<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/NCT02998177</url>
  </required_header>
  <id_info>
    <org_study_id>GMB-RP</org_study_id>
    <nct_id>NCT02998177</nct_id>
  </id_info>
  <brief_title>Characterization of Rebound Pain Following Peripheral Nerve Block and Its Association With Gut Microbiome Diversity</brief_title>
  <official_title>Characterization of Rebound Pain Following Peripheral Nerve Block and Its Association With Gut Microbiome Diversity</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cork University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cork University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objective of this study is to determine the association between gut microbiome diversity&#xD;
      and the characteristics of rebound pain at offset of peripheral nerve block in patients who&#xD;
      have undergone upper limb surgery. Other purposes of this study are to determine associations&#xD;
      between gut microbiome constitution and persistent post-surgical pain; and describing rebound&#xD;
      pain by quantifying its clinical, psychological and neurophysiological characteristics in&#xD;
      this patient cohort.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Based on an emerging understanding of the importance of the gut microbiome in the human and&#xD;
      animal responses to stress, it is clear that gut microbiota influence bidirectional signaling&#xD;
      between the central nervous system (CNS) and gut (microbiota-gut-brain axis). One element of&#xD;
      this influence is the role of gut microbiota in visceral hypersensitivity and pain. Important&#xD;
      clinical implications of this understanding have begun to emerge: for instance irritable&#xD;
      bowel syndrome (IBS) patient cohorts demonstrate distinct gut microbiome characteristics and,&#xD;
      in pre-clinical models, manipulation of the gut microbiome lessens visceral hypersensitivity.&#xD;
      To date, attempts to improve pain symptoms in IBS using probiotics have been modestly and&#xD;
      variably successful.&#xD;
&#xD;
      One research area which offers potential to the discovery of novel analgesic therapies is the&#xD;
      activation of endogenous opiate pain processing including augmentation of descending&#xD;
      inhibition. (Broadly, identification of new targets/alkaloid modification/ proteomics efforts&#xD;
      have been unsuccessful). Manipulation of microbiota-gut-brain axis by administering&#xD;
      probiotics offers one potential route for such activation. There are many of examples of such&#xD;
      manipulation altering animal behavior and physiology. In theory, opportunities for such&#xD;
      manipulation might exist during or close to early life stress or before noxious stimuli such&#xD;
      as elective surgery.&#xD;
&#xD;
      The relationship between the gut microbiome and somatic or neuropathic pain has not been&#xD;
      studied. Certain of the pathways and regulators of visceral pain and hypersensitivity are&#xD;
      also critical in somatic pain handling. These include peripheral sensitization of primary&#xD;
      sensory afferents, central sensitization in particular of spinal ascending neurons and&#xD;
      alteration of descending inhibitory pathways. These neuroplastic changes have been well&#xD;
      documented in the surgical setting in the examination of persistent post-surgical pain.&#xD;
&#xD;
      &quot;Rebound pain&quot; is a quantifiable difference in pain scores when the block is working, versus&#xD;
      the increase in acute pain that is encountered during the first few hours after the effects&#xD;
      of perineural single-injection or continuous infusion local anesthetics resolve. Rebound pain&#xD;
      may represent a manifestation of hypersensitivity and offer an accessible clinical model&#xD;
      suitable for examining the association between gut microbiome diversity and perioperative&#xD;
      neuroplastic changes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2016</start_date>
  <completion_date type="Actual">June 16, 2017</completion_date>
  <primary_completion_date type="Actual">June 16, 2017</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>Association between gut microbiome α diversity and the magnitude of rebound pain (Numerical Rating Scale)</measure>
    <time_frame>Perioperative period</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Association between gut microbiome α diversity and magnitude of postoperative pain (Numerical Rating Scale).</measure>
    <time_frame>Perioperative period</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association between gut microbiome α diversity and analgesic consumption (mg/24 hours).</measure>
    <time_frame>Perioperative period</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association between gut microbiome α diversity and salivary cortisol concentration (ng/ml).</measure>
    <time_frame>Perioperative period</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association between gut microbiome α diversity and Pain Perception Threshold (PPT, mAmp).</measure>
    <time_frame>Perioperative period</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association between gut microbiome constitution (α diversity) and incidence of persistent post-surgical pain.</measure>
    <time_frame>Up to 4 weeks postoperatively</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pearson's correlation coefficient for i. Maximum Numerical Rating Scale (NRS) score for rebound pain vs. ii. Pain Perception Threshold (PPT, mAmp) and Pain Tolerance Threshold (PTT, mAmp) based on Quantitative Sensory Testing.</measure>
    <time_frame>Up to 48 hours postoperatively</time_frame>
  </secondary_outcome>
  <enrollment type="Actual">20</enrollment>
  <condition>Pain, Postoperative</condition>
  <condition>Gastrointestinal Microbiome</condition>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Pre- and postoperative faecal samples and preoperative salivary samples are going to be&#xD;
      taken.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        ASA I-II patients scheduled to undergo upper limb surgery under brachial plexus block will&#xD;
        be recruited.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18-80 years&#xD;
&#xD;
          -  Patients undergoing hand surgery for Dupuytren's contracture correction or open&#xD;
             reduction and internal fixation of distal radius fracture under axillary brachial&#xD;
             plexus block&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindication of regional anaesthesia, patient is allergic to local anesthetics&#xD;
&#xD;
          -  Chronic pain syndrome&#xD;
&#xD;
          -  History of peripheral neuropathy&#xD;
&#xD;
          -  Preexisting nerve damage in the operated arm (sensory or motor deficit)&#xD;
&#xD;
          -  Axillary surgery in the past&#xD;
&#xD;
          -  Uncontrolled pain (Verbal Rating Score ≥5 out of 10 at rest despite adequate analgesic&#xD;
             measures)&#xD;
&#xD;
          -  Clinically significant cognitive impairment (Minimental state score &lt; 24)&#xD;
&#xD;
          -  Language barrier&#xD;
&#xD;
          -  Depression&#xD;
&#xD;
          -  Diabetes&#xD;
&#xD;
          -  Obesity (BMI&gt;35)&#xD;
&#xD;
          -  Antibiotic therapy in the preceding 30 days&#xD;
&#xD;
          -  Probiotics&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>George Shorten, Professor</last_name>
    <role>Study Chair</role>
    <affiliation>Professor of Anaesthesia and Intensive Care Medicine, Consultant Anaesthetist, University College Cork / Cork University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Anaesthesiology, South Infirmary-Victoria University Hospital</name>
      <address>
        <city>Cork</city>
        <state>Co. Cork</state>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Division of Anaesthesia and Intensive Care, Cork University Hospital</name>
      <address>
        <city>Cork</city>
        <state>Co. Cork</state>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Ireland</country>
  </location_countries>
  <reference>
    <citation>Enck P, Zimmermann K, Menke G, Klosterhalfen S. Randomized controlled treatment trial of irritable bowel syndrome with a probiotic E.-coli preparation (DSM17252) compared to placebo. Z Gastroenterol. 2009 Feb;47(2):209-14. doi: 10.1055/s-2008-1027702. Epub 2009 Feb 5.</citation>
    <PMID>19197823</PMID>
  </reference>
  <reference>
    <citation>Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH, Mazmanian SK. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013 Dec 19;155(7):1451-63. doi: 10.1016/j.cell.2013.11.024. Epub 2013 Dec 5.</citation>
    <PMID>24315484</PMID>
  </reference>
  <reference>
    <citation>Williams BA, Bottegal MT, Kentor ML, Irrgang JJ, Williams JP. Rebound pain scores as a function of femoral nerve block duration after anterior cruciate ligament reconstruction: retrospective analysis of a prospective, randomized clinical trial. Reg Anesth Pain Med. 2007 May-Jun;32(3):186-92. doi: 10.1016/j.rapm.2006.10.011.</citation>
    <PMID>17543812</PMID>
  </reference>
  <reference>
    <citation>Williams BA. Forecast for perineural analgesia procedures for ambulatory surgery of the knee, foot, and ankle: applying patient-centered paradigm shifts. Int Anesthesiol Clin. 2012 Winter;50(1):126-42. doi: 10.1097/AIA.0b013e31821a00d0.</citation>
    <PMID>22227428</PMID>
  </reference>
  <reference>
    <citation>Clarke SF, Murphy EF, O'Sullivan O, Lucey AJ, Humphreys M, Hogan A, Hayes P, O'Reilly M, Jeffery IB, Wood-Martin R, Kerins DM, Quigley E, Ross RP, O'Toole PW, Molloy MG, Falvey E, Shanahan F, Cotter PD. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014 Dec;63(12):1913-20. doi: 10.1136/gutjnl-2013-306541. Epub 2014 Jun 9.</citation>
    <PMID>25021423</PMID>
  </reference>
  <reference>
    <citation>Lapthorne S, Pereira-Fantini PM, Fouhy F, Wilson G, Thomas SL, Dellios NL, Scurr M, O'Sullivan O, Ross RP, Stanton C, Fitzgerald GF, Cotter PD, Bines JE. Gut microbial diversity is reduced and is associated with colonic inflammation in a piglet model of short bowel syndrome. Gut Microbes. 2013 May-Jun;4(3):212-21. doi: 10.4161/gmic.24372. Epub 2013 Apr 2.</citation>
    <PMID>23549027</PMID>
  </reference>
  <reference>
    <citation>O'Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EM, Cryan JF, Dinan TG. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry. 2009 Feb 1;65(3):263-7. doi: 10.1016/j.biopsych.2008.06.026. Epub 2008 Aug 23.</citation>
    <PMID>18723164</PMID>
  </reference>
  <reference>
    <citation>DuPont AW, DuPont HL. The intestinal microbiota and chronic disorders of the gut. Nat Rev Gastroenterol Hepatol. 2011 Aug 16;8(9):523-31. doi: 10.1038/nrgastro.2011.133.</citation>
    <PMID>21844910</PMID>
  </reference>
  <reference>
    <citation>Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain. 1975 Sep;1(3):277-299. doi: 10.1016/0304-3959(75)90044-5.</citation>
    <PMID>1235985</PMID>
  </reference>
  <reference>
    <citation>Melzack R. The McGill pain questionnaire: from description to measurement. Anesthesiology. 2005 Jul;103(1):199-202. doi: 10.1097/00000542-200507000-00028.</citation>
    <PMID>15983473</PMID>
  </reference>
  <reference>
    <citation>Stalder T, Kirschbaum C, Kudielka BM, Adam EK, Pruessner JC, Wust S, Dockray S, Smyth N, Evans P, Hellhammer DH, Miller R, Wetherell MA, Lupien SJ, Clow A. Assessment of the cortisol awakening response: Expert consensus guidelines. Psychoneuroendocrinology. 2016 Jan;63:414-32. doi: 10.1016/j.psyneuen.2015.10.010. Epub 2015 Oct 20.</citation>
    <PMID>26563991</PMID>
  </reference>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>November 28, 2016</study_first_submitted>
  <study_first_submitted_qc>December 15, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 20, 2016</study_first_posted>
  <last_update_submitted>August 19, 2017</last_update_submitted>
  <last_update_submitted_qc>August 19, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 22, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cork University Hospital</investigator_affiliation>
    <investigator_full_name>Dr. David Brenner</investigator_full_name>
    <investigator_title>Peripheral Nerve Block Fellow</investigator_title>
  </responsible_party>
  <keyword>Postoperative pain</keyword>
  <keyword>Rebound pain</keyword>
  <keyword>Gut microbiome</keyword>
  <keyword>Gut microbiota</keyword>
  <keyword>Peripheral nerve block</keyword>
  <keyword>Axillary brachial plexus block</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/NCT02998177
org study id: GMB-RP
nct id: NCT02998177
lead sponsor: 
has dmc: No
The objective of this study is to determine the association between gut microbiome diversity
      and the characteristics of rebound pain at offset of peripheral nerve block in patients who
      have undergone upper limb surgery. Other purposes of this study are to determine associations
      between gut microbiome constitution and persistent post-surgical pain; and describing rebound
      pain by quantifying its clinical, psychological and neurophysiological characteristics in
      this patient cohort.
Based on an emerging understanding of the importance of the gut microbiome in the human and
      animal responses to stress, it is clear that gut microbiota influence bidirectional signaling
      between the central nervous system (CNS) and gut (microbiota-gut-brain axis). One element of
      this influence is the role of gut microbiota in visceral hypersensitivity and pain. Important
      clinical implications of this understanding have begun to emerge: for instance irritable
      bowel syndrome (IBS) patient cohorts demonstrate distinct gut microbiome characteristics and,
      in pre-clinical models, manipulation of the gut microbiome lessens visceral hypersensitivity.
      To date, attempts to improve pain symptoms in IBS using probiotics have been modestly and
      variably successful.

      One research area which offers potential to the discovery of novel analgesic therapies is the
      activation of endogenous opiate pain processing including augmentation of descending
      inhibition. (Broadly, identification of new targets/alkaloid modification/ proteomics efforts
      have been unsuccessful). Manipulation of microbiota-gut-brain axis by administering
      probiotics offers one potential route for such activation. There are many of examples of such
      manipulation altering animal behavior and physiology. In theory, opportunities for such
      manipulation might exist during or close to early life stress or before noxious stimuli such
      as elective surgery.

      The relationship between the gut microbiome and somatic or neuropathic pain has not been
      studied. Certain of the pathways and regulators of visceral pain and hypersensitivity are
      also critical in somatic pain handling. These include peripheral sensitization of primary
      sensory afferents, central sensitization in particular of spinal ascending neurons and
      alteration of descending inhibitory pathways. These neuroplastic changes have been well
      documented in the surgical setting in the examination of persistent post-surgical pain.

      "Rebound pain" is a quantifiable difference in pain scores when the block is working, versus
      the increase in acute pain that is encountered during the first few hours after the effects
      of perineural single-injection or continuous infusion local anesthetics resolve. Rebound pain
      may represent a manifestation of hypersensitivity and offer an accessible clinical model
      suitable for examining the association between gut microbiome diversity and perioperative
      neuroplastic changes.
observational model: Case-Only
time perspective: Prospective
measure: Association between gut microbiome α diversity and the magnitude of rebound pain (Numerical Rating Scale)
time frame: Perioperative period
measure: Association between gut microbiome α diversity and magnitude of postoperative pain (Numerical Rating Scale).
time frame: Perioperative period
measure: Association between gut microbiome α diversity and analgesic consumption (mg/24 hours).
time frame: Perioperative period
measure: Association between gut microbiome α diversity and salivary cortisol concentration (ng/ml).
time frame: Perioperative period
measure: Association between gut microbiome α diversity and Pain Perception Threshold (PPT, mAmp).
time frame: Perioperative period
measure: Association between gut microbiome constitution (α diversity) and incidence of persistent post-surgical pain.
time frame: Up to 4 weeks postoperatively
measure: Pearson's correlation coefficient for i. Maximum Numerical Rating Scale (NRS) score for rebound pain vs. ii. Pain Perception Threshold (PPT, mAmp) and Pain Tolerance Threshold (PTT, mAmp) based on Quantitative Sensory Testing.
time frame: Up to 48 hours postoperatively
Pre- and postoperative faecal samples and preoperative salivary samples are going to be
      taken.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: George Shorten, Professor
role: Study Chair
affiliation: Professor of Anaesthesia and Intensive Care Medicine, Consultant Anaesthetist, University College Cork / Cork University Hospital
facility: 
facility: 
country: Ireland
citation: Enck P, Zimmermann K, Menke G, Klosterhalfen S. Randomized controlled treatment trial of irritable bowel syndrome with a probiotic E.-coli preparation (DSM17252) compared to placebo. Z Gastroenterol. 2009 Feb;47(2):209-14. doi: 10.1055/s-2008-1027702. Epub 2009 Feb 5.
PMID: 19197823
citation: Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH, Mazmanian SK. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013 Dec 19;155(7):1451-63. doi: 10.1016/j.cell.2013.11.024. Epub 2013 Dec 5.
PMID: 24315484
citation: Williams BA, Bottegal MT, Kentor ML, Irrgang JJ, Williams JP. Rebound pain scores as a function of femoral nerve block duration after anterior cruciate ligament reconstruction: retrospective analysis of a prospective, randomized clinical trial. Reg Anesth Pain Med. 2007 May-Jun;32(3):186-92. doi: 10.1016/j.rapm.2006.10.011.
PMID: 17543812
citation: Williams BA. Forecast for perineural analgesia procedures for ambulatory surgery of the knee, foot, and ankle: applying patient-centered paradigm shifts. Int Anesthesiol Clin. 2012 Winter;50(1):126-42. doi: 10.1097/AIA.0b013e31821a00d0.
PMID: 22227428
citation: Clarke SF, Murphy EF, O'Sullivan O, Lucey AJ, Humphreys M, Hogan A, Hayes P, O'Reilly M, Jeffery IB, Wood-Martin R, Kerins DM, Quigley E, Ross RP, O'Toole PW, Molloy MG, Falvey E, Shanahan F, Cotter PD. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014 Dec;63(12):1913-20. doi: 10.1136/gutjnl-2013-306541. Epub 2014 Jun 9.
PMID: 25021423
citation: Lapthorne S, Pereira-Fantini PM, Fouhy F, Wilson G, Thomas SL, Dellios NL, Scurr M, O'Sullivan O, Ross RP, Stanton C, Fitzgerald GF, Cotter PD, Bines JE. Gut microbial diversity is reduced and is associated with colonic inflammation in a piglet model of short bowel syndrome. Gut Microbes. 2013 May-Jun;4(3):212-21. doi: 10.4161/gmic.24372. Epub 2013 Apr 2.
PMID: 23549027
citation: O'Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EM, Cryan JF, Dinan TG. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry. 2009 Feb 1;65(3):263-7. doi: 10.1016/j.biopsych.2008.06.026. Epub 2008 Aug 23.
PMID: 18723164
citation: DuPont AW, DuPont HL. The intestinal microbiota and chronic disorders of the gut. Nat Rev Gastroenterol Hepatol. 2011 Aug 16;8(9):523-31. doi: 10.1038/nrgastro.2011.133.
PMID: 21844910
citation: Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain. 1975 Sep;1(3):277-299. doi: 10.1016/0304-3959(75)90044-5.
PMID: 1235985
citation: Melzack R. The McGill pain questionnaire: from description to measurement. Anesthesiology. 2005 Jul;103(1):199-202. doi: 10.1097/00000542-200507000-00028.
PMID: 15983473
citation: Stalder T, Kirschbaum C, Kudielka BM, Adam EK, Pruessner JC, Wust S, Dockray S, Smyth N, Evans P, Hellhammer DH, Miller R, Wetherell MA, Lupien SJ, Clow A. Assessment of the cortisol awakening response: Expert consensus guidelines. Psychoneuroendocrinology. 2016 Jan;63:414-32. doi: 10.1016/j.psyneuen.2015.10.010. Epub 2015 Oct 20.
PMID: 26563991
responsible party type: Principal Investigator
investigator affiliation: Cork University Hospital
investigator full name: Dr. David Brenner
investigator title: Peripheral Nerve Block Fellow
mesh term: Pain, Postoperative
sharing ipd: No