Effectiveness of the Biopsychosocial Model Versus the Measurable Neurophysiological Model in Patients With Temporomandibular Joint Arthropathies

doi:10.21203/rs.3.rs-2982618/v1

OBJECTIVE

To evaluate the efficacy patients treated based on the biopsychosocial model, with a Michigan-type myorelaxant/stabilization splint combined with alternative therapies, and Neurophysiological model with intermediate Occlusal Devices in patients with temporomandibular joint (TMJ) arthropathies based on two different treatment philosophies.

PATIENTS AND METHODS:

This was an interventional and longitudinal study of the randomized clinical trial with blinding. The survey was approved by the CEP under: CAAE 66446216.6.0000.5207. Statistical analyzes were performed based on the selection of 43 patients with diagnosis of temporomandibular arthropathies after examination of the Diagnostic Criteria for Temporomandibular Dysfunction (DC / TMD) and assistance with images such as CT scans and magnetic resonance imaging. The patients were divided into two groups: G1-Biopsychosocial group and G2-Neurophysiological group. The variables studied were pain, mandibular function, need for alternative therapies and physiological parameters of muscle recruitment and masticatory cycle, measured by electromyography and kinesiography, respectively. All patients were followed for a minimum period of 06 to 09 months.

RESULTS

The results were favorable to both treatment groups in relation to the decrease in pain symptomatology, but were more consistent and remained smaller at the end of the evaluation in the neurophysiological group. Also significant was the difference in muscle recruitment during treatment with the G2 and less use of alternative therapies for pain control compared to the Biopsychosocial group.

CONCLUSIONS

Even in the case of a preliminary and unpublished study, this research provides strong indications of the benefit of the treatment with the Neurophysiological model in patients with TMJ arthritis, as well as the improvement of the symptomatic aspects, there was a clear improvement in muscle recruitment patterns, masticatory cycle, bone marrow regeneration and joint disc recapture. Further research with anti-etiologic treatment model should be performed to confirm these results.

CLINICAL RELEVANCE:

This innovative research highlights a new model for diagnosing and treating TMJ pathologies beyond traditional palliative treatment measures, enabling a more assertive anti-etiological treatment.

Temporomandibular Joint Disorders

Occlusal Splints

Orthotic Devices

Electromyography

Neurophysiological Monitoring

In 1983, the American Dental Association recommended that temporomandibular disorders (TMD) be used as an umbrella for a group of conditions previously referred as temporomandibular pain-dysfunction syndrome[1–3]. They were thought to be differentiated principally by the extent to which they involve the muscles of mastication and/or the temporomandibular joint (TMJ) itself[4]. In 1992, under the biopsychosocial paradigm, the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) protocol was published[5]. It consists of Axis 1, focused on detection of signs and symptoms of TMD, and Axis 2, focused on psychological disorders such as stress, anxiety, and depression. For Axis 1, the protocol proposed an algorithm of a classification that, despite considering imaging in its original publication, was heavily based on subjective symptoms, such as location of pain (muscle, joint area, or both) and a questionnaire with self-reported subjective data from the patient. Most large studies done under its paradigm did not base or complement the diagnosis with TMJ imaging[6–8]. Later, a Validation Project determined that validity of Axis I of the RDC/TMD protocol was below the target sensitivity of 0.70 and specificity of 0.95[9], especially when the diagnosis algorithm was matched against nuclear magnetic resonance imaging (MRI). A subsequent publication of the Validation Project considered the RDC/TMD to be unacceptable for the diagnosis of intra-articular disorders including both disc displacements and degenerative joint changes, and “less than desirable” for the diagnosis of joint pain[10]. Consequently, the protocol was updated in 2014[11] and, later in 2016[12], some refinements were suggested to improve the diagnosis capability, resulting in the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), which is a broader classification with a clear concern for better incorporating etiological and pathophysiological data into the model.

In terms of treatment, the biopsychosocial paradigm relies on a multifactorial approach to treat both arthrogenous and myogenic orofacial pain related to TMD, patient education and self-management, psychotherapy, physical therapy, pharmacological therapy, occlusal splint, and, to a lesser extent, surgery. In general, the idea is to try to manage the different factors that may play a role in initiating, maintaining, perpetuating, or aggravating the condition, such as stress, anxiety, muscle tension, and parafunctional habits, among others. However, the lack of integration of neurophysiological measurements at the individual level leaves the scientific support of this model completely dependent on subjective parameters, without considering measured objective data on the progression, stagnation, or regression of the disease. Most publications base the success of treatment on the patient's subjective perception of pain and range of motion (ROM), which is insufficient to define the functional status of the craniomandibular complex and the structural stability of the TMJ. In many cases, this phenomenon leads to development of persistent pain and/or relapse of multiple unsuccessful treatments that tend to go from conservative to extremely invasive[13–16].

In parallel, over the last decades, there have been many studies showing the association between temporomandibular arthropathy and craniofacial orthopedic problems such as retrognathism, asymmetry, and occlusal instability, despite the presence or absence of pain[13, 17–24]. Etiological factors of arthropathies of others body joints such as autoimmunity; infection; trauma; microcirculation, endocrine, metabolic and biomechanical problems[25–36] have also been demonstrated in the TMJ. However, the majority of large studies have not addressed these factors in properly designed trials. Currently, the evolving technology and cumulative knowledge in craniomandibular pathophysiology, neurophysiology, and biomechanics allows researchers to integrate the etiological factors to a measurable approach to assess the TMJ status (to evaluate its impacts on craniomandibular orthopedics and occlusion stability, muscle function, the masticatory pattern, and airway) in a model where the systemic condition of the patient, the biological terrain, is also considered at the individual level. This is called the measurable model of TMJ neurophysiology and pathology. Therefore, this study aimed to compare two approaches to treat TMD: one based on the protocols of the biopsychosocial paradigm and the other based on the mensurable neurophysiology and TMJ pathology paradigm.

Patient selection and sample calculation

The trial was carried out at the Faculty of Dentistry of the University of Pernambuco (FOP/UPE), Camaragibe, PE, Brazil. Patients seeking orofacial pain treatment or referred to treatment at the FOP/UPE were screened. The inclusion criteria were: pain in the TMJ for > 3 months, pain on palpation at the TMJ, the presence of joint noise during mandibular function (clicking and/or crepitation), limited mouth opening (< 40 mm), limitation of mouth lateral movements and protrusion (< 8 mm), and a visual analog scale (VAS) score between 20 and 90 mm. The exclusion criteria were: patients who had received treatment in the last 3 months for TMD; inability to maintain dental occlusion or poorly adapted prosthodontics, and patients with primary complaints of orofacial pain clearly not directly related to TMD. This initial screening resulted in a total of 215 patients presenting signs and symptoms of TMD as the chief complaints (Flowchart 1).

The sample size for the trial was calculated a priori with the BioEstat 5.0 software based on an independent pilot study with 12 patients divided into two groups of six subjects each. Considering Student's t-test for independent samples to assess the pain variable (the mean and standard deviation), an α level (significance) of 5%, and a β level (power) of 80%, each group would require 20 patients.

A second line of exclusion criteria was applied to avoid patients not eligible for the DC/TMD protocol and also to avoid those who presented TMD as well as comorbidities that could generate confounding bias. Of the original 215 subjects, 141 were excluded for the following reasons: odontalgia (n = 32), missing anterior teeth without proper rehabilitation (n = 31), chronic primary cephalgia (migraine/tension type headache; n = 21), neuropathic pain (n = 18), cervicalgia (n = 13), bruxism (n = 10), sinusitis (n = 9), repetitive ear infection (n = 3), rheumatoid arthritis (n = 2), and fibromyalgia (n = 2). The 74 remaining subjects presented clear signs and symptoms and no major comorbidities; however, 8 subjects were children and, therefore, were excluded from the sample.

The DC/TMD was then applied to 66 participants. Panoramic radiography, laminography, and/or cone beam computed tomography (CBCT) were performed on all patients to assist the proper DC/TMD classification and imaging interpretation was performed by one calibrated radiologist. In addition, a calibrated digital algometer was used to aid in physical examination (FPX10 Algometer, 5 0.005 kgf; Wagner Instruments, Greenwich, CT, USA). Eleven subjects, with minor signs and symptoms, were excluded because they had no indication for occlusal splints or pharmacological treatment. They were informed about their benign condition and responded well to simple self-management techniques. Three other subjects did not want to be part of the randomization process. The remaining 52 patients were selected for randomization and made up a relatively homogenous sample of patients presenting persistent and clinically relevant TMD, with a significant impact to quality of life and no clear identifiable comorbid at this point.

Randomization and group allocation

Randomization was carried out through the program available on the website www.random.org/. A total of 27 subjects were allocated to Group 1 (G1), which consisted of standard multifactorial care under the biopsychosocial paradigm of TMD/orofacial pain, and 25 subjects were allocated to Group 2 (G2), which consisted of a medical model of joint pathology investigation applied to the field of TMD, based on measurable neurophysiological data, laboratory tests, and nuclear MRI for both the diagnosis and the treatment management.

G1: The biopsychosocial model

Patients in G1 underwent an intense educational process about their condition. They were informed about the non-malignant nature of their disease and the importance of treatment as a fundamental point of clinical improvement, and they were required to watch a video about self-management of orofacial pain. They were also instructed on how to apply moist heat for muscle pain and how to perform ROM exercises and ice application for joint pain. An upper arch Michigan-type myorelaxant plate/stabilization splint, described in the literature as a flat occlusal plate made of hard acrylic or polycarbonate material and designed to promote occlusal stability and decrease muscle tension[37–39], was produced for all patients in this group. Bite registration was obtained by mandibular manipulation; the occlusion registration was taken in wax, not exceeding 3 mm (preferably between 2 and 3 mm). The cast models were mounted in a semi-adjustable articulator with the corresponding bite registration. The splints were then constructed of thermo-polymerized acrylic and adjusted according to the standard, with evenly distributed occlusal contacts from the lower jaw teeth as well as proper canine and incisal guidance during excursive movements (Fig. 1). Analgesic and nonsteroidal anti-inflammatory drugs were also prescribed as necessary. Physical therapy, dry needling, and acupuncture was also applied as needed.

Figure 1

G2 group: mensurable model of neurophysiology and TMJ pathology for diagnosis and treatment

Patients in G2 also underwent the same educational process about self-management of symptoms and alternative treatments. However, considering that the taxonomic nature of DC/TMD classification is insufficient for the differential diagnosis in terms of TMJ pathology[32, 40–45], a more detailed assessment was performed to identify evidence of infection, autoimmunity, inflammation, and/or biomechanical problems (trauma, microtrauma/occlusion). Therefore, only patients in G2 underwent nuclear MRI before and after treatment; blood serological tests for known arthritogenic pathogens such as antistreptolysin O (ALSO) for beta-hemolytic Streptococcus and immunoglobulin G (IgG) and IgM for Mycoplasma pneumoniae and Chlamydia/Chlamydophila pneumoniae; signs of inflammation such as FAN-HEp-2 (antinuclear factor), high-sensitivity C-reactive protein [hs-CRP]), and the erythrocyte sedimentation rate (ESR); and extensive neurophysiological and pathological screening with biometric tools such as surface electromyography (EMG), jaw tracking, and mastication analysis.

Once the data were collected, a differential diagnosis of arthropathy in regard to infection, autoimmunity, inflammation, and biomechanical problems was performed. The patients were then informed of the nature of their condition, allowing them to understand treatment goals and limitations, and the importance of their commitment to treatment according to their specific arthropathy.

G2 treatment protocols

Treatment for patients in G2 was designed to reestablish orthopedic craniomandibular homeostasis by means of decompression obtained with electronic deprogramming and maintained by an anatomic-functional orthotic[32, 46, 47], fitted in the lower arch, combined with an intervention targeting the main etiological factors (infection, autoimmunity, and inflammation), according to the differential diagnosis. Due to limitations in the study design and resources, it was not possible to diagnose and treat possible underlying microcirculation, vascular, endocrine, and metabolic problems that may have been implicated.

Orthopedic decompression and three-dimensional (3D) alignment of the mandible

All patients in G2 underwent electronic deprogramming of the mandibular muscles with a transcutaneous electrical nerve stimulation (TENS) device (BioTENS™, BioResearch Associates Inc. Milwaukee, WI USA), in conjunction with a jaw tracking device (JT-3D™, BioResearch Associates Inc. Milwaukee, WI USA) to assist in determining the neuromuscular rest position of the mandible and to evaluate the freeway space and the 3D position of the jaw. This functional information was combined with MRI data to help determine the craniomandibular relationship with optimized biomechanics and less joint nociception. Then, an orthopedic bite registration was made with polyvinyl siloxane. The casts were mounted in a simple articulator with the corresponding orthopedic registration. A lower anatomical and functional acrylic orthotic was constructed based on the 3D craniomandibular relationship (Figs. 2 and 3). The patients were asked to use the anatomical-functional orthotic at all times, including for mastication, removing it only for cleaning. As mentioned previously, the purpose was to support the decompression achieved by the electronic deprogramming and to establish orthopedic homeostasis, which was impaired by structural damage to the TMJ[31, 40, 48–50]. The patients were informed about the implication of the impact of orthopedic maxillary-mandibular change in occlusion due to prolonged use, as well as its goals and limitations.

Figure 2 and 3

Temporomandibular arthropathy of infectious origin

Based on a combination of imaging, serological and biometric data, the patients in G2 who were considered to have active temporomandibular arthropathy of an infectious origin were treated by proper antibiotic treatment, a slightly modified version of the protocol by Carter et al. (2010). Patients presenting TMJ damage attributed to previous infection that appeared to have resolved or were in a non-active situation were not treated with antibiotics. They were informed about their condition and oriented to recognize and report any sign of arthritogenic activity that could indicate reinfection from either endogenous or exogenous origin. This is important because some intracellular arthritogenic pathogens may assume a long-lasting latent state[51–54] or induce autoimmune reactive arthritis[53, 55–58]. They were also informed about the impact of this diagnosis on TMJ stability over time and their commitment to treatment and awareness of the aforementioned circumstances.

Temporomandibular arthropathy of autoimmune origin

Based on a combination of imaging, blood analysis markers, and biometric data, the patients in G2 who were considered positive for autoimmunity were subsequently evaluated by rheumatologists to determine whether they fulfilled the criteria for any specific rheumatic disease. The decision to use or not use disease-modifying anti-rheumatic drugs (DMARD) or other anti-rheumatic drugs was left to the rheumatologist, according to the severity, arthritogenic activity, and, eventually, a medical diagnosis of a rheumatic disease. Subclinical to mild autoimmune manifestation, with either local (TMJ) or systemic (other joints and/or organs) symptoms, were treated conservatively with supplements that have been described in the literature as immunomodulators and clinically indicated to control oxidative stress, such as vitamin D3, omega 3, and resveratrol[59–62]. In addition, basic nutritional information was provided to avoid dietary toxins associated with autoimmunity[63]. In some cases, low doses of naltrexone[46, 64–66] were prescribed by a preventive medicine physician.

Patients with this diagnosis were informed about the progressive nature of autoimmune conditions, especially the fluctuation between flare-ups and silent periods of arthritogenic activity. It was explained how this process impacts TMJ stability over time and, consequently, the occlusion. The patients were also informed about the importance of their own commitment to nutrition, supplementation, and lifestyle changes to gain control in terms of immunomodulation and deceleration of autoimmune activity.

Biomechanical (related to trauma and microtrauma/occlusion) and inflammatory arthropathies

Biomechanical and inflammatory components of temporomandibular arthropathy were identified both alone and in combination with infection and/or autoimmunity, because trauma is a completely independent variable (as an etiological factor), while inflammation may be found in any type of temporomandibular arthropathy. In subjects with only biomechanical components, the treatment focused only on the orthopedic aspect of the treatment. When possible, inflammation was preferably managed from an etiological perspective instead of by palliative care. However, all accessory palliative and pharmacological medicines (analgesic, non-steroidal anti-inflammatory drugs, myorelaxants, antidepressants, etc.) were available for patients in G1 were also available for patients in G2, if needed.

In summary, all patients in G2 were informed about the etiological and pathophysiological nature of their diagnosis and the goals and limitations of their individualized treatment, which consist of three pillars: (1) the orthopedic realignment and maintenance with an anatomical-functional orthotic; (2) cause-focused etiological treatment for both local (TMJ) and systemic (biological terrain) factors, and (3) biometric data and imaging monitoring to evaluate how the TMJ is responding to treatment, recalibrating or changing the orthotic every time the measured neurophysiological parameters demonstrated a need, due to joint nociception or remodeling.

Data collection and assessment tools for all patients

The parameters described below were evaluated in three stages for both groups: time one (T1), before treatment and after the initial exams, time two (T2), 2–3 months after the start of the treatment with intraoral appliance, time three (T3), 6–9 months after beginning of treatment. Pain intensity evaluation was carried out with a standard 100 mm VAS with a numerical order from 0 (without pain) to 10 (maximum possible pain). ROM measurements at maximum mouth opening without assistance, right and left lateral excursion, and protrusion were recorded with a digital caliper, duly calibrated and measured by a trained evaluator (Table 1).

Masticatory muscle recruitment was recorded using a computed surface EMG unit (BioEMG™, Bioresearch Associates Inc. Milwaukee, WI USA). Six channels were used for the anterior temporalis, masseter, and anterior digastric muscles for both sides. The tests were dynamic, consisting of opening and closing, maximal clenching, swallowing, and the EMG decompression test with cotton rolls[40].

Blinding and calibration

Aside from being aware that intraoral devices were an integral part of treatment, patients were blind to the inherent procedures of each group and to the specific features of the appliances. Each patient was scheduled so that they had no contact with any other patient.

Patients in G1 were treated by a certified orofacial pain specialist who could perform all standard procedures to adjust the Michigan splint, as well as prescribe alternative therapy (pharmacological, physical therapy, dry needling, counseling, etc.). This specialist did not have access to the patients in G2 and was blind to all data related to G2. Patients in G2 were treated by a certified TMJ pathology professional, who could perform all procedures to calibrate the anatomical-functional orthotics under the TMJ pathology and neurophysiology paradigm and prescribe complementary treatment targeting etiological factors. This professional did not have access to the patients in G1 and was blind to all data related to G1. A third independent evaluator, blind to the patient allocation, was in charge of collecting the VAS, ROM, and EMG decompression test data at the three evaluation times (T1, T2, and T3).

MRI and blood test analysis

This evaluation was only done for the G2 group because it is an integral part of TMJ pathology screening protocol[32, 46, 47]. One calibrated radiologist, blind to the treatment, analyzed the TMJ MRI scans at diagnosis and after treatment and described the morphology; the disc and condyle positioning; the tissue features of the disc; the retrodiscal area and ligaments; and the presence of facets, erosions, joint effusion, and bone marrow abnormalities such as necrosis and sclerosis.

Blood laboratory results and interpretation

Patients with FAN-HEp2 titers equal or above 1/160 were considered positive. The FAN-HEp2 pattern was also considered. An ASLO titer ≥ 150 IU/mL was considered positive. The CRP test was considered high (positive) with values between 1.0 and 4.0 mg/dL, and the ESR was positive for values > 19 mm for women and > 9 mm for men. Quantitative indirect immunofluorescence (IFI) for IgG and IgM was performed to detect serum antibodies against most known arthritogenic pathogens such as Chlamydia trachomatis, C. pneumoniae, and M. pneumoniae. The serological IgG and IgM results were interpreted according to the kinematics and half-life of the antibodies. IgG was interpreted as indicative of previous contact with antigens and IgM was interpreted as indicative of recent contact and active infection. However, non-detection by IFI did not necessarily imply the absence of the antibody: The timing for detection may not have been appropriate. In addition, the absence of IgM does not rule out infection when IgG is positive, because some metabolically active intracellular arthritogenic pathogens may downregulate antigen expression by the host cell[56, 67]. Due to these particularities, IgG and IgM IFI was repeated in a timely manner. The interpretation is summarized below:

IgG (-) and IgM (-) means the patient is negative for an infection. The test should be repeated in 45 days.

IgG (-) and IgM (+) means that the patient is positive for a recent/acute infection. Specific antibiotic therapy is indicated.

IgG (+) and IgM (+) means that the patient is positive for an ongoing infection. Specific antibiotic therapy is indicated.

IgG (+) and IgM (-) with a high IgG titer (two times the threshold cutoff) means that the patient has an ongoing infection. It is possible that the test was done just after the half-life of IgM. A paired test should be performed* for confirmation in 60 days. If other clinical parameters indicative of infection are present, antibiotic treatment may be indicated.

IgG (+) and IgM (-) with a low IgG titer means that the patient has been exposed to pathogens and has recovered. The patient is less likely to have an active infection, but a paired test* is required in 60 days.

*An increase in the IgG titer in a paired test is indicative of an active infection, independently of the IgM titer.

Statistical analysis

Inferential analyses were considered significant when the p-value was < 0.05. The Shapiro–Wilk test was used to determine whether the data followed a normal distribution. Student’s t-test for independent samples was used to analyze normally distributed data. For data without a normal distribution, the Mann–Whitney U test was used for intergroup evaluation and the Wilcoxon test was used for intra-group evaluation.

The sex distribution and the DC/TMD protocol diagnostic classification (categories I, II, and III) were similar in G1 and G2. For G2, the category II (internal disorders) and III (degenerative processes) diagnoses were adjusted after MRI. The reclassification resulted in 10 patients with TMJ presenting disc displacement with reduction (DDwR) and 5 patients with disc displacement without reduction (DDwoR). Considering the MRI-adjusted G2 cases, the number of patients with TMJ and degenerative joint disease (DJD) increased from 6 to 14. For the patients in G1 who underwent CBCT, the number of patients with DJD increased from 5 to 8 after adjustment (Table 2).

Table 2

Demographic characteristics of the patients in Group 1 (G1, biopsychosocial model) and Group 2 (G2, neurophysiological model).
Variable	G1		G2		p
Treatment
	n	%	n	%
Total	22	100	21	100
Age (years)
Mean ± standard deviation	36.05 ± 11.05		38.95 ± 13.66		0.446^a
Up to 40 years	14	63.64	13	61.90
> 41 years	8	36.36	8	38.10	1.000^b
Sex
Male	3	13.64	2	9.52	1.000^b
Female	19	86.36	19	90.48
DC/TMD	n (bilateral)		n (bilateral)
Myalgia/local myalgia	10 (6)		9 (6)
Myofascial pain	12 (5)		14 (5)
Referred myofascial pain	3		2
Arthralgia	13(5)		13 (4)		DC I: 1.000^b
DDwR	13 (4)		11 (3)
DDwR and locking	1 (1)		2
DDwoR without MO limitation	3		4
DDwoR with MO limitation	1		1
Degenerative process	5 (2)		6 (1)		DC II/III: 1.000^b
^a Student’s t-test for independent samples; significant when p < 0.05 ^b Fisher’s exact test; significant when p < 0.05 DC/TMD: Diagnostic Criteria for Temporomandibular Disorders; DDwR, disc displacement with reduction; DDwoR, disc displacement without reduction; MO: mouth opening

Pain intensity

Pain intensity decreased in G1 and G2, but there was a significant difference in the VAS score at T3 between G1 and G2 (Table 3). Patients in G2 presented a progressive improvement between the evaluation times, while patients in G1 had a slight increase in the pain score at T3 compared with T2 (Fig. 4).

Table 3

Mean and standard deviation of pain variables and functional parameters of mandibular movements.
Variable	Treatment group	T1 (base-line), mean (SD)	T2 (2–3 months), mean (SD)	T3 (6–9 months), mean (SD)	p¹	p²	p³
VAS	Biopsychosocial model	6.55 ± (1.22)	3.82 ± (2.58)	4.00 ± (1.31)	< 0.0001	< 0.0001	0.6002
	Neurophysiological model	6.57 ± (1.83)	3.29 ± (2.35)	2.14 ± (1.65)	0.0002	< 0.0001	0.0057
	p*	0.7614	0.4369	0.0004
MMO	Biopsychosocial model	44.27 ± (7.38)	45.27 ± (7.19)	44.32 ± (8.04)	0.5090	0.6677	0.6874
	Neurophysiological model	42.00 ± (7.16)	43.71 ± (7.32)	44.95 ± (7.35)	0.2273	ns**	0.1033
	p*	0.3884	0.5598	0.6099
MP	Biopsychosocial model	3.82 ± (1.05)	3.95 ± (1.36)	4.00 ± (2.29)	0.6465	0.8068	0.6248
	Neurophysiological model	3.81 ± (1.29)	4.57 ± (1.57)	5.10 ± (1.30)	0.0884	0.0029	0.0832
	p*	0.8364	0.2961	ns**
LR	Biopsychosocial model	7.00 ± (2.43)	6.27 ± (2.43)	6.36 ± (2.54)	0.1930	0.4209	0.8405
	Neurophysiological model	6.43 ± (1.96)	7.19 ± (2.62)	7.19 ± (2.39)	0.2013	0.1148	0.6529
	p*	0.4297	0.3192	0.1855
LL	Biopsychosocial model	6.91 ± 2.11	6.45 ± 2.26	5.68 ± 2.12	0.4955	ns**	0.1337
	Neurophysiological model	6.52 ± (1.94)	6.95 ± (2.06)	7.05 ± (2.60)	0.2084	0.1914	0.9721
	p*	0.7155	0.3496	0.0722
p¹: T1 versus T2, Wilcoxon nonparametric test between paired samples p²: T1 versus T3, Wilcoxon nonparametric test between paired samples p³: T2 versus T3, Wilcoxon nonparametric test between paired samples p: nonparametric Mann–Whitney test ns*: not significant after Bonferroni correction adjusted with α < 0.05 LL: laterality left; LR: laterality right; MMO: maximum mouth opening; MP: mandibular protrusion; VAS: visual analog scale

ROM

There was no significant difference in the maximum mouth opening, protrusion, and right and left lateral excursion between G1 and G2. However, the baseline values were already within the normal standard (Table 3).

Surface EMG evaluation

The analysis of muscle recruitment with and without intraoral devices was measured as percentages of absolute values (in µV) of inhibition during Learreta’s decompression test[40]. This expresses the impairment of the elevator muscles of the mandible during maximal occlusion due to joint or teeth nociception under compression. Because the exclusion criteria of the sampling process excluded tooth problems that could interfere with this analysis prior to randomization, the test reflected the nociceptive status of the joint under pressure. Healthy joints are expected to have better recruitment (less inhibition) of the main agonist muscles (Table 4).

There was high nociceptive inhibition of the temporalis and masseter muscles for both G1 and G2 at baseline (T1), without a significant difference between the groups (p > 0.05). This could be explained by the homogeneity of the two groups in terms of demographic variables, pain scores, and DC/TMD classification, as the subjects were randomly allocated.

However, at T2 the difference between the two groups was significant (p = 0.0070 for the temporalis and p = 0.0173 for the masseter) in favor of G2. For the temporalis, the mean bilateral inhibition for G2 dropped from 27.22% at T1 to 12.53% at T2. For G1, inhibition slightly worsened from 26.03% at T1 to 28.66% at T2. For the masseter, the mean bilateral inhibition for G2 dropped from 33.68% at T1 to 13.42% at T2. For G1, inhibition dropped slightly from 37.80% (T1) to 34.12% (T2). In summary, at T2, patients in G2 had significantly recovered muscle function, while patients in G1 still had significant masseter inhibition and even presented a worsening in temporalis function.

At T3, temporalis function improved in both groups; however, the difference between the two groups increased significantly in favor of G2 (p = 0.0034). For patients in G1, temporalis inhibition was reduced to 23.07%, which means that temporalis recruitment presented a discrete recovery from T2 and ended just slightly above the baseline level. Patients in G2 recovered almost full function at T3, presenting only 5.93% inhibition.

Patients in G1 presented clear worsening of masseter function when comparing T3 with T2, with 36.99% inhibition, although they did not return to baseline values. On the other hand, patients in G2 recovered almost full function at T3, presenting only 6.58% inhibition. This could explain the worsening of pain symptoms in patients in G1 at T3 (Fig. 5).

Alternative therapies

The number of participants who used alternative therapies was noticeably higher in G1: These patients constantly used at least one alternative therapy. No patient in G2 needed to use drug therapy such as cyclobenzaprine or tricyclic antidepressants. It is noteworthy that alternative therapies, especially the use of antidepressant medications, were available to both groups of patients with chronic pain.

Alternative therapies included analgesics, tricyclic antidepressants, cyclobenzaprine, moist heat compresses, acupuncture (traditional Chinese medicine), low-level laser therapy, TENS, manual physiotherapy, and autoregulation (including guidelines, video on pain perception, and biofeedback). Note that no patients in G2 used drug therapy with tricyclic antidepressants or cyclobenzaprine (Fig. 6).

G2 intragroup results

MRI versus laboratory blood tests

The MRI findings were compared with the results of blood analysis for patients in G2. There were several significant associations: between IgG for Chlamydia pneumoniae and sclerosis of the medullary bone (p = 0.027), between condylar thinning and FAN-Hep2 positivity (p = 0.007), between CRP and disc displacements (p = 0.038), and between CRP and lesions of retrodiscal ligaments (p = 0.028). There were no significant associations between inflammatory markers (CRP and the ESR) and joint effusion, erosion, flattening, osteophytes, or pseudocysts (Table 5).

Table 5

Magnetic resonance imaging findings with auxiliary laboratory tests in autoimmunity and reactive arthritis
	MRI	IgG pneumoniae	P¹	IgM pneumoniae	P²	ASLO	P³	FAN-HEp-2	P⁴	ESR	P⁵	CRP	P⁶
Condylar thinning	6/21	6/14	0.477	2/9	1.000	0/2	1.000	5/5	0.007	5/16	1.000	3/8	0.675
DD	15/21	11/14	0.712	7/9	1.000	1/2	1.000	3/5	0.627	8/16	0.305	2/8	0.038
Effusion	7/21	6/14	0.724	2/9	0.681	1/2	1.000	1/5	1.000	4/16	0.723	3/8	1.000
Erosion	1/21	1/14	1.000	1/9	1.000	0/2	1.000	1/5	0.354	1/16	1.000	1/8	0.483
Bone marrow sclerosis	14/21	14/14	0.027	6/9	1.000	1/2	1.000	3/5	0.998	10/16	1.000	2/8	0.092
Flattening	18/21	11/14	0.065	6/9	0.329	2/2	0.557	3/5	0.236	14//16	1.000	6/8	0.596
Disc ligament injury	16/21	9/14	0.474	6/9	0.666	1/2	0.463	2/5	0.281	8/16	0.165	2/8	0.028
Osteophyte	12/21	9/14	0.737	4/9	0.694	2/2	0.502	1/5	0.322	8/16	0.746	2/8	0.215
Pseudocyst	0/21	0/14	1.000	0/9	1.000	0/2	1.000	0/5	1.000	0/16	1.000	0/8	1.000
p: Fisher's exact test; p¹: p value in the comparison between MRI findings and pneumoniae IgG; p²: p value in the comparison between MRI and pneumoniae IgM findings; p³: p value in the comparison between MRI and ASLO findings; p⁴: p value in the comparison between MRI findings and ANA-Hep2; p⁵: p value in the comparison between MRI and ESR findings; p⁶: p value in the comparison between MRI and PCR findings. DD: disk displacement; MRI: Nuclear magnetic resonance; IgG: Immunoglobulin G; IgM: Immunoglobulin M;ASLO: Antistreptolysin O; CRP: Ultrasensitive C-reactive protein and ESR: Red blood cell sedimentation rate.

MRI before and after treatment: Descriptive comparison

There were 15 cases with displaced discs, of which 3 were bilateral. From these 15 cases, 10 were DDwR and 5 were DDwoR. There was evidence of previous and/or current infection in 11 cases, evidence of autoimmunity in 3 cases, and evidence of underlying systemic inflammation (unfavorable biological terrain) in 8 cases. Six cases were considered to present irreversible damage to disc and ligament structures.

With 3D craniomandibular orthopedic alignment and joint decompression supported by the anatomic-functional orthotics, there were 7 disc recaptures from a total of 15 patients in G2 with previously displaced discs: 2 recaptures out of 5 patients with DDwoR and 5 recaptures out of 10 patients with DDwR. Out of the DDwR cases, there was one bilateral recapture out of 3 cases. Excluding the cases that were considered irreversible, 7 of 9 cases (77%) showed structural recovery (Fig. 7).

Fourteen cases had bone marrow abnormalities (necrosis/sclerosis), with laboratory evidence of previous and/or ongoing infection in all cases, evidence of autoimmunity in 3 cases, and evidence of underlying systemic inflammation (unfavorable biological terrain) in 10 cases. Five of the 14 cases had significant bone marrow regeneration. It is interesting to note that these 5 cases of regeneration occurred in the same patients who took longer antibiotic therapy (6 months on the modified Carter protocol), due to signs of arthritogenic activity, masticatory cycle deterioration, and high titers of paired IgG and IgM for the bacteria M. pneumoniae and C. pneumoniae (Fig. 8).

In the literature, the diagnosis of TMD is presented as something uncertain and sometimes controversial. To standardize research and clinical practice, protocols such as the previously used RDC/TMD and the currently use DC/TMD had been applied in most studies and accepted as the standard diagnostic tool[6–8, 68]. However the DC/TMD developers themselves found that the algorithm presented low sensitivity indexes for internal disorders (disc displacements and degenerative process) when imaging was not applied, especially CBCT and MRI[11, 12]. This phenomenon occurred in this research: While the DC/TMD was effective for obtaining a uniform sample based on the homogeneity of the demographic variables and DC/TMD diagnosis between G1 and G2 after randomization, adjustments had to be made based on imaging. It is also interesting to note that the adjustments were greater in G2 than in G1, because MRI was mandatory for patients in G2, while patients in G1 had basic imaging studies (panoramic radiography and laminography) and some had CBCT.

The difference in imaging techniques relies on the paradigm behind the two groups. For G1, the guidelines are based on the biopsychosocial paradigm in which TMD is classified basically into three major categories (muscular TMD, disc disorders, and DJD), based on anamnesis, physical examination, and a self-reported questionnaire that generates an algorithm for classification. The algorithm is mostly independent of imaging, with pain as the guiding symptom for decision-making and even treatment planning[69], while imaging is recommended only when there is difficulty categorizing the patient based on the major classifications and/or their subdivisions[70]. This is easily verifiable by the large number of studies utilizing this model that did not apply imaging[6–8, 71], and the guidelines recommend using imaging only in clinical situations where there are signs of other conditions (“red flags”), difficulty in clarifying the TMD classification, or when a patient does not respond to treatment[38, 72, 73]. However, G2 was based on the mensurable neurophysiology and TMJ pathology paradigm[32, 33, 46] in which, in addition to anamnesis, physical examination, and a self-reported questionnaire, MRI, laboratory blood tests, and pathophysiological measurements are mandatory. Therefore, G1 reflects the research and clinical reality of the biopsychosocial paradigm, while G2 reflects the clinical reality of the TMJ pathological and neurophysiological paradigm.

As the design of the study presented some inherent challenges, it was necessary to have a common element for both groups so that subjective and objective variables could be compared between the groups while keeping the patients and evaluators blind to the paradigms, and without mischaracterizing the two paradigms. So, all patients had to be eligible to be treated with some sort of intraoral appliance. Hence, the subjects who could be treated by alternative approaches but had no indication or contraindication for a Michigan splint or a neurophysiological orthotic were excluded from the sample prior to randomization. Besides, because both paradigms rely on more than intraoral appliances for treatment, complementary and alternative procedures, inherent to each model, were not only allowed but recommended, so each group could be fully treated according to its respective standards.

It is important to consider that alternative treatments were made available to all patients, and all patients were informed about their diagnosis and treatment. They also received a full explanation and training in self-management techniques. The available alternative therapies were: analgesics, tricyclic antidepressants, cyclobenzaprine, moist heat compresses, acupuncture (TCM), low-level laser therapy, TENS, manual physiotherapy, and autoregulation/biofeedback. Self-management care was explained and trained based on seven key points: (1) avoid deleterious habits, (2) control overloading the muscle or TMJ by avoiding chewing hard food or opening the mouth too wide, (3) work on body posture, (4) perform cervical stretching, (5) thermotherapy (moist heat or ice compresses) combined or not combined with anti-inflammatory ointment (camphor free), (6) sleep hygiene, and (7) exercise.

Pain improvement occurred in both groups, especially at T2, in which pain scores were very similar for both groups. However, at T3, patients in G2 had continued to improve while patients in G1 had worsened, with a significant difference between groups. Most patients in G1 did not return to their baseline level, a phenomenon corroborated by a meta-analysis[74], concluded that a myorelaxant plate/stabilization splint provides a short-term benefit for patients with TMD (3–6 months). After that, stabilization splints tend to equalize with other therapeutic modalities[74–78]. There is also evidence that stabilization splints combined with other modalities could have a better result. However, in the present study, even combination of a Michigan splint with alternative treatments did not prevent worsening of the symptoms and function from T2 to T3.

It is interesting to note that symptom worsening of patients in G1 at T3 correlates with the deterioration of muscle function measured by EMG. This could be explained by several inherent aspects of the biopsychosocial paradigm of TMD: (1) It does not base its approach on a differential diagnosis of underlying pathological conditions (infection, autoimmunity, etc.), and therefore the treatment is not directed toward control of etiological factors. (2) It does not incorporate into the treatment's model the individualized correction of orthopedic craniomandibular misalignment due to structural alterations of the joints. (3) It does not utilize proper biometric tools to manage the biomechanics and neurophysiological variables during treatment, and therefore there is absolutely no control on how the Michigan splint affects neurophysiology. (4) It relies on subjective data rather than measurable parameters. (5) The patient's self-management care is mostly palliative, while a differential diagnosis in terms of TMJ pathology would allow a proactive commitment directed toward specific etiological factors.

By contrast, patients in G2 using an anatomical-functional orthotic for craniomandibular orthopedic correction presented a progressive improvement over time, even after 6 months. This phenomenon could be explained by several factors. First, the 3D orthopedic alignment between the mandible and maxilla was based on the less nociceptive position of the TMJ and also based on muscle ergonomics that allowed proper biomechanics and neural motricity that could be measured and confirmed by biometrics and imaging, showing, respectively, optimized function and structural recovery/improvements, such as recaptured disc and recovered joint spaces. This orthopedic correction, by itself, favors homeostasis of the stomatognathic system. Second, the etiology-focused approach aimed at managing the underlying pathological conditions such as autoimmunity, infection, and inflammation favored TMJ stability and long-lasting results because it allowed for reversal of degeneration, cicatrization, or deceleration of the degeneration rate. Third, education for the participants based on the particularities of their specific etiological diagnosis enabled patients to be more proactive and responsible with their own treatment, favoring a reduction in anxiety and other psychosomatic variables, as recently demonstrated[79–81].

The orthopedic correction applied in G2 shares similarities to Jankelson’s neuromuscular methodology, where a TENS unit is used to pulse and electronically deprogram the masticatory muscle, in order to obtain a “bite position” based on muscle relaxation that he called myocentric occlusion[82–86]. However, Jankelson’s work was from the 1960s and 1970s, before the development of MRI, which now allows professionals to visualize and understand the arrangement of internal structures of the TMJ in each patient. Moreover, certain scientific knowledge and proper laboratory blood analysis and other technologies were not available at that time. Hence, the orthopedic craniomandibular position used in this work differs from the neuromuscular myocentric occlusion because it was determined by the combination of MRI, etiological, and systemic information with the biometric instrumentation data.

Research has demonstrated that temporomandibular arthropathy characterized by volumetric and morphological damage of internal structures, such as disc displacement, deformities, erosions, and resorption, changes the craniomandibular orthopedic spatial position, resulting in occlusion and facial problems (mandibular retrusion, asymmetry, open bites, etc.[18–20, 24, 87, 88]. This is very clear in relapses of orthognathic surgery and orthodontic treatments due to condylar resorption or any kind of joint damage[14, 89–91]. Thus, when dealing with TMJ pathology, there is a need to modify the myocentric position according to the status of the joint during treatment because either the TMJ arthropathy continues to follow its course or it is recovering from it.

Therefore, anatomical-functional orthotics for patients in G2 provided occlusal support to orthopedically manage the situation. In other words, the idea of “correct the bite” comes from an orthopedic rather than a dental occlusion perspective. The aim is to control, stabilize, or even revert the joint problem, allowing the occlusion to fit the TMJ status as it changes over time. In parallel, it is necessary to control the etiological factors to optimize treatment; otherwise, relapses and symptoms flare ups may be uncontrolled.

In summary, although both groups presented short-term improvements in pain scores (at 2–3 months), over 6 months, patients in G2 had significantly fewer clinical symptoms than patients in G1. Moreover, they were more independent of alternative therapies, using them only sporadically, and none of them required cyclobenzaprine or tricyclic antidepressants. Patients in G2 also presented significant measurable data showing neuromotor and pathophysiological recovery, supporting the subjective report of improvement in pain as shown in the literature, while the results of patients in G1 could not be differentiated from the placebo effect, regression to the mean, and/or, in fact, some level of treatment effect.

G2 intragroup discussion

The differential diagnosis procedures in G2 revealed that 73% of the patients classified as presenting disc disorder and all of the patients presenting degeneration of the TMJ also presented serological evidence of past or ongoing infection by classical arthritogenic bacteria. This is corroborated by other studies that also found high prevalence of infection related to disc disorders and degeneration. Henry et al. (1999)[28] reported that in a group of patients with internal derangement and/or DJD who had failed conventional non-surgical or surgical treatment, 20% of the cases showed the presence of C. trachomatis in the posterior bilaminar tissue based on immunostaining. When a specific polymerase chain reaction (PCR) assay targeting two genes of C. trachomatis was performed, the percentage of affected cases increased to 39%. Paegle[92], based only on serum IgG titers for Chlamydia spp. found that 45% of the patients with monoarthritis and chronic closed lock of the TMJ had evidence of previous infection, while only 14% of the control group had previous exposure to the pathogen, with statistically significant differences between patients and control subjects (P = .007). Another publication[29] also employed a specific PCR assay with biopsy of the retrodiscal tissue of damaged TMJ and found that C. trachomatis alone accounted for 42% of the cases. When Mycoplasma genitalium considered, the percentage TMJ affected by infection increased to 65%. However, in the daily clinical set, biopsy of TMJ tissue is neither practical nor recommended due to its invasiveness and the structural damage of the procedure might do more harm than good, resulting in a diagnosis but compromising treatment. Less-invasive synovial fluid sampling is also not accurate because these arthritogenic pathogens are intracellular by nature and synovial fluid markers of their presence occurs only when they have already spread to extracellular tissue[56, 93–95]. So, as in the medical field, indirect diagnosis based on imaging and blood analysis were the standard protocol in this trial.

The slightly higher percentage in our work could be explained by the fact (1) we searched for a broader spectrum of bacteria, (2) we used an advanced paired test over time to overcome possible false negative cases, and (3) we also grouped past infection cases together with ongoing infection, all under the umbrella of “evidence of infection.” This was necessary because, differently from the other publications mentioned above, our work was the only one dealing with treatment. Obligate intracellular pathogens such as C. trachomatis and C. pneumoniae, and facultative intracellular parasites such as M. genitalium and M. pneumoniae may assume a latent form, with no to extremely low metabolic rates that downregulates their antigen expression, leading to false negatives of ongoing infection[53]. They can assume an aberrant persisting form for long periods of time[54, 96] and may generate flare ups once there is any window of opportunity due to host immunological stress[67], similarly to viruses such as herpes simplex and zoster. In addition, they may not leave the host[51, 55–57, 94, 97, 98].

So, for treatment purposes, the cases that were considered as having a “past infection” without any evidence of ongoing arthritogenic activity were not submitted to antibiotic treatment—but they remained under surveillance. Patients with this diagnosis were educated to recognize any clinical “red flag” that could indicate a possible reactivation of infection and a specific protocol of paired serological data was followed. Only those cases that presented evidence of ongoing infection were submitted to antibiotics. It is noteworthy that the DJD cases that presented regeneration of the joints after treatment were precisely the same cases that had required prolonged antibiotic therapy.

Twenty percent of the patients with disc disorders and DJD showed autoimmunity. This is interesting because it could be linked to infection, because these bacteria can directly damage the joints and they are known to trigger autoimmune disease in patients with genetic susceptibility[51, 99, 100]. In addition, the autoimmune damage of the TMJ could also be an early manifestation of a systemic condition[101]. However, in the absence of a medical diagnosis of a rheumatic disease, the differential diagnosis was established as an autoimmune temporomandibular arthropathy[33] and treatment was performed as described in the Methodology section. Systemic inflammation accounted for a significant portion of the cases and were treated as described previously to promote long-lasting results.

After completing the trial, for ethical reasons crossover treatment was offered for those patients who were still experiencing pain. Four patients in G1 in severe pain migrated to G2 treatment and subsequently recovered and were discharged. No patient in G2 migrated to G1 treatment. Their post-trial data were not included in this paper.

This trial has demonstrated that both treatment approaches may relive symptoms, but the patients treated based on the biopsychosocial model, with a Michigan-type myorelaxant/stabilization splint combined with alternative therapies, only presented short-term benefits for 2–3 months, followed by symptom worsening after 6 months. Subjects under this treatment paradigm were also significantly more dependent on palliative and pharmacological care over time. This seems to be related to impaired function as shown by EMG data, where the temporalis presented a worsening at T2 but a slight recovery at T3, just above the baseline, while the masseter showed significant functional deterioration at T3. The patients treated based on the measurable model of TMJ pathology and neurophysiology, with its anatomical-functional orthosis combined with an etiological-focused arthropathy management, presented longer lasting symptom relief and significant less dependance on alternative/palliative therapy. This improvement was supported by the EMG data, showing progressive recovery of muscle function at both T2 and T3 and MRI before and after treatment showing regeneration, disc recovery, and/or stagnation of joint lesions for the majority of cases.

Please include the study's present Author's Contribution, Conflict of Interest, Funding, Ethical Approval, Informed Consent statements in this section)

Acknowledgements:

The authors are grateful to the Brazilian fostering agencies Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES [Coordination for the Advancement of Higher Education Personnel]) and Conselho Nacional de Desenvolvimento Científco e Tecnológico (CNPq [National Council of Scientifc and Technological Development]). The authors also are grateful to Dr. Marcus Vinícius Martins Corrêa (Diamantina, Minas Gerais, Brazil), for their collaboration on the collection of the sample.

Data avaliability: The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author’s contribution: 1, 2 and 3 - authors who carried out the clinical research (application of the treatment, data collection and blinding); 1, 2, 4 and 5 - these authors contributed strongly to the writing of the manuscript; authors 4 and 5 planned the design and outline of the study; All authors reviewed the manuscript.

Conflict of interest: The authors declare no competing interests.

Funding: No funding was obtained for this study.

Ethical approval: The project was approved by the Ethics Committee for Research of the University of Pernambuco, Brazil, under the CAAE number 66446216.6.0000.5207 of the Brazilian National Research Platform.

Informed consent: Informed consent was obtained from all individual participants included in the study

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Flowchart 1 is available in Supplementary Files section.

No competing interests reported.

Flowchart.png

Effectiveness of the Biopsychosocial Model Versus the Measurable Neurophysiological Model in Patients With Temporomandibular Joint Arthropathies

Status:

Version 1

Abstract

OBJECTIVE

PATIENTS AND METHODS:

RESULTS

CONCLUSIONS

CLINICAL RELEVANCE:

Figures

INTRODUCTION

METHODOLOGY

Statistical analysis

RESULTS

DISCUSSION

CONCLUSION

Declarations

References

Flowchart 1

Additional Declarations

Supplementary Files

Status:

Version 1