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. 2025 Jun 18;166(9):2103-2115.
doi: 10.1097/j.pain.0000000000003555.

Early life adversity increases risk for chronic post-traumatic pain, data from humans and rodents

Lauren A McKibben  1 , Alice Woolard  1   2 , Samuel A McLean  3   4 , Ying Zhao  1 , Taanvii Verma  1 , Jacqueline Mickelson  1 , Hongxia Lu  4 , Jarred Lobo  1 , Stacey L House  5 , Francesca L Beaudoin  6 , Xinming An  1 , Jennifer S Stevens  7 , Thomas C Neylan  8 , Tanja Jovanovic  9 , Laura T Germine  10   11   12 , Scott L Rauch  10   12   13 , John P Haran  14 , Alan B Storrow  15 , Christopher Lewandowski  16 , Phyllis L Hendry  17 , Sophia Sheikh  17 , Christopher W Jones  18 , Brittany E Punches  19   20 , Lauren A Hudak  21 , Jose L Pascual  22   23 , Mark J Seamon  23   24 , Claire Pearson  25 , David A Peak  26   27 , Roland C Merchant  28 , Robert M Domeier  29 , Niels K Rathlev  30 , Brian J O'Neil  31 , Leon D Sanchez  27   28 , Steven E Bruce  32 , John F Sheridan  33   34 , Ronald C Kessler  35 , Karestan C Koenen  36 , Kerry J Ressler  12   37 , Sarah D Linnstaedt  1
Affiliations

Early life adversity increases risk for chronic post-traumatic pain, data from humans and rodents

Lauren A McKibben et al. Pain. .

Abstract

Traumatic stress exposures (TSEs) are common in life. Although most individuals recover after a TSE, a substantial subset develop adverse post-traumatic neuropsychiatric sequelae such as chronic post-traumatic musculoskeletal pain (CPMP). Vulnerability factors for CPMP are poorly understood, which hinders identification of high-risk individuals for targeted interventions. One known vulnerability factor for many pain types is exposure to early life adversity (ELA), but few studies have assessed whether ELA increases risk for CPMP. This study used data from the Advancing Understanding of RecOvery afteR traumA study, a prospective human cohort study of TSE survivors, to test the hypothesis that ELA increases risk for CPMP. In addition, in secondary analyses, we assessed which subtypes of ELA (including childhood bullying) were most predictive of CPMP and whether a rat ELA model consisting of neonatal limited bedding, combined with single prolonged stress (SPS) in adulthood, would accurately model human findings. In Advancing Understanding of RecOvery afteR traumA study participants (n = 2480), using multinomial logistic regression modeling of 4 identified latent pain classes, we found that ELA increased vulnerability to the high unremitting pain class (odds ratio [OR] = 1.047, P < 0.001), the moderate pain class (OR = 1.031, P < 0.001), and the moderate recovery pain class (OR = 1.018, P = 0.004), with physical abuse, emotional abuse, and bullying being the strongest predictors of high pain class assignment. Similarly, in male and female Sprague Dawley rats, in comparison with SPS alone, neonatal limited bedding combined with SPS caused increased baseline sensitivity and prolonged mechanical hypersensitivity (F(11,197) = 3.22, P < 0.001). Further studies in animals and humans are needed to understand mechanisms by which ELA confers vulnerability to CPMP.

Keywords: Bullying; Childhood abuse; Childhood trauma questionnaire; Chronic pain; Early life adversity; Motor vehicle collision; Multinomial modeling; Musculoskeletal pain; Neonatal limited bedding; Post-traumatic; Single prolonged stress; Traumatic stress; von Frey.

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Conflict of interest statement

• Dr. McLean has served as a consultant for Walter Reed Army Institute for Research, Arbor Medical Innovations, and BioXcel Therapeutics, Inc.

• Dr. Neylan has received research support from NIH, VA, Rainwater Charitable Foundation, Heart and Armor Foundation, and consulting income from Otsuka Pharmaceuticals.

• Dr. Jovanovic receives support from the National Institute of Mental Health, R01 MH129495.

• 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. Pascual is president elect of the Society for Clinical Care Medicine.

• 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 been a paid scientific consultant for the US Department of Justice and Covington Burling, LLP over the last three years. She receives royalties from Guilford Press and Oxford University 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.

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