Predicting chronic postsurgical pain: current evidence and a novel program to develop predictive biomarker signatures

Abstract

Chronic pain affects more than 50 million Americans. Treatments remain inadequate, in large part, because the pathophysiological mechanisms underlying the development of chronic pain remain poorly understood. Pain biomarkers could potentially identify and measure biological pathways and phenotypical expressions that are altered by pain, provide insight into biological treatment targets, and help identify at-risk patients who might benefit from early intervention. Biomarkers are used to diagnose, track, and treat other diseases, but no validated clinical biomarkers exist yet for chronic pain. To address this problem, the National Institutes of Health Common Fund launched the Acute to Chronic Pain Signatures (A2CPS) program to evaluate candidate biomarkers, develop them into biosignatures, and discover novel biomarkers for chronification of pain after surgery. This article discusses candidate biomarkers identified by A2CPS for evaluation, including genomic, proteomic, metabolomic, lipidomic, neuroimaging, psychophysical, psychological, and behavioral measures. Acute to Chronic Pain Signatures will provide the most comprehensive investigation of biomarkers for the transition to chronic postsurgical pain undertaken to date. Data and analytic resources generatedby A2CPS will be shared with the scientific community in hopes that other investigators will extract valuable insights beyond A2CPS's initial findings. This article will review the identified biomarkers and rationale for including them, the current state of the science on biomarkers of the transition from acute to chronic pain, gaps in the literature, and how A2CPS will address these gaps.

Figure 1.

Schematic diagram showing different types of biomarkers combined to form a biosignature. Single biomarkers may be measured across multiple domains, including brain imaging, quantitative sensory testing and function, blood-derived factors, and psychosocial measures. Combining biomarkers from within the same category and from multiple categories would produce a biosignature.

Figure 2.

A conceptual framework for the biomarkers collected as part of the A2CPS program. These biomarkers span (1) patient-reported outcomes (PROs) that include a variety of symptoms and psychosocial factors, (2) brain imaging, (3) quantitative sensory testing (QST), and (4) biological factors across genetics, extracellular RNA, proteins, and metabolites. The PROs include factors related to the person and the pain condition as well as external factors that can influence pain. Brain imaging will use multiple techniques to assess functional connectivity, white matter tractography and diffusion imaging, and pattern responses to nociceptive stimuli. QST will be used to test for sensitivity to noxious stimuli, central excitability, and central inhibition. A biosignature for risk for development of, or resilience to, chronic pain after surgery will be developed by combining variables across the biopsychosocial continuum of outcomes. A2CPS, Acute to Chronic Pain Signatures; fc-fMRI, functional connectivity-magnetic resonance imaging; MRI, magnetic resonance imaging. Figure copyright by Johns Hopkins University.

Figure 3.

The A2CPS Consortium structure consists of 4 main components spread across multiple sites, including a Clinical Coordinating Center (CCC), 2 Multisite Clinical Centers (MCCs), a Data Integration and Resource Center (DIRC), and 3 Omics Data Generation Centers (ODGCs). Each component has specific tasks supporting the collection and generation of data; these groups work together to accomplish the goals of the Consortium with collaboration from the NIH. Data generated from the A2CPS will be made available to the scientific community for further study. The 2 MCCs are responsible for participant recruitment, enrollment, and data collection. The DIRC combines biostatisticians, informaticians, and database experts with pain scientists into a single integrated team who integrate efforts of all funded components of the Consortium and serves as a community-wide nexus for protocol, assay, and data standards. The DIRC also leads an outreach component, including a public website (www.a2cps.org), a portal for Consortium members, and will provide user-friendly, publicly accessible data to the scientific community for novel discovery approaches. The CCC leads development and maintenance of procedures and is responsible for coordinating with the central Institutional Review Board (cIRB). Finally, 3 ODGCs each focus on different omics analyses, including genetic variants and exRNA, proteomics, and lipidomics and metabolomics. In addition to the funded components of the Consortium, volunteer external Program Consultants, composed of senior scientists invited by the NIH, are responsible for providing NIH with their individual opinion of progress toward the goals of the program. Volunteer biomarker experts, invited by NIH, provided feedback on selection of biomarkers early in the program, and 2 patient representatives, invited by the NIH, provide ongoing feedback on clinical protocols, recruitment, and retention to ensure the participants' needs are best considered. The Consortium is led by a Steering Committee with leadership representation from each component and the NIH. A2CPS, Acute to Chronic Pain Signatures; NIH, National Institutes of Health. Figure copyright by Johns Hopkins University.

Figure 4.

General protocol for A2CPS: Assessments are collected across a 12-month period with PROs, QST, omics, and imaging data collected from all subjects before surgery. After surgery, daily pain trajectories for the first month are collected. PRO biomarkers are collected at 4 to 6 weeks and 3 months postsurgery. QST, imaging and blood draws for omics are also collected at 3 months postsurgery. The primary, secondary, and exploratory outcomes are collected from all participants at 6 months, and there is a short 12-month optional follow-up questionnaire. A2CPS, Acute to Chronic Pain Signatures; MRI, magnetic resonance imaging; PRO, patient-reported outcome; QST, quantitative sensory testing. Figure copyright by Johns Hopkins University.