Current Research in the Treatment of Alcoholism in Liver Transplant Recipients

Transcription

1 Current Research in the Treatment of Alcoholism in Liver Transplant Recipients R.M. Weinrieb and C.P. O Brien From the Treatment Research Center, University of Pennsylvania, Philadelphia, Pennsylvania. Address reprint requests to C.P. O Brien, MD, Professor and Vice Chairman, Treatment Research Center, University of Pennsylvania, 3900 Chestnut St., Philadelphia, PA Copyright r 1997 by the American Association for the Study of Liver Diseases /97/ $3.00/0 C ombined efforts from nearly all branches of medical science over the last 30 years have brought practitioners of transplant medicine from the first human liver transplantation to a point today where 5-year survival rates exceed 70%. Curiously, after so much admirable progress, there are no studies in the pretransplant or posttransplant literature that address the treatment of the most common cause of end-stage liver disease in the western world, alcoholism. In the United States, alcoholism affects approximately 5% to 10% of all male drinkers and 3% to 5% of all female drinkers, resulting in costs of more than $130 billion annually. These costs are made up of direct treatment expenses as well as costs attributable to morbidity, mortality, and loss of job productivity. A significant proportion of those costs result from liver transplantation in alcoholic patients. Controversy over the value of transplantation in alcoholic patients is further influenced by studies in the literature reporting posttransplant relapse rates varying from 10% to 80%. Unfortunately, these figures are difficult to interpret because the lack of rigorous methodology in most studies. Considering the staggering costs of transplantation, the serious shortages of available organs, and the diversity of opinions in the literature, it is imperative to study rigorously the impact of alcoholism treatment in this special population. In the early 1980s, our group initiated research of naltrexone (ReVia; Dupont Pharma, Wilmington, DE) in conjunction with psychotherapy for treatment of alcoholism. 1,2 Naltrexone is an opiate-receptor antagonist that originally received Food and Drug Administration (FDA) approval for the treatment of opioid dependence in Unfortunately, despite naltrexone s clearly effective pharmacological ability to block the effects of exogenously administered opiates, in actual practice naltrexone has not been accepted by most heroin addicts. Although it has become the treatment of choice for opiate dependence among physicians, nurses, and pharmacists who must work around opioids regularly, naltrexone is rarely prescribed for typical street heroin addicts. Studies at our site in the treatment of alcoholism with naltrexone showed that naltrexone significantly reduced heavy drinking. Our findings were replicated, resulting in the recent FDA approval of naltrexone for the treatment of alcohol dependence. This was the first medication approved by the FDA for the treatment of alcoholism since disulfiram was approved more than 45 years ago. In the remainder of this article, we review pertinent aspects of how these findings are currently being applied to the study of alcoholic patients who have received liver transplants. The primary purpose of this article is to provide the background information and rationale for the design of this recently initiated study. We first describe the path to these discoveries by illustrating how the biopsychosocial model of addictions was linked to basic science research and subsequently culminated in the clinical pharmacotherapy investigations in alcoholism with naltrexone. We then describe the potential usefulness of naltrexone in alcoholic patients who have received liver transplants within the framework of the background, significance, and study design used. Much of this article is adapted from another report in press, and interested readers are urged to read it for more complete information. 3 The Biopsychosocial Model of Alcoholism Treatment The biopsychosocial model, as it applies to treatment of alcoholism, involves the integration of comprehensive aspects of a patient s medical, psychological, and social treatment needs. The biopsychosocial model also favors integrating the latest scientific knowledge of biology, psychiatry, genetics, and the environment, thereby assisting the clinician in directing the best possible treatment for an individual patient s needs. Alcoholism currently is viewed as presenting along a spectrum of sever- 328 Liver Transplantation and Surgery, Vol 3, No 3 (May), 1997: pp

2 Current Research in Treatment 329 ity, and researchers have recently made exciting discoveries that have resulted in expansion of our understanding of the biological basis of alcoholism and the ways we approach treatment. For example, there is strong evidence that vulnerability to alcoholism has biological underpinnings. However, research focused on discovering the genetic determinants of alcoholism is ongoing, and scientists have not yet localized a gene or set of genes associated with alcoholism. The origins and maintenance of alcoholism are correspondingly influenced by environmental factors such as the ease of alcohol s availability and whether the alcoholic chooses to engage in healthy substitute activities as an alternative to drinking. Pharmacotherapy Research in the Treatment of Alcoholism In this section, we explain some of the theory that went into the idea of using adjunctive medications for alcoholism treatment. We then review the relationship between alcoholism and naltrexone in terms of the biochemical association between alcohol drinking and the endogenous opioid system. Part of the rationale for using medications to treat alcoholism resulted from the many other studies that examined the effectiveness of psychosocial treatments alone for alcoholism but produced only modest results. We have learned, for example, that almost half of all alcohol-dependent individuals who are treated in outpatient or inpatient treatment settings relapse to drinking after 3 months. 4 Another important contributor to alcoholism treatment options, with an estimated 1 million alcoholics participating in more than 100 different countries, is Alcoholics Anonymous (AA). 5 However, the General Services Office of AA estimates that up to 50% of the participants drop out by the 3rd month, and up to 88% drop out by 1 year. Although no research data have been gathered as to what factors contribute to the significant drop-out rate, we may speculate that attrition rates are related to the need for those individuals to receive additional professional attention. Based on this information, researchers were prompted to study whether there were measurable benefits to the addition of pharmacotherapy to psychosocial treatments. Briefly summarizing, results from some of the key placebo-controlled and open-label studies of disulfiram, lithium, tricyclic antidepressants, buspirone, and serotonin-reuptake inhibitors (sertraline, fluoxetine, and paroxetine) have shown no consistently favorable results over placebo. European researchers have reported positive results with acamprosate. Interested readers are urged to read two excellent reviews of the pharmacotherapy research in alcoholism by Kranzler and Anton 6 and O Brien et al. 7 Alcohol has been found to exert pharmacological effects on dopaminergic, serotonergic, GABAergic, and opioidergic neurotransmitter systems. This next section reviews the animal data, which strongly suggest the connection between the opioidergic neurotransmitter and alcohol drinking. Pathopysiological Rationale The preclinical data concerning the effect of naltrexone on alcohol drinking have been particularly persuasive. As summarized by Volpicelli et al, 8 the link between animal and human research may be described as follows. (1) Alcohol drinking has been shown to stimulate endogenous opioid activity in animals and in humans at risk for alcoholism, specifically the release of endogenous opioids such as b-endorphin. 9 This finding is consistent with the observation that alcohol and opiates show pharmacological cross-tolerance in humans and animals. (2) In rats, low doses of morphine stimulate alcohol drinking, 10,11 and higher doses reduce alcohol preference. The low-dose effect is interpreted as priming the system just as a small dose of cocaine primes the animal with past cocaine experience to want more cocaine. Higher doses of morphine may satiate the system with exogenous opiates and thus reduce the drive to obtain endogenous opioid effects by ingesting alcohol. (3) Opioid antagonists decrease alcohol preference in alcohol-prefering animals, including those bred for alcohol preference and those with poststress alcohol drinking. 12,13 (4) Among the effects of alcohol is an increase in levels of extracellular dopamine in the nucleus accumbens, a part of the brain reward system. A similar increase is produced by other drugs of abuse such as cocaine, amphetamine, and heroin and is believed to be associated with behavioral reinforcement. In the case of alcohol, the dopamine release is mediated by endogenous opioid pathways because the ef-

3 330 Weinrieb and O Brien fect can be blocked by opiate-receptor antagonists such as naltrexone. 14 The dopamine increase also occurs in rats placed in an environment in which they expect to receive alcohol. Because small increase in dopamine may have a priming effect and increase craving or drive to obtain more of the effect, this phenomenon shows a possible mechanism of cue-induced craving. 15 Taken together, these data are consistent with the hypothesis that alcohol ingestion stimulates the release of endogenous opioids, which mediates an increase in some of the rewarding effects (the high ) brought on by alcohol drinking. Perhaps we can view the initial drink as having a priming effect that stimulates further drinking. As seen in the animal data, because these effects are modulated through opioid mechanisms, use of an opioidantagonist such as naltrexone could block the alcohol-induced high (or priming effect) and interfere with the steadfast cycle of drinking and craving alcohol. We now briefly describe the methodology conducted in the human studies showing that naltrexone blocked alcohol s reinforcing effects by blocking opiate receptors and, in so doing, reduced or eliminated alcohol preference. We conclude with a description of an ongoing research project at our center that is the first National Institutes of Health (NIH) grant ever funded to study the outcome of alcoholism treatment after liver transplantation. The project proposes to study the safety and efficacy of naltrexone combined with brief psychotherapy in alcoholic patients after liver transplantation. Finally, future directions for alcoholism research in liver transplant patients are outlined. conducted by Volpicelli et al, 2 later replicated by O Malley et al. 17 Subjects and Methods Both studies were double-blind, randomized, placebo-controlled trials conducted at single sites in patients diagnosed with alcohol dependence by DSM-IIIR criteria. 18 Admission criteria required that patients be deemed psychiatrically and medically stable before enrollment. Subjects could not have had recent opiate use or have been dependent on any drug other than nicotine. All subjects were detoxified from alcohol before they were given naltrexone, 50 mg once daily by mouth, or an identicalappearing placebo for up to the 12-week duration of the trial. Subjects in the study of Volpicelli et al were predominantly black male veterans in their 40s, approximately half of those in the sample were married, and slightly less than half were employed full-time. In the combined analysis of the two studies, 65% of the study population were Hispanic or white, slightly more than half were employed, and approximately one third were married. The total sample consisted of 186 patients who were randomized and received medication in the double-blind period. There were no significant differences between the naltrexone and placebo groups for any of the demographic variables such as age, sex, or race. All subjects received psychosocial treatment in addition to the medication. Although the study of O Malley et al used random assignment to either coping skills training or supportive therapy, all patients in the study of Volpicelli et al received partial day-hospital treatment for the first month and twice-weekly group therapy for the remainder of the study. Efficacy From Research Two independent clinical trials showed the efficacy of adjunctive naltrexone in the treatment of alcohol dependence and resulted in the FDA s approval of naltrexone for that purpose. We present this combined analysis. Because the treatment-by-study interaction term evaluated by the Cox regression model for time-to-event data was not significant for any measure, data from the two studies were able to be combined. Interested readers are urged to consult the review by O Malley et al, 16 which is used for much of this section. Review of this study is recommended in addition to review of the study Results Effectiveness of the medication was judged by analyzing the time to first drink and time to the first episode of heavy drinking, defined in weeks of randomized study medication administration. Alcohol consumption was measured by the number and percentage of days nonabstinent and the degree of alcohol craving. Although the two studies differed in their definitions of relapse, nonabstinence was differentiated from heavy drinking in this combined analysis according to the following definitions: nonabstinence, either discontinuation of the study because of a drinking episode, or any alcohol

4 Current Research in Treatment 331 consumption recorded in a subject s case record; heavy drinking, five or more drinks in 1 day for men or four or more drinks in 1 day for women. Heavy drinking criteria were also met if the subject dropped out of the trial because of a relapse or drank more than eight drinks in a week. An analysis of variance model for alcohol consumption was measured, and statistical significance was determined when the test statistic yielded a twotailed probability of #.05. Results showed that time to first drink significantly favored naltrexone over placebo at week 12. Abstinence rates were 54% for naltrexone and 31% for placebo (Fig. 1). Patients who received placebo were nearly twice as likely to drink as naltrexonetreated patients during the 12 weeks of the trial. Comparison of subjects who did not have an episode of heavy drinking favored naltrexonetreated subjects (75%) over those who received placebo (48%) (Fig. 2). Slip Versus Heavy Drinking It is important to be aware that most alcohol treatment studies do not differentiate between a minor relapse or slip and a heavy drinking episode. We view alcoholism as a chronic, relapsing disorder, 19 and although we emphasize that slips should not be misunderstood as something we encourage or necessarily expect, our clinical and research experience has taught us that relapses do occur in a majority of alcoholics studied. Therefore, we distinguish slips from heavy drinking because there are good data showing that heavier drinking results in more serious consequences to the health and well-being of the alcoholic patient. 20 In an ideal situation, an alcoholic patient in treatment who experienced a minor slip would return to the counselor and confront whatever factors may have led to that slip. It is hoped that an understanding of the slip will have contributed to an important lesson about how to further protect oneself against future episodes of drinking. Naltrexone was proposed as an adjunctive medication to assist the alcoholic patient in this aspect of the recovery process. Inherent in this example is the notion that naltrexone, by blocking the alcoholmediated high, provides the alcoholic patient with a better chance of remaining in treatment and therefore minimizes or even eliminates further morbidity resulting from the alcoholism. In fact, data show that naltrexone significantly decreases the alcohol high, and although naltrexone does not differentially prevent subjects from sampling alcohol (approximately 50% of subjects in the both groups slipped), results show that naltrexone treatment results in a 50% reduction in rates of relapse to heavy drinking and a 36% reduction in rates of nonabstinence compared with placebo. A saying well known to members of AA is one drink is too many and one hundred is not enough. Naltrexone seems to interfere with this alcohol priming effect, perhaps providing another layer of support for alcoholics for whom this AA adage applies. Perhaps the most clinically relevant limitation of these research projects revolves around the lack of current knowledge about which practices constitute the best clinical guidelines for treatment with naltrexone. Although studies are ongoing, we do not have scientifically based information as to the appropriate dose of naltrexone under different treatment conditions or the ideal duration of pharmacotherapy. Although we are relatively assured of naltrexone s safety in patients with intact liver function, we do not yet have data on the long-term effects of naltrexone in this population. 8 Naltrexone in the Treatment of Alcoholic Patients Receiving Liver Transplants Our group is currently studying the safety and efficacy of naltrexone in the treatment of alcoholism in patients receiving liver transplants. This project is supported by the NIH National Institute on Alcohol Abuse and Alcoholism (NIAAA) and by our Veterans Affairs Research Center. Background The latest United Network of Organ Sharing (UNOS) estimates are that 18.8% of all adult liver transplants are performed because of alcoholic cirrhosis. 21 This means that of all possible causes resulting in the need for liver transplantation in the United States, alcoholism is the most common antecedent. As previously mentioned, the literature is replete with complex and controversial arguments regarding the ethics of performing liver transplants in alcoholic patients. Fueling the controversy is a body of literature with widely differing results regarding recidivism rates, survival and morbidity statistics, psychiatric comorbidity statistics, and the value and time frames for pretransplant abstinence requirements as predictors of posttransplantation sobriety. Consequently we are

5 332 Weinrieb and O Brien Figure 1. Time to first episode of heavy drinking among nonabstinent patients combined analysis (Kaplan-Meier). *Logrank test of difference between placebo (W, n 5 93) and naltrexone (Q, n 5 93). (Reprinted with permission from O Malley et al 16 ) studying the effectiveness of naltrexone pharmacotherapy for alcoholic patients after liver transplantation coupled with a promising brief and economical psychosocial treatment for alcoholism called motivational enhancement therapy (MET). 22 MET is an individualized treatment based on principles of motivational psychology. As developed for the recent NIAAA Project MATCH study, MET consists of a four-session treatment package designed to mobilize the patient s motivations and resources in the direction of abstinence and reduction of drinking. MET is a cost- and time-effective method of treatment that is standardized and operationalized, thus serving to minimize individual therapist confounds in a study such as this. Importantly, MET can be provided by social workers, counselors, or nurses in a primary care provider s office compared with the traditional use of psychiatrists or psychologists who provide more expensive and time-consuming forms of psychotherapy. Consequently, it is a relatively cost-effective and accessible treatment. Study Design A total of 60 subjects will be randomly assigned to one of three conditions. The comparison condi- Figure 2. Time to first episode of heavy drinking among all patients combined analysis (Kaplan- Meier). *Log-rank test of difference between placebo (W, n 593) and naltrexone (Q, n 593). (Reprinted with permission from O Malley et al 16 )

6 Current Research in Treatment 333 tions will consist of placebo plus MET, naltrexone plus MET, and treatment as usual. Patients in the treatment as usual condition will be advised by their surgeons to attend AA meetings because that is the advice most commonly offered to the majority of alcoholic patients after transplantation. Subjects will be asked to take naltrexone, 50 mg by mouth once daily, compared with identical placebo capsules or treatment as usual for 6 months after transplantation. An additional 18 months of follow-up data will be collected after the initial 6-month treatment phase. If they are proved effective, both naltrexone and MET may be administered by professional health care personnel in the primary care setting. Objectives The primary objectives of the research are as follows. Treatment response. Appropriate measures of alcohol craving, alcohol consumption (data will be obtained from both the patient and a significant other), heavy drinking (relapse rates) v slips, blood chemistries, completion of the pharmacotherapy regimen, and program retention will be studied. Compliance. As in all areas of medicine, medication compliance often determines the success or failure of the intended treatment. Previous studies of naltrexone in the treatment of alcoholism have shown the greatest reductions in heavy relapse rates in the most compliant patients. 23 It is hypothesized that the more compliant patients who have been randomized to receive active naltrexone will have the best outcome overall. Patients will be told that compliance will be assessed by a variety of methods, including self-reports, urine naltrexone levels, and urine markers of riboflavin in placebo. Compliance with the medications will also be assessed according to a method described by Sullivan et al, 24 who found that adding riboflavin to the study medication gave approximately the same results as the simple procedure in which the research pharmacist provides subjects with more pills than necessary, and the number of pills varies randomly each week. An independent research assistant requests that the patients return the unused pills, then the assistant counts and records the results. Safety. Although there has never been a documented case of liver failure caused by naltrexone, the Physician s Desk Reference 25 warns against its use in cases of acute hepatitis or liver failure. Therefore, we will carefully monitor liver function tests to assess safety. It is known from studies using high-dose naltrexone therapy (350 mg/d) in nonalcoholic populations that doses more than six times the recommended dose for alcoholism (50 mg/d) may result in an increase in liver enzyme levels (serum transaminase levels). However, this form of liver enzyme induction is dose dependent, not idiosyncratic, and most importantly has been shown to be reversible. 26 According to Berg et al, 27 there is insufficient evidence to conclude that naltrexone is hepatotoxic at dosages recommended in the treatment of alcohol, i.e., 50 mg/d. Clinically significant elevations of serum transaminase levels are rare with modest naltrexone dosages. Berg et al therefore surmise that the risk-benefit equation for the use of naltrexone in alcohol-dependent populations appears justified when weighed against the known hepatotoxic effects of continued alcohol abuse. Another important medical concern for liver transplantation patients taking naltrexone is whether naltrexone may improve natural killer (NK) cell activity, thereby interfering with immunosuppressive medication and triggering liver rejection. Preclinical studies (M. Ochshorn and M.J. Kreek, personal communication, 1994) indicate that large intravenous doses of naloxone are necessary to improve NK cell activity and that the relatively small oral doses of naltrexone used for the treatment of alcoholism are unlikely to affect NK activity. Furthermore, studies have shown that NK cell activity does not target liver grafts. In fact, even if naltrexone did improve NK cell activity, it may be of help in preventing the occurrence of other viral infections known to jeopardize the graft s integrity such as Epstein-Barr virus (A. Naji, personal communication, 1994). Nevertheless, we will measure NK cell activity. Alternative measures of alcohol use. We will determine whether a new blood biochemical measure, carbohydrate-deficient transferrin (CDT), can provide a more accurate assessment of alcohol consumption in alcoholic patients after liver transplantation compared with and in combination with existing measures such as serum g-glutamyl transferase (GGT) level, aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, alcohol breath test results, and informant and self-report information. CDT levels have been shown in alcoholic patients not requiring liver

7 334 Weinrieb and O Brien transplantation to increase after consumption of 50 to 80 g (up to six standard drinks) of ethanol per day for at least a week and normalize slowly during abstinence. 28 One study found that CDT level was a better indicator than GGT, AST, or mean corpuscular volume (MCV) level for monitoring of abstinence in patients with chronic alcoholic liver disease, 29 and CDT with GGT levels may be the most sensitive indicators of relapse. 30 The half-life of CDT is approximately 15 days, and in healthy alcoholic subjects CDT has a sensitivity of 82% and a specificity of 97%. 28 This will be the first study to examine CDT levels in alcoholic patients after liver transplantation. Cost-effectiveness. As indicated in the introduction, costs for liver transplantation are significant. Management for complicated end-stage liver disease may cost $50,000 to $60,000 for the first hospital admission. 31 Add to that figure approximately $300,000 for surgery and another $10,000 to $15,000 per year for life for medications. We will compare the medical costs and employment income of the three groups of patients over an 18-month period. Risk variables. It is important to investigate predictor variables for alcohol relapse because it may be necessary some day to base organ rationing on scientific data. A number of variables have been found to predict negative posttreatment outcomes in alcoholic patients who do not receive liver transplants, including history of frequent relapse, presence of DSM-IV axis I psychopathology, lack of social support, low self-efficacy, poor coping skills, and low motivation We plan to determine whether these predictive risk factors, which have been associated with relapse in alcoholic patients who do not receive liver transplants, also predict relapse in alcoholic patients who have had liver transplants. Results At this time, data are unavailable because the study is ongoing and the blind has not been broken. We have evaluated nearly 100 potential alcoholic liver transplant recipients since the start of the project in October 1995, and approximately half of that sample has been eligible for the study based on the DSM-IV diagnosis of alcohol dependence and acceptance to the transplant waiting list. Because of the long waiting list time, only 6 living transplant patients are currently eligible for or enrolled in the study. Six other patients were never enrolled in the study because they died before transplantation or shortly thereafter. While patients are awaiting transplantation, we compare them prospectively with a matched group of alcoholics not in need of liver transplantation who are in treatment in one of our outpatient substance abuse clinics. The purpose of this information-gathering study is to investigate aspects of both groups at baseline, either when they enter treatment or when they are evaluated for transplant eligibility. Multiple objective measures of the patient s alcohol and drug use are ascertained by alcohol breath tests, urine drug screens, serum CDT samples, and routine measurement of serum liver enzymes. We are also examining lifetime alcohol-drinking patterns, quantity and frequency of recent alcohol use, alcohol craving, psychiatric symptoms, and quality of life measures by selfreport and structured interviews. Preliminary evidence suggests that there are no clear differences between groups on all measures except for more illness in the pretransplant population. There are also significantly higher rates of chronic hepatitis C virus infection in alcoholic patients who need transplants. Implications for future study may be aimed at drug use prevention efforts in alcoholic patients because it appears that the majority of patients with hepatitis C had a remote history of intravenous drug use. However, until the study is completed these data are tentative. A Final Comment At our Hospital of the University of Pennsylvania site, each patient s eligibility is decided by a team of transplant surgeons, gastroenterologists, psychiatrists, social workers, nurses, and clergy. Similar to the University of Michigan at Ann Arbor liver transplant group, our program does not insist on a 6-month period of sobriety for our patients to be eligible for transplantation. We addressed this issue in a letter to the board of directors of the UNOS in reference to their recently proposed mandate that patients must demonstrate a 6-month continuous period of sobriety to be eligible transplant candidates. 41 Given the complexities involved in evaluating prognosis, we have found no clear evidence that a minimum 6-month period of sobriety will result in higher rates of posttransplant sobriety. Although it is logically defensible, we believe a 6-month mandate is too rigid and may lead to unintended consequences. As mentioned above,

8 Current Research in Treatment 335 we know that most alcoholic patients not in need of transplantation will relapse within the first few months of treatment. We believe that if a patient has a minor slip while awaiting transplantation but remains in alcoholism treatment and confronts the issues that led to the slip, he or she may actually represent a better long-term risk than an alcoholic patient with far worse prognostic features who was able to remain abstinent until transplantation but never confronted the normal struggles of recovery. We advocate for the same goals stipulated in the UNOS Objectives of Equitable Organ Allocation, which are to provide for accountability and public trust, and to allocate organs based upon medical criteria, striving to give equal consideration to medical utility and justice. 41 As psychiatrists who specialize in the study and treatment of alcohol-related disorders, we are committed to the process of recommending alcoholic liver transplant candidates who are the most likely to remain abstinent and compliant after transplantation. We view this task in light of the overall picture of the candidate s life by examining past strengths and weaknesses, the record of compliance in the pretransplant period, and the overall social situation. We raise this issue here because we view addictive disorders as chronic, relapsing illnesses in need of treatment. Therefore, we must be careful not to impose scientifically unsubstantiated requirements on our alcoholic patients. In so doing, we risk inhibiting their likelihood of having honest admissions of relapse while awaiting transplantation and thereby forfeiting a chance to receive alcoholism treatment at the risk of being rejected from their only alternative to death. In conclusion, we hope that by more rigorously studying the treatment of alcoholism in this special population, we may someday put to rest some of these very serious issues which so powerfully affect our patients lives. References 1. Volpicelli JR, O Brien CP, Alterman AI, Hayashida M. Naltrexone and the treatment of alcohol dependence: Initial observations. In: Reid LD (ed). Opioids, bulimia, and alcohol abuse & alcoholism. New York: Springer- Verlag, 1990: Volpicelli JR, Alterman AI, Hayashida M, O Brien CP. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 1992;49: Weinrieb RM, O Brien CP. Naltrexone in the treatment of alcoholism. Annu Rev Med 1997;48: Miller WR, Hester RK. 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