Causal Mediation in the Development of Painful Temporomandibular Disorder

  • Anne E. Sanders
    Address reprint requests to Anne E. Sanders, PhD, Department of Dental Ecology and Center for Pain Research and Innovation, School of Dentistry, Room 4502 Koury Oral Health Sciences Building, CB #7450, Chapel Hill, NC 27599-7450.
    Department of Dental Ecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Center for Pain Research and Innovation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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  • Aderonke A. Akinkugbe
    Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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  • Roger B. Fillingim
    Pain Research and Intervention Center of Excellence, University of Florida, Gainesville, Florida
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  • Richard Ohrbach
    Department of Oral Diagnostic Sciences, University at Buffalo, Buffalo, New York
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  • Joel D. Greenspan
    Department of Neural and Pain Sciences, and Brotman Facial Pain Clinic, University of Maryland School of Dentistry, Baltimore, Maryland
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  • William Maixner
    Center for Translational Pain Medicine, Department of Anesthesiology, Duke University, Durham, North Carolina
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  • Eric Bair
    Center for Pain Research and Innovation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Department of Endodontics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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  • Gary D. Slade
    Department of Dental Ecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Center for Pain Research and Innovation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Published:December 17, 2016DOI:


      • People with poor sleep quality reported worsening of perceived stress.
      • Poor sleep increased risk for temporomandibular disorder (TMD) directly and indirectly via perceived stress.
      • A third of the effect of poor sleep quality on TMD was mediated by perceived stress.


      We explored causal mediation of sleep quality and perceived stress in development of painful temporomandibular disorder (TMD). Sleep quality and perceived stress were assessed at baseline and quarterly intervals thereafter in 2,737 initially TMD-free adults in the Orofacial Pain Prospective Evaluation and Risk Assessment study (OPPERA) prospective cohort study. During follow-up, incident TMD cases were classified using research diagnostic criteria. Mediation analysis was conducted using a weighted Cox proportional hazards regression model that estimated hazard ratios (HRs) and 95% confidence limits (CL) of first-onset TMD. Models determined whether: 1) poor sleep quality during follow-up mediated the effect of baseline perceived stress on first-onset TMD, and 2) perceived stress during follow-up mediated the effect of baseline poor sleep quality on first-onset TMD. In both analyses, the total effect was decomposed into natural direct and indirect effects. Poor baseline sleep quality led to heightened perceived stress that then contributed to TMD development. When the total effect of poor sleep quality (HR = 2.10, CL = 1.76, 2.50) was decomposed, 34% of its effect was mediated by perceived stress (indirect effect HR = 1.29, CL = 1.06, 1.58). The effect of perceived stress on first-onset TMD was not mediated by sleep quality. Improving sleep may avert escalation of stress, limiting effects of both factors on TMD development.


      Causal mediation analysis highlights mechanisms by which poor sleep quality promotes development of TMD. First, poor sleep quality exerts a direct effect on pain. Second, it triggers a heightened perception of stress, which acts as an intermediate factor in the causal pathway between poor sleep quality and first-onset TMD pain.

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