Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Spinal cord injury (SCI) is associated with severe neuropathic pain that is often refractory to pharmacological intervention. Preliminary data suggest brivaracetam is a mechanism-based pharmacological intervention for neuropathic pain in SCI. Based on this and other reports in the literature, SCI-related neuropathic pain is hypothesized to occur largely because of upregulation of synaptic vesicle protein 2A (SV2A) within the substantia gelatinosa of the injured spinal cord. Furthermore, compared to placebo, brivaracetam treatment is hypothesized to reduce severe below-level SCI neuropathic pain and increases parietal operculum (partsOP1/OP4) connectivity strength measured by resting-state functional Magnetic Resonance Imaging (rsfMRI). Circulating miRNA-485 levels may be associated with change in pain intensity due to brivaracetam treatment. The study aims to determine the efficacy of brivaracetam treatment for SCI-related neuropathic pain.

Purpose:

Spinal cord injury (SCI) is associated with severe neuropathic pain that is often refractory to pharmacological intervention. Our preliminary data suggest brivaracetam is a mechanism-based pharmacological intervention for neuropathic pain in SCI. Based on our data and other reports in the literature, we hypothesize that SCI-related neuropathic pain occurs largely because of upregulation of synaptic vesicle protein 2A (SV2A) within the substantia gelatinosa of the injured spinal cord. We further hypothesize that, compared to placebo, brivaracetam treatment reduces severe below-level SCI neuropathic pain and increases parietal operculum (parts OP1/OP4) connectivity strength measured by resting-state functional Magnetic Resonance Imaging (rsfMRI). We also hypothesize that circulating miRNA-485 levels may be associated with change in pain intensity due to brivaracetam treatment. To test these hypotheses, we will conduct a randomized, double-blind, placebo-controlled clinical trial to determine the efficacy of brivaracetam treatment for SCI-related neuropathic pain. We therefore propose the following:

Specific Aims:

Specific Aim 1: Determine whether a 7-week course of daily brivaracetam reduces below-level neuropathic pain in SCI. The objective of this aim is to assess efficacy of a 7-week course of brivaracetam to reduce neuropathic pain in men and women with SCI. We will assess change in pain intensity and related outcomes, including mood, satisfaction with life, and community integration. We will monitor drug adverse events and tolerability.

Specific Aim 2: Determine whether a 7-week course of daily brivaracetam increases parietal operculum brain connectivity. The objective of this exploratory aim is to assess the effect of a 7-week course of brivaracetam treatment on parietal operculum activation and connectivity in SCI. We will assess changes in cortical activity of related pain perception regions and networks in the brain in response to brivaracetam treatment compared to placebo using rsfMRI and pain-related task-based fMRI. To achieve this aim, we will test the working hypothesis that brivaracetam increases parietal operculum activation and connectivity compared to placebo, using rsfMRI, task-based fMRI, and a validated image processing protocol. We will also examine changes in network connectivity and brain activity in the insula, because of its concurrent reported importance for neuropathic pain in SCI. We will assess the association between functional connectivity of the parietal operculum and the insula and change in pain intensity in response to brivaracetam treatment.

Specific Aim 3: Determine whether baseline microRNA-485 levels are associated with response to brivaracetam treatment. The objective of this exploratory aim is to assess microRNA expression as a potential predictive biomarker of response to brivaracetam treatment. To achieve this, we will test the working hypothesis that baseline circulating miR-485 levels predict change in pain intensity in response to brivaracetam treatment. To test this, we will use Next-Generation sequencing. We will assess miR-485 levels at baseline and after a three-month treatment course.

Significance of Research Question/Purpose:

There is currently no effective pharmacological treatment for severe neuropathic pain in SCI. Identification of an oral medication that is effective, safe, and well tolerated would represent a major improvement in the clinical approach to neuropathic pain in SCI. Additionally, there are no validated predictive biomarkers of response to pharmacological therapy in neuropathic pain after SCI. This work is innovative as it seeks to develop a new, mechanism-based pharmacological intervention for neuropathic pain in SCI. Additionally, this project seeks to identify novel biomarkers of neuropathic pain and response to therapy. Development of a reliable, easy to measure biomarker that distinguishes responders from non-responders would dramatically improve clinical care for this condition. Successful completion of this work will rapidly lead to larger clinical trials testing drug efficacy and validating novel predictive biomarkers of treatment response.

Inclusion Criteria:

• 18 years of age or older
• Injured for > 3 months
• Completed inpatient rehabilitation and living in the community
• Chronic sublesional neuropathic pain defined as persistent pain (VAS grade 3-10) for three months or more
• For people of child-bearing potential: currently practicing an effective form of two types of birth control (defined as those, alone or in combination, that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly).

Exclusion Criteria:

• Progressive myelopathy secondary to posttraumatic cord tethering or syringomyelia
• Active use of drugs known to interact with brivaracetam: rifampin, carbamazepine, sodium oxybate, buprenorphine, propoxyphene, levetiracetam, and phenytoin.
• Brain injury or cognitive impairment limiting the ability to follow directions or provide informed consent
• Pregnancy or lactation
• Epilepsy or active treatment for seizure disorder
• Past or current suicidality
• Active treatment for psychiatric disease
• Drug addiction
• Moderate or heavy alcohol intake (up to four alcoholic drinks for men and three for women in any single day, and a maximum of 14 drinks for men and 7 drinks for women per week)
• Hepatic cirrhosis, Child-Pugh grades A, B, and C
• Impaired renal function (GFR<60ml/minute)
• Contraindications to brivaracetam or pyrrolidine derivatives including allergy
• Active clinically significant disease (e.g., renal, hepatic, neurological, cardiovascular, pulmonary, endocrine, psychiatric, hematologic, urologic, or other acute or chronic illness) that, in the opinion of the investigator, would make the patient an unsuitable candidate for this trial.
• History of malabsorption or other gastrointestinal (GI) disease that may significantly alter the absorption of brivaracetam
• Use of any investigational drug 30 days prior to enrollment in this study
• Enrollment in another clinical trial.