Repurposing Sulfasalazine in a Two-Arm Phase Two Double-Blind Randomized Clinical Trial for the Adjunct Management of Breast Cancer-Induced Bone Pain

摘要 癌症引起的骨痛（CIBP）在美国和世界其他地区是一个重要的健康问题。与 随着癌症治疗方案的改进，越来越多的癌症患者现在活得更长 然而，经历着慢性疼痛。转移到骨头会造成严重的和使人衰弱的疼痛。的金标准 用于控制疼痛的药剂是阿片类药物。癌症患者需要增加阿片类药物的剂量， 控制他们的痛苦。不幸的是，阿片类药物具有显著的副作用。人们做了很多尝试来创造 更好的疼痛控制方案，同时减少阿片类药物，但大多数患者根本没有达到更好的控制 在CIBP。完全消除阿片类药物不是一个合理的方法。控制CIBP的更好方法， 较低的阿片类药物将是添加具有不同作用机制的非阿片类药物。这可能更好 控制疼痛，同时降低所需的阿片类药物，从而减少副作用。柳氮磺胺吡啶是这样的 可能性它是一种抗炎药，具有既定的安全性。它已经使用了五十多年了 用于治疗某些炎症性疾病。此外，柳氮磺胺吡啶有能力减少 癌细胞的存活以及降低炎症介质的量。柳氮磺胺吡啶抑制了 半胱氨酸和谷氨酸从癌细胞中流出。半胱氨酸是细胞存活所必需的， 应激，而细胞外谷氨酸激活疼痛受体。因此，柳氮磺胺吡啶将作为抗- 炎症剂，加速癌细胞损伤的试剂，并减少谷氨酸的释放， 激活疼痛纤维这种具有三种作用机制的药物可能会降低所需的阿片类药物的量 对于CIBP患者。降低阿片类药物剂量将减少不必要的副作用。本临床的目的 一项临床试验是将柳氮磺胺吡啶与阿片类药物联合给药CIBP患者，并描述其阿片类药物的使用情况， 改善他们的痛苦。我们的中心假设是，在阿片类止痛药中加入柳氮磺胺吡啶 方案将减少阿片类药物的使用量，从而减少阿片类药物引起的副作用 同时减轻疼痛并提高整体生活质量。我们还预测柳氮磺胺吡啶可能会减少 炎症介质以及血清中的肿瘤标记物。这项研究将在一个双- 采用盲法随机化方式，有两个独立但相关的特定目标（SA）和一个探索性目标（EA）。 我们将评估柳氮磺胺吡啶是否会改善我们的主要和次要结局。我们的首要 结果是阿片类药物减少。次要结局是疼痛减轻和治疗质量改善。 寿命（SA 1）。其次，我们将评估血清谷氨酸和IL-6，TNF-α和肿瘤标志物的水平， 柳氮磺胺吡啶治疗后（SA 2）。我们希望柳氮磺胺吡啶减少炎症介质。 第三，我们将评估柳氮磺胺吡啶治疗前后血清肿瘤标志物的水平， 与肿瘤影像学研究（EA 1）相关。我们预期柳氮磺胺吡啶可降低血浆肿瘤标志物。的 所获得的数据可以为医生提供额外的选择来管理CIBP患者。

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. Thirdly, we will assess the levels of serum tumor markers before and after treatment with sulfasalazine and correlate with tumor imaging studies (EA1). We expect sulfasalazine to decrease plasma tumor markers. The data obtained may provide physicians with additional options to manage CIBP patients.