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Keywords:

  • Liver;
  • methadone;
  • transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Cirrhosis resulting from hepatitis C virus is presently the most common indication for liver transplantation (OLT) in the United States. A number of U.S. transplant centers require cirrhotics who are using methadone to discontinue it before proceeding with OLT. We sought to examine the outcomes of those patients who had undergone OLT at the Mount Sinai Medical Center.

A retrospective chart review of 36 subjects on methadone maintenance treatment (MMT), and off heroin, at the time of OLT was performed.

The median daily methadone dose pre-OLT was 50 mg. Post-OLT, there was an increase in methadone dose in 15 subjects, a decrease in four subjects, and no dose change in 17 subjects. Four subjects had documented single episodes of intravenous drug use post-OLT; only one subject had a dose change after the event. Patient and graft survival rates were comparable to the national average.

There was no significant difference in post-OLT outcome in patients on MMT when compared with the general population. The few episodes of drug relapse were not related to changes in the methadone dose. Efforts should be made to allow methadone-using cirrhotics better access to OLT without regard to methadone dosage.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Cirrhosis resulting from hepatitis C virus (HCV) is currently the most common indication for liver transplantation (OLT) in the United States (1). Intravenous drug use is a common source of infection, and 80% of intravenous drug users acquire it during their first year of use. As a result, 70–96% of patients enrolled in methadone maintenance treatment (MMT) programs are HCV antibody-positive (3–5). Decompensated HCV is now a major cause of morbidity and mortality in patients using methadone (1).

Studies have shown that MMT in conjunction with appropriate medical follow up, along with psychiatric, socioeconomic and drug counseling, has a >90% chance of preventing former heroin addicts from relapse (6). However, methadone is still viewed by many as ‘a substitute for another drug addiction’ (7). Patients are felt to be at a prohibitively high risk for recidivism and potentially may not be compliant with the strict medication regimens and frequent follow-up visits required post-transplantation (1). As a result, many US liver transplant centers do not accept patients for evaluation while they are using methadone (1,8). Although criteria for OLT for patients with a history of substance abuse include insight, abstinence, and a mandatory waiting period, some experts still question the candidacy of patients for MMT and deny this patient population access. Because of the fear of being denied access to transplantation, patients may not openly admit to their methadone use during their evaluation. This lack of disclosure could compromise their health because of the potential for unrecognized opiate withdrawal.

Among methadone-dependent patients who have undergone OLT, little is known regarding their outcome and their risk for recidivism (1,9). Mount Sinai Medical Center's approach has been to evaluate patients on MMT and, if considered adequate candidates, to grant OLT. Using this approach, we sought to examine the outcomes of all patients receiving methadone maintenance who have undergone OLT at our medical center over the last 12 years.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

We conducted a retrospective review of all patients with a history of methadone use undergoing OLT at The Mount Sinai Medical Center from 1990 to 2001. All information was obtained using the database of the Recanati/Miller Transplantation Institute. A total of 40 patients was initially identified; four subjects were excluded because of death within 3 months of transplantation. There was no evidence of recidivism in these patients. As a result, 36 subjects were included in this study, nine of whom are now deceased. All subjects, some of whom were also weaning themselves from smoking, alcohol, and other forms of substance abuse, had documentation of at least 6 months of being drug- and alcohol-free before consideration for transplant evaluation, and were rigorously interviewed by both a transplant social worker and psychiatrist. Candidates with a history of alcohol codependence were required to undergo drug rehabilitation (e.g. Alcoholics Anonymous) if they were deemed likely to relapse. The patients were not advised to wean or discontinue their methadone pre or post-liver transplantation unless there was evidence of profound hepatic encephalopathy. It was felt that aggressive weaning of methadone might predispose these ill patients to recidivism. Post-OLT, these patients were interviewed periodically, along with members of their family or friends, regarding their use of heroin and other substances of potential abuse.

Methadone prescriptions, along with dose monitoring, were accomplished at the patients' respective MMT programs. Upon each hospitalization at our institution, their current dosages were confirmed with these programs.

Routine toxicology screens were not conducted at our institution pre or post-OLT unless there was suspicion of recidivism (recurrent heroin use). If recidivism was detected pre-OLT, the patient was taken off the waiting list and placed back on it only after undergoing counseling by our team and complying with the necessary treatment (e.g. substance abuse rehabilitation). A period of time, ranging from 6 months to a year, would then need to pass in order for these to be accomplished.

The post-OLT follow-up protocol was identical to our nonmethadone-using patient population: the patients were seen twice weekly for the first month, weekly for the second month, monthly for the third to fifth month, and every 3 months until 1 year after OLT. Thereafter, they were referred back to their referring physicians and followed up by the authors at varying intervals. Concurrently, these patients were also followed up by their dependency coordinators at their respective MMT programs. Post-OLT routine psychiatric evaluation is included in our program's follow-up care.

Post-OLT immunosuppression was undertaken with the oral use of a calcineurin inhibitor (tacrolimus or cyclosporine) and a steroid (prednisone); mycophenolate mofetil was added if renal function was not optimal. Drug trough levels for tacrolimus and cyclosporine were obtained and the drug dosages were adjusted according to the results. These levels were taken twice weekly for the first 2 months, weekly for the next 2 months, and then monthly thereafter. Prednisone was tapered after the first 2 months in 2.5-mg decrements until completely weaned off. Treatment for acute graft rejection differed between the HCV and non-HCV patients: patients with HCV did not receive steroid therapy for mild rejection episodes, and received 1 g of intravenous methylprednisolone for moderate–severe rejection; non-HCV patients received 1 g of methylprednisolone for mild rejection episodes and 2 g for moderate–severe rejection. Tacrolimus/cyclosporine dosages were optimized whenever rejection episodes were documented.

The variables included in this study were gender, age at the time of OLT, etiology of liver disease, duration of methadone use, duration of alcohol use if concurrent, interval between the time of the initial OLT evaluation and the actual time of OLT with the respective methadone dosage, the methadone dosage at 6-month intervals post-OLT and at the time of last follow up, any episode of post-OLT heroin use, number of allograft rejection episodes, and the length of follow up in days post-OLT. The study was approved by The Mount Sinai Medical Center Institutional Review Board.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The clinical characteristics of the subjects are shown in Table 1. Of the 36 subjects, 31 were male and five were female. The median age at the time of transplant was 47 years (range: 38–66).

Table 1.  Characteristics of subjects receiving methadone
 Patients who underwent liver transplantation while using methadone
Total number of patients36
Gender distribution (male : female)31 : 5
Median age at time of transplantation47 years
Etiology of liver disease
 Hepatitis C35
 Hepatitis B1
Concomitant alcohol abuse history10
Median duration of methadone use15 years
Median duration of alcohol abstinence5 years
Median interval from initial transplant evaluation to time of transplantation462 days
Median methadone dose during transplant evaluation50 mg
Median methadone dose at time of transplantation50 mg
Median methadone dose at last follow up60 mg
Number of patients with an increase in methadone dose15 (42%)
Median dose increase40 mg
Number of patients with a decrease in methadone dose4 (11%)
Median dose decrease10 mg
Number of patients without change in methadone dose17 (47%)
Median duration of hospital stay post-transplantation22 days
Number of patients experiencing ≥1 episode of acute cellular rejection within 1 year post-transplantation25 (69%)
Employment history (full- or part-time)
 Pre-transplantation8 (22%)
 Post-transplantation3 (8%)
Number of patients with documented use of intravenous drugs post-transplantation4 (11%)
Median duration of follow up1250 days
Total number of deaths post-transplantation9 (25%)
Patient survival
 1 years35/36 (97%)
 3 years30/36 (83%)
 5 years29/36 (81%)
Graft survival
 1 years32/36 (89%)
 3 years27/36 (75%)
 5 years26/36 (72%)

Thirty-five out of the 36 subjects (97%) had HCV; nine had a concomitant history of alcohol abuse. One subject had nonreplicating hepatitis B and also a history of alcohol abuse. Among the subjects with alcohol abuse, the median duration of alcohol abstinence was 5 years (range: 1–10). The median duration of methadone use before OLT evaluation was 15 years (range: 4–31).

The median interval from the time of initial OLT evaluation to the time of OLT was 462 days (range: 9–2899). The median methadone dosage at the time of evaluation and at the time of OLT was 50 mg (range: 5–100).

The median methadone dosage at the time of last follow up was 60 mg (range: 5–150). There was an increase in methadone dose in 15 subjects (median of 40 mg; range: 5–65); the median period was 7 months (range: 2 weeks – 20 months). Six of these subjects had had their doses decreased immediately post-OLT.

Twenty-five out of 36 subjects (69%) had at least one episode of acute cellular rejection of their allografts 1 year post-OLT. There was no suspicion of medical noncompliance in these subjects.

The median length of follow up was 1250 days (range: 208–4598) for all deceased and surviving subjects. Among the surviving subjects, the median length of follow up was 1269 days (range: 321–4598); the deceased subjects had a median length of follow up of 999 days (range: 208–2561). The nine deceased subjects did not succumb to events related to recidivism or methadone use; causes of death included graft failure as a result of recurrent hepatitis C (five), hepatocellular carcinoma (one), cerebrovascular accident (one), and sepsis (two).

Four subjects (11%) experienced recidivism, 2 months to 2 years after transplantation; two of them had their methadone dosage increased. The interval between the time of OLT and the time of heroin use ranged from 2 months to 2 years. The clinical characteristics of these patients are shown in Table 2.

Table 2.  Characteristics of subjects with recidivism
Patient no.Age at OLTDuration of methadone use (in years)Concomitant alcohol abuse historyYears of alcohol abstinence before evaluationInterval from evaluation to OLT (in days)Methadone dose at evaluation (in mg)Methadone dose before OLT (in mg)
14512noN/A9237070
245 8yes51426040
34713noN/A2268080
44513noN/A4118060
Patient no.Interval from OLT to drug use (in months)CommentsStatus
  1. OLT = organ liver transplant; MMT = methadone maintenance treatment.

1 2Single relapse; patient-reported. Methadone dose was increased from 70 to 100 mgAlive at 1121 days
2 2Single relapse; patient-reported. No change in methadone doseDied 208 days post-OLT (4 months postrelapse) from metastatic hepatocellular carcinoma
322Single relapse; by random urine testing. No change in methadone doseDied 2514 days post-OLT (5 years postrelapse) from fungal sepsis
424Single relapse; urine testing after suspicious behavior was reported by MMT clinic. No change in methadone doseDied 999 days post-OLT (9 months postrelapse) from recurrent disease/allograft failure

One-, 3-, and 5-year patient survival rates were 97%, 83%, and 81%, respectively, with graft survival rates for the same periods being 89%, 75%, and 72%, respectively.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

There are now 3.9 million people infected with the hepatitis C virus in the United States, of whom 2.7 million have progressed to develop chronic liver disease (10). The highest seroprevalence for HCV (70–96%) is noted in intravenous drug users (IVDU) and also in those enrolled in MMT programs (3–5). The latter group has only recently been included in HCV treatment protocols (2,11), with comparable results to non-IVDU groups. In the recent National Institute of Health Consensus Conference on HCV, methadone treatment, aside from not being a contraindication to HCV treatment, was noted to reduce high-risk behavior that could transmit the viral infection. Furthermore, it was noted that HCV treatment could be successful even with the lack of drug or alcohol abstention or with the use of methadone. As a result, a key recommendation from this conference was to organize treatment trials for the active IVDU population in order to minimize further complications of the disease. Presently, at least 27% of US liver transplant centers require discontinuation of methadone use before transplant evaluation/listing (8), despite its status as a legal drug. As a result, patients may be dissuaded from seeking proper health care or may place themselves at risk for opiate withdrawal or unanticipated drug–drug interactions through denial of methadone use. Although there has been a recent report of five MMT patients who underwent OLT successfully (9), there are very scant data regarding transplant outcome in patients on MMT.

Since 1949, methadone has been shown to successfully eliminate heroin use in more than 90% of users, and to contribute significantly to their quality of life with less illicit drug use, and hence less risk of acquiring illnesses associated with this habit, less morbidity as a result of better medical follow up, less criminal activity, and less unemployment (6). High relapse rates are noted once patients leave MMT programs (7).

Methadone has the stigma of being just a drug substitution, potentially leading to other forms of drug addiction. In appropriate doses, it should not lead users to experience intoxication or sedation (12). Furthermore, its slow onset of action yields a blunted euphoric effect, making it undesirable for users seeking a ‘high’.

Little has been written regarding OLT in methadone users (1). Previous studies on addiction and transplantation have centered on alcohol use. Historically, there was initial concern in allowing patients with alcoholic cirrhosis to undergo OLT based on the pervasive view that in light of the ongoing organ shortage, alcoholic liver disease was self-inflicted and that the risk for recidivism post-OLT was high. Poor post-OLT outcome has previously been noted in actively drinking patients (13). However, other studies have found no effect on graft and patient survival, nor compliance with immunosuppression despite recidivism rates estimated at 25% (14) and 32% (15), respectively. Reports of renal transplantation in former drug addicts have not shown a poor outcome; however, recidivism was not rigorously investigated in these studies (16).

During the stressful process of transplant evaluation, our program does not encourage the methadone dose to be decreased or discontinued, as it is felt that an increased risk of relapse may occur. Of the 36 subjects studied, appreciable hepatic encephalopathy requiring a decrease in methadone dosage did not occur. Following OLT, the same methadone dosage should be maintained, but with the addition of regular postoperative analgesia. It is a common misconception that the patient's regular methadone dosage alone is sufficient to provide adequate analgesia (17). Five (14%) of our subjects had their methadone dosage increased early postoperatively, presumably related to inadequate analgesia. They comprised 33% of the total subjects who had increases in methadone dosage post-OLT.

Forty patients on MMT have been transplanted at our institution. During the time period in which these patients were studied, a total of 162 patients were referred to our center for transplant evaluation; 95 of these patients (59%) were accepted for listing. While on the waiting list, four patients were documented to have recidivism. Besides the requisite 6-month abstinence, other factors that assisted our evaluation included the patient's compliance (e.g. to follow-up care, with continuing abstinence), the presence of a strong support system (e.g. family members, friends), and a willingness to seek drug rehabilitation, if indicated; employment was not a major criterion. Care for this group of patients was not carried out any differently from patients who were not on methadone. Although our study was performed without the benefit of a control population, the subjects' ages at the time of transplantation and gender were similar to the nonmethadone-using patients who underwent OLT for hepatitis C at our institution. There was very little change in the methadone dosage between the time of transplant evaluation and the time of OLT, with median daily dosage approximating 50 mg. As the subjects were on steady methadone doses for extended periods of time, it may have made them less likely to develop post-OLT recidivism. The anesthesiologists were informed of the patients' use of methadone before the transplantation procedure; no specific interventions were taken in the operating room for these patients. Post-operatively, a decrease in the dosage was noted only in four out of the 36 patients. The remaining subjects either had their dosage increased or had no change made. None of the four subjects who admitted to heroin use post-OLT had their doses decreased before their period of indiscretion. One of the four subjects had the methadone dose increased from 70 mg to 100 mg after the episode of heroin use; before their demize, none of the other three subjects had reported further heroin use despite not having their methadone doses increased. No other substances of abuse were reported or discovered. The risk of experiencing acute cellular rejection in this group was similar to what has been reported in the general population (18). None of our patients experienced psychologic or psychiatric problems during the early post-OLT period that were deemed to be specific for those with a history of substance abuse.

Our post-OLT HCV patients (including those using methadone) were seen at a clinic session separate from the non-HCV patients, with the goal of closely monitoring interferon treatment, along with the drug's potential adverse effects. Patients with recurrent HCV were not treated with a protocol regimen, and only variably treated at all. Pain secondary to HCV management was treated with oral analgesics; no specific allowances were made to increase the methadone dosages. The number of methadone-using patients undergoing HCV treatment is too small to ascertain whether they required increased methadone dosages or needed to discontinue HCV treatment more frequently. Our subjects were followed for an average period of 4 years, an appreciable time during which to detect recidivism. Patient survival rates have been greater than the average: 97%, 83% and 81% for 1, 3, and 5 years, respectively, with graft survival rates of 89%, 75%, and 72% for the same periods, respectively.

In summary, we investigated the outcome of 36 patients who were on methadone before OLT and found no differences in patient and graft survival when compared with the general OLT population. This is by far the largest experience to date, both in terms of the number of patients and the length of follow up, in assessing the outcomes of a highly selected population of methadone patients undergoing OLT. Four of these patients had episodes of heroin use post-OLT; these episodes were not related to changes in methadone dosage. Post-transplant, the great majority of the subjects did not revert to heroin or other illicit drug use. Overall, our experience with these patients in MMT programs was similar to outcomes in patients undergoing OLT for alcoholic cirrhosis; in fact, our recidivism rate appears lower than that reported for the latter group. As with the issue of transplanting patients with alcoholic cirrhosis, in the past, the allocation of limited resources, such as liver allografts, for patients using methadone is not a straightforward decision. The data presented may assist in showing that these patients can be good transplant candidates. Thus, patients in MMT programs should not be denied access to OLT; continued stable methadone use does not impair transplant success or effective immunosuppression. This will become increasingly important as the number of patients with decompensated cirrhosis and hepatocellular carcinoma in MMT programs further increases.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
  • 1
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    Wiesner RH, Demetris AJ, Belle SH et al.. Acute hepatic allograft rejection: incidence, risk factors, and impact on outcome. Hepatology 1998; 28: 638645.