Scientific and Therapeutic Aspects of Botulinum Toxinedited by M.F. Brin, J. Jankovic, and M. HallettLippincott Williams & Wilkins, Philadelphia, � 2002.

25Botulinum Toxin A Therapy forTemporomandibular Disorders

Marvin Schwartz and Brian Freund

DEFINING TEMPOROMANDIBULARDISORDER

Temporomandibular disorder (TMD) is a collec-tive term used to describe a group of pathologicconditions involving the temporomandibularjoint (TMJ), masticatory muscles, and/or associ-ated structures. As such, the TMDs encompassa wide variety of medical disorders of orthopedicand myofascial origin that closely resemblethose described for other joint and muscular con-ditions. The unique nature of TMD resides inthe proximate anatomy of numerous other facialand cranial structures, thereby complicating, in-teracting with, and mimicking other sources ofhead and neck pain (Figs. 25.1 and 25.2).Symptoms commonly associated with TMDs

include:

• Difficulty speaking• Difficulty eating• Difficulty sleeping• Chronic headaches• Earaches, hearing impairment• Jaw dysfunction including hyper- and hypo-mobility

• General orofacial pain

The differential diagnosis for TMD is a gal-lery of conditions applicable to almost all headand neck pain. Table 25.1 provides an incom-plete list (1).An historical review by Kaplan (2) reveals

that TMD was described as early as 1920 in theguise of ‘‘abnormalities of mandibular articula-tion’’ (Wright, 1920; Goodfriend, 1933). Subse-quent nomenclatures for TMD and its subtypes

259

reinforce the observations, vanities and biasesof the investigators, including:

• Costen’s syndrome (Costen, 1956)• TMJ dysfunction syndrome (Schore, 1959)• TM pain syndrome (Schwartz, 1959)• Pain dysfunction syndrome (Voss, 1964)• Myofacial pain dysfunction syndrome orMPDS (Laskin, 1969)

• Myoarthropathy of the TMJ (Graber, 1971)• Occlusomandibular disturbance (Gerber,1971)

• Internal joint derangement (Farrar, 1971)

Statistics from epidemiologic studies are dif-ficult to compare as a universally accepted clas-sification system for TMD does not exist (seebelow). De Kanter and coworkers published theresults of their meta-analysis of 51 studies in1993 (3). The results were confounded by somelimitations, including a lack of uniformity inclassification. However, more than 15,000 sub-jects in 23 studies reported a dysfunction rate of30%. Professionally assessed dysfunction wasidentified in 44% of subjects. While the statisticsmay be difficult to pin down, it is clear thatTMDs are common in nonpatient populations(4).Thorough reviews of data from large studies

reveal that 20% to 25% of a population (5,6)sought professional care for their TMD at somepoint in their life. Significantly, advanced carerequiring the expertise of specialists was re-quired in 5% to 10% of the population (7–10).The economic and societal costs are substantial(11).

SCIENTIFIC AND THERAPEUTIC ASPECTS OF BOTULINUM TOXIN260

FIG. 25.1. The Joint

CLASSIFICATION OF TMD

At this writing, there exists no unanimity in theTMD community regarding a single universallyacceptable taxonomy. A comprehensive, histori-cal overview and analysis by Ohrbach andStohler (12) of proposed systems include Bell,1960, 1982, 1986; American Academy of Crani-omandibular Disorders, 1980, 1990; Block,1980; President’s Conference on the Examina-tion, Diagnosis and Management of TMJ Disor-ders, 1982; Farrar, 1982; Eversole andMachado,1985; Fricton, 1988; International HeadacheSociety (fits ICD system), 1988; Stegenga et al.(based on system of American Rheumatism As-

TABLE 25.1. Differential diagnosis of TMD

Source of pathology Common examples

Systemic diseases

Myofascial pain

Skeletal pain

Proximate anatomic structure painIntracranial pathologyNeurologic disorders

Psychogenic pain disorders

Multiple myeloma; diabetes mellitus; systemic lupus erythematosus(SLE); giant-cell arteritis

Masticatory muscles; cervical muscles; frontalis-occipitalis and otherfacial muscles involved in tension headaches, cervicogenic headaches,myofascial pain dysfunction (MPD), fibromyalgia

Osteomyelitis; neoplasia; fibrous dysplasia; gout; osteomalacia; Paget’sdisease

Odontogenic; ophthalmic; otic; nasal; sinus; salivary; Eagle’s syndromeNeoplasm; aneurysm; abscess; hemorrhage; hematoma; edemaMigraine variants; cluster headaches; neuralgias; paroxysmal hemicrania;

cranial arteritis; carotidyniaPsychotic syndromes; mood disturbances; anxiety disorders; organic

disorders; somatoform disorders

FIG. 25.2. The Musculature

sociation), 1989; and Research Diagnostic Crite-ria (RDC), 1992. Currently, the RDC and ICDsystems appear to be used more commonly thanany of the others.Despite the differences, a practical review of

these classification systems yields several com-mon underlying themes. First, while most of theschemes attempt to provide comprehensive cov-erage of all possible pathologic conditions, themost prevalent clinical TMDs are primary crani-omandibular pains. These are usually divided,based upon anatomic etiology, among pain orig-inating in the TMJ proper or intracapsular (i.e.,arthrogenic) and pain originating in themuscula-

BOTULINUM TOXIN A THERAPY FOR TEMPOROMANDIBULAR DISORDERS 261

ture (i.e., myogenic). Second, there is a notableoverlap between TMD taxonomy and those ofother disciplines caring for patients with primaryhead and neck pain (below). Third, stress, psy-chologic factors, and chronicity are common andsignificant factors in TMD, as with most compli-cated head and neck pain. The contribution ofcentral input and neuroplasticity is significantand must be considered in the successful diagno-sis and management of TMD.

INTERDISCIPLINARYMANIFESTATIONS OF TMD

A studied approach transcending medical anddental disciplines yields numerous instances ofoverlap that have historically resulted in the arti-ficial segmentation of TMDs. Three poignantexamples are presented.Tension headaches (TH): The majority of TH

anatomically originate or involve the temporalisand/or masseter muscles. As such, there is nodistinction between the classification of thisclinical phenomenon as a myogenous TMD ver-sus a TH. It is of little coincidence that someTH researchers use temporalis muscle pain in-duced by tooth clenching as a valuable experi-mental model (13).Oromandibular dystonia: Belonging to the

group of movement disorders characterized byinvoluntary spasms and muscle contractions thatinduce abnormal movements and postures, thisparticular subset constitutes a focal form thatinvolves the musculature of the masticatory ap-paratus and lower face. It manifests as distortedoral position and function resulting in difficultyin speaking, eating, swallowing, and facial ap-pearance. Although it is a neurologic disorder,there is no doubt of its inclusion as a subset ofTMDs owing to the involvement of the mastica-tory apparatus.Bruxism: This clinical entity may occur as a

solitary form of TMD involving only the muscu-lature or as an initiating and/or perpetuating fac-tor in more involved forms of TMD involvingjoint damage. Taking a wider view of the litera-ture brings an interesting correlation. Bruxismmanifests many of the characteristics of dystoniaincluding similar epidemiology, as well as the

features of pain and exacerbation by externalfactors such as fatigue, stress, and emotional ex-tremes. Wooten-Watts, Tan, and Jankovic (14)postulated the possibility that bruxism may bea form of dystonia. With this knowledge, it isentirely possible to view the current treatmentof bruxism with intraoral appliances or occlusaladjustments as ‘‘sensory tricks’’ that relieve thedystonia. Perhaps this explains the success of amyriad of splint designs and occlusal therapiesdespite the lack of fundamental understandingof their basis of action. It may also explain thecommon failure of splint and occlusal therapiesin some TMD cases. After all, the sensory trickis not the same for all patients with dystonias.

PATHOPHYSIOLOGY OF TMD

Themasticatory system is a dynamic one involv-ing joint, musculature and supporting structures.A simple etiology for TMD is not usually found.Rather, it is a combination of factors that leadto overuse or abuse of the apparatus and result-ant pain (15–18). These factors include:

• Parafunctional muscle activity (e.g., bruxing,clenching)

• Trauma (e.g. whiplash, subluxation)• Psychological factors• Occlusion• Systemic diseases (e.g., arthritis)

In the majority of cases, TMDmay be consid-ered to be a multifactorial disease.

TREATMENT OF TMD

The range of treatment modalities available forthe treatment of TMD is as extensive as the pre-sentations of the different disorders found underthis umbrella. It is not surprising, therefore, thatthere is no consistently effective method of treat-ment. However, directed treatment of the arthro-genic and myogenic components often yieldssuccess, as these are the most common cause forpatient presentation (19).Treatment of joint pathology includes suppor-

tive care, indirect joint care and direct interven-tion. Supportive care includes pharmacotherapy,rest, physical therapies, and psychotherapy

SCIENTIFIC AND THERAPEUTIC ASPECTS OF BOTULINUM TOXIN262

(20–23). Indirect joint care techniques take ad-vantage of the fact that the dentition is an ap-pendage of the mandible as are the TMJs. Ma-nipulation of the teeth and mandible can affectthe TMJ. Therefore, orthotics such as oral splintsand alterations of the dentition and its alignmentcan be used to change joint function (24,25).Finally, surgical intervention in the form ofarthrocentesis, arthroscopy, and open arthro-tomy are available for the advanced correctionof arthrogenic pathology (26–29).The care of the myogenic component of TMD

has been limited largely to supportive care.Physical therapies, oral pharmacotherapy, bio-feedback, and other modalities usually provideshort-term and inadequate relief in more severecases. However, the importance of muscle ther-apy is significant because the majority of TMDcases include a myogenous component as an eti-ologic and/or perpetuating factor. Relaxation ofthe appropriate muscles yields significant thera-peutic gains due to direct muscle effects and in-direct joint effects (30–32). Therefore, an idealagent would provide enduring and specific mus-cular therapy with an acceptable side effect pro-file. Botulinum toxin type A (BTX-A) wouldappear to fulfill these criteria better than anyother currently available modality.Because most patients present with simultane-

ous arthrogenic and myogenic aspects to theirTMD, best results are obtained when providingcare for both the concurrently.

EVOLUTION OF BTX-A THERAPY FORTMD

The long history of BTX-A treatment of move-ment disorders led to the early treatment of theoromandibular dystonia subset of TMD by pi-oneers in the field [Blitzer et al. (33), Brin andBlitzer (34), and Tan and Jankovic (35)]. Suc-cess in the form of improved function and ame-lioration of cosmetic disability was demon-strated. Even more significantly, early evidenceof pain relief was reported. In light of the simi-larities between bruxism and dystonias, an at-tempt to treat bruxism with BTX-A followed.The innovators have reported early successeswith this therapy for bruxism (36,37).

Concurrent basic scientific evidence of BTX-A effects beyond the neuromuscular junctionsupports the unfolding picture of a therapy thathas broad-reaching significance for the treat-ment of pain.Muscle spindle: Sensory motor transmission

is affected by BTX-A (38). Afferent musclespindle discharge is modified and intrafusalmuscle spindles atrophy in response to BTX-A(39). These studies support an afferent mecha-nism of BTX-A that may play a role in painmodulation.Antinociceptive effects: Cui and Aoki (40) ob-

served that subcutaneous BTX-A prophylaxiseffectively relieved pain associated with forma-lin-induced inflammation in rats. This report fur-ther supports the hypothesis that BTX-A pos-sesses an antinociceptive effect that isindependent of its effects on neuromusculartransmission.CNS effects: Aoki (41) demonstrated a retro-

grade neuronal uptake of radioactively labeledBTX-A into the central nervous system (CNS).Ishikawa and colleagues (42) observed thatBTX-A inhibits the release of substance P fromtrigeminal nerves. BTX-A may also act via acentral mechanism after retrograde transportinto the CNS.The association of pain relief with BTX-A

therapy for movement disorders and bruxismprovided an early glimpse into the potential forthis therapy for complicated TMDs. Fundamen-tal principles of myofascial pain overlay on thejoint pathology, chronic myofascial pain, reduc-tion of joint loading by diminution of the activityof the major jaw-closing muscles, and enhance-ment of postsurgical physical rehabilitation weredaily, unresolved clinical challenges that re-sulted in failures of treatment. The promise of acomprehensive, long-lasting therapy was worthyof investigation.To date, the only published TMD clinical

work has been produced at The Crown Instituteand its predecessor. Three studies were under-taken in the past few years.

Feasibility Study

Using the past experience from the dystonia fieldand dosages used in the masticatory muscles in

BOTULINUM TOXIN A THERAPY FOR TEMPOROMANDIBULAR DISORDERS 263

oromandibular dystonias, a handful of patientswere recruited for a proof-of-concept trial (un-published). Despite the fact that these patientshad the most severe forms of TMD that wereresistant to other treatments, the early findingswere encouraging. All of the patients experi-enced a clinical effect ranging from weakenedchewing muscles to profound and prolongedpain relief.Two unexpected findings were identified. The

multiple injections into already aching muscleswere very painful for some patients, to the extentthat they refused follow-up BOTOX injectionswithout some form of sedation/anesthesia. Sec-ond, injection of BOTOX only into the clinicallysymptomatic muscle(s) resulted in a compensa-tory overactivity and pain in the agonist muscles.This mirroring effect, also seen in cervicogenicheadaches, compelled bilateral injection of themusculature subsequently. Finally, particularnote was made of the importance of chronicityand complexity of the pain. The more chronicpain sufferers obtained less relief qualitatively.Furthermore, few of the subjects experiencedpure myogenic pain. Most had concomitantarthrogenic pain and experienced chronic head-aches, including tension and migraine head-aches. This observation would consistently re-peat in future work in this field and is consistentwith findings in the headache field wherechronic sufferers rarely present with pure head-ache forms.

Preliminary Study

This first clinical trial (43) was undertaken toobjectively demonstrate the effectiveness ofBOTOX in providing relief of symptomatologyassociated with TMD and to begin to establisha dose response curve (Table 25.2).

TABLE 25.2. Outcomes for 150 patientsrandomized to 100 U or 150 U BOTOX

Low dose High dose group (n � 8) group (n � 11)

Improvement 25% 91%No change 75% 9%Worse 0% 0%Mean onset (weeks) 2.0 1.2Mean duration (weeks) 3.0 6.2

FIG. 25.3. Injection Sites: Masseter and Tempor-alis

Nineteen patients (mean age, 31 years) wererecruited for this randomized study that was nei-ther controlled nor blinded. Eight patients re-ceived a total of 100 U of BOTOX distributedequally to the two masseter and two temporalismuscles (Fig. 25.3). Each muscle received fiveinjections of 5 U BOTOX (diluted to 5 U/0.1cc) delivered via percutaneous injection underEMG guidance. The remaining 11 patients re-ceived the same dose to the temporalis musclesand double the dose (50 U) to each massetermuscle in the form of five injections of 10 UBOTOX (diluted to 10 U/0.1 cc) for a total of150 U BOTOX per patient. All patients werefollowed for 3 months using numerous objectiveand subjective criteria.This preliminary study demonstrated several

significant findings:

• No toxicity or side effects were encounteredby any patient despite the use of doses up to3 times the amounts previously reported forthe treatment of dystonias involving thesemuscles.

• There was a dose-dependent, statistically sig-nificant difference in clinical improvement in-dices between the two groups. Despite thesmall sample size, statistical significance wasmost likely attainable as a result of the pro-found difference between the group responses.

SCIENTIFIC AND THERAPEUTIC ASPECTS OF BOTULINUM TOXIN264

The dosage for the two groups differed by afull 50%.

• The speed of onset and duration of actiontrended toward dose dependence.

The details of this study were published in1998 (43). The encouraging results promptedthree important sequelae. First, BTX-A treat-ment became an important, albeit experimental,adjunct in the treatment of TMD for patientswith chronic pain with a myogenic source. Itsutility for nonsurgical patients, as well as pre-and postsurgical patients, proved clinically sig-nificant. Second, addressing patient needs be-came more achievable, but accurate diagnosisbecame more important. BTX-A seemed to haveonly an indirect effect on arthrogenic pathology,perhaps by unloading the joint as a result of areduction in jaw-closing muscle strength, but amore direct effect on myogenic pain and chronicpain. Treatment exclusively with BTX-A for acombined (arthrogenic and myogenic) TMDcould not yield relief as good as BTX-A com-bined with directed joint care. Third, a need fora follow-up study with refinements and a largersample size was indicated.Coincidentally and importantly, many of

these patients who reported a prior medical his-tory of headaches described profound improve-ment or prevention during the course of thestudy.

Pilot Study

This follow-up clinical trial (44,45) was de-signed to correlate treatment effect to differentTMD diagnostic subcategories, to assess clinicalcorrelates such as psychological and demo-graphic profiles, and to establish a temporal rela-tionship between follow-up measures (objectivepain, subjective pain, maximum contraction,range of motion) and muscle relaxation.Fifty subjects with TMD were recruited and

46 completed the study. The design was pro-spective with no controls as the very effectivedose of 150 U of BOTOX (high-dose groupabove) established previously was used for allpatients. The mean age was 40.5 years (range,16 to 75 years). Each patient was followed at 2-

week intervals for a total of 8 weeks. Outcomemeasures included pain by visual analog scale(VAS), tenderness to palpation, functional indexbased on multiple VAS, interincisal oral open-ing, and mean maximum voluntary contraction(MVC) as measured with a custom strain gaugedevice.Preliminary results were published in 1999 in

the Journal of Oral and Maxillofacial Surgery(44), and final results were reported in 2000 inthe British Journal of Oral and MaxillofacialSurgery (45). In summary, the following signifi-cant findings are enumerated:

• Statistically significant improvement frompretreatment levels in pain experience, tender-ness to palpation, functional index, and mouthopening were observed.

• These outcome measures remained signifi-cantly different from the pretreatment findingsat 8 weeks.

• No significant difference was found betweendiagnostic categories, and between demo-graphic and psychological profiles.

• MVC initially diminished but then returned topretreatment values.

This study strongly demonstrates that BTX-A therapy produces a reduction in symptoms andan improvement in functional abilities for pa-tients with TMD. The prospects for this newmo-dality of TMD care were clearly positive. Anadvanced study was indicated and a Phase IImulticenter clinical trial began in 2001 with sup-port from Allergan Inc. of Irvine, California(makers of BOTOX).An apparently paradoxical finding of this

study was that all measured patient improve-ments extended temporally beyond the muscle-relaxing effects as measured objectively by thebite meter. This fact belies the simplistic notionof BTX-A having purely a muscle-relaxing ef-fect, and, along with other recent, disparate ob-servations regarding BTX-A use in treating mi-graines and its effect on locations other than theneuromuscular junction (e.g., nociceptive affer-ents), leads one to search for broader under-standing of the observed phenomena. A unifyinghypothesis is presented below.

BOTULINUM TOXIN A THERAPY FOR TEMPOROMANDIBULAR DISORDERS 265

FIG. 25.4. Patients affected byBOTOX vs. time.

Long-term Follow-up

Seventeen patients have now been followed formore than 1 year. While this is not a part of anyofficial study, the observations are presented inchart form (Fig. 25.4). Improvement within 2weeks following BOTOX injections in almost90% of patients is a consistent finding in prac-tice. The effect lasts from 1 to 3 months, usuallydependent on severity of the TMD. The plateauat approximately 25% beyond 9 months is inter-esting andmay be significant. This is either dem-onstrative of the natural extinction of the diseaseor a truly profound long-term effect of BTX-Atherapy. Further studies are warranted.

FINAL THOUGHTS: MAKING SENSEOF IT ALL

On cursory examination, it is easy to view BTX-A therapy as a simple muscular agent that hasfound utility in another orthopedic application,i.e., relating to the TMJ. TMD, however, is not asimple orthopedic problem. It is often associatedwith headaches and cervicogenic pain. BTX-A’seffectiveness extends beyond the muscle-relax-ing effect. BTX-A is also useful in treating otherhead and neck primary pains such as migraine.There is a commonality between TMD, head-aches, and neck pain in presentation and re-sponse to treatment. These cannot all be coinci-dental. Furthermore, there is pain relief andfunctionality that outlasts the muscle relaxant ef-fect of BTX-A. A unifying model based upon

known neuroanatomy, neurophysiology, andcurrent understanding of TMD, headaches, andcervicogenic pain is presented.The trigeminal nucleus (TN), with emphasis

on subnucleus caudalis and interpolaris, receivesalmost all primary afferent input from all of thecraniofacial structures, including the intracranialvasculature and dura. It also receives input fromthe cervical region and cranial nerves VII, IX,X, and XII. Unique to the TN, as compared tospinal nerves, is this extensive convergence pat-tern of cranial and cervical nerves. Further inputto the nucleus is provided from higher centers,many times in the form of inhibitory and regula-tory influences.Second-order afferent neurons synapse within

the nucleus and project extensively to other partsof the brainstem and higher centers. Some ofthese neurons are involved in multisynapticbrainstem paths that function in craniofacial andcervical muscle reflex pathways, as well as auto-nomic reflex responses. The filtered afferent no-ciceptive signals ultimately project to the cortexfor interpretation as pain. An excellent reviewwith extensive and thorough referencing is pro-vided by Sessle (46). In summary, the TN is thefirst gateway for afferent head and neck inputwith wide-ranging integrative function and sig-nificant output activity directly through thebrainstem and indirectly through higher centers.The modulation of nociceptive transmission

in the TN bears significance in clinical practiceas numerous pain phenomena can be explainedat the cellular level. Peripheral sensitization, ex-

SCIENTIFIC AND THERAPEUTIC ASPECTS OF BOTULINUM TOXIN266

FIG. 25.5. A model of trigeminal nucleus functional trigeminopathy

pansion of receptor fields, recruitment of A-betafibers and wind-up are all understood in the con-text of the function of the TN and its constituentparts.

TRIGEMINOPATHY: DEFINITION

The term ‘‘trigeminopathy’’ is intended to unifycurrent understanding of primary head and neckpain. It builds on the knowledge base that existsand is therefore consistent with current thoughtson the diagnosis, classification and treatment ofthese pains. It is defined as a diverse group ofprimary head and neck pains that share thesefeatures:

• Afferent trigger(s) stimulation• TN stimulation• Receptive efferent target(s) activation

The afferent triggers may be peripheral orcentral and are usually a combination of both.In a state of homeostasis, the TN continuouslyreceives numerous inputs, both excitatory andinhibitory in nature, that result in an outputwhich signals normalcy. There is a sense of bal-ance. In a headache sufferer, this balance is upsetbeginning with an afferent barrage. This afferentoverdrive is triggered only in susceptible indi-viduals. In migraine sufferers the result of astimulus (often peripheral such as food) is anintracranial vascular response mediated, in sus-

ceptible individuals, by a channelopathy that re-sults in an excitatory neural message barrage tothe TN. This results in a stimulation of the TN.The TN performs an integrative function thatresults in selective efferent output, both centraland peripheral. In people who have receptiveefferent targets, their activation manifests as aclinical sign or symptom. The susceptibility ofefferent targets is variable within and betweenindividuals. In the case of migraine, centers inthe hypothalamus, the periaqueductal gray,raphe nuclei, red nucleus, and others have beenidentified with positron emission tomography(PET) scans and magnetic resonance imaging(MRI) to be responsible for symptoms such asaura, nausea and vomiting, photophobia, phono-phobia, and more [reviewed recently by Har-greaves and Shepheard (47)]. This same schemamay be used to understand TMD and cervico-genic pain.The philosophic significance of trigeminopa-

thy lies in the fundamental shift from the currentpractice of diagnosis of head and neck painsbased on symptomatology, especially difficultbecause of efferent variability, to a mechanisticdiagnosis based on the underlying physiologicdisturbance. The core commonality is the TNand its integrative function. Almost all afferentinput is funneled into the TN, and almost allefferent outcomes commence at the TN.Just as the medical community now under-

stands the term ‘‘coagulopathies’’ to be a group

BOTULINUM TOXIN A THERAPY FOR TEMPOROMANDIBULAR DISORDERS 267

of related abnormalities pertaining to our hemo-static system, so trigeminopathies refers to agroup of related abnormalities pertaining to painmechanisms of the head and neck. Perhaps thisnew understanding will be one of the more sig-nificant legacies of BTX-A treatment of primaryhead and neck pain.

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