Ultra-Low-Dose Opioid Antagonists Enhance Opioid Analgesia and Reduce Tolerance

Ultra-low-dose opioid antagonists have been shown to enhance opioid analgesia and attenuate the tolerance to analgesic effects normally seen with chronic opioid administration. This chapter reviews the early work with ultra-low-dose opioid antagonists starting with electrophysiological recordings of dorsal root ganglion neurons and continuing to antinociception in rodents. These pharmacological findings have not adhered to typical dose response curves and have instead been reported to occur at wide ranges of extremely low doses of several opioid antagonists as well as with the rare opioid agonist. Optimal dose ranges have also been reported to vary with sex and strain of rat. Translation into small clinical studies has been met with varied results, related to variations in dose, route of administration, and antagonist selected. Nevertheless, the clinical studies that have demonstrated enhanced analgesia or opioid sparing effects have utilized opioid antagonist doses in lower dose ranges than the studies that failed to demonstrate efficacy. Furthermore, a large double-blind, placebo- and active-controlled clinical trial demonstrated enhanced opioid analgesia with the extremely low dose of 2 μg naltrexone/patient/day. Preclinical data also extend the effects of ultra-low-dose opioid antagonists to neuropathic pain, which is comparatively resistant to opioid treatment and, interestingly, to cannabinoid analgesia. The mechanism of action has been shown to be the prevention of a chronic opioid-induced mu opioid receptor—G protein coupling switch that is associated with analgesic tolerance and dependence. Finally, recent data shows that this G protein coupling switch is controlled by filamin A and that a high-affinity interaction of naloxone or naltrexone with this scaffolding protein mediates their prevention of the altered coupling.