What are the potential side effects of Naltrexone, especially in patients with pre-existing liver conditions?

Naltrexone Side Effects

The most common side effects of naltrexone include nausea, constipation, headache, dizziness, insomnia, and dry mouth, while the most serious concern is hepatotoxicity, particularly in patients with pre-existing liver disease. 1

Common Side Effects

Gastrointestinal and neurological symptoms dominate the side effect profile:

• Nausea is the most frequently reported side effect, occurring commonly enough to warrant dose reduction strategies 1
• Constipation affects a significant proportion of patients on naltrexone therapy 1
• Headache and dizziness are common neurological complaints that may impair driving ability 1, 2
• Insomnia and sleep disturbances occur frequently 1
• Dry mouth (xerostomia) is a persistent complaint 1

Serious Safety Concerns

Hepatotoxicity

Naltrexone carries significant risk of liver injury, particularly at higher doses and in patients with underlying liver disease:

• Cases of hepatitis and clinically significant liver dysfunction have been observed in clinical trials and postmarketing surveillance 2
• Transient, asymptomatic hepatic transaminase elevations occur in clinical practice 2
• The FDA has documented that naltrexone can cause hepatocellular injury, especially at doses above the standard 50 mg daily 3, 2
• Liver function tests should be obtained at baseline and monitored every 3-6 months during treatment 1, 4, 3

Hepatotoxicity in Patients with Pre-existing Liver Disease

The evidence regarding naltrexone safety in liver disease has evolved significantly:

• Historically, naltrexone was contraindicated in patients with alcoholic liver disease due to hepatotoxicity concerns 5, 3
• However, recent high-quality evidence from 2022-2025 demonstrates that naltrexone is safe in patients with compensated cirrhosis 6, 7, 8
• A 2022 retrospective cohort of 160 patients showed that those with liver disease, including 47 with cirrhosis, had lower liver enzyme levels after versus before naltrexone prescription 6
• A 2024 study of 3,285 patients with cirrhosis found no cases of drug-induced liver injury using RUCAM scoring, with no deaths or new decompensations attributed to naltrexone 7
• Naltrexone remains contraindicated in patients with acute hepatitis or decompensated cirrhosis 5, 3
• In decompensated cirrhosis, bioavailability increases approximately 10-fold, requiring case-by-case assessment 2, 9

Precipitated Opioid Withdrawal

Naltrexone can trigger severe, potentially life-threatening withdrawal in opioid-dependent patients:

• Patients must be completely opioid-free for a minimum of 7-10 days before starting naltrexone 2
• Patients transitioning from buprenorphine or methadone may be vulnerable to precipitated withdrawal for up to two weeks 2
• Precipitated withdrawal can be severe enough to require hospitalization and intensive care unit management 2
• Symptoms include confusion, somnolence, visual hallucinations, severe vomiting, diarrhea requiring IV fluids, and can appear within 5 minutes of ingestion 2
• All patients, including those being treated for alcohol dependence, must be screened for opioid use before starting naltrexone 2

Psychiatric Effects

Depression and suicidality require monitoring:

• Depression, suicide attempts, and suicidal ideation have been reported in postmarketing surveillance 2
• Bupropion (in the combination naltrexone/bupropion) carries a black box warning for increased suicidal thoughts in young adults under 24 years 1
• Patients and families should be counseled to monitor for emergence of depressive symptoms 2

Cardiovascular Effects

Blood pressure and heart rate monitoring is required:

• Naltrexone/bupropion combination can cause elevated heart rate and blood pressure 1
• The medication should be avoided in patients with uncontrolled hypertension 1
• Long-term cardiovascular safety data for naltrexone/bupropion remains unclear after early termination of outcome trials 1

Critical Contraindications and Drug Interactions

Absolute contraindications include:

• Current opioid use or opioid dependence without adequate opioid-free period 2
• Acute hepatitis or decompensated cirrhosis 5, 3
• Concurrent use with monoamine oxidase inhibitors (for naltrexone/bupropion) 1
• Patients requiring opioid analgesics for pain management 4, 2

Important drug interactions:

• Naltrexone blocks the effects of all opioid-containing medications, including analgesics, antidiarrheals, and antitussives 2
• In emergency situations requiring opioid analgesia, much larger doses may be needed, resulting in deeper and more prolonged respiratory depression 2
• Concomitant use with disulfiram is not ordinarily recommended due to dual hepatotoxicity risk 2
• Lethargy and somnolence have been reported with concurrent thioridazine use 2

Special Populations

Pregnancy and lactation:

• All weight loss medications, including naltrexone, are contraindicated in women who are pregnant or actively trying to conceive 1
• Women of reproductive potential must use reliable contraception 1, 2

Renal impairment:

• Naltrexone and its metabolite are excreted primarily in urine; caution is recommended in renal impairment 2

Overdose Risk After Discontinuation

Patients face increased overdose risk after stopping naltrexone:

• Patients who previously used opioids become more sensitive to lower opioid doses after naltrexone discontinuation 2
• Opioid tolerance decreases during naltrexone treatment, creating risk of accidental overdose if opioids are resumed 4, 2
• Patients and families must be educated about this increased sensitivity and overdose risk 2