Christine B. Sieberg, Ph.D. - US grants

Project Summary/Abstract Pediatric chronic pain is a serious public health problem resulting in high levels of healthcare utilization and disability. The physical and psychological consequences associated with chronic pain impact overall health and can predispose the development of adult chronic pain. Specifically, there has been an inadequate amount of research conducted on pediatric persistent postsurgical pain (PPP), which is urgently required given that over 5 million children undergo surgery each year and 25% of adults presenting to chronic pain clinics identify surgery as the antecedent. The proposed translational research project utilizes animal models, humans, genetics, and psychophysiological techniques to enhance our understanding of these mechanisms. The long- term goal of this K23 award is for the candidate to establish an independent translational research career aimed at developing mechanistically based behavioral interventions. The intent of the proposed project is to develop an animal model exploring how gene-environmental interactions, age, and biological sex contribute to pre- and post surgical pain thresholds, which will serve as a first step to functionally assaying genetic mechanisms we hope to discover in the gene association arm of our human studies. The human arm of this project is two-fold; examining the role of childhood stress and genetic pain risk on current pain and functioning in a large cohort of adult surgical patients, as well as continuing an IRB-approved study examining the sensory, psychosocial, and genetic predictors of PPP and related functional disability in pediatric patients with either idiopathic scoliosis undergoing spinal fusion surgery or developmental dysplasia of the hip undergoing hip osteotomy. This population was selected as a model condition because these are orthopedic conditions affecting children, the children are otherwise healthy, and both surgeries are quite invasive and complex with our research indicating that that a high proportion of these patients go onto to develop moderate to severe pain after surgery. The primary training objective is to acquire expertise in pain genetics, animal models, and translational research. The candidate will accomplish this through: 1) mentorship in a clinical/research environment, 2) hands-on training in animal models and genetics by the candidate's sponsor and co-sponsors complemented by didactics in genetics and advanced statistics, and 3) execution of the proposed research plan. These studies will provide the necessary data to inform the development of an R01 to focus on an epigenetic model to identify study genes, which markedly alter the risk profile for PPP and which will inform the development of new drug targets and behavioral interventions for those at greatest risk.

Project Summary/Abstract Pediatric chronic pain is a serious public health problem resulting in high levels of healthcare utilization and disability. The physical and psychological consequences associated with chronic pain impact overall health and can predispose the development of adult chronic pain. Specifically, there has been an inadequate amount of research conducted on pediatric chronic postsurgical pain (CPSP), which is urgently required given that over 5 million children undergo surgery each year and 25% of adults presenting to chronic pain clinics identify surgery as the antecedent. The current translational research project utilizes animal models, humans, genetics, and psychophysiological techniques to enhance our understanding of these mechanisms. The long- term goal of this K23 award is for the candidate to establish an independent translational research career aimed at developing mechanistically based behavioral interventions. The intent of the proposed project is to develop an animal model exploring how gene-environmental interactions, age, and biological sex contribute to pre- and post-surgical pain thresholds, which will serve as a first step to functionally assaying genetic mechanisms we hope to discover in the gene association arm of our human studies. The human arm of this project is two-fold; examining the role of childhood stress and genetic pain risk on current pain and functioning in a large cohort of adult surgical patients, as well examining the sensory, psychosocial, and genetic predictors of CPSP and related functional disability in adolescent patients with idiopathic scoliosis (AIS) undergoing spinal fusion surgery. This population was selected as a model condition as patients with AIS are usually otherwise healthy, the surgery is invasive and complex and the candidate?s research indicates that that a high proportion of these patients go onto to develop moderate to severe pain 5 years after surgery once the patients are adults. The primary training objective of the K23 has been to acquire expertise in pain genetics, animal models, and translational research. The candidate is accomplishing this through: 1) mentorship in a clinical/research environment, 2) hands-on training in animal models and genetics by the candidate?s sponsor and co-sponsors complemented by didactics in genetics and advanced statistics, and 3) execution of the proposed research plan. These studies will provide the necessary data to inform the development of an R01 to focus on an epigenetic model to identify study genes, which markedly alter the risk profile for CPSP and which will inform the development of new drug targets and behavioral interventions for those at greatest risk.

Project Summary Statement of the Problem: Chronic post-surgical pain (CPSP), defined as pain lasting longer than two-months after surgery, is a significant public health problem affecting up to 80% of patients presenting for surgery. There are far-reaching consequences for quality of life and physical and emotional functioning for those affected by CPSP and complicating this crisis is the number of opioids prescribed after surgery with over 80% of patients receiving opioid prescriptions after low-risk surgery. Integrative research and effective treatment strategies are lacking. Overview of Research in the Laboratory: My grant funded research, including my current K23 Award, has focused on identifying biopsychosocial predictors of CPSP through the use of pre-clinical and clinical models and assuming a life-span perspective for identifying predictors and prevention of CPSP. In 2013, I published the largest prospective study to date identifying long-term pain trajectories and predictors of CPSP in young people and in 2018 results of Aim 1 of my K23 Award, utilizing an animal model of CPSP, received Editor?s Choice. My approach is to integrate clinical, psychological, and brain measures in order to understand the neurobiological processes that contribute to the evolution or resilience of CPSP. Goals for the Next 5 Years: In the next 5 years, I will continue to utilize a translational approach to examine risk factors for CPSP and extend upon my K23 work to: 1) utilize psychophysics and neuroimaging to understand the effects of CPSP on synaptic plasticity from adolescence into adulthood and 2) evaluate the effects of an evidence-based behavioral pain intervention, compared to Treatment as Usual, on the fNIRS signal in groups of adolescent and adult patients diagnosed with CPSP in order to compare Responders (improvement in pain severity, interference, & functioning) vs. Non-Responders. The projects outlined in the MIRA will be accomplished by my continued collaborations with colleagues who have expertise in surgery, pain psychophysics, neuroscience, and neuroimaging. Overall Vision of the Research Program: The goals of the R35 will be to: 1) enhance our understanding of the neurobiology of CPSP; 2) provide a metric to follow patients with CPSP in the clinic; 3) provide a metric for those who will chronify; 4) understand the age- related differences in CPSP; and 5) define an initial paradigm that may enhance our capability for developing individually tailored patient-oriented interventions at both a behavioral and pharmacological level.