Non-Opioid Pramipexole and Pain

Study Overview
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Brief Summary
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The long-term goal of this proposal is to identify non-opioid drugs that harness endogenous anti-inflammatory mechanisms resulting in the suppression of proinflammatory cytokines such as IL-1ß providing a novel approach to treat chronic pain in people while lacking potential for addictive side effects. Specific Aim I: pramipexole blocks the activation of NLRP3 and consequent production and release of the proinflammatory cytokines IL-1ß, IL-6 and TNF-α, and increases production of the anti-inflammatory cytokine interleukin-10 (IL-10). The goal of Aim I (Phase I) experiments is to examine the specific anti-inflammatory mechanisms of pramipexole on PAMP, DAMP and opioid stimulated immune cells, THP-1 cells will be used. Specific Aim II: pramipexole treatment will provide therapeutic benefit to patients experiencing suboptimal pain relief from current standard therapy with concurrent reduction of TLR4-NLRP3-cytokine expression in peripheral blood mononuclear cells. The goal of Aim II (Phase II) will be to determine the therapeutic benefit of pramipexole for pain, which is a repurposing of this FDA-approved drug with a good safety profile. 1.2. Our overarching hypothesis is that pramipexole will control clinical pain by suppressing the activation of the TLR4-NLRP3-IL-1ß pathway and prevent IL-1ß release from peripheral immune cells. These findings have provided the current impetus to examine pain therapeutic drugs targeting immune-related factors either upstream or downstream of IL-1ß signaling.

Detailed Description
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The long-term goal of this proposal is to identify non-opioid drugs that harness endogenous anti-inflammatory mechanisms resulting in the suppression of proinflammatory cytokines such as IL-1ß providing a novel approach to treat chronic pain in people while lacking potential for addictive side effects. This study is conducted to determine the therapeutic benefit of pramipexole for pain, which is a repurposing of this FDA-approved drug with a good safety profile. In collaboration with Dr. Koshkin (co-I at UNMH Pain Clinic), patients from the UNM pain clinic will be recruited who are experiencing modest or suboptimal pain relief. The patient will meet the CTSC Clinical Research Coordinator, who will escort the patient to the Clinical Research Lab. At the time, an explanation of the study, consent, the Brief Pain Inventory survey will be completed, blood draw and Clincard will be given to the patient ($15/visit). Scheduling for the midterm visit to the CTSC (at the end of two weeks) will be determined. At the time of consent, all patients will be under standard pain treatment and will be randomized into two groups: (1) patients receiving pramipexole in addition to their standard ongoing pain treatment, or (2) no pramipexole but will continue to receive the standard pain treatment. Patients will be followed up in the morning at weekly intervals to provide pain scores either by phone (for week 1 and 3), or by return visit (for end of week 2 and at the end of week 4) until study termination which is at the end of week 4.. At the initiation of the study and at the end of 4 weeks, blood will be collected and analyzed for mRNA for TLR4, p38, NFkB, NLRP3-ASC, Caspase-1, IL-1ß, TNF-α, HMGB1, and IL-10. The dose and route of administration of pramipexole will be identical to that previously approved for the treatment of Restless Legs Syndrome and according to manufacturer's recommended prescribing protocol (Mirapex, Boehringer Ingelheim Int. GmbH). Briefly, oral dosage will be titrated each week to achieve a weekly total daily dose of 0.125 (mg), 0.250, or 0.5. Patients will take one capsule containing pramipexole of placebo 2-3 hours before bedtime. Patient recruitment, assessment of Brief Pain Inventory (BPI): Pain scores and blood draws will be conducted at the CTSC Participant Clinical Interactions Unit with the CTSC Clinical Research Coordinator. Blood samples collected by the CTSC Clinical Research Coordinator will be analyzed at the Center for Molecular Discovery by personnel from Dr. Milligan's lab, trained by personnel from the Center for Molecular Drug Discovery (Director; Dr. Sklar, co-I). Personnel from the Milligan lab have expertise in inflammatory marker analysis from PBMCs [57, 58]. All freshly collected blood samples will be frozen and stored by the Clinical Research Coordinator at the CTSC Clinical Laboratory and will be transported to the Center for Molecular Drug Discovery once ALL of the samples for the study have been collected for mRNA and protein analysis. This is to allow for assay to be conducted at the same time to avoid potential effect of 'time of assay' that may impact data. All subjects will therefore meet with the CTSC Clinical Research Coordinator for a total of 3 times; at the initiation of the study, at mid-term when the second batch of drug is dispensed and unused drug is returned, and at termination for a second and final blood draw and providing all completed Brief Pain Inventory surveys (4/patient). At the termination of the study, patients will turn in their paper copies of the Brief Pain Inventory questionnaire completed for each week of the study (total 4 weeks). Original data records are important to demonstrate all necessary physical documentation of the study. The long-term goal of this proposal is to identify non-opioid drugs that harness endogenous anti-inflammatory mechanisms resulting in the suppression of proinflammatory cytokines such as IL-1ß providing a novel approach to treat chronic pain in people while lacking potential for addictive side effects.

Official Title
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Non-opioid Pramipexole Suppresses Immune NLRP3 Reactivity for Pain Control

Conditions
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Chronic Pain

Intervention / Treatment
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* Drug: Pramipexole Oral Tablet
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Nonmalignant chronic pain patients at University of New Mexico Pain Clinic, reporting suboptimal pain control, who state an interest to try something new to improve pain relief Pain score of 5 or greater (0-10 scale) Pain lasting more than 3 months Exclusion Criteria: Patients who do not speak English or Spanish Patients unable to consent Women who are not post-menopausal, or who have not undergone an oophorectomy/hysterectomy Patients who have chronic pulmonary, kidney or liver disease Patients with a body mass index (BMI) ≥35 Patients with a cancer diagnosis within the last 2 years (except non-melanoma skin cancer) Patients who are currently lactating Patients with a history of orthostatic hypotension Patients diagnosed with a dissociative disorder Patients with Parkinson's disease, and/or currently taking dopamine agonist prescription medications Prisoners and other institutionalized individuals

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Standard Treatment + Placebo<br>Patients reporting sub-optimal results of pain therapy, assigned to placebo in addition to routine care. | Other: Placebo<br>* Administration of placebo<br>|
| Experimental: Standard Treatment + Pramipexole<br>Patients reporting sub-optimal results of pain therapy, assigned to receive pramipexole in addition to routine care. | Drug: Pramipexole Oral Tablet<br>* Initial dosage of 0.125 mg pramipexole daily, potentially titrated upward in 0.125 increments to a maximum of 0.5 mg daily, for 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brief Pain Inventory score | Change in self-reported effect of pain on quality of life. The Brief Pain Inventory, Short Form, instrument will be used. It consists of two parts. The first part records anatomical location, and severity (0-10 scale; 10= worst pain) at its worst, at its least, on average over the past 24 hours, and immediately during the office visit. The second part records pain treatments received, the relief they provide (0-10 scale, 10 =most relief) and the extent to which pain interferes with certain affective and physical parameters (0-10 scale, 10 =worst disruption) including general activity, mood, walking ability, work, relations with others, sleep, and enjoyment of life. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mRNA Analysis | Separate gene expression analysis of each cytokine following blood collection before and after treatment will be TLR4, p38, NFkB, NLRP3-ASC, Caspase-1, IL-1ß, TNF-α, HMGB1, and IL-10 mRNA using standard operating procedures for mRNA analysis against a standard housekeeping gene. Patients' changes in specific mRNA levels will be correlated to patients' changes in pain scores. | 4 weeks |