A matched comparison study of medical and psychiatric complications and anesthesia and analgesia requirements in methadone-maintained liver transplant recipients

Authors

  • Robert M. Weinrieb,

    Corresponding author
    1. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
    2. Department of Psychiatry of the Philadelphia Veterans Administration Medical Center, Philadelphia, PA
    • The Treatment and Evaluation Center of the University of Pennsylvania, 3440 Market Street, Suite 370, Philadelphia, PA, 19104
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    • Telephone: 215-746-7705; FAX: 215-746-7733

  • Rebecca Barnett,

    1. Department of Anesthesia, University of Pennsylvania, Philadelphia, PA
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  • Kevin G. Lynch,

    1. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
    2. Department of Psychiatry of the Philadelphia Veterans Administration Medical Center, Philadelphia, PA
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  • Maria DePiano,

    1. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
    2. Department of Psychiatry of the Philadelphia Veterans Administration Medical Center, Philadelphia, PA
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  • Alfred Atanda,

    1. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA
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  • Kim M. Olthoff

    1. Department of Surgery, University of Pennsylvania, Philadelphia, PA
    2. Department of Surgery, Division of Transplantation of Children's Hospital of Philadelphia, Philadelphia, PA
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Abstract

Approximately 85% of patients receiving methadone maintenance therapy (MMT) for opiate dependence in the United States are infected with hepatitis C virus (HCV). MMT is significantly underrepresented in most liver transplant programs, but the number of patients receiving MMT is increasing and few data are available to guide treatment. We evaluated MMT in our program (27 pretransplant and 10 posttransplant cases) for medical and psychiatric complications and anesthesia and analgesia requirements. After transplant, 10 patients receiving MMT were compared with a matched control group of 19 patients who were not receiving MMT and not dependent on opiates. Fewer patients receiving MMT retained a spot on the transplant waiting list (65%) than patients not receiving MMT (80%); 30% of patients receiving MMT pretransplant used heroin, cocaine, or marijuana, and more than 25% were lost to follow-up. Liver disease according to mean Child-Turcotte-Pugh (CTP) score and transplant waiting times was similar between the 2 groups. Patients receiving MMT required significantly more intraoperative anesthesia and postoperative analgesia (mean fentanyl 3,175 μg/d, SD = 2,832; intravenous morphine 67.86 mg/d, SD = 38.84, respectively) compared with patients not receiving MMT (mean fentanyl 1,324 μg/d, SD = 1,122; intravenous morphine 12.17 mg/d, SD = 10.24, respectively). More patients receiving MMT had severe recurrent HCV infection (60%) and worse survival (60%) versus patients not receiving MMT (21% and 78.9%, respectively). Follow-up times did not differ between groups (MMT: mean 4.19 years, median 1.15 years, SD = 7.6; non-MMT: mean 2.68 years, median 2.19 years, SD = 1.73). Finally, patients receiving MMT required an average methadone dose increase of 60% from pretransplant to posttransplant. Postoperative analgesia guidelines are described. Posttransplant, 20% of patients receiving MMT used alcohol or illicit drugs. Data do not support withholding the provision of liver transplantation to patients receiving MMT, but larger, well-controlled studies are warranted. (Liver Transpl 2004;10:97–106.)

Sharing injection drug-use equipment among heroin addicts is the predominant medium for transmission of hepatitis C virus (HCV) in the United States.1 The result is that approximately 85% of the approximately 179,000 patients receiving methadone maintenance therapy (MMT) for opiate dependence in the United States are HCV infected.2 Because 20% of patients with chronic HCV infection will develop cirrhosis and 20% of cirrhotic patients will require liver transplantation, it is estimated that at least 6,000 patients receiving MMT will need liver transplantation in this country once they have progressed to the stage of decompensated liver disease. Despite the fact that HCV-related cirrhosis is the most common indication for liver transplantation in the United States, patients receiving MMT are significantly underrepresented in most liver transplant programs.2, 3 It seems likely that insurance reimbursement, stigma, insufficient knowledge of MMT, and fears about return to drug use after transplantation explain why only 10% of liver transplant programs surveyed in the United States had experience with more than 5 patients receiving MMT.3–5 Furthermore, limited outcome data are available to guide transplant clinicians in treatment decisions affecting patients receiving MMT. Accordingly, the purpose of this article is to report our center's experience with patients receiving MMT who were evaluated for liver transplant and to compare their psychiatric and medical outcomes with a matched cohort of non-opioid–dependent liver transplant recipients (patients not receiving MMT).

In 1995, our transplant group experienced an increase in referrals for liver transplant evaluations in patients receiving MMT. At that time, there were no known reports available concerning liver transplantation in this group of patients. Given that there were no data refuting the prudence of providing liver transplantation to patients receiving MMT, we elected to accept these patients to our waiting list if they were receiving stable doses of methadone and had demonstrated abstinence from drugs and alcohol for at least 6 months. In keeping with data from nontransplant patients receiving MMT showing the benefits of MMT in reducing relapse rates and decreasing morbidity and mortality,6–8 we advised the patients receiving MMT to remain taking a methadone dose sufficient to improve their chances of remaining abstinent from opiates and other drugs of abuse while awaiting transplant.

At the time of this writing, only 3 reports describing outcomes in patients receiving MMT had been published in the literature.5, 9, 10 More will be said about these reports later in this article, but the authors' general conclusion was that patients receiving MMT should be selected for liver transplant on an individual basis if they meet the same psychosocial eligibility criteria as other patients without opiate dependence. Conclusions were based on evidence that liver transplant recipients receiving MMT had comparably good rates of survival and medication compliance and relatively low rates of illicit drug use compared with patients not receiving MMT. In contrast, worse perioperative health and more psychiatric problems were reported in patients receiving MMT. The authors of these reports broke new ground in a previously unexplored patient population, but because most transplant programs do not perform transplantations in many patients receiving MMT, inferences based on these results are limited by small sample sizes, inconsistent objective evidence of drug use, and absence of a control group in all reports.

Abbreviations

MMT, methadone maintenance therapy; HCV, hepatitis C virus; PI, primary investigator; CTP, Child-Turcotte-Pugh; ETOH, alcohol; HBV; hepatitis B virus; SICU, surgical intensive care unit; PCA, patient controlled analgesia; IV, intravenous.

Methods

We evaluated all patients receiving MMT pretransplant who were referred to our center for transplant evaluation and performed an in-depth comparison of all patients receiving MMT posttransplant with a matched control group. On the basis of what we believe to be the most clinically relevant aspects of the aforementioned research, we compared patients receiving MMT pretransplant with the general population of patients not receiving MMT in regard to survival, acceptance to the waiting list, and alcohol and illicit drug use. A separate cohort of patients receiving MMT posttransplant were compared with patients not receiving MMT in regard to waiting list time, severity of liver disease at transplant, and perioperative medical and psychiatric morbidity and mortality. Finally, we compared intraoperative anesthesia and postoperative pain medication requirements between the 2 groups, and on the basis of our clinical observations, we suggest guidelines for pain management in liver transplant recipients receiving MMT.

Patients

This study was approved by the Institutional Review Board of the University of Pennsylvania. All patients who were evaluated for or underwent a liver transplantation at the University of Pennsylvania's Multi-Organ Transplant Center were included. Our sample consisted of 37 patients receiving MMT who were evaluated by the Primary Investigator (PI) (R.W.) at our transplant center from a total of 2,061 patients who were evaluated from December 1995 to January 8, 2003, for a potential liver transplant. A case-matched sample of 19 liver transplant recipients not receiving MMT and not dependent on opiates were selected as a control group at random from a pool of 76 possible matches that were drawn from the total population of 690 transplant recipients. To control for selection bias, the control group's demographics were matched to the patients receiving MMT in regard to age (within 5 years), cause(s) of liver disease, date of transplant (within 2 years), gender, and, where possible, race. Severity of liver disease on the day of transplant was measured for each patient by the Child-Turcotte-Pugh (CTP)11 score, but patients were not matched to this variable because we wanted to compare hepatic health between the 2 groups. Twice as many patients were chosen for the control group as for the MMT group to provide a more representative sample of control patients. A ratio of 2:1 (non-MMT:MMT) was chosen because between 2 and 18 matches of patients not receiving MMT were found for each patient receiving MMT and 2 was the lowest common denominator. In 1 case, we could find only 1 patient not receiving MMT who matched with a corresponding patient receiving MMT. These 19 patients were compared with 10 patients receiving MMT who underwent liver transplantation.

Assessments

Information from existing clinical records was gathered by the PI (R.W.), a liver transplant surgeon (K.O.), a liver transplant anesthesiologist (R.B.), and 2 research assistants with no connection to the clinical care of the patients (M.D. and A.A.). Patients underwent a thorough psychiatric evaluation for transplant eligibility by the PI at least once, and most were evaluated again for pain management and postoperative psychiatric problems within 1 or 2 days of receiving their liver transplant. Patient data were extracted from a patient tracking database, inpatient and outpatient medical charts, and discussions with transplant nurse coordinators and transplant physicians.

Outcome Measures

All patients receiving MMT pretransplant who were evaluated at our center (n = 27) were assessed for rates of survival, rates of acceptance to the waiting list, and drug or alcohol use. Patient information was accumulated until January 8, 2003, and then data collection was ceased. Ten patients receiving MMT posttransplant were compared with a control group of 19 patients not receiving MMT. Follow-up data for the patients posttransplant were collected until September 1, 2003. We report the number of days on the waiting list for transplant and severity of liver disease at the time of transplant by the Child-Tucotte-Pugh (CTP) score.11 CTP scores for this study were calculated by obtaining retrospective laboratory values (serum bilirubin, prothrombin time, or international normalized ratio and albumin) and severity of ascites and encephalopathy. Anesthesia and pain control requirements were tallied from operating room records. Postoperative pain medication requirements were calculated by converting doses of opiate analgesia recorded in the charts to equivalent average daily doses of intravenously administered morphine. Methadone doses on each day of transplant for the patients receiving MMT were compared with the dose at the time of discharge from the hospital. Finally, medical and psychiatric complications and survival rates were assessed posttransplant for all patients in the study.

Statistical Method

Our research questions were addressed using summary statistics and 2-group comparisons. Chi-square tests were used for comparisons on discrete responses. Continuous responses were compared using t tests, with some responses being log-transformed to reduce levels of skewness. If transformations did not sufficiently improve the response distribution, a nonparametric 2-sample test (Tarone-Ware) was used instead.

Results

Pretransplant MMT Group

Demographics

The pretransplant MMT group consisted of 22 men and 5 women (Table 1). The average age at intake was 46 years old (range 34–55 years). The racial composition was white (74%), black (22%), and other (4%). The primary diagnoses were hepatocellular carcinoma (4%), ethanol abuse/dependence (26%), HCV (26%), ethanol abuse/dependence and HCV (26%), and cryptogenic (18%).

Table 1. Pre-Transplant Methadone Maintained Liver Transplant Patients—Waiting List and Survival Status
 N (% of Total)Currently Alive N (%)Deceased N (%)Status Unknown N (%)
  • *

    Numerals in bold are calculated as a proportion of the total sample size.

  • **

    N (% of total waitlisted).

Total sample*27 (100)15 (55.5)5 (18.5)7 (26)
Ever placed on waiting list20 (74)10 (67)4 (80)6 (86)
Never on waiting list7 (26)5 (33)1 (20)1 (14)
Removed from waiting list6 (30)**2 (33)04 (67)

Disposition of pre-transplant patient population receiving MMT

As of January 8, 2003, 27 patients receiving MMT had been evaluated for liver transplant at our center; 15 were alive, 5 had died, and the survival status of 7 was unknown. Of 20 patients initially accepted to the waiting list, 6 were removed from the waiting list for using alcohol (n = 1), heroin (n = 3), benzodiazepines, and marijuana (n = 2). Of 7 patients not yet placed on the waiting list, 2 were nearing completion of the medical testing required for wait listing. Of the remaining 5 patients, 2 were removed from consideration because of poor follow-up with medical testing, 2 were removed for relapsing to illicit drug use, and 1 died.

Posttransplant Data

Demographics and diagnostic criteria

As the result of matching, there were no significant differences between the patients receiving and not receiving MMT in demographics or diagnoses (Tables 2–4. The average age of patients in the MMT group at the time of transplant was 48 years, compared with 49 years for those in the non-MMT group. Racial distributions for patients in the MMT group were the following: white (80%), African American (10%), and Native American (10%). Racial distributions for patients in the non-MMT group were the following: white (90%) and African American (10%). There was 1 female patient in the MMT group, and the non-MMT group was matched accordingly. The most common diagnoses responsible for transplant in the MMT and control groups were alcohol abuse/dependence and HCV (50% and 53%, respectively). The second most common diagnosis in the MMT group was HCV alone (20%). The remaining diagnoses in the MMT group were alcohol alone (10%), hepatocellular carcinoma and HCV (10%), and hepatitis B virus, HCV, and hepatocellular carcinoma (10%). The second most common diagnoses in the control group were HCV alone (21%), alcohol alone (11%), hepatocellular carcinoma and HCV (11%), and hepatitis B virus, HCV, and hepatocellular carcinoma (5%).

Table 2. Methadone Maintained, Opioid Dependent Liver Transplant Recipients
Subject No.Age at Transplant (Years)Gender/RacePrimary DiagnosesWaiting Time to Transplant (Days)CTP Score at TransplantPre-transplant Oral Methadone Dose (mg qd)Intra-operative Anesthesia Requirements (Fentanyl mcg)Post-operative Analgesia Requirements (Avg. mg/d I.V. Morphine Equivalents)Posttransplant Oral Methadone Dose at Discharge
  • *

    Patient transplanted at another center.

  • **

    Patient data incomplete.

140M/CETOH, HCV8513452,90035.545 mg qd
243M/CETOH, HCV14912755,00064.330 mg bid
345M/CETOH86093035018.1545 mg qd
446M/CETOH, HCV2718852,8009285 mg qd
547F/AIHCV56585510,000115.950 mg AM and 75 mg hs
648M/CHCV, HCC1,558101004,00088.580 mg bid
750M/CHBV, HCV, HCC391151202,400111.370 mg bid
851M/AAETOH, HCV365Unavailable*50Unavailable*Unavailable*Unavailable*
954M/CHCV73011453,00074.645 mg bid
1057M/CHCV, HCC363965750Incomplete data**65 mg qd
Table 3. Non-Methadone Maintained, Non-Opioid Dependent Liver Transplant Recipients (Matched Control Group)
Subject No.Age at Transplant (Years)Gender/RacePrimary DiagnosesWaiting Time to Transplant (Days)CTP Score at TransplantIntraoperative Anesthesia Requirements (Fentanyl, mcg)Post-operative Analgesia Requirements (Avg. mg/d I.V. Morphine Equivalents)
  1. Abbreviations: C, caucasian; O, other.

143M/CETOH, HCV52781,00018.1
243F/OHCV16131,0006.06
344M/CETOH, HCV799101,00024.7
444M/CETOH, HCV36871,10023.4
546F/OHCV74991,50030.6
647M/CETOH, HCV2971535020.2
748M/CETOH, HCV26985,0002
848M/CETOH, HCV19214508.36
948M/CHCC, HCV31671,0004.5
1048M/CETOH, HCV253147504.1
1149M/OETOH, HCV860855010.5
1251M/CHBV, HCV1,518141,5004
1351M/CHCV1052,0009.35
1451M/CETOH174125004
1551M/CETOH60102,0004.3
1652M/CETOH, HCV5121,3005.7
1752M/CHCC, HCV3481055036.2
1856M/CHCV1,10471,00010.6
1959M/CETOH, HCV17181,3004.5
Table 4. Summary-Perioperative Results for Methadone Maintained and Non-Methadone Liver Transplant Recipients
 Methadone N = 10Nonmethadone N = 19Statistical Test
  • *

    Calculation based on 9 patients for whom data was available.

  • **

    Calculation based on 8 patients for whom data was available.

Avg. age at transplant (yrs)4849T-test (t(27) = −.573, P = .57)
Gender (%)90% Male, 10% Female90% Male, 10% FemaleX2 (1) = .002, P = .97
Race (%)80% Caucasian, 20% Other90% Caucasian, 10% OtherX2 (1) = .50, P = .48
Diagnosis (%)ETOH/HCV (50%),ETOH/HCV (53%)X2 (4) = .23, P = .10
 HCV alone (20%)HCV alone (21%) 
 ETOH alone (10%)ETOH alone (11%) 
 HCC/HCV (10%)HCC/HCV (11%) 
 HBV/HCV/HCC (10%)HBV/HCV/HCC (5%) 
Waiting time for transplant–mean no. days (SD)533.70 (137.09)422.95 (94.01)T-test (t(27) = .68, P = .50)
CTP score on day of transplant–avg. (SD)10.30 (0.76)*10.05 (0.68)T-test (t(27) = .23, P = .82)
Intraoperative anesthesia-fentanyl, natural log of avg. mcg/day (SD)7.65 (1.05)*6.86 (.95)T-test (t(27) = −2.05, P = .05)
Post-operative analgesia–I.V. morphine equivalents avg. mg/day (SD)67.86* (38.84)**12.17 (10.24)T-test (t(26) = 5.94, P = .00)
Pre-operative methadone dose–(avg. mg/day)65Not applicableNot applicable
Post-operative oral methadone dose day of discharge (avg. mg/day)82*Not applicableNot applicable
Patient survival (%)6078.9X2 (1) = 1.18, P = .28
Post-transplant survival–Mean no. days1,421 (614, 2228)1,595 (1,296, 1,893)Tarone ware
 (Confidence interval) median no. days14551912(tw (1) = 1.19, P = .27)
Post-transplant follow-up mean no. days (SD)1,529 (2774)980 (633)T-test (t(27) = −.835, P = .41)
 median no. days420800 
Post-transplant recurrent HCV infection (N/%)6/10 = 60%4/19 = 21%X2 (1) = 4.39, P = .04

Waiting time for transplant

No statistically significant differences were found between the groups from the date of being placed on the waiting list to the date of transplant (Table 4). Patients receiving MMT waited a mean of 1.5 years (SD = 1.2 years), and patients not receiving MMT waited a mean of 1.2 years (SD = 1.1 years).

CTP score on day of transplant

No significant differences were found for mean CTP scores in the MMT group (10.3, SD = 0.76) compared with the non-MMT group (10.05, SD = 0.68) (Table 4).

Intraoperative anesthesia and postoperative analgesia requirements

Intraoperative anesthesia was analyzed by comparing mean doses of intravenous fentanyl. The mean fentanyl dose per patient in the MMT group was significantly higher (3,175 μg/d, SD = 2,832) than in the non-MMT group (1,324 μg/d, SD = 1,122). The results of a t test using natural logs of fentanyl doses (t [27] = −2.05, P = .05) (Table 4) are reported because of data skewness. One patient was excluded from this analysis because he underwent transplantation at another center, and perioperative information was not available.

Postoperative analgesia administered to patients in the surgical intensive care unit immediately after surgery was highly variable according to physician preference. Most patients received intravenous morphine sulfate on an as-needed basis in the surgical intensive care unit, but after transfer to the recovery floor, most patients used patient-controlled analgesia (PCA) with good results. The mean daily postoperative analgesia doses were unequivocally higher in the MMT group (67.86 mg/d intravenous morphine, SD = 38.84) compared with the non-MMT group (12.17 mg/d intravenous morphine, SD = 10.24). Two patients were excluded from this analysis: 1 patient whose data was unavailable because he underwent transplantation at another center and 1 patient whose chart notes described only the first 2 postoperative days. On the latter patient's first postoperative day, he required the pretransplant dose of methadone (65 mg) administered daily through a nasogastric tube in addition to fentanyl (300 μg/h) delivered by PCA. On postoperative day 2, he received the same dose of methadone plus Dilaudid ([hydromorphone, Knoll Pharmaceutical Corporation, Mt. Olive, NJ] 7 mg/h with 5 mg every 10 minutes on demand by PCA). For patients receiving MMT in this analysis, morphine equivalents did not include daily methadone doses. Patients in the MMT group received methadone on a daily basis separately from their postoperative pain medication.

Preoperative versus postoperative oral methadone dose at hospital discharge

On the day before transplant, patients receiving MMT averaged 65 mg/d of methadone (range 30 mg–120 mg) compared with 82 mg/d (range 45 mg–160 mg) on the day of discharge posttransplant. Methadone doses did not change for 3 patients and decreased from 75 mg/d to 60 mg/d for 1 patient after a prolonged hospitalization. Thus, 50% of patients receiving MMT required an average increase of 60% of their methadone dose by the day of discharge from the hospital.

Postoperative complications

Clinically significant HCV recurrence rates, defined for the purposes of this study as fibrosis or cirrhosis with ascites, encephalopathy, or death, occurred in 21% of the non-MMT group versus 60% of the MMT group (Table 4). This was statistically significant according to the χ2 test (χ2 [1] = 4.39, P = .04). Additional problems encountered in the non-MMT group included 2 patients who experienced depression requiring treatment (11%) and 1 recovering alcoholic who “slipped” and drank 3 beers on 1 occasion (5%). In comparison, 20% of patients in the MMT group developed psychiatric problems. One patient became depressed and attempted suicide, and 1 patient required treatment for hypomania. One patient receiving MMT abused cocaine and died of recurrent HCV infection, and 1 patient required hospitalization after developing alcohol-induced pancreatitis and pneumonia (20%).

Patient survival and duration of follow-up

A total of 60% of patients receiving MMT who underwent transplantation between December 1995 and January 2003 were alive compared with 78.9% of the matched control patients (χ2 [1] = 1.18, P = .28) (Table 4). Although distributions of survival time showed no significant difference between the groups, median survival results trended toward reduced longevity for the patients receiving MMT compared with the patients not receiving MMT (mean survival of 3.89 years and median survival of 3.99 years vs. mean survival of 4.37 years and median survival of 5.24 years, respectively). Length of follow-up time, defined as the number of days from each patient's date of transplant to the date of death or September 8, 2003 (the date the last patient receiving MMT underwent transplantation), was not significantly different between the patients receiving and not receiving MMT (mean 4.19 years, median 1.15 years, SD = 7.6; mean 2.68 years, median 2.19 years, SD = 1.73, respectively).

Discussion

Three reports describing outcomes in patients receiving MMT have been published since we began our investigation. Gordon et al.9 described 22 patients receiving MMT who were evaluated for transplant at the Lahey Clinic in Massachusetts between 1995 and 2001. Thirteen patients were deemed ineligible for unspecified reasons. Five patients were accepted to the waiting list but were subsequently removed for uncontrolled narcotic use (n = 2), incomplete evaluation (n = 2), and a narcotics-related arrest (n = 1). Four patients receiving MMT underwent transplantation, but details regarding their condition were not described.

Liu et al.10 reported on 34 patients receiving MMT who underwent transplantation between 1989 and 1999 at Mt. Sinai Hospital in New York. The posttransplant survival rates of 94% at 1 year and 77% at 3 years in the patients receiving MMT did not differ from the survival rates in patients not receiving MMT. Postoperative pain management posed no clinical problems; however, 4 patients resumed “isolated and limited” illicit injection drug use. Similar to our finding, deaths were usually attributable to rapidly progressive recurrent HCV.

The only research publication on this topic describes 5 patients receiving MMT who underwent transplantation at the Albert Einstein Medical Center in Philadelphia, Pennsylvania between 1993 and 1999.5 All patients abstained from illicit drugs for at least 6 months before being placed on the waiting list and were unable to discontinue their methadone. It was not mentioned whether tapering off methadone was initiated by the patients or stipulated by their transplantation program. The average length of stay in the intensive care unit and postoperative recovery were significantly greater for patients receiving MMT than patients not receiving MMT. Four patients had serious postoperative medical complications, including an hepatic artery thrombosis requiring a second transplant, peritonitis with a wound dehiscence, bile leak, and pulmonary edema with an ileus. Two patients experienced graft rejection, and 1 patient died of a myocardial infarction 6 months posttransplant. Compliance with postoperative medical care was very good, and mean survival was 3.3 years (range 188 days–5.7 years). No patients were reported to have used illicit drugs after transplant.

In addition to the aforementioned reports, an editorial in response to the Einstein study and 2 surveys of liver transplant program practices regarding liver transplant recipients who received MMT have been published.4, 12, 13 Excellent discussions about the merit of providing liver transplantation to recovering opiate addicts receiving MMT are provided.4, 13 These discussions are especially important given the current shortage of available livers for an ever-increasing number of patients in need.

Our investigation began with the hypothesis that patients receiving MMT pretransplant would be less likely to be placed on the liver transplant waiting list than patients not receiving MMT. This hypothesis derived from clinical experience and research indicating that patients receiving MMT may be perceived by transplant team members as being at increased risk for return to drug use or noncompliance with medical care because of complex medical and psychosocial problems.14 At our center, 37 patients were evaluated for a liver transplant (27 pretransplant and 10 posttransplant), and 30 patients were eventually placed on the waiting list (81%). Six (20%) of the total sample of patients on the waiting list who were receiving MMT pretransplant were removed for using illicit drugs or noncompliance with medical care. Thus, 65% of all patients receiving MMT who were evaluated for liver transplantation at our center received and retained a spot on the waiting list compared with 80% for the overall population of patients. Gordon and colleagues9 reported that only 18% of the patients receiving MMT whom they evaluated were retained on the waiting list in their program.

It was also hypothesized that once patients receiving MMT were waitlisted, they would have worse survival than patients not receiving MMT. In fact, approximately 19% of patients receiving MMT died while undergoing the liver transplant evaluation process at our center compared with a death rate of 20% for the overall sample of liver transplant candidates on our program's waiting list. Thus, patients receiving MMT at our center were no more likely to die than patients of the general population not receiving MMT awaiting transplant at our center.

A critical goal for patients receiving MMT is to remain drug-free and sober while awaiting transplant, yet despite careful selection of MMT candidates, our retrospective analysis revealed that 8 of 27 patients (30%) in the pre-transplant group used illicit drugs or alcohol while on the waiting list or during the evaluation for transplant. It was not possible for us to retrospectively assess pre-transplant drug or alcohol use in the post-transplant group because those data were not available. A prospective evaluation of urine drug tests combined with self-report and collateral information from a significant other is clearly needed to confirm these findings. It is also important to assess whether pretransplant drug use predicts posttransplant relapse. Gordon et al.9 reported similar proportions of patients receiving MMT who used or sold illicit drugs in their center (5/22 patients, 23%).

Not surprisingly, patients receiving MMT used a great deal more intraoperative anesthesia and postoperative analgesia than patients not receiving MMT. This makes physiologic sense because μ-opiate pain receptors in patients receiving MMT would be expected to be significantly down-regulated from years of methadone use. This would result in requirements for higher doses of opiate pain medication to obtain clinically effective pain relief. This theory is supported by the fact that most patients receiving MMT required an average of 60% more methadone at discharge compared with the methadone dosages on admission for transplant.

Comparable to the results from the Mt. Sinai study,10 our study showed that posttransplant medical complications (particularly recurrent HCV) were worse in the MMT group. Although HCV recurrence is nearly ubiquitous in HCV-infected liver transplant recipients, patients who develop clinically significant recurrent HCV after transplant often have rapidly progressive fatal outcomes.15 Perhaps patients receiving MMT are more physically and/or nutritionally debilitated at the time of transplant from many years of tobacco, drug, and/or alcohol use compared with patients not receiving MMT. The fact that the CPT scores for patients receiving MMT were similar to those for patients not receiving MMT on the day of transplant and that the duration of posttransplant follow-up was similar among the groups argues against this point. However, the previously punishing lifestyles of patients receiving MMT may have led to immune system impairments not accounted for by the CPT score of liver failure. Further study is needed to elucidate this important finding.

Finally, despite the fact that patients receiving MMT at our center did not differ from a matched control group of patients not receiving MMT in regard to waiting time for transplant or follow-up after transplant or have worse severity of liver disease at transplant, they did demonstrate lower rates of posttransplant survival (60% vs. ∼79%, respectively). Although this group difference did not reach statistical significance, it may be clinically significant because posttransplant survival for the entire patient population during the same 7-year period of data collection was 81%. Furthermore, both groups of patients had similar severity of illness and were matched according to when they received their transplants. Given that 44% of transplant programs surveyed do not even consider patients receiving MMT for transplantation, it is conceivable that insufficient knowledge of MMT by community physicians may have delayed referrals of patients receiving MMT for transplant evaluation.4 It is an empirical question whether such delays could have resulted in further physical deterioration in patients receiving MMT compared with patients not receiving MMT. Similar to the results of Kanchana et al.,5 our results also showed a trend toward reduced longevity in patients receiving MMT versus patients not receiving MMT. These trends represent an inexplicable difference compared with the excellent survival rates reported by the Mt. Sinai group for their patients receiving MMT (94% at 1 year and 77% at 3 years)10 and merit further study.

Guidelines for postoperative pain control after liver tranplant in opiod dependent patients receiving MMT

As a result of our direct clinical experience and in-depth chart review, we found the following techniques to be the most effective for providing safe and effective pain control in patients receiving MMT who underwent liver transplantation.

  • 1On admission to the hospital, transplant physicians should verify the dose of methadone that patients are receiving by direct contact with the methadone maintenance program providers. Patients may not know their correct doses and might exaggerate their dosages if they think they might be under-dosed.
  • 2Patients should receive the same methadone dose that they received in their methadone program every day, up to and including the day of transplant.
  • 3Immediately after surgery, patients receiving MMT should receive their usual methadone dose in the surgical intensive care unit (administered through a nasogastric tube), unless they received a dose within the past 24 hours. Dividing methadone into equal 12-hour administrations may minimize fluctuating blood levels in a newly functioning liver. For immediate postoperative pain, morphine (1–5 mg intravenous bolus) may be given every 15 to 30 minutes on the patient's request and the clinician's judgment of the patient's level of consciousness.
  • 4Once patients are stable and released to the recovery floor with a clear mental status, they should continue to receive their pretransplant methadone dose every 12 hours. For pain, intravenous morphine or Dilaudid should be added to the standing methadone dosage through a PCA pump. Patients receiving MMT must be told that they will not begin to crave heroin and become readdicted to opiates when they use a PCA pump for pain control. Explaining that pain is best managed when treated early helps prevent patients receiving MMT from delaying PCA administration because of fears that they will be seen as “drug seeking” by the treatment team.
  • 5Analgesic doses may vary. A basal rate of morphine 3 to 5 mg every hour with morphine 2 to 5 mg or more every 10 to 15 minutes on demand was typical. Patients did not always complain of pain but did appear irritable or restless because they were in opiate withdrawal without being fully aware of it. Observe for classic signs and symptoms of opiate withdrawal: rhinorrhea, yawning, dilated pupils, cool damp skin at the base of the neck or just below the sternal notch, and, in severe cases, piloerection. Titrate treatment to patient's comfort, and treat patients until they have a pupillary diameter of approximately 2 mm.
  • 6As patients are able to ambulate and tolerate food orally, they will need to be prepared for discharge by tapering off the PCA pump and converting the basal rate to an oral methadone dose to be given in divided doses. Many patients will require a total dose of methadone that is up to 50% higher than when they were first admitted.
  • 7Discharging the patient with a 1- or 2-week supply of Percocet (acetominophen/oxycodone, Endo Pharmaceuticals, Chadds Ford, PA) for breakthrough pain is legitimate, but the patient, the patient's family, and the methadone treatment providers must be made aware of the prescription and told to contact the prescribing physician if they notice signs that the patient is losing control over his or her pain medication. For example, impaired consciousness (nodding out), general malaise, slurred speech, or multiple excuses for “losing my pills.” Although methadone itself can be an excellent analgesic, its onset of action may be too slow for acute pain relief in some patients. The only way a patient can receive methadone is by calling the methadone treatment providers at the time of discharge and having a written prescription for the new dose of methadone.
  • 8Finally, after searching Micromedex and Lexicomp drug-interaction databases, we were unable to find any known drug–drug interactions between methadone and the following commonly used posttransplant medications: prednisone (Deltasone, Pharmacia, Corporation, Peapack, NJ), azathioprine (Imuran, Prometheus, Inc, San Diego, CA), cyclosporine (Neoral, Novartis, Pharmaceuticals, East Hanover, NJ), FK-506 (tacrolimus, Fujisawa, Deerfield, IL), mycophenolate mofetil (Cellcept, Roche Laboratories, Nutley, NJ), ranitidine (Zantac, GlaxoSmithKline, Upper Merion, PA), mycostatin (Nystatin, Apothecon, Princeton, NJ), trimethoprim/sulfamethoxazole (Bactrim, Roche Laboratories, Nutley, NJ), ursodiol (Actigal, Novartis, East Hanover, NJ), or ampicillin/sulbactam (Unasyn, Pfizer, United States Pharmaceuticals, New York, NY).

Conclusions

The central limitation of our study was the small sample size. Nevertheless, there is such limited information regarding liver transplantation for patients receiving MMT that we believe this study makes an important, albeit preliminary, contribution to the literature.

We were surprised to find that survival of patients receiving MMT while awaiting transplant was approximately the same as that of patients not receiving MMT and that approximately as many patients receiving MMT as patients not receiving MMT were retained on the waiting list. Still, approximately one third of patients used illicit drugs or alcohol, and more than one quarter of patients were lost to follow-up. We found 3 main observations concerning the patients posttransplant: (1) Patients receiving MMT used more intraoperative and postoperative pain medication, but they fared well with proper postoperative pain management. (2) Patients receiving MMT had significantly worse posttransplant medical complications and similar rates of psychiatric problems. However, a return to alcohol or illicit drug use occurred in 20%, a relatively low figure compared with outcomes in most substance abuse treatment facilities, but worrisome in a posttransplant population. (3) Patients receiving MMT had diminished rates of survival compared with a matched control group.

In summary, in this pilot investigation, patients receiving MMT posed a greater challenge to treatment with liver transplant than patients not receiving MMT, especially pretransplant. However, our data do not indicate that it is an injustice to patients not receiving MMT to offer liver transplantation to carefully selected patients receiving MMT. On the contrary, this study admonishes us to discover whether these observations will hold in a larger, well-controlled, prospective study. Because we are seeing increasing numbers of patients receiving MMT in need of a transplantation, we must not hesitate to discover how best to assist patients receiving MMT in their pursuit of a liver transplant.

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