<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/NCT03298711</url>
  </required_header>
  <id_info>
    <org_study_id>B-1709-423-308</org_study_id>
    <nct_id>NCT03298711</nct_id>
  </id_info>
  <brief_title>Central Sensitization and Alteration of Circulating Neurosteroid</brief_title>
  <official_title>Relationship Between Central Sensitization and Alteration of Circulating Neurosteroid Following Bilateral Total Knee Arthroplasty</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Seoul National University Bundang Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Seoul National University Bundang Hospital</source>
  <brief_summary>
    <textblock>
      For patients who underwent two-stage replacement of both knee joints (one knee surgery - one&#xD;
      week term- the other knee surgery), postoperative pain and analgesic usage with&#xD;
      patient-controlled analgesia (PCA) increased at the second stage, which suggests that central&#xD;
      sensitization occurs within a short period (one week) in patients who undergo total knee&#xD;
      arthroplasty (TKA). Neurosteroids act on NMDA and AMPA receptors, GABAa receptors, and&#xD;
      voltage-dependent Ca2+ or K+ channels of sensory neurons to increase invasive or neuropathic&#xD;
      pain and, conversely, to exhibit analgesic and anticonvulsant effects. These actions mean&#xD;
      that the neurosteroid acts as an endogenous regulator of pain control and central&#xD;
      sensitization. The purpose of this study is to confirm that the&#xD;
      hypothalamus-pituitary-adrenal (HPA) axis, which is the main body of endocrine neurosteroid,&#xD;
      is associated with increased pain sensitivity after TKA. The concentrations of cortisol and&#xD;
      dehydroepiandrosterone (DHEA) in the saliva of patients who undergo two-staged bilateral knee&#xD;
      replacement surgery (one knee surgery - one week term- the other knee surgery) will be&#xD;
      measured at each stage and analyzed for correlation between concentration-related changes of&#xD;
      HPA and postoperative knee pain variations.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 20, 2017</start_date>
  <completion_date type="Actual">May 6, 2020</completion_date>
  <primary_completion_date type="Actual">May 6, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>The profiles of cortisol in the saliva</measure>
    <time_frame>From the evening (9PM) before the operation day to the morning (60 minutes after the wake-up) of the operation day, for each stage of the operation.</time_frame>
    <description>The cortisol concentrations in the saliva, at the evening before the operation (21:00-22:00), just after wake-up in the morning of operation day, and 30 and 60 minutes after the wake-up.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The profiles of DHEA in the saliva</measure>
    <time_frame>From the evening (9PM) before the operation day to the morning (60 minutes after the wake-up) of the operation day, for each stage of the operation.</time_frame>
    <description>The DHEA concentrations in the saliva, at the evening before the operation (21:00-22:00), just after wake-up in the morning of operation day, and 30 and 60 minutes after the wake-up.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Post operative knee pain</measure>
    <time_frame>At 24h and 48h after the operation, for each stage of the operation.</time_frame>
    <description>At rest and at maximum knee flexion, visual analogue scale (VAS) score of knee pain;</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Analgesic usage (PCA)</measure>
    <time_frame>At 24h and 48h after the operation, for each stage of the operation.</time_frame>
    <description>Fentanyl usage with PCA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Analgesic usage (rescue)</measure>
    <time_frame>At 24h and 48h after the operation, for each stage of the operation.</time_frame>
    <description>The number of rescue analgesics treatments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Antiemetic usage</measure>
    <time_frame>At 24h and 48h after the operation, for each stage of the operation.</time_frame>
    <description>The number of antiemetics treatments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diurnal slope</measure>
    <time_frame>From the evening (9PM) before the operation day to the morning (60 minutes after the wake-up) of the operation day, for each stage of the operation.</time_frame>
    <description>slope for diurnal cortisol decline from the time point immediately upon awakening to nighttime</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CARi</measure>
    <time_frame>At the morning of operation day, for each stage of the operation</time_frame>
    <description>net increases in cortisol levels within the first 30 min after awakening</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CARauc</measure>
    <time_frame>At the morning of operation day, for each stage of the operation</time_frame>
    <description>cortisol secretion area under the curve with respect to ground from the time point immediately after waking to 60 min after waking</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daucawk</measure>
    <time_frame>At the morning of operation day, for each stage of the operation</time_frame>
    <description>DHEA secretion area under the curve with respect to ground from the time point immediately after waking to 60 min after waking</description>
  </secondary_outcome>
  <enrollment type="Actual">69</enrollment>
  <condition>Arthroplasty, Replacement, Knee</condition>
  <condition>Pain, Postoperative</condition>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      The Saliva in which the concentrations of cortisol and DHEA will be measured and analyzed for&#xD;
      correlation between concentration-related changes and postoperative knee pain variations.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients who visit Seoul National University Bundang Hospital for two-staged bilateral&#xD;
        total knee arthroplasty.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Two-staged bilateral total knee arthroplasty (one knee - one week - the other knee)&#xD;
&#xD;
          -  American Society of Anesthesiologists (ASA) class I, II&#xD;
&#xD;
          -  Postmenopausal women aged under 71&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have used analgesics before surgery, such as chronic pain patients&#xD;
&#xD;
          -  ≥ ASA class III, including patients with renal impairment or symptomatic&#xD;
             cardiovascular disease&#xD;
&#xD;
          -  Patients who refuse to participate in the study or from whom receive informed consent&#xD;
             cannot be received.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jin-Woo Park, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Seoul National University Bundang Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Seoul National University Bundang Hospital</name>
      <address>
        <city>Seongnam-si</city>
        <state>Gyeonggi-do</state>
        <zip>13620</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <reference>
    <citation>Losina E, Katz JN. Total knee replacement: pursuit of the paramount result. Rheumatology (Oxford). 2012 Oct;51(10):1735-6. doi: 10.1093/rheumatology/kes199. Epub 2012 Jul 28. No abstract available.</citation>
    <PMID>22843792</PMID>
  </reference>
  <reference>
    <citation>Rosseland LA, Solheim N, Stubhaug A. Pain and disability 1 year after knee arthroscopic procedures. Acta Anaesthesiol Scand. 2008 Mar;52(3):332-7. doi: 10.1111/j.1399-6576.2007.01541.x.</citation>
    <PMID>18269385</PMID>
  </reference>
  <reference>
    <citation>Harden NR, Bruehl S, Stanos S, Brander V, Chung OY, Saltz S, Adams A, Stulberg DS. Prospective examination of pain-related and psychological predictors of CRPS-like phenomena following total knee arthroplasty: a preliminary study. Pain. 2003 Dec;106(3):393-400. doi: 10.1016/j.pain.2003.08.009.</citation>
    <PMID>14659522</PMID>
  </reference>
  <reference>
    <citation>Pruessner JC, Wolf OT, Hellhammer DH, Buske-Kirschbaum A, von Auer K, Jobst S, Kaspers F, Kirschbaum C. Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity. Life Sci. 1997;61(26):2539-49. doi: 10.1016/s0024-3205(97)01008-4.</citation>
    <PMID>9416776</PMID>
  </reference>
  <results_reference>
    <citation>Kim MH, Nahm FS, Kim TK, Chang MJ, Do SH. Comparison of postoperative pain in the first and second knee in staged bilateral total knee arthroplasty: clinical evidence of enhanced pain sensitivity after surgical injury. Pain. 2014 Jan;155(1):22-27. doi: 10.1016/j.pain.2013.08.027. Epub 2013 Aug 30.</citation>
    <PMID>23994101</PMID>
  </results_reference>
  <results_reference>
    <citation>Shin HJ, Kim EY, Na HS, Kim TK, Kim MH, Do SH. Magnesium sulphate attenuates acute postoperative pain and increased pain intensity after surgical injury in staged bilateral total knee arthroplasty: a randomized, double-blinded, placebo-controlled trial. Br J Anaesth. 2016 Oct;117(4):497-503. doi: 10.1093/bja/aew227. Epub 2016 Oct 17.</citation>
    <PMID>28077538</PMID>
  </results_reference>
  <results_reference>
    <citation>Jo KB, Lee YJ, Lee IG, Lee SC, Park JY, Ahn RS. Association of pain intensity, pain-related disability, and depression with hypothalamus-pituitary-adrenal axis function in female patients with chronic temporomandibular disorders. Psychoneuroendocrinology. 2016 Jul;69:106-15. doi: 10.1016/j.psyneuen.2016.03.017. Epub 2016 Mar 31.</citation>
    <PMID>27082645</PMID>
  </results_reference>
  <results_reference>
    <citation>Park JY, Ahn RS. Hypothalamic-pituitary-adrenal axis function in patients with complex regional pain syndrome type 1. Psychoneuroendocrinology. 2012 Sep;37(9):1557-68. doi: 10.1016/j.psyneuen.2012.02.016. Epub 2012 Mar 24.</citation>
    <PMID>22445364</PMID>
  </results_reference>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>September 22, 2017</study_first_submitted>
  <study_first_submitted_qc>September 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 2, 2017</study_first_posted>
  <last_update_submitted>October 20, 2020</last_update_submitted>
  <last_update_submitted_qc>October 20, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Seoul National University Bundang Hospital</investigator_affiliation>
    <investigator_full_name>Jin-Woo Park</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>Central Nervous System Sensitization</keyword>
  <keyword>Neuropeptides</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pain, Postoperative</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03298711
org study id: B-1709-423-308
nct id: NCT03298711
lead sponsor: 
For patients who underwent two-stage replacement of both knee joints (one knee surgery - one
      week term- the other knee surgery), postoperative pain and analgesic usage with
      patient-controlled analgesia (PCA) increased at the second stage, which suggests that central
      sensitization occurs within a short period (one week) in patients who undergo total knee
      arthroplasty (TKA). Neurosteroids act on NMDA and AMPA receptors, GABAa receptors, and
      voltage-dependent Ca2+ or K+ channels of sensory neurons to increase invasive or neuropathic
      pain and, conversely, to exhibit analgesic and anticonvulsant effects. These actions mean
      that the neurosteroid acts as an endogenous regulator of pain control and central
      sensitization. The purpose of this study is to confirm that the
      hypothalamus-pituitary-adrenal (HPA) axis, which is the main body of endocrine neurosteroid,
      is associated with increased pain sensitivity after TKA. The concentrations of cortisol and
      dehydroepiandrosterone (DHEA) in the saliva of patients who undergo two-staged bilateral knee
      replacement surgery (one knee surgery - one week term- the other knee surgery) will be
      measured at each stage and analyzed for correlation between concentration-related changes of
      HPA and postoperative knee pain variations.
observational model: Case-Only
time perspective: Prospective
measure: The profiles of cortisol in the saliva
time frame: From the evening (9PM) before the operation day to the morning (60 minutes after the wake-up) of the operation day, for each stage of the operation.
description: The cortisol concentrations in the saliva, at the evening before the operation (21:00-22:00), just after wake-up in the morning of operation day, and 30 and 60 minutes after the wake-up.
measure: The profiles of DHEA in the saliva
time frame: From the evening (9PM) before the operation day to the morning (60 minutes after the wake-up) of the operation day, for each stage of the operation.
description: The DHEA concentrations in the saliva, at the evening before the operation (21:00-22:00), just after wake-up in the morning of operation day, and 30 and 60 minutes after the wake-up.
measure: Post operative knee pain
time frame: At 24h and 48h after the operation, for each stage of the operation.
description: At rest and at maximum knee flexion, visual analogue scale (VAS) score of knee pain;
measure: Analgesic usage (PCA)
time frame: At 24h and 48h after the operation, for each stage of the operation.
description: Fentanyl usage with PCA
measure: Analgesic usage (rescue)
time frame: At 24h and 48h after the operation, for each stage of the operation.
description: The number of rescue analgesics treatments
measure: Antiemetic usage
time frame: At 24h and 48h after the operation, for each stage of the operation.
description: The number of antiemetics treatments
measure: Diurnal slope
time frame: From the evening (9PM) before the operation day to the morning (60 minutes after the wake-up) of the operation day, for each stage of the operation.
description: slope for diurnal cortisol decline from the time point immediately upon awakening to nighttime
measure: CARi
time frame: At the morning of operation day, for each stage of the operation
description: net increases in cortisol levels within the first 30 min after awakening
measure: CARauc
time frame: At the morning of operation day, for each stage of the operation
description: cortisol secretion area under the curve with respect to ground from the time point immediately after waking to 60 min after waking
measure: Daucawk
time frame: At the morning of operation day, for each stage of the operation
description: DHEA secretion area under the curve with respect to ground from the time point immediately after waking to 60 min after waking
The Saliva in which the concentrations of cortisol and DHEA will be measured and analyzed for
      correlation between concentration-related changes and postoperative knee pain variations.
study pop: 
sampling method: Probability Sample
criteria: 
gender: Female
minimum age: N/A
maximum age: 70 Years
healthy volunteers: No
last name: Jin-Woo Park, MD
role: Principal Investigator
affiliation: Seoul National University Bundang Hospital
facility: 
country: Korea, Republic of
citation: Losina E, Katz JN. Total knee replacement: pursuit of the paramount result. Rheumatology (Oxford). 2012 Oct;51(10):1735-6. doi: 10.1093/rheumatology/kes199. Epub 2012 Jul 28. No abstract available.
PMID: 22843792
citation: Rosseland LA, Solheim N, Stubhaug A. Pain and disability 1 year after knee arthroscopic procedures. Acta Anaesthesiol Scand. 2008 Mar;52(3):332-7. doi: 10.1111/j.1399-6576.2007.01541.x.
PMID: 18269385
citation: Harden NR, Bruehl S, Stanos S, Brander V, Chung OY, Saltz S, Adams A, Stulberg DS. Prospective examination of pain-related and psychological predictors of CRPS-like phenomena following total knee arthroplasty: a preliminary study. Pain. 2003 Dec;106(3):393-400. doi: 10.1016/j.pain.2003.08.009.
PMID: 14659522
citation: Pruessner JC, Wolf OT, Hellhammer DH, Buske-Kirschbaum A, von Auer K, Jobst S, Kaspers F, Kirschbaum C. Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity. Life Sci. 1997;61(26):2539-49. doi: 10.1016/s0024-3205(97)01008-4.
PMID: 9416776
citation: Kim MH, Nahm FS, Kim TK, Chang MJ, Do SH. Comparison of postoperative pain in the first and second knee in staged bilateral total knee arthroplasty: clinical evidence of enhanced pain sensitivity after surgical injury. Pain. 2014 Jan;155(1):22-27. doi: 10.1016/j.pain.2013.08.027. Epub 2013 Aug 30.
PMID: 23994101
citation: Shin HJ, Kim EY, Na HS, Kim TK, Kim MH, Do SH. Magnesium sulphate attenuates acute postoperative pain and increased pain intensity after surgical injury in staged bilateral total knee arthroplasty: a randomized, double-blinded, placebo-controlled trial. Br J Anaesth. 2016 Oct;117(4):497-503. doi: 10.1093/bja/aew227. Epub 2016 Oct 17.
PMID: 28077538
citation: Jo KB, Lee YJ, Lee IG, Lee SC, Park JY, Ahn RS. Association of pain intensity, pain-related disability, and depression with hypothalamus-pituitary-adrenal axis function in female patients with chronic temporomandibular disorders. Psychoneuroendocrinology. 2016 Jul;69:106-15. doi: 10.1016/j.psyneuen.2016.03.017. Epub 2016 Mar 31.
PMID: 27082645
citation: Park JY, Ahn RS. Hypothalamic-pituitary-adrenal axis function in patients with complex regional pain syndrome type 1. Psychoneuroendocrinology. 2012 Sep;37(9):1557-68. doi: 10.1016/j.psyneuen.2012.02.016. Epub 2012 Mar 24.
PMID: 22445364
responsible party type: Principal Investigator
investigator affiliation: Seoul National University Bundang Hospital
investigator full name: Jin-Woo Park
investigator title: Assistant Professor
mesh term: Pain, Postoperative
sharing ipd: No