2025/07/24 by Sean Mackey · 1 voice
Economics, Econometrics and Finance · Medicine · #Biomedical Ethics and Regulation #Health Systems, Economic Evaluations, Quality of Life #Health and Medical Research Impacts
paper · doi:10.1097/01.asm.0001125748.29617.0f
openalex publication_date 2025/07/24 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/23
Dr. Sean Mackey presenting the 24th Annual FAER-Helrich Research Lecture, titled “From Pain's Enigma to Clinical Transformation: Unraveling Mechanisms, Forging Biomarkers, and Empowering Clinicians and Patients,” at ANESTHESIOLOGY® 2024 in Philadelphia.The journey from treating pain as a subjective experience to delivering precision medicine represents one of the most significant transformations in our field. As I reflected during last year's FAER-Helrich Research Lecture, my own career trajectory began with a Foundation for Anesthesia Education and Research (FAER) Research Training Grant (RTG) characterizing CNS correlates of pain using neuroimaging. This initial support catalyzed research which would eventually help establish that objective biomarkers of pain were possible. What made FAER uniquely valuable, however, went far beyond financial support. When I submitted my first FAER proposal, Steven Shafer, MD, FASA, – ASA Monitor Editor-in-Chief – dedicated an entire weekend to copyediting my grant with me. Though unfamiliar with my research focus, he taught me two enduring lessons: the power of well-crafted scientific prose and the importance of paying it forward to future generations. Later, immediate past FAER President Jim Eisenach, MD, provided career-altering advice by encouraging me to bypass the traditional NIH K award path and aim directly for R01 funding – guidance that accelerated my independent research career by years. These personal investments in early-career investigators exemplify how FAER's impact extends far beyond funding. Pain's persistent challenge Pain affects over 50 million Americans, with high-impact chronic pain disabling more than 20 million adults, at an annual cost exceeding half a trillion dollars (MMWR Morb Mortal Wkly Rep 2018;67:1001-6; Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. 2011). Many of these chronic pain cases originate from acute pain after injury or surgery, positioning anesthesiologists at a critical intervention point. Our understanding of pain mechanisms has vastly outpaced the precision of our diagnoses, treatment selections, and outcome predictions. These remain stubbornly imprecise – often based on trial-and-error approaches that fail many patients. Biomarkers: Moving beyond subjective assessment Pain biomarkers represent a transformative opportunity to move from subjective assessment to objective, mechanism-based approaches (Reg Anesth Pain Med 2025;50:110-20; Pain Rep 2019;4:e762). Early neuroimaging work from anesthesiologists and others established proof of concept for diagnostic and prognostic pain biomarkers, but we've since recognized that pain's complexity demands multimodal biomarker approaches (Pain 2014;155:2502-9; PLoS One 2011;6:e24124; Pain 2017;158:1069-82; Pain Rep 2019;4:e762; Cereb Cortex 2014;24:1037-44; N Engl J Med 2013;368:1388-97; Nat Rev Neurol 2020;16:381-400; Reg Anesth Pain Med 2025;50:110-20). Neuroimaging biomarkers can now identify pain signatures, detect central sensitization, and predict treatment responses. Molecular biomarkers – from inflammatory cytokines to neurotrophic factors – provide insights into underlying pathophysiology. Genetic and epigenetic markers help explain individual variability in pain experiences. Emerging electrophysiological techniques like EEG offer additional windows into dysfunctional pain processing, while behavioral assessment through quantitative sensory testing and actigraphy provides critical functional data (J Neurosci Methods 2023;385:109766; Nat Rev Neurol 2020;16:381-400; Reg Anesth Pain Med 2025;50:110-20; Gut Microbes 2023;15:2195792; Neuroimage 2024;296:120681). The future of pain diagnosis, management, and prognosis lies in composite biomarker signatures integrating neuroimaging, molecular, electrophysiological, and behavioral data to capture the full biopsychosocial experience of pain. This integration enhances both diagnostic accuracy and therapeutic precision (Nat Rev Neurol 2020;16:381-400; Reg Anesth Pain Med 2025;50:110-20; Sci Transl Med 2021;13:eabj7358). Learning health systems: Continuous improvement through practice While biomarkers form the foundation, learning health systems represent the framework that will transform pain care. As called for by the National Academy of Medicine, a learning health system captures routine clinical care and outcomes to generate evidence that improves future care (The Learning Healthcare System: Workshop Summary. 2007; Engineering a Learning Healthcare System: A Look at the Future: Workshop Summary. 2011). For pain medicine, this means collecting validated outcomes data during regular clinical visits, analyzing patterns, and using those insights to refine practice. In other words – where today's practice provides tomorrow's evidence that will inform future practice (Pain 2016;157:2033-44; Anesthesiol Clin 2023;41:503-17). At Stanford, we answered the call from the National Academy of Medicine by developing the CHOIR open-source learning health platform. CHOIR enables real-time quality improvement by collecting and integrating patient-reported outcomes, interactive pain body maps, biomarker data, EMR data, and treatment information (Headache 2021;61:872-81; PLoS Comput Biol 2022;18:e1010496; Pain Rep 2021;6:e880; Pain 2016;157:2033-44). CHOIR generates real-world research insights that cannot be captured with traditional clinical trials (Cancer 2021;127:3254-63; JAMIA Open 2023;6:ooad054; Sci Adv 2021;7:eabj0320; Lupus 2025;34:47-56; Anesthesiol Clin 2023;41:503-17; Pain 2015;156:2627-33; Pain Med 2020;21:3172-9; Pain Pract 2023;23:904-13; Pain Pract 2024;24:856-65). We extended CHOIR's capability by directly integrating “Empowered Relief” – an NIH-validated single-session behavioral pain intervention – into the platform (Pain Rep 2024;9:e1116; Trials 2018;19:165). Empowered Relief is a digital biopsychological pain treatment program that can be scaled to provide effective management of chronic pain to underserved and poorly resourced regions. The integration of Empowered Relief into the CHOIR platform provides real-time engagement tracking and longitudinal monitoring of outcomes. Patients receive evidence-based behavioral therapy exactly when needed, while the system automatically collects longitudinal data on their response. This creates a continuous improvement loop for both individual care and intervention refinement. Our future direction will integrate multimodal biomarker signatures into this ecosystem for advanced clinical decision support. By combining practical molecular markers, electrophysiological readings, and behavioral patterns with patient-reported outcomes, we are developing predictive algorithms to guide treatment selection for interventions like Empowered Relief. This convergence of biomarkers, digital therapeutics, and learning health systems is the future of pain medicine. Patient-centric, objective data will drive personalized pain care, closing the loop between research discovery and clinical implementation. The result is democratized research. Every visit with every clinician contributes to advancing our knowledge and improving outcomes. The path forward Anesthesiologists are uniquely positioned to lead this pain care transformation. However, significant challenges remain. Implementing advanced pain management technology faces significant hurdles: costs, technical complexity, clinical integration, and ethical concerns – all while operating within clinical realities and regulatory frameworks. “Layered practicality” is key – using strategic biomarker subsets rather than comprehensive monitoring. Cost management can include cloud computing and open-source analytics, while technical implementation requires standardized data models and validation systems. Systems must personalize beyond population trends, delivering concise, explainable outputs integrated with existing clinical workflows. Implementation should progress through validation stages with continuous oversight, ensuring transparency and patient representation throughout the process. Overcoming these challenges will require ongoing investment in research, infrastructure, and training. This is where FAER's role is crucial in supporting the next generation of physician-scientists driving this field forward. Pain medicine's data-driven future lies at the intersection of validated biomarkers and learning health systems. This intersection will combine mechanism-based diagnosis with continuous learning cycles to deliver personalized, accessible, and evidence-based pain care. My path from FAER grantee to pain medicine researcher is a reminder of how critical early research support is in advancing our field. Equally important are the mentorship, guidance, and community that FAER and other granting agencies create. FAER cultivates young physician-scientists who will turn today's challenges into tomorrow's breakthroughs. Through this investment in research, innovation, and most importantly, people, we move closer to our goal of precision pain medicine for everyone.Sean C. Mackey, MD, PhD, 2003 FAER Research Training Grant Recipient, Redlich Professor of Anesthesiology, Perioperative and Pain Medicine, Chief, Division of Pain Medicine, Vice Chair for Clinical Research, Department of Anesthesiology, Perioperative and Pain Medicine, and Program Director, Stanford Pain NIDA T32 Program, Stanford University School of Medicine, Palo Alto, California. @DrSeanMackey