Patient Bone-Related Safety of Botox® for Treatment of TMJ Disorders

Update: The results of Dr. Herring’s study described below were published online: Effect of multiple injections of botulinum toxin into painful masticatory muscles on bone density in the temporomandibular complex

Karen Raphael, PhD, a long-time TMD researcher now at the New York University College of Dentistry, has provided the following commentary on the Susan Herring Botox® article, along with information on her plans for clinical studies of TMD patients who have been treated with Botulinum Toxin for TMD Pain.

As a clinical research scientist focusing on the causes and treatment of TMD disorders, I had long heard that some doctors and dentists have tried to reduce TMD muscle pain by injecting Botox® into the chewing (masticatory) muscles. Although this potent biological toxin, used in minute dosages, has been approved by the Food and Drug Administration (FDA) for certain muscle-related conditions since 1989, its injection into the masticatory muscles is considered off-label and unapproved  by the FDA in terms of both safety and efficacy. In the past decade, TMD patients have increasingly asked: Is Botox® safe for use in this manner? Is Botox® effective?  Are potential risks worth the potential benefits? In light of aggressively marketed continuing education courses, in which more and more health professionals are being trained to use Botox® to treat a variety of painful muscle conditions, these are critical questions.

The existing clinical research literature provides little help. The National Institute of Dental and Craniofacial Research (NIDCR) still lists Botox® as a treatment option, but notes that recent clinical trials have been inconclusive about its effectiveness for chronic TMD. Indeed, existing studies have been conducted on small samples, in which it is easy to ‘miss’ either a potentially clinically significant benefit or a clinically significant adverse effect.  Thus, the benefit and risks of Botox® treatment for TMD have yet to be clearly established in an adequately sized, randomized and controlled clinical trial.

The urgency to study potential risks of Botox® injections into the masticatory muscles derives from a growing body of animal studies. Most concerning are the rabbit studies conducted by Dr. Sue Herring’s lab at the University of Washington and later animal studies conducted in other countries and with other small animals. These studies generally find dramatic changes in bone quality and volume, particularly in the mandibular condyle, the head of the lower aw bone, after just a single injection of Botox®. In humans, Botox® causes a temporary partial paralysis of the injected muscle, which wears off after about 3 months. Treatment is typically repeated at 3-month intervals, if the patient perceives benefit and can afford the high cost. Thus, there is the possibility of cumulative and dramatic changes to the TMJ area as the bone responds to changing muscle loading. Bone is a dynamic tissue that normally undergoes cycles of resorption and formation in a process called remodeling. In the event that the mandible is not subjected to the forces of the masticatory muscles (because they are paralyzed) bone resorption may overwhelm bone formation.  Thus patients considering or currently receiving Botox® injections for their TMD pain may be at serious risk for loss of mandibular bone density and volume. Nevertheless, whether findings from animal studies can be applied to humans remains a question. None of the existing clinical trials conducted among TMD patients has examined bone-related changes following Botox® injections.

Conducting studies in patients that parallel animal studies presents challenges. Patients cannot be “sacrificed” to precisely assess their bone volume or quality! Moreover, if serious bone-related changes do occur following masticatory injections with Botox®, it would not be ethical to conduct a large clinical trial on TMD patients. Thus, we took an observational approach to tackle the issue of bone safety in TMJ patients.

We began by conducting a pilot study; published in 2014.¹ Recruitment was based in part on queries to participants in a Botox®-related survey posted on The TMJ Association website. As part of that survey, we asked participants whether they might be willing to consider participation in a Botox®-related study, if they were eligible. Ultimately, we recruited 7 women who had received at least 2 Botox® treatments for their TMD pain in the past year and 9 demographically matched TMD patients who had never received Botox® injections for their pain. We used a low-radiation technology called “Cone Beam Computed Tomography” (CBCT) to provide high quality images of their TM joint area. Two oral and maxillofacial radiologists then evaluated each image, without knowing whether the patient had or had not received Botox® treatment. They focused particularly on areas of the mandibular condyle that would be most sensitive to reduced loading caused by Botox®-induced muscle paralysis. Indeed, in rating the trabecular region (the softer, spongy type of bone) of the mandibular condyle, the radiologists agreed perfectly with one another in evaluating each image and in concluding that there was reduced bone density in all of the Botox®-treated TMD patients but in none of the patients who were not treated with Botox®. This pilot study formed the impetus for a larger grant recently funded by the National Institute of Dental and Craniofacial Research.

In our new study, we will be recruiting patients systematically from 5 clinical practices in either New York City or Los Angeles, where high-end and identical-model CBCT imaging machines are located. A group of 50 TMD patients who have had 3 or more Botox® injection sessions in their masticatory muscles will be compared with 50 TMD patients who have never had Botox® injections in their masticatory muscles.  Those who have received Botox® treatment will not have done so for research purposes, but for personal reasons related to clinical preference and resources. All participants will be asked about their recent health experiences, treatment experiences and symptoms, and will be asked to undergo two types of low-radiation imaging sessions: one with CBCT imaging of their TMJ area and another with a standard clinical bone density (“DEXA”) scan of their hip and spine. We will also request that they permit us to review their treatment records, to determine whether certain doses of Botox® injections in masticatory muscles and particular treatment intervals are more likely to be associated with reduced density in TMJ bones, even after accounting for possible differences in overall bone density as assessed by standard bone density DEXA scans. Images will also be assessed for more serious changes, such as microscopic fractures, and state-of-the-art software will be used to assign specific density and volume values to different areas of bone.  If no serious and significant TMJ bone differences are found between the two groups of TMJ patients, we anticipate conducting a large randomized and controlled clinical trial of Botox® efficacy for TMD pain. On the other hand, if we do find that patients receiving multiple Botox® treatments are more likely to display disturbing and potentially dangerous bone changes, we will have documented an important public health risk. These findings may have implications for some other muscle-related conditions for which Botox® treatment has already been approved by the FDA.

TMD patients have been victimized in the past by the premature use of invasive treatments of unknown efficacy and risk: failed TMJ implants. We will do everything within our power as research scientists to ensure that this type of disaster does not happen again.

Unfortunately, patients cannot directly volunteer to participate in this study, because we are enrolling “clinical practices” from which patients will be systematically evaluated for appropriateness and willingness to participate. On the other hand, if you live in the New York or Los Angeles area and receive treatment by a clinician who uses Botox® to treat at least some of his or her TMD patients, please let us know. We would welcome the opportunity to identify and potentially enroll additional clinician-collaborator locations. We are just starting patient recruitment and expect to complete recruitment within two years. Results will become available within several months after all statistical analyses are complete.

Reference:

¹ Raphael KG; Tadinada A; Bradshaw JM; Janal MN; Sirois DA; Chan KC; Lurie AG. Osteopenic consequences of botulinum toxin injections in the masticatory muscles: a pilot study. Journal of Oral Rehabilitation. 41(8):555-63, 2014 Aug.

Note from the Author:

Among the many services provided by The TMJ Association, our research group at New York University benefited from a service that readers may not know that TMJA provides: the networking of researchers.  This occurs not just through professional academic meetings, but through one-on-one contacts with scientists whose work may benefit by linking with the work of other scientists.  In 2010, TMJA president Terrie Cowley first let me know of Sue Herring’s animal work related to Botox®. Sue and I engaged in several subsequent communications that informed the design of the current study. Based on Terrie’s scientific networking skills, we are proud to have been able to design and conduct one of the rare examples of ‘translational’ animal-to-human research.