What Is Oral Naltrexone?
Naltrexone hydrochloride is a relatively pure and long-lasting opioid antagonist. Oral naltrexone has been used to treat opioid dependence for many years and has been approved to treat alcohol use disorders (AUDs) since 1994. Naltrexone reduces both the rewarding effects of alcohol and craving for it.
Brief History of Development
Naltrexone was first synthesized in 1963 by Endo Laboratories, which was acquired by DuPont in 1969. Naltrexone was initially developed to treat addiction to opioids and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of addiction to drugs such as heroin, morphine, and oxycodone in 1984. DuPont branded naltrexone as Trexan® and promoted it for the treatment of opioid addiction.
Animal studies conducted in the 1980s established that naltrexone decreased alcohol consumption through its action at the opiate receptors. Human clinical trials followed that confirmed that naltrexone, when used in combination with psychosocial therapy, could reduce cravings for alcohol and decrease relapse rates to alcohol use (O’Malley et al., 1992; Volpicelli, Alterman, Hayashida, & O’Brien, 1992; Volpicelli, Watson, King, Sherman, & O’Brien, 1995).
With FDA approval of naltrexone to treat AUDs in 1994, DuPont renamed the drug ReVia®. ReVia and a generic version of naltrexone are now manufactured by Barr Pharmaceuticals. Mallinckrodt also manufactures naltrexone under the brand name Depade®.
Drinking alcohol enhances endogenous opioid activity. Several researchers who conducted animal studies observed that, under certain conditions, administration of small doses of morphine (an opioid agonist) increased consumption of alcohol in rats (Czirr, Hubbell, Milano, Frank, & Reid, 1987; Reid, Czirr, Bensinger, Hubbel, & Volanth, 1987; Reid, Delconte, Nichols, Bilsky, & Hubbell, 1991). Some researchers also reported that administration of opioid antagonists, including naloxone (which is similar to naltrexone), decreased alcohol consumption (Hubbell et al., 1986; Reid et al., 1991). It can be concluded that the rewarding effects of alcohol are mediated at least partly through the opiate system. Two teams of researchers, Woodson and Holman and Benjamin and colleagues (as cited in Spanagel & Zieglgansberger, 1997), reported that these rewarding effects are reduced when opioid antagonists block opiate receptor occupancy, thereby decreasing the amount of the neurotransmitter dopamine released from the nucleus accumbens. According to Spanagel and colleagues (as cited in Spanagel & Zieglgansberger, 1997), the mesolimbic dopamine reward system is important in initiating and maintaining the use of many substances of abuse, including alcohol, and may mediate both the positive effects of alcohol and the development of craving.
Oral naltrexone is rapidly and nearly totally absorbed in the gastrointestinal tract and is metabolized almost exclusively by the liver to the primary active metabolite, 6-β-naltrexol. Peak naltrexone plasma concentrations are reached within 1 hour of dosing. The long-acting properties of naltrexone are due primarily to 6-β-naltrexol, which has an elimination half-life of 13 hours. Naltrexone achieves therapeutic effectiveness rapidly following the initiation of oral dosing.
Why Use Oral Naltrexone?
Naltrexone appears to be effective for attenuating craving in people who are alcohol dependent (Monti et al., 1999, 2001). By blocking craving, naltrexone may enhance the ability of patients to abstain from drinking. By blocking the pleasure from alcohol, naltrexone also may reduce the amount of heavy drinking in those who do drink.
A meta-analysis (Bouza, Magro, Muñoz, & Amate, 2004) of 19 controlled clinical trials of naltrexone for treatment of AUDs (most of which were randomized and single or double blind) found that, compared with using placebo, short-term treatment (less than or equal to 12 weeks) with naltrexone significantly improved relapse rates during active treatment and a medication-free followup period. Short-term naltrexone treatment was also linked with a lower percentage of drinking days, fewer drinks per drinking day, longer times to relapse, more days of abstinence, and lower total alcohol consumption during treatment. Naltrexone may afford people with AUDs a measure of control that can prevent a slip from becoming a full-blown relapse. A European meta-analysis (Roozen et al., 2006) corroborated the positive findings of the Bouza and other studies.
A more thorough discussion of oral naltrexone efficacy studies is in the TIP’s online literature review (http://www.kap.samhsa.gov).
Naltrexone has a low incidence of common adverse events. Naltrexone’s FDA-approved label includes a black-box warning regarding hepatotoxicity, although these reversible effects tend to be associated with much higher doses than those used in routine clinical practice (e.g., 300 mg/day or more) and tend to occur only after a patient is on these high doses for extended periods.