Botox(R) (Botulinum Toxin A;BTA), the most potent neurotoxin known to humankind, is widely used to treat myofascial temporomandibular muscle and joint disorders (TMJD), even though efficacy and safety of this off-label use are largely untested. Injection of BTA into masticatory muscles represents its first use in muscles acting on a load-bearing joint, and introduces potential for unknown adverse effects on bone resulting from diminished load. Our long-term aim is to conduct a Phase II randomized controlled clinical trial to evaluate efficacy with a properly sized sample, and assess a previously unexamined risk of BTA injections: disuse osteopenia in the TMJ, suggested by disturbing findings from the animal literature which show major reductions in volume and density of the mandibular condyle and alveolar region after a single masseter injection of BTA in rabbits. Because extrapolation of these data to humans suggests major safety risks, the FDA has asked for an Investigative New Drug (IND) application before proceeding with the RCCT, including data showing that BTA is "reasonably safe" for use in this patient group and with this mode of administration. No such human data exist. Thus, the main aim of this R01 grant is to provide the first evaluation of bone-related risks of BTA when injected into masticatory muscles of human subjects. We adopt an innovative naturalistic approach that avoids the "Catch-22" introduced by needing safety data to do an RCCT about safety, through four studies. First, we will compare bone quality in approximately15 patients before and after they have received a minimum of three BTA treatments, similar to a traditional Phase I approach. Second, we will compare bone quality in cohorts of 100 myofascial TMJD patients that have elected (or not) to receive at least three cycles of BTA injections in the masticatory muscles. Third, we will compare condylar volume of each of these cohorts to a reference group of historical controls. Fourth, we will assess reasons for discontinuation among a small sample of myofascial TMJD patients who have elected to have one or two treatment cycles of BTA for myofascial pain, to assess the potential role of adverse events in early discontinuation. Our safety assessment falls into two domains. (a) One is translational research based assessment, using innovative imaging methods to assess markers of mandibular bone quality. In particular, we will use a low-radiation dose cone beam CT to derive images from which precise estimates of bone density and volume can be made. (b) The second safety domain is the relative frequency of traditional clinical adverse events (AEs) and serious adverse events (SAEs), with special focus on potential bone-related AEs. Results from this study will provide: (1) actionable data on bone- related safety concerns raised in preclinical studies and now translated to humans, and (2) necessary material to submit an FDA IND application that would permit a Phase II study to evaluate risk and benefit of BTA for treatment of TMJD pain.
Use of botulinum toxin (BTA) as an off-label treatment for myofascial TMJD is increasing, with little evidence that BTA is either safe or efficacious. If the current study suggests that it can cause major health risks similar to those found in animal studies, regulatory agencies can immediately advise patients and clinicians to cease use of BTA for TMJD pain treatment. If shown to be reasonably safe, a Phase II risk/benefit study can be conducted.