Non-Opioid Pramipexole and Pain

Early Phase 1

Completed

Conditions: Chronic Pain

Interventions: Drug: Pramipexole Oral Tablet
Other: Placebo

Registration Number: NCT03842709

Lead Sponsor: University of New Mexico

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 13

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard Treatment + Pramipexole	Pramipexole Oral Tablet	Patients reporting sub-optimal results of pain therapy, assigned to receive pramipexole in addition to routine care.
Standard Treatment + Placebo	Placebo	Patients reporting sub-optimal results of pain therapy, assigned to placebo in addition to routine care.

Primary Outcome Measures

Name	Time	Method
Brief Pain Inventory Score	4 weeks	Change in self-reported effect of pain on quality of life. The "Brief Pain Inventory, Short Form," instrument will be used. It records severity (0-10 scale; 10= worst pain) at its worst.

Secondary Outcome Measures