ADDTREX

Indications

• Opioid dependence
• Alcohol use disorder
• Management of opioid overdose (as part of a comprehensive treatment strategy)

Dosage

Children: Refer to BNF for Children for appropriate dosing in children and adolescents.

Adults: Refer to BNF for specific dosing guidelines. Typical adult dose for alcohol dependence is 50 mg once daily.

Mechanism of action

Naltrexone acts as a competitive antagonist at mu (μ), kappa (κ), and delta (δ) opioid receptors in the central nervous system, with the highest affinity for the μ receptor. By binding to these receptors, naltrexone prevents the activation of opioid receptors by endogenous opioids, thereby attenuating the effects of opioid drugs, including euphoria and respiratory depression. The major metabolite, 6-β-naltrexol, also possesses antagonist properties, contributing to the overall effects of the drug.

Pharmacodynamics

As a pure opioid antagonist, naltrexone significantly reduces or completely blocks the subjective effects associated with opioid use, including euphoria and craving. It is particularly useful in preventing relapse in individuals recovering from opioid addiction, as it can precipitate withdrawal symptoms in those who are physically dependent on opioids, thus discouraging continued use.

Pharmacokinetics

Naltrexone is well-absorbed after oral administration, with peak plasma concentrations typically reached within one hour. It undergoes extensive first-pass metabolism in the liver, primarily to its active metabolite, 6-β-naltrexol. The elimination half-life of naltrexone is approximately 4 hours, while that of 6-β-naltrexol is longer, supporting prolonged receptor antagonism. Both naltrexone and its metabolite are excreted primarily in urine.

Adverse effects

• Nausea
• Vomiting
• Headache
• Dizziness
• Fatigue
• Anxiety
• Insomnia
• Abdominal pain
• Myalgia

Interactions

• naltrexone+opioids: Unknown (decreases efficacy)

Precautions

• Use with caution in patients with liver impairment.
• Monitor for signs of opioid withdrawal in opioid-dependent patients when initiating treatment.

Pregnancy

Naltrexone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether naltrexone is excreted in human milk. Caution should be exercised when administering to nursing women.

Storage

Store at room temperature, away from light and moisture.

Formulations

• Oral tablet

Indications

• Opioid dependence
• Alcohol dependence
• Adjunct to prevent relapse in formerly opioid-dependent patients

Dosage

Adults: Initially, 25 mg daily, then increased to 50 mg daily. The total weekly dose may be divided and given on 3 days of the week for improved compliance.

Mechanism of action

Naltrexone works by competitively inhibiting opioid receptors, particularly the mu-opioid receptor. This action blocks the euphoric and sedative effects of opioid drugs, thereby reducing the reinforcing effects that can lead to opioid misuse. It also modulates the reward pathway associated with alcohol consumption, helping to decrease cravings and consumption.

Pharmacodynamics

As an opioid antagonist, naltrexone exhibits a high affinity for opioid receptors. When administered, it displaces opioids from these receptors, preventing their activation. This results in the attenuation of the effects of opioids, including analgesia and euphoria. In alcohol dependence, naltrexone modulates the release of neurotransmitters associated with reward and craving, leading to decreased alcohol consumption and cravings.

Pharmacokinetics

Naltrexone is administered orally and is well-absorbed from the gastrointestinal tract. It undergoes extensive first-pass metabolism in the liver, resulting in an oral bioavailability of approximately 5-40%. The drug is primarily metabolized by the liver via cytochrome P450 enzymes, producing active metabolites like 6-beta-naltrexol. The elimination half-life of naltrexone is roughly 4 hours, while its active metabolite has a longer half-life, contributing to the duration of action. Naltrexone is excreted mainly in urine, both as unchanged drug and metabolites.

Contra-indications

• Severe hepatic impairment
• Acute hepatitis
• Acute hepatic failure
• Current opioid dependence
• Hypersensitivity to naltrexone or any component of the formulation

Adverse effects

• Nausea
• Vomiting
• Abdominal pain
• Decreased appetite
• Anxiety
• Restlessness
• Tachycardia
• Tremor
• Sleep disorders
• Dizziness
• Chest pain
• Weight loss
• Myalgia
• Skin reactions
• Mood alterations
• Hallucinations
• Withdrawal syndrome

Interactions

• Opioids: Naltrexone may precipitate withdrawal symptoms in opioid-dependent patients
• CNS depressants: Enhanced sedation or respiratory depression may occur
• Alcohol: Concurrent use may increase adverse effects

Precautions

• Hepatic impairment: Use with caution in mild to moderate impairment; avoid in severe impairment
• Renal impairment: Caution in mild to moderate impairment; avoid in severe impairment
• Pre-treatment screening for opioid dependence is necessary
• Monitor for signs of suicidal behavior and liver function during treatment

Pregnancy

Use only if the potential benefits justify the risks to the fetus, as there is limited data on safety.

Breast-feeding

Avoid due to potential toxicity to the infant.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets
• Oral solution
• Capsules
• Oral suspension

Mechanism of action

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. Naltrexone competes for opiate receptors and displaces opioid drugs from these receptors, thus reversing their effects. It is capable of antagonizing all opiate receptors.

Pharmacodynamics

Naltrexone, a pure opioid antagonist, is a synthetic congener of oxymorphone with no opioid agonist properties. Naltrexone is indicated in the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids. It markedly attenuates or completely blocks, reversibly, the subjective effects of intravenously administered opioids. When co-administered with morphine, on a chronic basis, naltrexone blocks the physical dependence to morphine, heroin and other opioids. In subjects physically dependent on opioids, naltrexone will precipitate withdrawal symptomatology.