Ultra-Low-Dose Naloxone or Naltrexone to Improve Opioid Analgesia: The History, the Mystery and a Novel Approach

Abstract

Combining opioid agonists with ultra-low (typically pg-ng/kg) doses of the opioid antagonists naloxone or naltrexone can enhance analgesic efficacy and decrease certain side effects. Such combinations have also been shown to decrease tolerance, dependence and addictive potential in animals. We now know that ultra-low-dose naloxone/naltrexone effects occur by preventing a G protein coupling switch (Gi/o to Gs) of the mu opioid receptor (MOR) that occurs briefly after acute administration or persistently after chronic administration of opioids. The picomolar binding site for naloxone or naltrexone in these effects is on the scaffolding protein filamin A (FLNA), rather than on opioid receptors. Interestingly, a second, nanomolar binding site on FLNA may disrupt the benefits of binding the picomolar site, perhaps explaining why ultra-low-dose naloxone/naltrexone effects vanish at just slightly higher doses. A novel analgesic drug candidate aims to avoid this issue by binding only the high-affinity FLNA site, while simultaneously activating MOR. Binding this single site on FLNA also provides anti-inflammatory activity.