What is the rationale for using naltrexone (Naltrexone) in the treatment of alcohol use disorder?

Rationale for Naltrexone in Alcohol Use Disorder

Naltrexone is a pure opioid antagonist that reduces alcohol consumption by blocking opioid receptors in the brain's reward pathway, thereby decreasing alcohol craving and the euphoric effects of drinking. 1

Neurobiological Mechanism

• Naltrexone works by competitively antagonizing mu opioid receptors, which dampens the activation of the dopamine-mediated reward pathway that is stimulated by alcohol consumption 2, 3
• By blocking these opioid receptors, naltrexone reduces the reinforcing effects of alcohol, making drinking less rewarding and decreasing the craving for continued use 1, 4
• Unlike disulfiram, naltrexone is not aversive therapy and does not cause a disulfiram-like reaction with alcohol ingestion 1

Clinical Efficacy Evidence

Naltrexone has demonstrated superior efficacy compared to placebo across multiple measures of drinking behavior in controlled trials. 1

• In a pivotal trial of 104 alcohol-dependent patients, naltrexone 50 mg daily achieved abstention rates of 51% versus 23% with placebo, and relapse rates of 31% versus 60% 1
• A second trial with 82 patients showed lower relapse rates (21% vs 41%), reduced alcohol craving, and fewer drinking days compared to placebo 1
• Extended-release naltrexone reduces drinking days by 2.0 days per month and heavy drinking days by 1.2 days per month compared to placebo, with larger reductions seen in trials lasting longer than 3 months 5
• Naltrexone supported abstinence, prevented relapse, and decreased alcohol consumption in clinical studies, though it was not uniformly helpful to all patients 1

Role in Comprehensive Treatment

Naltrexone should only be used as an adjunct to comprehensive psychosocial treatment, not as monotherapy. 6, 1

• The American Association for the Study of Liver Diseases recommends that naltrexone or acamprosate may be considered in combination with counseling to decrease the likelihood of relapse in patients who achieve abstinence 6
• Clinical trials demonstrating efficacy used naltrexone 50 mg daily for 12 weeks as an adjunct to social and psychotherapeutic methods under conditions that enhanced patient compliance 1
• Naltrexone is expected to have therapeutic effect only when given under external conditions that support continued medication use, as it does not reinforce compliance like opioid agonist therapies 1

Practical Dosing and Administration

• The standard dose is 50 mg once daily, which produces adequate clinical blockade of opioid effects 1
• Alternative supervised dosing schedules include 50 mg every weekday with 100 mg on Saturday, 100 mg every other day, or 150 mg every third day 1
• Extended-release injectable naltrexone (Vivitrol) 380 mg monthly is also FDA-approved and may improve compliance 3

Critical Safety Considerations and Contraindications

Naltrexone has been shown to cause hepatocellular injury and is not recommended in patients with alcoholic liver disease. 6, 2

• The European Association for the Study of the Liver states that naltrexone has not been tested in patients with cirrhosis and its use in this population is not recommended due to potential hepatotoxicity 6
• Liver function tests should be monitored at baseline and every 3-6 months during treatment 2, 3
• Patients must be completely opioid-free for a minimum of 7-10 days before starting naltrexone to avoid precipitating severe withdrawal 1
• Naltrexone cannot be used in patients requiring opioids for pain control, as it blocks pain relief from opioid agonists 2, 3

Alternative Medications for Patients with Liver Disease

• For patients with alcoholic liver disease requiring pharmacotherapy, baclofen represents the only alcohol pharmacotherapy tested in alcoholics with significant liver disease and may be a better alternative 6, 2
• Acamprosate may also be considered as an alternative, particularly for patients with liver concerns, as it helps reduce withdrawal symptoms and maintain abstinence 6, 2

Common Pitfalls to Avoid

• Do not initiate naltrexone in patients with any degree of alcoholic liver disease due to hepatotoxicity risk 6, 2
• Do not start naltrexone without confirming adequate opioid-free period, as precipitated withdrawal can be severe 1
• Do not use naltrexone as monotherapy; it requires integration with comprehensive psychosocial support to be effective 6, 1
• Do not expect uniform success; naltrexone produces modest improvement in conventional treatment outcomes and requires compliance-enhancing strategies 1