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大的健康问题。与 改进治疗方案管理癌症，现在更多的癌症患者寿命更长 然而，正在经历慢性疼痛。转移到骨骼会引起严重的和衰弱的疼痛。黄金标准 止痛药物是阿片类药物。癌症患者需要服用越来越多的阿片类药物以 控制他们的痛苦。可悲的是，阿片类药物伴随着显著的副作用。已经进行了许多尝试来创造 在减少阿片类药物的同时更好地控制疼痛大多数患者根本没有达到更好的控制效果 CIBP。完全消除阿片类药物不是一个合理的方法。一种更好的控制CIBP和 较低的阿片类药物将添加一种具有不同作用机制的非阿片类药物(S)。这可能会更好 控制疼痛，同时降低所需的阿片类药物，从而减少副作用。柳氮磺吡啶就是这样的 有可能。它是一种抗炎药物，具有既定的安全性。它已经使用了50多年了。 用于治疗一些炎症性疾病。此外，柳氮磺胺吡啶有能力降低 降低肿瘤细胞存活率，降低炎症介质数量。柳氮磺胺吡啶抑制血管内流 半胱氨酸和谷氨酸从癌细胞中流出。半胱氨酸是细胞抗氧化性生存所必需的 压力，而细胞外谷氨酸激活疼痛感受器。因此，柳氮磺吡啶将作为一种抗癌药物 发炎剂，一种加速癌细胞损伤和减少谷氨酸释放的试剂 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数量 适用于CIBP患者。降低阿片类药物的剂量将减少不必要的副作用。这项临床试验的目的 试验是对CIBP患者联合应用柳氮磺胺吡啶和阿片类药物，并描述他们的阿片类药物的使用和 改善他们的疼痛。我们的中心假设是在阿片类止痛药中加入柳氮磺吡啶 团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 同时减轻痛苦，提高整体生活质量。我们还预测柳氮磺吡啶可能会降低 血清中的炎性介质和肿瘤标志物。这项研究将在两个月内进行 盲目随机方式，有两个独立但相关的特定目标(SA)和一个探索性目标(EA)。 我们将评估柳氮磺吡啶是否会改善我们的初级和次级结果。我们的初选 结果是阿片类药物的减少。次要结果是减少疼痛和提高手术质量。 生命(SA1)。其次，检测治疗前血清谷氨酸、IL-6、肿瘤坏死因子-α和肿瘤标志物的水平 柳氮磺胺吡啶(SA2)治疗后。我们预计柳氮磺吡啶可以减少炎症介质。 第三，我们将评估柳氮磺胺吡啶治疗前后的血清肿瘤标志物水平。 与肿瘤影像研究(EA1)相关。我们期望柳氮磺吡啶能降低血浆肿瘤标志物。这个 获得的数据可能为医生提供更多的选择来管理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.