Respiratory depression from opioids is an important clinical problem that impedes safe delivery of pain relief especially in children. My clinical experience as a pediatric pain physician - anesthesiologist, and my research background in morphine pharmacogenomics, have both pointed to the imperative of an a priori preventive approach to this problem. The proposed prospective study is based upon robust associations for morphine induced respiratory depression (MIRD) with race and genetic variants [ATP-Binding Cassette (ABCB1) transporter, the endocannabinoid system (Fatty Acid Amide Hydroxylase/FAAH) and the ?-opioid receptor (OPRM1)], as well as better prediction of MIRD with ABCB1-FAAH interactions, that we observed in our preliminary studies. Due to the multifactorial nature of MIRD, I envision an algorithm that incorporates multiple factors (genetic, clinical and their interactions) to provide best predictive outcomes. My long-term goal is to become an independent and high impact research scientist with a focus on perioperative application of pharmacogenomics to improve the safety and efficacy of pediatric healthcare. My institution, Cincinnati Children's Hospital (CCHMC), one of the nation's largest pediatric hospitals, ranks 2nd among pediatric medical centers in NIH-funded research and 3rd among all Honor Roll hospitals in the U.S. News &World Report survey (2012). It has a dedicated Genetics Pharmacology Service, state-of-the art research resources and a vibrant intellectual ambience that provides a conducive environment for my research, complimented by the unique facilities at Dr. Sadee's laboratory at Ohio State University (OSU). My mentoring team include my primary mentors, who are NIH funded seasoned experts in translational outcomes research, functional pharmacogenomics and molecular genetics, and have extensive experience mentoring junior investigators: Dr. Heubi, CCHMC's Principal Investigator (PI) for the Clinical and Translational Science Award (CTSA), which pioneers novel translational research and Dr. Sadee, PI for the NIH/NIGMS sponsored XGEN project at OSU, Columbus, OH, my mentor from the PGRN network;on-site co-mentors, Drs. Vinks, Sadhasivam and Martin at CCHMC, who will mentor me in the areas of pharmacometrics, clinical pharmacogenetics and statistical genetics. A structured mentoring plan has been designed to facilitate smooth interactions, including bimonthly visits to OSU, online data sharing and weekly Skype meetings with Dr. Sadee, weekly face-to-face meetings with on-site mentors and co-mentors, and regular video-conferences among all. My research career development plan spans hands-on laboratory training, clinical research experience, and structured didactics in key areas: 1) Pharmacogenomics, genetic study design and analysis, 2) Functional genomics and molecular genetics, 3) Clinical trial design, research ethics and Bioinformatics, 4) Effective scientific communication and grant writing, and 5) Pharmacokinetic-Pharmacodynamic (PK-PD) analysis. The scientific objective of this application, in alignment with my long-term goal, is to identify ad characterize determinants of MIRD in children. The central hypothesis is that the risk of MIRD is determined by interacting clinical and identifiable genetic factors responsible for variations in response. The hypothesis will be tested by pursuing the following specific aims in 300 children (aged 10-18 years) undergoing spine surgery:
Specific Aim 1. Determine if race and sex contribute to MIRD risk;the working hypothesis is that risk of MIRD (defined clinically: respiratory rate <8 per minute for >3 minutes, and experimentally: depressed carbon dioxide minute ventilation response) is increased in individuals of European descent (genetically defined using ancestry information markers using a Genome Wide Association Study array) and female sex. Using logistic regression we will test for associations;known clinical predictors like morphine doses, hyperoxemia, pain scores and co-administration of sedatives will be included as covariates.
Specific Aim 2. Determine if specific genetic variants contribute to MIRD risk;the hypothesis is that inter-patient variability in MIRD is associated with specific ABCB1, FAAH and OPRM1 variants and their interactions. Analysis will be done using logistic regression after population stratification. Significant variables from Aim 1 will be included as covariates. Exploratory Aim: Explore associations with MIRD for variants in select genes involved in the opioid-MIRD and morphine pharmacokinetic (PK) pathway using a discordant phenotype approach to maximize identification of associations. Morphine concentration data will be analyzed to evaluate genetic effects on PK/PD. The rationale for the proposed research is that it facilitates my development as an independent clinician scientist, cross-trained in translational research and pharmacogenomics, while advancing the understanding of safer use of opioids in clinical practice, and the use of multifactorial predictive modeling in pediatric healthcare situations. This study is innovative in its systematic and rigorous approach in investigating the effects of clinical, novel genetic factors and their interactions, on objective and life threatenin respiratory depression phenotypes, and morphine PK/PD, in a pediatric post-surgical homogenous pain model. The proposed research is significant as it is expected to result in transformative, preemptive individualized risk stratification which can guide clinical decision making for tailored safer use of morphine, while providing strong preliminary data for a competitive R01 application in the future. This proactive approach to risk stratification is a necessary departure from the status quo, which is an inadequate and reactive trial-and-error clinical dosing strategy.

Public Health Relevance

The proposed research is relevant to public health because it advances the understanding of safer use of opioids for pain relief, and the clinical integration of multifactorial predictive modeling in pediatric healthcare. Thus, it is especially relevant to the part of NIH's mission that pertains to cross-training a physician in translational research and pharmacogenomics, while supporting patient-oriented research to improve drug safety, quality of perioperative pediatric healthcare and clinical implementation of pharmacogenomics research information.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZRG1)
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Ren, Zhaoxia
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Chidambaran, V; Venkatasubramanian, R; Zhang, X et al. (2016) ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children. Pharmacogenomics J :
Chidambaran, V; Mavi, J; Esslinger, H et al. (2015) Association of OPRM1 A118G variant with risk of morphine-induced respiratory depression following spine fusion in adolescents. Pharmacogenomics J 15:255-62
Chidambaran, Vidya; Venkatasubramanian, Raja; Sadhasivam, Senthilkumar et al. (2015) Population pharmacokinetic-pharmacodynamic modeling and dosing simulation of propofol maintenance anesthesia in severely obese adolescents. Paediatr Anaesth 25:911-23
Chidambaran, Vidya; Costandi, Andrew; D'Mello, Ajay (2015) Propofol: a review of its role in pediatric anesthesia and sedation. CNS Drugs 29:543-63