Combinational therapy utilizing an opioid (oxycodone) and a bisphosphonate (zolendronic acid) in inflammatory arthritis: immunological mechanisms

Abstract

This study evaluated the effect of Combinational therapy utilizing an opioid (oxycodone) and a bisphosphonate (zolendronic acid-ZA) in inflammatory arthritis in rats. Bisphosphonates inhibit bone destruction and are shown to increase bone density in animal models of rheumatoid arthritis (RA) while opioids are used as adjunct drugs for analgesia and are also known to have anti-inflammatory effects. Combination therapy significantly reduced bone damage and showed analgesic effects. The treatment also reduced the levels of proinflammatory cytokines in the tibial- tarsal joint area and decreased the levels of the calcium binding protein S100A8 in chondrocytes, pannus and surface. Oxycodone and zolendronic acid in combination proved to be very effective in combating arthritis by having anti-inflammatory and analgesic effects as well as inhibiting bone damage. Individual treatment reduced arthritic severity by 81% and 63% at an optimum dose of oxycodone 5mg/kg and ZA 3µg/kg respectively. Combinational therapy was effective in reducing arthritic severity at lower dose than individual therapy; the optimum dose combination oxycodone 5 mg/kg and ZA 1µg/kg. Paw pressure thresholds significantly decreased in treated arthritic rats (P<0.05), while control animals showed significant hyperalgesia. Single dose of the combination treatment was as effective as multiple doses. Cytokines that are abundantly produced in the inflamed rheumatoid synovial fluid, such as tumour necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-17, play crucial roles in the pathophysiology of RA were evaluated to study the role of these cytokines in RA pathogenesis. Further, calcium binding protein S100A8 that has been implicated in disease status and correlate well to radiological damage was evaluated. Immunohistochemistry showed increased concentrations of calcium-binding protein S100A8 in the tibial- tarsal joint (P<0.05, ANOVA), compared to control animals. Results also indicated decreased levels of TNF- α, IL-1 β beta and IL-17 in treated animals as compared to controls. The present study has shown a comparison between chronic and acute models of adjuvant arthritis to study the effects of combination therapy at different times throughout the course of this chronic disease. It was observed that combination treatment had significant effect on both the chronic as well as acute models in attenuating arthritis. Both oxycodone and zolendronic acid significantly modulate the immune system by inhibiting the recruitment and /or proliferation of macrophages in arthritic rats. The results suggest that combining oxycodone and zolendronic acid has a potential therapeutic importance in the treatment of arthritis.