<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/NCT01702389</url>
  </required_header>
  <id_info>
    <org_study_id>2011/1639</org_study_id>
    <secondary_id>2011-002734-39</secondary_id>
    <secondary_id>11/14666</secondary_id>
    <nct_id>NCT01702389</nct_id>
  </id_info>
  <brief_title>Opioid-induced Hyperalgesia After Remifentanil Infusion</brief_title>
  <official_title>Can Opioid-induced Hyperalgesia be Prevented by Gradual Dose Reduction vs. Abrupt Withdrawal of Remifentanil?</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Oslo University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Oslo University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Remifentanil is a rapid-acting opioid which has been widely used in pain treatment during&#xD;
      surgery for the last 15 years 1. Remifentanil is rapidly eliminated (minutes) from the body&#xD;
      after end of infusion, and this makes it easily manageable compared to other opioids.&#xD;
      However, there are both experimental and clinical studies indicating that remifentanil, after&#xD;
      end of infusion, triggers increased pain sensation and increased opioid consumption&#xD;
      post-operatively. Increased post-operative opioid consumption should be avoided due to the&#xD;
      adverse effects of these drugs (nausea/vomiting, pruritus, dizziness, fatigue and reduced&#xD;
      respiratory rate). Thus, it's important to investigate relevant strategies to avoid the&#xD;
      increased pain sensation (opioid-induced hyperalgesia = hypersensitivity to pain stimuli)&#xD;
      after end of infusion of remifentanil after surgery. Several experimental and clinical trials&#xD;
      have been conducted in this field. Ketamine has been shown to block this effect, but its&#xD;
      adverse effect profile (i.a. hallucinations) makes it not suitable in normal clinical use. In&#xD;
      a study of healthy volunteers, it has been demonstrated that parecoxib (a COX-2 selective&#xD;
      NSAID) can prevent remifentanil-induced hyperalgesia. Our group has previously shown that a&#xD;
      relatively COX-1 selective NSAID (ketorolac) can prevent hyperalgesia in an experimental pain&#xD;
      model.&#xD;
&#xD;
      This is of interest since NSAIDs are frequently administered as premedication before surgery.&#xD;
      There are several disadvantages associated with the use of COX-2 inhibitors, e.g. the risk of&#xD;
      myocardial infarction after long-term use (&gt; 1 year), and potentially reduced bone healing&#xD;
      after orthopedic surgery. However, this has not been shown with short-term use (days/week).&#xD;
      The disadvantages associated with the use of e.g. ketorolac (a COX-1 inhibitor) are i.a.&#xD;
      increased bleeding tendency, which is unfavourable for the surgeon, and increased risk of&#xD;
      gastric ulcer. Therefore, it is of interest to investigate other ways of preventing&#xD;
      opioid-induced hyperalgesia. In a recent animal study it has been shown that gradual dose&#xD;
      reduction of remifentanil (vs. abrupt withdrawal of a relatively high remifentanil dose) can&#xD;
      prevent the development of hyperalgesia after end of infusion. In this study we will i.a.&#xD;
      investigate whether this is also the case in humans. In this new model, the study&#xD;
      participants will get remifentanil infusion with two different dose reduction regimes:&#xD;
      gradual reduction or abrupt withdrawal.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">December 2012</completion_date>
  <primary_completion_date type="Actual">December 2012</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Hyperalgesia measured by numeric rating scale for pain</measure>
    <time_frame>3 weeks</time_frame>
    <description>Two pain models will be used - a heat-pain and a cold-pain model. Testing will be done before, during and after remifentanil infusion. NRS (Numeric rating Scale) will be used for pain scoring.&#xD;
Heat model:&#xD;
A computer-controlled Medoc ATS Thermal stimulator (3 x 3 cm) is applied to the left volar forearm at pre-defined areas.&#xD;
Cold model:&#xD;
In the cold test the study participant should keep his right hand in circulating cold water (3 ̊C) in up to 90 seconds.&#xD;
The pain models will be applied during three separate trials using remifentanil infusion with abrupt withdrawal, remifentanil infusion with gradual withdrawal and saline infusion(placebo).</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Hyperalgesia</condition>
  <arm_group>
    <arm_group_label>Remifentanil</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The study has only one arm. Same group of volunteers will receive remifentanil infusion with abrupt withdrawal, remifentanil infusion with gradual dose reduction and saline infusion at three separate trials.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Remifentanil</intervention_name>
    <arm_group_label>Remifentanil</arm_group_label>
    <other_name>Ultiva</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male&#xD;
&#xD;
          -  Age 18-60&#xD;
&#xD;
          -  Body mass index 17-30&#xD;
&#xD;
          -  Healthy volunteers&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of medication; alternative medicine&#xD;
&#xD;
          -  Substance abuse&#xD;
&#xD;
          -  Allergies towards medication used in the study&#xD;
&#xD;
          -  Participation in other clinical studies the previous 6 months&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marlin Comelon, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Oslo UH</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Oslo University Hospital</name>
      <address>
        <city>Oslo</city>
        <zip>0424</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Norway</country>
  </location_countries>
  <reference>
    <citation>Servin FS. Remifentanil: an update. Curr Opin Anaesthesiol. 2003 Aug;16(4):367-72. doi: 10.1097/01.aco.0000084479.59960.3f.</citation>
    <PMID>17021484</PMID>
  </reference>
  <reference>
    <citation>Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain. 2003 Nov;106(1-2):49-57. doi: 10.1016/s0304-3959(03)00276-8.</citation>
    <PMID>14581110</PMID>
  </reference>
  <reference>
    <citation>Hood DD, Curry R, Eisenach JC. Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg. 2003 Sep;97(3):810-815. doi: 10.1213/01.ANE.0000078811.80093.88.</citation>
    <PMID>12933407</PMID>
  </reference>
  <reference>
    <citation>Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg. 1998 Jun;86(6):1307-11. doi: 10.1097/00000539-199806000-00033.</citation>
    <PMID>9620525</PMID>
  </reference>
  <reference>
    <citation>Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000 Aug;93(2):409-17. doi: 10.1097/00000542-200008000-00019.</citation>
    <PMID>10910490</PMID>
  </reference>
  <reference>
    <citation>Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, Chauvin M. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005 Jul;103(1):147-55. doi: 10.1097/00000542-200507000-00022.</citation>
    <PMID>15983467</PMID>
  </reference>
  <reference>
    <citation>Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schuttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology. 2003 Jul;99(1):152-9. doi: 10.1097/00000542-200307000-00025.</citation>
    <PMID>12826855</PMID>
  </reference>
  <reference>
    <citation>Troster A, Sittl R, Singler B, Schmelz M, Schuttler J, Koppert W. Modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by parecoxib in humans. Anesthesiology. 2006 Nov;105(5):1016-23. doi: 10.1097/00000542-200611000-00024.</citation>
    <PMID>17065897</PMID>
  </reference>
  <reference>
    <citation>Lenz H, Raeder J, Draegni T, Heyerdahl F, Schmelz M, Stubhaug A. Effects of COX inhibition on experimental pain and hyperalgesia during and after remifentanil infusion in humans. Pain. 2011 Jun;152(6):1289-1297. doi: 10.1016/j.pain.2011.02.007. Epub 2011 Mar 10.</citation>
    <PMID>21396775</PMID>
  </reference>
  <reference>
    <citation>Drdla R, Gassner M, Gingl E, Sandkuhler J. Induction of synaptic long-term potentiation after opioid withdrawal. Science. 2009 Jul 10;325(5937):207-10. doi: 10.1126/science.1171759.</citation>
    <PMID>19590003</PMID>
  </reference>
  <verification_date>October 2014</verification_date>
  <study_first_submitted>October 4, 2012</study_first_submitted>
  <study_first_submitted_qc>October 5, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 8, 2012</study_first_posted>
  <last_update_submitted>October 28, 2014</last_update_submitted>
  <last_update_submitted_qc>October 28, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 29, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Oslo University Hospital</investigator_affiliation>
    <investigator_full_name>Marlin Comelon</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>opioid induced hyperalgesia</keyword>
  <keyword>Pain</keyword>
  <keyword>Postoperative pain</keyword>
  <keyword>Hyperalgesia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hyperalgesia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Remifentanil</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01702389
org study id: 2011/1639
secondary id: 2011-002734-39
secondary id: 11/14666
nct id: NCT01702389
lead sponsor: 
has dmc: No
Remifentanil is a rapid-acting opioid which has been widely used in pain treatment during
      surgery for the last 15 years 1. Remifentanil is rapidly eliminated (minutes) from the body
      after end of infusion, and this makes it easily manageable compared to other opioids.
      However, there are both experimental and clinical studies indicating that remifentanil, after
      end of infusion, triggers increased pain sensation and increased opioid consumption
      post-operatively. Increased post-operative opioid consumption should be avoided due to the
      adverse effects of these drugs (nausea/vomiting, pruritus, dizziness, fatigue and reduced
      respiratory rate). Thus, it's important to investigate relevant strategies to avoid the
      increased pain sensation (opioid-induced hyperalgesia = hypersensitivity to pain stimuli)
      after end of infusion of remifentanil after surgery. Several experimental and clinical trials
      have been conducted in this field. Ketamine has been shown to block this effect, but its
      adverse effect profile (i.a. hallucinations) makes it not suitable in normal clinical use. In
      a study of healthy volunteers, it has been demonstrated that parecoxib (a COX-2 selective
      NSAID) can prevent remifentanil-induced hyperalgesia. Our group has previously shown that a
      relatively COX-1 selective NSAID (ketorolac) can prevent hyperalgesia in an experimental pain
      model.

      This is of interest since NSAIDs are frequently administered as premedication before surgery.
      There are several disadvantages associated with the use of COX-2 inhibitors, e.g. the risk of
      myocardial infarction after long-term use (> 1 year), and potentially reduced bone healing
      after orthopedic surgery. However, this has not been shown with short-term use (days/week).
      The disadvantages associated with the use of e.g. ketorolac (a COX-1 inhibitor) are i.a.
      increased bleeding tendency, which is unfavourable for the surgeon, and increased risk of
      gastric ulcer. Therefore, it is of interest to investigate other ways of preventing
      opioid-induced hyperalgesia. In a recent animal study it has been shown that gradual dose
      reduction of remifentanil (vs. abrupt withdrawal of a relatively high remifentanil dose) can
      prevent the development of hyperalgesia after end of infusion. In this study we will i.a.
      investigate whether this is also the case in humans. In this new model, the study
      participants will get remifentanil infusion with two different dose reduction regimes:
      gradual reduction or abrupt withdrawal.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Prevention
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Hyperalgesia measured by numeric rating scale for pain
time frame: 3 weeks
description: Two pain models will be used - a heat-pain and a cold-pain model. Testing will be done before, during and after remifentanil infusion. NRS (Numeric rating Scale) will be used for pain scoring.
Heat model:
A computer-controlled Medoc ATS Thermal stimulator (3 x 3 cm) is applied to the left volar forearm at pre-defined areas.
Cold model:
In the cold test the study participant should keep his right hand in circulating cold water (3 ̊C) in up to 90 seconds.
The pain models will be applied during three separate trials using remifentanil infusion with abrupt withdrawal, remifentanil infusion with gradual withdrawal and saline infusion(placebo).
arm group label: Remifentanil
arm group type: Experimental
description: The study has only one arm. Same group of volunteers will receive remifentanil infusion with abrupt withdrawal, remifentanil infusion with gradual dose reduction and saline infusion at three separate trials.
intervention type: Drug
intervention name: Remifentanil
arm group label: Remifentanil
other name: Ultiva
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Marlin Comelon, MD
role: Principal Investigator
affiliation: Oslo UH
facility: 
country: Norway
citation: Servin FS. Remifentanil: an update. Curr Opin Anaesthesiol. 2003 Aug;16(4):367-72. doi: 10.1097/01.aco.0000084479.59960.3f.
PMID: 17021484
citation: Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain. 2003 Nov;106(1-2):49-57. doi: 10.1016/s0304-3959(03)00276-8.
PMID: 14581110
citation: Hood DD, Curry R, Eisenach JC. Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg. 2003 Sep;97(3):810-815. doi: 10.1213/01.ANE.0000078811.80093.88.
PMID: 12933407
citation: Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg. 1998 Jun;86(6):1307-11. doi: 10.1097/00000539-199806000-00033.
PMID: 9620525
citation: Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000 Aug;93(2):409-17. doi: 10.1097/00000542-200008000-00019.
PMID: 10910490
citation: Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, Chauvin M. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005 Jul;103(1):147-55. doi: 10.1097/00000542-200507000-00022.
PMID: 15983467
citation: Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schuttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology. 2003 Jul;99(1):152-9. doi: 10.1097/00000542-200307000-00025.
PMID: 12826855
citation: Troster A, Sittl R, Singler B, Schmelz M, Schuttler J, Koppert W. Modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by parecoxib in humans. Anesthesiology. 2006 Nov;105(5):1016-23. doi: 10.1097/00000542-200611000-00024.
PMID: 17065897
citation: Lenz H, Raeder J, Draegni T, Heyerdahl F, Schmelz M, Stubhaug A. Effects of COX inhibition on experimental pain and hyperalgesia during and after remifentanil infusion in humans. Pain. 2011 Jun;152(6):1289-1297. doi: 10.1016/j.pain.2011.02.007. Epub 2011 Mar 10.
PMID: 21396775
citation: Drdla R, Gassner M, Gingl E, Sandkuhler J. Induction of synaptic long-term potentiation after opioid withdrawal. Science. 2009 Jul 10;325(5937):207-10. doi: 10.1126/science.1171759.
PMID: 19590003
responsible party type: Principal Investigator
investigator affiliation: Oslo University Hospital
investigator full name: Marlin Comelon
investigator title: Principal Investigator
mesh term: Hyperalgesia
mesh term: Remifentanil