Source: Health Products Regulatory Authority (IE) Revision Year: 2022 Publisher: AOP Orphan Pharmaceuticals Gmbh, Leopold-Ungar-Platz 2, A-1190 Vienna, Austria
Pharmacotherapeutic group: Drugs used in alcohol dependence
ATC code: N07BB04
Naltrexone is a specific opioid antagonist with only minimal agonistic activity. It acts by stereospecific competition with receptors which are mainly located in the central and peripheral nervous system. Naltrexone competitively binds to these receptors and blocks the access for exogenously administered opioids.
Naltrexone treatment does not lead to physical or mental dependence. No tolerance for the opioid antagonising effect is seen.
The mechanism of action of naltrexone in alcoholism is not completely elucidated, however an interaction with the endogenous opioid system is suspected to play an important role. Alcohol consumption in humans has been hypothesised to be reinforcing through an alcohol-induced stimulation of the endogenous opioid system.
Naltrexone is not an aversive therapy and does not cause a disulfiram-like negative reaction when alcohol is ingested.
The prominent effect of naltrexone treatment of alcohol-addicted patients seems to be a reduction of the risk of a full relapse with uncontrolled binge-drinking after having consumed a limited amount of alcohol. This gives the patient a “second chance” to escape the otherwise mutually reinforcing mechanisms of a full relapse with complete loss of control. Naltrexone also seems to have an effect on the primary craving as it is non-reinforcing on isolated consumption of limited amounts of alcohol.
Naltrexone is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration.
It undergoes a liver first-pass effect and peak plasma concentration is reached within approximately one hour.
Naltrexone is hydroxylated in the liver basically to the main active metabolite 6-beta-naltrexol and, to a lesser extent, to 2-hydroxy-3-methoxy-6-beta-naltrexol.
The plasma-half-life of naltrexone is approximately 4 hours, the average blood level is 8,55 ng/ml, and plasmaprotein-binding is 21%. The plasma-half-life of 6-beta-naltrexol is 13 hours.
The medicinal product is excreted primarily renally. About 60% of the peroral dose is excreted within 48 hours as glucuronidised 6-beta-naltrexol and naltrexone.
Five to ten times higher plasma concentrations of naltrexone have been reported in cirrhotic patients.
Preclinical data reveal no special hazard for humans based on conventional studies of safety, pharmacology,repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. However, there is some evidence on hepatotoxicity with increasing dose, since reversible increases of liver enzymes have been found in humans with therapeutic and higher doses (see section 4.4 and 4.8).
Naltrexone (100 mg/kg, approximately 140 times the human therapeutic dose) caused a significant increase of pseudo-pregnancy in rats. A decrease of the pregnancy rate of mated female rats also occurred. The relevance of these observations to human fertility is not known.
Naltrexone has been shown to have an embryocidal effect in the rat and rabbit when given in doses approximately 140 times the human therapeutic dose. This effect was demonstrated in rats dosed with 100 mg/kg of naltrexone prior to and throughout gestation, and rabbits treated with 60 mg/kg of naltrexone during the period of organogenesis.
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