Current / Past Issues

Cocaine (including crack) abuse among persons in methadone maintenance treatment (MMT) is associated with numerous medical problems, criminal behavior, and poor psychosocial functioning. As previously discussed in AT Forum,[1,2] in some clinic populations, more than 70% of patients are cocaine users at admission and many continue such use during treatment.

Research on how to control cocaine abuse in MMT patients has been ongoing.

A Targeted Approach
In a new study, to be published this winter,[3] Stephen Magura, PhD and colleagues at NDRI investigated whether subjects in an enhanced MMT program would reduce their cocaine use more than those receiving standard treatment.

New York City-based NDRI (National Development and Research Institutes) is the largest independent organization devoted to behavioral science research on issues of drug abuse, AIDS, and related problems. With a staff of 200 professionals, it has been an independent entity primarily funded by federal grants since 1967.

For this NIDA-funded study, Magura and his team enrolled 141 cocaine-using patients at 4 MMT clinics operated by Beth Israel Medical Center, New York. Among those, 84 patients received standard MMT plus targeted psychosocial therapy sessions directed specifically at reducing cocaine use. There also were voucher incentives (up to $15/week in value) for completing tasks as part of individualized Treatment Reinforcement Plans, such as attending therapy sessions or self-help groups, avoiding drug-use triggers, or looking for employment (but not for stopping cocaine use). The remainder (57) participated in the usual MMT program.

MMT Works; Enhancements Unproductive
Methadone maintenance had a significant influence in reducing cocaine abuse; however, adding specialized therapy and incentives to the standard MMT regimen was not of benefit. In other words, treatment condition – enhanced vs. standard – did not make a significant difference. In the combined groups of patients, however, there was a significant decline in past-month average days of cocaine use from baseline at entry (15.2 days) to the 2-4 month followup point (6.5 days), and this persisted at 8-12 months (5.1 days; see graph).

Magura observes that the averages may be somewhat misleading, since many patients – 40% of all subjects – did become cocaine-abstinent. Interestingly, persons newly enrolled in MMT reduced their cocaine use more than patients already in treatment when the study started. Overall retention in the MMT clinics was good, since 73% were still enrolled at one year.

The essential lesson from this study appears to be that MMT participation helps reduce continuing cocaine abuse, but it may be unproductive to layer-on more intensive program services for this purpose. Magura says that a better understanding is needed of what makes for effective cocaine abuse treatment.

No Dope Means No Coke
Magura believes that polydrug-abusing patients actively participating in MMT are helped both by the elimination or reduction of opioid use and a treatment environment that significantly deters other drug abuse. Heroin and cocaine are often used either to reinforce or modulate each other's actions; for instance, opioids may help regulate cocaine's stimulant effects. Moreover, he notes, patients often say, "No dope means no coke." That is, once heroin or other opioid use is eliminated, the need and desire for cocaine also is diminished.

In Magura's study, there were significant reductions in illicit opioid use in both groups during the 1-year period, with about two-thirds becoming opioid-abstinent (although these results are not reported in their article). It might be expected that adequate doses of methadone would help achieve abstinence from drugs in addition to illicit opioids. However, among their study subjects the average dose was 78 mg/day at 12 months and only a few were receiving more than 100 mg/day of methadone (120 mg/d maximum).

Adequate Methadone Necessary
Many patients continuing cocaine use might have been receiving suboptimal methadone doses. Tennant and Shannon have reported that cocaine seems to accelerate elimination of methadone, making ordinary doses inadequate for many patients.[4] At lower methadone doses of 30-80 mg/d, most patients in their study were chronically abusing cocaine. Even at 100 mg/d, about 72% of subjects had subtherapeutic methadone serum concentrations (<100 ng/mL). When methadone dose limits were raised to 160 mg/d there was greater cocaine abstinence.

Research on the effects of MMT often overlooks the importance of truly adequate methadone dose. Methadone serum levels are rarely measured and reported as part of the research designs; hence, the proportion of patients possibly under-medicated is unknown. Magura observes that requiring blood drawing is fairly difficult to do and research funding is often insufficient to allow for the extra effort and testing involved.

Still, patients receiving inadequate methadone doses may be spending a part of each day in uncomfortable opioid withdrawal, which might motivate them to use cocaine, or other drugs, to self-medicate those symptoms. It seems a critical objective of effective MMT would be to provide adequate methadone first and then see what else might make a constructive difference during treatment.

Magura concedes that, at this stage, there are no specific pharmacologic treatments for cocaine abuse and few behavioral-modification approaches that have demonstrated long-lasting efficacy. Nonetheless, research into these issues is continuing, although there are few incentives for MMT programs to institute the sort of evidence-based changes that might be appropriate.

Whether or not the ongoing MMT program accreditation process will accelerate further research initiatives and prompt necessary changes remains to be seen.

1. Leavitt SB. Coke confounds MMT: the cocaine conundrum. Available at: www.atforum.com (see under Current/Past Issues; Unpublished Articles).
2. Leavitt SB. Update: stimulant use disorders. 2000 (winter);9(1). Available at: www.atforum.com.
3. Magura S, Rosenblum A, Fong C, Villano C, Richman B. Treating cocaine-using methadone patients: predictors of outcomes in a psychosocial clinical trial. J Subst Use Misuse. 2002 (December); in press.
4. Tennant F, Shannon J. Cocaine abuse in methadone maintenance patients is associated with low serum methadone concentrations. J Addict Dis. 1995;14(1):67-74

---

Part 4 : Hope for Liver Transplantation

"I've been on methadone maintenance for 24 years, with hepatitis C for at least 27 years. After treatment for hepatitis failed, I was told that I'll never get a liver transplant if I stay on methadone. …any suggestions?"

Unfortunately, the dilemma of this methadone maintenance treatment (MMT) patient is commonplace. Yet, there is hope for him and others in MMT who are persistent in their search for needed liver transplants.

Transplantation Denied
As the first article in this series pointed out,[1] as many as 14,000 persons in U.S. MMT programs may eventually need liver transplants for survival, primarily due to chronic hepatitis C (HCV). Yet, such patients are seriously underrepresented on transplant waiting lists.

Many transplant programs, while claiming to evaluate patients on an individual basis, refuse to consider MMT patients or require that they first withdraw from methadone.[2,3] A pivotal survey by Koch and Banys reported in 2001 that 44% of liver transplant centers did not accept persons on methadone and only 180 MMT patients had ever received transplants by those that did accept them.[4] An earlier survey by Awad and Chin [5] similarly found that, while many centers said they considered MMT patients, 41% never listed such patients for transplant.

Methadone seems to be unofficially perceived as an unnecessary and potentially complicating factor in liver transplantation. This might at least partially derive from the stigma and prejudice shadowing addiction in general and methadone in particular.

Invalid Concerns
A number of concerns have been expressed about liver transplantation in MMT patients, which are summarized in the table. These are either unlikely to occur or can be successfully addressed if they do occur. There is no scientific rationale to support why taking methadone should rule out potentially life-saving interventions for liver disease.[6]

A hallmark of effective MMT programs is the aggressive promotion of abstinence from all addictive substances, strict compliance with therapeutic regimens, frequent medical follow-up, and rehabilitation of social, psychological, and vocational functioning. Hence, MMT would be invaluable for preparing former illicit-drug abusers for transplantation and in helping to maximize favorable outcomes.

Available research has demonstrated that prior substance-use disorders are not medically sound reasons for exclusion from liver transplantation, and pretransplant abstinence requirements are poor predictors of clinical outcomes or abstinence after transplant.[7] However, Koch and Banys most recently commented that there is an implicit assumption that former substance abusers will relapse or become noncompliant with treatment, and these social value judgments once applied to the alcoholic population appear even more stringently and unfairly directed toward recovering illicit-drug users.[8]

They note that such reservations are ethically questionable and have no supporting evidence in the scientific literature.[8] In the case of MMT, available reports indicate that posttransplant outcomes and compliance in stable methadone-maintained patients are at least comparable to the rest of the population, and these patients are no more likely to relapse to illicit-drug addiction than other formerly substance-dependent persons – usually much less so.

Favorable Evidence
To date, there have been only two published investigations of liver transplantation specifically in MMT patients. In a report from Albert Einstein Medical Center, Philadelphia,[9] 5 MMT patients underwent liver transplantation between March 1993 and May 1999, representing 2.7 percent of all liver transplants at the center during that time period. All patients were very ill prior to surgery and there were significant but manageable postoperative complications in 4 of them.

Overall, outcomes and long-term survival in the MMT patients were comparable to other patients, and none of them returned to illicit-drug or alcohol use after transplantation. The authors concluded that MMT patients with end-stage liver disease should be considered for transplantation and that "weaning completely off methadone should not be an essential requirement prior to consideration."

In a larger study, Lau and colleagues described 34 MMT patients receiving liver transplants from 1989 to 1999 at Mount Sinai Medical Center, New York City.[10] The 1-year and 3-year survival rates (94% and 77%, respectively) were equivalent to all other liver transplant recipients at that institution. The authors concluded that continuing methadone maintenance did not complicate outcomes in any way.

In this study,[10] 4 methadone-maintained patients (about 12%) resumed illicit-drug injecting after transplant; however, according to Lawrence Liu, MD (Liver Fellow, Mount Sinai Medical Center) posttransplant drug use actually involved isolated and limited events, rather than serious relapse. Also, this 12% drug-use rate – often labeled "recidivism" – is lower than for recovering drug- or alcohol-dependent transplant recipients not in MMT.[11,12]

There is a question as to whether transplanted MMT patients were receiving adequate methadone doses. In the Mount Sinai cases, presurgical doses ranged from 5 to 100 mg/day (median 60 mg/d). Liu comments that dosing was controlled solely by the respective MMT programs rather than the transplant team, and he believes there might be a false perception that lower methadone doses are more favorable for transplantation. He recalls that, for no apparent reason, one patient had his dose reduced from 70 mg/day at the time of transplant evaluation to 5 mg/day by the day of surgery.

Similarly, Kenneth Rothstein, MD, Associate Director of the Center for Liver Disease at Albert Einstein and a coauthor of the case series report, notes that methadone dosing – averaging only 29 mg/day – was managed entirely by the respective MMT programs. Patients' doses might have been decreased, thinking it would better qualify them as transplant candidates. The fact that none of the patients in this report [9] relapsed to illicit-drug use might attest more to the efficacy of MMT as a supportive addiction treatment environment than to the adequacy or necessity of lower methadone doses.

Unnecessary Apprehension
As for the other concerns noted in the table, any apprehension regarding MMT patients seems unnecessary. Koch and Banys noted in their survey[4] that posttransplant difficulties with medication adherence (compliance) or followup care was reported by only 15% of centers experienced with MMT patients, and these were of minor significance that did not affect transplantation outcomes. In general, noncompliance to some extent may be exhibited by up to 20% of all posttransplant recipients, including missed clinic visits, forgotten drug doses, reducing drug doses, or even stopping one or more medications.[13]

Furthermore, interactions between posttransplant medications and methadone have not been documented in the literature. In the Koch and Banys survey,[4] none of the liver transplant centers reported immunosuppressant-drug interactions with methadone. Liu concurs that no adjustments due to methadone have been required to the standard posttransplant drug regimen at Mount Sinai.

Transplant teams unfamiliar with MMT have been concerned about managing pain in patients already taking an opioid drug (methadone). The Koch and Banys survey found that only three programs (8%) experienced any difficulties with postoperative pain management in MMT patients.[4] Rothstein observes that, in their case series, only 1 of 5 MMT patients receiving transplant required an opioid analgesic for postoperative pain; the others were managed with standard pain medications, just as all other patients. Similarly, Liu says that pain management in their MMT patients has followed usual procedures without problems.

Methadone Accepted
Liu asserts that Mount Sinai continues to consider MMT patients for liver transplantation. As of last June (2002), there were 32 methadone-maintained patients on their waiting list, and they perform liver transplants in 4 to 5 such patients each year.

He further notes that, of 36 methadone-maintained liver recipients on whom they now have from 1 to 12 years of followup data, survival has been 75%, compared with typical 5-year survival of 70%. Mortality has been largely associated with recurrent HCV infection and rapid progression to cirrhosis.

Edwin Salsitz, MD, Director of Methadone Medical Maintenance (MMM) at Beth Israel Medical Center, New York, says that several of his HCV-positive patients have received liver transplants at Mount Sinai Medical Center, while others were transplanted at NYU Medical Center and one at the University of Pittsburgh.

In all, 7 of Salsitz's patients have received liver transplants and 3 were able to return to work full time. He notes that none of them encountered resistance in getting listed due to their being on methadone; however, these were long-term patients, stabilized on methadone, and with strong family and financial support.

He concedes that patients with less tenure in MMT and without such adequate support might face challenges in finding a transplant center willing to consider them. The assistance and encouragement of MMT staff can be important in overcoming any hurdles.

Better Communication Needed
To a considerable extent, there appears to be a disconnect between addiction treatment providers and the liver transplantation field. Transplant teams would benefit from a better understanding of substance dependency and the stages of addiction recovery, particularly relating to MMT. Similarly, MMT staff need to become familiar with the liver transplantation process.

Appropriate patient referrals from MMT program staff to liver transplant centers will be essential for serving the interests of patients and the respective institutions. According to Rothstein, the very small proportion of liver transplants in MMT patients at Albert Einstein was not due to any reluctance by the transplant team to consider such patients. He believes that MMT staff and referring physicians may presume that patients continuing on methadone will be automatically rejected as candidates, and he hopes to convince them otherwise in the future.

Similarly, Liu, at Mount Sinai Medical Center, expressed an interest in closer contact with patients' MMT programs. Currently, there is communication by transplant coordinators only if the referring physician is at the respective MMT clinic, which usually is not the case.

Critical Concepts
In sum, according to current evidence, methadone-maintained patients appear to be suitable candidates for liver transplantation, just as any other persons in need. MMT patients should not be expected to withdraw from methadone or reduce their dose, as this places them at high risk for illicit-drug relapse, which would disqualify them for transplant candidacy.[15,16]

Patients also should be actively participating in counseling and ongoing recovery efforts.[17] MMT patients should exhibit relatively stable psychosocial functioning and an ability to comply with their medical care, as would be expected of any patients.[18]

Additional critical concepts may be summarized:

Long-term posttransplant outcomes in MMT patients have been as favorable as in other patient populations.
Finally, in response to the patient's plea for suggestions at the beginning of this article, the best advice might be to start looking. There are enlightened liver transplant centers that will consider him. Hopefully, their ranks will be increasing.

1. Leavitt S. Critical Concerns. Addiction Treatment Forum. Fall 2001;10(4). Available online at: www.atforum.com.
2. Peck P. Liver transplant: no methadone users need apply, please. WebMD Health [online serial]. February 27, 2001. Available at: http:// my.webmd.com/content/article/1728.73678.
3. Kinross I. Methadone clients denied life-saving liver transplants. J Addict Mental Health. 2001 (March/April).
4. Koch M, Banys P. Liver transplantation and opioid dependence. JAMA. 2001;285(8):1056-1058.
5. Awad J A, Chin B. Survey of methadone maintenance policies of US liver transplant centers. Hepatology. 2000;32(4 Pt. 2):246A. Abstract 338.
6. Stephenson J. Former addicts face barriers to treatment for HCV. JAMA. 2001;285(8):1003-1005.
7. Beresford TP, Everson GT. Liver transplantation for alcoholic liver disease: bias, beliefs, 6-month rule, and relapse – but where are the data? Liver Transpl. 2000;6(6):777-778.
8. Koch M, Banys P. Methadone is a medication, not an addiction [editorial]. J Liver Transpl. 2002: in press.
9. Kanchana TP, Kaul V, Rothstein KD, Manzarbeitia C, Reich DJ, Munoz SJ. Is liver transplantation appropriate in patients on methadone maintenance? Liver Transpl. 2002: in press. [Previously published as an abstract: Rothstein K et al. Hepatology. 2000;32(4 Pt. 2):245A.]
10. Lau N; Schiano T; O'Rourke M, et al. Survival and recidivism risk in methadone-dependent patients undergoing liver transplantation. Hepatology. 2000;32(4 Pt. 2):245A. [Abstract 337]
11. Effective Medical Treatment of Opiate Addiction. NIH Consensus Statement. Bethesda, MD: National Institutes of Health; 1997(Nov 17-19);15(6):1-38. (See also: JAMA. 1998;280:1936-1943.)
12. Lucey MB, Carr K, Beresford TP, et al. Alcohol use after liver transplantation in alcoholics: a clinical cohort follow-up study. Hepatology. 1997;25:1223-1227.
13. Gaston R. Graft loss and its relation to non- compliance. Presentation at: First International Symposium on Transplant Recipient Compliance; April 3, 1998; Arlington, VA.
14. Leavitt S. Methadone and the immune system. Addiction Treatment Forum. Spring 2002;11(2). Available online at: www.atforum.com.
15. ASAM (American Society of Addiction Medicine). Policy Statement on Methadone Treatment. Chevy Chase, MD: ASAM; 1991. Available at: http:// www.asam.org. Accessed April 29, 2002.
16. Joseph H, Stancliff S, Langrod J. Methadone maintenance treatment (MMT): a review of historical and clinical issues. Mt Sinai J Med. 2000;67(5-6):347-364.
17. Stowe J, Kotz M. Addiction medicine in organ transplantation. Prog Transplant 2001;11(1):50-57.
18. Crone CC. Transplanting patients on methadone maintenance therapy? Medscape [serial online]. December 7, 2000. Available at: http://www. medscape.com. Accessed August 29, 2001.