Background: Chronic pain following traumatic stress exposure (TSE) is common. Increasing evidence suggests inflammatory/immune mechanisms are induced by TSE, play a key role in the recovery process versus development of post-TSE chronic pain, and are sex specific. In this study, we tested the hypothesis that the inflammatory marker C-reactive protein (CRP) is associated with chronic pain after TSE in a sex-specific manner. Methods: We utilized blood-plasma samples and pain questionnaire data from men (n=99) and (n=223) women enrolled in AURORA, a multi-site emergency department (ED)-based longitudinal study of TSE survivors. We measured CRP using Ella/ELISA from plasma samples collected in the ED ('peritraumatic CRP', n=322) and six months following TSE (n=322). Repeated measures mixed-effects models were used to assess the relationship between peritraumatic CRP and post-TSE chronic pain. Results: Peritraumatic CRP levels significantly predicted post-TSE chronic pain, such that higher levels of CRP were associated with lower levels of pain over time following TSE, but only in men (men:β=-0.24, p=0.037; women:β=0.05, p=0.470). By six months, circulating CRP levels had decreased by more than half in men, but maintained similar levels in women (t(290)=1.926, p=0.055). More men with a decrease in CRP levels had decreasing pain over time versus women (men:83% women:65%; Z=2.21, p=0.027). Conclusions: In men but not women, we found circulating peritraumatic CRP levels predict chronic pain outcomes following TSE and resolution of CRP levels in men over time might be associated with increased pain recovery. Further studies are needed to validate these results.

Dr. McKibben is funded by the National Institute of General Medical Sciences (T32GM008450). LAS is employed by and owns shares in EpiCypher Inc but has no competing interests in this work. The findings and discussion presented here do not represent the views of EpiCypher Inc and are solely those of LAS. Dr. Neylan has received research support from NIH, VA, and Rainwater Charitable Foundation, and consulting income from Otsuka Pharmaceuticals. In the last three years Dr. Clifford has received research funding from the NSF, NIH and LifeBell AI, and unrestricted donations from AliveCor Inc, Amazon Research, the Center for Discovery, the Gates Foundation, Google, the Gordon and Betty Moore Foundation, MathWorks, Microsoft Research, Nextsense Inc, One Mind Foundation, and the Rett Research Foundation. Dr Clifford has financial interest in AliveCor Inc and Nextsense Inc. He also is the CTO of MindChild Medical with significant stock. These relationships are unconnected to the current work. Dr. Germine receives funding from the National Institute of Mental Health (R01 MH121617) and is on the board of the Many Brains Project. Her family also has equity in Intelerad Medical Systems, Inc. Dr. Rauch reported serving as secretary of the Society of Biological Psychiatry; serving as a board member of Community Psychiatry and Mindpath Health; serving as a board member of National Association of Behavioral Healthcare; serving as secretary and a board member for the Anxiety and Depression Association of America; serving as a board member of the National Network of Depression Centers; receiving royalties from Oxford University Press, American Psychiatric Publishing Inc, and Springer Publishing; and receiving personal fees from the Society of Biological Psychiatry, Community Psychiatry and Mindpath Health, and National Association of Behavioral Healthcare outside the submitted work. Dr. Jones has no competing interests related to this work, though he has been an investigator on studies funded by AstraZeneca, Vapotherm, Abbott, and Ophirex. Dr. Pascual is president elect of the Society for Clinical Care Medicine. Dr. Datner serves as a Medical Advisor for Cayaba Care. Dr. Harte has no competing interest related to this work, though in the last three years he has received research funding from Arbor Medical Innovations, and consulting payments from Memorial Sloan Kettering Cancer Center, Indiana University, The Ohio State University, Wayne State University, and Dana Farber Cancer Institute. In the past 3 years, Dr. Kessler was a consultant for Cambridge Health Alliance, Canandaigua VA Medical Center, Holmusk, Partners Healthcare, Inc., RallyPoint Networks, Inc., and Sage Therapeutics. He has stock options in Cerebral Inc., Mirah, PYM, and Roga Sciences. Dr. Koenen has done paid consulting for the US Department of Justice and Covington and Burling, LLP. She receives royalties from Oxford University Press and Guilford Press. Dr. Ressler has performed scientific consultation for Bioxcel, Bionomics, Acer, and Jazz Pharma; serves on Scientific Advisory Boards for Sage, Boehringer Ingelheim, Senseye, and the Brain Research Foundation, and he has received sponsored research support from Alto Neuroscience. Dr. McLean has served as a consultant for Walter Reed Army Institute for Research, Arbor Medical Innovations, and BioXcel Therapeutics, Inc.

Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of General Medical Science of the National Institutes of Health under Award Numbers U01MH110925 (McLean, Ressler, Kessler, and Koenen), K01AR071504 (Linnstaedt), R01AR081454 (Linnstaedt), R01NS118563 (Linnstaedt and McLean), and T32GM008450 (T32 fellow McKibben). Additional funding was provided by the Rita Allen Foundation (Linnstaedt), the US Army MRMC, One Mind, and The Mayday Fund.

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