Naltrexone is in fact not inactive in the absence of exogenous opioids. This is because the drug blocks the actions of the body’s endogenous opioid peptides (enkephalin, endorphin, and dynorphin); this can cause negative emotional effects (such as depressed mood), which reduce patient compliance (7). As a result, naltrexone is mostly effective for highly “motivated” addicted individuals whose employment can be used to coerce compliance. Based on animal studies showing that alcohol’s and nicotine’s addicting actions are mediated in part via activation of endogenous opioidergic neurons (Fig. 4-1), naltrexone has been used to treat addiction to these drugs as well. Some efficacy is observed clinically, but the effects of naltrexone are relatively small in magnitude and effective for a subset of patients only (9).
Opioidergic Agents
Naltrexone and, to a lesser extent, nalmefene, both of which are opioid antagonists with no intrinsic agonist properties, have been studied for the treatment of alcohol use disorder. In 1984, naltrexone was approved by the FDA for the treatment of opioid dependence; in 1994, it was approved for the treatment of alcohol use disorder. Nalmefene is approved in the United States as a parenteral formulation for the acute reversal of opioid effects (e.g., after opioid overdose or analgesia). Naltrexone
The approval by the FDA of naltrexone for alcohol use disorder was based on the results of two single-site studies, which showed it to be efficacious in the prevention of relapse to heavy drinking (18,19). In a 12-week trial in a sample of alcoholdependent veterans, Volpicelli et al. (18) found naltrexone to be well tolerated and to result in significantly less craving for alcohol and fewer drinking days than placebo. Among patients who drank, naltrexone also limited the progression from initial sampling of alcohol to a relapse to heavy drinking, presumably because of their experiencing less euphoric effects of alcohol, suggesting that naltrexone blocked the endogenous opioid system’s contribution to alcohol’s “priming effect” (20)
References
Ries, Richard, Shannon C. Miller, Richard Saitz, and David A. Fiellin, eds. 2014. The ASAM principles of addiction medicine. Fifth edition. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.