Putting Addiction Treatment Medications to Use: Lessons Learned
George E. Woody
University of Pennsylvania School of Medicine
Philadelphia Veterans Affairs Medical Center
The medications development program of the National Institute on Drug Abuse (NIDA) was formed in 1989 following congressional legislation with appropriations specifically targeted for that purpose. At the time of the legislation the Food and Drug Administration (FDA) had no formal guidelines for determining whether an addiction treatment medication was safe and effective, even though several had been widely accepted and used for many years. Among these were benzodiazepines for alcohol withdrawal, disulfiram for the prevention of relapse to alcohol dependence, phenobarbital for detoxification from sedative dependence, clonidine and methadone for detoxification from opioid dependence, methadone for opioid maintenance; naltrexone for prevention of relapse to opioid dependence, and nicotine replacement therapy for nicotine dependence.
The role of the pharmaceutical industry was seen as important in advancing the medications development program. Thus one of the first tasks of the new NIDA program was to develop guidelines so that companies would know the criteria used by the FDA in order for a medication to gain approval. A task force was established that worked in conjunction with the FDA, NIDA, industry representatives, and a wide range of consultants to develop guidelines. A series of meetings were held over a period of 2 years, and guidelines were written and approved by the FDA in 1996.
Knowing that the guideline development and approval process could take several years, and with the above-mentioned precedents in mind,
NIDA chose a director and staff for the medications program and immediately began work. The highest priorities were to complete the testing of LAAM (levo-alpha acetyl methadol) for opioid maintenance and submit the data for FDA approval, find a medication that was useful in treating cocaine dependence, and continue studies of buprenorphine for opioid detoxification and maintenance. The importance of this effort was high due to the limited number of medications available to treat addiction, the size of the target populations, the limitations of currently available therapies, and the emergence of HIV disease along with data showing that addiction treatment reduced the chances for HIV infection (Avins et al., 1997; Metzger, Navaline, and Woody, 1998; Shoptaw et al., 1997; Woody et al., 2003).
Implicit in these efforts was the assumption that both the short- and long-term outcomes of addicted individuals could be improved with medication. This assumption was consistent with data showing that detoxification alone usually did not alter the long-term course of addiction, and with prior experience and data showing that some medications were safe and effective for specific indications.
Although the medications development program was anchored in the broader tradition of clinical drug testing and the need to meet FDA standards, many clinicians thought that treatment outcome was often maximized when medication was used in combination with psychosocial interventions such as counseling or psychotherapy (Resnick et al., 1981; Khantzian, 1985). The early methadone maintenance studies by Dole and Nyswander (1965) emphasized this point, as did the first FDA methadone regulations, and later studies confirmed it (McLellan et al., 1993). It was also clear that some addicted persons were able to achieve remission with psychosocial treatment alone (DeLeon, 1984; Hubbard et al., 1997) and that others remitted spontaneously or by attending self-help groups (Bailey and Leach, 1965). But despite their demonstrated benefits, it was clear that many addicted individuals failed to achieve optimal results with the current medications and drug-free treatments. The new program was simply an attempt to expand the available options by additional testing of medications that had shown promise, getting them approved by FDA, and finding new medications for addictions such as cocaine and other stimulant dependencies for which none currently existed.
The medications program has tested more than 50 pharmacotherapies for cocaine dependence and obtained FDA approval for LAAM, conducted studies that further documented the safety and efficacy of methadone maintenance, guided studies that contributed to the recent FDA approval of sublingual buprenorphine/naloxone (Suboxone) and buprenorphine (Subutex), facilitated the development of depot naltrexone for preventing
relapse to opioid dependence, and studied lofexidine and dextromorphan for opioid detoxification.
Despite the demonstrated efficacy of methadone and LAAM in altering the long-term course of opioid dependence, these medications are used by less than 20 percent of the opioid-dependent population in the United States at any single point in time. This figure is calculated using the Office of National Drug Control Strategy (2002, p. 22) estimate of 898,000 heroin-dependent people in 2000, adding the fact that persons addicted to prescription opioids were not in the estimate and accepting the Center for Substance Abuse Treatment figure of 205,000 persons on methadone or LAAM in 2001 (R. Lubran, personal communication, May 2001). Naltrexone, initially developed to prevent relapse to opioid dependence and later found to be effective for preventing relapse to alcohol dependence, appears to be used by less than 5 percent of the target populations in the United States. Notable exceptions to these gaps between treatment need and actual use are medications to treat withdrawal—benzodiazepines for alcohol, clonidine for opioid, and phenobarbital or benzodiazepines for sedatives (Kosten and O’Connor, 2003).
There are many reasons for this lack of penetration of methadone, LAAM, and naltrexone into the target populations, but onerous regulation and lack of political support are among the foremost. An example of these problems is the absence of methadone or LAAM treatment programs in six states (M. Parrino, personal communication, 2003). This appendix discusses both general and specific factors that have inhibited the use of addiction treatment medications in the United States, specifically methadone, LAAM, and naltrexone. It will also speculate on the reasons that similar inhibitions have not occurred with detoxification medications and end with lessons learned from the experience with addiction treatment medications that might be useful in the effort to develop and apply vaccines to prevent or modify the course of substance use disorders.
Unresolved Ambivalence About the Nature of Addiction
One of the greatest barriers to wider use of methadone, LAAM, and naltrexone has been unresolved ambivalence about whether addiction is a morality/self-control problem or a medical disorder. This ambivalence has a long history that has flip-flopped between these two positions in the United States and other countries (Lowinson et al., 1992; Fischer et al., 2002), and it has very important treatment implications. For example, if addiction is a medical disorder characterized by abnormal biological pro-
cesses, then use of medications and other biologically based therapies to treat it would seem appropriate. However, if addiction represents a failure of morality or self-control, then psychosocial, religious, or criminal interventions would seem more appropriate. Think of how foolish it would appear to try to develop a vaccine for marital infidelity or stock market manipulation!
It is clear that the prevailing view in the United States throughout most of the 20th century was that addiction is a morality/self-control problem (Lowinson et al., 1992). This emphasis is seen clearly in the large proportion of funds spent for law enforcement compared to treatment and by strict antidrug laws and liberal use of prison sentences as opposed to treatment for large numbers of drug offenders. It is also seen by the marked reductions in money spent on substance abuse treatment over the past 10 years. For example, in the private sector between 1988 and 1998 the value of health insurance in medium to large companies decreased by 12 percent, while there was a 75 percent decrease in funds spent for substance abuse treatment (Galanter et al., 2000). In the public sector between 1995 and 2000, the Department of Veterans Affairs withdrew 47.5 percent of the funds it had been spending on specialty substance abuse treatment while at the same time increasing funds for other medical services by 10 percent (Chen, Wagner, and Barnett, 2001).
The increased use of mandated treatment rather than incarceration for nonviolent drug offenders and the rapid expansion of drug courts (Shichor and Sechrest, 2001) can be interpreted as an attempt to find a middle ground between the morality/self-control and medical views. The benefits that may result from a combination of legal pressure and treatment are seen in a study of the Delaware prison system showing improved outcomes for individuals who received treatment while in prison, with even better outcomes if treatment continued following prison release (Martin et al., 1999; Inciardi, Martin, and Butzin, in press). Unfortunately, funds to support the increased numbers of individuals who are or could be mandated to receive treatment have not always been made available. In addition, few private insurance plans pay for maintenance treatment, and courts rarely refer opioid-dependent patients to methadone maintenance, which, paradoxically, is the single treatment with the greatest level of empirical support (National Institutes of Health Consensus Panel, 1998). These practices further reduce the chances of narrowing the gap between the theoretical and actual uses of this medication.
Interestingly, the dominance of the morality/self-control view does not appear to have affected the use of detoxification agents in most treatment settings. Physicians and the public at large readily accept the fact that alcohol and opioids can produce physiological dependence and that certain medications are safe, effective, and needed for detoxification. Most
insurance companies seem to agree because they usually pay for medically assisted detoxification, at least for a few days if done in outpatient settings. Prison settings are an exception since patients often report that detoxification services are not available during incarceration, a problem that was confirmed in a nationwide survey of jails it which it was found that only 20 percent provided detoxification (Peters, May, and Kearns, 1992), which is still probably true today.
If these funding patterns reflect underlying assumptions about the cause of and cure for addiction, it would appear that the general public, many political leaders, insurance companies, and many physicians do not accept the fact that some individuals need medication to prevent relapse and alter the long-term course of addiction. Put another way, the idea that addiction is for many a chronic and relapsing disorder with significant environmental and behavioral components, such as hypertension, diabetes, and asthma, that can be helped by medication (McLellan et al., 2000) does not seem to have been widely accepted outside the area of addiction research and treatment (Leshner, 1999).
Lack of Consumer Advocacy
Advocacy with the impact of groups such as ACT-UP or the National Association for the Mentally Ill has never existed for addiction treatment with one exception—addicted Vietnam War veterans. During the later stages of the war there were numerous reports of heroin addiction among troops, including stories that veterans were going into opioid withdrawal on flights home from Vietnam. These reports caused widespread concern resulting in a political consensus that Vietnam service was contributing to heroin dependence. There were two powerful and well-supported responses: (1) rules were developed mandating that military personnel could not leave Vietnam until they provided a drug-free urine sample and (2) special funding was allocated by Congress for the Department of Veterans Affairs to establish addiction treatment programs.
Funds for the new VA programs were protected by legislation that prevented the money from being spent on anything but specialty substance abuse treatment. The programs grew, as did the number of veterans treated for substance use disorders within this funding structure until the mid-1980s when the funds lost their special protection and were merged with general hospital budgets. At about this time the rate of program growth slowed and then began a sharp decline in 1995 in association with the funding cuts described above. Congressional hearings on whether to restore funding and services to the 1995 levels were held in 1999 (Report of Minority Staff Review of VA Programs for Veterans with Special Needs to Senator Rockefeller, July 27, 1999) but have not yet had their intended
result. Interestingly, the advocacy that started the VA programs was not generated by consumers but rather by popular and congressional concerns about heroin addiction being associated with military service in Vietnam.
One factor contributing to this absence of consumer advocacy is that many persons who have recovered or are doing well in treatment are very reluctant to speak out for fear of adverse social consequences. This is especially true for persons who have been addicted to heroin, cocaine, and other illegal drugs (Parrino, personal communication, 2002). In addition, many addicted persons have serious behavioral problems that generate negative emotional responses from neighbors, the general public, and sometimes even their own families, thus making it difficult to obtain support for anything other than an expansion of criminal justice responses to the problem.
Narrow Interpretation of the 12-Step Approach
The fact that benefits could result from collaboration between 12-step programs and the medical profession was mentioned in the writings of the founders of Alcoholics Anonymous (1955). But somehow that message became modified such that many 12-step programs developed a drug-free philosophy to such an extent that individuals being treated in residential programs or participating in 12-step meetings were pressured to stop all psychoactive medication even if they were taking it for major depression or other nonsubstance-related mental disorders (Woody, 2003). In many cases, the result was an institutionalized opposition to the use of medication except for detoxification.
Much addiction treatment in this country developed outside the existing medical system. Addiction treatment was essentially neglected in medical education, and very few physicians became involved in it. The result was that for many years Alcoholics Anonymous was the only place to turn for help, and treatment became dominated by a nonmedical approach involving staff with little or no medical training. A current example of this problem was seen in an informal survey of staffing patterns in 150 addiction treatment programs that had been randomly selected from Substance Abuse and Mental Health Services Administration records. It was found that none except the methadone programs had a physician and that many of the methadone programs had only enough medical coverage to write prescriptions and satisfy minimal regulatory requirements (A.T. McLellan, 2003, personal report).
Weak Efficacy of Some Approved Medications
Naltrexone has been shown to be effective for preventing relapse to alcohol dependence in the majority of controlled studies where the naltrexone condition showed a 15 to 20 percent advantage over a placebo (Morris et al., 2001). Unfortunately, the largest study done to date showed no differences between the naltrexone and control groups, though patients in each group improved significantly (Krystal et al., 2001). A conclusion that can be drawn from an overview of these studies is that naltrexone has an effect on preventing relapse to alcohol dependence but that overall it is relatively weak. Were the effect to be strong, some positive effect of naltrexone over the control condition likely would have emerged in the VA study. This weak efficacy, combined with the resistance of many treatment staff to using medications for relapse prevention, and the fact that many patients with alcohol dependence respond to psychosocial treatment alone have contributed to the low acceptance of naltrexone. New evidence has shown that a subgroup of naltrexone patients with one or two copies of the Asp40 allele of the gene coding the mu opioid receptor may have a robust response to naltrexone as compared to subjects without this allele (Oslin et al., 2003). If this finding is replicated, the overall weak effect of naltrexone may not generalize to this subgroup.
The experience with nicotine replacement therapies and buproprion treatment for nicotine dependence shares a few commonalities with the naltrexone/alcohol studies and methadone maintenance. Although nicotine in the form of tobacco has been used since early history, its use did not become highly problematic for large populations until the introduction of the cigarette. Although movements existed in Europe in the 17th century to ban tobacco, it was used primarily as snuff and did not affect the wider society. However, with the introduction of machine-made cigarettes and sophisticated advertising campaigns, the general population was exposed to an extremely efficient nicotine delivery system and large numbers of people became dependent on nicotine in tobacco. Initially, the use of cigarettes was not considered a health problem, but some people did think it was a bad habit. It was not until the negative health consequences of tobacco use became significant and well known, especially lung cancer and cardiovascular disease, that physicians began to recommend that patients not smoke. It quickly became apparent that large numbers of smokers, despite good intentions, were unable to stop. Ways to assist smokers in achieving abstinence began to be explored. Medically, it was soon obvious that one of the factors in continued tobacco use was a nicotine-specific abstinence syndrome. Various forms of nicotine replacement were studied, and today there are currently four forms of nicotine replacement available in the United States (Hurt et al., 2003), two of which (nicotine gum and nicotine patches) are over-the-counter medications.
The over-the-counter mode of making medications available has implications that both favor and inhibit their appropriate use. On the one hand, the medications are available without seeing a physician and going to the trouble and expense of receiving and filling a prescription; however, the easy availability of OTC medications decreases the probability that patients will receive appropriate education on how to administer the medication and tobacco cessation counseling. For instance, will patients buying nicotine gum know that it should not be chewed the same way regular gum is chewed but rather in a specific way to optimize sublingual absorption of the nicotine? Do patients who use this medication receive counseling from their physicians other than brief advice? In addition, most health insurance plans will not pay or reimburse for OTC medications.
It is important that the treatment process be made as effective as possible because, short of inpatient hospitalization and treatment, even with nicotine patches there is only a 20 to 30 percent success rate for long-term abstinence (Hays et al., 2001). Given the potential drawbacks of the OTC approach, it is likely that the overall effectiveness of the patch or the gum is reduced because OTC use far outpaces prescription nicotine nasal spray or inhaler. Another barrier to effective utilization of nicotine replacement therapies is that all are marketed for short-term use, thus indicating that, like other addiction treatment situations, there is general acceptance of medication for detoxification but a resistance to using it for long-term relapse prevention. However, many patients use nicotine replacement as maintenance therapy but without formal instructions or approval, implying perhaps that they are misusing the medications and “exchanging one addiction for another,” which is a frequent criticism of methadone and LAAM maintenance.
A nonnicotine approach to the treatment of nicotine dependence is the use of antidepressants, specifically bupropion. But the lack of strong evidence of therapeutic efficacy is probably the largest barrier to bupropion’s acceptance as a treatment for nicotine dependence. While it has been shown in clinical trials to be more effective than a placebo in helping subjects achieve abstinence (Hurt et al., 1997), it has also been shown to have limited efficacy in producing sustained abstinence (Hall et al., 2002). It is available only by prescription, and the manufacturer decided it was necessary to come out with a new formulation and name for bupropion for the indication of smoking cessation. This change distinguishes it from the bupropion to be used to treat depression and can be interpreted as indicating a reluctance on the part of the manufacturer to associate a medication with known efficacy for an “acceptable” indication (depression) with a “tainted” disorder like addiction.
Poor Patient Acceptance of Some Medications
The best example of this problem is naltrexone used for the prevention of relapse to opioid dependence. Studies have shown that less than 5 percent of patients for whom it is suggested end up taking it for 30 days or more (Greenstein et al., 1981). This figure can be improved by contingency management (Carroll et al., 2001), and it is higher for persons who are under social or legal pressure to comply, such as a physician whose license is contingent on doing well in treatment or a person on probation or parole who will be returned to jail if he or she relapses to opioid dependence (Cornish et al., 1997). Poor compliance with treatment has been particularly frustrating to treatment providers because naltrexone is, in a pharmacological sense, an ideal medication for preventing relapse to opioid dependence due to its effective blockade of mu opioid receptors.
A second though less extreme example is clonidine for opioid detoxification. Though widely used, dropout rates have been two to three times higher than with methadone or other opioid agonists (Ling, 2003).
Perception That Addiction Treatment Does Not Work
The perception that addiction treatment does not work results from the observation that patients in treatment may substantially reduce their drug use but do not always stop; that relapse occurs even among patients who have been abstinent for weeks, months, or even years; and that investments in treatment are not worth the money (McFarland et al., 2003). It contributes to the gap between treatment need and availability—why spend money for something that does not work?—and appears to stem from the belief that sustained abstinence is not simply the optimal but the only clinically meaningful outcome. It seems closely related to the belief that addiction is a moral problem for which reductions in severity, even if accompanied by improvements in quality of life, reduced chances for HIV infection, increased employment, less crime, and lower death rates, do not count because the immoral behavior has merely improved but not completely stopped.
This perception is inconsistent with data discussed above that for many people addiction more closely resembles a chronic relapsing disorder like diabetes or hypertension rather than an acute disorder such as appendicitis or a broken leg. If seen as a medical disorder that for many is chronic and relapsing, reductions in severity are meaningful but not ideal outcomes. For example, lowering the blood sugar of a diabetic from 400 to 150 or the blood pressure of a hypertensive person from 200/120 to 140/ 90 are meaningful but not ideal outcomes, though widely considered as evidence that treatment is effective. An analogy with addiction treatment
would be reducing heroin use with methadone maintenance from three times a day, 7 days a week to once a day, 2 days a week, or reducing cocaine use from 10 days a month to 1 day a month (Crits-Christoph et al., 1997; Woody et al., 2003). In each case the severity of the addiction was substantially reduced and, though not eliminated, was accompanied by meaningful benefits.
An example of the same phenomenon in the case of alcohol treatment was seen in a study in which 150 subjects who met the criteria for alcohol dependence of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) were randomly assigned to topiramate or placebo. At the end of 12 weeks, subjects on topiramate had 2.88 fewer drinks per day, 3.1 fewer drinks per drinking day, 27.6 percent fewer heavy drinking days, 26.2 percent more days abstinent, lower levels of gamma glutamyl transferase, and less craving than subjects receiving placebo (Johnson et al., 2003). Here, as in other addiction treatment studies, a reduction in the severity of the target symptom (drinking) and evidence of improved liver function were considered successful outcomes even though full, sustained remission was not generally achieved.
A similar situation could arise in vaccine development. Efforts are being made to develop both preventive and therapeutic vaccines for HIV disease (Check, 2003). It is likely that therapeutic vaccines would be considered effective if they reduced the viral load of an HIV-infected person and prolonged his or her life. The very same result could occur with a therapeutic vaccine for addiction; however, it would be considered ineffective if the only acceptable outcome was permanent cessation of drug use.
Efforts to Reduce Health Costs
Using medication requires medical personnel, who are the most expensive treatment staff. Administrators trying to reduce health care costs have strong incentives to minimize the number (and salaries) of doctors and nurses working in addiction treatment programs. Such reductions in personnel were seen in the changes that occurred at the VA that were described earlier. These financial pressures may serve as disincentives for medically trained persons to become involved in addiction treatment and further diminish the chances for the staffing patterns that are necessary when medications are used.
Reluctance of Pharmaceutical Companies to Become Involved
Pharmaceutical companies have been the leaders in medication development, but costs are very high and few new molecular compounds reach
the market; thus a company must have a chance at making a profit simply to cover development costs. The poor reimbursement and financial pressures to hold down costs of addiction treatment are clearly disincentives for companies to engage in developing addiction treatment medications. High levels of comorbidity and adverse events that could be attributed to a new medication further reduce incentives for companies to become involved in this area.
These problems contributed to NIDA’s involvement in the development of LAAM, which was a very slow process, partly due to NIDA’s inexperience in drug development at the time and also partly due to bad luck relating to the failure of a key contractor to provide credible preclinical data on LAAM. It will be very important for NIDA to partner with the National Institute of Allergy and Infectious Diseases (NIAID), the AIDS Vaccine Coalition, or other entities that have experience in vaccine development so as to avoid these problems.
Incorrect Information About Treatment
This problem has most prominently focused on methadone maintenance and is reflected in statements made by political leaders. For example, in October 1998 three senators submitted a resolution, which stated that “… the Federal Government should adopt a zero-tolerance drug-free policy that has as its principal objective the elimination of drug abuse and addiction, including both methadone and heroin” (Congressional Record, Senate Resolution 295- S12186-S12187, 1998). This resolution was followed by introduction of the Addiction Free Treatment Act of 1999, which proposed to reduce the availability of maintenance treatment using methadone and LAAM (Addiction Free Treatment Act of 1999, 106th Congress S. 423). The resolution added: “Heroin addicts and methadone addicts are unable to function as self-sufficient, productive members of society” and concluded that “Congress should work … to develop an effective drug control policy that … is based on detoxification and the comprehensive treatment of the pathology of drug addiction.”
Considering the source, these statements are difficult to understand and inconsistent with the large amount of data showing that efforts to treat the “comprehensive pathology of drug addiction” have often failed, which is the reason that methadone was developed, and that patients on methadone are often able to function and be “self-sufficient, productive members of society.” In addition, the beliefs expressed in this proposed legislation are easily interpreted as disincentives to use medication to treat addiction since the only acceptable policy involved being drug-free.
Federal and State Regulations
The Institute of Medicine published a comprehensive report on the effect of regulations on access to treatment with methadone or LAAM. The report led to a shift in monitoring methadone programs from the regulatory approach of the FDA to accreditation involving the Joint Commission on Accreditation of Healthcare Organizations, the Commission on Accreditation of Rehabilitation Facilities, or state agencies. This change was only recently put into effect; thus its results are unclear.
The problems identified in the IOM report provided the basis for the Addiction Treatment Act of 2000, which allows agonist and other medications that are classified as Schedule III or below and approved for addiction treatment to be used under less restrictive circumstances than has been the case with methadone. Related to this legislation was the approval of buprenorphine/naloxone (Suboxone) for maintenance treatment of opioid dependence as a Schedule III medication. This congressional action is clearly intended to make addiction treatment medications more available and less stigmatized; however, its effects are unclear since the changes only went into effect in October 2002.
The public and the medical profession accept the fact that medicines are needed to treat withdrawal, but fewer believe they are needed over the long term. This belief seems to result from the view that addiction is a moral rather than a medical problem. Lack of appreciation that addiction is a medical disorder and that many individuals need long-term treatment is likely to negatively impact the use of vaccines.
Research should continue on the biological aspects of substance dependence. The work of authors who successfully make public data showing that addiction has biological as well as behavioral components and that addiction more closely resembles a medical disorder than a moral problem should be extended (Leshner, 1997; McLellan et al., 2000). Data can help resolve the ambivalence about the nature of addiction.
The perception that meaningful treatment outcome is an all-or-nothing phenomenon is widely held but often untrue. Many treatments used in medicine would be considered failures if held to the same standard. The same problem could emerge with vaccines. Data showing that treatment can often produce meaningful benefits to individuals and society even though the ideal outcome—complete and sustained abstinence—does not occur should be presented and reviewed. Data are available to make this point from almost every addiction treatment study that has ever been done and concluded that treatment is effective.
The lack of medical staff in addiction treatment prevents more widespread use of medications. This problem is closely related to the issue of whether addiction is a problem of morality or a medical disorder. It is also related to the more general issues of parity in mental health and to attempts to hold down treatment costs that involve disproportionate cuts in funding for substance abuse treatment. Any effort that can achieve parity in mental health and addiction treatment and that can minimize the costs of effective vaccines will help, as would a political consensus that addiction is a treatable disorder.
Lack of positive effects or the presence of adverse effects will discourage staff acceptance and patient compliance. Painful vaccines, especially if they need to be administered frequently, are not likely to be widely used. These points should be strongly considered in vaccine development. Good efficacy and few side effects are especially important goals for medications or vaccines used to treat individuals with substance use disorders since their tolerance for adverse effects can be limited.
Lack of experience in medications development and bad luck contributed to the slow approval of LAAM. It will be very important for NIDA to partner with NIAID, the AIDS Vaccine Coalition, pharmaceutical companies, or other entities that have experience in vaccine development so as to avoid these problems.
Alcoholics Anonymous. (1955). The story of how many thousands of men and women have recovered from alcoholism, 2nd ed. New York: AA World Services.
American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association.
Avins, A.L., Lindan, C.P., Woods, W.J., Hudes, E.S., Boscarino, J.A., Kay, J., Clark, W., and Hulley, S.B. (1997). Changes in HIV-related behaviors among heterosexual alcoholics following addiction treatment. Drug and Alcohol Dependence, 44(1), 47-55.
Bailey, M.B., and Leach, B. (1965). Alcoholics Anonymous: Pathway to recovery: A study of 1058 members of the AA fellowship in New York City. New York: National Council on Alcoholism.
Carroll, K.M., Ball, S.A., Nick, C., O’Connor, P.G., Egan, D.A., Frankforter, T.L., Triffleman, E.G., Shi, J., and Rounsaville, B.J. (2001). Targeting behavioral therapies to enhance naltrexone treatment of opioid dependence—efficacy of contingency management and significant other involvement. Archives of General Psychiatry, 58(8), 755-761.
Check, E. (2003). AIDS researchers seek criteria for vaccines. Nature, 423(6936), 107.
Chen, S., Wagner, T.H., and Barnett, P.G. (2001). Expenditures for substance abuse treatment in the Department of Veterans Affairs: 1993-1999. Health Affairs, 20(4), 169-175.
Cornish, J.W., Metzger, D., Woody, G.E., Wilson, D., McLellan, A.T., Vandergrift, B., and O’Brien, C.P. (1997). Naltrexone pharmacotherapy for opioid dependent federal probationers. Journal of Substance Abuse Treatment, 14(6), 529-534.
Crits-Christoph, P., Siqueland, L., Blaine, J.D., Frank, A., Luborsky, L., Onken, L.S., Muenz, L., Thase, M.E., Weiss, R.D., Gastfriend, D.R., Woody, G.E., Barber, J.P., Butler, S.F., Daley, D., Bishop, S., Najavits, L.M., Lis, J., Mercer, D., Griffin, M.L., Moras, K., Beck, A. (1997). The National Institute on Drug Abuse Collaborative Cocaine Treatment Study. Archives of General Psychiatry, 54(8), 721-726.
DeLeon, G. (1984). The therapeutic community: Study of effectiveness. Rockville, MD: National Institute on Drug Abuse.
Dole, V.P., and Nyswander, M.E. (1965). A medical treatment for diacetylmorphine (heroin) addiction. Journal of the American Medical Association, 193, 646-650.
Fischer, B., Rehm, J., Uchtenhagen, A., and Kirst, M. (2002). Compulsory treatment—what do we know and where should we go? European Addiction Research, 8(2), 52-53.
Galanter, M., Keller, D.S., Dermatis, H., and Egelko, S. (2000). The impact of managed care on substance abuse treatment: A report of the American Society of Addiction Medicine. Journal of Addictive Diseases, 19(3), 13-34.
Greenstein, R.A., O’Brien, C.P., Woody, G., Long, M., Coyle, G., Grabowski, J., and Vittor, A. (1981). Naltrexone: A short-term treatment alternative for opiate dependence. American Journal of Drug and Alcohol Abuse, 8(3), 291-300.
Hall, S.M., Humfleet, G.L., Rues, V.I., Munoz, R.F., Hartz, D.T., and Maude-Griffin, R. (2002). Psychological intervention and antidepressant treatment in smoking cessation. Archives of General Psychiatry, 59(10), 930-936.
Hays, J.T., Wolter, T.D., Eberman, K.M., Croghan, I.T., Offord, K.P, and Hurt, R.D. (2001). Residential (inpatient) treatment compared with outpatient treatment for nicotine dependence. Mayo Clinic Proceedings, 76(2), 124-133.
Hubbard, R.L., Craddock, S.G., Flynn, P.M., Anderson, J., and Etheridge, R.M. (1997). Overview of 1-year follow-up outcomes in the Drug Abuse Treatment Outcome Study (DATOS). Psychology of Addictive Behaviors, 11(4), 261-278.
Hurt, R.D., Sachs, D.P.L., Glover, E.D., Offord, K.P., Johnston, J.A., Dale, L.C., Khayralla, M.A., Schroeder, D.R., Glover, P.N., Sullivan, R., Croughan, I.T., and Sullivan, P.M. (1997). A comparison of sustained-release bupropion and placebo for smoking cessation. New England Journal of Medicine, 337(17), 1195-1202.
Hurt, R.D., Ebbert, J.O., Hays, J.T., and Dale, L.C. (2003). Pharmacologic interventions for tobacco dependence. In A.W. Graham (Ed.), Principles of addiction medicine, 3rd ed. Chevy Chase, MD: American Society of Addiction Medicine.
Inciardi, J.A., Martin, S.S., and Butzin, C.A. (in press). Five-year outcomes of therapeutic community treatment of drug-involved offenders after release from prison. Crime and Delinquency.
Johnson, B.A., Ait-Daoud, N., Bowden, C.L., DiClemente, C.C., Roache, J.D., Lawson, K., Javors, M.A., and Ma, J.Z. (2003). Oral topiramate for treatment of alcohol dependence: A randomized controlled trial. Lancet, 361(9370), 1677-1685.
Khantzian, E.J. (1985). The self-medication hypothesis of addictive disorders: Focus on heroin and cocaine dependence. American Journal of Psychiatry, 142(11), 1259-1264.
Kosten, T.R., and O’Connor, P.G. (2003.) Management of drug and alcohol withdrawal. New England Journal of Medicine, 348(18), 1786-1795.
Krystal, J.H., Cramer, J.A., Krol, W.F., Kirk, G.F., and Rosenheck, R.A. (2001). Naltrexone in the treatment of alcohol dependence. New England Journal of Medicine, 345(24), 1734-1739.
Leshner, A.I. (1997). Addiction is a brain disease, and it matters. Science, 278(5335), 45-47.
Leshner, A.I. (1999). Science-based views of drug addiction and its treatment. Journal of the American Medical Association, 282(14), 1314-1316.
Lowinson, J.H., Payte, J.T., Joseph, H., Marion, I.J., and Dole, V.P. (1992). Methadone maintenance. In J.H. Lowinson, P. Ruiz, R.B. Millman, and J.G. Langrod (Eds.), Substance abuse: A comprehensive textbook (pp. 405-414). Philadelphia: Williams and Wilkins.
Martin, S.S., Butzin, C.A., Saum, C.A., and Inciardi, J.A. (1999). Three-year outcomes of therapeutic community treatment for drug-involved offenders in Delaware: From prison to work release to aftercare. Prison Journal, 79(3), 294-320.
McFarland, B.H., Lierman, W.K., Penner, N.R., McCamant, L.E., and Zani, B.G. (2003). Employee benefits managers’ opinions about addiction treatment. Journal of Addictive Diseases, 22(2), 15-29.
McLellan, A.T., Arndt, I.O., Metzger, D.S., Woody, G.E., and O’Brien, C.P. (1993). The effects of psychosocial services in substance abuse treatment. Journal of the American Medical Association, 269(15), 1953-1959.
McLellan, A.T., O’Brien, C.P., Lewis, D., and Kleber, H.D. (2000). Drug addiction as a chronic medical illness: Implications for treatment, insurance and evaluation. Journal of the American Medical Association, 284(13), 1689-1695.
Metzger, D.S., Navaline, H., and Woody, G.E. (1998). Drug abuse treatment as AIDS prevention. Public Health Reports, 113(Suppl 1), 97-106.
Morris, P.L., Hopwood, M., Whelan G., Gardiner, J., and Drummond, E. (2001). Naltrexone for alcohol dependence: A randomized controlled trial. Addiction, 96(11), 1565-1573.
National Institutes of Health Consensus Conference. (1998). Effective medical treatment of opiate addiction. Journal of the American Medical Association, 280(22), 1936-1943.
Office of National Drug Control Strategy. (2002). 2002 Final report on the 1998 National Drug Control Strategy: Performance measures of effectiveness. Available:http://www.whitehousedrugpolicy.gov/publications/policy/02pme/pmepdf/pme.pdf [January 2, 2004].
Oslin, D.W., Berrettini, W., Kranzler, H.R., Penninati, H., Gelernter, J., Volpicelli, J.R., and O’Brien, C.P. (2003). A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology, 28(8), 1546-1552.
Peters, R.H., May, R.I., and Kearns, W.D. (1992). Drug treatment in jails: Results of a nationwide survey. Journal of Criminal Justice, 20, 283-295.
Resnick, R.B., Washton, A.M., and Stone-Washton, N. (1981). Psychotherapy and naltrexone in opioid dependence. In L.S. Harris (Ed.), Problems of drug dependence (pp. 109-115). Rockville, MD: U.S. Department of Health and Human Services.
Shichor, D., and Sechrest, D. (2001). Introduction: Special issue on drug courts. Journal of Drug Issues, 31, 1-6.
Shoptaw, S., Frosch, D.L., Rawson, R.A., and Ling, W. (1997). Cocaine abuse counseling as HIV prevention. AIDS Education and Prevention, 9(6), 511-520.
Woody, G.E. (2003). Treating dually diagnosed patients. Psychiatric Times, 20(1), 29-30.
Woody, G.E., Gallop, R., Luborsky, L., Blaine, J., Frank, A., Gastfriend, D., Crits-Christoph, P., and the Cocaine Psychotherapy Study Group. (2003). HIV risk reduction in the NIDA cocaine psychotherapy study. Journal of Acquired Immune Deficiency Syndromes, 33(1), 82-87.