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Chronic Pain

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Pain

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Quality of Life

Chronic Graft Versus Host Disease

280 mg dried cannabis pellet -(9% THC / 2% CBD per pellet)

280 mg dried extracted cannabis pellet (0% THC / 0.6% CBD per pellet)

1 pellet smoked three times a day with titanium pipe (280 mg dried cannabis pellet - 9% THC / 2% CBD per pellet)

PPP001

1 pellet smoked three times a day with titanium pipe (280 mg dried cannabis pellet - 0% THC / 0.6% CBD per pellet)

placebo

Antonio Vigano, MD, MSc

Cancer causes pain in many of the patients that it affects. Physicians specialized in palliative care help advanced cancer patients to maintain as good pain control as possible through the use of medications such as opioids. Even with palliative care and optimal use of medications, many patients still suffer enormously as the cancer spreads. Because of this, some cancer patients also try or use cannabis in different ways to relieve their pain and improve the way they feel. However, there has not been much high-quality research done yet to prove whether or not cannabis products are truly useful to relieve severe cancer pain. This study is to test if advanced cancer patients who use inhaled medical cannabis (PPP001), in addition to palliative care management, will experience improvement in quality of life and relieve uncontrolled pain, providing safety conditions.

This is a 4-week randomized, double-blind, placebo-controlled, parallel group design trial to evaluate the safety and efficacy of inhaled PPP001 to improve quality of life (HRQoL) and reduce pain intensity, in patients with uncontrolled cancer pain and incurable malignancy.

Nine hundred forty six adult patients, male and female, with chronic cancer pain (at least 3 months in duration) and advanced disease, with an average weekly pain intensity score greater than 4 on a 11 points Numerical Rate Scale (NRS), will be prospectively recruited and invited to participate in this trial.

Informed consent will be obtained by a Research Assistant.

After baseline documentation with standardized scales, patients will be randomized to one of 2 parallel groups:

Group A: 4 weeks PPP001-kit three times daily; Group B: 4 weeks placebo-kit three times daily; The inhalation of PPP001 or placebo-kit will be allowed three times a day at 4-6 hour intervals. Rescue medication will also be allowed.

Patients will have a dose titration phase during the first week, followed by an additional 3-week period of treatment. The dose escalation will allow patients to adapt to the potential AEs of cannabis.

Patients will have follow-up after 1 week and 4 weeks of treatment. Once the patient has completed 4 weeks of inhaled PPP001 or placebo, it will be rolled into a long-term follow-up phase until drop-out or death. All patients, including the ones in the placebo group, will be allowed to receive the active treatment once the 4-weeks trial has finished, and continue it until death or drop-out.

Safety and Efficacy of Smoked Cannabis for Improving Quality of Life in Advanced Cancer Patients

Safety and Efficacy of PPP001-kit for Improving Health Related Quality of Life in Advanced Cancer Patients With Uncontrolled Pain: A Randomized, Double-blind, Placebo-Controlled, Parallel Group Study

Does the daily use of PPP001-kit improve European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 15 Palliative (EORTC-QLQ-C15-PAL). Scale range is 1 to 4; 1 (Not at All) being the worst rating to the maximal rating of 4 (Very Much).

Changes in pain as measured by the Brief Pain Inventory-Short Form (BPI-SF) scale. Scale range is 0 to 10; 0 (No pain) being the best rating to the maximal rating of 10 (Pain as bad as you can imagine).

Changes in symptom burden as measured by the revised Edmonton Symptom Assessment System version with Constipation and Sleep was added to assess improvement in symptom burden (ESAS-r-CS). Scale range is 0 to 10; 0 (No symptom) being the best rating to the maximal rating of 10 (Worst possible score for symptom).

Changes in Palliative Performance Scale (PPSv2) version 2. Scale range is a left to right and downward scale for participant to find the best description of their palliative performance. Worst being 0% score representing Dead to PPS 100% representing Full ability to interact and function.

Changes in Caregivers Quality of Life Index- Cancer (CQOLC). Scale range is 0 to 4; 0 meaning Not at All affected and 4 meaning Very Much affected.

Changes in validated Udvalg for klinische Undersøgelser (UKU) Side Effects Rating Scale, Self-rating version for Patients (UKU-SERS-Pat). Scale range is 0 to 3 for rating the degree of severity and a second scale for the investigator that assigns a casual relationship of improbable, possible or probable.

Changes in validated Mini-Cog. Scale range is numerical and rates the ability to recall words and ability to draw a clock showing numbers from 1 to 12 and then drawing the given time.

Changes in a 100-mm VAS of good drug effect, and a VAS for the items "high," "relaxed," "stressed," and "happy" (0 = not at all, 10 = extremely)

Changes in concurrent medications will be measured using the Medication Quantification Scale (MQS) version III. The MQS version III is a method of quantifying different pain drug regimens by evaluating the use of 22 distinct drug classes (e.g., nonsteroidal anti-inflammatory drugs \[NSAIDs\], antidepressants, benzodiazepines, opiates). A single value is calculated based on a patient's pain medication profile, taking into account dosages, and the types of pain medications prescribed.

Changes in validated European Quality of Life-5 Dimensions (EQ-5D). First scale range provides 5 statements that describe the participants health TODAY; it includes 5 different health assessments. The second scale is 0 to 100 and requires that the participant places a mark on the scale showing how good or bad they feel TODAY; 0 meaning The worst health they can imagine; 100 meaning the best health they can imagine.

Changes in pain as measured by the Numerical Rating Scale (NRS). The NRS is a measure of the average weekly pain intensity score greater than on a 0 to 10 points scale where 0 is No Pain and 10 is the worst pain.

Changes in validated Memorial Delirium Assessment Scale (MDAS). Scale range is 0 to 3; 0 meaning None and 3 meaning Severe.

Rescue medication will be based on the calculation of 10% of the total morphine equivalent daily dose (MEDD). The reduction or increase in the total MEDD will be recorded after starting treatment with PPP001.

Tetra Bio-Pharma

Neoplasms

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Analgesics

All Drugs and Chemicals

Central Nervous System Depressants

Anti-Infective Agents

Anti-Inflammatory Agents

Antirheumatic Agents

Gastrointestinal Agents

Analgesics, Opioid

Sulfasalazine

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

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.

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.

Placebos

Mohab M Ibrahim, PhD., MD

Mohab Ibrahim, PhD., MD

Mohab Ibrahim, MD., Ph.D

Vangie Steinbrenner

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.

The research pharmacist will randomize and prepare the drugs so that the drugs look similar, the pharmacist will dispense the drugs into vials, and label the drug so is not identified.

Sulfasalazine in Decreasing Opioids Requirements in Breast Cancer Patients

Double Blind Trial Investigating the Role of Sulfasalazine in Decreasing Opioids Requirements in Breast Cancer Patients

By adding Sulfasalazine we hope to decrease the amount of pain intensity.

By adding Sulfasalazine we hope to decrease the daily use of opioids, lowering side effect of opioids, and capacity to perform more daily activities

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Efficacy of Smoked Cannabis for Improving Quality of Life in Advanced Cancer Patients	NCT03339622	Cancer Chronic Pain Du...	PPP001 placebo	18 Years -	Tetra Bio-Pharma
Sulfasalazine in Decreasing Opioids Requirements in Breast Cancer Patients	NCT03847311	Breast Cancer Chronic Pain Du...	Sulfasalazine Placebos	18 Years - 94 Years	University of Arizona
Safety and Efficacy of Smoked Cannabis for Improving Quality of Life in Advanced Cancer Patients	NCT03339622	Cancer Chronic Pain Du...	PPP001 placebo	18 Years -	Tetra Bio-Pharma
Safety and Efficacy of Smoked Cannabis for Improving Quality of Life in Advanced Cancer Patients	NCT03339622	Cancer Chronic Pain Du...	PPP001 placebo	18 Years -	Tetra Bio-Pharma

Spots Global Cancer Trial Database for chronic pain due to malignancy (finding)