Is there a place for medical treatment in the social policy toward drug dependence?

IS DRUG ADDICTION A TREATABLE MEDICAL ILLNESS?
A Comparison With Other Chronic Illnesses
1 The Treatment Research Institute, 2 The Penn-VA Center for Studies of Addiction at the University of Pennsylvania, 3 The Brown University Center for Alcohol and Addiction Studies, 4 The Center for Addiction and Substance Abuse at Columbia University and 5Brown University Reprint Requests to A. Thomas McLellan C/O Treatment Research Institute 600 Public Ledger Building, 150 S. Independence Mall West, Philadelphia PA 19106 Supported by Physicians for National Leadership in Drug Treatment and by grants from the Department of Veterans Affairs, the National Institute on Drug Abuse, the Center for Substance Abuse Treatment and the Robert Wood Johnson Foundation.
ABSTRACT (203 words)
Background: Drug addiction produces serious, pervasive and expensive social problems such
that "the drug issue" has been considered a "social problem" rather than a "health problem." We examine research evidence on whether drug addiction can be considered a chronic medical illness -comparing the etiology, presentation, course and treatment response to three other chronic illnesses - adult onset diabetes, hypertension and asthma. Methods: A focused literature review comparing some of the defining characteristics of chronic
illnesses (e.g. etiology, genetic heritabillity, diagnosis and pathophysiology) and response to treatment (compliance and relapse) in drug dependence and in other chronic illnesses. Results: Personal choice, family and environmental factors are involved in the etiology and
course of all these disorders. Genetic heritability influences are also comparable. Potent, well tolerated medications are available for the treatment of most addictions. Medication compliance and relapse rates were similar across all illnesses. Conclusion: There is ample scientific evidence indicating that drug addiction is a chronic
medical illness. Like other chronic illnesses, there is presently no cure for addiction but medical treatments can provide cost effective reductions in drug use, and its attendant public health problems. These data suggest an expanded role for physicians and medical interventions in the Key Words: Drug Dependence Treatment, Chronic Illness, Outcome of Treatment, Genetics of
Addiction, Relapse Rates Following Treatment, Compliance with Treatment INTRODUCTION
Many expensive and disturbing social problems in this country can be traced directly to drug addiction. A recent study (1) estimated that addiction costs American society approximately $70 billion each year in health care, crime, welfare and lost productivity. These effects of drugs on all social systems in our country have been important in shaping the public view that the “drug problem” is primarily a social issue requiring interdiction and law enforcement, rather than a health concern requiring prevention and treatment. This is a view that is apparently shared by many physicians. Few medical schools have an adequate required course in addiction. It has been repeatedly documented over the past three decades that a majority of physicians do not screen for alcohol or other drug dependence during routine examinations (2). Apparently there is the feeling that such screening efforts are wasted since in a recent survey, a majority of general practice physicians and nurses indicated that none of the currently available medical or health care interventions would be appropriate or effective in treating addiction (3). Is the movement from simply the use of alcohol or drugs to addiction a "disease process;" and is it responsive to medical interventions? To structure our examination of this issue we looked for parallels in etiology, course of illness and treatment response between addictive disorders and other chronic diseases such as adult onset diabetes, hypertension and asthma. We focused primarily on illicit drug addiction (less upon tobacco and alcohol addiction) since it is widely viewed as simply wilfull misconduct. The three comparison illnesses were selected because the adult onset forms involve genetic, cultural and behavioral factors in their etiology and course; and while they cannot be cured, there are effective treatments available. Genetic Factors in Drug Dependence - Although most diseases are not genetically
transmitted and many inherited characteristics are not diseases, genetic heritability is one of many criteria that can signify a medical illness. One of the best methods to estimate the level of genetic contribution within all the family, cultural and environmental variables that are operational is to compare the rates of a disorder in monozygotic and dyzygotic twins. For example, heritability estimates (H2) from twin studies of hypertension range from .25 - .50 depending upon the sample and the diagnostic criteria used (4, 5). Similarly, twin studies of diabetes offer heritability estimates of .80 for Type 1 (6) to.30 - .55 for Type 2 diabetes (7). Twin studies of adult onset asthma have produced a broader range of heritability estimates, ranging from .36 to .70 (8). In the addiction field, five twin studies have been published over the past five years (9) and all found significantly higher rates of dependence among monozygotic than dyzygotic twin pairs. Twin studies of heroin dependence produced heritability estimates of .34 to .48 among males (10, 11). Similar studies of alcohol dependence have produced heritability estimates of .55 to .65 among males (12, 13). Though there are still very few studies of heritability in addiction the evidence thus far suggests significant contribution of genetic influence in approximately the same range as for chronic illnesses such as asthma and hypertension. Voluntary and Involuntary Factors in Drug Dependence - Since the use of alcohol and
other drugs is initially a voluntary action, behavioral control or "will power" is obviously a very important factor in the onset of addictive disorders. Doesn't this voluntary initiation of the disease process immediately set addiction apart from other medical illnesses? In fact, there are many other illnesses where voluntary choices initiate and sustain a disease process, especially when these voluntary behaviors interact with genetic and cultural factors. Hypertension is an example. Among males salt sensitivity is a genetically transmitted risk factor for the eventual development of at least one form of hypertension (14). However, only half of those who inherit salt sensitivity go on to develop hypertension. This is because the use of salt is a voluntary behavior, influenced by familial and cultural salt use patterns, but primarily by individual choice. Diet, stress level, and exercise are also determined by familial, cultural and environmental influences but particularly by personal choice. In turn, these are major influences on the etiology and course of adult onset forms of hypertension, asthma and diabetes (15 - 17). Indeed, many who ultimately require maintenance medications for adult onset diabetes, asthma and hyperension could have reduced their emerging symptoms and forestalled additional treatment. if they had taken the voluntary action to change their diets, decrease stress and increase excercise. The other side of the argument is that involuntary components are also embedded within seemingly volitional choices. For example, although the choice to try a drug is voluntary, many of the physiological and psychological effects of that drug use are genetically determined and can modify the course of continued use in an involuntary manner. For example, work by Schuckit and colleagues has shown that sons of alcohol dependent fathers are born with more tolerance to alcohol’s effects than sons of non-alcoholic fathers (18). Specifically, dysphoria and “hangover” from drinking are experienced by sons of alcoholic fathers only at very high doses. In contrast, approximately 35% of Chinese and Japanese are homozygous for an aldehyde dehydrogenase gene that produces skin “flushing" and an especially unpleasant subjective reaction to alcohol (19). This involuntary, negative reaction to the voluntary act of drinking markedly reduces the appeal of alcohol in this group. In fact, there have been no Chinese alcoholics found with this genotype (20). Thus, while the initial choice to use drugs or alcohol may be largely voluntary, progression to dependence may be influenced by many involuntary factors such as genetic heritability and learning, as discussed below. Pathophysiology in Drug Dependence - Continued repetition of "voluntary" drug taking can
change imperceptibly into “involuntary” drug taking, ultimately to the point where the behavior is driven by compulsive craving for the drug. We do not yet understand this process and there are still fundamental questions regarding the mechanisms by which repeated doses of alcohol or other drugs produce paradoxically increasing tolerance to the effects of those drugs but decreasing volitional ability to forego the drug. As suggested by Koob and Bloom (21), the challenge is to find the sequence by which molecular events modify cellular events, to produce profound and lasting changes in cognitions, motivations and behaviors. Research on the neurochemical, neuroendocrine and genetic changes associated with these aspects of drug dependence has been summarized in recent special issues of Science (22), Lancet (23) and the Institute of Medicine (24). Here we summarize just three aspects of the pathophysiology of continued drug use. There is now clear evidence that most addictive drugs have well specified effects on the brain circuitry that is involved in the control of motivated and learned behaviors, particularly the ventral tegmental area connecting the limbic cortex through the midbrain, to the nucleus accumbens (22 - 24). Neurochemically, all of the major drugs of abuse (alcohol, opiates, cocaine, nicotine) have significant effects on the dopamine system, although through different mechanisms. Significantly, the ventral tegmental area and the dopamine system have been associated with the feelings of euphoria produced by naturally occurring reinforcers (24 - 26). For example, animals who receive mild electrical stimulation of the dopamine system contingent upon a lever press response, will rapidly learn to press that lever tens of thousands of times, ignoring normal needs for water, food or rest, in order to maintain the stimulation of that system (24 - 26). Cocaine, opiates and several other dependence producing drugs stimulate this reward circuitry in a supernormal manner. Thus, it is possible to understand how addictive drugs can produce immediate and profound desire for their readministration. What is less clear from these data is why simply preventing the administration of these drugs for some period of time (as in detoxification) would not correct the situation, set the system back to normal and lead to a "sadder but wiser" individual who would be less (instead of more) likely to readminister those drugs. Two possible answers emerge from work done to date (21 - 24). The most direct answer is that use of a drug at some combination of dose, frequency and chronicity produces enduring and possibly permanent pathophysiological changes in the reward circuitry (24 - 27), in the levels of many neurochemicals (28, 29) and in the stress response system (30, 31). It is not clear, just how much drug use is required to create these changes, how enduring the various effects are, or whether these effects will ever return to normal. Somatic signs of withdrawal generally last several days, motivational aspects of withdrawal and cognitive impairment may last several months (27) and the learned aspects of tolerance to the drug may never return to normal (32, 33). Researchers have found impairments in the dopamine system (reduced D2 binding), poor cortical blood flow and reduced prefrontal metabolism in former cocaine users who have been abstinent for three to six months (28, 29, 33). These studies suggest that the neurochemical and possibly the neuroendocrine systems of abstinent drug dependent patients, are functioning irregularly and at a reduced level for a A second explanation for the enduring pathology seen among drug dependent persons and their tendency to become re-addicted lies in the integration of the reward circuitry with the motivational, emotional and memory centers that are co-located within the limbic system. Connections among these "survival circuits" are apparently designed to give prominence and emotional significance to the normal biological events that usually precede arousal of those circuits (food, danger, and sex). The pairing of people, places and things with activation of these circuits through drug use, leads to rapid and entrenched learning or "conditioning." Ultimately, these cues acquire some of the properties of the drug itself, including the ability to produce significant physiological reactions such as autonomic arousal, withdrawal and profound desire or craving for It is likely that both the direct changes produced by the drugs themselves and the conditioned effects are involved in the ultimate explanation of continued vulnerability to relapse, even among motivated, abstinent, formerly drug dependent individuals (21 - 24). At the same time, all people have had their reward circuitry associated with natural reinforcers such as food, sex, sleep, and even some drug use. Why don't all people use natural rewards compulsively? What aspects of brain function distinguish those who use drugs but don't become addicted, from those who use similar amounts and at similar frequencies but do become compulsive users? Some combination of genetic and learned factors is likely involved but there is much that remains to be explained. Treatment Response in Drug Dependence?
Even if addiction "looks like" other chronic illnesses in etiology and pathophysiology, a key public health question is whether substance dependence responds to medical treatments. A review of the now more than 200 randomly controlled trials of various types of addiction treatments is beyond the scope of this paper. A recent review of both randomized clinical trials and large-scale field studies published by the Institute of Medicine (35) has shown robust and clinically significant reductions in substance use and improvements in personal health and social function of treated patients. However, most of the interventions reviewed did not include medications. If physicians are expected to play a role in the treatment of drug dependence, it is reasonable to ask whether effective medications are available. The latest scientific efforts to develop new medications for the treatment of addiction have been reviewed elsewhere (27, 36, 37). Here we present a brief overview of Medications for Opioid Addiction - Opiate receptor agonists, partial agonists and antagonists are the three primary types of medications available for treating opioid dependence. Agonist medications are prescribed acutely as part of an opioid detoxification protocol or chronically in a "maintenance" regimen (to reduce drug craving, maximize the patient's tolerance and eliminate the effects of lower potency "street" opiates). Methadone and its long acting form (48 - 72 hour duration), Levo Alpha Acetyl Methadol (LAAM) have been used effectively as maintenance medications because of their slow onset of action and long half life. Studies validated by a panel of impartial physicians and scientists in a National Institutes of Health consensus conference confirmed major reductions in opiate use, crime and the spread of infectious diseases associated with A partial agonist, buprenorphine, is now under consideration by the FDA for treatment of opioid dependence in general practice settings (39). Buprenorphine is administered sub-lingually and is also effective in reducing opiate craving for 24 - 36 hours (39, 40). The partial agonist actions of buprenorphine may have some advantages over methadone, such as few or no withdrawal symptoms upon discontinuation and lower risk of overdose even if combined with other opiates (40). Opioid receptor antagonists such as naltrexone produce neither euphoria nor dysphoria when prescribed to abstinent opiate addicts, and have been on the market since 1984 (41). Naltrexone is an orally administered opiate antagonist that blocks actions of externally administered opiates through competitive binding for 48 to 72 hours (27, 36). Like methadone, naltrexone is a maintenance medication but compliance has been generally poor with most field studies showing retention rates of less than 20%. It may be most useful therefore, in selected populations, when combined with social, employment or criminal justice sanctions to increase compliance. For example, naltrexone has been used in the monitored treatment of physicians, lawyers, nurses and other professionals (42) where maintaining a license to practice is contingent upon maintaining abstinence. In a recent controlled trial with opiate-dependent federal probationers, Cornish and colleagues showed that naltrexone combined with standard probation produced 70% less opiate use and 50% less re-incarceration than probation alone (43). Medications for Alcohol Dependence - Disulfiram (Antabuse®) has been used in the treatment of alcohol dependence for three decades. It produces vomiting, facial flushing and headaches if a patient drinks alcohol. Because of the severity of these effects disulfiram has been used with only a relatively select group of well-supervised patients (44). More recently, the opiate antagonist naltrexone has been approved by the FDA for reducing drinking among alcohol dependent patients. It blocks alcohol mediated stimulation of endogenous opioids, thus blunting some of alcohol's "high" effects (45, 46). Naltrexone also has some side effects (nausea, headaches) in a minority of patients but will not produce unpleasant physiological effects if the patient drinks (45, 46). More recently, European researchers have found encouraging results using acamprosate to block craving and return to alcohol abuse. While acamprosate acts primarily on glutamate receptors than naltrexone, the clinical results are remarkably similar (47). Alcohol dependent patients who take either medication have shown significantly lower relapse rates than those randomly assigned to Medications for Cocaine Dependence - Over the past ten years there have been many medications tried in the treatment of cocaine dependence but there is not yet a safe and effective agent (27, 36). Research continues in this important area and there have been indications of a potentially successful "vaccine" that may be able to rapidly bind to (48) or cleave (49) cocaine molecules, thereby inactivating them. This promising work is currently being tested in animal Comparison of Treatment Response
As indicated above, there are now several medications that have demonstrated effectiveness in the treatment of substance dependence. Addicted patients who comply with the recommended regimen of education, counseling and medication have favorable outcomes during, and for six to twelve months following treatment (35, 49 - 51). However, these medications must be taken on a regular basis and lack of patient compliance has limited their impact (36, 37, 42 - 45). Because of multiple co-morbid medical and social conditions and because of poor compliance with the pharmacological and behavioral components of the treatment regimen, only about 40% of treated alcohol, opioid or cocaine dependent patients are continuously abstinent for one year; although an additional 15% have not resumed dependent use (35, 49 - 51). Similarly, treatments for adult onset hypertension, diabetes and asthma are heavily dependent upon behavioral change and medication compliance to achieve full effectiveness. Studies have shown that less than 60% of adult, insulin-dependent diabetics fully comply with their medication schedule (52), and less than 40% of medication-dependent hypertensive or asthmatic adults comply fully with their medication regimens (15, 17). Also, less than 40% of patients with these disorders comply with recommended behavioral and diet changes (15 - 17). As in the treatment of addictions, compliance and outcomes in all three of these chronic medical illnesses, are poorest among patients with low socioeconomic status, low family or social supports and/or significant There is also similarity in relapse rates across these disorders. At least 30% of adult onset, insulin-dependent diabetic patients, and at least 40% of adult, medication-dependent hypertensive and asthmatic patients suffer significant symptom reoccurrence each year, requiring at least restabilization of the medication and sometimes hospitalization (15 - 17, 52). DISCUSSION
We have asked whether addictions to alcohol or other drugs could reasonably be considered "illnesses." Here we approached the question by analogy examining fundamental characteristics such as etiology, heritability and pathophysiology in addictive disorders and in three comparison illnesses: adult onset diabetes, hypertension and asthma. We found primarily similarities in terms 1) the role of personal choice, family, culture and environmental factors in the 2) genetic heritability (.4 - .6 H2 estimates) from twin studies, and 3) evidence of pathophysiological changes at the cellular and system levels. Although science has made substantial progress, we cannot yet fully account for the genetic and neurochemical processes that lead to diabetes, hypertension or asthma; or for the genetic, neurochemical and learned processes that transform controlled, voluntary “use” of drugs into uncontrolled, involuntary “addiction.” From a public health perspective, it is less important whether addiction "looks like" other chronic medical illnesses. More important is whether addictions are responsive to medically oriented treatments. In this regard, we found many controlled trials showing significant gains to both the patients and to society from behavioral treatments for all addictions (35, 49 - 51). There are also potent, well-tolerated medications for alcohol and opiate, but not cocaine dependence (37 - 46). Finally, when we compared published treatment response rates in addiction and in the comparison 1) rates of compliance with prescribed medication (40 - 60%) and behavioral change 2) rates of one-year relapse requiring medical intervention (approximately 40%), and 3) factors associated with non-compliance and relapse (low socioeconomic status, low family/social support, psychiatric co-morbidity). Of course there are differences between addiction and the selected comparison illnesses. Unlike any other chronic illness, drug dependence results from illegal behavior. In addition, behavioral changes in diet and lifestyle by themselves can reverse the early course of some forms of asthma, hypertension and diabetes. However, there is a later point in these illnesses where behavioral change alone is not sufficient for symptom remission and medications must be prescribed. In contrast, work by Vaillant has shown that some, even chronically addicted alcoholics can achieve almost full symptom remission without medical treatment, by eliminating alcohol and changing their lifestyle (53, 54). At the same time, our review suggests that few chronically addicted individuals achieve stable symptom remission without treatment and many more could be helped with medically CONCLUSION
Considered in total, our findings lead us to conclude that addiction is a treatable medical illness and that public health policy should include more and better treatments for addicted individuals. While there are no "cures" for any of the chronic medical illnesses discussed, medical science has led to major reductions in morbidity and mortality in all of them. Despite high rates of non-compliance and relapse, there is no serious argument as to whether the treatments for diabetes, hypertension or asthma are effective. Indeed, relapse among diabetic, hypertensive and asthmatic patients following cessation of their medications has been considered evidence of the effectiveness of those treatments. In contrast, relapse to drug or alcohol use following cessation of addiction treatment has often been considered evidence of treatment failure. Given the marked similarities between addiction and other chronic medical illnesses, it is striking that the majority of drug dependent individuals who enter contemporary treatments are not even seen by a physician, nor are they offered any of the effective medications that are currently available. While this could be considered malpractice in the treatment of chronic hypertension, diabetes or asthma, it is unfortunately, still standard practice in the treatment of addiction. 3427 words
REFERENCES
1) Rice D.P., Kelman S., & Miller L.S. (1991). Estimates of the economic costs of alcohol, and drug abuse and mental illness, 1985 and 1988. Public Health Reports, 106 (3), 280 - 292. 2) Fleming, M.F., & Barry, K.L. (1991). The effectiveness of alcoholism screening in an ambulatory care setting. J. Stud. Alcohol, 52, 3) Weisner, C.M., & Schmidt, L. (1993). Alcohol and drug problems among diverse health and social service populations. American Journal of Public Health, 83, 824 - 829. 4) Fagard, R., Brguljan, J., Staessen, J., Thijs,L., Derom, C., Thomis, M., & Vlietinck, R. (1995). Heritability of conventional and ambulatory blood pressures. A study in twins. Hypertension, 26 (6 5) Hong, Y., de Faire, U., Heller, D.A., McClearn, G.E., & Pedersen, N. (1994). Genetic and environmental influences on blood pressure in elderly twins. Hypertension, 24 (6), 663-670. 6) Kyvik, K.O., Green, A., & Beck-Nielsen, H. (1995). Concordance rates of insulin dependent diabetes mellitus: a population based study of young Danish twins. British Medical Journal, 311, 7) Kaprio, J., Tuomilehto, J., Koskenvuo, M., Romanov, K., Reunanen, A., Eriksson, J., Stengard, J., & Kesaniemi, Y.A. (1992). Concordance for type 1 (insulin-dependent) and type 2 (non-insulin- dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia, 35 (11), 8) Nieminen, M.M., Kaprio, J., & Koskenvuo, M. (1991). A population-based study of bronchial asthma in adult twin pairs. Chest, 100 (1), 70-75. 9) - Uhl, G.R. (1999) Molecular genetics of substance abuse vulnerability: A current approach. 10) Van den Bree, M.B.M., Johnson, E.O., Neale, M.C. and Pickens, R.W. (1998) Genetic and environmental influences on drug use and abuse/dependence in male and female twins. Drug and 11) Pickens, R.W., Elmer, G.I., LaBuda, M.C. & Uhl, G.R. (1996). Genetic Vulnerability to substance abuse. Berlin, Germany: Springer Verlag. 12) Tsuang, M.T., Lyons, M.J., Eisen, S., Goldberg, J., True, W., Lin, N., Meyer, J.M., Toomey, R., Faraone, S.V., & Eaves, L. (1996). Genetic influences on DSM-III-R drug abuse and dependence: A study of 3,372 twin pairs. American Journal of Medical Genetics, 67, 473 - 477. 13) Gynther, L.M., Carey, G., Gottesman, I.I., & Vogler, G.P. (1995). A twin study of non-alcohol substance abuse. Psychiatry Research, 56 (3), 213-220. 14) Svetkey, L.P., McKeown, S.P., & Wilson, A.F. (1996). Heritability of salt sensitivity in black Americans. Hypertension, 28(5), 854-858. 15) Graber, A.L., Davidson, P., Brown, A., McRae, J., & Woolridge, K. (1992) Dropout and relapse during diabetes care. Diabetic Care. 15: (11), 1477 - 1483. 16) Horowitz, R.I. (1993) Treatment adherence and risk of death after a myocardial heart infarction. 17) Dekker, F.W., Dieleman, F.E., Kaptein, A.A., & Mulder, J.D. (1993) Compliance with pulmonary medication in general practice. European Respiratory Journal. 6: (6), 886 - 890. 18) Schuckit, M.A., and Smith, T.L. (1996) An 8-year follow-up of 450 sons of alcoholics and controls. Arch. Gen. Psychiat. 53: 202 - 210. 19) Helzer,J.E., Canino, G.J., Yeh, E.K., Bland, R.C., Lee, C.K., Hwu, H.G., Newman, S. (1990) Alcoholism - North America and Asia. Arch. Gen. Psychiat. 47: 313 - 319. 20) Thomasson, H.R., Edenberg, H.J., Crabb, D.W., Mai, X.L., Jerome, R.E., Li, T.K., Wang, S.P., Lin Y.T., Lu, R.B., Yin, S.J. (1991) Alcohol and aldehyde dehydrogenase genotypes and alcholism in Chinese men. Am. J. Hum. Genetics. 48: 667 - 681. 21) Koob, G.F., & Bloom, F.E. (1988). Cellular and molecular mechanisms of drug dependence. 23) The Lancet (1996) Series on Addiction. Volume 347 (8993 - 8998) 24) National Academy of Sciences, Institute of Medicine (1995) Dispelling the Myths About Addiction . Washington, National Academy Press. 25) Phillips, A.G., Pfaus, J.G., & Blaha, C.D. Dopamine and motivated behavior: insights provided by in vivo analyses. (1995) In P. Willner, & J. Scheel-Kruger, (Eds.), The Mesolimbic Dopamine System: From Motivation to Action (pp.199-224). John Wiley & Sons. 26) Wise, R.A., & Bozarth, M.A. (1981). Brain substrates for reinforcement and drug-self- administration. Progress in Neuropsychopharmacology, 5, 467-474. 27) Institute of Medicine. (1995). Development of Medications for the Treatment of Opiate and Cocaine Addictions: Issues for the Government and Private Sector. C. E. Fulco, C. T. Liverman, L. E. Earley (Eds.). Washington, DC: National Academy Press. 28) Volkow, N.D. (1997) Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature, 386 (6227): 827 - 830. 29) Volkow, N.D., Fowler, J.S., Wang, G., Hitzemann, R., Logan, J., Schyler, D.J., Dewey, S.L., and Wolf, A.P. (1993). Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse, 14, 169-177. 30) Kreek, M.J. and Koob, G.F. (1998) Drug dependence: stress and dysregulation of brain reward pathways. Drug and Alcohol Dependence. 51 (1-2), 23 - 48. 31) Self, D.W. and Nestler, E.J. (1998) Drug dependence: stress and dysregulation of brain reward pathways. Drug and Alcohol Dependence. 51 (1-2), 49 - 60. 32) Volkow, N.D., Fowler, J.S., Wolf, A.P., Hitzemann, R., Dewey, S., Bendriem, B., Alpert, R., & Hoff, A. (1991). Changes in brain glucose metabolism in cocaine dependence and withdrawal. American Journal Psychiatry, 148 (5), 621-626. 33) Volkow, N.D., Hitzemann, R., Wang, G.J., Fowler, J.S., Wolf, A.P., Dewey, S.L. and Handelsman, L. (1992) Long-term frontal brain metabolic changes in cocaine abusers. Synapse . 34) O’Brien, C.P. (1975). Experimental analysis of conditioning factors in human narcotic addiction. Pharmacological Review, 27 (4), 533 - 543. 35) McLellan A.T., Belding M., McKay J.R., Zanis D. and Alterman A.I. Can the outcomes research literature inform the search for quality indicators in substance abuse treatment? In. M. Edmunds, R. Frank, M Hogan, D, McCarty, R. Robinson-Beale and C. Weisner (Eds.). Managing Managed Care: Quality Improvement in Behavioral Health. 1996. Washington, 36) O’Brien, C.P. (1997). A range of research-based pharmacotherapies for addiction. Science, 37) Anton, R.F. (1995). New Directions in the pharmacotherapy of alcoholism. Psychiatric Annals, 38) Report of the NIH Consensus Conference on the Treatment of Opiate Addiction. (1997). 39) Johnson, R.E., Cone, E. J., Henningfield, J.E., & Fudala, P.J. (1989). Use of buprenorphine in the treatment of opiate addiction. Clinical Pharmacology and Therapeutics, 46, 335 - 343. 40) Bickel, W. K., & Amass, L. (1995). Buprenorphine treatment of opioid dependence: A review. Experimental and Clinical Psychopharmacology, 3, 477 - 489. 41) Kleber, H.D. (1987) Clonidine and naltrexone in the outpatient treatment of heroin withdrawal. 42) Ling, W. & Wesson, D.R. (1984). Naltrexone treatment for addicted health care professionals: A collaborative private practice experience. Journal of Clinical Psychiatry, 45 (9), 46 - 48. 43) Cornish J., Metzger D., Woody G., Wilson D., McLellan A.T., Vandergrift B., & O'Brien C.P. (1998). Naltrexone pharmacotherapy for opioid dependent federal probationers. Journal of SubstanceAbuse Treatment. 13: 477 - 489. 44) Fuller, R.K., Branchey L., Brightwell D.R. et al. (1986) Disulfiram treatment of alcoholism: A Veterans Administration cooperative study. JAMA 256: 1449 - 1489. 45) Volpicelli, J.R., Alterman, A.I., Hayashida, M., & O’Brien, C.P. (1992). Naltrexone in the treatment of alcohol dependence. Archives of General Psychiatry, 49, 876-880. 46) O’Malley, S.S., Jaffe, A.J., Chang, G., Schottenfeld, R.S., Meyer, R.E., & Rounsaville, B. (1992). Naltrexone and coping skills therapy for alcohol dependence: A controlled study. Archives of 47) Sass, H., Soyka, M., Mann, K., & Zieglgasberger, W. (1996). Relapse prevention by acamprosate: results from a placebo-controlled study on alcohol dependence. Archives of General 48) Fox, B.S. (1997). Development of a therapeutic vaccine for the treatment of cocaine addiction. Drug and Alcohol Dependence. 48: 153 - 158. 49) Simpson, D. & Savage, L. (1980). Drug abuse treatment readmissions and outcomes, Archives 50) Hubbard, R.L., Marsden, M.E., Rachal, J.V., Harwood, H.J., Cavanaugh, E.R., & Ginzburg, H.M. (1989) Drug Abuse Treatment: A National Study of Effectiveness. Chapel Hill: Univ. of 51) Gerstein, D. & Harwood, H. (Eds.). (1990) Treating Drug Problems: A Study of the Evolution, Effectiveness, and Financing of Public and Private Drug Treatment Systems (Volume One). 52) Clark, L.T. (1991) Improving compliance and increasing control of hypertension: Needs of special hypertensive populations. American Heart Journal. 121: (2 pt 2), 664 - 669. 53) Vaillant, G.E. (1995) The Natural History of Alcoholism Revisited. Cambridge, Mass., 54) Vaillant, G.E. (1996) A long-term follow-up of male alcohol abuse. Arch Gen. Psychiat. 55:

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