Ultra-Low-Dose Naltrexone Decreases Dependence and Addictive Properties of Opioids

Abstract

Ultra-low-dose opioid antagonist cotreatment was first shown parad oxically to enhance opioid analgesia and to reduce analgesic tolerance and physical dependence. In this chapter, we review data demonstrating that ultra-low-dose naloxone or naltrexone reduces several components of opioid dependence and addiction. While the reduction in opioid dependence, first demonstrated as a reduction in somatic withdrawal signs, might seem merely a correlate of the attenuation in tolerance, the data reviewed here show that ultra-low-dose naltrexone also reduces the “psychological” or negative affective aspect of acute opioid withdrawal. In addition, the acute rewarding properties of opioids are reduced by ultra-low-dose naltrexone. The attenuation of rewarding effects occurs in the same ultra-low dose ranges shown to enhance analgesia, thus dissociating the rewarding or addictive effects of opioids from their analgesic properties. Furthermore, in intravenous self-administration procedures in rats, ultra-low-dose opioid antagonists coadmin-istered with opioids reduced their rewarding potency, reduced motivation to obtain the drug, and reduced “drug-seeking” in the absence of drug availability. Finally, in a Phase III clinical trial, the ultra-low-dose naltrexone component of Oxytrex™ significantly reduced physical signs of opioid dependence after abrupt cessation of treatment, compared to withdrawal from oxycodone alone. Together, the data reviewed in this chapter suggest a reduced potential for opioid dependence and addiction by certain ultra-low-dose opioid antagonists combined with opioids, concurrent with the enhanced analgesia from these opioid agonist/antagonist cotreatments.