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 opioid drugs from producing their typical effects such as euphoria, pain relief, and respiratory depression. According to the most recent study 1, naltrexone is a semisynthetic competitive opioid receptor antagonist that prevents patients from experiencing the euphoric effects of narcotics and alcohol. The study also mentions that naltrexone may reset the reward pathway through an opponent process mechanism. When used for alcohol dependence, naltrexone reduces alcohol cravings and the pleasurable effects of drinking by blocking endorphin activity, which normally contributes to alcohol's rewarding effects. Key points to consider when prescribing naltrexone include:
- The standard dosing for alcohol use disorder is 50 mg once daily orally
- For opioid dependence, it's typically 50 mg daily after complete detoxification from opioids
- Patients must be opioid-free for 7-10 days before starting naltrexone
- Naltrexone is also available as a monthly injectable formulation (Vivitrol, 380 mg)
- Patients should be aware that naltrexone will block the effects of any opioid medications, including those used for pain relief, and attempting to overcome this blockade by taking high doses of opioids could lead to serious injury, overdose, or death, as noted in 1. The medication works best when combined with counseling or behavioral therapy as part of a comprehensive treatment program.
From the FDA Drug Label
Naltrexone is a pure opioid antagonist. It markedly attenuates or completely blocks, reversibly, the subjective effects of intravenously administered opioids. ... Naltrexone blocks the effects of opioids by competitive binding (i. e., analogous to competitive inhibition of enzymes) at opioid receptors.
The mechanism of action (MOA) of Naltrexone is as a pure opioid receptor antagonist that works by competitive binding to opioid receptors, thereby blocking the effects of opioids. This blockade is potentially surmountable, but it can prevent the effects of opioids for an extended period, depending on the dose of naltrexone administered 2.
- The key action is the competitive binding to opioid receptors.
- This results in the blockade of opioid effects.
From the Research
Mechanism of Action of Naltrexone
The mechanism of action (MOA) of naltrexone involves its ability to bind to opioid receptors, specifically μ-opioid receptors, and block the subjective and analgesic effects of opioids 3. This is achieved through its action as a competitive antagonist at the μ, κ, and σ receptors, with a higher affinity for the μ receptor and lacking any μ receptor efficacy 4.
Key Aspects of Naltrexone's MOA
- Naltrexone does not produce physiologic dependence and precipitates withdrawal if administered to an opioid-dependent person, thus requiring detoxification before starting treatment 3.
- It has been shown to reduce the priming strength of opioid agonists, although its effectiveness may vary depending on the efficacy of the agonist 5.
- Naltrexone also interacts with κ-opioid receptors, altering their interactions with the lipid environment in the plasma membrane and exerting counteracting effects on alcohol-induced changes 6.
- Polymorphisms in the κ and δ opioid receptor genes can influence the effects of naltrexone on subjective responses to alcohol, suggesting pharmacogenetic effects in the opioid receptor system 7.
Receptor Interactions
- Naltrexone binds to μ-opioid receptors, blocking the effects of opioids and reducing the risk of relapse 3, 5.
- It also interacts with κ-opioid receptors, which are associated with dysphoria and aversive states, and may contribute to its therapeutic effects in alcohol use disorder 6, 7.
- The δ opioid receptor may also play a role in naltrexone's MOA, with polymorphisms in the OPRD1 gene influencing its effects on alcohol-induced stimulation and craving 7.