NIDA Research Priorities and Highlights
Role of Research
Drug addiction, like heart disease, can be a serious, life-threatening disease treatable by a combination of medications and behavioral therapies. One goal of drug addiction treatment is no different from the goal of treating heart disease: to prolong and improve the patient's quality of life. Over the years, researchers have amassed an impressive amount of scientific knowledge about the treatment of drug use and addiction. This research has clearly shown us that drug abuse treatment can reduce drug use, drug-related criminal behavior, and the health and social costs of drug use and addiction.
Modern approaches to treating addiction have benefited from two types of studies. Longitudinal studies of large populations have helped us identify behavioral and social antecedents to drug use that can be targets for therapeutic intervention. At the same time, neurobiological studies have elucidated the molecular underpinnings of addictive behavior and, in doing so, have identified numerous targets for drug development efforts. The result of this concerted effort is a host of new therapies, both behavioral and pharmacological, that can effectively treat many aspects of drug use and addiction.
In addition, research has helped develop more effective methods for delivering drug use and addiction treatments to affected populations. Research findings are driving changes in the health services delivery system and benefit increasing numbers of patients.
Despite the advances that we have seen in recent years, we need to do more. Therefore, NIDA has launched a major Treatment Initiative to further improve the effectiveness of drug abuse treatment. This Institutewide effort is being coordinated by NIDA's Division of Clinical and Services Research. A special subcommittee of NIDA's National Advisory Council on Drug Abuse is helping NIDA focus the Initiative's priorities. Over the next few years, the Treatment Initiative will increase NIDA's treatment research and will dramatically expand the dissemination of information about research-proven drug use treatments.
To increase the usefulness of NIDA's existing base of treatment knowledge, our comprehensive Initiative is sponsoring a series of research workshops to bring together experts in different areas of treatment. These experts are evaluating existing addiction treatments and are determining which treatments work best and how they work. They also will recommend additional research to develop new and more effective behavioral and pharmacological therapies. Ultimately, these efforts should expand the treatment options available to practitioners and should enable them to select the right combination for their patients.
To ensure that treatment providers apply the most current science-based approaches to their patients, NIDA has supported the development of the "Therapy Manuals for Drug Addiction" series. This series reflects NIDA's commitment to rapidly applying basic findings in real-life settings. The manuals are based on therapies with demonstrated efficacy from NIDA-supported drug use treatment studies. They are intended for use by drug abuse treatment practitioners, mental health professionals, and all others concerned with the treatment of drug addiction. The manuals present clear, helpful information to aid drug treatment practitioners in providing the best possible care that science has to offer. They describe scientifically supported therapies for addiction and give specific guidance on session content and on how to implement therapeutic techniques. Of course, there is no substitute for training and supervision, and these manuals may not be applicable to all types of patients nor compatible with all clinical programs or treatment approaches. These manuals should be viewed as a supplement to, but not a replacement for, careful assessment of each patient, appropriate case formulation, ongoing monitoring of clinical status, and clinical judgment.
Recent advances in drug use treatment are good news. Many studies have shown the effectiveness of drug use treatment, and our investment in basic research on the causes of addiction has given us the knowledge and the tools to develop drug use treatments that will work even better tomorrow. We believe that NIDA's comprehensive Treatment Initiative will be the catalyst for more effective drug use treatments that will substantially alleviate the heavy individual, family, and societal costs and consequences of this terrible disease. In fact, to dramatically improve treatment in this country, NIDA is about to establish a National Drug Treatment Clinical Trials Network. The Network will serve as the major mechanism for moving science-based treatments into practice. Some of the most promising discoveries of the past 3 years are described below.
Developing both medications and behavioral therapies to treat cocaine addiction remains one of NIDA's highest priorities. Truly outstanding work, some of which was discussed in earlier sections of this report, has provided at least a partial explanation for cocaine-induced behavioral and physiological effects, and epidemiological and treatment research to date has elucidated many of the clinical challenges yet to be met. The lag between an understanding of molecular, cellular, and neurobiological effects of cocaine and their relationship to behavioral responses induced by cocaine has resulted in the testing of pharmacological agents aimed at reducing cocaine use based on rationales limited by the scientific and clinical understanding of the disease at that time. However, the evolution of clinical trial methodologies that will yield more useful clinical information and will effectively test underlying hypotheses continues. The gaps in scientists' knowledge and limits
in clinical methodology have restricted the clinical application of many studies.
The current situation may soon change as several compounds are showing promise in animal studies and in the early stages of human clinical trials. Because cocaine has potent effects on the brain's dopamine neurotransmitter system, investigators are testing several compounds that might block cocaine's interactions with this key brain system. In fact, numerous studies in laboratory animals have shown that a family of compounds known as dopamine reuptake inhibitors can decrease cocaine self-administration at doses that do not interfere with behaviors rewarded by food.
In one study involving baboons and rhesus monkeys, investigators administered the drug GBR, a potent, long-acting inhibitor of dopamine uptake, and found that it eliminated cocaine self-administration. The animals tolerated the drug well with only minimal side effects. Human clinical trials of this drug are in the planning stage. Additional work with a chemically modified analog of GBR found that within several days of dosing rhesus monkeys with this compound, cocaine-maintained responding had decreased more than 80 percent without any change in food-maintained responding. Moreover, this selective effect lasted almost 30 days following a single injection of the GBR analog.
Rapid progress also is being made in the development of improved behavioral therapies. In 1998 NIDA published two volumes in its "Therapy Manuals for Drug Addiction" series that deals with cocaine addiction. "Manual 1, A Cognitive-Behavioral Approach: Treating Cocaine Addiction" focuses on using this well-established and well-tested short-term therapeutic approach to help cocaine-addicted individuals become abstinent from cocaine and other substances. The underlying assumption is that learning processes play an important role in the development and continuation of cocaine use and dependence. These same learning processes can be used to help individuals reduce their drug use. The emphasis of cognitive-behavior therapy is to teach patients to recognize the situations in which they are most likely to use cocaine, avoid these situations when appropriate, and cope more effectively with a range of problems and problematic behaviors associated with substance use.
"Manual 2, A Community Reinforcement Approach: Treating Cocaine Addiction" focuses on the Community Reinforcement Approach (CRA), which is an intensive, behavioral treatment for drug use where the patients earn points redeemable for retail items for remaining in treatment and abstinent from cocaine. The general approach taken to achieve this goal is perhaps best described as individualized, empirically based, and behavioral. Although patients are expected to be extremely active participants in the treatment process, this manual prepares therapists for difficulties and noncompliance with therapeutic activities. The therapist is taught to recognize these problems for what they are-problem behaviors in need of therapy, not as a reason to discharge patients from treatment.
A variety of effective treatments are available for heroin addiction, although treatment tends to be more effective when heroin abuse is identified early. Methadone, a synthetic opiate that blocks the effects of heroin and eliminates withdrawal symptoms, has a proven 30-year record of success for people addicted to heroin. In fact, recent data show that only 27 percent of former heroin users were still using heroin a year after participating in an outpatient methadone therapy program. When prescribed properly, methadone is not intoxicating or sedating, and its effects do not interfere with ordinary activities, such as driving a car. The medication is taken orally, and it suppresses narcotic withdrawal for 24 hours. Patients are able to perceive pain and have emotional reactions. Most important, methadone relieves the craving associated with heroin addiction; craving is a major reason for relapse. Among methadone patients, normal street doses of heroin have been found ineffective at producing euphoria, thus making the use of heroin more easily extinguishable.
Methadone's effects last for about 24 hours-four to six times as long as those of heroin-so people in treatment need to take it only once a day. Also, methadone is medically safe even when used continuously for 10 years or more. Combined with behavioral therapies or counseling and other supportive services, methadone enables patients to stop using heroin (and other opiates) and to return to more stable and productive lives.
Indeed, research is showing how to more effectively use this agent in a variety of treatment settings. For example, one study evaluated the relative efficacy of two strategies for reducing illicit substance use in a methadone maintenance setting: urinalysis-contingent reinforcement versus participation in Training in Interpersonal Problem Solving groups, an 8-week therapy designed to promote problem solving skills. This study found that the urinalysis-contingent group showed greater improvement in rates of abstinence from illicit drugs and better met criteria for clinical improvement than the psychoeducational group. It appears that reinforcement of the psychoeducational group attendance is not as effective for reducing illicit drug use among methadone maintenance patients as urinalysis-contingent reinforcement.  The same research group found that a task-oriented behavioral intervention lasting 12 weeks was more effective than a urinalysis-contingent approach. In addition, only the task-oriented treatment group demonstrated improvement in abstinence rates that were maintained after the intervention was discontinued. The results from this study suggest that reinforcement of clearly defined behavioral tasks targeted to treatment plan goals increases involvement in behaviors inconsistent with drug use among methadone maintenance patients.
A newer drug, l-alpha-acetyl-methadol (LAAM) resembles methadone; it is a synthetic opiate that can be used to treat heroin addiction. LAAM can block the effects of heroin for up to 72 hours with minimal side effects when taken orally. In 1993 the Food and Drug Administration (FDA) approved the use of LAAM for treating patients addicted to heroin. Its long duration of action permits dosing just three times per week, thereby eliminating the need for daily dosing and take-home doses for weekends. Although adoption of LAAM has been relatively slow, it has become increasingly available in clinics that already dispense methadone.
Naloxone and naltrexone are medications that also block the effects of morphine, heroin, and other opiates. As antagonists, they are especially useful as antidotes. Naltrexone has long-lasting effects, ranging from 1 to 3 days, depending on the dose, blocks the pleasurable effects of heroin, and is useful in treating some highly motivated individuals, such as professionals who do not want to lose their jobs. Naltrexone has also been found to be successful in preventing relapse by former opiate addicts released from prison on probation.
Although not yet approved for the treatment of opioid addiction, buprenorphine is another medication being studied by NIDA as a treatment for heroin addiction. Buprenorphine is a particularly attractive treatment because it does not produce the same level of physical dependence as other opiate medications, such as methadone. Discontinuing buprenorphine is easier than stopping methadone treatment because there are fewer withdrawal symptoms.
In early 1998 NIDA completed a large multicenter clinical trial on buprenorphine and the combination dosage buprenorphine/naloxone in the United States and Puerto Rico to determine the drug's efficacy and safety as a treatment for heroin addiction. Although data from the study are still being analyzed, NIDA officials are encouraged by buprenorphine's performance. A preliminary analysis has shown that buprenorphine-based products significantly reduced patients' craving for heroin. As the leading Federal agency responsible for bringing new treatment medications and approaches to the national forefront, NIDA is supportive of activities that would expand access to treatment, such as having newly approved medications made available to treatment providers, including those in general practice settings.
The severe nature of opiate withdrawal symptoms can be an impediment to opiate addiction therapy. Investigators have now tested several inhibitors of the enzyme nitric oxide synthase (NOS) for their effectiveness in attenuating signs of opiate withdrawal and affecting blood pressure in rats. Several signs of opiate withdrawal reduced by the NOS inhibitors were similarly attenuated by clonidine, which is used clinically to treat heroin withdrawal. One of the NOS inhibitors tested-7-nitroindazole, a selective inhibitor of neuronal NOS-did not elevate blood pressure and attenuated more withdrawal signs than other NOS inhibitors. Because hypertension is a component of opioid withdrawal in humans, the effectiveness of 7-nitroindazole to attenuate signs of morphine withdrawal without affecting blood pressure suggests that this drug may have human therapeutic potential. 
Meanwhile, researchers are still working to improve behavioral approaches that can be used alone or in combination with pharmacological treatments to increase the likelihood of therapeutic success. For example, one group of investigators has shown that a relatively low-cost visual enhancement to drug use counseling, called node-link mapping, leads to better treatment outcomes than counseling-as-usual for patients in outpatient methadone treatment. "Mapping" is associated with greater patient commitment to treatment in terms of session attendance, improved relationships with the counselor, and fewer urine samples positive for opioid and cocaine metabolites. A followup study also shows patients assigned randomly to mapping counseling reported less criminal activity and exposure to HIV risks due to the reduced use of needles in the 12 months after treatment than did patients in the standard counseling condition. Among patients staying less than 6 months in treatment, those in the mapping group had fewer urines that tested positive for opiates at followup and were also significantly lower in dirty-needle risks than standard counseling patients. Thus, mapping-enhanced counseling may be especially beneficial for patients who leave treatment prematurely. The cumulative evidence from this and previous studies indicates that mapping represents a tool that has promise for improving the effectiveness and efficiency of drug use counseling programs. 
Treating Substance Use in the Context of Psychiatric Disorders
Drug use disorders are frequently associated with psychiatric disorders; more than half of those with a lifetime diagnosis of a drug use disorder also have a lifetime diagnosis of a mental disorder. Despite the common co-occurrence of drug use disorders and psychiatric disorders, many people who have both of these problems tend to fall through the cracks of service delivery systems.
Research on the treatment of individuals with comorbid mental and addictive disorders holds promise for a greater understanding of the relationship among these disorders and the potential for better treatments. One important thrust of this research centers on the observation that some people who use illicit drugs do so as a form of self-medication for psychiatric disorders, such as depression. One group of investigators, for example, studied the use of imipramine, a common antidepressant medication, to treat opiate-dependent patients who were also diagnosed with a depressive disorder and who were receiving treatment at community-based methadone maintenance clinics. In this patient population, 57 percent of those who received imipramine reduced their substance use, reported reduced craving, and experienced improved mood compared with only 7 percent who received the placebo instead of imipramine.  Another group of researchers treated adolescents in a residential treatment setting with fluoxetine, which is also an effective antidepressant. Nearly 90 percent of the adolescents in this trial showed marked improvement in mood and wished to continue taking fluoxetine after the study was completed. 
A group of adolescents with both drug dependency disorder and bipolar illness were treated with lithium, the standard therapy for bipolar disorder. Results of this trial showed lithium therapy to significantly reduce symptoms of both the psychiatric and substance abuse disorders. 
An improved overall understanding of addiction, coupled with the identification and acceptance of nicotine as an addictive drug, have been instrumental in the development of medications and behavioral treatments for nicotine addiction. In essence, science-driven treatment development has provided to consumers the option to easily purchase effective treatments, such as the nicotine patch and nicotine gum, in their local drugstores and supermarkets. Science has also shown that treating addiction with medications alone is not nearly as effective as when the medication is coupled with a behavioral treatment. Although substantial progress has been made in developing both pharmacological and behavioral treatments that have proven effective for many people, much more remains to be done.
Since the introduction of nicotine gum and the transdermal patch, estimates based on FDA and pharmaceutical industry data indicate that more than 1 million individuals have been successfully treated for nicotine addiction. In 1996 a nicotine nasal spray, along with a nicotine inhaler in 1998, became available by prescription. All the nicotine replacement products-gum, patch, spray, and inhaler-appear to be equally effective. In fact, the over-the-counter availability of many of these medications, combined with increased public service announcements in the media about the dangers of smoking, has produced a marked increase in successful quitting each year.
Some innovative research has shown that computerized scheduling of nicotine gum use can help increase the number of smokers who remain abstinent once they stop smoking. Using a credit card-sized computer that prompts the user when to begin and stop chewing each piece of nicotine gum, investigators showed that nearly three times as many computer-scheduled users, compared with those who just used nicotine gum, were abstinent after treatment. Computer-scheduled users reported chewing more gum than noncomputer users during the first week of abstinence, and the amount of gum chewed was related to success rate. A 1-year followup showed that those who had used the computer while quitting smoking were three times more likely to still be abstinent compared with those who had just used nicotine gum alone.
Although the major focus of pharmacological treatments of nicotine addiction has been nicotine replacement, other treatments are being developed for relief of nicotine withdrawal symptoms. For example, the first nonnicotine prescription drug, bupropion, an antidepressant marketed as ZybanĘ, has been approved for use as a pharmacological treatment for nicotine addiction. In December 1996, a Federal advisory committee recommended that FDA approve bupropion to become the first drug that could be taken in pill form to help people quit smoking and the first to be nicotine-free.
Behavioral interventions can play an integral role in nicotine addiction treatment. Over the past decade, this approach has spread from primarily clinic-based, formal smoking cessation programs to application in numerous community and public health settings, and now by telephone and in written formats as well. In general, behavioral methods are employed to identify high-risk relapse situations, create an aversion to smoking, develop self-monitoring of smoking behavior, and establish competing coping responses. Other key factors in successful treatment include avoiding smokers and smoking environments and receiving support from family and friends. The single most important factor, however, may be the learning and use of coping skills for both short- and long-term prevention of relapse. Smokers not only must learn behavioral and cognitive tools for relapse prevention but also must be ready to apply those skills in a crisis.
One study of two behavioral treatments for tobacco dependence in women with heart disease-a coping-skills relapse prevention (RP) intervention and an educational intervention based on the health belief model (HBM)-found a significant reduction in mean smoking rate in both treatment conditions across sessions, with a nonsignificant trend favoring RP treatment over HBM. However, there was evidence of important differential treatment effects that depended on patient characteristics, such as age and baseline level of self-esteem. For older subjects, the probability of quitting smoking was higher when receiving RP rather than HBM. For younger subjects, the probability of quitting smoking was relatively equal for the two treatments. Subjects with high self-esteem responded better with RP, and those with low self-esteem responded relatively equally to the two treatments. 
Another study examined the effects of four different smoking schedules on cessation outcome to determine which had the highest abstinence rate after a year following treatment. The highest abstinence rates-44 percent and 32 percent- were found in the two groups that were allowed to smoke at prescheduled times only. For example, in the group that had gradually reduced smoking at prescheduled times, abstinence was 44 percent, a remarkably high rate considering that the nicotine patch was not used. In contrast, the worst results-18 percent abstinence-occurred in the group that reduced smoking by lighting up at self-selected times. Apparently, these smokers were choosing optimal times and situations for enjoyment-and subsequently had a high relapse rate. In comparison, the prescheduling of cigarettes meant that smoking occurred at times unrelated to critical events, such as a cup of coffee, meal, or period of boredom. As a result, much of the enjoyment was taken out of smoking, the stimulus control by critical events was disrupted, and the opportunity to learn how to cope with smoking urges was increased. The results of this research are particularly important because many smokers who try to quit choose the "common sense" procedure of cutting down at self-selected times-one of the worst procedures they could devise. 
The treatment of smokeless tobacco addiction presents yet another challenge to the research community. One group studied the effects of group behavioral treatment versus minimal contact and of nicotine versus placebo gum on efforts to stop using smokeless tobacco. Study results showed that nicotine gum is not more successful than placebo gum with either minimal intervention or as an adjunct to behavioral treatment, although nicotine gum did reduce withdrawal symptoms. The ineffectiveness of nicotine gum on treatment outcome may be attributed to the relatively low level of nicotine in the gum or its similarity to smokeless tobacco. The study also found that behavioral treatment produced greater success than minimal contact, both during and shortly after treatment. It may be that smokeless tobacco users are more likely to be able to return to abstinence after a lapse if they are involved with a more intensive treatment approach. 
Health Services Research
The successful prevention and treatment of drug dependence and addiction depend on coordination of professional and material resources in a rational, systematic, and cost-effective manner. Preventive interventions that have been demonstrated to work must be replicated in less controlled environments to assess their effectiveness with various populations and in various contexts. Treatment outcomes also must be assessed to determine the most effective clinical approaches to treatment. Such studies fall under the rubric of health services research, and NIDA continues to expand its efforts in this area to determine appropriate mechanisms to maximize the linkages among existing school, community, and other service delivery systems and drug abuse prevention efforts and between primary medical care and drug use treatment. These efforts should permit effective expansion of the quantity and quality of available preventive interventions and treatments. Furthermore, they should make possible the development of new methods, diagnostics, and preventive and therapeutic measures for use in prevention service delivery and primary care settings.
The importance of this research is underscored by the latest data on the cost of drug use. Figures released in May 1998 show that drug use cost the Nation approximately $98 billion in 1992. This is a 50-percent increase over the $65 billion national drug use cost in 1985. More than 80 percent of the increase in estimated costs of drug use are due to real changes in drug-related emergency room episodes, criminal justice expenditures, and service delivery patterns. With an economic burden of this magnitude, the importance of health services research cannot be underestimated. Little research has been conducted on the costs and benefits of preventive interventions. However, results of the Midwestern Prevention Project indicate that every dollar spent on prevention programming saved $67 per affected family in health and social costs. 
A large study tracking more than 10,000 drug users enrolled in nearly 100 treatment programs in 11 cities found that at least four major types of drug use treatment can be effective in reducing drug use. The study, known as the Drug Abuse Treatment Outcome Study (DATOS), also found that most drug use treatment modalities produced decreases in illegal acts and increases in full-time work. 
DATOS investigators studied patients in the four most common kinds of treatment programs: outpatient methadone programs, long-term residential programs, outpatient drug-free programs, and short-term inpatient programs. The researchers found that methadone treatment reduced heroin use by 70 percent. In the followup year, 27.8 percent of patients in outpatient methadone treatment reported weekly or more frequent heroin use, down from 89.4 percent reporting heroin use prior to admission. The team also found that both long-term residential and outpatient drug-free treatment resulted in 50-percent reductions in weekly or more frequent cocaine use at the 1-year followup point. Reductions in drug use were significantly greater for patients in treatment for 3 months or more.
The studies found that the major predictors for staying in treatment were high motivation; legal pressure to stay in treatment; no prior trouble with the law; psychological counseling while in treatment; and a lack of other psychological problems, especially ASPD.
The knowledge gained from DATOS will focus future research on studies designed to further refine and strengthen treatments for drug use and addiction. The study will also be used to examine treatment outcomes and the cost-effectiveness of drug use treatment, describe the evolving treatment system, research relationships between patient and program factors, and identify research gaps that will inform future research agendas.
Despite the positive findings for the effectiveness of treatment, DATOS found that many drug use treatment patients admitted to treatment in the early 1990s received a decreasing number of services compared with patients admitted to treatment a decade earlier. More than half of patients in all four types of treatment reported that they received no services specifically for medical, psychological, vocational, family, social, or legal problems. There is some evidence that core services, such as counseling and prescribing appropriate dosages of medications, have improved, ameliorating to some degree the erosion of treatment support services.
There is a significant co-occurrence of mental health and drug use problems, and approaches to treating both conditions simultaneously have a significant rate of success. However, a survey of 45 administrators from randomly selected drug treatment programs in Los Angeles County about the adequacy of mental health services within their program and the drug treatment system found that approximately half agreed that dually diagnosed clients are not served within the system. In fact, nearly 70 percent noted that their programs restrict admission of such clients. Administrators of outpatient drug-free programs and methadone maintenance programs were more likely to characterize their mental health services as inadequate or unavailable than were administrators of other types of programs. Yet, despite this poor assessment, administrators expressed only mild support for providing additional training in this area either for themselves or for their counselors. Administrators may not perceive a need to enhance their mental health services if severely mentally ill clients are restricted from entering their programs. 
The dynamic nature of managed care organizations (MCOs) creates both problems and opportunities for generalist physicians who see substance-using patients. A study of MCOs indicated that problems include fiscal incentives that may run counter to the physician role and more fragmented communication between physicians and other addiction service providers when psychiatrists, mental health nonphysician clinicians, and other specialty programs are carved out into separate delivery systems.
Opportunities include the potential for psychiatric consultation liaison, expanded physician intervention and case management roles, more health plan resources focused on prevention and treatment, and profiling to achieve overall improvements in service delivery. MCOs may rely more heavily on generalist physician involvement with substance-using patients if potential benefits of linking substance use treatment and primary care can be realized. 
Along those lines, researchers have conducted a study to identify specific patient problems and to match professional services to those problems in four drug abuse treatment programs. Patients from an employee assistance program entered treatment and were randomly assigned to either standard treatment-patients were treated in the usual manner-or matched services- patients received at least three professional sessions directed at their significant employment, family, or psychiatric problems. Matched patients stayed in treatment longer, were more likely to complete treatment, and had better posttreatment outcomes than patients who received treatment as usual in these programs. The strategy of matching appropriate services to patients' specific treatment problems was clinically and administratively practical, attractive to patients, and responsible for a 20- to 30-percent increase in effectiveness. 
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