Peripheral TMD Pain Mechanisms and the Effect by Botulinum Toxin A

NCT05720065 | Recruiting Phase 2

• 1 other identifier: 2022-05453-01
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to investigate the effect of botulinum toxin on neurons' plasticity in the masseter muscle in humans with and without painful myogenous temporomandibular disorders (TMDM). The main questions it aims to answer are:

• does treatment with botulinum toxin alter gene expressions, epigenetic signatures, and cells plasticity in the masseter muscles of TMDM patients?
• do any such changes differ between patients with local and regional TMDM?
• does treatment with botulinum toxin influence pain characteristics (intensity, frequency, and sensibility) and other variables in patients with TMDM and are there correlations between significantly changed expression of biomarkers and other variables? Participants will be examined with a questionnaire, clinical examination (including quantitative sensory testing; QST), and microbiopsy sampling from one of the masseter (MM) and anterior tibialis (AT) muscles and are then randomized to treatment with botulinum toxin or control (isotonic saline). Follow-ups occur after one and three months for all patients, and six months with questionnaire, clinical examination, and collection of post-treatment microbiopsies to see if botulinum toxin alter peripheral molecular events and clinical variables.

Conditions

Temporomandibular Disorders

Keywords

Temporomandibular Disorders; Botulinum Toxin A; Myalgia; Randomized; Clinical Trial; Pain; Gene; Neural Plasticity

Outcome Measures

Primary Outcomes (5)

• Change of gene expression measured with bulk RNA-seq

  Gene expression in the anterior tibialis muscle (internal control) will be subtracted from the masseter and the patients will then be clustered according to DEGs and compared to baseline.

  1-6 months

• Change of RNA expression measured with single-cell RNA (scRNA) seq/spatial trnascriptomics.

  ScRNA-seq will be analyzed by SEURAT

  1-6 months

• Change of expression of sensory neuron markers measured with IHC

  The expression will be measured as the change of frequency (%) of selected sensory neuron markers.

  1-6 months

• Change of proteome measured with proteomics

  The expression wil be measured with two-dimensional gel electrophoresis, followed by liquid chromatography-tandem mass spectrometry and protein network analyses.

  1-6 months

• Change of proteome measured with affinity-based proteomics.

  The protein expression will be measured with affinity proteomics using Olink platforms will be done, which enables analysis of several hundreds of proteins in one analysis

  1-6 months

Secondary Outcomes (7)

• Change of pain intensity compared to baseline using 0-10 numeric rating scales (NRS)

  1-3 months

• Global improvement using Patient Global Impression of Change Scale (PGIC)

  1-3 months

• Change of pain quality compared to baseline using the McGill Pain questionnaire (MPQ)

  1-3 months

• Number of participants with adverse events assessed with questionnaire

  1 week

• Number of participants with adverse events assessed with questionnaire

  1-3 months

Other Outcomes (5)

• Change of thermal detection and pain thresholds measured with Thermotest.

  1-3 months

• Change of pin-prick pain measured with Medipin

  1-3 months

• Change of temporal summation pain compared to baseline

  1-3 months

Study Arms (2)

Botulinum toxin

ACTIVE COMPARATOR

Single bilateral injection into three standardized points of the masseter muscles and two of the anterior temporalis muscle. The total dose administered is 100 U (10 U/point) which is dissolved in 1 mL of isotonic saline. Thus, 0.1 ml of botulinum toxin solution is injected in each point.

Drug: Botulinum toxin type A

Isotonic saline

PLACEBO COMPARATOR

Single injection of 1 mL isotonic saline (0.9 mg/mL) into the same five points per side in a similar manner as for botulinum toxin.

Drug: Isotonic saline 0,9%

Interventions

Botulinum toxin type A DRUG

Randomized double-blind administration

Also known as: Botox®️ (100 U, AbbVie AB, Solna, Sweden)

Botulinum toxin

Isotonic saline 0,9% DRUG

Randomized double-blind administration

Also known as: Natriumklorid Braun (0,9 mg/mL, B. Braun Medical AB, Danderyd, Sweden)

Isotonic saline

Eligibility Criteria

• Age: 20 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• a diagnosis of TMDM myalgia or myofascial pain according to the DC/TMD criteria
• females with adequate contraceptives and a negative pregnancy test
• pain upon digital palpation of at least one of the masseter muscle
• a characteristic pain intensity of \> 40/100
• a negative pregnancy test at the day of treatment

You may not qualify if:

• difficulties understanding the Swedish language
• systemic inflammatory connective tissue diseases
• widespread pain
• neuromuscular disorders
• diagnosed or severe psychiatric disease
• neuropathic pain
• pain of dental origin
• history of trauma to the face, head or neck
• pregnancy or nursing
• known allergy to botulinum toxin or antibiotics
• use of muscle relaxants, antidepressant, neuropsychiatric, anticoagulant drugs, or aminoglycoside antibiotics
• previous treatment with botulinum toxin during the last 12 months
• use of analgesic or anti-inflammatory medication during the 48 hours preceding biopsy
• skin infection over injection/biopsy site

Sponsors & Collaborators

• Karolinska Institutet: lead

Study Sites (1)

Department of Dental Medicine, Karolinska Institutet

Huddinge, Stockholm County, SE14104, Sweden

RECRUITING

Related Publications (7)

• 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.

  PMID: 24482784 BACKGROUND

• Ernberg M, Hedenberg-Magnusson B, List T, Svensson P. Efficacy of botulinum toxin type A for treatment of persistent myofascial TMD pain: a randomized, controlled, double-blind multicenter study. Pain. 2011 Sep;152(9):1988-1996. doi: 10.1016/j.pain.2011.03.036. Epub 2011 Apr 22.

  PMID: 21514731 BACKGROUND

• Mecklenburg J, Wangzhou A, Hovhannisyan AH, Barba-Escobedo P, Shein SA, Zou Y, Weldon K, Lai Z, Goffin V, Dussor G, Tumanov AV, Price TJ, Akopian AN. Sex-dependent pain trajectories induced by prolactin require an inflammatory response for pain resolution. Brain Behav Immun. 2022 Mar;101:246-263. doi: 10.1016/j.bbi.2022.01.016. Epub 2022 Jan 19.

  PMID: 35065194 BACKGROUND

• Srzentic K, Fornelli L, Tsybin YO, Loo JA, Seckler H, Agar JN, Anderson LC, Bai DL, Beck A, Brodbelt JS, van der Burgt YEM, Chamot-Rooke J, Chatterjee S, Chen Y, Clarke DJ, Danis PO, Diedrich JK, D'Ippolito RA, Dupre M, Gasilova N, Ge Y, Goo YA, Goodlett DR, Greer S, Haselmann KF, He L, Hendrickson CL, Hinkle JD, Holt MV, Hughes S, Hunt DF, Kelleher NL, Kozhinov AN, Lin Z, Malosse C, Marshall AG, Menin L, Millikin RJ, Nagornov KO, Nicolardi S, Pasa-Tolic L, Pengelley S, Quebbemann NR, Resemann A, Sandoval W, Sarin R, Schmitt ND, Shabanowitz J, Shaw JB, Shortreed MR, Smith LM, Sobott F, Suckau D, Toby T, Weisbrod CR, Wildburger NC, Yates JR 3rd, Yoon SH, Young NL, Zhou M. Interlaboratory Study for Characterizing Monoclonal Antibodies by Top-Down and Middle-Down Mass Spectrometry. J Am Soc Mass Spectrom. 2020 Sep 2;31(9):1783-1802. doi: 10.1021/jasms.0c00036. Epub 2020 Aug 19.

  PMID: 32812765 BACKGROUND

• Christidis N, Kang I, Cairns BE, Kumar U, Dong X, Rosen A, Kopp S, Ernberg M. Expression of 5-HT3 receptors and TTX resistant sodium channels (Na(V)1.8) on muscle nerve fibers in pain-free humans and patients with chronic myofascial temporomandibular disorders. J Headache Pain. 2014 Sep 26;15(1):63. doi: 10.1186/1129-2377-15-63.

  PMID: 25261281 BACKGROUND

• Wheelock AM, Wheelock CE. Trials and tribulations of 'omics data analysis: assessing quality of SIMCA-based multivariate models using examples from pulmonary medicine. Mol Biosyst. 2013 Nov;9(11):2589-96. doi: 10.1039/c3mb70194h.

  PMID: 23999822 BACKGROUND

• De la Torre Canales G, Alvarez-Pinzon N, Munoz-Lora VRM, Vieira Peroni L, Farias Gomes A, Sanchez-Ayala A, Haiter-Neto F, Manfredini D, Rizzatti-Barbosa CM. Efficacy and Safety of Botulinum Toxin Type A on Persistent Myofascial Pain: A Randomized Clinical Trial. Toxins (Basel). 2020 Jun 15;12(6):395. doi: 10.3390/toxins12060395.

  PMID: 32549196 BACKGROUND

Related Links

• Random generator

MeSH Terms

Conditions

Temporomandibular Joint Disorders; Myalgia; Pain

Interventions

Botulinum Toxins, Type A

Condition Hierarchy (Ancestors)

Craniomandibular Disorders; Mandibular Diseases; Jaw Diseases; Musculoskeletal Diseases; Joint Diseases; Muscular Diseases; Stomatognathic Diseases; Neuromuscular Diseases; Nervous System Diseases; Musculoskeletal Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Botulinum Toxins; Metalloendopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Metalloproteases; Bacterial Proteins; Proteins; Amino Acids, Peptides, and Proteins; Bacterial Toxins; Toxins, Biological; Biological Factors

Study Officials

• Malin Ernberg

  Karolinska Institutet

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Malin Ernberg, PhD

CONTACT

+46706368236; malin.ernberg@ki.se

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 7, 2023
• First Posted: February 9, 2023
• Study Start: September 20, 2023
• Primary Completion: June 30, 2025
• Study Completion (Estimated): August 31, 2027
• Last Updated: February 17, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR, ANALYTIC CODE
• Time Frame: Data will be available after study termination and saved in the databases for 10 years whereafter they are discarded.
• Access Criteria: The database is made available to other researchers only for non-commercial research that has permission from the ethics committee after approval by the research leader (controlled access). Data is also uploaded into a database of aggregated genomic data that is shared with the research community (unlimited access).

Locations

SE (1)