How does Naltrexone (opioid receptor antagonist) block the effects of ethanol (alcohol)?

From the Guidelines

Naltrexone blocks the effects of alcohol by decreasing the concentration of dopamine in the brain and dampening activation of the reward pathway by alcohol, thereby decreasing excessive drinking and recurrence rates and increasing abstinence duration in patients with alcohol dependence. This is achieved through its action as an opioid antagonist, which reduces the pleasurable feelings associated with alcohol consumption 1. The standard dose for alcohol use disorder is 50 mg once daily, though some patients may start at 25 mg to minimize side effects like nausea 1.

Key Points

• Naltrexone works by reducing the rewarding and reinforcing effects of alcohol, making it less pleasurable and satisfying for patients to drink 1.
• The medication can be taken as needed before situations where drinking might occur (targeted approach) or daily (continuous approach), with the latter being more common.
• Naltrexone is available as an oral tablet or as a monthly injectable form (Vivitrol, 380 mg) 1.
• For best results, naltrexone should be combined with counseling or behavioral therapy to address the underlying issues contributing to alcohol use disorder 1.

Important Considerations

• Naltrexone is not recommended in patients with alcoholic liver disease (ALD) due to the risk of toxic liver injury 1.
• The medication works on a neurochemical level rather than making someone sick when they drink (unlike disulfiram), and patients can still become intoxicated but typically find drinking less pleasurable and satisfying, which helps reduce consumption and cravings 1.

From the FDA Drug Label

The mechanism of action of naltrexone hydrochloride in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone hydrochloride, an opioid receptor antagonist, competitively binds to such receptors and may block the effects of endogenous opioids Opioid antagonists have been shown to reduce alcohol consumption by animals, and naltrexone hydrochloride has been shown to reduce alcohol consumption in clinical studies.

Naltrexone blocks the effects of alcohol by competitively binding to opioid receptors, which may block the effects of endogenous opioids. The exact mechanism is not fully understood, but it is suggested that the endogenous opioid system is involved.

• Key points:
  • Naltrexone is an opioid receptor antagonist
  • It competitively binds to opioid receptors
  • It may block the effects of endogenous opioids
  • The exact mechanism in alcoholism is not understood 2

From the Research

Mechanism of Naltrexone in Blocking Alcohol Effects

• Naltrexone is an opioid receptor antagonist that blocks the activation of the endogenous opioid system, which is involved in the affectively reinforcing properties of substance use 3.
• The therapeutic effects of naltrexone are mediated by blockade of central mu opioid receptors, with evidence supporting a role of mu opioid receptors in the central nucleus of the amygdala, nucleus accumbens, and ventral tegmental area in the therapeutic actions of naltrexone for alcohol dependence 4.
• Naltrexone also interacts with kappa-opioid receptors (KOP) in the plasma membrane, affecting the receptor and its environment, which may contribute to its therapeutic effect in alcohol use disorder (AUD) 5.

Effects of Naltrexone on Alcohol Use

• Naltrexone has been shown to reduce the risk of relapsing to heavy drinking compared to placebo, with a modest effect size 6.
• Naltrexone moderates the association between alcohol use and affect, disrupting the reinforcing properties of alcohol and reducing the craving for alcohol 3, 4.
• The use of naltrexone has been found to be effective in maintaining abstinence in alcohol-dependent persons, particularly in those with high craving 4.

Pharmacological Basis of Naltrexone

• Naltrexone is a broad opioid-receptor antagonist that has been approved by the United States Food and Drug Administration for the treatment of alcohol dependence 6.
• The pharmacokinetics and safety data of naltrexone have been established, with the most common side-effect being nausea and hepatotoxicity being a concern at higher doses 6, 7.
• The emerging literature on naltrexone pharmacogenetics has the potential to identify responders based on genetic variation and individualize the use of this medication 7.