COMPOSITIONS AND METHODS FOR THE TREATMENT OF TEMPOROMANDIBULAR JOINT DISORDER

This application claims priority to United States provisional patent application 63/412,191 , filed September 30, 2023, the contents of which are incorporated herein in their entirety.

TECHNICAL FIELD

This invention relates to compositions and methods for the treatment of temporomandibular disorders.

BACKGROUND OF THE ART

Temporomandibular disorders (TMD) are a diverse group of musculoskeletal and neuromuscular conditions, divided into those involving the temporomandibular joint (TMJ) and those affecting the masticatory muscles [1], Prevalence estimates range from 5% to 12% of adults, and the risk of TMD onset may be highest between ages 18 and 44 years [2,3], with their prevalence in females about 30% more than in males.

TMD are often characterized by pain in the temporomandibular joint (TMJ), in the masticatory (chewing) muscles, or in both [3], TMJ pain is described as craniofacial/myofascial pain involving the TMJ as well as muscle innervations of the head and neck, and masticatory muscles. Headache, joint sounds, and otologic symptoms are also common indicators/ symptoms of TMD [4], Symptoms can range from mild discomfort to debilitating pain, and may involve a reduction in jaw function [1],

In a 2015 study, patient-reported outcome measures showed a direct correlation between TMD and low quality of life (QoL), with a 2021 metanalysis in young and middle-age adult patients with TMD confirming that QoL is significantly more adversely affected in patients with higher pain intensity [5], Therefore, goals of TMD management are to alleviate pain and to improve jaw function and QoL.

Although over-the-counter (OTC) and prescription medications, including non-steroidals, may help in reducing TMD pain, long-term use of these drugs is not recommended.

There remains a need for effective alternative treatments for TMD. BRIEF SUMMARY

In a first embodiment, there is provided a transdermal pharmaceutical composition for the treatment of temporomandibular disorders comprising a therapeutically effective amount of at least one cannabinoid, wherein the composition is in the form of a cream.

Also provided is:

2. The transdermal pharmaceutical composition according to embodiment 1 , wherein the at least one cannabinoid is cannabidiol, preferably cannabidiol isolate.

3. The transdermal pharmaceutical composition according to embodiment 1 or 2, further comprising one or more or all of an emulsifier, an emollient, an antioxidant, a thickener, a humectant, a preservative, a chelating agent, a skin conditioner, an antimicrobial, an antiinflammatory and a UV-protectant.

4. The transdermal pharmaceutical composition according to any one of embodiments 1 to

3, comprising between about 88 % w/w and about 98 % w/w water, emulsifying wax and cannabidiol; with the remainder of the composition comprising some or all of an emollient, an antioxidant, a thickener, a humectant, a preservative, a chelating agent, a skin conditioner, an antimicrobial, an anti-inflammatory and a UV-protectant.

5. The transdermal pharmaceutical composition according to any one of embodiments 1 to

4, comprising: Water; Emulsifying wax (NF); Cyclopentasiloxane; Ethylhexyl Stearate; Sorbitol; Glycerin; Phenoxyethanol; Disodium EDTA; Ethylhexylglycerin; Aloe barbadensis leaf juice; and Tocopheryl acetate.

6. The transdermal pharmaceutical composition according to any one of embodiments 1 to

5 comprising 2 % w/w to 20 % w/w cannabinoid, preferably 3 % w/w to 15 % w/w cannabinoid, more preferably 5 % w/w to 15 % w/w cannabinoid.

7. The transdermal pharmaceutical composition according to any one of embodiments 1 to

6 comprising: between about 30% w/w and about 90% w/w water; between about 10% w/w and about 30% w/w emulsifying wax; between about 0.1 % w/w and about 3% w/w cyclopentasiloxane; between 0.1 % w/w and about 3% w/w ethylhexyl stearate; between 0.3% w/w and about 1 % w/w sorbitol; between about 0.3% w/w and about 1 % w/w glycerin; between about 0.3% w/w and about 1% w/w phenoxyethanol; between about 0.1% w/w and about 0.3% w/w disodium EDTA; between about 0.3% w/w and about 1% w/w ethylhexylglycerin; up to about 0.1 % w/w aloe barbadensis leaf juice; and/or up to about 0.1 % w/w tocopheryl acetate.

8. The transdermal pharmaceutical composition according to any one of embodiments 1 to

7, further comprising ethoxydiglycol, preferably in an amount of between about .5 % w/w and about 2 % w/w based on the weight of the composition, more preferably about 1 w/w based on the weight of the composition.

9. The transdermal pharmaceutical composition according to any one of embodiments 1 to

8, wherein the composition includes less than 50%, less than 45%, less than 40% or less than 35% hydrocarbons, waxes and polyols.

10. The transdermal pharmaceutical composition according to any one of embodiments 1 to

9, wherein the composition includes less than 5%, less than 1 % or no plant oils.

11. A metered dispenser containing the transdermal pharmaceutical composition according to any one of embodiments 1 to 10.

12. The metered dispenser according to embodiment 11 , wherein the dispenser dispenses a metered dose that contains between 1 mg and 8 mg CBD, preferably between 2 and 6 mg CBD, optionally a metered dose of between 2.5 mg and 3.5 mg, preferably about 2.8 mg or a metered dose of between 5 mg and 6 mg, preferably about 5.6 mg.

13. A method of treating or preventing at least one symptom of a temporomandibular disorder comprising topically administering in the region of the masseter muscle a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1 to 10 to a subject in need thereof.

14. A method of treating or preventing temporomandibular joint pain comprising topically administering in the region of the masseter muscle a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1 to 10 to a subject in need thereof.

15. The method according to embodiment 13 or 14, wherein the subject has been diagnosed with a temporomandibular disorder, in particular, a chronic temporomandibular disorder. 16. The method according to any one of embodiments 13 to 15, comprising administering the pharmaceutical composition of any one of embodiment 1 to 10 to the subject in need thereof using the metered dispenser according to embodiment 11 or 12.

17. The method according to any one of embodiments 13 to 16, wherein the at least one symptom is acute pain in the region of the masseter muscle and the pharmaceutical composition is applied by the subject for immediate pain relief.

18. The transdermal pharmaceutical composition of any one of embodiments 1 to 10 or the metered dispenser according to any one of embodiments 11 to 12, for use in the treatment or prevention of at least one symptom of a temporomandibular disorder and/or temporomandibular joint pain in a subject in need thereof.

19. The transdermal pharmaceutical composition or the metered dispenser according to embodiment 18, wherein the composition is topically administered in the region of the masseter muscle.

20. The transdermal pharmaceutical composition or the metered dispenser according to embodiment 18 or 19, wherein the subject has been diagnosed with a temporomandibular disorder, in particular, a chronic temporomandibular disorder.

21 . The transdermal pharmaceutical composition or the metered dispenser according to any one of embodiments 18 to 20, wherein the symptom is acute pain in the region of the masseter muscle and the pharmaceutical composition is applied by the subject for immediate pain relief.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows a front side view of a metered dispenser according to an embodiment.

Figure 2 shows a bottom side view of a metered dispenser according to an embodiment.

Figure 3 shows an exploded view of a metered dispenser according to an embodiment.

Figure 4a shows a mixing lid for a metered dispenser according to an embodiment.

Figure 4b shows a mixing paddle of the mixing lid for metered dispenser according to an embodiment. Figure 5 shows a photograph of a dispenser according to an embodiment.

DETAILED DESCRIPTION

Provided herein are compositions and methods for the treatment of temporomandibular disorders (TMDs) and, in a particular embodiment, TMDs that include temporomandibular joint (TMJ) pain. The compositions provided herein include at least one cannabinoid.

As used herein "cannabinoid" refers to any of the class of chemical compounds referred to as cannabinoids that act on cannabinoid receptors and modulate activity of the endocannabinoid system. “Cannabinoid” can also include combinations of different cannabinoids. Known cannabinoids include THC (tetrahydrocannabinol); THCA (tetrahydrocannabinolic acid); CBD (cannabidiol); CBDA (cannabidiolic acid); CBN (cannabinol); CBG (cannabigerol); CBC (cannabichromene); CBL (cannabicyclol); CBV (cannabivarin); THCV (tetrahydrocannabivarin); CBDV (cannabidivarin); CBCV (cannabichromevarin); CBGV (cannabigerovarin); CBGM (cannabigerol monomethyl ether); CBE (cannabielsoin); and CBT (cannabicitran). In a preferred embodiment, the compositions provided herein contain cannabidiol. In preferred embodiments, the cannabinoid component consists or consists essentially of cannabidiol. Preferably, cannabidiol is the sole cannabinoid in the composition. Preferably, the cannabinoid component comprises less than 1 % THC, preferably less than 0.3% THC. Preferably, the pharmaceutical composition does not include detectable levels of THC. Preferably, the cannabinoid is CBD isolate.

TMD pain may be acute, chronic, or a combination of both, typically provoked by function. Furthermore, in the recent large Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) Study, patients with TMD were identified as falling into three categories: first, as having low experimental pain sensitivity and low psychological distress, second, as having higher pain sensitivity, and the third, identified as having higher pain sensitivity and psychological distress [6],

Trauma or postural tension, known as ‘peripherally-acting’ conditions or ‘centrally-acting’ comorbidities such as fibromyalgia, and anxiety or depression, may also be associated with a heightened risk of TMD progressing from an acute to a chronic state [7,4], Therefore, alleviating TMD pain may help avert it from becoming chronic.

Although analgesic medications may reduce TMD pain, their long-term use can be deleterious. As demonstrated in the Examples, transdermal CBD compositions as provided herein improve QoL for patients with TMD. Further, while cannabis oil preparations have been used in the treatment of pain, these compositions are highly variable in composition and, consequently dosing, and can be difficult to apply.

As used herein, “therapeutically effective amount” refers to an amount effective, at dosages and for a particular period of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the pharmacological agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the pharmacological agent to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the pharmacological agent are outweighed by the therapeutically beneficial effects.

As used herein “subject” refers to an animal being administered a cannabinoid composition as provided herein, in one embodiment a mammal, in one embodiment a human patient. As used herein “treatment” and grammatical variations thereof refers to administering a composition of the present invention to a subject to prevent (completely or in part) or ameliorate a disease or condition or a symptom thereof. This treatment may be to alleviate pain or the use may be prophylactic to prevent pain. Symptoms of TMD that may be prevented orameliorated can include (but are not limited to) facial pain, headache, ear pain and joint sounds. The treatment may require administration of multiple doses, which may be at regular intervals.

In one embodiment, there is provide a pharmaceutical cannabinoid composition for topical application to the masseter region of a patient for the treatment of TMD. The at least one cannabinoid, preferably cannabidiol, is formulated in a cream.

As used herein, a “cream” refers to a water-based semisolid preparation containing less than 50% (% w/w) hydrocarbons, waxes or polyols, in some embodiments, less than 45%, less than 40%, less than 35%, or less than 30% hydrocarbons, waxes or polyols. A cream may be differentiated from an ointment, which contains equal to or more than 50% hydrocarbons, waxes, or polyols.

Without limiting the generality of the foregoing, the composition according to the invention contain minimal amounts of oils, preferably less than 10% (% w/w), more preferably less than 5%. Many cannabinoid products contain cannabinoid oils and, frequently, other plant oils. Preferably, the compositions according to the present invention contain less than 5% plants oils, preferably less than 1 % plant oils and, most preferably, compositions according to the present invention are not formulated using plant oils. The cannabinoid is suitably contained in a cream composition that includes one or more, in some embodiments, all of an emulsifier, an emollient, an antioxidant, a thickener, a humectant, a preservative, a chelating agent, a skin conditioner, an antimicrobial, an anti-inflammatory and a UV-protectant. In some embodiments, the composition includes between about 88 % w/w and 98 % w/w water, emulsifier, preferably emulsifying wax and cannabinoid, preferably CBD isolate, with the remainder of the composition comprising one or more of an emollient, an antioxidant, a thickener, a humectant, a preservative, a chelating agent, a skin conditioner, an antimicrobial, an antiinflammatory and a UV-protectant. In some embodiments, the cream composition contains all of an emollient, an antioxidant, a thickener, a humectant, a preservative, a chelating agent, a skin conditioner, an antimicrobial, an anti-inflammatory and a UV-protectant. As is known to persons of skill in the art, a single ingredient may provide more than one function and so, for example, sorbitol may act as both a humectant and a thickener. In some embodiments, there is provided a composition for the treatment of TMD that includes some and preferably all of:

In some embodiments, the composition consists or consists essentially of the ingredients in Table 1 and, optionally, ethoxydiglycol.

In some embodiments, the concentration of the cannabinoid, preferably cannabidiol within the composition is between about 1 % and about 20% by weight. In some embodiments between about 2% and about 20% by weight, preferably between about 3% and about 15% by weight or between about 5% and 15% by weight (e.g. 3% to 10 % or 5% and 10% by weight). Preferably, the composition is prepared from CBD isolate (purified, crystallized CBD).

In some embodiments, the composition contains between about 30% w/w and about 90% w/w water. In some embodiments, the composition contains between about 10% w/w and about 30% w/w emulsifying wax. In some embodiments, the composition contains between about 0.1 % w/w and about 3% w/w cyclopentasiloxane. In some embodiments, the composition contains between 0.1 % w/w and about 3% w/w ethylhexyl stearate. In some embodiments, the composition contains between 0.3% w/w and about 1 % w/w sorbitol. In some embodiment, the composition contains between about 0.3% w/w and about 1% w/w glycerin. In some embodiments, the composition contains between about 0.3% w/w and about 1 % w/w phenoxyethanol. In some embodiments, the composition contains between about 0.1 % w/w and about 0.3% w/w disodium EDTA. In some embodiments, the composition contains between about 0.3% w/w and about 1 % w/w ethylhexylglycerin. In some embodiments, the composition contains up to about 0.1 % w/w aloe barbadensis leaf juice (e.g. 0.001 % w/w to 0.1 % w/w). In some embodiments, the composition contains up to about 0.1 % w/w tocopheryl acetate (e.g. 0.001 % w/w to 0.1 % w/w).

In some embodiments, the composition further contains between .5 % w/w and 2 % w/w ethoxydiglycol, preferably about 1 % w/w ethoxydiglycol.

In some embodiments, the composition consists or consists essentially of the ingredients in Table 1 and, optionally ethoxydiglycol, in the amounts provided above.

In some embodiments, the ingredients are combined with mixing and, in particular, high shear mixing. Optionally, the cannabidiol is combined with ethoxydiglycol to levigate prior to combining with the remaining ingredients. The use of an isolated cannabidiol ingredient formulated in a transdermal base, as exemplified above, enables the cannabidiol to penetrate deep into tissues when applied transdermally. Further, the composition benefits from a low/non-greasy and low/non-oily feel, which is particularly important for a product that will be applied to the facial area. In this regard, the product may be more compatible with the subsequent application of cosmetic products.

In various embodiments, the composition may be packaged in any suitable container, e.g. a lidded jar or pot, a bottle (e.g. a pump bottle) or a tube.

In some embodiments, the composition is provided in a prefilled metered dosing applicator, such as described herein, which enables controlled direct application of a metered amount of cream composition. As shown in the examples, this effective transdermal application mechanism may be suitable for both use by a subject as-needed to relieve acute TMD symptoms (including pain), while also providing sustained relief from the symptoms of TMD, when regularly applied.

The use of isolated cannabidiol eliminates other products naturally available in cannabis oils and provides an effective consistent product.

The present inventors have surprising and unexpectedly determined that the compositions provided herein can be topically administered regularly in the doses detailed herein with minimal or no irritation over a prolonged period (e.g. daily for more than two weeks) to provide sustained relief from or reduction of temporomandibular joint (TMJ) pain. Further, as detailed in the examples, these relatively low doses can be used in the treatment of both chronic and acute TMJ pain.

Unlike oil-based ointments, the cream formulations as provided herein are non-comedogenic and can be dispensed in a metered dose for consistent application.

In an embodiment, there is provided a metered dispenser (10) for the treatment of TMD, as shown in figures 1-3. The dispenser (10) includes a barrel for containing the CBD composition as described herein. The barrel (12) may suitably be formed of polypropylene, suitably comprising a UV inhibitor. The barrel (12) may be clear or may include a clear window enabling a user to view the CBD composition within the barrel. In some embodiments, the dispenser includes a scale on the surface of the barrel providing the user with a visual indication of the amount of CBD composition dispensed and/or remaining within the barrel. A dosing knob (14) rotatable by a user is operably connected to nut (16), screw (18), elevator (20) and ring (22) to effect dispensing of a pre-set dose of the CBD composition. Suitably, dispenser (10) includes an applicator cap (24). Applicator cap (24) is suitably secured to barrel (12) and may include a plurality of dispensing outlets or nozzles, facilitating even application of the CBD composition to the skin of a user. Suitably, dispenser (10) includes a removable protective cover (26) over applicator cap (24). In one embodiment, the dispenser provides an indication to a user when a single dose of the CBD composition has been dispensed, in one embodiment, an audible click.

Dispenser (10) may suitably be provided as a preloaded dispenser and may be provided in an outer container provided with a child-proof protective lid.

In one embodiment, the dispenser is a prefilled single use device.

In one embodiment, the dispenser provides a metered dose of between 1 mg and 8 mg CBD, preferably between 2 and 6 mg CBD. In one embodiment, the dispenser provides a metered dose of between 2.5 mg and 3.5 mg, preferably about 2.8 mg. In a further embodiment, the dispenser provides a metered dose of between 5 mg and 6 mg, preferably about 5.6 mg.

In one embodiment, there is provided a method of treating or preventing at least one symptom of a TMD comprising topically administering in the region of the masseter muscle a therapeutically effective dose of the pharmaceutical composition as described.

In one embodiment, there is provided a method of treating or preventing TMJ pain comprising topically administering in the region of the masseter muscle a therapeutically effective dose of the pharmaceutical composition as described.

In some embodiments, a therapeutically effective amount of the composition is suitably between about 0.25 g and about 1 .0 g.

In some embodiments, these methods comprise administering a therapeutically effective dose of the pharmaceutical composition employing the metered dispenser as described herein

In some embodiments, the pharmaceutical composition is administered, daily or twice daily and/or, in some embodiments, the pharmaceutical composition is administered as-needed by a user in response to TMJ pain.

As evidenced in the Examples below, the compositions and methods provided herein can provide both immediate and long-term relief from symptoms of TMD.

All documents referenced herein are incorporated by reference, however, it should be appreciated that any patent, publication, or other disclosure material, in whole or in part, that is incorporated by reference herein is incorporated only to the extent that the incorporated material does not conflict with definitions, statements, or other disclosure material set forth in this disclosure. As such, and to the extent necessary, the disclosure as explicitly set forth herein supersedes any conflicting material incorporated herein by reference.

Terms such as "at least", "or more", and the like, include the number recited and such terms refer to ranges; ranges provided here can be subsequently broken down into sub-ranges.

It will be understood that numerous modifications thereto will appear to those skilled in the art. Accordingly, the above description and accompanying drawings should be taken as illustrative of the invention and not in a limiting sense. It will further be understood that it is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features herein before set forth, and as follows in the scope of the appended claims.

The embodiments of the invention described above are intended to be exemplary only. The scope of the invention is therefore intended to be limited solely by the scope of the appended claims.

EXAMPLES

1

A 38-year-old female presented with periodically acute TMJ pain, which was caused by a motor vehicle accident in 2003, during which she suffered facial fractures and a TMJ dislocation. Although initial facial wounds healed, this patient continued to be impacted by significant limitations in her physical, social, and emotional quality of life (QoL) due to her TMD pain. Her ability to care for her children, to travel long distances (by car or plane) plus the necessity to pace activities were all aspects of her life inherently affected by the pain. Barometric-, weather- or exercise-related triggers exacerbated her condition, leaving her to struggle daily to manage the pain.

Ibuprofen, acetaminophen and/or essential oils such as peppermint oil had proven somewhat effective for the patient. Interestingly, while peppermint oil could reduce the pain (scale of 1-10; 1-minimal impact; 10-maximal impact) about 2 points almost immediately, acetaminophen alone did not touch the pain. Indeed, only the combination of acetaminophen and ibuprofen was effective for severe pain; however, all these treatments only worked for approximately 30 minutes. The patient was concerned about daily use since she was aware that ibuprofen and acetaminophen were not recommended for long-term use. The patient was provided a metered dispenser of transdermal CBD cream of the composition provided in Table 1 , which delivered precise doses of CBD (2.8 mg) onto the skin. Since this cream was absorbed at the application site only, the patient’s concerns about systemic issues were diminished. Furthermore, she stated, as she began using the transdermal CBD cream for acute TMJ pain incidences, she noticed immediate pain relief (a reduction of at least 5 points), lasting from 60 minutes to several hours. The patient continued to use the transdermal CBD cream daily, declaring that her TMD pain continued to ease, while her QoL has improved considerably

A 38-year-old female initially experienced TMJ pain around age of 15 years. While her family physician diagnosed her myofascial pain as TMD, the cause of the pain remains idiopathic. Currently a dentist by profession, this patient presented with TMJ pain that she claimed had not significantly impacted her daily activities of living; however, when questioned further, she admitted to frequent ‘attacks’ of acute pain, usually related to stress resulting in clenching her jaw, which invariably led to TMD pain.

Although this patient did not consider her pain to be chronic, she had experienced TMD pain persistently since age 15 years old, which could be an indication of the chronicity of the pain. Moreover, her QoL continued to be affected with occasional pain and headaches due to the TMD pain, which could reach a 7 in intensity. She also declared that at times, she had difficulty concentrating.

The patient stated she used ibuprofen to treat the TMD pain, which often alleviated completely with the medication; however, she did have some concern about long-term use of OTC nonsteroidal anti-inflammatories (NSAIDs). The patient was provided a metered dispenser of transdermal CBD cream of the composition provided in Table 1 having a cannabidiol concentration of 1.2%, which delivered precise doses of CBD (2.8 mg) She reported she experienced almost immediate (10-15 minutes) relief from herTMD pain (decreased to a 2), which also lasted for several hours.

The patient now considers the transdermal CBD cream a vital tool to help her alleviate the TMD pain without the use of systemic medication.

Example 3

Three participants were recruited for a comparative study, two of whom work in healthcare and are well-acquainted with drug products and their applications. A transdermal pharmaceutical cream was prepared as provided in Table 1. LivRelief™ Transdermal CBD Cream, which held significant market share in Canada where the study was performed, was selected as a comparator product. The study also included a placebo cream with no CBD or ingredients associated with pain relief. The three different creams were transferred into unlabelled bottles, which were subsequently labeled as A, B, and C to maintain impartiality. The participants were asked to use the products over a period of 3-4 weeks, during which they took notes on their experiences with each product. At the conclusion of the use period, interviews were conducted to gather more in-depth insights into the experiences and impressions of each product.

Participants were asked for their impressions on effectiveness, cream properties, and comfort of use over the study period. All participants found the cream according to an embodiment of the present invention to be effective, while having preferred properties. The cream according to an embodiment of the present invention was particularly noted for its non-greasy texture and was described as cosmetically elegant.

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