This month we present the last set of findings from “Act Two” of the Oral Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. [The Journal of Pain, Volume 14, Issue 12, Supplement, December 2013, pp. T1-T124.] Recall that these investigators recruited some 3,000 men and women between 18 and 44 years old who agreed to be studied over several years at four academic sites: Chapel Hill, NC; Baltimore, MD; Gainesville, FL; and Buffalo, NY. All were TMD free at the beginning of the study. The researchers collected a wide range of physiological and psychological data, constituting different “domains,” at the start of the study, hoping they would be able to identify risk factors distinguishing those individuals who developed first-onset TMD from those who did not.
In the final analysis the team had prospective data on 2,737 subjects of whom 260 developed first-onset TMD over a five-year study period. This month we report on findings in two domains.
One domain concerns pain sensitivity and certain autonomic factors governed by the autonomic nervous system (the system that controls vital processes like heart rate and blood pressure). Essentially, do people who develop TMD have a heightened sensitivity to pain to begin with? And what about their heart rate or blood pressure?
Pain sensitivity - The answer to the heightened pain sensitivity question is yes, but a qualified yes. At the outset, volunteers underwent a series of experimental pain tests rating their pain on a numerical scale in response to varying intensities of a mechanical stimulus applied to the skin as well as to pressure and heat applied on or around the temporomandibular joint and other parts of the body. Researchers recorded pain thresholds (when an individual first experiences pain) and whether there was “temporal summation”— a progressive worsening of pain evoked by slowly repeating a mildly noxious stimulus. The findings indicated that greater pain sensitivity (lowered thresholds for when pain was first experienced) when pressure was applied to the joint and a number of chewing muscles was the pain measure most significantly associated with first-onset TMD. TMD incidence was also associated with pain ratings for several other measures, including a series of mechanical or heat stimuli and greater maximum pain ratings of heat stimuli. Overall, however, subjects’ ratings of experimental pain were either not statistically significant in relation to TMD development or only weakly associated.
The investigators noted that their findings with regard to first-onset TMD are in marked contrast to an earlier OPPERA case-control study comparing TMD-free individuals (the controls) to patients with chronic TMD (the cases). That study found 29 out of 36 measures of experimental pain sensitivity were associated with chronic TMD. The investigators suggest that these additional pain measures may be critical in the transition from acute to chronic TMD.
Autonomic factors - Investigators initially collected data on heart rate, blood pressure and heart rate variability under various conditions of rest or stress. Only one of these measures—a higher heart rate at rest–was predictive of first-onset TMD. Again, this is in contrast with the case-control study mentioned before. Just as in the pain sensitivity study, a much higher number of these same autonomic factor measures were associated with chronic TMD, again suggesting that the measures in question have more to do with the transition from acute to chronic TMD and merit further study in that regard.
The second domain concerns genetics: are there genetic factors that predispose individuals to TMD?
Genetic studies - Studies over the decades, including comparisons of twins, leave no doubt that genes play a role in the development of TMD but how much of a role, which genes, and how they function, are open questions. Genetic factors are especially complex in conditions like TMD, which are considered multifactorial in origin: the disease results from the interaction of presumably many genes, each making a small contribution, plus environmental, gender, and behavioral factors.
In search of genetic answers, OPPERA researchers used DNA purified from blood samples collected from the volunteers. Their highly sophisticated techniques of analysis make use of the fact that there are many minor variations in the genomes of individuals that involve only a single letter change in the genetic code. These “single nucleotide polymorphisms” called “SNPs” (pronounced snips) number in the millions. They are scattered across the genome both within and between genes and can be used to distinguish one genome from another. For example, if individuals with a given disease have a particular SNP at some place in their genomes in contrast to a control group who lack that SNP and who are disease free, researchers can presume that that particular genetic variant is a marker associated with the disease and perhaps can provide a clue of what went wrong.
What the OPPERA investigators did was to narrow their search to look at a set of 3,295 SNPs found in the sequences of 358 genes known to be involved in pain systems to see if any of these SNPs occurred significantly more in people who developed TMD compared to those who did not. No such luck. This was not surprising given the complex causes of TMD, as well as the small size of the sample (the 260 genomes of people with first-onset TMD).
Intermediary phenotypes - When the researchers turned their attention not to the genomes of those diagnosed with first-onset TMD, but to the genomes of individuals with selected risk factors that had been discovered in other OPPERA studies, their analyses paid off. For example, in analyzing the genomes of individuals who reported nonspecific orofacial symptoms like stiffness, fatigue, or cramping, the researchers found SNPs associated with several genes involved in pain systems. In all, they looked at eight risk factors identified in other OPPERA Two research, including the presence of other painful conditions, a low pressure pain threshold, and psychological symptoms of distress, and found other gene linkages based on SNP analysis.
The investigators conclude that this approach, exploring the genomes of “intermediary phenotypes,” meaning individuals who do not have TMD but could be considered in a pre-TMD stage, can be very fruitful. It can point to genes of interest, help to define sub-populations of TMD patients, and provide new targets for drugs to treat these sub-populations.