Treatment of addictive behaviors in liver transplant patients
Very little addiction treatment research has been done concerning smoking cessation, illicit drugs, or even alcohol abuse in liver transplant patients.
Our data suggest that a surprising number of patients who are awaiting a liver transplant for alcohol-related end-stage liver disease will return to drinking before transplantation.
We found that motivational enhancement therapy afforded no marked benefit over treatment as usual for drinking, smoking, mood, or general health outcomes in alcoholics awaiting liver transplantation.
Stably abstinent methadone-maintained opiate-dependent patients should not be tapered off methadone; are generally good candidates for liver transplant; show low relapse rates into illicit use of opiates; and may be at risk for more medical complications than their counterparts.
Pre- and posttransplantation smoking rates are high and cause marked morbidity and mortality. Transplant teams should encourage smoking cessation treatments.
Marijuana use in liver transplant recipients is not uncommon, and apart from the risk of developing aspergillosis, additional health risks have not yet been identified. Liver Transpl 13:S79–S82, 2007. © 2007 AASLD.
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The typical transplant candidate must be evaluated for present or past addiction to tobacco, alcohol, opiates, marijuana, and other drugs of addiction. In patients with alcoholic cirrhosis or chronic viral hepatitis, an addiction history may be directly related to the pathogenesis of liver failure. Most liver transplant patients with alcohol-use disorders are also nicotine dependent, and abuse of illicit drugs is not infrequent. Even when the cause of liver failure is inherited or cryptogenic, it is necessary to consider addictions to cigarettes, alcohol, or recreational drugs.
Little information exists describing the health consequences of illicit drug use after transplantation; however, return to drinking is thought to pose one of the most important risks to the health and survival of an alcoholic liver transplant recipient. Studies suggest that continued nicotine use may be even more harmful than drinking after transplantation. Of those recipients who drink heavily, it is estimated that up to 85% will die or experience physical harm.1 Therefore, a comprehensive approach to treatment of the transplant recipient should include management of harmful addictions.2
Historically, it was assumed that the insights gained from alcoholism treatment research outside the transplantation context would be applicable to liver transplant patients. However, more than 10 years ago, Wagner et al.3 noted that unlike most nontransplanted alcoholics, many of the liver transplant alcoholics evaluated by their group quit drinking on their own and denied a need for further intervention. These observations were validated by our group when we compared non–liver transplant alcohol-dependent patients to alcoholic patients undergoing liver transplantation and found that the latter cohort displayed far lower measures of motivation for alcoholism treatment and that few ever participated in alcoholism treatment or attended an Alcoholics Anonymous meeting.4, 5
On the basis of the finding that motivation for alcoholism treatment in liver transplant patients was low, our group chose to study motivational enhancement therapy (MET) compared with the opiate blocker naltrexone and placebo in a 3-arm pilot study. Naltrexone was selected because of its ability to reduce craving and reduce relapse rates in nontransplant alcohol-dependent patients who slipped.6 Unexpectedly, we were unable to complete the study because recruitment was stalled by lack of acceptance of the study by our alcohol-dependent transplant recipients. They indicated that severe illness, their fear of naltrexone-induced hepatotoxicity, and their belief that alcoholism was no longer a problem were their reasons for declining to enter our study.7
A pilot study conducted in Birmingham, England, evaluated three 1-hour outpatient sessions of Social Behavior and Network Therapy, which used techniques of MET in 20 alcoholic liver transplant recipients.8 Measures of alcohol consumption were taken by random self-report and by blood alcohol levels assessed before transplant and repeated once at 6 months after transplantation. Eight (42%) of 19 reported drinking some alcohol after transplantation; of these, 4 (21%) drank weekly, and 1 (5%) drank more than 21 units per week. Patients also reported that the sessions were less judgmental and more constructive than what they had received in the community. Although the study was not a randomized clinical trial, the results suggested that English alcoholic liver transplant patients were amenable to therapy when it was provided in a nonjudgmental and supportive manner.
We then undertook a prospective randomized, controlled study of psychotherapy compared with treatment as usual in alcoholic patients with liver failure who were awaiting transplantation.9 A key element in the study design was a process to allow subjects to admit to alcohol use without jeopardizing their position on the transplant waiting list. Only in circumstances of a life-threatening emergency would this confidence be broken. After completing baseline measures, subjects were randomized to receive either 7 individual sessions of MET with case management, each lasting 50 minutes, or treatment as usual, which entailed a referral to community Alcoholics Anonymous and a standard Intensive Outpatient Program. A total of 91 subjects were randomized, of whom 66% were followed for 48 weeks. We found no benefit for MET over treatment as usual in that approximately 25% of either group drank during the period of observation. These data suggest that clandestine alcohol use is common in alcoholics even when awaiting liver transplantation.
OPIOID DEPENDENCE TREATED WITH OPIOID SUBSTITUTION THERAPY
Because 85% of persons receiving opioid substitution therapy (methadone maintenance, buprenorphine, or buprenorphine-naloxone) for opiate dependence in the United States are hepatitis C virus positive, it is becoming more common for methadone-maintained patients to undergo evaluation for liver transplantation. The standard of care is to continue methadone administration during evaluation, transplantation, and thereafter, rather than to attempt to wean the candidate off methadone. This is because relapse to opiate use typically exceeds 80% in stably abstinent methadone-maintained patients who are then tapered off methadone.10 Three small retrospective series, comprising 78 subjects in total, have reported on the outcome of liver transplantation in this subpopulation.11–13 Table 1 summarizes the conclusions of these reports.
Table 1. Characteristics of Methadone-Maintained Liver Transplant Recipients
|Are more likely than their peers to be removed from the waiting list.|
|Typically require more intraoperative anesthesia and postoperative analgesia.|
|May have severe recurrent hepatitis C virus infection.|
|May have worse survival, but substance abuse relapse is rare.|
|Many require increased methadone doses.|
OPIATE USE FOR PAIN RELIEF WITH OPIOID SUBSTITUTION THERAPY
The only published data on the treatment of pain in the opioid-dependent liver transplant population is from a retrospective comparison study of acute postoperative pain requirements in which guidelines for patient management were provided.13 Although there are no known published data on the longer-term postoperative management of pain in this population, chronic pain is highly prevalent in the opiate abuse population. In general, it is important to distinguish pseudoaddiction from real addiction in such cases. Pseudoaddiction is the term used to describe the behavior of patients who are legitimately in need of better pain control, but their requests for more opioid analgesia make them appear to be drug seeking.
A consensus guideline from the American Society of Interventional Pain Physicians identified 6 factors associated with aberrant use of opioids in clinical practice on the basis of a comprehensive review of previous literature, as follows: (1) excessive opioid needs, (2) deception or lying to obtain controlled substances, (3) doctor shopping, (4) nonfunctional status, (5) exaggeration of pain, and (6) prescription forgery.14 By contrast, it is also important to recognize that it is common for opioid-dependent transplant patients in stable recovery to purposely refrain from adequate pain control in an effort not to be seen as drug seeking or because they are afraid of becoming readdicted. Because it can be difficult to distinguish real pain from malingered pain in opioid-dependent patients with chronic pain, special services from pain specialists may be needed.
The prevalence of tobacco use is high in adult patients before and after liver transplantation. We have not required liver transplant patients to stop smoking, although there would be obvious benefits in pulmonary health if subjects were to stop. DiMartini et al.15 have prospectively studied tobacco use in alcoholic liver transplant recipients. They found that alcoholic recipients who have a history of recent tobacco addiction resume smoking very soon after liver transplantation, and once smoking has been restarted, they increase their consumption over time, and quickly become tobacco dependent. We should not be in doubt of the harmful effects of cigarettes in the liver transplant population. Indeed, it is likely that even a relatively short interval off cigarettes before transplantation would enable more rapid restoration of spontaneous unassisted ventilation after surgery.
In addition, Pungpapong et al.16 reported that the frequency of hepatic artery thrombosis was increased in liver transplant recipients who were smokers, suggesting that smoking increases the risk of postoperative vascular complications. There are also serious long-term cardiovascular consequences of smoking after transplantation. Liver transplant recipients frequently have many cardiovascular risk factors such as hypertension and diabetes, to which the addition of smoking further enhances their cumulative risk. It is no surprise that heart attack and stroke are important sources of morbidity and mortality in medium- and long-term survivors of liver transplantation. Furthermore, we should not ignore the potential for synergy between the oncogenic influence of immunosuppression and cigarette use.17 Late deaths due to lung and oropharyngeal cancer in have been reported in transplant recipients who are tobacco users.
Despite the evidence that tobacco use is a serious problem in liver transplant patients, there are no systematic studies of tobacco cessation in liver transplant candidates or recipients, although protocols to assist in smoking cessation as part of cardiovascular risk reduction have been proposed.2, 18 A recent review in nontransplanted patients found very limited data comparing people with a history of an alcohol use disorder to those without an alcohol use disorder who attempt to quit smoking; however, the available evidence suggests that there are no marked differences in quit rates between these 2 groups when nicotine replacement therapies are used (e.g., gum, patch, inhaler, Bupropion, Varencicline).19 In general, nicotine quit rates from most interventions lasting 12 weeks do not exceed 20% by 1 year after intervention, although one study evaluating a 52-week intervention suggested a quit rate of 50%.20
Our experience suggests that marijuana use may be widespread among candidates for liver transplantation. Patients often claim to use it to treat nausea or to stimulate appetite. Discovery of marijuana metabolites in the urine of a candidate is often an impediment to approval of funding by third-party payers. However, we are aware of no case series studying the effect (if any) of smoking marijuana on liver transplant outcome. Because we know that cannabis is associated with temporary short-term memory loss and there are isolated reports of aspergillosis associated with smoking contaminated marijuana in a bone marrow transplant recipient and a renal transplant recipient, we discourage the use of marijuana.21–23 We do not advocate withholding transplantation on its account, nor do we require treatment in an addiction facility before transplantation, unless we consider its use symptomatic of a more severe addiction. In the nontransplanted population, treatment of cannabis dependence has typically relied on psychotherapeutic techniques, although studies of rimonabant, an orally administered tablet with cannabis (CB1) receptor antagonist capability, are currently underway.
OTHER DRUGS OF ADDICTION
Aside from an occasional patient who uses cocaine before or after transplant, we find virtually no use of methamphetamine or heroin in our alcohol-dependent liver transplant patients. In general, treatment of cocaine dependence is difficult, with only moderate success rates; however, recent research suggests that modafinil, a drug used to treat narcolepsy, when combined with cognitive behavioral therapy, enhances cocaine abstinence.24 We believe an active cocaine user should not be considered for liver transplantation. Although we only have our extensive clinical experience to support our recommendations, we require such patients to complete a substance abuse treatment program with documented drug-free urine for at least 6 months before we will reconsider them for transplant eligibility. Although benzodiazepines are relatively contraindicated in patients with liver failure, they are sometimes prescribed to patients for anxiety or insomnia. This may be problematic for the abstinent alcoholic with end-stage liver disease for 2 reasons. First, patients with liver failure are more sensitive to sedation and confusion as a result of hepatic encephalopathy and reduced drug clearance. And second, abstinent alcohol-dependent patients who ingest benzodiazepines may be at increased risk of benzodiazepine abuse, and this may lead to alcohol craving and relapse.