Dental Researchers Tackle Persistent Pain
words by Merry Sue Baum / photographs by Andrew Hanenberg
he body’s orofacial region could be called its command center. With its vast network of nerves and blood vessels, entwined among muscles and bones of the head, face and jaws, it supports an amazing array of vital functions. In its daily operations, the orofacial area is responsible for the ability to see, hear, taste and smell, as well as the life-supporting tasks of breathing, eating and drinking. And, it
enables us to perform the uniquely human function of speaking.
Because the region is so anatomically intricate, diagnosing and treating pain there can be challenging. Malfunctions can occur in any combination of the systems, making the source of pain difficult to track down. In fact, often orofacial pain patients spend years seeing a variety of doctors and dentists and trying every known treatment.
There is more hope for these patients, however, thanks to innovative research being conducted at New Jersey Dental School. Scientists there are finding new ways to make earlier, more definitive diagnoses in cases of orofacial pain and provide faster, more effective treatments to help the millions of sufferers.
Understanding Neuropathic Pain
One of the many types of orofacial pain is known as chronic neuropathic pain, which commonly follows nerve injuries. It is a debilitating condition and is notoriously difficult to treat. Recent studies indicate that the immune system plays an important role in initiating and maintaining this condition, particularly cytokines, proteins that regulate inflammatory responses.
Interleukin-17, or IL-17, a pro-inflammatory cytokine, has been extensively studied recently and found to be a key factor in maintaining inflammatory responses in a number of diseases, including periodontitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and asthma. Until now, however, no one has looked at IL-17's involvement in chronic neuropathic pain. Department of Diagnostic Sciences and Oral Biology PhD candidate Junad Khan, BDS, MSD, MPH, and postdoctoral visiting assistant professor Noboru Noma, PhD, from Nihon University in Tokyo, Japan, decided to be the first. They recently completed a study titled “Interleukin-17 Levels in Rat Models of Nerve Damage and Neuropathic Pain,” which has been accepted for publication by the journal Neuroscience Letters.
Using four different nerve injury models in rats, the scientists studied IL-17 levels in the injured nerves. Three days after injury and again at eight days, the researchers measured the rats’ pain levels and hypersensitivity using touch and heat. They compared those pain levels to baseline levels on the same rats and to pain levels in a group of control rats. They found that after three days, or the early onset of the neuropathic pain, there was no significant increase in IL-17. After eight days when the pain is considered to be in its chronic phase, however, the level was considerably higher “These findings indicate that IL-17 is playing a dominant role in the chronic stages of neuropathic pain, but not in the initiation phase, which we did not know before,” said Junad. “The next step is to inject the rat — at the nerve site or systemically —with compounds that have the potential to inhibit IL-17. We can then see if the chronic pain is reduced or even reversed. This is a major step forward in managing chronic neuropathic pain.”
Looking Beyond the Psyche
Atypical odontalgia (AO) has presented a challenge to the dental community for decades. Defined as a moderate, dull, aching or throbbing toothache without detectable clinical or radiographic pathology, it is thought to be a type of neuropathic pain. Its etiology, however, is still not known. AO sometimes occurs after a root canal or a tooth extraction, which has led to it being dubbed “phantom tooth pain.” Millions of Americans have AO, but only a low percentage is successfully treated. These frustrated sufferers often have unnecessary and irreversible dental procedures, including having root canal treatments in some teeth and having some — or even all — of their teeth removed. This usually only makes the pain worse or causes it to spread. Many AO patients say that the most painful part of the condition, however, is hearing people tell them, “It’s all in your head.”
Researchers at NJDS believe AO does, indeed, have clinical causes and are committed to finding them. They are also looking for new, faster ways to diagnose AO, since it is currently identified through process of elimination that can take months or even years. A recent study resulted in new findings and a new simple testing method that has since been used by other investigators. The researchers used Quantitative Sensory Testing (QST), a method of assessing the sensory profile in patients using thermal, mechanical and electrical stimuli. The AO patients and a group of controls underwent QST to determine their extra-oral (outside the mouth) detection and pain thresholds for heat and electrical stimuli. They were also examined for cold sensitivity on the mucosa, or gums, around the painful or missing tooth. “We routinely use a cold test directly on a tooth to determine its vitality,” says Julyana Zagury, DMD, MS, infectious disease fellow and one of the investigators. “To assess these patients, however, we used it on the mucosa.” Since there were no standardized methods to perform intra-oral cold testing, the scientists began with an FDA-approved device meant for extra-oral cold and thermal testing. It was too large for intra-oral testing. Existing intra-oral probes did not work either, so they decided to try a cotton swab sprayed with ethyl chloride. It had never been done before, but it worked.
The scientists found no significant difference between the AO patients and the control group in the heat and electrical detection and pain thresholds. However, the duration of the cold sensation after removal of the stimulus, known as after sensation, was different. “In the AO patients, the cold after sensation lasted for an average of one minute,” says Zagury. “In the controls, it lasted only a few seconds. We now have another tool we can use to diagnose AO. It is often difficult to distinguish these patients from patients with a toothache or a cracked tooth. And all it takes is a simple cotton swab and some ethyl chloride.” The study, “Prolonged Gingival Cold Allodynia: A Novel Finding in Patients with Atypical Ondontalgia,” has been published in the journal Oral Surgery, Oral Medicine, Oral Pathology and Endodontics. The investigators from the Diagnostic Sciences Department are Julyana Zagury, DMD, MS, and co-investigator Eli Eliav, DMD, PhD, chair and principal investigator; Gary Heir, DMD, clinical professor; Sowmya Ananthan, DMD, clinical instructor; and Richard Pertes, DMD, clinical professor. Two faculty members in the Department of Oral Medicine at Hebrew University-Hadassah in Jerusalem, Israel, were also part of the study. They are Yair Sharav, DMD, MS, and Rafael Benoliel, BDS, LDS, RCS.
Determining Susceptibility for AO
Studies have shown that 3 to 6 percent of patients who undergo root canal treatment develop AO. Why do some people acquire this painful condition and others do not? What makes them susceptible? Researchers at NJDS are working to find out.
As part of a study, the scientists are accessing the pain modulation system of AO patients, which has never been done anywhere in the world. Cibele Nasri-Heir explains that a person perceives pain after a peripheral nerve is stimulated, and a signal is transmitted to the brain. This signal may be modulated, or modified, before reaching the cortex of the brain and consciousness. That means every person’s modulation system is unique. That’s why the exact same stimulus evokes different levels of pain perception in everyone: One person may perceive it as excruciating and another may find it only mildly uncomfortable.
The researchers examined the status of pain modulation systems in AO patients and in a group of healthy controls, using two types of dynamic pain psychophysical tests. The first, Temporal Summation (TM), accesses the hyper-excitability of the central nervous system. The second, Conditioning Pain Modulation (CPM), reflects the activity of the descending pain modulatory system, or the central nervous system’s ability to control or reduce pain. The scientists applied stimuli to the affected area surrounding the painful tooth, to the corresponding area surrounding the unaffected tooth on the opposite side of the mouth, and to the participants’dominant forearm.
What they discovered was the AO patients perceived the stimuli as more painful than the healthy subjects, and that the AO patients’ ability to control or reduce pain is impaired; it is not as efficient as the control group. This was only the case, however, in the area surrounding the affected teeth, not in the area surrounding the unaffected teeth or on the forearm.
“These are very novel and important findings,” says Nasri-Heir. “This sheds new light on the etiology of AO. The fact that the AO patients showed an altered perception to the stimuli in the affected area supports the hypothesis that AO is neuropathic pain rather than an idiopathic pain syndrome. These findings will also help us provide more targeted treatments, since there are drugs that are more effective in patients with impaired modulation systems.”
The study, “Atypical Odontalgia and Endodontic Treatment, Sensory and Genetic Study,” is being funded by the NIH. Investigators are Cibele Nasri-Heir, DDS, MSD, research teaching specialist, and Eli Eliav, DMD, PhD, interim chair, both from Diagnostic Sciences; Gary Hartwell, DDS, professor and chair of the Department of Endodontics; Scott Diehl, PhD, director, Center for Pharmacogenomics; PhD candidate Junad Khan, BDS, MDS, MPH; and David Yarnitsky, MD, Rambam Medical Center, Haifa, Israel.