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The Scoop on TMD Pharmaceuticals

Let's say the National Institutes of Health just handed us a multi-million dollar grant to get to the bottom of TMD and find a cure once and for all. I mean, we could start handing out heating pads left and right, but that kind of relief can only get us so far. Whenever I try a different form of therapy or medication, I like to think about the biology, right down to the cellular and molecular level. Why are the cells that make up my jaw region being such jerks?

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The TMJ Association is pleased to partner with Inspire to bring you the TMJ Cafe, a free online support network and discussion community for those with Temporomandibular Disorders (TMD). We invite you to meet others like you, share experiences and tips for getting through the day, and give and receive support.

Sustained and Repeated Mouth Opening Leads to Development of Painful Temporomandibular Disorders Involving Macrophage/Microglia Activation in Mice

Temporomandibular disorder (TMD) is a set of heterogeneous musculoskeletal conditions involving the temporomandibular joint (TMJ) and/or the masticatory muscles. Up to 33% of the population has had at least one symptom of TMD with 5-10% of them requiring treatment. Common symptoms include limited jaw movement, joint sound, and pain in the orofacial area. Once TMD becomes chronic, it can be debilitating with comorbidities that greatly reduce one's overall quality of life. However, the underlying mechanism of TMD is unclear due to the multicausative nature of the disease.

Prevalence of TMD in Sjӧgren Syndrome Patients

Sjӧgren's Syndrome seems to play a role in temporomandibular joint disorders.

Early Molecular Response and Microanatomical Changes in the Masseter Muscle and Mandibular Head After Botulinum Toxin Intervention in Adult Mice

The Botox-injected masseters had greatly increased expression of genes involved in muscle atrophy at the 1 week time point compared to the control side muscles. At the end of the study, 2 weeks after injection, the Botox-injected masseters were about 20% smaller than the control side masseters, and the Botox-side condyles had lost about 40% of relative bone area compared to the control side condyles.

Centralized Pain in TMD: Is It All in the Head?

  • Jun 8, 2018

We are pleased to introduce Sophia Stone, a new contributor to The TMJ Association, whose passion is to separate temporomandibular (TMD) fact from TMD fiction. Sophia has a background in medicine and research and can draw on her personal experience as a TMD patient. She has recently moved to the Washington, DC, area and works as a content developer for a company preparing applicants for tests that are required for admission to professional health schools. She enjoys traveling, hopes to train for her next marathon, and occasionally eats crunchy foods she’s not supposed to.

Centralized Pain in TMD: Is It All in the Head?

I really love science. So much that I was part of an MD/PhD program so that I could be married to science for the rest of my life, but TMD (in part) thwarted those plans. Like many healthy 20-somethings, I developed TMD seemingly out of the blue during medical school. Admittedly this was a pretty stressful time of my life.

Fast forward a few years, I spent — and spend — a lot of my free time reading about TMD and trying to piece together all the different theories and ideas out there. The problem is that it’s hard to get consistent advice from one healthcare provider to another, and even the scientific literature is littered with conflicting findings. Sigh.

Even with my background, it’s been hard to sort through the fact and fiction. That’s largely why I decided to start dissecting scientific articles, helping make this information more digestible and available to the rest of the TMD community, and geeking out about science. In these articles I will be discussing everything from review papers to new and interesting research findings, starting with the review paper Pain Mechanisms and Centralized Pain in Temporomandibular Disorders by Harper and colleagues (Harper DE, Schrepf A, Clauw DJ, 2016), published in the Journal of Dental Research.

Background

Have you ever tried a treatment for TMD that you thought should work but didn’t? Or a treatment that did work, but you have no idea why? I’ve been there, bought the t-shirt.

Normally, we expect the pain we experience from some stimulus to be directly proportional to the actual tissue damage present, whether in the jaw or anywhere else in the body, really. But in some chronic pain conditions, like TMD, the perception of pain doesn’t match the actual amount of tissue damage present. Furthermore, there are vast disparities in how different people with the same diagnosis respond to different therapies. Why then is chronic pain so much worse than it “should” be, in many cases, and why are some treatments seemingly effective for some but not for others?

Well, first of all, TMD encompasses a broad range of symptoms and causes, as well as varied responses  to treatment. My TMD is likely very different from your TMD. In fact, this review paper states that TMD can be defined as “persistent pain in the general orofacial region not clearly identifiable as headache.” Well, that’s helpful…

So, what’s really going on here?

Pain Centralization

The authors propose that we can categorize TMD patients on a spectrum based on how centralized their pain is. By centralized, they don’t mean where the pain is localized in the body. In this context, the word “centralized” refers to the central nervous system (i.e., the brain and spinal cord), or in other words, how much does the central nervous system amplify, maintain, or generate pain, even with little or no pain signals from the peripheral location in the body where we feel our pain.

According to the authors, on one end of this spectrum, one’s pain is more “peripherally-caused,” meaning that the perceived pain in a peripheral location of the body, such as the jaw, is due almost entirely to the pain signals originating in the damaged joint or muscle tissue. On the other end of this spectrum, one’s pain is more “centrally-caused,” meaning that much of the perceived pain is not explained by the actual tissue damage, but rather explained by changes to the central nervous system.

The idea behind “centralized pain” is that the brain and spinal cord “remember” your pain and become hyperreactive to pain signals. This is thought to lower your threshold for pain and remind you that you’re in pain. We can therefore define centralized pain as chronic pain where changes in the brain or spinal cord maintain or worsen your perception of pain.

The Evidence

Do I buy it? Well, let’s check out the evidence. What evidence is there that central sensitization plays a role in TMD? If TMD pain is really a brain-and-spinal-cord issue, then you’d expect the misfiring central nervous system to amplify pain not just in the TMJ region, but also elsewhere the body. (Note the irony of “centralized” pain really meaning that pain sensitivity is more widespread in the body.) The evidence for centralized pain playing a role in TMD can be grouped into 5 categories.

  1. Comorbidities

If you have experienced chronic TMD, statistics say that you likely have or will have another (comorbid) pain condition: more than half of TMD patients also experience headache/migraines, pain in other joints, neck pain, or lower back pain, and if you only have facial or jaw pain, you’re in the lucky minority (17%).

So why do so many TMD patients experience pain elsewhere? The authors argue that the centralization hypothesis is part of the explanation when pain is not isolated to the jaw.

  1. Hyperalgesia

Not only are TMD patients at greater risk for comorbid pain, but some experience greater sensitivity to pain (“hyperalgesia”)—and to other sensations!—in other parts of their bodies. It’s thought that everyone fits on a bell-shaped curve for pain sensitivity: one person who touches a hot stove might fall to the floor in anguish, while another might shrug it off and casually turn off the burner. It’s not that the latter person is necessarily “tougher,” but rather more likely has a higher nervous system  threshold for pain.

Research suggests that TMD patients with more centralized pain fall on the more pain-sensitive, or “hyperalgesic,” part of this bell curve. What’s really interesting is that not only are these patients more sensitive to pain in other parts of the body, but there’s also some evidence that patients with centralized pain might be more sensitive to other types of sensations as well, including pressure or even sound (tinnitus, anyone?).

This is backed up by brain imaging studies using fMRI (functional magnetic resonance imaging) that show that the brain centers that process pain signals show more activity in those with more centralized chronic pain (this is known to be the case in fibromyalgia, but it’s less clear for TMD due to conflicting findings, which we’ll discuss later).

  1. Genetics

There’s also been some interesting genetics work in other chronic pain conditions that suggests that genes and heredity could account for approximately 50% of one’s likelihood for developing chronic pain. I know 50% is a lot, but why not more? What causes one person with a “chronic pain” version of a gene to develop chronic pain, but not another with that exact same gene? Well, my mother suffers from migraines so there’s a chance we share some genes that make us hypersensitive and predispose us to chronic pain more than my sister who may not have inherited those pain-senstive genes.  

The point is that some genes might make someone more susceptible to TMD, increasing the risk, but still requiring other factors such as environmental triggers to actually develop TMD. In my case, the activating trigger might have been stress. For someone else, the activating event might be physical trauma caused by whiplash, or psychological trauma, or an autoimmune disorder. That said, not everyone with stress or whiplash develops TMD, and not everyone with TMD experiences chronic TMD, so genes might help us figure out who is more predisposed to pain becoming chronic and why.

Evidence for the genetic connection to centralization of TMJ pain comes from a large study on TMD pain known as OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment; Maixner et al., 2011). The investigators found a number of gene variants that may be predictive of TMD pain. Most of them are related to neurotransmitters (chemical messengers that neurons use to communicate) or to inflammation pathways. Other studies have shown that TMD patients with a more centralized pattern of pain have higher levels of inflammatory markers. These studies support the idea that centralized TMJ pain may be exacerbated or maintained by changes to neurotransmitters or inflammation in the brain.

  1. Somatic symptoms

Chronic TMD sufferers with centralized pain have something else in common: somatic symptoms. These can include problems with sleep, mood, memory, and fatigue. Not much fun, right? Well, this also supports the idea that something is going on in the brain that’s responsible for these symptoms as well as TMD pain.

  1. Psychosocial factors

What I’m not about to do is tell you that TMD pain is all in the head. It isn’t. But some psychosocial factors like depression and anxiety are more common in chronic pain patients (chronic pain isn’t exactly fun). And beyond that, mental health variables might even be a risk factor for chronic pain such as TMD, or predict how successful treatment will be. For example, someone prone to ruminating or catastrophizing (imagining the worst outcomes) might be more pessimistic about their prognosis, but they might be helped by therapies like cognitive-behavioral techniques to change their outlook. .

There are several possibilities going on here. One is that psychosocial factors like depression and anxiety affect brain chemistry, which in turn affects one’s predisposition to TMD. Another possibility is that a common variable (such as genetics) makes one prone both to psychosocial issues and chronic pain. Stay tuned!

What It All Means

Here’s what the authors think might be going on. Someone leads a normal, healthy life for years, though little does that person know that perhaps some of her genes cause her to have an imbalance in the neurotransmitters in her brain, such as serotonin. These neurotransmitter abnormalities might cause her to have sleep, memory, or mood problems. It also causes her to be more sensitive to pain, though day-to-day this might not be very noticeable. Then this individual gets in a car accident, or starts a stressful job and  her nerve circuitry isn’t as well-equipped to handle this degree of psychological or physical stress. Since this individual is more pain-sensitive than the average person, she develops chronic TMD pain that’s out of proportion to any actual tissue damage in the TMJ region.

Great! So can you tell me which neurotransmitters have been causing me all this trouble?? Unfortunately, no – or at least not yet. But future research that sheds light on this could help us figure out what treatments might help, which patients will be responsive to these treatments, and which treatments might make them worse. Furthermore, understanding the mechanisms behind centralized TMD pain down to the molecular level might help explain why some current treatments (e.g., tricyclic antidepressants or cognitive-behavioral therapy) work, even if today we still don’t entirely know how or why they help some patients.

Why Should We Care?

Why should anyone care? Why should this matter to healthcare providers? The idea is that by understanding the nuances between different subsets of TMD patients, healthcare providers may be better able to provide more personalized care based on how centralized one’s pain is. Instead of using guesswork for each patient, physicians might be able to predict which therapies will (hopefully) work for you, but might not work as well for the next patient.

We still don’t exactly know which treatments are guaranteed to be effective for different subgroups of TMD patients. However, if a treatment isn’t working for you (say, a splint or a new medication), that doesn’t necessarily mean you need to up the ante and seek a more drastic intervention; rather, it may be that something else is going on that can better explain your pain. For example, the authors think that those with “peripherally-caused” pain, whose pain is best explained by the actual tissue damage in their jaw, might respond to anti-inflammatories, such as NSAIDs or steroids. However, those with more “centrally-caused” pain might respond better to drugs that affect their neurotransmitters, such as tricyclic antidepressants, drugs targeting serotonin or norepinephrine, or non-drug therapies like cognitive-behavioral therapy and aerobic exercise that can affect neurotransmitter levels.

Well, a lot of these studies used fancy technology like neuroimaging and genetics work – that sounds expensive. How’s that going to help me? One of the coolest—and least intuitive—things I realized in medical school is how much we can learn about our bodies just by observing. Healthcare providers can figure out how big our liver is, or if we have anemia, or if there is fluid in our lungs, just with astute observation and some very basic diagnostic skills. And in fact, doctors can probably learn something about how centralized one’s TMD pain is with a few simple tests. For example, they might assess how you respond to pressure or mild pain on your arms and legs, or ask if you’ve noticed that you’re more sensitive to touch, sound, or light than most people you know.

Before we start poking and prodding ourselves, there’s an elephant in the room I should address. One of the major flaws with this hypothesis is that a lot of this research has been performed in fibromyalgia or other chronic pain sufferers – and a lot of the research conducted with TMD patients has yielded conflicting findings. The authors think the reason for this has to do with the diverse mechanisms and causes behind TMD, and more specifically, that TMD patients may fall on a continuum of how centralized their pain is. Grouping all TMD patients together in small studies makes it hard to tell whether a particular treatment is effective if it works in some patients but not others. That’s like studying whether flu medicine works using a study sample that contains both healthy and sick patients. The sick patients may improve, but that effect might be masked by the fact that the healthy patients don’t get better, or might even feel worse due to the side effects. The authors argue that studies really ought to parse out TMD populations by whether the pain is primarily caused by peripheral or central factors.

I’m not my own doctor, but I can relate to so much of this discussion: some of the things I’ve tried haven’t worked when I was hopeful that they would, whereas other therapies helped more than I expected them to. One thing I do know is that my own symptoms vary with how stressed I am, and my TMD is best when I’m hopeful – for the next new therapy, and for the power of my mind to influence how I perceive and deal with my pain. Knowing that a new treatment might be on the horizon gives me hope that we’ll understand TMD just a little bit better and provide better (and evidence-backed!) care to TMD patients.

TMJ Disorders

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