At what level of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevation should naltrexone be suspended?

Guidelines for Suspending Naltrexone Based on AST and ALT Elevations

Naltrexone should be suspended when ALT or AST levels reach ≥5× baseline or ≥500 U/L (whichever occurs first) in patients with elevated baseline liver enzymes, or ≥8× ULN in patients with normal baseline liver enzymes. 1

Discontinuation Criteria Based on Baseline Liver Function

For Patients with Normal Baseline Liver Enzymes (ALT/AST <1.5× ULN):

• Suspend naltrexone when:
  • ALT or AST ≥8× ULN 1
  • ALT or AST ≥3× ULN with total bilirubin ≥2× ULN or INR >1.5 1
  • ALT or AST ≥3× ULN with symptoms (severe fatigue, fever, right upper quadrant pain, nausea, vomiting) 1
  • ALT or AST ≥5× ULN persisting for more than 2 weeks 1

For Patients with Elevated Baseline Liver Enzymes (ALT/AST ≥1.5× ULN):

• Suspend naltrexone when:
  • ALT or AST ≥5× baseline or ≥500 U/L (whichever occurs first) 1
  • ALT or AST ≥2× baseline or ≥300 U/L (whichever occurs first) AND total bilirubin ≥2× ULN 1
  • ALT or AST ≥2× baseline or ≥300 U/L (whichever occurs first) WITH symptoms (severe fatigue, fever, right upper quadrant pain, nausea, vomiting) 1

Monitoring Recommendations

• Obtain baseline liver function tests before initiating naltrexone therapy 2
• Monitor liver enzymes periodically during treatment, especially in the first few months 2
• If ALT/AST levels decrease during treatment (reduction >50% of baseline values), use the new nadir as the new baseline for monitoring decisions 1
• More frequent monitoring (every 2-5 days) is recommended when liver enzymes start to rise 1

Special Considerations

• FDA labeling notes that naltrexone at doses higher than recommended (300 mg/day) has been associated with significant transaminase elevations 2
• In clinical trials, most transaminase elevations occurred in patients with pre-existing liver disease, particularly hepatitis C 3, 4
• Studies have shown that standard doses of naltrexone (50 mg/day oral or 380 mg monthly injectable) are generally safe even in patients with HIV and hepatitis C co-infection 3, 5
• Some studies suggest naltrexone may actually improve liver enzymes in alcoholic patients who reduce their drinking 6, 7

Resumption of Therapy

• Naltrexone can be restarted only if another etiology for liver enzyme elevation is identified and liver enzymes return to baseline 1
• Do not restart naltrexone in patients who had signs or symptoms consistent with hepatic injury or ALT/AST >3× ULN unless another explanation accounts for the liver injury 1

Common Pitfalls to Avoid

• Don't use the same thresholds for patients with normal and abnormal baseline liver enzymes 1
• Don't automatically discontinue naltrexone with mild, asymptomatic elevations in liver enzymes, as this may be transient 1
• Don't ignore symptoms of liver injury even with modest enzyme elevations 1
• Don't fail to consider other causes of liver enzyme elevations, particularly in patients with substance use disorders who may have other risk factors 3, 4