity and Mortality Weekly Report 42:696-704. CDC (Centers for Disease Control and Prevention). 1994. HIV/AIDS Surveillance Report 6~1~:8-12.

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