Nalmefene Causes Greater Hypothalamic-Pituitary-Adrenal Axis Activation than Naloxone in Normal Volunteers: Implications for the Treatment of Alcoholism


  • This work was supported in part by the National Institutes of Health-National Institute on Drug Abuse Research Center Grant DA-P50-05130, National Institutes of Health-National Institute on Drug Abuse Research Scientific Award Grant K05-DA00049, and the National Institutes of Health-National Center for Research Resources (NCRR) General Clinical Research Center Grant M01-RR00102.

Reprint requests: James H. Schluger, M.D., The Laboratory on the Biology of the Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10021-6399.


Among other actions, opioid antagonists modulate the control endogenous opioids exert on the hypothalamic-pituitary-adrenal (HPA) axis. Naloxone, nalmefene, and naltrexone are the opioid antagonists approved for use in man and are primarily μ-opioid selective. Naltrexone and nalmefene have been demonstrated to be useful in the treatment of alcoholism. Compared with naloxone, nalmefene has a longer half-life, is more potent at the preceptor, and has a higher affinity for K- and §-opioid receptors. We conducted an inpatient study comparing the effects of 10 and 30 mg doses of intravenous naloxone and nalmefene in normal, nonsubstance nor alcohol-abusing, volunteers. Significant increases in ACTH and cortisol were observed after both antagonists, without an apparent dose-response relationship; however, both doses of nalmefene resulted in greater HPA axis activation than either dose of naloxone (ACTH: p <0.005). These results indicate that K- and 8-opioids may play important roles in the regulation of the HPA axis; nalmefene may be useful as both a probe to explore the HPA axis physiology and as a pharmacotherapeutic agent.