<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03029494</url>
  </required_header>
  <id_info>
    <org_study_id>IP- 2014-09-3070</org_study_id>
    <nct_id>NCT03029494</nct_id>
  </id_info>
  <brief_title>Oxidative Stress and Opiorphin in Temporomandibular Disorders</brief_title>
  <acronym>ROStrO-TMD</acronym>
  <official_title>The Role of Oxidative Stress and Opiorphin in Temporomandibular Disorders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Croatian Science Foundation</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Croatian Science Foundation</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objective of this study is to quantify salivary oxidative stress biomarkers in patients&#xD;
      with temporomandibular disorders and to quantify recently isolated endogenous peptide&#xD;
      opiorphin in saliva of these patients. As chronic exposure to stress may cause hyperalgesia&#xD;
      as a result of the stress response in the hypothalamic-pituitary-adrenal axis, aim is to test&#xD;
      this as an underlying mechanism by correlating opiorphin and oxidative stress markers to&#xD;
      salivary cortisol levels. The aim is to assess the association of oxidative stress salivary&#xD;
      biomarkers with muscle and joint pain and to measure opiorphin, a potential biomarker of&#xD;
      different pathological states.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Temporomandibular disorders (TMD) are most common chronic orofacial pain conditions of&#xD;
      non-dental origin, with prevalence in the general population of 3.6% to 7%. Despite signs and&#xD;
      symptoms being well described in the literature, there is still an absence of underlying&#xD;
      pathophysiological mechanisms. Evidence based strategies for diagnosis and management of&#xD;
      temporomandibular pain still aren't available. Psychological and mechanical stress factors&#xD;
      could contribute to oxidative stress (OS) and lead to TMD. Therefore, identification of&#xD;
      oxidative stress biomarkers would objectively indicate implication of OS in TMD pain onset&#xD;
      mechanisms, and provide a basis for early detection, and a potential target for therapeutic&#xD;
      agents to prevent progression to more severe dysfunction.&#xD;
&#xD;
      Aim is to quantify salivary OS markers and total antioxidant capacity (TAC), as well as&#xD;
      recently isolated endogenous peptide opiorphin (OP) (2006 Inst. Pasteur), in TMD patients and&#xD;
      compare them to controls. As chronic exposure to stress may cause hyperalgesia as a result of&#xD;
      the stress response in the hypothalamic-pituitary-adrenal (HPA) axis, aim is to test this as&#xD;
      an underlying mechanism by correlating OP and OS markers to salivary cortisol (SC) levels.&#xD;
&#xD;
      Hypotheses: OS has a role in TMD onset and maintenance, thus salivary markers of OS will&#xD;
      increase and/or TAC will decrease; OP influences orofacial pain syndromes, such as TMD, and&#xD;
      its salivary level will differ between TMD patients and controls. If decreased OP levels in&#xD;
      TMD patients were encountered, we hypothesize that OP downregulation contributes to TMD onset&#xD;
      as its analgesic effect is absent. Conversely, increased OP levels would suggest that OP is&#xD;
      upregulated merely as a reaction to painful stimuli. Disbalanced SC levels in TMD patients&#xD;
      would corroborate involvement of HPA axis in TMD mechanism, which is known to affect the&#xD;
      intensity of OS.&#xD;
&#xD;
      Saliva of 50 TMD patients (diagnosed by validated diagnostic criteria and MRI) and 50&#xD;
      controls will be collected. OS markers (8-hydroxydeoxyguanosine, malondialdehyde, etc.) will&#xD;
      be assessed by ELISA with spectrophotometric detection and by spectrophotometric reagent&#xD;
      kits. OP levels will be measured by HPLC-MS/MS method, originally developed and validated by&#xD;
      team members. The electrochemiluminescence immunoassay ECLIA will be used for measuring SC.&#xD;
&#xD;
      Pain and stress will be subjectively assessed using questionnaires: all subjects will fill in&#xD;
      Perceived Stress Scale 10 (PSS-10); in TMD patients the worst experienced pain will be&#xD;
      recorded using Visual Analogue Scale at the initial and at subsequent visits, as well as&#xD;
      Graded Chronic Pain Scale (GCPS), Visual Analogue Scale (VAS), Patient Health Questionnaire&#xD;
      (PHQ), Jaw function limitation scale (JFLS), Oral Behaviours Checklist and Oral Health Impact&#xD;
      Profile (OHIP)-14.&#xD;
&#xD;
      TMD patients will be randomized in 2 treatment groups (1: stabilization splint + placebo&#xD;
      pills; 2: placebo splint + 1g of vitamin C daily). Measurements will be repeated after 3 and&#xD;
      6 months of treatment. Monitoring of OP, OS markers and SC during that period will, depending&#xD;
      on observed changes in TMD symptoms, further elucidate underlying proposed mechanism by&#xD;
      performing multivariate analyses including treatment outcomes.&#xD;
&#xD;
      This translational research aims to make basic science findings useful for clinical&#xD;
      applications. Findings of higher concentrations of OS biomarkers would, besides their&#xD;
      significance as &quot;a piece of puzzle&quot; of TMD mechanism, could also be important in&#xD;
      establishment of TMD diagnosis and as prospective therapeutic targets. Salivary opiorphin,&#xD;
      due to its proven analgesic effect might additionally serve as a possible drug for orofacial&#xD;
      pain syndromes.&#xD;
&#xD;
      Novel approach to understanding neuroendocrine mechanisms in TMD and their links to OS, as&#xD;
      well and use of saliva as non-invasively available diagnostic biofluid represent significant&#xD;
      scientific advances.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">October 1, 2015</start_date>
  <completion_date type="Anticipated">September 30, 2019</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>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:&#xD;
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.</intervention_model_description>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>It will be a single-blind interventional study (as placebo splint cannot be mistaken for a stabilization splint by a clinician).</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change of salivary oxidative stress markers concentration</measure>
    <time_frame>baseline, 6th month</time_frame>
    <description>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.&#xD;
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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change of pain intensity in TMD patients</measure>
    <time_frame>baseline, 3rd month, 6th month</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The quality of life change in TMD patients</measure>
    <time_frame>baseline, 6th month</time_frame>
    <description>The quality of life for OLP patients will be determined using &quot;Oral health impact profile&quot;(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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the amount of maximal comfortable mouth opening in TMD patients</measure>
    <time_frame>baseline, 6th month</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the perceived stress</measure>
    <time_frame>baseline, 6th month</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Temporomandibular Disorders</condition>
  <arm_group>
    <arm_group_label>Treatment 1: stabilization splint, placebo oral tablet</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>stabilization splint during night and 1 placebo oral tablet daily, for 6 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment 2: placebo splint, vitamin C</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>placebo splint during night and 1000 mg Vitamin C tablet daily, for 6 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>determination of oxidative stress biomarkers and cortisol in saliva of healthy control subjects</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>stabilization splint</intervention_name>
    <description>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.</description>
    <arm_group_label>Treatment 1: stabilization splint, placebo oral tablet</arm_group_label>
    <other_name>occlusal splint</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>sugar pill manufactured to mimic 1000 mg Vitamin C</description>
    <arm_group_label>Treatment 1: stabilization splint, placebo oral tablet</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>placebo splint</intervention_name>
    <description>Ineffectively designed oral appliance: an acrylic palatal plate will be used (without influence on occlusion, TMJ and masticatory muscles).</description>
    <arm_group_label>Treatment 2: placebo splint, vitamin C</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Vitamin C</intervention_name>
    <description>1000 mg</description>
    <arm_group_label>Treatment 2: placebo splint, vitamin C</arm_group_label>
    <other_name>ascorbic acid</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  for TMD patients: diagnosis of TMD using Croatian version of research diagnostic&#xD;
             criteria for temporomandibular disorders (RDC/TMD)&#xD;
&#xD;
          -  for control group: gender- and age-matched healthy volunteers&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  for TMD patients: patients younger than 18 years; smoking; other local diseases and/or&#xD;
             systemic disorders; the use of anti-inflammatory drugs, analgesics and/or muscle&#xD;
             relaxants; individuals who had already been under treatment for TMD&#xD;
&#xD;
          -  for control group: younger than 18 years; cardiac/circulatory/metabolic/muscle&#xD;
             abnormalities; smoking; the use of medications, supplements or dietary aids that might&#xD;
             affect the outcome results&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Iva Z Alajbeg, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>School of Dental Medicine, University of Zagreb</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Iva Z Alajbeg, PhD</last_name>
    <phone>00385917930164</phone>
    <email>ialajbeg@sfzg.hr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ivan Z Alajbeg, PhD</last_name>
    <phone>00385915051271</phone>
    <email>alajbeg@sfzg.hr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>School of Dental Medicine, University of Zagreb</name>
      <address>
        <city>Zagreb</city>
        <state>N/A = Not Applicable</state>
        <zip>10000</zip>
        <country>Croatia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Iva Z Alajbeg, PhD</last_name>
      <phone>00385917930164</phone>
      <email>ialajbeg@sfzg.hr</email>
    </contact>
  </location>
  <location_countries>
    <country>Croatia</country>
  </location_countries>
  <results_reference>
    <citation>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.</citation>
    <PMID>15829878</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>15635556</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>11005733</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>21457291</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>28013436</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>15179561</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>23869629</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>26622281</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>25889823</PMID>
  </results_reference>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>January 19, 2017</study_first_submitted>
  <study_first_submitted_qc>January 20, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 24, 2017</study_first_posted>
  <last_update_submitted>January 20, 2017</last_update_submitted>
  <last_update_submitted_qc>January 20, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 24, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Zagreb</investigator_affiliation>
    <investigator_full_name>Iva Alajbeg</investigator_full_name>
    <investigator_title>Prof.</investigator_title>
  </responsible_party>
  <keyword>oxidative stress</keyword>
  <keyword>saliva</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Temporomandibular Joint Disorders</mesh_term>
    <mesh_term>Temporomandibular Joint Dysfunction Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ascorbic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>December 2, 2020</submitted>
    <submission_canceled>December 2, 2020</submission_canceled>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03029494
org study id: IP- 2014-09-3070
nct id: NCT03029494
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: 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 purpose: Diagnostic
masking: Single (Participant)
masking description: It will be a single-blind interventional study (as placebo splint cannot be mistaken for a stabilization splint by a clinician).
measure: Change of salivary oxidative stress markers concentration
time frame: baseline, 6th month
description: 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.
measure: Change of pain intensity in TMD patients
time frame: baseline, 3rd month, 6th month
description: 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.
measure: The quality of life change in TMD patients
time frame: baseline, 6th month
description: 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.
measure: Change in the amount of maximal comfortable mouth opening in TMD patients
time frame: baseline, 6th month
description: 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.
measure: Change in the perceived stress
time frame: baseline, 6th month
description: 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.
arm group label: Treatment 1: stabilization splint, placebo oral tablet
arm group type: Experimental
description: stabilization splint during night and 1 placebo oral tablet daily, for 6 months
arm group label: Treatment 2: placebo splint, vitamin C
arm group type: Active Comparator
description: placebo splint during night and 1000 mg Vitamin C tablet daily, for 6 months
arm group label: Control group
arm group type: No Intervention
description: determination of oxidative stress biomarkers and cortisol in saliva of healthy control subjects
intervention type: Device
intervention name: stabilization splint
description: 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.
arm group label: Treatment 1: stabilization splint, placebo oral tablet
other name: occlusal splint
intervention type: Drug
intervention name: Placebo Oral Tablet
description: sugar pill manufactured to mimic 1000 mg Vitamin C
arm group label: Treatment 1: stabilization splint, placebo oral tablet
intervention type: Device
intervention name: placebo splint
description: Ineffectively designed oral appliance: an acrylic palatal plate will be used (without influence on occlusion, TMJ and masticatory muscles).
arm group label: Treatment 2: placebo splint, vitamin C
intervention type: Dietary Supplement
intervention name: Vitamin C
description: 1000 mg
arm group label: Treatment 2: placebo splint, vitamin C
other name: ascorbic acid
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Iva Z Alajbeg, PhD
role: Principal Investigator
affiliation: School of Dental Medicine, University of Zagreb
last name: Iva Z Alajbeg, PhD
phone: 00385917930164
email: ialajbeg@sfzg.hr
last name: Ivan Z Alajbeg, PhD
phone: 00385915051271
email: alajbeg@sfzg.hr
facility: 
status: Recruiting
contact: 
country: Croatia
citation: 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.
PMID: 15829878
citation: 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.
PMID: 15635556
citation: 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.
PMID: 11005733
citation: 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.
PMID: 21457291
citation: 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.
PMID: 28013436
citation: 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.
PMID: 15179561
citation: 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.
PMID: 23869629
citation: 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.
PMID: 26622281
citation: 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.
PMID: 25889823
responsible party type: Principal Investigator
investigator affiliation: University of Zagreb
investigator full name: Iva Alajbeg
investigator title: Prof.
mesh term: Temporomandibular Joint Disorders
mesh term: Temporomandibular Joint Dysfunction Syndrome
mesh term: Ascorbic Acid
sharing ipd: No
submitted: December 2, 2020
submission canceled: December 2, 2020