Naltrexone

Uses

Naltrexone is used for the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids. Naltrexone has not been shown to provide any therapeutic benefit except as part of an appropriate plan of management for the addictions.

Naltrexone is also used to associated treatment for these conditions: Alcohol Dependency, BMI >30 kg/m2, Cholestatic pruritus, Opioid Dependence, Severe Pain

How Naltrexone works

Naltrexone is a pure opiate antagonist and has little or no agonist activity. The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone is thought to act as a competitive antagonist at mc, κ, and δ receptors in the CNS, with the highest affintiy for the μ receptor. Naltrexone competitively binds to such receptors and may block the effects of endogenous opioids. This leads to the antagonization of most of the subjective and objective effects of opiates, including respiratory depression, miosis, euphoria, and drug craving. The major metabolite of naltrexone, 6-β-naltrexol, is also an opiate antagonist and may contribute to the antagonistic activity of the drug.

Dosage

Naltrexone dosage

Opioid dependence:

• Initially:25 mg; increase to 50 mg daily if no withdrawal signs occur.
• Maintenance: 350 mg wkly given as 50 mg daily or divided in 3 doses (given on 3 days of the wk) for improved compliance.

Adjunct in alcohol dependence: 50 mg daily.

Side Effects

Abdominal pain, nausea, vomiting; anxiety, insomnia, lethargy, headache, musculoskeletal pain; anorexia, diarrhoea, constipation; increased thirst; chest pain; chills, dizziness; sexual dysfunction; rash, liver function abnormalities and reversible idiopathic thrombocytopenia. Inj-site reactions.

Toxicity

In the mouse, rat and guinea pig, the oral LD₅₀s were 1,100-1,550 mg/kg; 1,450 mg/kg; and 1,490 mg/kg; respectively. High doses of naltrexone (generally >1,000 mg/kg) produce salivation, depression/reduced activity, tremors, and convulsions.

Precaution

Hepatic or renal impairment. Monitor LFTs regularly. Patients should be opioid-free for at least 7-10 days prior to initiating naltrexone therapy. Strictly warn patients against the use of opioids while on naltrexone. Monitor for inj-site reactions. Pregnancy, lactation. History of bleeding disorders (including thrombocytopenia).

Interaction

May reduce effects of opiate-containing preparations e.g. those used for cough and cold, diarrhoea and pain. Increased or decreased serum levels with drugs that alter hepatic metabolism. Potentially increased hepatotoxic effects with disulfiram. Increased risk of naltrexone-induced lethargy and somnolence with thioridazine. May increase insulin requirements.

Food Interaction

• Take with or without food. The absorption is unaffected by food.

Naltrexone Alcohol interaction

[Moderate] GENERALLY AVOID:

Coadministration of naltrexone with other agents known to induce hepatotoxicity may potentiate the risk of liver injury.

Naltrexone, especially in larger than recommended doses (more than 50 mg/day), has been associated with hepatocellular injury, hepatitis, and elevations in liver transaminases and bilirubin.

Other potential causative or contributory etiologies identified include preexisting alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other hepatotoxic drugs.

The use of naltrexone with other potentially hepatotoxic agents should be avoided whenever possible (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice).

Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.

Periodic monitoring of hepatic function is advisable.

Naltrexone Drug Interaction

Moderate: duloxetine, bupropionUnknown: aripiprazole, amphetamine / dextroamphetamine, diphenhydramine, omega-3 polyunsaturated fatty acids, clonazepam, lamotrigine, escitalopram, pregabalin, fluoxetine, quetiapine, topiramate, cyanocobalamin, ascorbic acid, cholecalciferol, lisdexamfetamine, alprazolam, sertraline, cetirizine

Naltrexone Disease Interaction

Major: hepatic dysfunctionModerate: hepatic/renal dysfunction

Volume of Distribution

• 1350 L [intravenous administration]

Elimination Route

Although well absorbed orally, naltrexone is subject to significant first pass metabolism with oral bioavailability estimates ranging from 5 to 40%.

Half Life

4 hours for naltrexone and 13 hours for the active metabolite 6 beta-naltrexol.

Clearance

• ~ 3.5 L/min [after IV administration]

Elimination Route

Both parent drug and metabolites are excreted primarily by the kidney (53% to 79% of the dose), however, urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose and fecal excretion is a minor elimination pathway. The renal clearance for naltrexone ranges from 30 to 127 mL/min and suggests that renal elimination is primarily by glomerular filtration.

Pregnancy & Breastfeeding use

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Patients concurrently dependent on opioids; acute hepatitis or hepatic failure; acute opioid withdrawal; patients on therapeutic opioid analgesics.

Acute Overdose

Symptoms: Clonic-tonic convulsions and respiratory failure.

Management: Supportive and symptomatic.

Storage Condition

Store at 20-25° C.

Innovators Monograph

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