Clinical trial NCT03847311
Conditions: Breast Cancer Chronic Pain Due to Malignancy (Finding)
Sponsor: University of Arizona
Start date: 2021-05-03; Completion date: 2023-10-09
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: Subjects will receive sugar pill. arm 2: Subjects will receive the active drug.
Interventions: intervention 1: Sulfasalazine intervention 2: Placebos
Intervention descriptions: intervention 1: This group will receive supplies for 3 months of sulfasalazine at an initial dose of 0.5 gram three times a day for a week then at a dose of 1 gram three times a day for the remainder of the 3 months. Subjects will be asked to take their medications with every meal in addition to their regular pain medications. intervention 2: This group will receive supplies for 3 months of sugar pills three times a day for 3 months. Subjects will be asked to take their medications with every meal in addition to their regular pain medications.

Protocol documents:
ICF_001.pdf: 
Official Title: 
Sulfasalazine in Decreasing Opioids Requirements in 
Breast Cancer Patients 
NCT number: 
3847311 
Document Type: 
Informed Consent Form 
Date of the 
Document: 
07/16/2021 


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Consent to Participate in Research
Study Title:  Double Blind Trial Investigating the Role of Sulfasalazine in Decreasing the Opioid 
Requirement in Breast Cancer Patients
Principal Investigator:  Mohab Ibrahim, MD., Ph.D
Summary of the research
This is a consent form for participation in a research study. Your participation in this research 
study is voluntary. It contains important information about this study and what to expect if you 
decide to participate.  Please consider the information carefully. Feel free to ask questions 
before making your decision whether or not to participate.
Cancer pain in general, and cancer-induced bone pain in particular, is a significant health 
problem in the USA and the rest of the world.  Patients with cancer-induced bone pain now are 
taking ever-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.  A better approach to better control cancer-induced bone pain and lower the 
amount of opioids used would be to add a non-opioid agent that has a different mechanism of 
action(s).  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 an anti-inflammatory 
drug with established safety profile.  It has been in use for over fifty years for the treatment of 
inflammatory conditions such as rheumatoid arthritis.
Sulfasalazine acts as an anti-inflammatory, agent and decreases production of glutamate, which 
activates pain receptor.  In addition, it has been shown to accelerate cancer cells death.  By 
different mechanisms of actions Sulfasalazine may lower the amount of opioid needed to treat 
cancer-induced bone pain while maintaining or improving pain control.  Lowering of opioid 
dosing may also decrease the side effects associated with opioid use that in turn may improve 
your quality of life.
This is a research study. If you choose to participate in this study, and are eligible to participate. 
You will be randomly assigned (like the possibility of getting “heads” or “tails” when flipping a 
coin) to receive either the study medication (Sulfasalazine) or Placebo (a substance that has no 
therapeutic effect,) (50% change to get one of them).  Neither you, nor the study doctor can 
choose which medication you will receive.  Your decision to take part in this study is voluntary, 
you are free to choose to take part or not.


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Why is this study being done?
Breast cancer is a very difficult and complex medical problem.  Pain usually comes with cancer.  
The current drugs available to treat cancer pain are usually strong opioids.  Even with high 
doses of opioids, the cancer pain may not be well controlled. Additionally, high doses of opioid 
may result in significant side effects.  This study is designed to investigate the possibility of 
better cancer pain control with less opioids by adding the non-opioid medication, sulfasalazine.
What will happen if I take part in this study? 
If you decide to participate in this study, you will be asked to sign this consent form.  Once you 
have signed the informed consent form and have met all eligibility criteria to participate, the 
following procedures will be conducted for your baseline visit.  You will be randomly assigned 
to either a placebo group (a substance that has not therapeutic effect) or the drug group 
(sulfasalazine).  You have 50% chance of being in either group.  The study start date and the 
outcome assessment timeline will begin from the date of your Placebo or drug administration. 
During your initial visit, we will collect several pieces of data from you that are considered 
standard of care.  Demographics, your work status, disability status, type of work, whether a 
previous pain physician has evaluated or provided treatment in the past, a detailed description 
of the pain (burning, electrical, shooting…etc.) and its location.  A detailed physical examination 
assessing the motor strength of the upper extremities, sensations to light touch and reflexes 
will be completed. You will be asked to give a numerical value for your pain (a scale from 0-10 
where 0 is no pain and 10 is the worst pain imagined) and a Mini Mental State test.  
We will also ask you to complete the following questionnaires at the beginning of the study, 
during the study and end of the study (for a total of 12 times.

EORTC QLQ-C30, this provides an overall assessment of the quality of life

Modified pain clinic questionnaire, which asks about the intensity and characteristic of 
your pain and daily activity.

Brief Pain Inventory questionnaire, this assesses the severity of pain and its impact on 
functioning.
On a daily basis, you will complete a diary of your daily pain medications, you will also 
document your study medication on this form.
For the follow up visits, data similar to the information gathered at the initial visit will be 
collected. The description of the pain (burning, electrical, shooting…etc.) and its location will be 
reviewed.  A physical examination assessing for pain and sensation to light touch that is part of 
the standard of care will be provided for you.  Blood and urine samples will be collected at 
every follow up visit.  We will be performing blood tests to check for your liver and kidney 
function.  We will be collecting your urine sample for monitoring of the, renal (kidney) functions 
for safety measures only.  This is to ensure your safety as the study drug may have rare, but 
serious side effects.  We will not be testing for any illicit drugs from these collected samples.  
Additionally, we will test for pregnancy at the start of the study and at week 6 into the study 
unless you have documented hysterectomy (surgical removal of the uterus) or are post-


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menopausal.  If applicable, we will also document tumor size, from available PET Scans at the 
beginning and end of the study.
The following is a schedule for the expected visits for this study after your baseline visit is 
completed:

Day 0 – Initial dose of placebo or study drug.

Week 2, 4, 6, 8, 10, 12  follow-up office visit. 

Complete an EORTC QLQ-C30 questionnaire.  This provides an overall assessment of the 
quality of life.

Complete a modified pain clinic questionnaire, which asks about the intensity and 
characteristic of your pain and daily activity.

Hand in your pain medication diary.

Physical Examination.

Mini Mental State Test

Blood work and urinalysis. These are done to check your kidney function and liver 
function tests, blood counts.  These are conducted as routine standard cancer 
treatments.  In addition 10 milliliters (2 teaspoons) of blood will be collected at your 
baseline visit, 6 week visit and last visit to analysis for inflammatory mediators and 
tumor markers. 

At the week six follow-up visit, there will also be a pregnancy test performed for those 
who need to be monitored.

The 12 week visit will be the END OF STUDY visit.
Throughout the study, you will have normal access to all your pain medications as usual, if 
needed.
 
How long will I be in this study?
The study start date and the outcome assessment timeline will begin from the date of your first 
placebo/drug administration. The study is expected to be 3 months long.
How many people will take part in this study?
Up to forty subjects will be enrolled in this study.
What benefits can I expect from being in this study?
You may or may not benefit as a result of participating in this study.  You may notice decreased 
pain intensity, decreased opioid requirement, or decreased side effects from opioids.
 
What risks, side effects or discomforts can I expect from being in the study?
Sulfasalazine has been in use for many decades in the United States.  The medication is very 
well tolerated.  The most common side effects include anorexia, headache, nausea, and 


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vomiting. However, on rare occasions, serious side effects have been reported that may result 
in blood disorder, gastrointestinal reaction (unpleasant or bothersome reaction in the mouth, 
esophagus, stomach or intestine), central nervous system reaction, renal reaction (reactions 
involving the kidneys), anaphylaxis (severe and possibly life-threatening allergies), folate 
deficiency, nephrolithiasis (kidney stones), oropharyngeal pain (pain in the mouth or 
esophagus), angioedema (severe allergic reaction involving tongue swelling, may be life-
threatening), purpura (purple skin rash) , pallor (looking pale), or even death.  Your treating 
physician will discuss with you if there is any concern of taking this medicine and your current 
ongoing cancer therapies.
What other choices do I have if I do not take part in this study?
You may choose not to participate in this study without penalty or loss of benefits to which you 
are otherwise entitled.  If you choose not to participate you will have access to regular pain 
management as covered by your medical insurance.
When may participation in the study be stopped?
The study may be stopped by the investigator for any of the following reasons:
1) Violation of any of the inclusion criteria.
2) Aggressive behavior towards the pain or palliative clinic staff.
3) Development of new or discovery of already existing medical condition(s) that was not 
present during the initial screening if such condition(s) may interfere with the study.
4) Sustaining an injury that may require additional pain medication or may interfere with 
accurate gathering of the data.
5) Hospitalization for any reason that prevents you from taking the study medication as 
instructed.
6) Any situation that hinders your access to study medications and follow-up appointment.
7) Refusal to accurately filling pain diaries and reporting them honestly to the pain or 
palliative clinic staff.
8) Becoming pregnant or expressing desire to become pregnant (the study medications 
may have adverse effects on a developing fetus or a nursing infant).
9) You decide to stop the study for any reason. 
10) Significant deviation from normal blood test values. 
What happens if I am injured because I took part in this study?
If you suffer an injury from participating in this study, we will identify the proper specialist to 
assist in managing the side effects. 
You will be provided with any new information that develops during the course of the research 
that may affect your decision whether or not to continue participation in the study.
The University of Arizona and Banner-University Medical Center have no funds set aside for the 
payment of treatment expenses for this study.


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What are the costs of taking part in this study?          
There are no anticipated additional costs for you to be in this study, except for your time.  
Regular medical care performed while participating in study will be billed to you and / or your 
insurance company as usual. Not all insurance companies are willing to pay for services 
performed in a clinical trial.  Please speak with your insurance company to find out what you 
may be financially liable for.
Will I be paid for taking part in this study?
You will be compensated for a total of $150 for the completion of the study. You will receive 
$50 after signing the consent, $50 after week 6 and $50 at the end of the study for a total of 
$150. If you quite the study or discharged from the study, you will not be asked to pay back the 
money you received, but you may not receive the subsequent payment. 
Compensation for participation in a research study is considered taxable income for you. We 
are required to obtain your name, address, and Social Security number for federal tax reporting 
purposes. If your compensation for this research study or a combination of research studies is 
$600 or more in a calendar year (January to December), you will receive an IRS Form 1099 to 
report on your taxes.  
Will my data or specimens be stored for future research?             
A small amount of blood will be stored in a -80 freezer and will be analyzed at a later time point 
for inflammatory mediators and tumor markers as indicated in this consent form.  The sample 
will be labeled with your study ID number and date of the blood draw.
Will my specimens be sold for commercial profits?         
No, your specimens will not be sold for commercial profit. 
Will I hear back on any results that directly impact me?            
Results from the blood tests may be shared with the subjects if they are clinically significant and 
have an impact on the study.  
Will Whole Genome Sequencing be done with my specimen?          
No, there will be no Genome Sequencing done with your specimen.
Will my study-related information be shared, disclosed, and kept confidential?
It is anticipated that there will be circumstances where your study related information and 
Protected Health Information (PHI) will be released to persons and organizations described in 
this form. If you sign this form, you give permission to the research team to use and/or disclose 
your PHI for this study. Your information may be shared or disclosed with others to conduct the 


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study, for regulatory purposes, and to help ensure that the study has been done correctly. 
These other groups may include:

Office for Human Research Protections, Food and Drug Administration, or other federal, 
state, or international regulatory agencies

Banner University Medical Group and Banner Health

The University of Arizona (UA) and the UA Institutional Review Board 

Your primary care physician or a specialist taking care of your health.
If you agree to take part in this study a copy of this signed informed consent form will be saved 
into your electronic medical record (EMR) at Banner Health. As a result, healthcare providers 
and staff who are not working on this study, but who may provide you medical treatment in the 
future, will know that you are taking part or took part in this study. 
Your PHI may no longer be protected under the HIPAA privacy rule once it is disclosed by the 
research team. 
What study-related information and PHI will be obtained, used or disclosed from my 
medical record at Banner?
Information related to this research study that identifies you and your PHI will be collected 
from your past, present, and future hospital and/or other health care provider medical records.
The PHI you are authorizing to be used and/or disclosed in connection with this research study 
is:

Any data collected related to this study.

Past medical and surgical history

Current medications

Age

Gender
Demographic information to be disclosed may include, but is not limited to, your name, 
address, phone number, or social security number. If you receive compensation for 
participating in this research study, information identifying you may be used or disclosed as 
necessary to provide that compensation.
Your existing health records may include information related to the diagnosis or treatment of 
sexually transmitted disease (STD), acquired immunodeficiency syndrome (AIDS), human 
immunodeficiency virus (HIV), other communicable diseases, genetic information (e.g., genetic 
testing), and/or alcohol and/or drug abuse. The study staff and study sponsor’s monitor may 
see this information while reviewing your regular health records for this study, but they WILL 
NOT create, collect, or disclose this type of information for the purposes of this research study.
When will my authorization expire?


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There is no expiration date or event for your authorization. Therefore, unless you cancel this 
authorization (as instructed below) this authorization will continue to be effective.
Do I have to sign this authorization form?
You do not have to sign this authorization. However, if you decide not to sign, you will not be 
able to participate in this research study; and it will not affect any non-study Banner Health 
medical treatment or health care, payment, enrollment in any health plans, or benefits.
What do I need to know if I decide to cancel my authorization?
After signing the authorization, you may decide to cancel your previous authorization for the 
research team to use your PHI. If you cancel the authorization, you will no longer be able to 
stay in the research study. Please note that any PHI collected before you cancel the 
authorization may still be used. You may revoke the authorization by contacting the Principal 
Investigator in writing. Contact information is under “Who can answer my questions about the 
study” at the end of this document. 
Will access be limited to your research study record during this study?
You may not have access to the research information developed as part of this study until it is 
completed.  If you’re interested, a brief summary of the results can be mailed to you.
Who can answer my questions about this study?
If at any time you feel you have had a research-related injury, or for questions, concerns, or 
complaints about the study you may contact t Mohab Ibrahim, MD, PhD at 520-874-7246.
For questions about your rights as a participant in this study or to discuss other study-related 
concerns or complaints with someone who is not part of the research team, you may contact 
the 
Human 
Subjects 
Protection 
Program 
at 
520-626-8630 
or 
online 
at 
https://research.arizona.edu/compliance/human-subjects-protection-program.
If you are injured as a result of participating in this study or for questions about a study-related 
injury, you may contact Mohab Ibrahim, MD, PhD at 520-874-7246
If you have questions, concerns, or complaints about the use or sharing of your health 
information or would like a copy of the Banner Notice of Privacy Practices, you may contact the 
Banner 
Research 
HIPAA 
Liaison 
at 
602-839-4583 
or 
BHResearchCompliance@bannerhealth.com. 
To cancel your authorization for access to PHI you must notify the Principal Investigator and/or 
Research Team in writing at the following address:
Research Coordinator
1501 N. Campbell Ave. Suite 4401
Tucson, Arizona  85724-5114


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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
Signing the consent form
I have read (or someone has read to me) this form, and I am aware that I am being asked to 
participate in a research study.  I have had the opportunity to ask questions and have had them 
answered to my satisfaction.  I voluntarily agree to participate in this study and I authorize the 
use and/or disclosure of my PHI. I am not giving up any legal rights by signing this form.  I will be 
given a signed copy of this form.
Printed name of subject
Signature of subject
Date
Investigator/Research Staff
I have explained the research to the participant or the participant’s representative before 
requesting the signature(s) above.  There are no blanks in this document.  A signed copy of this 
form has been given to the participant or to the participant’s representative.
Printed name of person obtaining consent
Signature of person obtaining consent
Date

Prot_002.pdf: 
Double Blind Trial Investigating the Role of Sulfasalazine in Decreasing Opioids Requirements 
in Breast Cancer Patients 
 
Page 1 of 5 
Version Date  7/16/2021 
Version 4 
Brief Summary 
Cancer pain in general, and cancer-induced bone pain in particular, 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 cancer, the number of patients with cancer 
are now living longer.  This great achievement created an unexpected problem.  For some 
cancer patients with bone metastases, pain is worse than the cancer itself. The golden standard 
to manage cancer-induced bone pain is opioids.  Patients with cancer-induced bone pain are 
now are taking ever-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 to better control cancer-induced bone pain and lower the amount of opioids used 
would be to add a non-opioid agent that has a different mechanism of action(s).  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 an anti-inflammatory drug with 
established safety profile.  It has been in use for over fifty years for the treatment of 
inflammatory conditions such as rheumatoid arthritis.  In addition to its anti-inflammatory 
characteristics, sulfasalazine has the capacity in decrease the survival of cancer cells and also to 
lower the amount of inflammatory mediators released by cancer cells. In short, sulfasalazine 
inhibits the influx of cysteine into cancer cells and the efflux of glutamate from cancer cells.  
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 three mechanisms of actions may lower the amount of opioid needed for cancer 
patients with cancer-induced bone pain while maintaining or improving their pain control.  
Lowering of opioid dosing may also decrease the side effects associated with opioid use which 
in turn may improve their quality of life.  The objective of this clinical trial is to co-administer 
sulfasalazine with opioids to patients with cancer-induced bone pain and characterize their pain 
and their opioid use.  Our hypothesis is that adding sulfasalazine to the pain medication 
regiment will lower the amount if opioids used and lower the side effects.  This may improve 
the quality of life for cancer-induced bone pain patients and decrease the risks of using high 
amount of opioids for the patients, their families, and society in general. The primary objective 
of this study is to decrease the amount of opioid pain medication use after addition of 
sulfasalazine for 12 weeks while controlling pain. The secondary objective is to decrease the 
intensity of pain and increase the quality of life. 
Study Description 
This double-blind clinical trial is intended for patients with moderate to severe cancer-induced 
bone pain on stable doses of opioids.  This study is expected to last 12 weeks from the time a 


Double Blind Trial Investigating the Role of Sulfasalazine in Decreasing Opioids Requirements 
in Breast Cancer Patients 
 
Page 2 of 5 
Version Date  7/16/2021 
Version 4 
patient first receives the assigned treatment. Each patient will have 7 clinic visits that are 
related to the study. Initially, we will conduct urine pregnancy test before the start of the study 
and at week 6 except for patients with documented hysterectomies. If a patient suspects she 
may be pregnant, additional urine pregnancy test will be conducted.  If the results suggest 
possible pregnancy, the patient will be excluded from the study. 
Patients with breast cancer-induced bone pain will be identified and recruited from the chronic 
pain clinic and from the oncology clinic at the University of Arizona.  The consent process as 
well as the pain evaluation will be conducted at the Chronic Pain clinic at South Campus or at 
the oncology clinic at main campus. Patients that meet our inclusion criteria and consent to the 
study will be randomized into either a placebo (sugar pill) or sulfasalazine group.  We estimate 
that a sample size of 16 subjects per group will be necessary based on the power calculations 
shown below. Because not all subjects will complete the study and provide evaluable data, we 
will enroll 20 subjects per group. Forty patients will be stratified according to age and randomly 
assigned to either a placebo or active treatment group in a 1:1 ratio.  The randomization 
sequence will be generated by the Biostatistics Shared Resource of UACC using a computer-
generated process.  The assignment of patients will be revealed only to the pharmacist. The 
pharmacist will also not be involved in communicating with patients or analyzing the data. 
Neither the patients nor the treating physicians will know into which group individual patients 
will be assigned. Initially, all patients will be given written surveys designed to assess for opioid 
use, pain level, and quality of life.  
The treatment group will receive supplies for 3 months of sulfasalazine at an initial dose of 0.5 
gram three times a day for a week then at a dose of 1 gram three times a day for the remainder 
of the 3 months.  Patients will be asked to take their medications with every meal (assuming 
three meals a day) in addition to their regular pain medications.  The placebo group will be 
asked to take capsules filled with cornstarch three times a day in a similar manner. 
The patients will return to the pain clinic or the oncology clinic for follow ups at 2 weeks (+/- 1 
week), 4 weeks (+/- 1 weeks), 6 weeks (+/- 1 weeks), and 8 weeks (+/- 1 week), 10 weeks (+/- 1 
week), and 12 weeks (+/- 1 week) at which times all follow-up measures from the surveys will 
be collected. Additionally, a physical exam will be performed on every patient at every follow 
up appointment. The physical examination will be focusing on the mental status by asking Mini 
Mental State test.  We will also examine the abdomen by light and deep palpation.  Any 
deviation from the normal limits will result in un-blinding the effected patient (to elucidate 
whether he/she is a control or a treatment group) and withdrawal from the study.  If intestinal 
or urinary obstruction is suspected, the appropriate imaging studies will be conducted and a 
consultation with the appropriate surgical service will be requested if indicated.   
The following is a summery table of safety monitoring and assessments that will be conducted 
at every follow-up.  The pregnancy test will be conducted before the start of the study and at 
week 6 (not included in the following table) for pre-menopausal patients. 


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History will focus on symptoms of porphyria, intestinal, urinary obstruction, or blood dyscrasia. 
• Neuro exam Mini mental state test 
• Abd exam Light and deep palpation of the abdomen 
• CBC Complete blood count with differential 
• BMP Basic metabolic panel with renal function 
• LFT Liver function tests 
• UA Urinalysis 
Finally, blood and urine samples to monitor for side effects from the study medication. The 
manufacture of sulfasalazine recommends that blood test be done every two weeks to monitor 
for side effects. Sulfasalazine may cause anemia and decreased white blood cells. Additionally, 
it may cause liver and renal damage. Therefore, blood and urine will be collected at every 
follow up by a phlebotomist who is not part of the study. The collected samples will be labeled 
by the research team. The blood sample will be used for safety monitoring by analyzing the 
basic metabolic panel and complete blood count.  At the baseline, Week-6, and Week-12, 
additional blood will be immediately centrifuged and the plasma will be stored in a -80 degrees 
Celsius freezer for later analysis for inflammatory mediators and tumor markers. The collected 
urine will be used for urinalysis. Any significant deviation from the baseline values of the CBC, 
liver function, renal (basic metabolic panel) function, or UA will result in un-blinding of the 
effected patient, withdrawal from the study, and consultation with the appropriate service.  
  
Patients will be given four paper surveys to assess for pain level, pain medication use, and 
quality of life. We will utilize a modified pain assessment questionnaire which is used in our 
pain clinic to assess for pain intensity, frequency, duration, ability to fall and stay asleep, and 
ability to exercise, this will be completed weekly. We will also utilize the Brief Pain Inventory 
(short form) for additional pain assessment. The Brief Pain Inventory (BPI) is a valid, clinically 
useful pain assessment tool that has been used extensively in people with cancer Its purpose 
would be to assess the severity of pain and the impact of pain on daily functions. It includes a 
diagram to note the location of pain, questions regarding pain intensity (current, average, and 
worst using a 0 to 10 rating scale), and items that evaluate impairment due to pain. This would 
be used to assess their pain in a systematic approach. The short form survey should take about 
5 minutes and will be administered at study entry and end of study. There is no scoring 
algorithm but the arithmetic mean of the four severity items can be used as measures of pain 
severity and the arithmetic mean of the seven interference items can be used as a measure of 
pain interference.  
We will use the EORTC QLQ-C30 survey which assess global improvement in the quality of life. 
The EORTC QLQ-C30 version 3.0 will be used to assess quality of life. The questionnaire is 
multidimensional in structure, brief and easy to complete, and applicable across a range of 


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cultural settings. This questionnaire would be collected at the start of the trial, week 2, week 4, 
week 6, week 8, week 10 and the end of the 12 week pilot trial.  
Finally, patients will be provided with a pain medication log to document the amount of pain 
medications needed Subjects will record their opioid pain medication use - both long acting and 
breakthrough pain.  They will be asked to record their opioid pain use daily (both long acting 
and breakthrough pain meds). In addition, we will also capture data regarding NSAID’s, Tylenol 
and other medications used for pain and document the daily study medication.  A research 
nurse or study coordinator will make weekly calls to the patient to ensure they are taking 
assigned drug (placebo or sulfasalazine), assess side effects, and recording pain medication use. 
At the end of study, the drug diary will be collected. Due to the subjective of pain, we chose 
verified and well accepted surveys that are used in clinical settings to have a more relevant data 
for better interpretation. 
All surveys will be conducted at baseline before starting any treatment. The pain medication log 
will be done on daily basis. At the end of the study, all data will be gathered and compiled for 
statistical analysis. The study will be conducted at both the pain clinic at south campus and at 
the oncology clinic at main campus. 
In terms of the blood analysis for inflammatory mediators, ten milliliter blood sample will be 
collected at the baseline visit, week 6 and at the end of the study (week 12) for all enrolled 
patients. These three time points will allow us to understand the temporal effect of 
sulfasalazine on inflammatory mediators. The mid-time point will allow us to maximize the data 
extraction in case so patients may wish to quit the study before week 12. All samples will be 
collected from the antecubital fossa. The blood samples will be spun at 12,000 RVM for 10 
minutes and the serum will be stored in -80 degree Celsius freezer until analyzed. We will utilize 
commercially available enzyme-linked immunosorbent assay (ELISA) kits to measure the 
inflammatory mediators IL-6, and TNF-alpha. Glutamate will be measured using Amplex Red 
Glutamic Acid Oxidase Assay kit. Additionally, we will measure tumor markers for breast cancer 
including CA 27.29 and CEA using commercially available ELISA kits, we will also collect tumor 
measurements from standard of care PET scans to evaluate the tumor size. 
The data will be analyzed when all participants complete the trial. At that point we will unblind 
the subjects and finalize the data analysis.  
Inclusion Criteria: 
• Adult patients aged >18 and 95< year old.  
• Diagnosis of cancer with 3-day average numeric pain rating score (NPRS) for pain of at 
least 5/10 at baseline evaluation.  
• On opioid regiment for at least 3 weeks. This time frame will allow patients to have a 
stable opioid regiment as it typically takes a few weeks of titration of opioids to reach 


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an acceptable dosing. Having a stable opioid regiment will allow us to better be able to 
interpret the effects of sulfasalazine.  
• Pain duration of at least 6 weeks or more.  
• Prognosis greater than 6 months 
• Able to take oral medication.  
 
Exclusion Criteria:  
• Patients with intestinal or urinary obstruction or at risk of such disorders. 
• History of porphyria 
• History of blood dyscrasias, hepatic disease (ALT and AST greater than 2.5X the upper             
limit of normal). 
• History renal disease (serum creatinine greater than 1.5 mg/dl) 
•  Patients taking Lapatinib or Digoxin. 
•  No sustained hypercalcemia (blood calcium level greater than 10.4 mg/dl). 
• Hypersensitivity to sulfasalazine, its metabolites, sulfonamides, or salicylates. 
• The patient is or becomes incarcerated.  
• History of addictive behavior, severe clinical depression, or psychotic features.  
• Possible pregnancy or lactation. 
• Those receiving remuneration for their pain treatment (e.g., disability, worker’s 
compensation).  
• Those involved in active litigation relevant to their pain.