Ultra-low-dose opioid antagonists enhance opioid analgesia while reducing tolerance, dependence and addictive properties

Ultra-low-dose opioid antagonists, when combined with opiates, increase the analgesic efficacy and duration of analgesia of the opiate. This enhanced and prolonged analgesia was recently demonstrated in a 350-patient Phase II clinical trial of Oxytrex, a novel drug candidate that combines oxycodone with an ultra-low dose of the opioid antagonist naltrexone. Extensive preclinical data also show that the addition of ultra-low-dose opioid antagonists prevents analgesic tolerance to opiates as well as opioid dependence, measured by withdrawal signs. These drug combinations can also reverse established tolerance in rodents, unlike many other approaches shown to alleviate tolerance. The mechanism of action of ultra-low-dose opioid antagonists has been shown to be the prevention of excitatory signaling of opioid receptors, a phenomenon that opposes the normal inhibitory Correspondence/Reprint request: Dr. Lindsay H. Burns, Pain Therapeutics, Inc., South San Francisco, CA, USA Lindsay H. Burns 116 signaling of opioid receptors and contributes to opioid tolerance. Specifically, ultralow-dose opioid antagonists prevent the mu opioid receptor from coupling to G proteins that stimulate adenylyl cyclase, instead of coupling to the G proteins normally used by this receptor that inhibit this enzyme. Finally, while ultra-low-dose opioid antagonists enhance the analgesic efficacy of opiates, they decrease the addictive potential of opiates in rat models of drug reward, drug-taking and drug-seeking. These results suggest that the addictive properties of opiates can be partially dissociated from their analgesic effects and may be mediated in part by opioid-induced neuroadaptations interacting with learning processes. Moreover, Oxytrex and similar combinations of opiates with ultra-low-dose opioid antagonists, might significantly improve opioid therapy available today by enhancing analgesic efficacy, alleviating tolerance and physical dependence, and reducing the potential for opioid addiction.