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.
