Preclinical Evaluation of Mechanisms and Therapies for Persistent Post-Traumatic Headache (PPTH)
Abstract
Relevance to Topic Area(s): Our proposal is well aligned with two FY20 PRMRP topic areas: Chronic Migraine and Post-Traumatic Headache (primary focus) and Sleep Disorders and Restrictions. Specific areas of encouragement include research on optimal approaches to effective management of acute and chronic post-traumatic headache (PTH) pain, evaluation of efficacy of existing or emerging pharmaceuticals and research on treatment of sleep disorders, especially after traumatic brain injury (TBI). All of these are addressed in our proposal. TBI occurs frequently as a result of blows to the head due primarily to falls, motor vehicle accidents, assaults, sports-related injuries, exposure to blasts, and other injuries that are common in both the civilian and military populations. Each year in the U.S. this translates into approximately 2.8 million TBI-related emergency department visits with over 2 million individuals being diagnosed with mild TBI (mTBI). mTBI is commonly referred to as concussion and is defined as a transient alteration of brain function usually caused by a direct head impact. Military personnel represent a group at much higher risk for TBI than that observed in the general population. Between 2000 and 2016, approximately 360,000 U.S. Service Members were diagnosed with TBI, of which over 80% were classified as mTBI. In the military, the median healthcare cost for Veterans with TBI is three times higher than that for Veterans without TBI. PTH is the most common symptom following mTBI. Although some PTHs resolve quickly, a large proportion of individuals with PTH do not have headache resolution and demonstrate persistent PTH (PPTH). PPTH can manifest as repeated episodic headache attacks or continuous non-relenting pain. There are no approved treatments for PTH or PPTH, and other headache therapies typically provide little benefit for those who develop PPTH. mTBI patients also frequently report disruption of sleep. Pain can disrupt sleep and disrupted sleep can increase pain, creating a viscous spiral that greatly diminishes quality of life preventing active military Service Members from achieving in their jobs and negatively impacting Veterans in civilian life. Rationale of Our Application: Many if not most, patients present to the headache clinic with migraine-like symptoms weeks or months after their initial concussion injury. For many patients, PPTH may have already been established and may be maintained by adaptations within brain circuits resulting in pain and additional comorbidities including sleep-wake disturbances. The pathophysiology of PPTH likely differs from initial acute PTH, and treatments become more difficult as patients transition into the persistent state. We have developed a preclinical model of PPTH that is elicited by a weight drop onto a closed- and unfixed skull of a lightly anesthetized mouse. This allows for free motion of the head that imparts linear and rotational acceleration that mimic a typical human mTBI and are important to the injury process. In accordance with the clinical classification of mTBI, the injury in the mouse model causes no skull fractures, no seizures, no cavitation, and no lesion or significant neuronal loss as confirmed by magnetic resonance imaging (MRI). This model has allowed us to characterize PTH as an immediate, but transient, period of pain that is followed by a long-lasting PPTH phase with vulnerability to triggers that can promote headache in humans including stress. Goals and Approach: We wish to identify mechanism-based treatments that could be effective for PPTH even when administered after established mTBI-induced adaptations in brain circuits. We will investigate two potential therapies: (1) BTRX-335150, a novel kappa opioid receptor (KOR) antagonist that poses no risk of addiction and is currently in phase 2 clinical trials, and (2) onabotulinum toxin A (Botox) available for intradermal application. The potential utility of a KOR antagoni
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110569
Entities
People
- Frank Porreca
Organizations
- United States Army
- University of Arizona