What is the pharmacological action of naltrexone?

Pharmacological Action of Naltrexone

Naltrexone is a competitive opioid receptor antagonist that blocks mu, kappa, and delta opioid receptors, preventing the euphoric and reinforcing effects of opioids and reducing alcohol cravings through modulation of the endogenous opioid reward system. 1

Mechanism of Action

Opioid Receptor Antagonism

• Naltrexone competitively binds to opioid receptors, blocking the subjective and objective effects of exogenously administered opioids through competitive inhibition at the receptor level. 1
• The drug markedly attenuates or completely blocks, in a reversible manner, the euphoric effects of intravenously administered opioids such as heroin and morphine. 1
• This competitive binding is potentially surmountable, meaning extremely high doses of opioids could theoretically overcome the blockade, though this has resulted in excessive histamine release in experimental settings. 1

Duration and Dosing Relationships

• A single 50 mg dose of naltrexone blocks the pharmacologic effects of 25 mg of intravenous heroin for approximately 24 hours. 1
• Doubling the naltrexone dose provides opioid blockade for 48 hours, while tripling the dose extends blockade to approximately 72 hours. 1
• The plasma half-life of naltrexone is 4 hours, with its active metabolite 6-β-naltrexol having a half-life of 13 hours. 2, 1

Pharmacokinetics

Absorption and Bioavailability

• Naltrexone undergoes rapid and nearly complete absorption from the gastrointestinal tract, with approximately 96% of an oral dose absorbed. 1
• Despite excellent absorption, naltrexone undergoes significant first-pass hepatic metabolism, resulting in oral bioavailability ranging from only 5% to 40%. 1
• Peak plasma levels of both naltrexone and its metabolite occur within one hour of oral dosing. 1

Distribution and Metabolism

• The volume of distribution following intravenous administration is approximately 1350 liters, indicating extensive tissue distribution. 1
• Naltrexone is 21% bound to plasma proteins across the therapeutic dose range. 1
• Both parent drug and metabolites are excreted primarily by the kidneys (53% to 79% of the dose), though urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose. 1

Clinical Pharmacodynamics

Effects in Opioid Dependence

• When administered chronically with morphine, naltrexone blocks the development of physical dependence to morphine, heroin, and other opioids. 1
• In patients already physically dependent on opioids, naltrexone precipitates acute withdrawal symptoms due to displacement of opioids from receptors. 1
• Naltrexone prevents patients from experiencing the euphoric effects of narcotics and may reset the reward pathway through an opponent process mechanism. 2

Effects in Alcohol Dependence

• The mechanism in alcoholism involves blockade of endogenous opioid receptors, which dampens activation of the reward pathway by alcohol, thereby decreasing excessive drinking and increasing abstinence duration. 3, 4
• Naltrexone reduces alcohol consumption and craving, though it is not aversive therapy and does not cause a disulfiram-like reaction with ethanol ingestion. 1
• The drug is particularly effective in patients with high alcohol craving, and allelic variation in the mu opioid receptor gene predicts treatment response. 5

Combination Therapy: Naltrexone/Bupropion

• When combined with bupropion for obesity treatment, naltrexone antagonizes an inhibitory feedback loop that would otherwise limit bupropion's anorectic properties. 3
• This combination activates pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus, promoting release of α-melanocyte-stimulating hormone, an anorectic neuropeptide involved in body weight regulation. 3

Unique Pharmacological Properties

Lack of Intrinsic Activity

• Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties. 1
• The drug does produce some pupillary constriction through an unknown mechanism. 1
• Administration of naltrexone is not associated with the development of tolerance or dependence. 1
• Naltrexone has no abuse potential and produces mild, transient side effects. 6

Clinical Implications of Mechanism

Pain Management Considerations

• Naltrexone blocks the analgesic effects of opioid medications, making it unsuitable for patients requiring opioid pain control. 4
• For elective surgical procedures, oral naltrexone should be held for 2-3 days prior to surgery if opioids are expected, while extended-release injectable naltrexone requires 24-30 days after the last injection. 4, 2

Overdose Risk

• Patients who discontinue naltrexone have markedly increased risk of opioid overdose and death due to loss of opioid tolerance during treatment. 4
• The competitive antagonism means that previous opioid doses may be lethal after naltrexone discontinuation due to decreased tolerance. 4