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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DE017018-09
Application #
8525386
Study Section
Special Emphasis Panel (ZDE1-JR (16))
Program Officer
Kusiak, John W
Project Start
2005-09-15
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$4,146,067
Indirect Cost
$306,872
Name
University of North Carolina Chapel Hill
Department
Dentistry
Type
Schools of Dentistry
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Akinkugbe, A A; Sharma, S; Ohrbach, R et al. (2016) Directed Acyclic Graphs for Oral Disease Research. J Dent Res 95:853-9
Sanders, Anne E; Akinkugbe, Aderonke A; Bair, Eric et al. (2016) Subjective Sleep Quality Deteriorates Before Development of Painful Temporomandibular Disorder. J Pain 17:669-77
Maixner, William; Fillingim, Roger B; Williams, David A et al. (2016) Overlapping Chronic Pain Conditions: Implications for Diagnosis and Classification. J Pain 17:T93-T107
Tchivileva, Inna E; Ohrbach, Richard; Fillingim, Roger B et al. (2016) Temporal change in headache and its contribution to risk of developing first-onset TMD in the OPPERA study. Pain :
Fillingim, Roger B (2016) Individual Differences in Pain: Understanding the Mosaic that Makes Pain Personal. Pain :
Bair, Eric; Gaynor, Sheila; Slade, Gary D et al. (2016) Identification of clusters of individuals relevant to temporomandibular disorders and other chronic pain conditions: the OPPERA study. Pain 157:1266-78
Ohrbach, R; Dworkin, S F (2016) The Evolution of TMD Diagnosis: Past, Present, Future. J Dent Res 95:1093-101
Schiffman, Eric; Ohrbach, Richard (2016) Executive summary of the Diagnostic Criteria for Temporomandibular Disorders for clinical and research applications. J Am Dent Assoc 147:438-45
Slade, G D; Ohrbach, R; Greenspan, J D et al. (2016) Painful Temporomandibular Disorder: Decade of Discovery from OPPERA Studies. J Dent Res 95:1084-92
Meloto, Carolina B; Bortsov, Andrey V; Bair, Eric et al. (2016) Modification of COMT-dependent pain sensitivity by psychological stress and sex. Pain 157:858-67

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