Jaw muscles myofascial pain and botulinum toxin

Abstracts

JUSTIFICATIVA E OBJETIVOS: Disfunção temporomandibular (DTM) abrange um conjunto de alterações craniofaciais, que pode envolver a articulação temporomandibular (ATM), os músculos da mastigação e/ou estruturas associadas. As DTM musculares são as mais frequentes e um dos seus subtipos compreende a dor miofascial. A toxina botulínica tipo A (BoNT A), tem sido objeto de estudos no controle da dor, incluindo dor miofascial, e está relacionada ao mecanismo de alívio da dor, não somente nos receptores da junção neuromuscular. O objetivo deste estudo foi acessar os artigos que abordam o uso da BoNT A no tratamento da dor miofascial nos músculos da mastigação. CONTEÚDO: Foi realizada uma busca nas bases de dados Pubmed, LILACS e BVS, de 2000 a abril de 2012, cruzando-se os descritores: toxinas botulínicas tipo A, síndromes da dor miofascial, dor facial, síndrome da disfunção da articulação temporomandibular, pontos-gatilho, bruxismo, articulação temporomandibular, músculo masseter e músculo temporal. Como critérios de inclusão foram analisados estudos randomizados, duplamente encobertos ou encobertos, com 10 ou mais participantes, de aspectos metodológicos aleatórios, que relacionassem o uso da toxina botulínica na dor miofascial da DTM nos músculos da mastigação, mais especificamente masseter e temporal, limitados para o idioma inglês encontrando-se seis estudos que foram incluídos neste estudo. CONCLUSÃO: O uso da BoNT A não se mostrou mais eficiente no tratamento da dor miofascial do que os tratamentos convencionais já estabelecidos. Por existirem diversas variáveis não controladas nos poucos estudos pertinentes, mais estudos, com metodologias criteriosas, são necessários para viabilizar sua aplicação em pacientes refratários à dor submetidos previamente a tratamentos conservadores.

Dor facial; Síndrome da disfunção da articulação temporomandibular; Síndromes da dor miofascial; Toxinas botulínicas tipo A

REVIEW ARTICLE

Jaw muscles myofascial pain and botulinum toxin^*

Magali Dall' Antonia^I; Regina Martins de Oliveira Netto^I; Monique Lalue Sanches^II; Antonio Sérgio Guimarães^III

^ISpecialist in Temporomandibular Disorders and Orofacial Pain, Paulista School of Medicine, Federal University of São Paulo (EPM-UNIFESP). São Paulo, SP, Brazil

^IIProfessor of the Temporomandibular Disorder and Orofacial Pain Ambulatory, Paulista School of Medicine, Federal University of São Paulo (EPM-UNIFESP). Assistant Professor of the Santa Cecilia University (UNISANTA). Santos, SP, Brazil

^IIIIn charge of the Temporomandibular Disorder and Orofacial Pain Ambulatory, Paulista School of Medicine, Federal University of São Paulo (EPM-UNIFESP). São Paulo, SP, Brazil

Correspondence to

ABSTRACT

BACKGROUND AND OBJECTIVES: Temporomandibular disorders (TMD) involve a set of craniofacial changes, which may involve temporomandibular joint (TMJ), jaw muscles and/or associated structures. Muscle TMD is the most frequent, and one of its subtypes is myofascial pain. Botulinum toxin type A (BoNT A), has been studied to control pain, including myofascial pain, and is related to pain relief mechanisms not only in neuromuscular junction receptors. This study aimed at evaluating articles addressing BoNT A to treat jaw muscles myofascial pain.

CONTENTS: Pubmed, LILACS and BVS databases were queried from 2000 to April 2012, crossing the following keywords: botulinum toxin type A, myofascial pain syndromes, facial pain, temporomandibular joint disorder syndrome, trigger-points, bruxism, temporomandibular joint, masseter muscle and temporalis muscle. Inclusion criteria were randomized double blind or blind studies, with 10 or more participants, with randomized methodological aspects, relating the use of botulinum toxin for jaw muscles TMD myofascial pain, more specifically masseter and temporalis muscles, and limited to the English language. Six articles were found and included in this study.

CONCLUSION: BoNT A was not more effective to treat myofascial pain than established conventional treatments. Because there are many uncontrolled variables in the few related studies, more studies with judicious methodologies are needed to make feasible its use in patients refractory to pain and previously submitted to conservative treatments.

Keywords: Botulinum toxin type A, Facial pain, Myofascial pain syndromes, temporomandibular joint disorder syndrome.

INTRODUCTION

Temporomandibular disorders (TMD) involve a set of craniofacial changes with multifactorial or biopsychosocial etiology, which may involve the temporomandibular joint (TMJ), masticatory muscles and/or musculoskeletal structures associated to head and neck. Its primary symptom is pain, but may also present with jaw movements limitation and joint noises.

Whichever the nature of the pain, it brings changes in psychic behavior, with increased muscle tone e consequent presence of myofascial pain¹. Conversely, long-lasting pain has no biological value and may become the major reason for patients' distress. In addition to neurophysiologic phenomena, psychological, cognitive, behavioral and social aspects are also involved^1-3.

Muscle pain is transmitted by nervous afferent fibers groups III and IV to the central nervous system, which processes noxious stimulation quantity, intensity, duration and location. The excessive use of a muscle by repetitive movements leads to traumas which generate localized muscle contraction and the release of algogenous substances promoting local pain^2-4. This muscle disorder promotes excessive release of acetylcholine and an exacerbated crisis is perpetuated within the tight muscle band⁵.

Muscle TMDs are the most frequent and one of its subtypes is myofascial pain, characterized by a state of chronic, regional musculoskeletal pain, with specific signs and symptoms as the presence of myofascial trigger points (TP). TPs are hyperirritable nodes located in a tight muscle, tendon or fascial band which, when palpated, produce local pain and referred pain outside the painful area^6,7. The severity of symptoms caused by TPs varies from disabling and severe pain, to movement limitations and postural distortion⁷.

Botulinum toxin type A (BoNT A), currently called Onabotulinum toxin A by the Food and Drug Administration (FDA), has been studied to control pain, including myofascial pain, and is related to pain relief mechanisms, not only in neuromuscular junction receptors, but also in the nociceptive receptors system^4,8-12.

Considered lethal for many centuries, its clinical and muscular symptoms were described in detail in the early 19^th Century by the physician Justinus Kerner. However, Clostridium botulinum (C. botulinum), microorganism producing botulinum toxin, was only identified in 1895 in Belgium by Emile Pierre Marie Van Ermengem. BoNT is a neurotoxin produced by different micro-organisms initially called C. botulinum. Depending on the environment where they develop and produce their spores, they affect different subsets of live species producing variants¹³. Its initial classification in seven strains, called from A to G, is currently not satisfactory, and now C. botulinum is divided in four physiological groups together with Clostridium argentinense (C. argentinense), and aggregating Clostridium butyricum (C. butyricum) and Clostridium baratii (C. baratii) strains¹³.

BoNT A action mechanism propositions were suggested in mid 1950, showing that it blocked acetylcholine (ACh) release from motor nervous terminations^8,12. Once inside the body, the toxin would reach neuromuscular junctions where, after its internalization, binding to its receptor by endocytosis, it may develop the activity of blocking nervous impulse transmission for 8 to 16 weeks^13,14.

As from the 1980's, with the use of BoNT A by Alan Scott to correct strabismus in apes, its clinical application for therapeutic use has started¹⁵. BoNT A has been used for some neurological, urological, gastrointestinal and proctologic disorders. It is also widely used in Ophthalmology, ENT, Dermatology and Gynecology^8,16. It is indicated to treat Parkinson's disease¹⁷ and is being widely used to manage pain¹⁸. Currently, BoNT therapeutic capacity is being determined by categorization and genetic engineering to act in changing binding sites, in catalysis and duration of the toxin, allowing specific effects and several therapeutic actions such as: in SNARE mediation during secreting processes involved with diabetes, in respiratory disorders and even in processes controlling immune and inflammatory disorders¹⁹.

There are some restrictions to its use such as: drug allergy, pregnancy, lactation, difficult cooperation of patient (fear of the method), infection or inflammation in the proposed injection site, anatomic abnormalities making injection difficult or impossible (e.g., obesity or deformities), comorbidities (viral infection, chronic neuropathic pain), patients under anticoagulants or drugs which may interfere with muscular transmission, such as aminoglycosides, or with neuromuscular joint disorders (severe myasthenia, Lambert-Eaton syndrome, amyotrophic lateral sclerosis)^5,10,20,21. Among adverse effects there are: flu-like symptoms which may last from one to two weeks, muscle weakness depending on the injection site. This depends on operator's technique and dose used. There may be change in facial expression and difficulties to chew and swallow related to masseter muscle injection^5,8.

Recent studies were published showing possible antinociceptive effects of BoNT A to treat pain not necessarily originated by excessive muscle use^9,22. This possible antinociceptive mechanism could be explained by the fact that injured cells and primary afferent fibers release a series of chemical mediators, including substance P, neurokinin A and calcitonin gene-related peptide (CGRP), which have direct effects on the excitability of sympathetic sensory fibers. These mediators contribute to create a complex environment responsible for neurogenic inflammation^8,11,23,24.

BoNT A specificity for cholinergic neurons in the presence of specific receptors makes it inhibit other neurotransmitters such as norepinephrine in motor and neuromediator nerves, including epinephrine, norepinephrine and CGRP, bringing benefits to painful symptoms. BoNT A also suppresses the release of substance P, a peptide involved in neurogenic inflammation and pain disorders genesis, and the release of glutamate, another neurotransmitter involved with peripheral nociception and spinal cord dorsal horn^11,24,25.

For myofascial pain of masticatory muscles, recommended doses in the literature are: masseter (superficial and deep portion) 40-60 U per injected muscle in two or three sites of superficial masseter muscle, taking care with facial nerve motor part, and temporalis muscle (anterior, median and posterior portions) 30-50 U per muscle, injected in four sites of anterior, median and posterior bands of such muscle. Total dose should not exceed 200 U for masticatory muscles²⁰.

Because more than 70% of general population have at least one TMD symptom, and orofacial patients suffer its resulting clinical effects, and due to its physical, psychological and social impact, this study aimed at searching articles addressing BoNT to treat orofacial pain of masticatory muscles.

CONTENTS

Literature search strategies

Pubmed, LILACS and BVS databases were queried from 2000 to April 2012, crossing the following keywords: botulinum toxin type A versus myofascial pain versus facial pain versus temporomandibular joint disorder syndrome, versus trigger-points versus bruxism, versus temporomandibular joint versus masseter muscle versus temporalis muscle. Inclusion criteria were randomized, double blind or blind studies with 10 or more participants, with randomized methodological aspects, relating the use of BoNT for TMD myofascial pain of masticatory muscles, more specifically masseter and temporalis, limited to the English language.

Review articles, clinical reports, open label studies, animal model studies, articles not related to TMD myofascial pain, disk displacement, tension headache, migraine and muscle movement disorders were excluded. After crossing keywords in all possible manners and applying inclusion and exclusion criteria, six studies were included and are summarized in table 1.

Description of selected literature

In a crossover randomized double-blind placebo-controlled study, the efficacy of BoNT A was analyzed to manage moderate to severe chronic pain in masticatory muscles where 25 U were injected in each left and right temporalis muscle and 50 U in each right and left masseter muscle in three different sites per muscle²⁶. Data were collected every week and were crossed in 16 weeks. Visual analog scale (VAS) was used to measure pain intensity as primary variable. Secondary variables were: maximum painless mouth opening, muscle palpation in 12 points and four general questions. Only 10 patients have finished the study and there were no statistically significant differences between BoNT A and placebo. The study has not supported the use of BoNT²⁶.

In a different randomized, blind and placebo-controlled study, patients received BoNT injection in masticatory muscles: masseter, temporalis and medial pterygoid²⁷. All patients had chronic pain resulting from masticatory muscles hypermobility and had been previously treated with adequate conservative methods from 3 to 34 months. Pain symptoms were evaluated by VAS before and after treatment and the observation period was of three months, were 35 U BoNT A in saline, and NaCI solution as placebo were administered in temporalis and masseter muscles. Results have shown 91% improvement in the BoNT A group and just local pain improvement in the placebo group. The conclusion was that BoNT A is an innovative and effective method for chronic facial pain associated to muscle hyperactivity in patients not responding to conventional treatments²⁷.

Another publication was a double-blind, randomized, placebo-controlled study where patients had bruxism and masticatory muscles myofascial pain²⁸. Treatment protocol was muscular administration of four BoNT A (Botox, Allergan Inc., Irivine, CA) in masseter muscles on both sides and in anterior temporalis muscles on both sides, in a total of 100 U. Injections were controlled with topography and ultrasound. Clinical parameters were evaluated at baseline, one week, one month and six months after treatment and included pain at rest and during chewing, chewing efficiency, maximum mouth opening, protrusion and lateral protrusion, jaw movements limitation, subjective efficacy and tolerance to treatment. Results have shown improvement with BoNT A of jaw movements amplitude and pain at rest and during chewing. Clinical results variables were better with Botox as compared to placebo. Patients treated with BoNT A had better perception of treatment efficacy than those of the placebo group. Differences were not significant in some cases due to the small sample size. Authors have concluded that BoNT A was effective to decrease myofascial pain symptoms in patients with bruxism²⁸.

A randomized study with patients with myofascial pain and TP-associated headache has used lidocaine and dry-needling in the referred TP²⁹. Patients were divided in three groups: G1 dry-needling, G2 0.25% lidocaine without vasoconstrictor and G3 25 U or 50 U of BoNT. The following parameters were evaluated during 12 weeks: pain intensity levels, frequency, duration and sensitivity after injection, length of relief and use of rescue analgesics. All groups had favorable results for evaluated requisites, except for the use of rescue medication and sensitivity after injection, which was better for G3. Authors have concluded that, considering its low cost, lidocaine could be adopted as the substance of choice and BoNT would be reserved for refractory cases where expected effects of other therapies could not be reached²⁹.

Another crossover randomized double-blind and placebo-controlled study has evaluated the effect of BoNT A on persistent muscle TMD pain³⁰. Patients had TMD without adequate pain relief after conventional treatment and received BoNT injection; the control group received isotonic saline solution. Both drugs were randomly injected in three standardized sites of the masseter muscle on both sides. Patients were followed after one and three months. After this period, the following parameters were evaluated: pain, physical function, emotional function, overall improvement and side-effects, in addition to the need for analgesics, mouth opening limitation, pain at palpation of masticatory muscles on 20 sites, pressure pain threshold and tolerance to pain. There has been significant pain improvement (30%) one month after BoNT injection, but this was not true for saline solution injection, as shown by other studies. The conclusion was that this improvement is regardless of its muscle relaxation effects, because the relief may precede this relaxation, being also present outside the areas of BoNT injection. There has been no primary difference between drugs, and results have not shown a relevant clinical effect of BoNT A to treat persistent TMD myofascial pain or to bring about emotional changes³⁰.

A randomized controlled study has compared the effectiveness of BoNT and the treatment with fascial manipulation of masseter and bilateral temporal muscles¹⁴. All patients had myofascial pain and were distributed in Group A receiving BoNT in a single session and Group B receiving multiple muscle fascia manipulation sessions. Evaluated parameters were maximum pain level by VAS, maximum mouth opening, right and left protrusion and laterality in the beginning, at the end and one month later. Follow up time was three months. There has been pain improvement in both cases and BoNT was better with regard to jaw movement amplitude¹⁴.

Refractory patients are common in chronic diseases. Accurate myofascial pain diagnosis is difficult because its symptoms may be mistaken for other diseases, and basically depends on history and palpation exams, in addition to well trained professionals. BoNT is used to treat pain induced by spasm and dystonia because it paralyzes the overloaded muscle, but it is known that its analgesic effect is not only related to muscle relaxation and may be independent of it. So, hypothetically, BoNT A could be used to relieve myofascial pain due to its antinociceptive properties.

However, current studies still have several uncontrolled variables such as: small sample size, waiver of patients during the study, use of rescue drugs, differences in injection sites and doses used, which make these studies not reproducible. It is also necessary to investigate which would be its therapeutic benefits for these disorders, in addition to considering time between injections, the formation of antibodies and the complications of its use.

CONCLUSION

BoNT A was not more effective to treat myofascial pain than already established conventional treatments because there are few randomized, double-blind or placebo-controlled studies, which brings lots of controversies about its effectiveness. Further studies are needed to enhance the understanding of long-lasting pain pathophysiology and the mechanisms through which BoNT may change pain, in addition to the feasibility of its application in refractory myofascial pain patients, simultaneously with physical therapies.

REFERENCES

• 1. Teixeira MJ. Fisiopatologia da nocicepção e supressão da dor. JBA 2001;1(4):329-34.
• 2. Sessle BJ. Acute and chronic craniofacial pain: brainstem mechanisms and nociceptive transmission and neuroplasticity, and their clinical correlates. Crit Rev Oral Biol Med. 2000;11(1):57-91
• 3. Svensson P, Graven-Nielsen T. Craniofacial muscle pain: review of mechanisms and clinical manifestations. J Orofac Pain. 2001;15(2):117-45.
• 4. Mense S. Neurobiological basis for the.use of botulinum toxin in pain therapy. J Neurol. 2004;251(Suppl 1):I1-7.
• 5. Yeng LT, Teixeira MJ, Teixeira WGJ. Uso de toxina botulínica na dor musculoesquelética e nas algias craniofaciais crônicas. Rev Bras Med. 2005;62:476-85.
• 6. Shah JP, Gilliams EA. Uncovering the biochemical milieu of myofascial trigger points using in vivo microdialysis: an application of muscle pain concepts to myofascial pain syndrome . J Bodyw Mov Ther. 2008;12(4):371-84.
• 7. Gerwin RD, Dommerholt J, Shah JP. An expansion of Simons' integrated hypothesis of trigger point formation. Curr Pain Headache Rep. 2004;8(6):468-75.
• 8. Silva LCM, Neves RF. Respostas clínicas no uso da toxina botulínica para o tratamento da dor crônica musculoesquelética: uma revisão da literatura. Rev Dor. 2007;8(3):1080-4.
• 9. Freund B, Schwartz M. Temporal relationship of muscle weakness and pain reduction in subjects treated with botulinum toxin A. Pain. 2003;4(3):159-65.
• 10. Graboski CL, Gray DS, Burnham RS. Botulinum toxin A versus bupivacaine trigger point injections for the treatment of myofascial pain syndrome: a randomized double blind crossover study. Pain. 2005;118(1-2):170-5.
• 11. Colhado OCG, Boeing M, Ortega LB. Toxina botulínica no tratamento da dor. Rev Bras Anestesiol. 2009;59(3):366-81.
• 12. Aoki KR, Francis J. Updates on the antinociceptive mechanism hypothesis of botulinum toxin A. Parkinsonism Relat Disord. 2011;17(Suppl1):S28-33.
• 13. Sposito MMM. Toxina botulínica do tipo A: mecanismo de ação. Acta Fisiátrica. 2009;16(1):25-37.
• 14. Guarda-Nardini L, Stecco A, Stecco C, et al. Myofascial pain of the jaw muscles: comparison of short-term effectiveness of botulinum toxin injections and fascial manipulation technique. Cranio. 2012;30(2):95-102.
• 15. Scott AB. Botulinum toxin injection for eye muscles to correct strabism. Tr Am Ophth Soc 1981;79:734-70.
• 16. Jost WH. Other indications of botulinum toxin therapy. Eur J Neurol. 2006;13(Suppl 1):65-9.
• 17. Truong D, Jost WH. Botulinum toxin: clinical use. Parkinsonism Relat Disord. 2006;12(6):331-55.
• 18. Casale R, Tugnoli V. Botulinum toxin for pain. Drugs RD. 2008;9(1):11-27.
• 19. Pickett A, Perrow K. Towards new uses of botulinum toxin as a novel therapeutic tool. Toxins. 2011;3(1):63-81.
• 20. Clark GT. The management of oromandibular motor disorders and facial spasms with injections of botulinum toxin. Phys Med Rehabil Clin N Am. 2003;14(4):727-48.
• 21. Scott NA, Guo B, Barton PM, et al. Trigger point injections for chronic non-malignant musculoskeletal pain: a systematic review. Pain Med. 2009;10(1):54-69.
• 22. Lang AM. Botulinum toxin type A therapy in chronic pain disorders. Arch Phys Med Rehabil. 2003;84(3 Suppl 1):S69-73.
• 23. Rocha APC, Kraychete DC, Lemonica L, et al. Dor: aspectos atuais da sensibilização periférica e central. Rev Bras Anestesiol. 2007;57(1):94-105.
• 24. Dressler D, Saberi FA, Barbosa ER. Botulinum toxin: mechanisms of action. Arq Neuropsiquiatr. 2005;63(1):180-5.
• 25. Aoki KR. Botulinum toxin: a successful therapeutic protein. Curr Med Chem. 2004;11(23):3085-92.
• 26. Nixdorf DR, Heo G, Major PW. Randomized controlled trial of botulinum toxin A for chronic myogenous orofacial pain. Pain. 2002;99(3):465-73.
• 27. Von Linder JJ, Niederhagen B, Bergé S, et al. Type A botulinum toxin in the treatment of chronic facial pain associated with masticatory hyperactivity. J Oral Maxillofac Surg. 2003;61(7):774-8.
• 28. Guarda-Nardini L, Manfredini D, Salamone M, et al. Efficacy of botulinum toxin in treating myofascial pain in bruxers; a controlled placebo pilot study. Cranio. 2008;26(2):126-35.
• 29. Venâncio RA, Alencar FGP, Zamperini C. Botulinum toxin, lidocaine, and dry-needling injections in patients with myofascial pain and headaches. Cranio. 2009;27(1):46-53.
• 30. Ernberg M, Hedenberg-Magnusson B, List T, et al. Efficacy of botulinum toxin type A for the treatment of persistent myofascial TMD pain: a randomized, controlled, double-blind multicenter study. Pain. 2011;152(9):1988-96.
• 31. Manfredini D, Guarda-Nardini L. Botulinum toxin in the treatment of bruxism. In: Paesani DA, (editor). Bruxism: theory and practice. Berlin: Quintessence Publishing; 2010 p. 467-76.

*

Recebido da Escola Paulista de Medicina da Universidade Federal de São Paulo/Hospital São Paulo (EPM-UNIFESP/HSP). São Paulo, SP.

Publication Dates

• Publication in this collection
  17 Apr 2013
• Date of issue
  Mar 2013

History

• Received
  30 Nov 2012
• Accepted
  04 Feb 2013