Sulfasalazine in Decreasing Opioids Requirements in Breast Cancer Patients

Overview

Cancer in general, and breast cancer in specific, is a significant health problem in the USA and the rest of the world. With the improvement of new surgical approaches and chemotherapies to manage breast cancer, the number of patients with breast cancer are now living longer. This great achievement created an unexpected problem. For some breast cancer patients, with bone metastases, the pain is worse than the cancer. The golden standard to manage pain is opioids. Patients with cancer-induced bone pain are now taking increasing doses of opioids to control their pain. Sadly, opioids come with significant side effects that limit the amount of opioids that can be safely given. Many attempts have been tried to create better regiments for pain control to lower the need for opioids. There has not been significant success in that area. A better approach would be to add a non-opioid agent that has dual mechanisms of action. This may create synergism to better control pain while lowering the doses of opioids needed and lowering side effects. Sulfasalazine poses such quality it is a safe anti-inflammatory drug with established safety profile. It has been in use for over 50 years for the treatment of inflammatory conditions such as arthritis. In addition to its anti-inflammatory characteristics, sulfasalazine has the capacity to decrease the survival of cancer cells, also to lower the number of inflammatory mediators released by cancer cells. In short, sulfasalazine inhibit the influx of cysteine into cancer cells and the efflux of glutamate. Cysteine is needed for cell survival against oxidative stress, while glutamate activate pain receptors. Therefore, sulfasalazine will act as anti-inflammatory, an agent to accelerate cancer cells death and decreasing the released glutamate which activate pain receptors. This one agent with 3 mechanisms of actions may lower the amount of opioid needed for these patients while maintaining or improving their pain. Lowering of opioid dosing may also improve the side effects associated with opioid use. The purpose of this trial is to co-administer sulfasalazine with opioids to cancer patients and characterize their pain and the opioid use. Our hypothesis is that adding sulfasalazine to the pain medication, will lower the amount of opioids used and lower the side effects. This may improve the quality of life for patients and decrease the risks of using high amount of opioids for the patients, their families, and society in general.

In the United States, approximately one in two men and one in three women will develop cancer. Today, more than 15 million people live with cancer in the United States alone. The direct annual medical cost of cancer is over 86 billion US dollars. The indirect cost, representing loss of wages and productivity, exceeds 130 billion US dollars annually. It is estimated that 90% of all cancer patients report pain. About 63% of patients with advanced stage cancer or with metastasis suffer from pain that is classified as "moderate to severe". The majority of cancer patients suffer from excruciating pain. Even those who survive cancer may still experience pain. Of all cancer survivors, 59% report pain secondary to chemotherapy. Even after patients are cured from their cancer, 33% of these patients will still suffer from severe pain due to their chemotherapy. Inadequate pain management results in 67% of patients with severe pain. Notably, 32% of cancer patients reported a desire for suicide secondary to their pain. Opioids have been the gold standard to treat cancer pain. Sadly, there are many side effects associated with chronic opioid use. It has been shown in animal models that chronic use of opioids has been associated with paradoxical effects. Rats that have been exposed to chronic opioids developed hyperalgesia, which is an exaggerated response to a painful stimulus and allodynia, which is a painful response to a non-painful stimulus. There have been several mechanisms proposed to explain the paradoxical hyperalgesia phenomena observed. This phenomenon has been recognized in patients inflected with chronic pain and managed with chronic opioid. It has been long observed that patients with chronic pain require gradually increasing doses of opioids. The reasons for this increase in opioid requirement may be complicated. While the progression of the disease may play a significant part in increasing doses of opioid, other factors such as tolerance and opioid induced hyperalgesia cannot be ignored. Tolerance is a characteristic of opioids that is well investigated and results in increasing the doses of opioids to maintain the original analgesic effects. Changing of brain circuitry enables opioids to play a sinister role allowing it to produce pain. Additionally, patients develop physical dependence with their use of opioids. A more significant aspect of chronic use of opioid is the psychological dependence on opioids. While its understandable and necessary for cancer patients to have opioids to control their pain, finding adjuvant pain control therapy may lessen the amount of opioids needed. Using neuropathic pain medications as adjuvants to supplement opioids had mixed results. Therefore, a different agent with different mechanism is action may be needed for better pain control with less opioids. Cancer cells have high metabolic rate that generate high oxidative stress burden. Cancer cells require glutathione to combat oxidative stress for survival. Cysteine is required for the synthesis of glutathione. Cells acquire cysteine be exchanging intracellular glutamate for the extra cellular cysteine through the Cysteine/Glutamate antiporter. Excreting glutamate results in increased pain through the activation of N-methyl-D-aspartate receptor (NMDA). If an agent can be identified that inhibits the Cysteine/Glutamate antiporter, the cancer cells will have less chances of survival secondary to decreased glutathione that's is needed for protection from oxidative stress. Additionally, decreased amount of the glutamate secreted from the cells may lower the amount of pain produced. Sulfasalazine is a safe and well-established anti-inflammatory drug with potent inhibitory properties of the cysteine/glutamate antiporter. Utilizing sulfasalazine for cancer patients, in conjunction with opioids, may reduce the amount of opioids needed in two different methods. First, sulfasalazine may decrease the survival rate of cancer cells, thus lowering the mechanical burden of the cancer. Second, sulfasalazine may decrease the amount of glutamate released by cancer cell resulting in less activation of the NMDA receptor. The investigator proposes a clinical trial to administer sulfasalazine to initially focus on breast cancer patients with pain. The pain may be from the primary tumor or from metastasis. The investigator hypothesis that sulfasalazine will reduce cancer pain, the amount of the opioids needed, and the undesirable side effects associated with high doses of opioid.