U01HD116257

Implementing and personalizing best-in-class opioid-sparing pain management for major inpatient surgeries in children - Project summary: The multicenter PRECISE ANALGESIA (Prospective Randomized Evaluation of Analgesia for Cardiac and Idiopathic Scoliosis Spine Fusion Elective Surgery in Children) trials will A) implement and investigate the efficacy and safety of multidose methadone-based standardized enhanced recovery after surgery (ERAS) protocol, and B) develop personalized ERAS protocols including precision methadone and oxycodone dosing and personalized analgesia for the safe and effective opioid-sparing management of surgical pain after posterior spine fusion (PSF) and cardiac surgery (CS) in children.

PSF and CS are both extremely painful surgeries in children requiring long hospital stays and high opioid use associated with adverse effects (AEs), high incidence of opioid dependence (OD), and chronic post-surgical pain (CPSP).

Post-discharge prescribed oxycodone is used for >1-2 weeks, and opioid dependence occurs within 5 days in children.

20-50% of children develop CPSP, largely due to severe uncontrolled acute surgical pain, contributing to life-long risks for opioid use/misuse and the ongoing opioid epidemic.

There is an urgent need for safe, effective opioid-sparing analgesia as well as proactive risk predictions and personalized analgesia to provide best-in-class immediate surgical pain relief while minimizing the risk of opioid-induced respiratory depression (RD), sedation, postoperative nausea and vomiting (PONV), CPSP, and persistent opioid use/misuse.

Recently, we showed that a methadone-based standardized ERAS protocol shortened hospital stays (2-4 days), reduced prescribed opioid use (5-7 vs. 7-18 days), and the risks of CPSP.

Despite this improvement, with standardized methadone ERAS, 30-40% of children still experienced uncontrolled severe pain, PONV, and sedation from methadone and oxycodone.

Our preliminary data show that CYP2B6 and ORM1 genotypes and alpha acid glycoprotein (AAG) contribute to the variation in pharmacokinetics (PK), analgesia, and adverse outcomes.

Our preliminary data in children undergoing CS with cardiopulmonary bypass (CPB) reveal opioid-sparing and safe postoperative analgesia with methadone.

We will now study the effect of CPB on intraoperative methadone dosing with robust PK modeling to enable precision methadone dosing for the first time in children.

Our expert multidisciplinary team will enroll a total of 1000 children to conduct two parallel randomized clinical trials for PSF (500 children 12-<18 yrs from 4 clinical sites) and CS (500 children 1 month-10 yrs from 5 clinical sites).

Specifically, we will 1. conduct two randomized clinical trials in PSF and CS to compare acute pain relief, opioid-sparing efficacy, and safety of standardized perioperative multidose methadone-based ERAS vs. standard-of-care non-methadone-based analgesia.

2. Develop precision methadone dosing based on age, CYP2B6 and ORM1 variants, AAG, and CPB, and 3. identify patient profiles that predict benefit from the assigned analgesia protocol to optimize clinical outcomes.

Overall impact: Implementation of evidence-based standardized methadone-based ERAS pain management and individualized risk prediction will maximize acute surgical pain relief while minimizing opioid use and AEs in millions of children.

University Of Pittsburgh - Of The Commonwealth System Of Higher Education

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Pittsburgh, Pennsylvania 152221808 United States

Single Zip Code

HEAL Initiative: HEAL KIDS (Knowledge, Innovation and Discovery Studies) Pain: Acute Pain Clinical Trials Program (U01 Clinical Trial Required) (RFA-HD-24-011)

Amendment Since initial award the total obligations have increased 97% from $3,404,830 to $6,720,269.