Dr. Gary Slade
Dr. William Maixner
In December 2013, the Journal of Pain published a special issue that featured the latest findings from the NIDCR-supported clinical study Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA). The latest OPPERA findings, folded into eight original articles and a summary paper, presents the most in-depth picture to date of the factors that may contribute to a person developing a first bout of a painful temporomandibular disorder, or TMD.
Science Spotlight spoke recently to Gary Slade, B.D.Sc, D.D.P.H., Ph.D., and William Maixner, D.D.S., Ph.D., two of the study leaders. Both are affiliated with the University of North Carolina at Chapel Hill. Dr. Slade heads the oral epidemiology program at the School of Dentistry, and Dr. Maixner is the director of the Center for Neurosensory Disorders. As both were quick to point out, OPPERA is truly a team effort in the best sense of the term, involving leaders in TMD research at four study sites in the United States. In addition to the University of North Carolina, the sites include the University of Florida in Gainesville; the University of Maryland at Baltimore; and the University of Buffalo in New York. The data coordinating center is Battelle Centers for Public Health Research and Evaluation in Durham, North Carolina.
Before diving into the data, a thumbnail description of the study might help. OPPERA is considered unique for being the first natural history study of a chronic pain condition. The study has been rolled out in two phases, OPPERA I and II. The latest findings emerged from OPPERA I. Launched in 2006, OPPERA I has followed 2,737 healthy men and women to see who develops TMD and why. At enrollment, participants were between the ages of 18 and 44, asymptomatic of TMD, and had no history of the condition. The latest published data are based on a median 2.8 years of follow up, during which 260 participants developed their first case of painful TMD, which translates to an incidence rate of 4 percent per year in the study cohort. The above findings, as the second wave of data from OPPERA I, are referred to as OPPERA I Act II.
The OPPERA studies come with the scientific equivalent of a playbill. That’s the study’s conceptual model of TMD causation. Before raising the curtain on the latest findings, let’s discuss the conceptual model for a moment. I think it’s critical to understand OPPERA and its success.
Maixner: Sure. A number of conceptual models have been posited over the years in an attempt to frame the factors that can contribute to TMD. The most prominent is the biopsychosocial model. It proposes that TMD isn’t just a pain in the jaw, as thought many years ago. The condition arises from a complex interplay of biological, psychological, and social factors. This awareness helped to guide TMD research efforts in the latter part of the 20th century, but the biopsychosocial model wasn’t quite testable then in the rigorous manner that is the currency of science. What is different between now and the 1990s is the science has culminated in better testable models.
Maixner: We live in an unprecedented age of scientific discovery. The last two decades alone have provided groundbreaking research in areas such as psychophysics, psychology, genomics, autonomics, the latter being the study of systems that control body functions such as heart rate. The list goes on. It’s now possible to parlay all of the above into a set of protocols that permit the careful, quantitative assessment of risk factors that may contribute to the onset or progression of TMD. When OPPERA I was launched in 2006, it represented the first prospective study – meaning, looking forward in time – of a large cohort of asymptomatic individuals to see which ones do and don’t develop acute and chronic forms of a pain condition.
And why they do so.
Maixner: Precisely. Eight years later, I think the current set of OPPERA studies has demonstrated, first of all, that the pain field is ready to conduct these types of large studies that are so vital to its continued progress. Secondly, I think OPPERA represents the current best-practice methods to develop these future cohort studies.
A good place to see this is the conceptual model. It is illustrated in Figure 1 in the summary paper.
Slade: I know the figure is a lot to process all at once. But let me insert a quick comment. I think one of the points Bill was making is when we use the term “model,” it isn’t meant to connote one conceptual viewpoint. In other words, it’s not a stand-alone statistical model. Or, it doesn’t represent a specific canonical relationship between a ligand, its receptor, and a neurologic response. Instead, we devised a model for the broader task of assembling multiple concepts into one comprehensive model. Our conceptual model integrates leads from the last 50 years of basic and clinical pain research, folding in more than 200 possible factors for evaluation. These factors represent an investigative continuum, from genes to lifestyle to socioeconomic status. Using all of the above, we have formulated study designs that address possible interrelationships of the arrows and ovals within relevant populations.
What do the ovals represent in the middle of the page?
Slade: Each oval represents a principal intermediate phenotype, or in this case, a biopsychosocial state of being, that has the potential to escalate into chronic TMD. Evidence for their effects dates back to the 1990s and our initial pilot studies of chronic TMD. The left oval indicates intensified psychological stressors, and the right one represents a high state of pain amplification. Each involves a web of more specific risk factors, which are the arrows that feed into each oval. All are subject to genetic regulation, and interactions between the two occur in the presence of environmental factors.
Just to be clear, the eight studies published in the Journal of Pain apply mostly to the lower part of the triangle at the top – “subclinical signs and symptoms” and “transient TMD.” The latter, in this case, is first-onset TMD.
Maixner: That’s correct.
So, lifting the curtain on the results, what do these papers tell us about first-onset TMD?
Slade: Let’s start with the right oval. For first onset, there were certainly people who were relatively sensitive to pressure pain, that is the sensation that we experience from pressure applied to muscles and joints in the head and neck. But the effect of pain amplification on an initial bout of TMD was much less compared to what we saw with chronic TMD. We’ve speculated that maybe the pain amplification really kicks in with the transition from acute to chronic TMD. Now, that’s something that we haven’t studied in these publications. We’re certainly furiously investigating that now, as are others.
What about the psychological stress side?
Slade: We continue to see very strong effects in the area of somatic awareness. That roughly translates to body awareness. It is an awareness of things happening inside us. It isn’t just that I’m more aware of pain than you are. It might be that I tend to feel warmer in a hot room than you do. Or I tend to feel itchy in dry weather, and you don’t. So, this is probably capturing some basic survival sensations.
Maixner: I’d just like to make a point here. This construct of somatic symptoms or awareness. It has been misconstrued sometimes to mean that individuals who are high on these scales are malingerers. They make up complaints. I think one of the fundamental findings here is that whatever our assessment tools are tapping into, which is currently lumped into the category of somatic awareness, is not some type of a psychological construct separate from the body. In fact, we can measure some physiological markers that relate directly to the variability in somatic awareness. This tells us that there must be fundamental neurological bases of somatic awareness.
So we need to listen to the patients and the biology.
Maixner: And we need to believe that when they tell us that they can feel their heart pound or have enhanced responses to odorants, these are true statements. They’re not make believe. So I think this is a very important point because when one uses that term – somatization – it has a tendency to bias how individuals interpret what’s being said. From our perspective, it’s very clear. We are talking about a biological process that leads to some type of an augmentation in awareness, especially of visceral function.
Were there other psychological characteristics associated with first-onset TMD?
Slade: Yes. Some are very familiar, such as psychological stress. Others are less-frequently considered, such as material satisfaction. This category represents a psychological variant of socio-economic status, a subjective sense of one’s material lot in life. Although subjective, one’s perception is reality. Again, people are not malingering. This is the way our systems work.
What about the environmental contributions to first onset TMD?
Slade: This was one of our least developed investigative areas. We just didn’t have a lot to measure in the specific ways that would allow us to dig deeper. But if you think broadly of the environmental contribution, it does lead not only to socio-economic variables but also the demographics. This is a very basic and important part of this picture.
Slade: We found there is hardly any difference between males and females in their rates of developing first-time TMD. Females have only a slightly greater rate of developing first-time TMD. That’s fundamentally different from what we see in chronic TMD. People with chronic TMD are far more likely to be female than male.
Any idea why?
Slade: Well, again, there must be fundamental differences between acute and chronic TMD. One wonders whether the differences might relate to gender roles or possibly even something biological, such as hormones. Or are there other specific biologic processes that are activated? They switch on after the onset of acute TMD to determine who develops a chronic condition. So, again, that’s something we are furiously investigating.
This came out of the blue?
Slade: Absolutely. The other thing that came out of the blue is non-Hispanic whites previously were found to have much greater odds of developing chronic TMD. Not so in this study. African Americans did have a slightly higher rate of first onset TMD than whites, and we certainly could talk about race and ethnicity. But the more salient point is we’re seeing very different patterns demographically in the factors that predict first-onset and chronic TMD. We’ve got to believe that if we’re seeing it, there must be subtle biological variations that influence, first, the development of TMD and, second, its progression to chronic TMD.
Maixner: I think it is also important to note that only about half of those who develop first-onset TMD will progress to chronic disease. This shows that there obviously are risk variables and determinants at work that differentiate an acute and chronic outcome.
Genes are one of those risk modifiers. You’ve arrayed several candidate genes at the bottom of the figure.
Maixner: They represent multiple genes in the population. Each one will potentially express a relatively small effect to produce the aggregate of signs and symptoms that you see clinically. In other words, there will be clusters, or sets of genes, that contribute to biological pathways and which, in turn, contribute to the measureable phenotypes that we’ve shown in the figure. On very rare occasions, there probably will be mutations in specific genes that have high phenotypic penetrance and drive a TMD-like symptom in a profound way. But that will be in a very, very small percentage of the patients.
Now in OPPERA I Act II, the onset data, we didn’t see much in the way of genetic polymorphisms contributing to onset. So when we begin to look more proximal to specific intermediate phenotypes, we do find that there are genetic polymorphisms that are contributing to the phenotypes of interest that represent pretty profound risk markers for onset. This global stress scale that we report is really highly related with somatic awareness.
One of the potential problems with the OPPERA’s genetic component is it had limited power with just 260 cases.
Maixner: That’s right. These data clearly are just a start. But let me make two important points. One, we’re identifying genes that make sense, from a biological perspective, to be involved with these conditions. These genes represent valid targets for exploration in OPPERA II. Two, different approaches will be required validate these targets.
What do you mean?
Maixner: Replication, from a statistical perspective, is important for validating targets. But we’re not going to wait another seven years for all of the data to roll that might replicate our initial findings. We already are moving towards showing functional effects for some of these gene polymorphisms in cell systems and thereafter in mice. We will accept a few early false positives in order to move rapidly into in vivo biology to see, in fact, if some of these findings have biologically relevant effects on pain systems. If so, they represent potential targets for therapeutic development.
One thing that we haven’t discussed is increased age turned out to be a significant risk factor for first-onset TMD. That’s interesting because the age cutoff for OPPERA participants was 44 years old.
Slade: That’s right. During the planning phase of OPPERA I, our initial thought was to enroll participants between the ages of 18 and 34. That seemed totally reasonable 10 years ago. All the review articles stated that TMD occurs most frequently in fairly young women of reproductive age. That was the dogma. We decided nevertheless to push the envelope a bit. We extended the enrollment age to 44 and included males. In retrospect, I wish that we had extended the age limit even further to, say, age 64.
Slade: We noticed, even in our earlier case-control study, that the odds of chronic TMD increased from age 20 to 30 to 40. It was basically a straight-line relationship that didn’t peak, even in 40 to 44 years olds. The case-control data were very consistent with what we see in national health survey data, where the prevalence of TMD in the community at large is somewhere around the age of 50. It’s also interesting that this age-related peak is more apparent in females than in males.
What are the larger messages for clinicians from OPPERA I Act II? Maybe a good place to start is where we began. The summary paper states, “TMD is a complex condition best viewed within a biopsychosocial model of illness.”
Maixner: That’s a key point. In my thinking, OPPERA I and OPPERA II demonstrate unequivocally that first-onset and chronic TMD are complex disorders that must be understood within a biopsychosocial model of illness.
Maixner: Based on our assessment tools, about 15 percent of OPPERA participants diagnosed with chronic TMD have orofacial pain only. The other 85 percent fall into a broader category that we haven’t discussed yet, but which is critical to understand the myriad faces of TMD. The other 85 percent have developed additional comorbidities, many of which are painful in nature. I’m referring to conditions such as chronic fatigue syndrome, fibromyalgia, headache, irritable bowel syndrome, and low back pain. So, it remains true that clinicians can detect certain orofacial signs and symptoms to render a TMD diagnosis. But when we scrape a little deeper in these patients, it becomes clear that their conditions are much more than the chief complaint of facial pain. Far more often than not, people with TMD have additional disturbances. This begs the question of whether all of the pain is related to common genetic and biological factors. That’s yet to be adequately determined. But we’re certainly looking.
I’ve heard TMD sometimes described as a mind-and-body condition. And I mean that literally – affecting mind and body.
Slade: That’s a good description. The description also highlights another important point for clinicians. As we just mentioned, TMD is generally a condition that very likely extends beyond the head and neck. So, look below the collar. Also, look beneath the physiology to see the mind and mood. If we really can, think of the biology and things that are happening beyond the immediate “this is tender,” “this is clicking,” and so forth. Extend the gaze.
This is not a simple, yes-no diagnostic test.
Slade: That’s right. If you see what looks simple, you probably need to look further for the other things that are happening in this patient. These could relate possibly to a comorbidity. Or it could involve another aspect of their health status, possibly their environmental experiences, and perhaps their mood and psychological pain amplification profile.
Spend time with your patients and ask questions.
Slade: Yes. It isn’t just an extending-the-appointment kind of thing. We need to be willing to monitor symptoms from three months to six months and beyond. That doesn’t mean do nothing in the interim. But the point is we can only see so much by looking at the most obvious, proximal triggers.
Maixner: The other very important point for the clinicians is to stay tuned. We have only taken the first bite of the cherry. It’s clear to me that we will likely end up with diagnostic algorithms from OPPERA and potentially new therapeutic targets for the treatment of TMD and related conditions. Already we are deeply engaged in statistical methods for collapsing these 200-plus phenotypic variables and several hundred genetic variables into workable tools that we think could be introduced into the clinic, at least for validation, very soon. So, I’d like to make it clear that, yes, we’ve taken the first bite of the cherry and have published some very high quality work. But we are now using this information to bring new tools to the clinic. I envision a paper-and-pencil test and a set of very simple neurological tests that can be delivered in 15 to 20 minutes in a clinical setting. They will allow the clinician to classify a TMD patient into specific categories. These categories will help inform them about the nature of their patient’s disorder and the most effective treatment options available. In short, there will be very practical tools to come out of OPPERA for the clinician.
Thanks for the time and update.