Oxidative Stress and Opiorphin in Temporomandibular Disorders

NCT ID: NCT03029494

Last Updated: 2017-01-24

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

NA

Total Enrollment

80 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-10-01

Study Completion Date

2019-09-30

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Temporomandibular Disorders

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

TMD patients will be randomized into two treatment groups. Each group will have two sets of interventions: one presumably active treatment and other a placebo:

Treatment group 1: stabilization splint and placebo tablet daily. Treatment group 2: placebo (ineffectively designed) splint and 1000 mg Vitamin C tablet (an antioxidant agent) daily.
Primary Study Purpose

DIAGNOSTIC

Blinding Strategy

SINGLE

Participants
It will be a single-blind interventional study (as placebo splint cannot be mistaken for a stabilization splint by a clinician).

Study Groups

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Treatment 1: stabilization splint, placebo oral tablet

stabilization splint during night and 1 placebo oral tablet daily, for 6 months

Group Type EXPERIMENTAL

stabilization splint

Intervention Type DEVICE

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.

Placebo Oral Tablet

Intervention Type DRUG

sugar pill manufactured to mimic 1000 mg Vitamin C

Treatment 2: placebo splint, vitamin C

placebo splint during night and 1000 mg Vitamin C tablet daily, for 6 months

Group Type ACTIVE_COMPARATOR

placebo splint

Intervention Type DEVICE

Ineffectively designed oral appliance: an acrylic palatal plate will be used (without influence on occlusion, TMJ and masticatory muscles).

Vitamin C

Intervention Type DIETARY_SUPPLEMENT

1000 mg

Control group

determination of oxidative stress biomarkers and cortisol in saliva of healthy control subjects

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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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.

Intervention Type DEVICE

Placebo Oral Tablet

sugar pill manufactured to mimic 1000 mg Vitamin C

Intervention Type DRUG

placebo splint

Ineffectively designed oral appliance: an acrylic palatal plate will be used (without influence on occlusion, TMJ and masticatory muscles).

Intervention Type DEVICE

Vitamin C

1000 mg

Intervention Type DIETARY_SUPPLEMENT

Other Intervention Names

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occlusal splint ascorbic acid

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Croatian Science Foundation

OTHER_GOV

Sponsor Role lead

Responsible Party

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Iva Alajbeg

Prof.

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Iva Z Alajbeg, PhD

Role: PRINCIPAL_INVESTIGATOR

School of Dental Medicine, University of Zagreb

Locations

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School of Dental Medicine, University of Zagreb

Zagreb, N/A = Not Applicable, Croatia

Site Status RECRUITING

Countries

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Croatia

Central Contacts

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Iva Z Alajbeg, PhD

Role: CONTACT

00385917930164

Ivan Z Alajbeg, PhD

Role: CONTACT

00385915051271

Facility Contacts

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Iva Z Alajbeg, PhD

Role: primary

00385917930164

References

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De Leeuw R, Bertoli E, Schmidt JE, Carlson CR. Prevalence of post-traumatic stress disorder symptoms in orofacial pain patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005 May;99(5):558-68. doi: 10.1016/j.tripleo.2004.05.016.

Reference Type RESULT
PMID: 15829878 (View on PubMed)

De Leeuw R, Bertoli E, Schmidt JE, Carlson CR. Prevalence of traumatic stressors in patients with temporomandibular disorders. J Oral Maxillofac Surg. 2005 Jan;63(1):42-50. doi: 10.1016/j.joms.2004.04.027.

Reference Type RESULT
PMID: 15635556 (View on PubMed)

Kawai Y, Kubota E, Okabe E. Reactive oxygen species participation in experimentally induced arthritis of the temporomandibular joint in rats. J Dent Res. 2000 Jul;79(7):1489-95. doi: 10.1177/00220345000790071001.

Reference Type RESULT
PMID: 11005733 (View on PubMed)

Rodriguez de Sotillo D, Velly AM, Hadley M, Fricton JR. Evidence of oxidative stress in temporomandibular disorders: a pilot study. J Oral Rehabil. 2011 Oct;38(10):722-8. doi: 10.1111/j.1365-2842.2011.02216.x. Epub 2011 Apr 4.

Reference Type RESULT
PMID: 21457291 (View on PubMed)

Salaric I, Sabalic M, Alajbeg I. Opiorphin in burning mouth syndrome patients: a case-control study. Clin Oral Investig. 2017 Sep;21(7):2363-2370. doi: 10.1007/s00784-016-2031-9. Epub 2016 Dec 24.

Reference Type RESULT
PMID: 28013436 (View on PubMed)

Turp JC, Komine F, Hugger A. Efficacy of stabilization splints for the management of patients with masticatory muscle pain: a qualitative systematic review. Clin Oral Investig. 2004 Dec;8(4):179-95. doi: 10.1007/s00784-004-0265-4. Epub 2004 Jun 4.

Reference Type RESULT
PMID: 15179561 (View on PubMed)

Miricescu D, Totan A, Calenic B, Mocanu B, Didilescu A, Mohora M, Spinu T, Greabu M. Salivary biomarkers: relationship between oxidative stress and alveolar bone loss in chronic periodontitis. Acta Odontol Scand. 2014 Jan;72(1):42-7. doi: 10.3109/00016357.2013.795659. Epub 2013 Jul 22.

Reference Type RESULT
PMID: 23869629 (View on PubMed)

Lawaf S, Azizi A, Tabarestani T. Comparison of Serum and Salivary Antioxidants in Patients with Temporomandibular Joint Disorders and Healthy Subjects. J Dent (Tehran). 2015 Apr;12(4):263-70.

Reference Type RESULT
PMID: 26622281 (View on PubMed)

Wang J, Schipper HM, Velly AM, Mohit S, Gornitsky M. Salivary biomarkers of oxidative stress: A critical review. Free Radic Biol Med. 2015 Aug;85:95-104. doi: 10.1016/j.freeradbiomed.2015.04.005. Epub 2015 Apr 16.

Reference Type RESULT
PMID: 25889823 (View on PubMed)

Vrbanovic E, Lapic I, Rogic D, Alajbeg IZ. Changes in salivary oxidative status, salivary cortisol, and clinical symptoms in female patients with temporomandibular disorders during occlusal splint therapy: a 3-month follow up. BMC Oral Health. 2019 Jun 6;19(1):100. doi: 10.1186/s12903-019-0791-8.

Reference Type DERIVED
PMID: 31170954 (View on PubMed)

Alajbeg IZ, Lapic I, Rogic D, Vuletic L, Andabak Rogulj A, Illes D, Knezovic Zlataric D, Badel T, Vrbanovic E, Alajbeg I. Within-Subject Reliability and between-Subject Variability of Oxidative Stress Markers in Saliva of Healthy Subjects: A Longitudinal Pilot Study. Dis Markers. 2017;2017:2697464. doi: 10.1155/2017/2697464. Epub 2017 Nov 15.

Reference Type DERIVED
PMID: 29269980 (View on PubMed)

Other Identifiers

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IP- 2014-09-3070

Identifier Type: -

Identifier Source: org_study_id

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