VIENNA — Naltrexone can be safely administered to patients with alcohol use disorder (AUD) and compensated cirrhosis to help them achieve abstinence and decrease craving, results of the first such randomized controlled trial (RCT) show.
After 3 months, 64% of patients who received naltrexone were abstinent from alcohol , compared with 22% of patients who received placebo, Manasa Alla, MD, a hepatologist from the Institute of Liver and Biliary Sciences (ILBS), New Delhi, India, said here at the European Association for the Study of the Liver (EASL) 2023, where she presented the study findings.
Importantly, naltrexone was found to be safe for patients with compensated cirrhosis. “This fragile population of patients has limited drugs to help them quit alcohol. Naltrexone can be a valuable addition to their measures to reduce craving and on their journey to reach de-addiction and abstinence,” Alla, told Medscape Medical News.
Hepatotoxicity with naltrexone is reported to be rare, and data are limited. The US Food and Drug Administration (FDA) previously placed a warning on its use for patients with alcoholic liver disease and underlying cirrhosis.
As a clinician constantly challenged with treating patients with AUD and cirrhosis, Alla wanted to explore the safety of naltrexone and to test its suitability for these patients who struggle to quit alcohol.
“Here we aimed to primarily test the safety of naltrexone in achieving abstinence and reducing alcohol cravings in patients with alcohol-related cirrhosis,” she said, adding, “The FDA black box warning has been removed, but it has never been tested in an RCT in cirrhotic patients, so this is exactly what we did here.
“Naltrexone is a very good anti-alcohol-craving drug,” said Alla. “If we can establish its safety in cirrhotic patients, it may have very good potential in reducing AUD and reducing the related complications of continued alcohol intake.”
Safety, Abstinence, Lapse, and Relapse Assessed
The prospective, double-blind, single-center study at the ILBS, in New Delhi, enrolled 100 patients with alcohol dependence and cirrhosis between 2020 and 2022. Participants were randomly assigned in a 1:1 ratio to receive naltrexone (50 mg/d) or placebo for 12 weeks. All participants attended regular counseling sessions with the resident psychiatrist. At baseline, the biochemical- and drinking-related assessment scores between active and placebo groups of patients with compensated cirrhosis were matched.
Abstinence from alcohol was assessed through self-reported mean number of standard drinks (12 g alcohol per day). Findings were corroborated through an interview with a family member. Serum ethyl glucronide levels were measured in cases of discrepancy, reported Alla. A relapse was considered to be consumption of over four standard alcoholic drinks/month; a lapse was considered any other alcohol drinking event not classified as relapse.
The primary outcome was the proportion of patients who achieved and maintained alcohol abstinence at 12 weeks; secondary outcomes were the proportion of patients who took naltrexone without a liver-related adverse effect compared with placebo at 12 weeks, the number of relapses and lapses, the difference in craving scores on the Obsessive Compulsive Drinking Scale (OCDS) between groups at 4, 8, and 12 weeks and at 6 months and 12 months, and the proportion of patients who achieved and maintained alcohol abstinence at 6 months.
Abstinence at 3 Months
After 3 months, abstinence was noted in 64% of the study population who received naltrexone, compared to 22% of those who received placebo (P < .001). At 6 months, a higher proportion of patients in the naltrexone group achieved abstinence (22% vs 8% with placebo; P = .09).
“We still need to look at the longer-term effects of naltrexone,” Alla pointed out. “Here we gave the drug plus counseling for 3 months only, so despite encouraging findings, we need further studies to understand more.”
The researchers also analyzed the predictors of abstinence at 3 months. They found that patients who consumed fewer than 17 drinks per month at baseline were more likely to achieve abstinence (sensitivity, 81%).
“Our study showed that patients who are consuming less alcohol at baseline can quit alcohol if adequately motivated. We need the motivation, as well as the drug,” Alla noted.
She added that patient counseling was also very important and was provided for the 3 months of the study. “Even in the placebo arm, we had some patients who became abstinent [11/50 patients], but this dropped at 6 months [to 4/50].”
At 12 weeks, 28% in the naltrexone group experienced relapse, vs 72% in the placebo group (P < .001). Regarding the secondary outcome of craving scores and how they were affected by naltrexone, the mean OCDS-O (obsessive element) scores were 6.63, compared with 9.29 in naltrexone and placebo, respectively (P < .01). The mean OCDS-C (compulsive element) scores were 6.34 and 9.02, respectively (P < .01).
“Most important,” said Alla, “was the safety of naltrexone in this study.” There were no significant adverse events in either arm, and only one patient discontinued the drug in the naltrexone arm. Three patients in the naltrexone group who continued alcohol consumption developed jaundice, “so the jaundice can be attributed to continuous alcohol intake and may not be secondary to the naltrexone per se,” she added. “We concluded that naltrexone is safe in a compensated cirrhotic patient.”
Regarding other adverse events, 13.7% of patients experienced gastritis with naltrexone, vs 3.7% among patients who received placebo. Nausea was more common in the placebo group, at 11.1% compared with 6.8% among patients who received naltrexone. Vomiting was more common in the naltrexone arm, at 10.3% vs 7.4% with placebo. None of these differences reached statistical significance.
A longer-term study and comparisons to other drugs would provide valuable insights going forward, Alla told Medscape Medical News.
Moderator Aleksander Krag, MD, professor and head of hepatology at the University of Southern Denmark and Odense University Hospital, Denmark, commented on the study. “Any intervention that can reduce or stop alcohol use in patients with cirrhosis and more advanced cirrhosis will improve outcome as well as reduce complications and mortality,” he said.
“In some cases, alcohol rehabilitation can completely revert the damaged liver. We have lots of data that show that continuous alcohol use at the more advanced stages can be devastating and reduction [in alcohol use] improves outcome. Therefore, any intervention that can help us to achieve this on behalf of all patients is most welcome.”
Naltrexone (ADDTREX) and identical placebos were supplied by Rusan Pharma. Alla has disclosed no relevant financial relationships. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience and has participated in advisory boards for Norgine and Siemens outside the submitted work. He receives royalties from Gyldendal and Echosense.
International Liver Congress (ILC) 2023: Abstract GS-008-YI. Presented on June 23, 2023.
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