What is the mechanism of action of Naltrexone (opioid receptor antagonist)?

From the Guidelines

Naltrexone works primarily as an opioid receptor antagonist, blocking the effects of opioids by competitively binding to mu, kappa, and delta opioid receptors in the brain without activating them. This mechanism prevents opioids from producing their typical effects like euphoria, pain relief, and respiratory depression. For alcohol use disorder, naltrexone reduces cravings and the pleasurable effects of alcohol by blocking endorphin release, which normally contributes to alcohol's rewarding properties 1. The plasma half-life of naltrexone is 4 hours, and the half-life of the active metabolite, 6-b-naltrexol, is 13 hours, which accumulates during long-term therapy and may persist for 2 to 3 days after stopping 1.

Key Points

• Naltrexone is a semisynthetic competitive opioid receptor antagonist derived from oxymorphine via substitution of the N-methyl group with the methylcyclopropyl group 1.
• It prevents patients from experiencing the euphoric effects of narcotics and alcohol, and may also reset the reward pathway through an opponent process mechanism 1.
• The standard oral dosing is 50 mg once daily, though it's also available as a monthly 380 mg extended-release injection (Vivitrol) 1.
• Treatment typically continues for at least 3-6 months but may be maintained longer depending on clinical response.
• Naltrexone requires patients to be opioid-free for 7-10 days before starting to avoid precipitating withdrawal.
• Common side effects include nausea, headache, dizziness, anxiety, and fatigue.
• The medication is contraindicated in acute hepatitis or liver failure and requires liver function monitoring 1.

Clinical Considerations

• Naltrexone has been shown to be helpful in maintaining abstinence from opioids in motivated populations 1.
• It has limited success in other groups, and liver function tests are recommended at baseline and every three to six months due to the risk of hepatic injury at supratherapeutic doses 1.
• Naltrexone cannot be used in patients in whom opioids are required for pain control, because it will block pain relief from opioid agonists and cause withdrawal 1.

From the FDA Drug Label

Naltrexone hydrochloride blocks the effects of opioids by competitive binding (i.e., analogous to competitive inhibition of enzymes) at opioid receptors. Naltrexone hydrochloride, an opioid receptor antagonist, competitively binds to such receptors and may block the effects of endogenous opioids The mechanism of action of Naltrexone is as an opioid receptor antagonist, which works by competitive binding to opioid receptors, blocking the effects of opioids and endogenous opioids 2.

• The blockade produced by Naltrexone is potentially surmountable.
• Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties.

From the Research

Mechanism of Action of Naltrexone

• Naltrexone is a long-acting competitive antagonist at opioid receptors, which blocks the subjective and objective responses produced by intravenous opioid challenge 3.
• It blocks the opioid receptors that modulate the release of dopamine in the brain reward system, thereby blocking the rewarding effects of heroin and alcohol 4.
• Naltrexone is a semi-synthetic opioid with competitive antagonist activity at mu opioid receptors 5.
• Its anti-relapse action may be explained by its activity as a relatively selective competitive antagonist at mu-opioid receptors, which may be involved in the positively reinforcing effects of alcohol and/or the conditioned anticipation of these effects 6.
• Naltrexone also blocks alcohol-induced effects on kappa-opioid receptors in the plasma membrane, and its therapeutic effect in alcohol use disorder may be due to direct actions on kappa-opioid receptors and its effect on the surrounding lipid environment 7.

Key Findings

• Naltrexone reduces heroin craving and helps patients remain opioid-free 3.
• It does not significantly reduce craving in abstinent opioid-dependent patients, but rather abstinence from opioids is associated with less craving, independent of naltrexone use 4.
• Naltrexone has been shown to be effective in the treatment of alcohol and opioid dependence, and a long-acting injectable formulation has received FDA-approval for these indications 5.
• The pharmacology of naltrexone is complex, and its effects may be mediated by multiple mechanisms, including its actions on mu-opioid receptors and kappa-opioid receptors 6, 7.