Sulfasalazine in Decreasing Opioids Requirements in Breast Cancer Patients
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Breast Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 2/23/2019 |
| Start Date: | July 15, 2019 |
| End Date: | December 31, 2020 |
| Contact: | Mohab M Ibrahim, PhD., MD |
| Email: | mibrahim@anesth.arizona.edu |
| Phone: | 5208747246 |
Double Blind Trial Investigating the Role of Sulfasalazine in Decreasing Opioids Requirements in Breast Cancer Patients
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 treat 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, pain is worse than the cancer itself. The golden standard to manage pain is
opioids. These patients now are taking increasing doses of opioids to control their pain.
Sadly, opioids come with significant side effects. These side effects limit the amount of
opioids that can be safely administered. 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 actions. 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 amount 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 cancer patients while maintaining or improving their pain control. Lowering of opioid
dosing may also improve the side effects associated with opioid use. The purpose of this
clinical 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.
and the rest of the world. With the improvement of new surgical approaches and chemotherapies
to treat 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, pain is worse than the cancer itself. The golden standard to manage pain is
opioids. These patients now are taking increasing doses of opioids to control their pain.
Sadly, opioids come with significant side effects. These side effects limit the amount of
opioids that can be safely administered. 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 actions. 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 amount 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 cancer patients while maintaining or improving their pain control. Lowering of opioid
dosing may also improve the side effects associated with opioid use. The purpose of this
clinical 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.
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.
Inclusion Criteria:
- Adult patients capable of understanding and providing consent in English and capable
of complying with the outcome used.
- Diagnosis of cancer with pain moderate to severe pain on stable doses of opioids
- 3-day average numeric pain rating score (NPRS) for pain of at least 4/10 at baseline
evaluation.
- Patient consents to double blind design of the experiment in a shared decision- making
process with the treating physician.
- Pain duration of at least 6 weeks or more.
- Prognosis greater than 6 months.
Exclusion Criteria:
- Those receiving remuneration for their pain treatment (e.g., disability, worker's
compensation).
- Those involved in active litigation relevant to their pain.
- Subjects with intestinal or urinary obstruction or at risk of such disorders.
- Porphyria
- Blood dyscrasias, hepatic or renal disease.
- Taking medications that may interact with sulfasalazine.
- Taking Lapatinib or Digoxin.
- History of hypercalcemia.
- Hypersensitivity to sulfasalazine, its metabolites, sulfonamides, or salicylates.
- The Subject is incarcerated.
- Those unable to read English and complete the assignment in English.
- Addictive behavior, severe clinical depression, or psychotic features.
- Possible pregnancy or lactation.
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