Abstract
Background and aims
Naltrexone is a promising drug to treat alcohol use disorder with limited evidence of safety in liver diseases. An observational study was performed to study the safety, effectiveness, and tolerability of Naltrexone in the management of alcohol use disorder in patients with alcohol-associated cirrhosis.
Methods
Naltrexone was started in patients with alcohol-related liver disease for the management of alcohol use disorder in 86 patients who were followed up for 4 weeks. Baseline liver parameters were compared with those at 4 weeks to establish safety of the drug. Effectiveness was determined by observing reduction in AUDIT scores, craving, number and days of drinking. Self-report of side effects was noted.
Results
After 4 weeks of starting Naltrexone there was a decrease in AST-89.86 vs 57.61, ALT-50.19 vs 27.08, SAP-121.81 vs 98.19, GGT-166.93 vs 109 and MELD 16.32 vs 12.13 (none statistically significant). There was a statistically significant reduction in Serum Bilirubin- (4.31 vs 1.98), INR (1.49 vs 1.32), self-reported craving (3.71 Vs 1.97; P = 0.01), AUDIT scores (24.13 Vs 16.91; P <0.01) and number of drinking days in last one month (10.22 Vs 4.19; P = 0.03).
Conclusion
The reduction in all liver parameters and AUDIT scores and craving after treatment with Naltrexone supports its safety and utility in the management of alcohol use disorder in alcohol-related liver cirrhosis.
Keywords: naltrexone safety in alcohol associated cirrhosis, naltrexone effectiveness in alcohol associated cirrhosis, naltrexone for management of alcohol use disorder in liver cirrhosis
Alcohol consumption is a significant risk factor for cirrhosis of the liver and the associated mortality has been on the rise in recent years.1 Furthermore, continued ethanol use in patients with alcohol-associated liver cirrhosis is an important factor determining the progression of liver disease, its complications while abstinence improves survival.2,3 So, achieving and maintaining abstinence is the most important step in managing patients with alcohol-associated cirrhosis. A longitudinal cohort study comprising 9635 patients with alcohol dependence but no cirrhosis, found that pharmacotherapy for AUD was associated with a reduction in the occurrence of alcohol-induced liver disease. The most evident risk reduction was with the use of Naltrexone, Gabapentin, and Topiramate. Additionally, treatment with Naltrexone and Gabapentin also decreased the chances of decompensation in patients with cirrhosis.4
Naltrexone was approved in 1994 by the Food and Drug Administration (FDA) for the management of alcohol use disorders and has been proven to decrease relapse to heavy drinking and total alcohol consumption in patients without liver cirrhosis. Naltrexone acts as an antagonist on μ, κ, and δ-receptors and blocks the rewarding effects of alcohol, a phenomenon linked to the release of beta-endorphins.5 Common adverse effects include nausea, vomiting, abdominal pain, reduced appetite, dizziness, and insomnia. Hepatic dysfunction has been considered a relative contra-indication for the use of Naltrexone, but the evidence comes from a limited number of clinical reports.6 Although in the past, FDA issued a Black Box warning for (both oral and intramuscular) Naltrexone stating that excessive doses can cause hepatocellular injury and that it could not be given in acute hepatitis or liver failure. But recently Thompson et al. 2024 reported, through a study of 3285 patients, that if prescribed at the recommended doses, Naltrexone is safe in patients with cirrhosis (both compensated and decompensated)7 and8 and the warning has now been removed.
Even though there have been studies proving liver safety of Naltrexone in patients with alcohol use disorder, there is still apprehension amongst the clinicians regarding its use,9 especially in the presence of cirrhosis. Hence, we present the first Indian data to assess the safety and utility of Naltrexone in cirrhosis patients with continued alcohol consumption.
METHODS
Enrolment and Data Collection
Records of all consecutive patients with alcohol-associated cirrhosis; with continued alcohol consumption in till the month prior to hospital visit; who were started on Naltrexone (50 mg/day) between 15th December 2019 and 15th February 2020 were included in the current study. Naltrexone was started after acute withdrawal management (commonly known as ‘detoxification’) was completed. For safety, protocol data were collected from patients' blood reports and side effects using specially designed semi-structured proforma including clinical and biochemical parameters for this review. For efficacy data on AUDIT scores, alcohol use parameters and cravings were collected (based on self-report). For measurement of craving, a 5 point likert's scale was utilized at every follow-up (Visual Analog Scale). These scores are routinely calculated in patients with cirrhosis under Alcohol use disorder treatment at the Institute of Liver and Biliary Sciences' AUD clinic (outpatient-based). Inclusion criteria for starting Naltrexone were: patients who had failed abstinence with up to 30 mg/day of Baclofen (as part of routine clinical practice for AUD management); consumption of Alcohol (after diagnosis of liver disease) in the last 1 month. This is erroneously referred as “recidivism” in clinical practice.10 Liver decompensation (in the form of: presence of jaundice, ascites, hepatic encephalopathy) in the 2 months prior to inclusion was considered a contraindication to the initiation of Naltrexone (Exclusion criteria) Patients on any other medication for AUD were not included in this analysis. Family members' corroboration is part of the treatment protocols at the clinic. Adherence to therapy was documented from the outpatient prescription records on follow-up.
Outcome Assessment
This study was first conducted as a clinical pilot in the world DBRCT of Naltrexone in cirrhosis (IEC/2020/76/NA04). The following records were analyzed for the purpose of this study: (i) Socio-demographic parameters like age and sex; (ii) Liver disease parameters: CTP and MELD scores, Liver function tests (Serum Bilirubin, AST, ALT, SAP, GGT, and INR); and (iii) parameters related to Alcohol use disorders: AUD severity, AUDIT scores, Co-morbid psychiatric conditions, and quantitative alcohol consumption. AUD was defined based on standard DSM-5.0 definitions.11 The AUDIT has 10 questions and the possible responses to each question are scored 0, 1, 2, 3, or 4, with the exception of questions 9 and 10 which have possible responses of 0, 2 and 4. The range of possible scores is from 0 to 40 where 0 indicates an abstainer who has never had any problems from alcohol. A score of 1–7 suggests low-risk consumption according to World Health Organization (WHO) guidelines. Scores from 8 to 14 suggest hazardous or harmful alcohol consumption and a score of 15 or more indicates the likelihood of alcohol dependence (moderate-severe alcohol use disorder). Patients were explained about the need for AUD treatment and Naltrexone was initiated after their consent. Clinical records like other medications used for withdrawal management were noted as well.
Statistical Analysis
Records were entered in an MS Excel sheet and data was analyzed using SPSS v 25. The comparison of pre- and post-intervention liver and AUD-related parameters was done using paired t-test with two-tailed P value (P < 0.05 being considered significant).
RESULTS
The patients, who required any form of benzodiazepines even after withdrawal management was completed, were removed from the analysis (14/100) and hence results for 86 patients are being presented. The data of 86 patients were collected after screening 100 patients while attending outpatient services and followed up for a minimal duration of 4 weeks. There was a male preponderance (M: F = 83:3) with a mean age of 41.03 (±8.56) years. Most patients who were started on Naltrexone were CTP A (75%) and CTP B (22%). The majority had moderate (54.7%) to severe (32.5%) Alcohol use disorder based on DSM-5 criteria, with a mean AUDIT score of 24.13 (±5.04) and mean craving of 3.71 on a 5-point Likert's scale at baseline. 23 patients were smoking tobacco, 12 used smokeless tobacco, and 20 were using both forms. 27 patients had a comorbid anxiety disorder, 14 patients had depressive disorder, and 1 had other psychiatric illnesses (Table 1).
Table 1.
Baseline Data of Patients With Liver Cirrhosis and AUD.
| Parameters (N = 86) | Mean (±SD)/Median Interquartile range (IQR) | Frequency (percentage) | |
|---|---|---|---|
| Age (years) | – | 41.03 (±8.56) 45 (38–49) |
– |
| Baseline Liver status (CTP) | CTP A | 65 (75.61) | |
| CTP B | 19 (22.08) | ||
| CTP C | 2 (2.31) | ||
| MELD score | 16.62 (±7.69) | ||
| AUD severity (DSM-5) | Mild | 11 (12.8) | |
| Moderate | 47 (54.7) | ||
| Severe | 38 (32.5) | ||
| AUDIT score (range) | 24.13 (±5.04) | – | |
| Comorbid TUD | Smoking | 23 (26.76) | |
| Smokeless | 12 (13.95) | ||
| Combined | 20 (23.25) | ||
| None | 31 (36.04) | ||
| Comorbid psychiatric disorder | Anxiety | 27 (31.39) | |
| Depression | 14 (16.29) | ||
| Others | 1 (1.26) | ||
| None | 44 (51.16) | ||
∗HE- Hepatic encephalopathy; UGI- Upper gastro-intestinal; CTP-Child-Turcotte-Pugh; MELD-Model for End-stage Liver Disease; AUD- Alcohol Use Disorder; AUDIT- Alcohol use disorder identification test; TUD-Tobacco Use Disorder.
Safety
After 4 weeks of naltrexone (50 mg oral per day, monitored by family members), there was a decrease in all parameters, mean values pre and post-treatment being AST- 89.86 vs 57.61, ALT- 50.19 vs 27.08, SAP-121.81 vs 98.19, GGT-166.93 vs 109 (none statistical significance). There was a statistically significant reduction in Serum Bilirubin- (4.31 vs 1.98) and INR (1.49 vs 1.32). Moreover, there was a decrease in MELD score (16.32 vs 12.13; P = 0.41) but it could not achieve statistical significance.
Effectiveness
There was also a statistically significant improvement in self-reported craving (3.71 Vs 1.97; P = 0.01), AUDIT scores (24.13 Vs 16.91; P < 0.01), and number of drinking days in the last one month (10.22 Vs 4.19; P = 0.03). In none of the patients, Naltrexone had to be stopped due to severe side effects or new onset of Jaundice/worsening ascites. Although specific side effect profile was not found in clinical records. All patients received relapse prevention session as a part of routine clinical practice. At follow-up for liver disease-related visits, 77 (out of 86) reported abstinence from alcohol (Table 2, Table 3).
Table 2.
Safety of Naltrexone in Liver Cirrhosis With AUD.
| Parameter (N = 86) | Baseline (±SD) | Post Naltrexone (±SD) | P-value |
|---|---|---|---|
| AST (IU/L) | 89.86 (±51.52) | 57.61 (±26.61) | 0.17 |
| ALT (IU/L) | 50.19 (±22.14) | 27.08 (±10.55) | 0.10 |
| SAP (IU/L) | 121.81 (±20.29) | 98.19 (±30.96) | 0.15 |
| GGT (IU/L) | 166.93 (±133.54) | 139.88 (±73.38) | 0.26 |
| S. Bilirubin (mg/dl) | 4.31 (±3.24) | 1.98 (±1.25) | <0.01 |
| INR | 1.49 (±0.46) | 1.32 (±0.33) | <0.01 |
| MELD | 16.32 (±5.77) | 12.13 (±1.23) | 0.41 |
∗AST-Aspartate Aminotransferase; ALT-Alanine Aminotransferase; SAP- Serum Alkaline Phosphatase; GGT- Gamma-glutamyl Transferase, PT/INR- Prothrombin Time/International Normalized Ratio; MELD-Model for End-stage Liver Disease.
Table 3.
Effectiveness of Naltrexone for Alcohol Use Disorder in Liver Cirrhosis.
| Parameter (N = −86) | Baseline (±SD) | Post Naltrexone (±SD) | P value |
|---|---|---|---|
| AUDIT score | 24.13 (±4.81) | 16.91 (±4.30) | <0.01 |
| Average amount of alcohol consumed in 1 day in the last 1 month (g/day) | 75.29 (±18.72) | 27.22 (±12.33) | <0.01 |
| Average number of drinking days in last 1 month | 10.22 (±4.69) | 4.19 (±3.35) | 0.03 |
| Craving for alcohol (using VAS) | 3.71 (±0.69) | 1.97 (±0.24) | 0.01 |
∗VAS: Visual analog scale; AUDIT: Alcohol use disorder identification test.
Discussion
Our retrospective analysis indicated that Naltrexone at 50 mg oral dose per day is safe to use for AUD in patients with cirrhosis for a 4 week period. Recently, there has been an increasing amount of data on the efficacy of pharmacotherapy (for AUD) in liver cirrhosis patients and subsequent improvement in liver disease outcomes in both the short and long term.4,12 Naltrexone has shown promise in this group of patients for better liver health outcomes13 and our observation would guide in utilizing the same for Indian patients where high-resource addiction treatment has lesser reach.14
In our study, the majority of the sample population comprised males as has been seen in previous studies.15 This is due to the higher prevalence of alcohol dependence in males and lesser treatment seeking in females due to more stigmas associated with substance use disorders in women. The mean age of 41.03 years is comparable to that observed in previous studies.16 42 patients had a dual diagnosis with anxiety and depression being the two most prevalent comorbid psychiatric disorders. But none of them were on antidepressant medications. Other studies conducted to estimate the prevalence of dual diagnosis have also found anxiety and affective illness to be common in people suffering from substance use disorders.17
To establish the safety of Naltrexone in patients with liver cirrhosis values of liver enzymes were recorded at baseline and thereafter at 4 weeks from starting Naltrexone. Mean AST and ALT values showed no increase post-treatment with Naltrexone thus hinting towards the safety of Naltrexone in patients with liver cirrhosis. Other studies present in the literature have also concluded the same (6).18,19 There was reduction in SAP, MELD score, GGT, and serum Bilirubin levels as well which rules out the hepatotoxicity of Naltrexone. Similar results have been found in previous studies.15,20 In a study to assess the safety profile of Naltrexone, 865 patients with alcohol dependence were enrolled of which 570 received Naltrexone and 295 were in the reference group. Alanine aminotransferase (ALT) values at baseline and then weekly up to 12 weeks did not differ between the groups.15 In another study, in patients with normal and elevated baseline aspartate aminotransferase (AST) and ALT values, a greater reduction in the transaminases was seen with50 mg of Naltrexone.21 COMBINE trial was a multi-centric study performed on 108 subjects with alcohol use disorder (without pre-existing liver disease), in which no worsening was noted in AST, ALT, and serum bilirubin levels after 16 weeks of treatment with Naltrexone.18 In patients (n = 53) of opioid dependence receiving Naltrexone for 12 weeks (up to 350 mg/week), a significant reduction was seen in the levels of LDH and AST and this decrease was most notable for those with raised hepatic enzyme levels before initiation of pharmacotherapy with Naltrexone.20 Prolonged high doses of up to 150 mg/day have also been found to have no hepatotoxic effect in patients with impulse control disorder if NSAID use is restricted.22 Similar results were found in many studies on the liver safety in patients without cirrhosis (14,15,16). The reduction in alcohol use and the fact that almost 90% patients stopped alcohol consumption during the 4-week period, could also have contributed to the reduction in liver enzymes.
The average number of drinking days in the last 1 month and AUDIT score showed a statistically significant reduction after 4 weeks of treatment with Naltrexone. The amount of alcohol consumed in 1 day in the last 1 month also showed a decrease. Similar results have been observed in previous studies in which the efficacy of Naltrexone has been established through a reduction in heavy drinking, although the studies were carried out in subjects with no liver impairment.16,23 The craving as quantified by VAS also decreased significantly in the subjects which is in keeping with the other studies in which the craving reduction on Naltrexone was quantified by using Obsessive Compulsive Drinking Scale (OCDS).16,23
There were some inherent limitations of the study as it was an analysis of a single-center data using a limited non-randomized sample. Future studies can be planned using a multi-centric prospective design for better generalizability and substantive conclusions. Subjective markers like history given by the patient and family's corroboration were used to ensure abstinence and compliance with medications. For more accuracy, objective markers (like EtG and PeTH) for confirming abstinence could have been applied. Patients with failed abstinent attempts were also included and there was no comparison arm. The limited duration of data analysis was also a limitation. Adherence to therapy was documented from the outpatient prescription records on follow-up. Being a retrospective nature of the study, placebo effect could not be addressed. Our main objective of the study was to document the safety and possible efficacy of Naltrexone in patients with compensated alcohol-associated liver cirrhosis with continued alcohol use disorder. This can form the background for the formulation of randomized placebo-controlled trials in the future.
But despite these limitations, this study is the first of its kind to be conducted in the Indian population that gives a review of the real-world clinical data. It would be a major stepping stone in the treatment of alcohol use disorder in patients with liver cirrhosis as appropriate pharmacotherapy can be both life-changing and lifesaving in these patients. There is a need for controlled experimental studies in stable cirrhotic patients in future studies.
Credit authorship contribution statement
Study design- Dr. Mohit Varshney, Dr. Shasthry SM.
Sample collection and analyses- Dr. Mohit Varshney, Dr. Vinod Arora.
Interpretation of results- Dr. Mohit Varshney, Dr. Shasthry SM, Dr. Apinderjit Kaur.
Drafting the manuscript- Dr. Apinderjit Kaur, Dr. Mohit Varshney.
Final revision of manuscript- Dr. S.K. Sarin, Dr, Mohit Varshney, Dr Shasthry SM, Dr. Apinderjit Kaur, Dr, Vinod Arora.
Funding source
The authors declare no source of funding for this study. It was done as part of routine clinical observation at Alcohol use disorder clinic at ILBS, New Delhi.
Declaration of competing interest
The authors have no conflicts of interest to declare.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jceh.2024.102447.
Supplementary data
The following are the Supplementary data to this article:
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