Oxidative Stress and Opiorphin in Temporomandibular Disorders (ROStrO-TMD)

January 20, 2017 updated by: Iva Alajbeg, Croatian Science Foundation

The Role of Oxidative Stress and Opiorphin in Temporomandibular Disorders

The objective of this study is to quantify salivary oxidative stress biomarkers in patients with temporomandibular disorders and to quantify recently isolated endogenous peptide opiorphin in saliva of these patients. As chronic exposure to stress may cause hyperalgesia as a result of the stress response in the hypothalamic-pituitary-adrenal axis, aim is to test this as an underlying mechanism by correlating opiorphin and oxidative stress markers to salivary cortisol levels. The aim is to assess the association of oxidative stress salivary biomarkers with muscle and joint pain and to measure opiorphin, a potential biomarker of different pathological states.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Temporomandibular disorders (TMD) are most common chronic orofacial pain conditions of non-dental origin, with prevalence in the general population of 3.6% to 7%. Despite signs and symptoms being well described in the literature, there is still an absence of underlying pathophysiological mechanisms. Evidence based strategies for diagnosis and management of temporomandibular pain still aren't available. Psychological and mechanical stress factors could contribute to oxidative stress (OS) and lead to TMD. Therefore, identification of oxidative stress biomarkers would objectively indicate implication of OS in TMD pain onset mechanisms, and provide a basis for early detection, and a potential target for therapeutic agents to prevent progression to more severe dysfunction.

Aim is to quantify salivary OS markers and total antioxidant capacity (TAC), as well as recently isolated endogenous peptide opiorphin (OP) (2006 Inst. Pasteur), in TMD patients and compare them to controls. As chronic exposure to stress may cause hyperalgesia as a result of the stress response in the hypothalamic-pituitary-adrenal (HPA) axis, aim is to test this as an underlying mechanism by correlating OP and OS markers to salivary cortisol (SC) levels.

Hypotheses: OS has a role in TMD onset and maintenance, thus salivary markers of OS will increase and/or TAC will decrease; OP influences orofacial pain syndromes, such as TMD, and its salivary level will differ between TMD patients and controls. If decreased OP levels in TMD patients were encountered, we hypothesize that OP downregulation contributes to TMD onset as its analgesic effect is absent. Conversely, increased OP levels would suggest that OP is upregulated merely as a reaction to painful stimuli. Disbalanced SC levels in TMD patients would corroborate involvement of HPA axis in TMD mechanism, which is known to affect the intensity of OS.

Saliva of 50 TMD patients (diagnosed by validated diagnostic criteria and MRI) and 50 controls will be collected. OS markers (8-hydroxydeoxyguanosine, malondialdehyde, etc.) will be assessed by ELISA with spectrophotometric detection and by spectrophotometric reagent kits. OP levels will be measured by HPLC-MS/MS method, originally developed and validated by team members. The electrochemiluminescence immunoassay ECLIA will be used for measuring SC.

Pain and stress will be subjectively assessed using questionnaires: all subjects will fill in Perceived Stress Scale 10 (PSS-10); in TMD patients the worst experienced pain will be recorded using Visual Analogue Scale at the initial and at subsequent visits, as well as Graded Chronic Pain Scale (GCPS), Visual Analogue Scale (VAS), Patient Health Questionnaire (PHQ), Jaw function limitation scale (JFLS), Oral Behaviours Checklist and Oral Health Impact Profile (OHIP)-14.

TMD patients will be randomized in 2 treatment groups (1: stabilization splint + placebo pills; 2: placebo splint + 1g of vitamin C daily). Measurements will be repeated after 3 and 6 months of treatment. Monitoring of OP, OS markers and SC during that period will, depending on observed changes in TMD symptoms, further elucidate underlying proposed mechanism by performing multivariate analyses including treatment outcomes.

This translational research aims to make basic science findings useful for clinical applications. Findings of higher concentrations of OS biomarkers would, besides their significance as "a piece of puzzle" of TMD mechanism, could also be important in establishment of TMD diagnosis and as prospective therapeutic targets. Salivary opiorphin, due to its proven analgesic effect might additionally serve as a possible drug for orofacial pain syndromes.

Novel approach to understanding neuroendocrine mechanisms in TMD and their links to OS, as well and use of saliva as non-invasively available diagnostic biofluid represent significant scientific advances.

Study Type

Interventional

Enrollment (Anticipated)

80

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Croatia
    • N/A = Not Applicable
      • Zagreb, N/A = Not Applicable, Croatia, 10000
        • Recruiting
        • School of Dental Medicine, University of Zagreb

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • for TMD patients: diagnosis of TMD using Croatian version of research diagnostic criteria for temporomandibular disorders (RDC/TMD)
  • for control group: gender- and age-matched healthy volunteers

Exclusion Criteria:

  • for TMD patients: patients younger than 18 years; smoking; other local diseases and/or systemic disorders; the use of anti-inflammatory drugs, analgesics and/or muscle relaxants; individuals who had already been under treatment for TMD
  • for control group: younger than 18 years; cardiac/circulatory/metabolic/muscle abnormalities; smoking; the use of medications, supplements or dietary aids that might affect the outcome results

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: DIAGNOSTIC
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: SINGLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Treatment 1: stabilization splint, placebo oral tablet
stabilization splint during night and 1 placebo oral tablet daily, for 6 months
Device: stabilization splint
Hard acrylic type of splint with full coverage of occlusal surfaces of upper teeth, with a thickness of about 1.5 mm at the level of the first molar.
Other Names:
  • occlusal splint
Drug: Placebo Oral Tablet
sugar pill manufactured to mimic 1000 mg Vitamin C
ACTIVE_COMPARATOR: Treatment 2: placebo splint, vitamin C
placebo splint during night and 1000 mg Vitamin C tablet daily, for 6 months
Device: placebo splint
Ineffectively designed oral appliance: an acrylic palatal plate will be used (without influence on occlusion, TMJ and masticatory muscles).
Dietary supplement: Vitamin C
1000 mg
Other Names:
  • ascorbic acid
NO_INTERVENTION: Control group
determination of oxidative stress biomarkers and cortisol in saliva of healthy control subjects

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of salivary oxidative stress markers concentration
Time Frame: baseline, 6th month

Oxidative stress markers will be measured using spectrophotometric methods. Opiorphin levels will be measured by HPLC-MS/MS method, originally developed and validated by team members (Brkljacic L, Sabalic M, Salaric I, Jeric I, Alajbeg I et al, J Chromatogr B Analyt Technol Biomed Life Sci. 2011). The change of the single marker (opiorphin) concentration between the two time points is a measure of clinical efficacy of applied treatment modality.

In control group (healthy patients) measurement of oxidative stress markers and opiorphin will be performed only at first appointment in order to compare them with TMD patients baseline levels.
baseline, 6th month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of pain intensity in TMD patients
Time Frame: baseline, 3rd month, 6th month
The intensity of pain will be determined using a 100 mm visual analog scale (VAS) on day 0, day 90 and day 180. The change in the amount between the time points is a measure of clinical efficacy of applied treatment modality.
baseline, 3rd month, 6th month
The quality of life change in TMD patients
Time Frame: baseline, 6th month
The quality of life for OLP patients will be determined using "Oral health impact profile"(OHIP-14) questionnaire on day 0 and day 180. The change in the amount between the time points is a measure of clinical efficacy of applied treatment modality.
baseline, 6th month
Change in the amount of maximal comfortable mouth opening in TMD patients
Time Frame: baseline, 6th month
Maximal comfortable mouth opening is measured as the distance between the maxillary and mandibular incisal edges. Maximal comfortable opening is defined as the maximum distance the participant could open his/her mouth without experiencing any additional pain and discomfort. The change in the amount of maximal comfortable mouth opening between the time points is a measure of clinical efficacy of applied treatment modality.
baseline, 6th month
Change in the perceived stress
Time Frame: baseline, 6th month
General anxiety disorder (GAD - 7) scale will be used in order to determine how often the patient has been disturbed by different problems including feeling of nervousness and anxiety. The change in the amount between the time points is a measure of clinical efficacy of applied treatment modality. In control group (healthy patients) GAD-7 will be used only at first appointment.
baseline, 6th month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Croatian Science Foundation

Investigators

  • Principal Investigator: Iva Z Alajbeg, PhD, School of Dental Medicine, University of Zagreb

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

October 1, 2015

Primary Completion (ANTICIPATED)

September 30, 2018

Study Completion (ANTICIPATED)

September 30, 2019

Study Registration Dates

First Submitted

January 19, 2017

First Submitted That Met QC Criteria

January 20, 2017

First Posted (ESTIMATE)

January 24, 2017

Study Record Updates

Last Update Posted (ESTIMATE)

January 24, 2017

Last Update Submitted That Met QC Criteria

January 20, 2017

Last Verified

January 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IP- 2014-09-3070

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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