Posttraumatic Headache: Basic Mechanisms and Therapeutic Targets

Joshua Kamins, MD; Andrew Charles, MD


Headache. 2018;58(6):811-826. 

In This Article

Practical Strategies for Advancing the Understanding of PTH and Developing new Therapies

The development of treatments for PTH has been hindered by lack of evidence regarding its clinical features, clinical course, predisposing factors, basic mechanisms of resolution vs progression, predictive biomarkers, and acute and preventive therapy. Each of these areas represents an opportunity for the advancement of the understanding of the mechanisms of PTH and the care of those who suffer from it. An obvious first step is the large–scale collection of high quality, prospective data regarding PTH patients including personal and family history of headache, detailed information about the clinical features of headache and associated symptoms, clinical course over time, and the response to therapeutic interventions. The creation of an effective database for collection and storage of this information would be very helpful, but in order for this database to be useful, it is essential that there are high standards for the information that is collected and included. Genetic studies of well–defined patient groups or families with clear histories of PTH may provide important information. Well–designed functional and structural imaging studies of PTH have the potential to continue to provide critically important information about neural and vascular mechanisms that may be therapeutic targets. Imaging studies of brain perfusion and neurovascular function, brain metabolism, and connectivity may all contribute to new understanding of PTH. Structural imaging studies of white matter tracts and cervical nerve roots also hold promise for providing important new information.

Blood, saliva, CSF, or imaging biomarker studies have the potential to augment phenotypic observations regarding prognosis, appropriateness of early therapeutic intervention, and specific therapies that may be indicated. To date, biomarker studies in traumatic brain injury have focused primarily on diagnosis and stratification of the severity of brain injury.[122–124] None have thus far provided meaningful information about PTH. Biomarker studies evaluating prognostic indicators or therapeutic targets that guide the initiation of therapy and the specific type of therapy are critically needed. An obvious first target is measurement of neuropeptides such as CGRP and PACAP that could potentially be targeted with antibody or small molecule therapies.

As discussed above, there is a wide variety of targets for therapeutic approaches that could be addressed with clinical trials. The most straightforward studies could use currently available treatments that are reasonably tolerated – exercise, caffeine and other adenosine receptor antagonists and agonists, antiinflammatories, glutamate receptor antagonists, Substance P receptor (NK1) antagonists, hormonal therapies, and therapies targeting cervical nerve root branches are among currently available approaches that could be tried for PTH. Peripheral nerve and central neuromodulation approaches are also attractive candidates for treatment of PTH. There is rapidly mounting evidence in support of therapies targeting CGRP or its receptor for migraine; there is good reason to believe that these treatments, when available, will be effective for PTH as well.

There are a number of challenges with performing prospective clinical trials for PTH, including variability of mechanisms of injury and phenotype, determination of the appropriate time windows relative to trauma for the performance of studies, and determination of the most appropriate and meaningful outcome measures. Pilot studies for PTH therapies will likely need to address not only therapeutic efficacy, but also address these issues with trial design. And, while it is unlikely that randomized controlled studies will be performed for the majority of potential PTH therapies, it may be possible to perform pilot studies that could be leveraged by high quality data that capture detailed information about phenotype and clinical course across a large number of patients who experience head/neck trauma. This approach has already provided some meaningful information, but if done on a much larger scale could provide even more important insights. Data from genetic, imaging, and serum studies could be layered on top of the clinical data, but these more specialized (and expensive) studies should not hinder the development of an infrastructure to collect basic clinical information. Since only a small fraction of patients with PTH will see a headache specialist, it is important to activate this data–collection infrastructure on the "front lines" where head/neck trauma is commonly encountered; that is, in emergency departments, sports medicine, military health, and primary care settings. Ideally, a digital infrastructure for the large–scale collection of high quality patient–entered data could be developed, such that data could be collected outside of specialized centers.

The horizon is bright for the understanding and treatment of headache disorders. A better understanding of posttraumatic headache and its distinct vs shared mechanisms with primary headache disorders will position us to take advantage of advances in the field of headache medicine in general and apply these advances to the development of more definitive therapeutic approaches for posttraumatic headache.