The 2018 guidelines from the American Psychiatric Association on pharmacological treatment of patients with alcohol use disorder (AUD) states that while naltrexone have been extensively reviewed in placebo-controlled and some head-to-head trials for the treatment of AUD, there remains a significant need for further investigation into other pharmacotherapies for AUD. More comprehensive data is needed regarding the efficacy, effectiveness, and safety profile, including adverse events, of both existing and novel pharmacotherapies for AUD in populations with co-occurring psychiatric disorders, other substance use disorders, and various medical conditions. These medical conditions include obesity, major cardiac diseases, chronic kidney disease, significant liver conditions like cirrhosis, and individuals who have undergone liver transplantation. Such research is critical to understanding and optimizing treatment strategies for these complex patient populations. [1]
A 2021 publication examines the challenges and management strategies for patients with severe alcoholic hepatitis (AH) who undergo early liver transplantation (LT). The authors discuss the grim prognosis of severe AH, traditionally associated with a high mortality rate even with corticosteroid therapy and expert medical management. They highlight the significance of early liver transplantation, performed without the conventional 6-month pre-transplant alcohol abstinence, which has gained traction due to high mortality in severe AH patients unresponsive to medical treatment. The paper presents data from both European and U.S. centers, showcasing varied outcomes based on strict candidate selection and regional practices. European studies, such as one described by Mathurin et al., reported survival rates post-transplantation of 77% at 6 months and 71% at 2 years, whereas U.S. data, analyzed by Lee et al., indicated a 94% 1-year survival rate and 84% at 3 years, signifying a notable survival benefit. The 2021 article emphasizes the critical nature of minimizing alcohol relapse post-transplant to optimize patient and graft survival. It details the various approaches employed, such as multidisciplinary psychosocial evaluations involving social workers and addiction specialists to assess relapse risk. Furthermore, the paper highlights the role of post-transplant monitoring for alcohol use disorder, advocating for a combination of pharmacologic therapies, such as naltrexone and acamprosate, and behavioral treatments like cognitive behavioral therapy and motivational interviewing. The research underscores the need for personalized care strategies and integrated treatment models to effectively manage alcohol use disorder and enhance transplant outcomes in this high-risk patient population. [2]
A 2007 review discusses the evidence for pharmacological treatment of alcohol dependence in liver transplant recipients, focusing on disulfiram, naltrexone, and acamprosate. Naltrexone, while initially promising, shows little to no substantial effect on alcohol dependence based on large cooperative studies and has a rare potential for liver toxicity. Specifically, three studies were discussed that focused on liver transplant and non-transplant patients. One study in alcohol dependence liver transplant patients could not recruit the adequate number of patients due to the low but possible risk of liver injury. Two large prospective studies only observed a small benefit with naltrexone in non-transplant patients, which included a Veterans Affairs cooperative study where naltrexone was administered as an adjunct to standard psychosocial treatment. The authors conclude that naltrexone is a controversial agent with potential for damaging effects on the liver, suggesting its conventional use is not recommended. [3]
According to the LiverTox database, naltrexone is typically given to patients with a high background rate of liver disease (injection drug use or alcoholism) and has been associated with variable rates of serum enzyme elevations (0% to 50%), with values above 3 times the upper limit of normal occurring in approximately 1% of patients and occasionally leading to drug discontinuation. However, several studies have found that the rate of alanine aminotransferase (ALT) elevations during naltrexone therapy is similar to that with placebo. Notably, most serum aminotransferase elevations during naltrexone therapy are mild and self-limiting and often resolve even with continuation of therapy. While there have been rare reports of acute, clinically apparent liver disease in patients taking naltrexone, the role of the medication in liver injury has not always been clear. Additionally, no clear description of the clinical features of the injury are given. Overall, while naltrexone has often been considered hepatotoxic, it has not been definitively linked to cases of clinically apparent liver injury. [4]
A recent review published in 2022 discussing treatment of alcohol use disorder in patients with liver disease suggests using naltrexone with caution in cirrhosis patients since the medication is metabolized via the liver. Mild liver injury has been reported in approximately 1% of patients, but there have been no proven cases of clinically apparent liver injury. [5]
A 2025 article examines the utilization of naltrexone for treating AUD in patients with liver disease, highlighting misconceptions surrounding its hepatotoxicity. A comprehensive review of literature up to 2023, including a systematic review of 118 clinical trials with 20,976 participants, corroborates the efficacy of oral naltrexone (50 mg/day) in reducing alcohol consumption, with a number needed to treat (NNT) of 18 for preventing any return to drinking and 11 for heavy drinking. Despite this, only a small fraction of individuals with AUD receive pharmacotherapy in the United States. The findings from a retrospective cohort study of 9,131 Veterans Affairs patients with alcohol-associated cirrhosis reveal improved survival rates associated with naltrexone or acamprosate exposure, with longer medication exposure correlating with further survival benefits. The 2025 discussion extends to the safety of naltrexone, particularly following the FDA's removal of the black box warning for hepatotoxicity in 2013, noting minimal evidence of progression to liver disease. Significant outcomes from the COMBINE trial show only a minimal proportion of participants experiencing liver enzyme elevation on naltrexone without ensuing liver failure. Furthermore, a retrospective analysis of 2,940 Veterans Affairs patients with cirrhosis demonstrated a decrease in liver enzyme levels with naltrexone, with no episodes of liver decompensation or death attributable to the medication. Therefore, the evidence bases for naltrexone's safety include patients with Child-Pugh B cirrhosis, suggesting that hospitalization presents a critical opportunity for intervention, reducing heavy alcohol use, and preventing further liver complications through timely naltrexone initiation. [6]