The Inside Scoop (Nidcr)

The National Institute of Dental and Craniofacial Research (NIDCR), announced recently the launch of a seven-year clinical study that could accelerate research on better pain-controlling treatments for a jaw condition called temporomandibular joint and muscle disorders (TMJDs). Called Orofacial Pain: Prospective Evaluation and Risk Assessment, or OPPERA, the $19.1 million project marks the first-ever large, prospective clinical study to identify risk factors that contribute to someone developing a TMJ disorder.

A prospective study looks forward in time, tracking volunteers over several months or years to monitor the onset and natural course of a disease. The Inside Scoop recently spoke with Dr. William Maixner, the study’s principal investigator and a scientist at the University of North Carolina in Chapel Hill, to hear more about the study, its design, and possible benefits to people with TMJD. The adjective that has been used to describe the OPPERA study is "novel." Is that a fair description?

Yes, I think it’s very novel. We intend to identify key risk factors for painful TMJDs, using a prospective study design. By prospective design, I mean we are enrolling individuals who are initially free of the condition and will follow them from three to five years to see who develops a TMJD. Obviously not everyone will develop TMJD.

Based on your best estimates, how many might? Approximately five or six percent of enrollees. That translates to roughly 200 people in the study. What might these cases tell you? A tremendous amount about the initial risk factors for TMJ disorders. Right now, we know relatively little, and this study allows us for the first time to cast a wider informational net. How so? Each study participant will undergo a baseline evaluation of his or her jaw function, receive an initial pain sensitivity test, offer blood samples for gene analysis, and volunteer other potentially relevant information. Thereafter, participants will sit down regularly at home and complete a questionnaire with high sensitivity and specificity for the onset of TMJD.

We will ask those who respond in certain ways to visit the clinic, and we will examine them to see whether they meet the study's diagnostic criteria for TMJD. For those who do, we can compare their baseline data with those at disease onset and see which variables changed and possibly are predictive of TMJD.

As far as I know, and I've been involved in pain research for over 20 years, OPPERA is the first large, prospective risk factor study in the field of chronic pain. The operative word here is large, isn't it? That's right. We just finished a similar but much smaller three-year pilot study of 240 initially TMJD-free women. The pilot study confirmed that a prospective approach could indeed generate important new leads about the biological, psychological, and associated genetic factors that contribute to the onset and maintenance of TMJD. So, OPPERA really represents a major expansion of the pilot study.

All told, OPPERA will involve 3,200 people enrolled at clinical sites in New York, Maryland, North Carolina, and Florida. All participants must be in good health and between 18 and 44 years old. Let me note that the study will involve both sexes and welcomes all races and ethnicities. Why wasn't a large, prospective study attempted in the past? It wasn't possible scientifically even a decade ago. It's only been within the last few years that the needed conceptual framework has evolved to enable us to properly investigate the underlying biological, psychological, and genetic processes that mediate or modify pain transmission in people. TMJD describes not one but multiple disorders. Will you compile your data based on the various subtypes?

You point to a very important difficulty in the field. TMJD is sort of a catch-all term for pain and functional non-painful disorders that influence the muscles of mastication and the temporomandibular joint. OPPERA will identify key risk factors and determinants for the most common form of painful TMJD, which is characterized by muscle and/or joint pain. Commonly, painful TMJD arises for the first time in people between the ages of 18 and 35. That said, we will have the wherewithal to look at alterations in joint function that is independent of presence or absence of pain. But our main focus is on identifying the biological, psychological, and genetic risk determinants that lead to muscle and joint pain. So, in essence, you and your colleagues had to start somewhere? That's correct. I wish we had the resources to look at all TMJ disorders. For example, a number of patients have undergone surgery to have implants placed to replace the TMJ.

In some instances, an implant will break down over time, leading to severe pain and dysfunction. For these people, there clearly are underlying factors that differ from those that we're going to evaluate in OPPERA that contribute to their pain and dysfunction. But you're right, we had to start somewhere, and we decided to start with the most prevalent type of TMJ disorder. You mentioned collecting blood samples to look for genes. What might you find? Let's go back to the pilot study. That's probably the best way to answer your question.

We obtained blood samples from well over 200 participants that enabled us to analyze a gene that codes for the protein catechol-O-methyl transferase, or COMT. We did this because the COMT gene encodes a much-studied enzyme that helps to inactivate certain nerve signaling compounds called neurotransmitters. Moreover, animal studies have suggested the more efficient the COMT enzyme is structurally, the more efficiently a pain signal will be turned off. Now, in the pilot study, we discovered three relatively common versions of the COMT genes. To visualize this, think of each pattern as a series of letters in a paragraph. In this analogy, the paragraph represents the COMT gene sequence.

We found that women with one of these common patterns had a low sensitivity to pain - in other words, they had a higher pain threshold - and were as much as 2.3 times less likely to develop TMJD. We published these findings in 2005, and we are now examining several other genes that appear to influence pain sensitivity and the development of TMJD. And the OPPERA study will help to unravel more of the genetic basis of pain sensitivity?

Yes, in that we will look at a larger number of potentially relevant genes. By assessing each participant’s biological, psychological, and genetic composition, we should be able to define the contribution that genetics plays in influencing human pain sensitivity. We also should be able to define how genetics contributes to the risk of developing TMJD and related conditions. How might this biological information refine the diagnosis of TMJ disoders? We could begin to subclassify patients more precisely based on their genetic, biological, and psychological profiles. Right now, let's say a person has pain in their facial muscles and TMJ, which is commonly observed in the majority of TMJD patients.

While the diagnosis of TMJD with muscle and joint pain is descriptive, it is very general. Why? Well, it provides no information whatsoever about the underlying pathophysiological processes that cause the pain in these anatomical regions. That's precisely the type of information we need to target therapies that impact the pain and dysfunction-producing mechanisms seen in the individual patient. I know eyes often glaze over when scientists begin to speak with conviction about molecules and signaling pathways. But it's on this level where the battle against TMJD and related conditions will ultimately be won.

So, let's say, hypothetically, we added COMT gene status to the diagnostic criteria that I just mentioned. The specificity of the diagnosis increases. It would allow us for the first time to subdivide patients with myofascial and joint pain based on whether they are likely to have low, moderate, or high sensitivity to pain. It may also permit us to predict an individual's susceptibility to chronic pain conditions. What might these subclassifications mean for treatment? Ideally, this will allow us to tailor or individualize treatments based on the specific genetic factors that contribute to a specific subgroup of TMJD patients. Right now,

we have a multitude of treatment approaches for TMJD patients, but none is biologically specific. We still use a one-size-fits-all approach. We use medications, primarily NSAIDs and muscle relaxants. We recommend physical therapies and orthotic splints. We also have behavioral interventions, such as biofeedback and cognitive behavioral therapy. These treatments can be effective for many patients, but none are effective for all patients. In fact, at present, there are very few accepted methods for treating TMJD that are rigorously grounded in science. And that points to the need to tailor treatments to the specific disorder. That's correct.

If we can begin to subclassify patients, not lump them together under broad diagnostic headings, it may be possible to identify those who will best respond to certain types of interventions. It also may be possible to identify patients with a genetic profile that amplifies and increases one’s sensitivity to pain. If a patient's profile indicates they won't benefit from certain types of treatment, we need to know that at the outset. Right now, we don't have that level of specificity. One of your research interests is the concept of pain amplification in chronic disease. Is that right? That's right. One of our primary hypotheses is individuals who develop TMJD have alterations in pain regulatory systems, which amplifies pain signals and pain perception. Enhancement in pain processing is not unique to the regulation of orofacial pain. These systems are involved in regulating pain sensitivity and susceptibility in a variety of other organ systems.

In fact, TMJD patients frequently have a variety of other chronic sensory disorders. Are these the so-called co-morbidities? Exactly. With chronic sensory disorders, we find a high coincidence of conditions, such as irritable bowel syndrome, fibromyalgia, chronic fatigue, and so on. Because these pain conditions occur together and are also associated with enhanced sensitivity to pain, it's very likely that the outcomes and discoveries associated with the OPPERA study will have substantial relevance to these other conditions. Listening to you describe TMJD, the word that comes to mind is complex.

TMJD can be very complex, encompassing a range of fields from basic biology to philosophy. By that, I mean the concept of suffering is a philosophical, almost a metaphysical construct. What I personally find amazing about this field is that one really does require an interdisciplinary approach to study it, and it's very intellectually stimulating to conceptualize how one goes from genes to the metaphysical constructs that are part of TMJD and other chronic sensory disorders. Actually, it's a very, very rewarding field to study and research. You can do a lot of good for a lot of people. I sense from reading some recent journal articles that the complexity is starting to give way to discovery. Would you agree? Oh absolutely.

Just take a look at the OPPERA study. In addition to looking for risk factors, we have assembled an outstanding group of computational statisticians and geneticists. They are in a position to take the data generated by this study, model all of the variables, and, hopefully, glean helpful clues on how best to diagnose, treat, and/or prevent these disorders. And as you mentioned, that wasn't possible just a decade ago. That's right. We now have the intellectual framework in place to conduct well designed clinical studies.

I am just ecstatic to be a member of a group of outstanding scientists and a program that has the prospect of identifying better ways of diagnosing and treating TMJD and related conditions. It is my hope that OPPERA will yield results similar to those obtained in the field of cardiovascular medicine. How so? By identifying the risk factors for painful TMJD, similar to the way in which we have identified risk factors for cardiovascular diseases, we will find markers of vulnerability. But these markers, or points of vulnerability, may be more difficult to alter than, say, blood lipids, which can be lowered with a variety of medications. I predict we'll identify a number of risk determinants that predict an individual’s susceptibility to TMJD and related disorders when they encounter certain environmental exposures.

We may not be able to intervene as readily as, say, a cardiologist combating high cholesterol or high blood pressure. I think that will be down the road. The real issue now is whether OPPERA will identify key risk determinants, which will help us design both treatment and prevention programs. Anything else? I want to emphasize that I'm just one voice among an outstanding group of scientists involved in OPPERA. That's really a major point. For this study to succeed, a team effort is required, and we've assembled a very talented and high-quality team, and I’m really looking forward to working with this outstanding team on this important and timely study.