LDN

Naltrexone hydrochloride is a long-acting opioid receptor antagonist. FDA-approved products are naltrexone hydrochloride 50 mg oral tablets and naltrexone extended-release injectable suspension (Vivitrol, 380 mg IM monthly); naltrexone is also a component of an approved oral combination with bupropion. Lower oral strengths and topical forms are compounded pursuant to patient-specific prescriptions.

• Oral tablets: treatment of alcohol dependence, and blockade of the effects of exogenously administered opioids, as part of a comprehensive treatment program.
• Extended-release injection: alcohol dependence in patients able to abstain in an outpatient setting, and prevention of relapse to opioid dependence following opioid detoxification.
• Prescribers use compounded low-dose oral naltrexone (LDN, typically well under 50 mg) and topical naltrexone off-label; these uses are not FDA labeled.

Naltrexone competitively antagonizes mu, and to a lesser extent kappa and delta, opioid receptors, blocking the effects of exogenous opioids. At low doses it is hypothesized to cause transient opioid-receptor blockade with a rebound in endogenous opioid signaling and to antagonize toll-like receptor 4 on microglia; these mechanisms are not established. Proposed local actions of topical naltrexone on cutaneous opioid receptors are route-specific and hypothesized.

Oral naltrexone is well absorbed but undergoes extensive first-pass metabolism, with bioavailability of about 5 to 40%. It is metabolized by dihydrodiol dehydrogenase to the active metabolite 6-beta-naltrexol, not by CYP450. Half-life is about 4 hours for naltrexone and about 13 hours for 6-beta-naltrexol; both are excreted mainly in urine. Systemic absorption after topical application has not been well characterized.

• Patients receiving opioid analgesics, or with current physiologic opioid dependence, including those on methadone or buprenorphine.
• Acute opioid withdrawal, a failed naloxone challenge test, or a positive urine screen for opioids.
• Hypersensitivity to naltrexone or any component.
• Topical use only: application to open wounds or actively infected skin, unless the prescriber directs.

• Opioid overdose: attempts to overcome blockade with high opioid doses can cause fatal overdose; after stopping naltrexone or missing doses, reduced opioid tolerance increases overdose risk.
• Precipitated opioid withdrawal can be severe in patients not fully opioid-free; an opioid-free interval of 7 to 10 days (longer for long-acting opioids) is recommended before starting.
• Hepatotoxicity has occurred at doses above those labeled; use caution in hepatic disease and check liver tests if symptoms occur.
• Depression and suicidal thoughts have been reported in naltrexone-treated patients; monitor mood.
• Patients needing opioid analgesia may require regional anesthesia, non-opioid analgesics or monitored high-dose opioids in a setting equipped for resuscitation.
• Extended-release injection: injection-site reactions, eosinophilic pneumonia and hypersensitivity.

Opioid-containing medicines, including analgesics, cough products with codeine, and antidiarrheals such as diphenoxylate, lose their effect. Lethargy and somnolence were reported with thioridazine. Disulfiram and other hepatotoxic drugs add to liver risk.

Oral: nausea, headache, dizziness, fatigue, insomnia or vivid dreams, anxiety, abdominal pain, vomiting and decreased appetite. Low-dose use: sleep disturbance and vivid dreams are commonly reported. Injection: injection-site pain, induration and nodules. Topical: local irritation, redness or itching.

Human data on naltrexone in pregnancy are limited and do not establish a drug-associated risk; use if the prescriber judges benefit outweighs risk. Naltrexone and 6-beta-naltrexol pass into breast milk in small amounts; consider the benefits of breastfeeding with the mother's need for treatment.

Confirm opioid-free status before starting; liver tests at baseline and as clinically indicated; mood and suicidality; adherence and overdose-risk counseling in patients with opioid use disorder; local skin tolerance with topical use.

• Naltrexone Hydrochloride Tablets USP Prescribing Information.
• Revia (naltrexone hydrochloride tablets) Prescribing Information.
• Vivitrol (naltrexone for extended-release injectable suspension) Prescribing Information, Alkermes.