OPPERA Sings: Risk Factors for Jaw Pain Revealed in Large Prospective Study
Risk factors for temporomandibular disorder (TMD) reach far beyond the jaw joint, reveals the climactic second act of the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Building on a previous baseline study of chronic TMD cases and controls, William Maixner, University of North Carolina, Chapel Hill (UNC), US, and colleagues followed TMD-free adults, characterized in unprecedented detail, for several years to identify phenotypic and genetic predictors of first-onset TMD. The results, published in eight papers appearing in a December 2013 special issue of the Journal of Pain, identify a broad range of risk factors for TMD onset, with general health status making the greatest contribution, followed by psychological factors and orofacial clinical findings.
The results are inconsistent with the widely held belief that TMD is a pain disorder localized to the head and neck, instead suggesting a multi-factorial, biopsychosocial model of the illness, the authors said.
OPPERA “clarifies the relative importance of different risk factors in the development of TMD” and is “extremely well designed,” said Emeran Mayer, University of California, Los Angeles, US.
“The depth and breadth of the OPPERA project … make it an important and unique milestone in chronic orofacial pain research and, indeed, in chronic pain research more generally,” wrote Samuel Dworkin, University of Washington, Seattle, US, in an accompanying editorial.
Following jaw pain
TMD is a relatively common condition characterized by orofacial pain, limited jaw opening, and joint noises. After an acute TMD episode, remission occurs in about 50 percent of patients, while the remainder go on to develop a chronic form of the illness (Ohrbach and Dworkin, 1998). The goal of OPPERA, a multicenter, seven-year, and million endeavor that began in 2006, was to identify phenotypic and genetic risk factors that contribute to the onset and chronicity of TMD.
Illness chronicity was tackled in the first portion of the project (termed the OPPERA study: Act One), the results of which were published in a 2011 issue of the Journal of Pain (see PRF related news story and meeting report). Researchers collected blood samples and comprehensive information on 202 phenotypic variables from each participant for a baseline case-control study of chronic TMD. Results revealed that cases differed from controls across several phenotypic domains: sociodemographic variables, health status and clinical variables, psychological functioning, pain sensitivity, and autonomic responses. The study also identified several genetic associations with the disorder.
In Act Two, the researchers followed many of the original controls (as well as others, for a grand total of 2,737 adults) for a median of 2.8 years, in an ambitious—and onerous, noted Maixner—prospective study of first-onset TMD. As described by Eric Bair, UNC, and colleagues, subjects were assessed quarterly with questionnaires and follow-up visits to confirm diagnoses of TMD. A total of 260 participants developed the disorder, for an annual incidence rate of nearly 4 percent.
Predictive phenotypes
The prospective design of Act Two allowed OPPERA investigators to address causality and identify factors that “are not merely consequences of TMD or ‘collateral damage’ from its underlying causes,” wrote Gary Slade of UNC and co-authors in an accompanying summary and interpretation of the findings.
In an analysis of the sociodemographic predictors of initial-onset TMD by Slade and colleagues, greater age emerged as one of the top predictors, consistent with the findings of the case-control study of chronic TMD. In contrast, the effect of sex differed between the case-control and prospective studies: Females, who make up the majority of chronic TMD cases, had only a slightly higher incidence of first-onset TMD than males did. These data challenge the dogma that TMD primarily affects females in early adulthood, Maixner said.
Anne Sanders, of UNC, and colleagues observed that poor overall health status predicted the presence of first-onset TMD, as did comorbid conditions (both painful and not), a history of smoking, and sleep abnormalities at baseline. Contrary to the hypothesis that many of the psychological characteristics such as anxiety that are associated with chronic TMD are a consequence of having the painful condition. Roger Fillingim, University of Florida, Gainesville, US, and others found that many of the same characteristics (but not all) were also predictive of TMD onset.
Self-reported orofacial symptoms and behaviors were more strongly predictive of first-onset TMD than were findings from clinical exams, reported Richard Ohrbach, University of Buffalo, New York, US, and co-authors. An analysis by Joel Greenspan, University of Maryland, Baltimore, US, and co-authors revealed that pain sensitivity and measures of autonomic function were more strongly associated with chronic than first-onset TMD, suggesting these systems may be important in the transition from the acute to chronic forms of the disorder.
In an analysis of the combined effects of all 202 phenotypic measures, Bair and colleagues found that variables in the health status, psychological, and clinical orofacial domains were the strongest predictors of first-onset TMD. These findings are similar to the literature on first-onset irritable bowel syndrome following a gastroenteric infection, noted Mayer.
The strongest individual predictors in OPPERA were a higher number of comorbidities, more nonspecific orofacial symptoms, higher bodily pain scores, and study site. The large difference in incidence among the four sites is a limitation suggestive of the presence of additional environmental or cultural variables not measured in the study, said the authors.
“We now must recognize that TMD is not a localized orofacial pain condition. It is truly a multi-systems disorder characterized by a variety of comorbidities,” Maixner emphasized to PRF. Facial pain is certainly a component of the disorder, but there are several abnormalities in a variety of physiological systems, he added.
In the final paper, Shad Smith and Luda Diatchenko, UNC, and colleagues tackled the genetic underpinnings of TMD (see PRF related meeting report). Their analysis of over 3,000 single nucleotide polymorphisms (SNPs) encompassing 358 genes involved in pain perception did not find one that was significantly associated with TMD onset (although statistical power was limited). However, five SNPs were associated with intermediate phenotypes (such as nonspecific orofacial symptoms or heat pain temporal summation) that predicted first-onset TMD, providing genes for further study in larger samples.
OPPERA’s Encore
The team is now using these findings to identify subpopulations of patients that vary in their biopsychosocial profiles and in the types of treatments they might respond to. They’ve also just finished the first year of a second grant: a five-year, million study they’ve dubbed OPPERA II that prospectively assesses the phenotypic variables that contribute to the transition from acute to chronic TMD in a new, larger cohort.
In addition to the phenotypic analyses, two genomewide association studies (GWAS) are also planned as part of the new study: one currently underway using cases and controls from the first OPPERA study, and a second using a community-based replication cohort. The results of the two GWAS will be used to create a short list of genes for deep sequencing, Maixner said.
The current findings highlight that TMD is characterized by multiple comorbidities, so an additional focus of OPPERA II is a thorough assessment of the risk variables that contribute to the co-manifestation of a variety of pain conditions and sensory disorders. The findings may uncover shared mechanisms that contribute to common persistent pain conditions, said Maixner.
Allison Curley, PhD, is a neuroscientist-turned-science writer who resides in Pittsburgh, Pennsylvania, US.
Image: ©iStockphoto.com/janulla
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