Eva Widerstrom-Noga, Ph.D.

Neurotrauma-related Neuropathic Pain Phenotypes and Biomarkers; Standards for Pain Assessment, Taxonomy and Classification after Spinal Cord Injury

Background: Chronic pain is a serious and often insufficiently managed consequence of spinal cord injury and traumatic brain injury (SCI/TBI). This type of pain can be both persistent and severe causing significant psychosocial impact and substantially reduced quality of life beyond the other medical consequences of SCI/TBI. Neuropathic pain associated with SCI/TBI is not consistently relieved by currently available treatments and even the best pharmacological interventions require a relatively high numbers-needed-to-treat to obtain one person with 50% or more pain relief. Indeed, pain relief, together with issues related to occupational and sexual activities, has been identified as a significant unmet need after spinal cord injury. The refractory nature of pain following SCI/TBI and the associated psychosocial burden emphasize the need for a greater understanding of the pain phenotype, that is, the convergence of pathophysiological mechanisms, genotypic polymorphisms, and environmental factors that instruct the pain experience. While basic research has identified multiple underlying mechanisms of neuropathic pain and designed interventions to target them, significant knowledge gaps remain as to the best methods for the characterization of pain phenotypes. This is problematic because the pain phenotype can inform the underlying pain mechanism, and hence the best intervention. Because an individual’s experience of neuropathic pain is likely dependent on multiple mechanisms, this knowledge gap is a significant barrier to successful management of their pain.

My research program is focused on the identification of clinical correlates of underlying mechanisms of neuropathic pain after neurological injury in order to facilitate translation of basic research findings and the development of clinical interventions that can be tailored to an individual. My research focus is interdisciplinary and involves extensive multimodal evaluation of pain symptoms and psychosocial impact, and quantitative assessment of neurological function and biomarkers including high resolution MR spectroscopy of the brain (metabolites) and genetic analysis (polymorphisms). Additionally, I gather qualitative information to identify the existing barriers and facilitators to coping and pain management from people with spinal cord injury and persistent pain, the ultimate goal being to present information that can aid in the management of a patient’s pain.

Sensory signs: Understanding the relationship between sensory abnormalities and the neuropathic pain is critical if these measures are to be used to further the diagnosis of neuropathic pain and provide links to specific pain mechanisms. Previous results from our laboratory suggest that neuropathic pain is commonly exacerbated by multiple innocuous factors, situations, and behaviors. We also found that greater extent of sensory abnormalities was not only significantly associated with neuropathic pain but also with greater psychosocial impact. Similarly, recent data supported the reliability and validity of quantitative sensory testing (QST) in the SCI chronic pain population. Our data suggest that the use of QST is an important tool for defining pain phenotypes.

Pain phenotypes: Our analysis of pain history data from 156 persons with SCI and neuropathic pain provided support for the presence of specific pain symptom patterns or “profiles” after SCI that are associated with psychosocial factors. We have also shown that specific neuropathic pain phenotypes are perceived as particularly disturbing and predictive of using prescription medication. Further research combining pain and psychosocial characteristics with QST data provided evidence that multidimensional clinical neuropathic pain phenotypes can be characterized reliably in people with SCI with regard to pain severity, somatosensory function, and coping strategies. In summary, the identification of multidimensional pain phenotypes is a way to forward the understanding of the underlying mechanisms of pain and thus facilitate both translational pain research and design of more effective treatment strategies.

Brain imaging: Neuroimaging suggests that pain perception is dependent on a network of sensory cortical areas, limbic areas, associative cortex, and subcortical structures, such as the thalamus. Dysfunction in these networks may underlie the generation and maintenance of chronic pain and associated conditions. Magnetic Resonance Spectroscopy (MRS) is a non-invasive method to assess brain chemistry. MRS can determine the distribution and concentration of naturally occurring molecules such as N-acetylaspartate (NAA), one of the most common amino acids of the brain, myo-Inositol (Ins), glutamine/glutamate, and others. In our early work, MRS was used to assess metabolic activity in the thalamus of people with SCI and chronic pain. Severity of pain was found to be significantly correlated with low NAA and high Ins concentrations. The low levels of NAA were hypothesized to be related to a decreased function of inhibitory neurons in the thalamic region, whereas higher concentrations of Ins were hypothesized to reflect gliosis. Indeed, our follow on MRS studies of the thalamus and anterior cingulate cortex in people with and without SCI-related neuropathic pain after SCI have provided further evidence that a combination of decreased glutamatergic metabolism and the proliferation of glia and glial activation contributes to the development of severe neuropathic pain after SCI.

Standards for pain assessment and taxonomy: If a basic goal of SCI pain research is ultimately to understand the nature of pain in individuals with spinal cord injury, the development and use of valid and reliable pain measures, a taxonomy, and a pain classification system greatly enhance the field’s ability to move efficiently toward that end. So in addition to my research, I am directly involved with several international consortia that have the expressed goal of developing these guidelines and instruments.

Barriers/facilitators to pain management: Because the perception of pain and its impact is a highly personal experience, a qualitative study approach finding answers to questions that begin with “Why”, “How”, and “In what way” is an effective way to capture a holistic, complete picture of pain associated with SCI. My research is exploring several areas where important and critical knowledge gaps exist, i.e., barriers and facilitators to optimal pain management, including individual treatments and self-remedies, attitudes, coping, role of social support, and on the impact of pain on each individual, including barriers and facilitators to return-to-work and participation in clinical trials.