Research

CRPP Pain - Work Packages

PAIN – A COMPLEX AND DEBILITATING SEQUELAE

The management of patients with chronic pain is a problem shared by many medical disciplines. Chronic paincontinues to pose a major, unmet challenge for modern medicine with tremendous global healthcare costsaffecting approximately 19% of the population. With the increasing incidence and high prevalence of chronic pain conditions, coordinated interdisciplinary efforts (rheumatology, orthopedics, spine surgery, chiropractic medicine and neurology) in the diagnostic work-up (i.e., unified assessment of pain types, differentiation of distinct mechanisms) and targeted treatment strategies will be essential to improve our understanding and management of chronic pain.

Independent of the diverse clinical presentations of chronic pain conditions, a common underlying pathophysiological mechanism is sensitization along the nociceptive neuraxis. Sensitization processes can be driven by continuous or repetitive afferent inputs, while are also under the influence of supra-spinal modulation. The relative contributions of facilitatory and inhibitory mechanisms are likely to differ across various pain conditions and individual patients. By dissecting the impact of peripheral, spinal and supra-spinal processes we will provide a common framework for mechanistically oriented therapies across disease entities.

Understanding peripheral and central sensitization may promote not only better profiling and diagnosis of pain patients, but also the development of new mechanism-based therapies. Some of the mechanisms underlying sensitization can be translated from animals to humans providing new venues for the development of therapies and drug profiling.

 

FROM PHENOTYPES TO MECHANISMS

Through such a multi-disciplinary endeavor we pay tribute to the complex nature of pain and its biopsychosocial underpinnings arising from the interaction of multiple neural systems, i.e., peripheral nerves, spinal cord, brain stem and cortex, while also incorporating cognitive and affective processes. Our proposal encompasses a broad spectrum of chronic pain conditions, such as neuropathic pain after traumatic spinal cord injury (SCI),

degenerative cervical myelopathy (DCM), complex regional pain syndrome (CRPS), as well as low back pain (LBP) due to Modic changes or unknown etiology. In this way, we ensure an adequate coverage of contributions from different neural systems to the clinical challenge of ’pain’.

A particular strength of this CRPP with its four work packages (WPs) is that experts from diverse fields will collaborate to identify pathophysiological differences and commonalities across different diagnostic categories.

We will determine signs of nociceptive sensitization that are indicative of the neuroanatomical level of sensitization. This is the first step for targeted pain treatment where WP1 deconstructs the clinical pain phenotype employing a standardized clinical and neurophysiological test battery. Here we gather information on clusters of sensory abnormalities, integrity of residual afferent tracts, nociceptive processing, as well as sensory-autonomic interaction within and across the different diagnostic categories. Sensitization processes are examined in WP2 and WP3. WP2 will address peripheral sensitization processes by investigating the molecular signature of pain. This will provide insights into how nociceptors are sensitized and afferent input is structurally and functionally remodeled over time across a variety of pain conditions. The identification of pro-inflammatory mediators contributing to the clinical phenotype (WP1) will facilitate the development of targeted treatments. Central (spinal and supraspinal) sensitization processes will be investigated in WP3. Here we aim to determine the prevalence and magnitude of spinal and supraspinal sensitization across different chronic pain conditions, and to gain precise knowledge of descending pain modulation and its alteration in chronic pain states. Both WP2 and WP3 will be accompanied by animal studies designed to understand the mechanistic bases of peripheral sensitization (excitability of primary nociceptors) (WP2) and endogenous pain modulation (WP3). A more precise mechanistic understanding is essential for developing precision medicine with regard to pain. The close collaborations between clinical and basic pain research proposed in this CRPP will also be of immense importance for future projects where phenomena with respect to peripheral and central sensitization observed in humans will be back-translated into animal models. Finally, WP4 examines computational mechanisms of subjective pain perception. Using state-of-the-art computational neuroimaging methods, including ultra-high fields (7 Tesla) functional MRI, emerging hierarchical Bayesian theories of pain perception will be tested in healthy volunteers. In particular, we will strive for mathematically formal characterizations of the mechanisms that mediate the effects of expectations and subjective control. Notably, one of the paradigms that will be established in healthy volunteers will also be transferred to WP3, for  computational phenotyping of patients.

 

PRECISION MEDICINE AS A COMMON VISION

Our common goal with this CRPP is to move from the current empirical therapeutic approaches, often with many attempts and yet dissatisfactory outcomes) to personalized targeting of disorder-specific mechanisms in chronic pain patients. We are convinced that information exchange between clinical disciplines, i.e. neurology, rheumatology, chiropractic medicine, orthopedics, and basic research in neurobiology and neuromodeling will provide a successful venue for the generation of novel knowledge regarding pain mechanisms underlying different diseases. This will afford a sound scientific basis for improved patient treatment and informed clinical trials.