Introduction
Naltrexone is an opioid antagonist medication that has revolutionized the treatment of both alcohol use disorder and opioid use disorder. First approved by the FDA in 1984, this synthetic compound has become a cornerstone in addiction medicine. Unlike opioid agonists that activate opioid receptors, naltrexone blocks these receptors, effectively reducing cravings and preventing the rewarding effects of substance use. Available in both oral and long-acting injectable formulations, naltrexone represents a critical tool in comprehensive addiction treatment programs.
Mechanism of Action
Naltrexone competitively binds to mu-, kappa-, and delta-opioid receptors in the central nervous system. As a pure opioid antagonist, it has no intrinsic agonist activity. By occupying these receptors, naltrexone prevents exogenous opioids from binding and producing their euphoric effects. In alcohol use disorder, naltrexone's mechanism involves modulation of the mesolimbic dopamine pathway, reducing the reinforcing effects of alcohol and diminishing cravings. The drug's action on the endogenous opioid system appears to disrupt the cycle of addiction by interfering with the reward pathway activation that occurs with substance use.
Indications
FDA-approved indications:
- Treatment of alcohol dependence in combination with comprehensive psychosocial support
- Prevention of relapse to opioid dependence following opioid detoxification
Off-label uses (with varying evidence):
- Treatment of impulse control disorders
- Pruritus associated with chronic liver disease
- Autoimmune disorders (investigational)
Dosage and Administration
Oral formulation:- Initial dosing: Typically begins after 7-10 days of opioid abstinence
- Standard maintenance: 50 mg once daily
- Alternative regimen: 100 mg every other day or 150 mg every third day
- 380 mg administered intramuscularly every 4 weeks
- Administered by healthcare professional in the gluteal muscle
- Renal impairment: Use with caution in severe impairment
- Hepatic impairment: Contraindicated in acute hepatitis or liver failure
- Elderly: Consider reduced dosing based on renal/hepatic function
- Pediatrics: Safety and effectiveness not established
Pharmacokinetics
Absorption: Oral naltrexone undergoes significant first-pass metabolism with bioavailability of 5-40%. Peak plasma concentrations occur within 1 hour. The injectable formulation provides sustained release over approximately 4 weeks. Distribution: Widely distributed throughout the body with a volume of distribution of 16.1 L/kg. Protein binding is approximately 21%. Metabolism: Extensively metabolized in the liver primarily via dihydrodiol dehydrogenase to 6-β-naltrexol, which is also pharmacologically active. Elimination: Primarily renal excretion (53-79% of dose). Terminal half-life of naltrexone is approximately 4 hours, while 6-β-naltrexol has a half-life of 13 hours.Contraindications
- Patients receiving opioid analgesics
- Current opioid dependence or positive urine opioid screen
- Acute opioid withdrawal
- Acute hepatitis or liver failure
- History of hypersensitivity to naltrexone or formulation components
- Failed naloxone challenge test
Warnings and Precautions
Hepatotoxicity: Dose-related hepatocellular injury may occur. Monitor liver function tests before initiation and periodically during treatment. Precipitated withdrawal: May cause severe withdrawal symptoms if administered to patients with recent opioid use. Opioid overdose risk: Patients may have reduced tolerance to opioids after naltrexone discontinuation. Depression and suicidality: Monitor for emergence or worsening of depression/suicidal ideation. Eosinophilic pneumonia: Rare but serious complication reported with extended-release formulation.Drug Interactions
Opioid medications: Naltrexone will block the effects of opioid analgesics, anesthetics, and antitussives. Opioid-containing medications: Including some antidiarrheal preparations and cough suppressants. Thioridazine: May potentiate lethargy and somnolence. Disulfiram: Increased risk of hepatotoxicity when combined with naltrexone.Adverse Effects
Common (≥5%):- Nausea (10-33%)
- Headache (7-24%)
- Dizziness (4-13%)
- Nervousness (2-10%)
- Fatigue (4-14%)
- Insomnia (3-11%)
- Hepatotoxicity
- Precipitated opioid withdrawal
- Eosinophilic pneumonia (with injectable form)
- Depression and suicidal ideation
- Injection site reactions (with extended-release formulation)
Monitoring Parameters
- Liver function tests (baseline and at 3-6 month intervals)
- Signs and symptoms of opioid withdrawal
- Treatment adherence and compliance
- Mental status and mood changes
- Injection sites for extended-release formulation
- Alcohol and opioid use through self-report and toxicology screening
- Overall treatment progress and psychosocial functioning
Patient Education
- Naltrexone will block the effects of opioid pain medications; inform all healthcare providers about naltrexone use
- Carry medical identification indicating naltrexone treatment
- Do not attempt to overcome the blockade with large opioid doses due to risk of fatal overdose
- Report any symptoms of liver problems (yellowing skin/eyes, dark urine, abdominal pain)
- Continue participation in counseling and support programs
- Do not stop medication without consulting your healthcare provider
- For injectable formulation, report any breathing difficulties or injection site reactions
- Avoid alcohol consumption during treatment for alcohol use disorder
References
1. FDA Prescribing Information: Naltrexone Hydrochloride Tablets and Vivitrol® 2. Substance Abuse and Mental Health Services Administration. (2018). Naltrexone. 3. Jonasson U, et al.. Addiction. 2000;95(7):1049-1061. 4. Garbutt JC, et al. Effects of naltrexone on alcohol dependence. JAMA. 2005;293(13):1617-1625. 5. Lee JD, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention. Lancet. 2018;391(10118):309-318. 6. National Institute on Drug Abuse. (2020). Principles of Drug Addiction Treatment: A Research-Based Guide. 7. American Psychiatric Association. (2018). Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder.
