A novel controlled release drug delivery system for naltrexone administration combined with intermittent morphine to induce antinociception

Co-administration of ultra-low dose opioid antagonists and opioid agonists has been shown to have some advantages in pain management. Objectives: We tried to design a controlled release drug delivery system (CRDDS) to supply controlled release of ultra-low dose naltrexone (ULDN) which was accompanied with intermittent subcutaneous morphine injections. Injectable implants were prepared by dissolving PLGA (Resomer RG504H) in N-methyl-2-pyrrolidone(NMP) containing ethyl heptanoate. This CRDDS provided controlled release of ULDN in mice bodies and was followed by subcutaneous morphine injection (3 mg) at days 2, 5, 10, 15, 20, 25 and 30. Pain response was determined by Tail Flick test. Daily ULDN of 300 ng/kg led to the most effective antinociception rate and tolerance inhibition in mice after a short delayed time interval than those mice which received 3000 ng/kg/day naltrexone (P: 0.01) and those that received no naltrexone (P: 0.02). The CRDDS which was designed in this study shows acceptable outcomes in providing daily ULDN to increase morphine efficacy. The highest antinociception efficacy along with tolerance inhibition was observed when 300 ng/kg ULDN was administered daily followed by intermittent morphine subcutaneous injections.