Is monotherapy naltrexone (Naltrexone) a suitable treatment option for an adult patient with Alcohol Use Disorder (AUD) and a stable medical history, without severe liver disease or other contraindications?

Naltrexone Monotherapy for Alcohol Use Disorder

Naltrexone monotherapy is an appropriate and FDA-approved first-line treatment option for adults with AUD who have stable medical histories without severe liver disease, though it should ideally be combined with psychosocial interventions for optimal outcomes. 1

FDA Approval and Efficacy

• Naltrexone is one of three FDA-approved medications for AUD treatment, alongside disulfiram and acamprosate 2
• The standard dosing is 50 mg once daily orally (or 380 mg monthly intramuscular injection), which has demonstrated efficacy in 12-week placebo-controlled trials 1
• Naltrexone reduces the likelihood of return to any drinking by 5% and binge-drinking risk by 10% in randomized clinical trials 3
• The number needed to treat (NNT) is approximately 20 to prevent return to any drinking, compared to 12 for acamprosate 2

Mechanism and Clinical Application

• Naltrexone works as an opioid receptor antagonist that competitively binds to opioid receptors and blocks the effects of endogenous opioids, thereby reducing alcohol consumption 1
• The drug is not aversive therapy and does not cause a disulfiram-like reaction with alcohol ingestion 1
• Treatment duration in efficacy trials was 12 weeks, though clinical use may vary based on individual response 1

Critical Safety Considerations for Liver Disease

Hepatotoxicity Concerns

• Naltrexone undergoes hepatic metabolism and carries theoretical hepatotoxicity concerns 2
• The American Association for the Study of Liver Diseases notes that naltrexone has NOT been studied in patients with alcoholic liver disease (ALD), particularly those with alcoholic hepatitis or cirrhosis 2
• Disulfiram and naltrexone can cause liver damage, whereas acamprosate has no hepatic metabolism 2

Recent Safety Data (2022)

• A retrospective cohort study found that naltrexone is safe in patients with underlying liver disease, including compensated cirrhosis 4
• Patients with liver disease (including 47% with cirrhosis) had lower liver enzyme levels after versus before naltrexone prescription (p < 0.001) 4
• Two-year survival rates were 90.8% in cirrhosis patients and 81.3% in decompensated cirrhosis patients, though the study notes more safety data are needed for decompensated cirrhosis 4
• Shorter duration of naltrexone prescription (≤30 days) was an independent predictor of subsequent hospitalization (HR 2.50), suggesting longer treatment courses are beneficial 4

Clinical Algorithm for Naltrexone Use

Patient Selection Criteria

Appropriate candidates:

• Adults with AUD diagnosis (moderate to severe) 3
• Stable medical history without severe/decompensated liver disease 4
• Must be opioid-free for minimum 7-10 days before starting (including tramadol) 1
• No current opioid dependence or need for opioid pain medications 1

Relative contraindications:

• Severe hepatic impairment or decompensated cirrhosis (use with extreme caution and close monitoring) 2, 4
• Current opioid use or dependence 1
• Acute hepatitis 1

Pre-Treatment Assessment

• Perform naloxone challenge test if any question of occult opioid dependence exists 1
• Check baseline liver function tests (AST, ALT) 4
• Verify urine is negative for opioids 1
• Ensure no clinical signs of opioid withdrawal 1

Dosing Protocol

• Start with 25 mg on day 1 to assess tolerance 1
• If no withdrawal signs occur, advance to 50 mg once daily 1
• Alternative supervised dosing: 50 mg every weekday with 100 mg on Saturday, or 100 mg every other day, or 150 mg every third day 1
• Continue for at least 12 weeks, though longer duration (>30 days) is associated with better outcomes 1, 4

Integration with Psychosocial Treatment

• Naltrexone should be part of a comprehensive treatment program that includes psychosocial interventions 1
• The American Association for the Study of Liver Diseases emphasizes that integrating AUD treatment with medical care is the best option, though pharmacotherapy alone has demonstrated efficacy 2
• Available psychosocial modalities include cognitive-behavioral therapy (CBT), motivational enhancement therapy (MET), motivational interviewing, and mutual aid societies 2

Common Pitfalls to Avoid

• Do not initiate naltrexone in patients currently using opioids or who have not completed adequate opioid-free period (7-10 days minimum), as this can precipitate severe withdrawal 1
• Avoid use in patients with acute hepatitis or severe decompensated cirrhosis without careful risk-benefit assessment and close monitoring 2, 4
• Do not prescribe for less than 30 days without clear rationale, as shorter treatment duration is associated with worse outcomes 4
• Do not rely on medication alone—compliance-enhancing techniques and psychosocial support improve outcomes 1
• Monitor liver function tests during treatment, particularly in patients with pre-existing liver disease 4

Comparison with Alternative Medications

• Acamprosate has no hepatic metabolism and may be preferred in patients with significant liver disease, though it requires three-times-daily dosing (666 mg TID) 2, 5
• Baclofen is the only AUD medication studied in RCT for cirrhosis patients, showing benefit in both compensated and decompensated cirrhosis 2
• Topiramate shows consistent evidence for reducing drinking frequency and heavy drinking, though not FDA-approved for AUD 6

Underutilization in Clinical Practice

• Despite FDA approval and guideline recommendations, medications are prescribed to less than 9% of patients who would benefit 3
• Naltrexone use tripled from 0.53% in 2015 to 1.64% in 2018 among AUD admissions, but remains severely underutilized 7
• Both oral and injectable formulations are feasible to initiate in various settings, including prior to hospital discharge 8