Psychosomatics 42:110-116, April 2001
© 2001 The Academy of Psychosomatic Medicine
Alcoholism Treatment After Liver Transplantation: Lessons Learned From a Clinical Trial That Failed
Robert M. Weinrieb, M.D.,
Deborah H.A. Van Horn, Ph.D.,
A. Thomas McLellan, Ph.D.,
Arthur I. Alterman, Ph.D.,
Joseph S. Calarco, L.S.W.,
Charles P. O'Brien, M.D., Ph.D., and
Michael R. Lucey, M.D., FRCPI
Received April 28, 2000; revised October 5, 2000; accepted October 30, 2000. From The University of Pennsylvania Department of Psychiatry and Department of Medicine, Division of Gastroenterology; Philadelphia Veterans Affairs Medical Center Department of Psychiatry; and Horizon for Mental Health, North Wales, Pennsylvania. Address correspondence and reprint requests to Dr. Weinrieb, Treatment Research Center of the University of Pennsylvania, 3900 Chestnut Street, Philadelphia, PA 19104; e-mail: weinrieb_b{at}mail.trc.upenn.edu
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ABSTRACT
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Alcoholic liver disease is the second most common indication for liver transplantation in the United States. The lack of alcoholism treatment studies led us to study motivational enhancement therapy (MET) plus naltrexone after transplant. The authors could not complete this study. Sixty alcoholic patients were to receive MET plus naltrexone or placebo for 6 months. Fifty men and 5 women were screened. Nine died and 15 were not approached. Of 31 approached, 20 were ineligible, 11 refused, and 5 entered but dropped out before completion. Barriers to posttransplant alcoholism included infirmity, intensive medical management, and denial for alcoholism treatment. Because 30%–50% of alcoholic patients drink after transplant, the authors suggest using MET alone pretransplant.
Key Words: Alcoholism • Liver Transplantation
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INTRODUCTION
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Alcohol-related end-stage liver disease is the second most common diagnosis among patients receiving liver transplantation in the United States.1 Although most liver transplant programs obtain psychiatric evaluations of prospective alcoholic liver transplant candidates,2 substance abuse or psychiatric treatment interventions have not been researched. Given the enormous costs of the liver transplant procedure and postoperative care coupled with the scarcity of available livers for the increasing number of patients with liver failure, we chose to study the treatment of alcoholism in alcoholic liver transplant patients.
Nearly half of alcoholic patients return to drinking within the first few months after alcoholism treatment of any kind.3–6 A recent review of 17 published reports of alcoholic liver transplant recipients indicated that approximately 30%–50% also returned to some alcohol drinking by 5 years posttransplant.7 Approximately 10% of alcoholic liver transplant recipients return to heavy drinking after transplantation, and this subgroup encounters severe medical complications that can be attributed to alcohol use.8 Remarkably, most alcoholic liver transplant recipients in large transplant centers in the United States have not received any formal alcoholism treatment or report attending any pretransplant Alcoholics Anonymous (AA) meetings.9 Likewise Tang et al.10 found that most alcoholic patients after transplantation could not recall receiving any advice regarding the risks of returning to alcohol use. We could find no formal studies in the literature of any therapeutic intervention for patients with alcoholism awaiting or following liver transplantation.
When designing a clinical study of alcoholic liver transplant patients, we had to consider what form of treatment to deliver and whether to provide treatment in the pre- or posttransplant phase. A contingency contract is one type of pretransplant intervention that has been discussed in the literature. Nelson et al.11 published an eloquent clinical guide describing the process of potential liver transplant candidates signing a contract assuring abstinence from substances of abuse for the rest of their lives in order to gain a spot on the transplant waiting list. Although 45% of liver transplant programs surveyed in one report endorsed contingency contracts as "very important" in making the decision to wait list a patient,2 there are no studies demonstrating its perceived effectiveness. Furthermore, it can be argued that making patients sign such an agreement before transplant forces them to contradict a fundamental principle of AA—alcoholics should not become too self-assured about their sobriety and should take it "one day at a time."
Lucey et al.12 also consider contingency contracts to have limited practical value. A more widely accepted practice of pretransplant behavior contingency is to make wait listing contingent upon the acceptance (and completion) of substance abuse treatment. A possible advantage of this is allowing patients time to obtain treatment for addictions while providing transplant teams more time to assess compliance and behavioral change, but no studies have compared it with posttransplant addictions treatment.
At the time we designed this study, many pretransplant patients were affected by confusion caused by hepatic encephalopathy or were too ill to tolerate a pretransplant alcoholism treatment study. Thus, an alcoholism treatment intervention delivered in the posttransplant period seemed more likely to succeed.
Because of the complex nature of their medical care, we considered a brief form of alcoholism treatment to be the most appropriate for this population. Wagner et al.13 published an excellent review of the potential strengths of using relapse prevention therapy for alcoholic liver transplant patients. Though the hypotheses of the authors were unverified by research, our group and others have corroborated many of their clinical observations. For example, most alcohol-abusing liver transplant patients do not seek substance abuse treatment.9 Because relapse prevention therapy was developed in treatment-seeking substance abusers, we chose not to study it in this population. To our knowledge, there are no studies evaluating the treatment of addictions in the severely medically ill.
Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity) investigators found twelve-step facilitation therapy (TSF), cognitive behavioral therapy (CBT), and motivational enhancement therapy (MET) to be equally efficacious in the treatment of alcohol dependence, and we judged MET to be the best choice for this population.14–16 TSF and CBT require 12 sessions compared with MET which requires 4 sessions and was specifically designed to mobilize the patient's motivations and resources in the direction of abstinence. Finally, because of the potentially lethal effect of alcohol consumption following liver transplant and because naltrexone has been shown to be effective in reducing alcohol use in other alcoholic populations,6,17–21 we added naltrexone pharmacotherapy to MET.
Although we originally sought to study 60 patients at the University of Pennsylvania Liver Transplant Clinic, we were only able to recruit 5 out of 55 patients who received a liver transplant for alcohol related end-stage liver disease between December 1995 and March 1998. Below we describe the results of our efforts, and in particular, the unexpected difficulties we encountered when we tried to adapt established addiction therapies to this special population. We will conclude with a description of how these problems led to new research questions to further the knowledge of addiction treatment research in medical and surgical patients.
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METHODS
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Our goals were to evaluate the safety and comparative effectiveness of naltrexone (50 mg) or placebo (once/day) plus MET in the prevention of alcohol relapse in posttransplant liver recipients. Entry into this study was restricted to alcohol-dependent liver transplant recipients who last used alcohol no more than 12 months before being placed on a waiting list for liver transplant. Subjects were excluded if they had a psychiatric illness requiring medication at the time of the evaluation or had current evidence of psychoactive substance dependence disorders other than alcohol or nicotine. Criteria for exclusion from the study included the following: serum liver tests (AST, ALT, GGT, or bilirubin) greater than 5 times normal, concurrent use of disulfiram or antidepressants with putative antidipsogenic effects, or major illness, including dementia, which would prevent the patient from complying with the study.
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RESULTS
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Fifty-five transplant recipients were identified for further screening for study participation. They included 50 men (44 White and 6 African American) and 5 women (3 White and 2 African American). The average age at transplant was 47 years (range=38–62). The medical diagnoses responsible for transplant were the following: alcoholism only (n=21), alcoholism with hepatitis C (n=30), and alcoholism plus an additional diagnosis of either autoimmune hepatitis (n=1), cryptogenic cirrhosis (n=1), or hemochromatosis (n=1). One patient had alcoholism plus hepatitis C and hepatitis B. These 55 potential subjects made up 32% of the 170 primary graft recipients who were transplanted between December 1995 and March 1998.
Fifteen of the 55 potential subjects were not approached because they were difficult to contact and rarely came to the clinic. Nine died before outpatient contact could be made; it is unknown whether alcohol was responsible for any of their posttransplant deaths. The remaining 31 potential subjects were approached for research participation approximately 2 months after transplant. Twenty potential subjects were ineligible (patients gave more than one reason); 7 because the interval from their last drink before listing for transplant exceeded 12 months (2 from this subgroup were also maintained on methadone for opiate dependence); 5 did not meet DSM-IV criteria for lifetime alcohol dependence, although meeting criteria for alcohol abuse; 2 lived too far from the hospital to make regular visits, and 1 had concomitant alcohol and opiate dependence. That patient was being detoxified from dependence on opiate pain medication. Naltrexone is contraindicated in patients taking opiates because it will precipitate a painful abstinence syndrome.
Five potential candidates were too ill to undertake the proposed study. One was fungemic in the intensive care unit and one became severely depressed, relapsed heavily, and attempted suicide. He required hospitalization in a state psychiatric facility. One patient required inpatient physical rehabilitation and another had recurrent hepatitis C infection. One suffered from a complex neurologic syndrome.
Six of the 55 potential subjects refused to participate. Five of these subjects were overwhelmed by medical problems, including orthopedic surgical procedures and recurrent pain, immunosuppressant medication adjustments, and rehabilitation for pretransplant associated muscle loss and weakness. Three said it was too time consuming to commit to a research project and that they did not need therapy. Two no longer considered alcoholism a problem for them. Finally, one patient said that his inability to work before transplant resulted in serious financial debt and he needed to commit time to seeking employment. In sum, concerns about their already complex medical regimen and denial that alcoholism was a problem were the main reasons patients refused participation in our study.
As described above, only 5 subjects were randomized to the protocol. No patient completed more than 4 months of the 6-month treatment period. The 5 study participants were prescribed an average of 12 medications/day and the demands of posttransplant medical management or fear of hepatotoxicity contributed to the decision to abandon the study in all cases. An additional reason for drop out was competing demands on patients' time. Four of 5 denied any significant craving for alcohol and all denied drinking in the first posttransplant year.
By March 1998, study enrollment had been so poor that we realized the project, as planned, was not viable. We undertook a more detailed analysis of all aspects of our study, including reexamination of our premise that this population would need alcohol treatment. Thus, in the text that follows, we discuss the factors we now see as important in preventing our completion of this project.
Question 1: Do alcohol dependent liver transplant recipients need alcoholism treatment after transplant?
Answer. Alcoholic patients with liver failure who are referred for transplant evaluation undergo a careful assessment in an attempt to determine the likelihood that they will return to alcohol use.22,23 Between 30%–50% of transplanted alcoholic patients return to some alcohol use in the first 5 years after transplantation, and some (the proportion is not yet clear) resume pathological drinking patterns with harmful effects on their health. Therefore, we believe alcoholism treatment is needed. When we designed this study we made the assumption that alcoholic liver transplant recipients would be at greatest risk of drinking soon after recovery from transplant, similar to the recognized outcome of alcoholism treatment applied to alcoholics who are not in need of transplant. However, recent research has shown that most patients who return to drinking initiate their drinking more than 2 years after transplant and the rate of return to drinking increases with time.7 Indeed, by 1 year posttransplant, no patients in our study drank. We now believe posttransplant alcohol treatment would be better timed to occur later—perhaps 2 to 3 years following transplant and only when there are signs that such treatment is indicated.
Question 2: Why were the patients in the present study resistant to alcoholism treatment?
Answer. We were surprised that potential subjects for the present study declined to enter on the grounds that alcoholism was not now and never had been a problem for them. This was in sharp contrast with our experience in clinical studies of outpatient detoxification and alcoholism rehabilitation in which alcoholic patients identify themselves as possible subjects for study by requesting treatment for alcoholism. There was ample objective evidence for alcohol dependence in all these cases and we were surprised by the lack of insight into alcoholism. It prompted us to examine perceived need for treatment in a separate sample of 30 alcoholic patients awaiting liver transplant. This study also confirmed a lack of craving for alcohol in the liver transplant candidates, and their belief that alcoholism was not a significant problem for them.32 Interestingly, most pretransplant patients we evaluated swear they will never drink again and reject the thought that they might be "foolish enough to drink again after what I'd been through." Still approximately half may be at risk of returning to some alcohol use. Given the fact that we cannot predict which posttransplant patients will drink, and of those, who will develop alcohol-related problems, we now believe it is best to delay the offer of posttransplant alcohol treatment until there are early signs of drinking related problems—again, possibly 2–3 years posttransplant.
Question 3: What types of alcoholism treatment arelikely to be effective in alcoholic patients with end-stageliver failure?
Answer. Although we advocate therapies that will reduce the frequency of alcohol use by alcoholic patients after transplantation, we do not think most currently available pharmacotherapeutic adjuncts, such as disulfiram or naltrexone, will be useful, at least in the early posttransplant period. Because drinking while on disulfiram can result in hepatotoxicity, peripheral neuropathies, and acetonemia,24 we think it is too dangerous to recommend its use in patients following liver transplantation. We also do not recommend the use of disulfiram in cirrhotic alcoholic patients because of the risk of dangerous hypotension brought on by toxic levels of acetaldehyde.
Naltrexone, in combination with psychosocial therapies, has been shown in most randomized, double-blind, placebo-controlled studies to be a safe and effective adjunct to treat alcoholism. Efficacy was demonstrated by reducing cravings for alcohol, number of alcohol drinking days, and the likelihood of alcohol relapse while in treatment.17,21 Hence our selection of naltrexone as a study agent. However, one of the major differences between mainstream alcoholics and the liver transplant patients is the degree of debility and medical complexity after the transplantation. It is not unusual for liver transplant recipients to be taking 12 or more medications in their first postoperative year. In our study, the demands of this regimen made our potential subjects unsympathetic to additional medical treatments. Second, we discovered that a medication that carried even a small risk of hepatoxocity was unwelcome to liver transplant recipients. Naltrexone is reported in the Physicians' Desk Reference25 to be contraindicated in cases of acute hepatitis or severe liver disease due to the remote possibility that it might cause elevated liver enzymes. The warning is based on research using naltrexone in doses 6 to 8 times greater than doses typically used in the treatment of alcoholism. Liver biochemistry tests reversed to normal in all cases when naltrexone was stopped.26,27 Because of its long running safety record, including its lack of harmful effects when given to patients with chronic liver failure,28 we still believe naltrexone is likely to be safe for use in patients with newly transplanted livers. These medical opinions, although based on the best available evidence, were not convincing to most alcoholic liver transplant recipients. Their concern to avoid risk and other medical demands affected our ability to recruit participants into our study. As in many other areas of "research-to-practice," the potentially "best" scientific recommendation was not acceptable here and we now believe that requiring naltrexone in this population is not appropriate, at least without clear evidence of return to uncontrolled drinking.
An alternative medication that has a similar mechanism of action as naltrexone but without risk of liver damage is nalmefene. Nalmefene has shown to be effective in two controlled trials of nontransplant alcoholics.29,30 Although we are not aware of any reports of it for the treatment of alcoholism in the liver transplant population, nalmefene has been used successfully and safely in an open trial for the treatment of pruritis secondary to cholestatic liver disease.
A promising NMDA receptor antagonist with a good safety profile that is used widely in Europe is acamprosate. A large, controlled trial has recently been completed in the United States, and the outcome is awaited. An interesting recent study of the serotonin-3 antagonist ondansetron suggested that it is an effective treatment for patients with early-onset alcoholism.31 Clearly, more research into this area is warranted.
Question 4: Because the use of pharmacotherapy for alcoholism may be unacceptable to alcoholic patients after liver transplantation, which form of psychosocial alcoholism treatment appears to be needed?
Answer. We believe that MET is still a good choice. MET was designed especially for alcohol-abusing individuals with limited insight into the problems related to their drinking and may be more acceptable to this patient population than alternative psychosocial treatments that demand acknowledgement of drinking problems. For example, although all patients in our study were urged to attend AA meetings, only one did. Importantly for this group of medically frail patients, MET can be provided in the course of posttransplant medical management. MET can be provided by trained social workers, counselors, or nurses in a primary care provider's office compared with traditional referral to outpatient substance abuse treatment programs or to psychiatrists or psychologists who provide more expensive and time consuming treatment. Finally, MET has been standardized and operationalized, which facilitates evaluation.
Question 5: Are there other behavioral health services that alcoholic liver transplant patients should receive?
Answer. Both from the present study and our continuing work with alcoholic patients before and after liver transplantation, we have learned about the prevalence of other problems that can also interfere with life function. For example, many of our patients need job retaining skills and financial advice. Many are appropriately worried about being able to earn a living in a manner that may need to be quite different from their employment prior to their illness. Many alcoholic liver transplant recipients also suffer from depression, anxiety, and relationship problems that require counseling or psychiatric care. We believe the effect of the stress of transplantation on these patients makes simple alcohol treatment such as attendance at AA meetings only or weekly group therapy insufficient and unlikely to succeed.
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CONCLUSION
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Given what we now know about the medical and psychiatric conditions of these patients and their response to the medications offered or to AA—what would we do differently? First, we would recommend that therapy be initiated in the pretransplant waiting phase in order to avoid conflict with posttransplant management. This pretransplant therapy would be directed to increasing motivation for treatment and reinforcing the need for continued sobriety. We would not include a pharmaceutical agent unless there was evidence of drinking that was not responding. Finally, careful assessment and referral for anxiety and depressive disorders would be included since these disorders were prevalent in this study and in a cross-sectional study32 that we designed to address the observations made in this study. Because we were having so much difficulty recruiting for this study we asked "in what clinically important ways do alcoholic patients on a waiting list for liver transplant differ from a matched cohort of alcoholic patients presenting for alcoholism treatment without end-stage liver disease?" We hypothesized that we could use that information to design an alcoholism treatment intervention that would be more acceptable to this population.
Based on our experience in this present study and in our cross-sectional study, we developed a modified and expanded version of MET15 combined with case management. We are currently testing this treatment intervention for alcoholic liver transplant patients in the first 6 months of the pretransplant waiting period. For convenience of the patient, the 7-session course of therapy is integrated within the outpatient liver transplant clinic. The treatment is suited to the specific needs of each patient and is focused on maintenance of abstinence from alcohol. It also reduces psychiatric symptoms and life stressors while enhancing compliance with pretransplant medical recommendations. This is accomplished by using motivational enhancement techniques to address the full range of health behavior changes demanded of transplant patients in addition to providing case management to address ancillary service needs. In preliminary pilot testing of a single-session intervention with 10 patients, we found that the MET approach was well-accepted by patients, who addressed such diverse concerns as medication and dietary adherence, smoking cessation, and coping with social isolation. We have piloted the full seven-session intervention, including case management with 8 patients with no refusals to participate. One patient dropped out because of feeling too ill to attend sessions and 1 died during transplant surgery after two sessions. The remaining 6 patients have generally had good attendance and report that the treatment is helpful to them. We have found that even patients who were initially angry at being referred for "alcohol" treatment may be productively engaged in discussion of their drinking problems when their other self-identified health behavior problems are addressed. As in the single-session pilot test, MET counseling has focused on a broad range of behavior changes, including, but not limited to, long-term abstinence from alcohol. Case management needs have included transportation assistance, referrals to health care providers within the transplant center and in the community, and assistance in identifying services for other members of patients' families.
In conclusion, we have learned much about the needs of alcoholic liver transplant patients from the failure of this study and the observations of others. Although we thought we could study state-of-the-art, established alcoholism therapies in this population, we were forced to rethink our approach by the difficulties we encountered in recruitment and retention. This led us to design a study that would help us to characterize this population in greater detail. This information has been extremely useful in designing our next treatment intervention trial using MET combined with case management. We hope that by describing our experience of how "even the best laid plans can fail" that other researchers will be encouraged by our results and realize the value in testing new questions and learning from their mistakes along the way.
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ACKNOWLEDGMENTS
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Dr. Weinrieb was supported by NIH Grant #K20AA00197-01 (National Institute on Alcohol and Alcoholism, Clinician Scientist Development Award) during data acquisition for the content of this report. Dr. Van Horn was supported by NIH Grant #DA07705 (National Institute on Drug Abuse, Treatment Evaluation Center). Dr. O'Brien was supported by NIH Grant #5-P60-DA-05186 (Center for Research on Treatment and Prevention of IV Drug Abuse) and Grant # VA V101(91) P-9506090R, NIDA Interagency Agreement NIDA 1 YO1 DA 50038. Drs. Alterman, Van Horn, and McLellan were supported by NIH Grant #5-P50-DA09252 (Drug Dependence Instrument and Measures Development Center).
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ABSTRACT
INTRODUCTION
