While virtually everyone experiences acute pain at some time, it is chronic pain that exacts a profound burden on the public health, reducing quality of life for tens of millions Americans, and incurring substantial health care costs. Yet little is known about mechanisms that cause a transition from acute to chronic pain;subsequently, event the best of treatments have limited efficacy. One likely clue regarding etiology is that patients who have one form of chronic pain often experience chronic pain elsewhere in the body. In this project, we hypothesize that the transition from acute to chronic pain and the development of multiple chronic pain conditions, are caused by specific constellations of genetic variants and phenotypic risk factors (ie. psychological distress, pain amplification and clinical pain characteristics). This hypothesis is based on our studies of temporomandibular disorder (TMD) in the multi-site OPPERA project (Orofacial Pain, Prospective Evaluation and Risk Assessment;NIH/NIDCR U01-DE017018). In 2006-08, we enrolled 3,263 healthy adults, 233 of whom developed acute TMD during the 3-year follow-up period. Risk factors for acute TMD differed conspicuously from genetic and phenotypic risk factors for chronic TMD. Furthermore, 86% of chronic TMD cases had one or more of four chronic, idiopathic pain conditions: headache (HA), low back pain (LBP), irritable bowel syndrome (IBS) or widespread bodily pain (WBP). In this competitive renewal application, we propose three new aims designed to reveal novel information regarding the etiology and pathophysiology of chronic pain.
Aim 1 : To identify phenotypes and genotypes that predict risk of transition from acute TMD to chronic TMD, we will enroll a new cohort of 1,000 adults who have acute TMD, following them for six months to identify an expected 400 who progress to chronic TMD.
Aim 2 will identify risk factors for one or more of five: idiopathic pain conditions (IPCs): TMD, HA, LBP, IBS and/or WBP. Follow-up assessments will be conducted among people in the OPPERA-I prospective cohort study, identifying an expected 640 people who have ?1 IPC. Existing phenotypes and genotypes measured at baseline will be used to predict risk of 1 IPC vs. ?2 IPCs relative to controls.
Aim 3 will identify genetic variants associated with chronic TMD. A discovery-phase genome wide association study (GWAS) will use existing DNA from 1,000 OPPERA-I chronic TMD cases and 1,000 OPPERA-I controls. Replication will use a new cohort of n=1,000 chronic TMD cases and n=1,000 controls. Those findings will be contrasted with GWAS analysis of the cohort for Aim 1 to identify genes that contribute differentially to acute and chronic TMD. Based on these findings and validated associations from other studies, twelve genes will be selected for exon sequencing of rare genetic variants. Knowledge generated from these proposed studies will have a significant impact on scientific understanding of risk factors for multiple, overlapping pai conditions. Moreover, the findings will be of direct benefit for clinicians and for their patients, elucidating mechanisms underlying chronic and idiopathic pain in people with TMD.

Public Health Relevance

Chronic pain is a substantial public health problem affecting tens of millions of Americans, and the etiology of many of the most troubling pain conditions remains poorly understood. This project will study 6,000 adults to evaluate five such pain conditions when they first develop: temporomandibular disorder, headache, low back pain, abdominal/genital pain and widespread pain. Genetic, physiological, psychological and clinical characteristics will be measured to determine why pain becomes persistent, and why some people develop multiple of these chronic pain conditions.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDE1-JR (16))
Program Officer
Kusiak, John W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Dentistry
Chapel Hill
United States
Zip Code
Miller, Vanessa E; Poole, Charles; Golightly, Yvonne et al. (2018) Characteristics Associated With High-Impact Pain in People With Temporomandibular Disorder: A Cross-Sectional Study. J Pain :
Sanders, Anne E; Slade, Gary D (2018) Blood Lead Levels and Dental Caries in U.S. Children Who Do Not Drink Tap Water. Am J Prev Med 54:157-163
Fillingim, Roger B; Slade, Gary D; Greenspan, Joel D et al. (2018) Long-term changes in biopsychosocial characteristics related to temporomandibular disorder: findings from the OPPERA study. Pain 159:2403-2413
Sigurdsson, Martin I; Waldron, Nathan H; Bortsov, Andrey V et al. (2018) Genomics of Cardiovascular Measures of Autonomic Tone. J Cardiovasc Pharmacol 71:180-191
Smith, Shad B; Parisien, Marc; Bair, Eric et al. (2018) Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males. Pain :
Martin, Loren J; Smith, Shad B; Khoutorsky, Arkady et al. (2017) Epiregulin and EGFR interactions are involved in pain processing. J Clin Invest 127:3353-3366
Fillingim, Roger B (2017) Individual differences in pain: understanding the mosaic that makes pain personal. Pain 158 Suppl 1:S11-S18
Sanders, Anne E; Akinkugbe, Aderonke A; Fillingim, Roger B et al. (2017) Causal Mediation in the Development of Painful Temporomandibular Disorder. J Pain 18:428-436
Parisien, Marc; Khoury, Samar; Chabot-Doré, Anne-Julie et al. (2017) Effect of Human Genetic Variability on Gene Expression in Dorsal Root Ganglia and Association with Pain Phenotypes. Cell Rep 19:1940-1952
Ostrom, Cara; Bair, Eric; Maixner, William et al. (2017) Demographic Predictors of Pain Sensitivity: Results From the OPPERA Study. J Pain 18:295-307

Showing the most recent 10 out of 77 publications