Liver Transplantation September 2002 Volume 8 Number 9

Orthotopic liver transplantation (OLT) is well established as an effective treatment for patients with end-stage liver disease (ESLD). One of the major challenges currently facing OLT is that the number of candidates far exceeds available organs. As of May 2000, a total of 15,258 patients were on waiting lists. Hepatitis C is the leading cause for OLT, followed by alcoholic liver disease; both are primarily substance abuse-related diagnoses. Recipient selection is a critical aspect of OLT and involves a multidisciplinary approach. Patients undergo an extensive psychosocial evaluation in addition to medical evaluation. Currently, patients actively using illicit drugs are excluded from consideration for OLT.3-5 Methadone maintenance treatment (MMT) is routinely prescribed for patients during and after rehabilitation from heroin use. Patients on MMT appear to fare better with respect to social functioning, job rates, lower imprisonment, and human immunodeficiency virus infection compared with patients denied methadone after rehabilitation from heroin use. Although patients fully rehabilitated from previous drug use are considered OLT candidates, there is a paucity of data regarding OLT in patients administered methadone at the time of OLT as part of MMT.

Only 56% of transplant programs accept patients on MMT for OLT, and 32% of programs require discontinuation of MMT before OLT. This apparent discrimination against patients on MMT has occurred although there are no published reports about the outcome of OLT in patients on MMT. We describe our experience with patients on MMT who underwent OLT at our center.

Commentary from Jules Levin: At this year's NIH HCV Consensus Conference the panel supported not excluding IVDUs from HCV treatment and recognized the need to consider therapy for IVDUs since IVDU is the biggest contributer to HCV-infection. The HCV-infection rate in methadone programs is very high. If we as a society are going to address HCV as a serious disease, and it was said to be recognized as an epidemic at the NIH Meeting, we must come to grips with the IVDU population.

Abstract: Most transplant programs require abstinence of at least 6 months from alcohol and illicit drugs before orthotopic liver transplantation (OLT). However, there are no published data regarding OLT outcomes in patients who are currently on methadone maintenance treatment (MMT) as part of the treatment of their heroin addiction at the time of OLT. The objective of this study is to evaluate our experience regarding the outcome of OLT in patients with end-stage liver disease (ESLD) who were on MMT at the time of OLT. Between March 1993 and May 1999, a total of 185 patients with ESLD underwent OLT at our center. Five transplant recipients (2.7%) had a history of heroin abuse and had undergone drug and alcohol rehabilitation, but could not be weaned off methadone. Pre-OLT status, drug history, perioperative course, compliance with medical therapy, post-OLT follow-up, and patient and allograft survival were analyzed in detail in these patients. All patients on MMT underwent uneventful OLTs. Their compliance with medications and follow-up was excellent. One patient was weaned completely off methadone after OLT. Post-OLT mean hospital stay in this group was 43 ± 25 days. Although the number of patients was small, long-term outcome of liver transplant recipients on MMT appears similar to that of patients not on MMT who underwent OLT during this period. Our results suggest cirrhotic patients on MMT should be considered for OLT if they meet the same psychosocial requirements as patients with alcohol abuse. Furthermore, it is not necessary for patients to be weaned off methadone before OLT. (Liver Transpl 2002;8:778-782.)

Data from liver transplant recipients between March 1993 and May 1999 at the Center for Liver Disease, Albert Einstein Medical Center (Philadelphia, PA) were carefully reviewed. Of 185 patients who underwent OLT at our center during this period, 5 transplant recipients (2.7%) had a history of heroin abuse and had undergone drug and alcohol rehabilitation, but could not be weaned off MMT. These patients underwent a complete pre-OLT evaluation and were abstinent from drug and alcohol use for at least 6 months before listing for OLT. They also underwent extensive psychosocial evaluation and were deemed suitable liver transplant candidates only after psychosocial clearance, which consisted of clearance from a psychiatrist, social worker, and their rehabilitation center. The 5 patients described in this report were on MMT at the time of OLT.

In conclusion, our results show that patients on MMT can successfully undergo OLT. These patients must undergo proper rehabilitation and have a thorough psychosocial evaluation before they can be considered for OLT. Our results suggest that weaning completely off methadone therapy should not be an essential requirement before OLT. Although patients on MMT experienced greater perioperative morbidity, overall long-term patient and allograft survival were similar to other liver transplant recipients at our center. These patients show a degree of compliance similar to other transplant recipients. In summary, patients with ESLD on MMT should be considered for OLT after careful evaluation and screening.

EDITORIAL IN LIVER TRANSPLANTATION

In this issue, Kanchana et al report on five methadone maintenance patients who received liver transplantation for liver failure caused by hepatitis and alcoholic cirrhosis between 1993 and 1999. All of the patients had uneventful transplantation, reasonable medication compliance, and good follow-up evaluation. All were reported clear of illicit drugs and alcohol for the 6 months preceding transplantation. They were on low doses of methadone, and thus it is fair to assume that these patients were relatively stable and compliant with the abstinence goals of methadone treatment. In all likelihood, they were what physicians see as good patients, in concert with treatment goals and generally compliant with medical recommendations for their overall care. So why is this report significant? It is significant because it is the first to present evidence, albeit small, in favor of accepting an increasing number of methadone maintenance patients onto transplantation waiting lists. These patients are maintained on methadone as treatment for comorbid opiate dependence and have previously largely been excluded from transplantation without convincing evidence supporting this a priori exclusion.

There are very few prior reports in the literature describing transplantation outcomes of opiate-dependent patients. Gordon et al2 reported that in 20 heroin users receiving kidney transplants, there was no difference in graft survival, patient survival, rate of infection, or loss of graft. Stevens et al3 reported excellent results in 15 patients with opiate dependency in full recovery and concluded, "the reformed heroin addict is a good candidate for renal transplantation." They reached this conclusion despite finding that 10 of 15 patients were actively smoking marijuana.

Although this is a small sample, this study signals a shift toward evidence-based medicine as a basis for transplantation decisions in recovering heroin addicts. This has happened previously in the transplant community when the evidence supported transplantation for alcoholic cirrhosis.

The Third National Health and Nutrition Examination Survey (NHANES III) stated that an estimated 3.9 million US citizens (1.8%) have been infected with hepatitis C virus (HCV). Chronic HCV results in an estimated 8000 to 10,000 deaths each year. Because the prevalence of HCV infection is approximately threefold higher among people now between 30 and 49 years of age, the number of deaths resulting from HCV-related liver disease will likely increase substantially during the next two decades as this cohort reaches the ages at which complications from chronic liver disease typically occur.

The most frequent known vector for hepatitis C transmission is needle-sharing in intravenous drug users, with heroin injectors as the highest-risk group. According to the 2000 National Household Survey on Drug Abuse,5 an estimated 130,000 individuals had used heroin in the 30 days before the survey, and an estimated 2.8 million have used heroin at some time in their lives. There are an estimated 600,000 regular heroin users in the United States, but only approximately 175,000 are currently maintained on methadone maintenance treatment (MMT).6 Chetwynd et al7 tested for hepatitis C in a sample of 116 opiate-dependent patients and found a prevalence of 84.2%. Thus the number of HCV-positive MMT patients can be estimated at 150,000 at this point, and the potential need for liver transplantation estimated at 7500 just from this cohort. These estimates are, of course, based on in-treatment MMT patients; the actual numbers of at-risk intravenous drug users are much higher.

Because organs for transplantation are scarce, transplant centers have necessarily turned to various models of organ allocation. Jonsen8 has described the utilitarian model, the egalitarian model, and the social utility model. Only the latter is an avowedly moral model, and the one most likely to impede addicts in recovery from transplantation access.

The utilitarian model of medical effectiveness strives to give organs to patients who will have the most medical benefit based on studies of effectiveness. The basic tenet is that an organ should not be "wasted" on a patient who is, for example, expected to die because of another problem within a short time. This model has several shortcomings. First, there is a lack (and unfeasibility) of clear studies about all of the medical and psychosocial factors involved. Second, efficacy studies do not necessarily answer the question about where to draw the line for acceptance on a waiting list. For example, how does one choose between a young person with hypertension and cardiac risk factors, and an older, relatively more healthy individual? Third, earlier research may not take account of new advances in immunosuppressant medications and other changes in practice.

The egalitarian model recommends a random selection of recipients to ensure equality and maintain the dignity of recipients. Shortcomings of this model include practical problems, such as accounting for changes in acute medical status of individual patients, new patients on the list with high urgency for transplantation, and ethical disagreement over whether a "gift of life" should be left to a lottery.

The social utility model attempts to find a consensus about what characterizes a person as valuable for society and as having earned the right for placement on a transplant list. The social utility model is rarely used as the sole model in the United States; however, being the only model acknowledging value judgments, it is likely to be included in others models in a hidden fashion. Levenson and Olbrisch report results from a survey of all cardiac, liver, and renal transplant centers. They found that nonmedical reasons for rejection included a history of significant criminal behavior as an absolute contraindication for 17.4% and a relative contraindication in 45.7% of surveyed transplant programs. Corresponding exclusions for current federal prisoners are 39.1% and 30.4%. When a patient is judged unlikely to protect the graft because of a history of medical noncompliance, a variant of this moral model is active. Another variation of this moral model is used when the question of responsibility for the disease is discussed. It has been suggested that patients who have inflicted the organ-destroying disorder on themselves should be given lower priority over patients who became ill without any doing of their own. However, this rule is inconsistently applied because noncompliance with good medical advice is so ubiquitous in all patient populations. Many patients on transplant lists have prior histories of high-cholesterol diets, poor compliance with chronic medications, smoking, and other medical risk factors.

Methadone is a medication, not an addiction. Although methadone is most certainly an opioid that can produce physical dependence, its use by MMT patients is not best conceptualized as an addiction, but as a replacement medication. It is difficult to get high on it, it is not injectable, and the evidence for its long-term efficacy is overwhelming. Properly prescribed methadone is neither intoxicating nor sedating. It does not impair motor activities such as driving. Methadone suppresses narcotic withdrawal and drug craving for 24 to 36 hours, but patients still perceive pain and have emotional reactions. Adequate doses, usually above 60 mg per day, competitively block heroin effects and make "chipping" a waste of time and money. Above all, when used in a structured treatment program, it leads to greatly improved social functioning and not to the impaired functioning associated with heroin use.

MMT patients should not be excluded from transplant consideration. Methadone should not be a proxy for other kinds of psychosocial evaluations. Psychosocial factors remain important in eligibility assessment, but many methadone maintenance patients meet criteria for adequate psychosocial support. By complying with the very stringent rules of methadone programs, they have shown their capacity to comply with complex requirements to an extent that can rarely be matched by other transplant candidates. Requiring abstinence from illicit substances before transplant is likely to increase compliance and stability and has been shown to be an acceptable prerequisite. Belle et al19 report that criteria for recipient and donor selection change as centers gain experience. It seems important to distinguish between MMT patients who have turned their lives around from those who continue to use other illicit drugs, participate in criminal or antisocial activities (such as domestic violence), and remain psychosocially unstable. It is important that methadone not be considered a proxy for these aspects of a psychosocial evaluation. In our opinion, there are many MMT patients who should not be qualified for waiting lists because of chaotic, criminal, drug-using lifestyles or other psychosocial factors. Rather, it is that these factors need to be assessed in their own right. Mandatory discontinuation of methadone should not be required.

Discontinuation of methadone, particularly when unsupported by a residential treatment program such as a therapeutic community, is very likely to produce heroin relapse in previously stable patients and thus disqualify them for transplantation. The American Society for Addiction Medicine position paper of 1990 states, "for the majority of opioid dependent patients, methadone maintenance is the most effective long term modality. Withdrawal from methadone carries a substantial risk associated with relapse to intravenous drug use. Withdrawal should only be attempted when strongly desired by the patient and with adequate supervision and support."20 The 1997 NIH consensus statement21 reports that "it is now generally agreed that opiate dependence is a medical disorder and that pharmacologic agents are effective in its treatment" and "continuity of treatment is crucialand most, if not all, patients require continuous treatment over a period of years, and perhaps for life."

An evidence base needs to be developed for MMT patients who undergo transplantation. The experience with alcohol dependent patients shows that substance abuse disorders per se are no reason for exclusion for liver transplants. The implicit assumption that substance abusers will be noncompliant or will simply relapse remains prevalent. It is also possible that judgments of social value, which occurred in the alcoholic population, are even more salient in the opiate addicts. They have a higher likelihood of criminal history, lower social status, unemployment, and antisocial behaviors. It is, of course, entirely possible that these patients are at higher risk for noncompliance, as it was possible that alcoholics would resume drinking after transplant. At this point, however, these reservations remain speculative and have no supporting evidence in the literature. On the contrary, the few available reports, including the small sample reported in this issue, indicate that outcomes for MMT patients are no different than those fo the rest of the population.

Studies are needed to examine several kinds of outcomes-tolerance levels for opioid analgesics postoperatively, medication compliance, misuse of opioid analgesics, long-term graft outcomes, and overall compliance with medical regimens. Because most of these patients will have liver failure caused by hepatitis C, outcomes for MMT patients need to be compared with other cohorts of similarly infected patients.