The Effect of Botulinum Toxin A on Headache Attributed to TMD

The Effect of Botulinum Toxin A (BOTOX®) on Headache Attributed to TMD - An Open Label Trial

This study will evaluate the effect of of botulinum toxin on the treatment of Headache Attributed to TMD.

Study Overview

• Status: Completed
• Conditions: Secondary Headache Disorder
• Intervention / Treatment: Drug: Botulinum Toxin type A

Detailed Description

Temporomandibular Disorders (TMD) is a collective term, embracing a number of clinical problems that involve the masticatory muscles, the temporomandibular joint (TMJ) and the associated structures. The prime manifestation consists of pain of a persistent, recurring, or chronic nature . Pain-related TMD can affect the individual's daily activities, psychosocial functioning, and quality of life . The prevalence of TMD is about 10 % in the general population, making it the second most common musculoskeletal condition, after chronic lower back pain, that results in pain and disability . It has been estimated that the annual TMD management cost in the USA, excluding diagnostic imaging, in the last decade was approximately $4 billion.

The pathophysiology of pain-related TMD is poorly understood. However, multiple risk factors have been identified, such as, gender, pain during jaw function and palpation, oral parafunctions, other pain conditions, pain sensitivity and psychosocial characteristics. Because of its multifactorial nature, a multimodal conservative treatment approach is recommended, including patient education, behavioral management, physical therapy, pharmacotherapy, and occlusal splints.

Among the pain-related TMD conditions are "Headaches Attributed to TMD". This diagnosis has replaced "Headaches or facial pain attributed to Temporomandibular Joint (TMJ) disorder" described in the International Classification of Headache Disorders II (ICHD-2). It is characterized by pain in the temple area secondary to pain-related TMD that is modified by function and parafunction affected by jaw movement, function, or parafunction.

In general, headache treatment is either abortive or prophylactic. Abortive treatment manages acute headache and prophylactic treatment aims to reduce the frequency and severity of the attacks. Intramuscular injections with Botulinum Toxin (BTX) are used in the prophylactic treatment of migraine and tension type headaches. The mechanisms by which the analgesic effects of BTX are mediated are not fully understood. One mechanism is the inhibition of neurogenic inflammation by blocking neurotransmitter release from sensitized nociceptors, thus reducing peripheral sensitization. In vitro, BTX has been found to inhibit Calcitonin Gene-Related Peptide (CGRP), and BTX reduces the vascular response to algogenic substances such as capsaicin applied to human skin. Other potential analgesic mechanisms include retrograde transport of BTX by sensory neurons and inhibition of neurotransmitter release by their central terminals.

In recent years, BTX has also been used in the treatment of myogenous-TMD with mixed results. Two randomized controlled trials (RCTs) showed therapeutic benefits of BTX in the management of myogenous -TMD, while another 3 RCTs reported no significant effect of BTX in chronic myogenous -TMD pain. Varying patient samples, methodologies, and sample sizes may explain the differences. Additionally, the results have been compromised by poor methodologies, such as insufficiently powered clinical trials, and open-labeled studies. More recently, a systematic review of randomized controlled trials concluded that no consensus could be reached on the therapeutic benefit of BTX on TMD. More so, no trial on the effectiveness of BTX on the prophylactic treatment of headaches attributed to TMD has been reported to date.

The purpose of this study is to determine the effectiveness of Botulinum toxin - A in the management of headaches attributed to TMD.

Study Design The study will be carried out in the clinics of TMD and Orofacial Pain, School of Dental Medicine, University at Buffalo. A prospective open label design will be used to assess the effectiveness of BTX in the management of Headaches Attributed to TMD.

Recruitment will be done through advertising throughout the clinic and the community.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14214
      • University at Buffalo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Adults age 18 to 74 years old.
• Participants with Headaches Attributed to TMD based on Diagnostic Criteria for TMD (DC-TMD) criteria.
• A minimum of 15 headaches/events per month, for the last 3 months.
• Average pain intensity in the last month of ≥5 (0 to 10 scale) where 0 is no pain and 10 is the worst pain ever.

Exclusion Criteria:

• Pregnancy
• Participants with a history of neurological/neuromuscular disorders and bleeding disorders.
• Participants taking prescribed analgesics, muscle relaxants, amino glycosides, or anticholinesterases.
• Participants currently under BTX treatment.
• Participants currently under active treatment for TMD during the last month, which includes physical therapy and pharmacological management.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Botulinum Toxin type A; Participants will be injected intramuscularly with total of 50 Units, 25 units of Botulinum A per temporalis muscle. The BTX injection will be prepared by dissolving 100 U vial in 2 ml of 0.9 % of Sodium Chloride (NaCl), yielding 25 U/ml. Each participant will receive 0.1 ml of BTX/NaCl mixture in 5 spots per temporalis muscle.

Drug: Botulinum Toxin type A; All the participants meeting the inclusion criteria will be seen for a total of 4 visits and 3 phone interviews. Participants will complete a set of self-reporting questionnaires, assessing the disability associated with Headaches Attributed to TMD, and other pain-related TMD diagnoses, the impact of headaches on the quality of life, and psychosocial distress questionnaires. In addition, they will undergo 3 cycles of treatment, each 12 weeks apart.; Other Names: Botox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in number of Headaches Attributed to TMD (HA)	Self-report	Every 12 weeks up to 1 year
Reduction in Headache Impact Test-6 score (HIT-6)	Self-report.	Every 12 weeks up to 1 year
Pressure Pain Threshold	Using algometer at the temporalis and masseter muscles	Every 12 weeks up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Graded Chronic Pain Scale (GCPS), 1 and 6 months score	This scale provides the characterization of chronic pain as well as disability associated to the chronic pain. This scale includes 3 items for pain intensity and 4 items for function, one item for number of days of pain. Characteristic Pain Intensity (CPI): compute mean of items 2-4(pain right now, worst pain, average pain), and multiply by 10. Interference Score: compute mean of items 6-8 (daily activities, social activities, work activities), and multiply by 10. Interpretation Determination of Chronic Pain Grade Grade 0: (no pain, no disability) I Low intensity pain, without disability: (Less than 50 points in CPI and less than 3 point in disability) II: High Intensity pain, without disability: (Greater than or equal to 50 points in CPI and less than 3 point in disability III: Moderately limiting: N/A in CPI and 3-4 points in disability IV: Severely limiting: N/A in CPI and 5-6 points in disability	Every 12 weeks up to 1 year
Jaw Functional Limitation Scale	Comprised within a 20-item instrument. a single global score of "jaw functional limitation" can be computed as the mean of the available items. Sub-scale scores for each type of functional limitation are computed, as follows: Mastication: mean of items 1-6. Mobility: mean of items 7-10. Verbal and non-verbal communication: mean of items 13-20. Norms have not yet been established for this instrument.	Every 12 weeks up to 1 year
Migraine Disability Assessment/ HA-TMD	This self reported instruments comprise 6 items and based on the number of days of disability a MIDAS level is calculated as follows: 0 to 5- MIDAS Grade I, Little or no disability 6 to 10- MIDAS Grade II, Mild disability 11 to 20- MIDAS Grade III, Moderate disability 21+ MIDAS Grade IV, Severe disability	Every 12 weeks up to 1 year

Collaborators and Investigators

• Sponsor: State University of New York at Buffalo
• Investigators: Principal Investigator: Yoly M Gonzalez-Stucker, DDS, MS, MPH, University at Buffalo

Publications and helpful links

General Publications

• Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet JP, List T, Svensson P, Gonzalez Y, Lobbezoo F, Michelotti A, Brooks SL, Ceusters W, Drangsholt M, Ettlin D, Gaul C, Goldberg LJ, Haythornthwaite JA, Hollender L, Jensen R, John MT, De Laat A, de Leeuw R, Maixner W, van der Meulen M, Murray GM, Nixdorf DR, Palla S, Petersson A, Pionchon P, Smith B, Visscher CM, Zakrzewska J, Dworkin SF; International RDC/TMD Consortium Network, International association for Dental Research; Orofacial Pain Special Interest Group, International Association for the Study of Pain. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications: recommendations of the International RDC/TMD Consortium Network* and Orofacial Pain Special Interest Groupdagger. J Oral Facial Pain Headache. 2014 Winter;28(1):6-27. doi: 10.11607/jop.1151.

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2017
• Primary Completion (Actual): March 15, 2021
• Study Completion (Actual): March 15, 2021

Study Registration Dates

• First Submitted: July 31, 2017
• First Submitted That Met QC Criteria: November 14, 2017
• First Posted (Actual): November 17, 2017

Study Record Updates

• Last Update Posted (Actual): October 4, 2022
• Last Update Submitted That Met QC Criteria: September 30, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Headache; Headache Disorders, Secondary; Headache Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; Neuromuscular Agents; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
• Other Study ID Numbers: STUDY00000054

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No