NALTREXONE — 50 mg tablets (and extended‑release injectable)

Naltrexone is a pure opioid antagonist, structurally related to oxymorphone but with no opioid agonist properties. It was first approved by the FDA in 1984 for the treatment of opioid dependence and later received approval in 1994 for alcohol use disorder. It is available as a 50 mg oral tablet for daily dosing and as a 380 mg extended‑release intramuscular injection (Vivitrol) for once‑monthly administration. Naltrexone is a cornerstone of medication‑assisted treatment for addiction when combined with counseling and social support.

Mechanism of action: Naltrexone acts as a competitive antagonist at opioid receptors, with the highest affinity for mu receptors. It binds to these receptors and blocks them, preventing opioids from producing euphoric effects. In opioid‑dependent individuals, naltrexone precipitates withdrawal symptoms and is therefore contraindicated until complete detoxification. For alcohol use disorder, the exact mechanism is not fully understood, but it is believed that naltrexone blocks the release of endorphins triggered by alcohol, reducing the rewarding effects and craving. Importantly, naltrexone does not cause a disulfiram‑like reaction when combined with alcohol.

Pharmacokinetics: Oral naltrexone is well absorbed (approximately 96% absorbed from the GI tract) but undergoes extensive first‑pass metabolism, resulting in variable oral bioavailability ranging from 5% to 40%. Peak plasma concentrations occur within one hour. It is metabolized primarily to 6‑β‑naltrexol, which also has opioid antagonist activity. The elimination half‑life of naltrexone is 4 hours, while 6‑β‑naltrexol has a half‑life of 13 hours, allowing for once‑daily or less frequent dosing. The extended‑release injectable formulation bypasses first‑pass metabolism and provides therapeutic levels for approximately one month.

Standard vs. low‑dose naltrexone (LDN): At standard doses (50‑100 mg daily), naltrexone fully blocks opioid receptors. Low‑dose naltrexone (LDN, typically 1‑5 mg daily) is an off‑label use that works differently: the transient blockade is believed to paradoxically increase endogenous opioid production and modulate inflammation via toll‑like receptor 4 inhibition. LDN is used investigationally for conditions including fibromyalgia, multiple sclerosis, Crohn’s disease, and various dermatological conditions. These uses are not FDA‑approved and require compounded formulations from specialty pharmacies.

• Patients receiving opioid analgesics.
• Current opioid dependence (including those maintained on methadone, buprenorphine, or LAAM).
• Acute opioid withdrawal.
• Failed naloxone challenge test or positive urine screen for opioids.
• Acute hepatitis or liver failure.
• History of hypersensitivity to naltrexone or any component of the formulation.

• Opioid analgesics (codeine, morphine, oxycodone, fentanyl, tramadol, etc.): Naltrexone blocks their effects and may precipitate withdrawal. Avoid concomitant use. Patients requiring emergency pain management may need alternative non‑opioid analgesia or higher doses of opioids under strict medical supervision.
• Opioid‑containing medications (cough/cold preparations, antidiarrheals): May be ineffective or precipitate withdrawal. Avoid.
• Lofexidine: May decrease naltrexone serum concentration. Monitor for reduced efficacy.
• Disulfiram: Theoretical interaction (both hepatotoxic); use with caution and monitor LFTs closely.
• Thioridazine: Case reports of lethargy and somnolence with concomitant use.
• CYP450 enzyme interactions: Naltrexone does not significantly induce or inhibit CYP enzymes; major interactions via this pathway are unlikely.

• Pregnancy: FDA Category C. No adequate human studies; animal studies show embryotoxicity at high doses. Use only if benefit outweighs risk. Pregnant women with opioid use disorder may benefit from treatment, but naltrexone is not first‑line (methadone or buprenorphine preferred).
• Breastfeeding: Naltrexone and 6‑β‑naltrexol are excreted in breast milk. Considered compatible by some sources, but caution advised. Monitor infant for sedation, poor feeding.
• Pediatric use: Safety and efficacy not established for addiction indications. Limited data for Crohn’s disease (orphan designation) and off‑label LDN use; not approved.
• Geriatric use: No specific problems demonstrated, but elderly may have age‑related hepatic/renal impairment; monitor.
• Hepatic impairment: Contraindicated in acute hepatitis or liver failure. If AST/ALT >3 times ULN, monitor closely and adjust dose or withdraw temporarily. Not studied in severe hepatic impairment.
• Renal impairment: Use caution in moderate‑severe impairment (metabolite accumulates). Not studied in ESRD.

• Liver safety in advanced disease: Recent case series of patients with advanced alcohol‑associated liver disease (including Child‑Pugh A and B cirrhosis) receiving XR‑NTX 380 mg IM monthly showed no hepatotoxicity or hepatic decompensation, with 57% of patients demonstrating reduced alcohol consumption. Mild adverse effects (injection site pain, nausea, fatigue, sexual side effects) occurred in 29%.
• Administration: Must be administered by a healthcare professional as a deep intramuscular injection into the gluteal muscle. Rotate injection sites.
• Injection site reactions: Can be severe, including tissue necrosis, abscess, and hematoma. Report any concerning injection site changes to healthcare provider.

• Symptoms: Nausea, vomiting, diarrhea, abdominal pain, dizziness, depression, anorexia. No specific antidote.
• Management: Supportive care, monitoring of vital signs, activated charcoal if recent ingestion. Monitor for hepatotoxicity. No significant respiratory depression (unlike opioids).