Abstract Cancer-induced bone pain (CIBP) is a significant health problem in the USA and the rest of the world. With the improvement of treatment options to manage cancer, a greater number of cancer patients are now living longer yet, experiencing chronic pain. Metastasis to the bones inflicts severe and debilitating pain. The golden standard pharmaceutical agent to manage pain is opioids. Cancer patients need to take increasing doses of opioids to control their pain. Sadly, opioids come with significant side effects. Many attempts have been made to create better regiments for pain control while reducing opioids yet, most patients are simply not achieving better control of CIBP. Eliminating opioids entirely is not a reasonable approach. A better approach for controlling CIBP and lower opioids would be to add a non-opioid agent that has different mechanism(s) of action. This may better control pain while lowering opioids needed resulting in the reduction of side effects. Sulfasalazine is such possibility. It is an anti-inflammatory drug with an established safety profile. It has been in use for over fifty years for the treatment of some inflammatory conditions. In addition, sulfasalazine has the capacity to decrease the survival of cancer cells and also to lower the amount of inflammatory mediators. Sulfasalazine inhibits the influx of cysteine and the efflux of glutamate from cancer cells. Cysteine is needed for cell survival against oxidative stress, while extracellular glutamate activates pain receptors. Therefore, sulfasalazine will act as an anti- inflammatory agent, an agent to accelerate cancer cells damage, and decrease the release of glutamate that activates pain fibers. This one agent with three mechanisms of actions may lower the amount of opioids needed for patients with CIBP. Lowering of opioid dosing will decrease unwanted side effects. The purpose of this clinical trial is to co-administer sulfasalazine with opioids to patients with CIBP and characterize their opioid use and the improvement of their pain. Our central hypothesis is that adding sulfasalazine to the opioid pain medication regiment will reduce the amount of opioids used resulting in a reduction in opioid-induced side effects while reducing pain and improving the overall quality of life. We also predict that sulfasalazine may reduce the inflammatory mediators as well as tumor markers in the serum. This study will be conducted in a double- blind randomized fashion with two independent, but related, specific aims (SA) and one exploratory aim (EA). We will assess whether sulfasalazine will improve both of our primary and secondary outcomes. Our primary outcome is reduction in opioids. The secondary outcome is reduction in pain and improvement of the quality of life (SA1). Secondly, we will assess the levels of serum glutamate and IL-6, TNF-alpha and tumor markers before and after treatment with sulfasalazine (SA2). We expect sulfasalazine to decrease inflammatory mediators. ...