<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/NCT02976337</url>
  </required_header>
  <id_info>
    <org_study_id>H-15018869-TME</org_study_id>
    <nct_id>NCT02976337</nct_id>
  </id_info>
  <brief_title>Effect of High-dose Naloxone Following Third Molar Extraction</brief_title>
  <acronym>TME</acronym>
  <official_title>Effect of High-dose Target-controlled Naloxone Infusion on Pain and Hyperal-gesia in Patients Following Recovery From Impacted Mandibular Third Molar Extraction. A Randomized, Placebo-controlled, Double-blind Crossover Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>mads u werner</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Kentucky</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Copenhagen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Recent studies have focused on the role of endogenous opioids on central sensitization.&#xD;
      Central sensitization is known to be impaired or altered in chronic pain conditions, as&#xD;
      fibromyalgia or chronic tension headache.&#xD;
&#xD;
      Animal studies have shown reinstatement of mechanical hypersensitivity following naloxone&#xD;
      administration after resolution of an injury. This suggests latent sensitization. In the&#xD;
      present study, the investigators hypothesize that a high-dose target-controlled naloxone&#xD;
      infusion (total dose: 3.25 mg/kg) can reinstate pain and hyperalgesia 6-8 weeks after a&#xD;
      unilateral primary open groin hernia repair procedure. The investigators aim to show that&#xD;
      latent sensitization is present in humans and is modulated by endogenous opioids.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Naloxone is a combined mu-opioid-receptor (MOR) inverse agonist and antagonist drug, which&#xD;
      dose-dependently demonstrates hypoalgesic and hyperalgesic properties. Systemically&#xD;
      administrated naloxone (3.0-10.0 mg/kg) and naltrexone (0.3-3.0 mg/kg) have been used in&#xD;
      rodents to study the role of endogenous opioids on central processing of pain. It has been&#xD;
      hypothesized that the endogenous opioid modulation of pain is impaired or altered in chronic&#xD;
      pain conditions. Administration of naloxone and naltrexone following resolution of an&#xD;
      inflammatory injury, have demonstrated a reinstatement of hypersensitivity to noxious&#xD;
      stimuli, indicating a demasking of latent sensitization. It has thus been speculated that the&#xD;
      endogenous opioid system may play an important role in the transition of acute to chronic&#xD;
      pain in humans.&#xD;
&#xD;
      In an early human study using an electrical pain model, naloxone (21 microg/kg) increased the&#xD;
      established area of secondary hyperalgesia (a measure of central sensitization).&#xD;
&#xD;
      In a previous translational placebo-controlled, double-blind, randomized, cross-over study in&#xD;
      healthy humans, the investigators were unable to show naloxone-induced reinstatement of&#xD;
      secondary hyperalgesia after resolution of a first-degree burn-injury (BI; H-2-2012-036). The&#xD;
      investigators hypothesized, that the negative results were attributable to the low dose of&#xD;
      naloxone (21 microg/kg) or perhaps insufficient tissue injury to generate latent&#xD;
      sensitization.&#xD;
&#xD;
      The investigators therefore in a sequel study administered a higher dose of naloxone (2&#xD;
      mg/kg) 7 days after induction of a BI. The investigators demonstrated in 4 out of 12 subjects&#xD;
      reinstatement of secondary hyperalgesia. The magnitude of reinstatement was more pronounced&#xD;
      in high-sensitizers (subjects developing large secondary hyperalgesia areas immediately after&#xD;
      the BI) The aims of the present clinical study in patients are first, to replicate our&#xD;
      previous findings of naloxone-induced (3.25 mg/kg) unmasking of latent sensitization&#xD;
      utilizing the impacted mandibular third molar extraction (TME) model with a more pronounced&#xD;
      tissue injury than the BI-model. The endpoints are reinstatement of pain and hyperalgesia in&#xD;
      the resolution-phase, 4 - 5 weeks after TME-surgery. Second, the study examines a potential&#xD;
      dose-response relationship between three stable naloxone concentrations acquired by target&#xD;
      controlled infusion (TCI).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 12, 2017</start_date>
  <completion_date type="Anticipated">August 28, 2023</completion_date>
  <primary_completion_date type="Anticipated">February 28, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in the composite measure of pain (numerical rating scale (NRS); 0 = no pain; 10 = worst perceivable pain)</measure>
    <time_frame>1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.</time_frame>
    <description>during rest + masticatory pain + pain during external algometry (100 kPa) at the injury site</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Secondary hyperalgesia/allodynia area at mandibular skin sites directly overlying surgical and contralateral side</measure>
    <time_frame>1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.</time_frame>
    <description>Hyperalgesia/allodynia assessments with nylon monofilament (nominal value 4.93 [bending force: mean +/- SD = 69 +/- 14 mN]</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Online Reaction Time</measure>
    <time_frame>1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.</time_frame>
    <description>measured using http://getyourwebsiteherecom/jswb/rttest01.htm. This computer-application shows a red-green traffic light. Participants are instructed to press the button when the light changes from red to green. Three measurements are used and the median value is used as a representative estimate of reaction time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital Anxiety and Depression Scale (HADS)</measure>
    <time_frame>1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. Only pre-infusion</time_frame>
    <description>HADS is used to assess anxiety and signs of depression. Based on 14 questions about the subject's status in the previous week, HADS measures agitation/anxiety and depression via two subscales (each containing seven questions). Participants have to answer each question on a scale of 0 to 3. The two subscales are summed separately. The maximum score of each subscale is 21 points and a score of 11 or more points suggests that the participant might be suffering from anxiety or depression. In case of score &gt; 11 points in the depression subscale of the HADS, a physician will decide if there are clinical signs of depression. If there are signs of depression, this diagnosis will be told to the participant. The participant will be informed that the diagnosis of depression is based on clinical assessments - the HADS scale can be included in the diagnostic procedure. If it is the participants wish, he should visit his general practitioner for diagnosis and eventual treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain Catastrophizing Scale (PCS)</measure>
    <time_frame>1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. Only pre-infusion</time_frame>
    <description>PCS consists of 13 questions divided into three sections: rumination, exaggeration and helplessness. The questions are answered in accordance to a scale of 0 to 4. There is evidence of catastrophizing thoughts at a total score &gt; 30 points.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Opiate Withdrawal Scale (COWS)</measure>
    <time_frame>1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.</time_frame>
    <description>The Clinical Opiate Withdrawal Scale (COWS) is an examiner-based scale evaluating signs of opioid-withdrawal. Grading of symptoms, i.e. heart rate changes, sweating, restlessness, pupil size, bone or joint aches, running nose or tearing, nausea, vomiting, diarrhea, tremor, yawning, anxiety or irritability and &quot;goose-flesh&quot;, are made in 11 categories. COWS-scores are divided into: 5-12 = mild; 13-24 = moderate; 25-36 = moderately severe ;&gt; 36 = severe withdrawal reactions.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">14</enrollment>
  <condition>Healthy Subjects</condition>
  <condition>Hyperalgesia</condition>
  <condition>Inflammations, Endodontic</condition>
  <condition>Pain, Acute</condition>
  <condition>Sensitization, Central</condition>
  <arm_group>
    <arm_group_label>High-dose naloxone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Naloxone 4 mg/ml i.v. infusion, total 3.25 mg/kg, target controlled infusion with three infusion rates (0.25 mg/kg; 0.75 mg/kg; 2.25 mg/kg) each of 25 min duration)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Normal saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>0.9% physiological saline, i.v. infusion, total 0.81 ml/kg, target controlled infusion with three infusion rates (0.06 ml/kg; 0.19 ml/kg; 0.56 ml/kg) each of 25 min duration.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Naloxone</intervention_name>
    <description>active drug infusion</description>
    <arm_group_label>High-dose naloxone</arm_group_label>
    <other_name>Naloxon &quot;B. Braun&quot;</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Normal Saline</intervention_name>
    <description>placebo comparator</description>
    <arm_group_label>Normal saline</arm_group_label>
    <other_name>Physiologic Saline</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        INCLUSION CRITERIA:&#xD;
&#xD;
          -  Healthy male&#xD;
&#xD;
          -  Age, minimum 18 yrs and maximum 65 yrs&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
          -  Participants submitted to unilateral, primary, impacted, uncomplicated mandibular&#xD;
             third molar extraction 4 weeks (+ 3 days) prior to examination Day 1.&#xD;
&#xD;
          -  Standardized surgical procedure.&#xD;
&#xD;
          -  Urin-sample without traces of opioids (morphine, methadon, buprenorphine, codeine,&#xD;
             tramadol, ketobemidone, oxycodone, hydromorphone, dextromethorphan)&#xD;
&#xD;
          -  ASA I-II&#xD;
&#xD;
          -  Body mass index (BMI): 18 &lt; BMI &lt; 30 kg/m2&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Participants, who do not speak or understand Danish&#xD;
&#xD;
          -  Participants, who cannot cooperate with the investigation&#xD;
&#xD;
          -  Participants, who have had previous surgery in the mandibular region&#xD;
&#xD;
          -  Participants with pain at rest &gt; 3 (NRS [0: no pain; 10: worst perceivable pain])&#xD;
&#xD;
          -  Activity-related pain in the surgical field &gt; 5 (NRS)&#xD;
&#xD;
          -  Allergic reaction against morphine or other opioids (including naloxone),&#xD;
&#xD;
          -  Abuse of alcohol or drugs - according to investigator's evaluation&#xD;
&#xD;
          -  Use of psychotropic drugs (exception of SSRI)&#xD;
&#xD;
          -  Neurologic or psychiatric disease&#xD;
&#xD;
          -  Chronic pain condition&#xD;
&#xD;
          -  Regular use of analgesic drugs&#xD;
&#xD;
          -  Skin lesions or tattoos in the assessment areas&#xD;
&#xD;
          -  Nerve lesions in the assessment sites (e.g., after trauma, dental surgery)&#xD;
&#xD;
          -  Use of prescription drugs one week before the trial&#xD;
&#xD;
          -  Use of over-the-counter (OTC) drugs 48 hours before the trial&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mads U Werner, MD, DMSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Neuroscience Center, Copenhagen University Hospital, Denmark</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Bradley K Taylor, M.Sc., Ph.D.</last_name>
    <role>Study Chair</role>
    <affiliation>Department of Physiology, University of Kentucky Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mads U Werner, MD, DMSc.</last_name>
    <phone>28257703</phone>
    <phone_ext>+45</phone_ext>
    <email>mads.u.werner@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Neuroscience Center, Copenhagen University Hospital</name>
      <address>
        <city>Copenhagen</city>
        <zip>2200</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mads U Werner, MD, DMSc.</last_name>
      <phone>2825 7703</phone>
      <phone_ext>+45</phone_ext>
      <email>mads.u.werner@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Elisabeth K Jensen, MS</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Anders D Springborg, MB</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <reference>
    <citation>Brennum J, Kaiser F, Dahl JB. Effect of naloxone on primary and secondary hyperalgesia induced by the human burn injury model. Acta Anaesthesiol Scand. 2001 Sep;45(8):954-60. doi: 10.1034/j.1399-6576.2001.450806.x.</citation>
    <PMID>11576045</PMID>
  </reference>
  <reference>
    <citation>Pielsticker A, Haag G, Zaudig M, Lautenbacher S. Impairment of pain inhibition in chronic tension-type headache. Pain. 2005 Nov;118(1-2):215-23. doi: 10.1016/j.pain.2005.08.019. Epub 2005 Oct 3.</citation>
    <PMID>16202520</PMID>
  </reference>
  <reference>
    <citation>Price DD, Staud R, Robinson ME, Mauderli AP, Cannon R, Vierck CJ. Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain. 2002 Sep;99(1-2):49-59. doi: 10.1016/s0304-3959(02)00053-2.</citation>
    <PMID>12237183</PMID>
  </reference>
  <reference>
    <citation>van Wilgen CP, Keizer D. The sensitization model to explain how chronic pain exists without tissue damage. Pain Manag Nurs. 2012 Mar;13(1):60-5. doi: 10.1016/j.pmn.2010.03.001. Epub 2010 Jul 22.</citation>
    <PMID>22341140</PMID>
  </reference>
  <results_reference>
    <citation>Koppert W, Filitz J, Troster A, Ihmsen H, Angst M, Flor H, Schuttler J, Schmelz M. Activation of naloxone-sensitive and -insensitive inhibitory systems in a human pain model. J Pain. 2005 Nov;6(11):757-64. doi: 10.1016/j.jpain.2005.07.002.</citation>
    <PMID>16275600</PMID>
  </results_reference>
  <results_reference>
    <citation>Campillo A, Cabanero D, Romero A, Garcia-Nogales P, Puig MM. Delayed postoperative latent pain sensitization revealed by the systemic administration of opioid antagonists in mice. Eur J Pharmacol. 2011 Apr 25;657(1-3):89-96. doi: 10.1016/j.ejphar.2011.01.059. Epub 2011 Feb 4.</citation>
    <PMID>21300053</PMID>
  </results_reference>
  <results_reference>
    <citation>Taylor BK, Corder G. Endogenous analgesia, dependence, and latent pain sensitization. Curr Top Behav Neurosci. 2014;20:283-325. doi: 10.1007/7854_2014_351.</citation>
    <PMID>25227929</PMID>
  </results_reference>
  <results_reference>
    <citation>Corder G, Doolen S, Donahue RR, Winter MK, Jutras BL, He Y, Hu X, Wieskopf JS, Mogil JS, Storm DR, Wang ZJ, McCarson KE, Taylor BK. Constitutive mu-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science. 2013 Sep 20;341(6152):1394-9. doi: 10.1126/science.1239403. Erratum In: Science. 2013 Nov 8;342(6159):693.</citation>
    <PMID>24052307</PMID>
  </results_reference>
  <results_reference>
    <citation>Pereira MP, Werner MU, Ringsted TK, Rowbotham MC, Taylor BK, Dahl JB. Does naloxone reinstate secondary hyperalgesia in humans after resolution of a burn injury? A placebo-controlled, double-blind, randomized, cross-over study. PLoS One. 2013 May 31;8(5):e64608. doi: 10.1371/journal.pone.0064608. Print 2013.</citation>
    <PMID>23741350</PMID>
  </results_reference>
  <results_reference>
    <citation>Pereira MP, Donahue RR, Dahl JB, Werner M, Taylor BK, Werner MU. Endogenous Opioid-Masked Latent Pain Sensitization: Studies from Mouse to Human. PLoS One. 2015 Aug 25;10(8):e0134441. doi: 10.1371/journal.pone.0134441. eCollection 2015.</citation>
    <PMID>26305798</PMID>
  </results_reference>
  <results_reference>
    <citation>Edwards RR, Ness TJ, Fillingim RB. Endogenous opioids, blood pressure, and diffuse noxious inhibitory controls: a preliminary study. Percept Mot Skills. 2004 Oct;99(2):679-87. doi: 10.2466/pms.99.2.679-687.</citation>
    <PMID>15560360</PMID>
  </results_reference>
  <results_reference>
    <citation>Singla NK, Desjardins PJ, Chang PD. A comparison of the clinical and experimental characteristics of four acute surgical pain models: dental extraction, bunionectomy, joint replacement, and soft tissue surgery. Pain. 2014 Mar;155(3):441-456. doi: 10.1016/j.pain.2013.09.002. Epub 2013 Sep 6.</citation>
    <PMID>24012952</PMID>
  </results_reference>
  <results_reference>
    <citation>Glass PS, Jhaveri RM, Smith LR. Comparison of potency and duration of action of nalmefene and naloxone. Anesth Analg. 1994 Mar;78(3):536-41. doi: 10.1213/00000539-199403000-00021.</citation>
    <PMID>8109774</PMID>
  </results_reference>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>November 21, 2016</study_first_submitted>
  <study_first_submitted_qc>November 23, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 29, 2016</study_first_posted>
  <last_update_submitted>February 11, 2022</last_update_submitted>
  <last_update_submitted_qc>February 11, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 14, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Copenhagen</investigator_affiliation>
    <investigator_full_name>mads u werner</investigator_full_name>
    <investigator_title>Associate professor</investigator_title>
  </responsible_party>
  <keyword>Central sensitization</keyword>
  <keyword>Endogenous opioids</keyword>
  <keyword>Humans</keyword>
  <keyword>Latent sensitization</keyword>
  <keyword>Mandibular third molar extraction</keyword>
  <keyword>Naloxone</keyword>
  <keyword>Pain</keyword>
  <keyword>Pressure algometry</keyword>
  <keyword>Randomized controlled trial</keyword>
  <keyword>Secondary hyperalgesia</keyword>
  <keyword>Target controlled infusion</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulpitis</mesh_term>
    <mesh_term>Hyperalgesia</mesh_term>
    <mesh_term>Inflammation</mesh_term>
    <mesh_term>Acute Pain</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Naloxone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Data will be made available as a supplementum to the published scientific article. Anticipated available in Spring 2018.</ipd_description>
  </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/NCT02976337
org study id: H-15018869-TME
nct id: NCT02976337
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Recent studies have focused on the role of endogenous opioids on central sensitization.
      Central sensitization is known to be impaired or altered in chronic pain conditions, as
      fibromyalgia or chronic tension headache.

      Animal studies have shown reinstatement of mechanical hypersensitivity following naloxone
      administration after resolution of an injury. This suggests latent sensitization. In the
      present study, the investigators hypothesize that a high-dose target-controlled naloxone
      infusion (total dose: 3.25 mg/kg) can reinstate pain and hyperalgesia 6-8 weeks after a
      unilateral primary open groin hernia repair procedure. The investigators aim to show that
      latent sensitization is present in humans and is modulated by endogenous opioids.
Naloxone is a combined mu-opioid-receptor (MOR) inverse agonist and antagonist drug, which
      dose-dependently demonstrates hypoalgesic and hyperalgesic properties. Systemically
      administrated naloxone (3.0-10.0 mg/kg) and naltrexone (0.3-3.0 mg/kg) have been used in
      rodents to study the role of endogenous opioids on central processing of pain. It has been
      hypothesized that the endogenous opioid modulation of pain is impaired or altered in chronic
      pain conditions. Administration of naloxone and naltrexone following resolution of an
      inflammatory injury, have demonstrated a reinstatement of hypersensitivity to noxious
      stimuli, indicating a demasking of latent sensitization. It has thus been speculated that the
      endogenous opioid system may play an important role in the transition of acute to chronic
      pain in humans.

      In an early human study using an electrical pain model, naloxone (21 microg/kg) increased the
      established area of secondary hyperalgesia (a measure of central sensitization).

      In a previous translational placebo-controlled, double-blind, randomized, cross-over study in
      healthy humans, the investigators were unable to show naloxone-induced reinstatement of
      secondary hyperalgesia after resolution of a first-degree burn-injury (BI; H-2-2012-036). The
      investigators hypothesized, that the negative results were attributable to the low dose of
      naloxone (21 microg/kg) or perhaps insufficient tissue injury to generate latent
      sensitization.

      The investigators therefore in a sequel study administered a higher dose of naloxone (2
      mg/kg) 7 days after induction of a BI. The investigators demonstrated in 4 out of 12 subjects
      reinstatement of secondary hyperalgesia. The magnitude of reinstatement was more pronounced
      in high-sensitizers (subjects developing large secondary hyperalgesia areas immediately after
      the BI) The aims of the present clinical study in patients are first, to replicate our
      previous findings of naloxone-induced (3.25 mg/kg) unmasking of latent sensitization
      utilizing the impacted mandibular third molar extraction (TME) model with a more pronounced
      tissue injury than the BI-model. The endpoints are reinstatement of pain and hyperalgesia in
      the resolution-phase, 4 - 5 weeks after TME-surgery. Second, the study examines a potential
      dose-response relationship between three stable naloxone concentrations acquired by target
      controlled infusion (TCI).
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in the composite measure of pain (numerical rating scale (NRS); 0 = no pain; 10 = worst perceivable pain)
time frame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.
description: during rest + masticatory pain + pain during external algometry (100 kPa) at the injury site
measure: Secondary hyperalgesia/allodynia area at mandibular skin sites directly overlying surgical and contralateral side
time frame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.
description: Hyperalgesia/allodynia assessments with nylon monofilament (nominal value 4.93 [bending force: mean +/- SD = 69 +/- 14 mN]
measure: Online Reaction Time
time frame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.
description: measured using http://getyourwebsiteherecom/jswb/rttest01.htm. This computer-application shows a red-green traffic light. Participants are instructed to press the button when the light changes from red to green. Three measurements are used and the median value is used as a representative estimate of reaction time.
measure: Hospital Anxiety and Depression Scale (HADS)
time frame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. Only pre-infusion
description: HADS is used to assess anxiety and signs of depression. Based on 14 questions about the subject's status in the previous week, HADS measures agitation/anxiety and depression via two subscales (each containing seven questions). Participants have to answer each question on a scale of 0 to 3. The two subscales are summed separately. The maximum score of each subscale is 21 points and a score of 11 or more points suggests that the participant might be suffering from anxiety or depression. In case of score > 11 points in the depression subscale of the HADS, a physician will decide if there are clinical signs of depression. If there are signs of depression, this diagnosis will be told to the participant. The participant will be informed that the diagnosis of depression is based on clinical assessments - the HADS scale can be included in the diagnostic procedure. If it is the participants wish, he should visit his general practitioner for diagnosis and eventual treatment.
measure: Pain Catastrophizing Scale (PCS)
time frame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. Only pre-infusion
description: PCS consists of 13 questions divided into three sections: rumination, exaggeration and helplessness. The questions are answered in accordance to a scale of 0 to 4. There is evidence of catastrophizing thoughts at a total score > 30 points.
measure: Clinical Opiate Withdrawal Scale (COWS)
time frame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.
description: The Clinical Opiate Withdrawal Scale (COWS) is an examiner-based scale evaluating signs of opioid-withdrawal. Grading of symptoms, i.e. heart rate changes, sweating, restlessness, pupil size, bone or joint aches, running nose or tearing, nausea, vomiting, diarrhea, tremor, yawning, anxiety or irritability and "goose-flesh", are made in 11 categories. COWS-scores are divided into: 5-12 = mild; 13-24 = moderate; 25-36 = moderately severe ;> 36 = severe withdrawal reactions.
arm group label: High-dose naloxone
arm group type: Experimental
description: Naloxone 4 mg/ml i.v. infusion, total 3.25 mg/kg, target controlled infusion with three infusion rates (0.25 mg/kg; 0.75 mg/kg; 2.25 mg/kg) each of 25 min duration)
arm group label: Normal saline
arm group type: Placebo Comparator
description: 0.9% physiological saline, i.v. infusion, total 0.81 ml/kg, target controlled infusion with three infusion rates (0.06 ml/kg; 0.19 ml/kg; 0.56 ml/kg) each of 25 min duration.
intervention type: Drug
intervention name: Naloxone
description: active drug infusion
arm group label: High-dose naloxone
other name: Naloxon "B. Braun"
intervention type: Drug
intervention name: Normal Saline
description: placebo comparator
arm group label: Normal saline
other name: Physiologic Saline
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Mads U Werner, MD, DMSc
role: Principal Investigator
affiliation: Neuroscience Center, Copenhagen University Hospital, Denmark
last name: Bradley K Taylor, M.Sc., Ph.D.
role: Study Chair
affiliation: Department of Physiology, University of Kentucky Medical Center
last name: Mads U Werner, MD, DMSc.
phone: 28257703
phone ext: +45
email: mads.u.werner@gmail.com
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: Denmark
citation: Brennum J, Kaiser F, Dahl JB. Effect of naloxone on primary and secondary hyperalgesia induced by the human burn injury model. Acta Anaesthesiol Scand. 2001 Sep;45(8):954-60. doi: 10.1034/j.1399-6576.2001.450806.x.
PMID: 11576045
citation: Pielsticker A, Haag G, Zaudig M, Lautenbacher S. Impairment of pain inhibition in chronic tension-type headache. Pain. 2005 Nov;118(1-2):215-23. doi: 10.1016/j.pain.2005.08.019. Epub 2005 Oct 3.
PMID: 16202520
citation: Price DD, Staud R, Robinson ME, Mauderli AP, Cannon R, Vierck CJ. Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain. 2002 Sep;99(1-2):49-59. doi: 10.1016/s0304-3959(02)00053-2.
PMID: 12237183
citation: van Wilgen CP, Keizer D. The sensitization model to explain how chronic pain exists without tissue damage. Pain Manag Nurs. 2012 Mar;13(1):60-5. doi: 10.1016/j.pmn.2010.03.001. Epub 2010 Jul 22.
PMID: 22341140
citation: Koppert W, Filitz J, Troster A, Ihmsen H, Angst M, Flor H, Schuttler J, Schmelz M. Activation of naloxone-sensitive and -insensitive inhibitory systems in a human pain model. J Pain. 2005 Nov;6(11):757-64. doi: 10.1016/j.jpain.2005.07.002.
PMID: 16275600
citation: Campillo A, Cabanero D, Romero A, Garcia-Nogales P, Puig MM. Delayed postoperative latent pain sensitization revealed by the systemic administration of opioid antagonists in mice. Eur J Pharmacol. 2011 Apr 25;657(1-3):89-96. doi: 10.1016/j.ejphar.2011.01.059. Epub 2011 Feb 4.
PMID: 21300053
citation: Taylor BK, Corder G. Endogenous analgesia, dependence, and latent pain sensitization. Curr Top Behav Neurosci. 2014;20:283-325. doi: 10.1007/7854_2014_351.
PMID: 25227929
citation: Corder G, Doolen S, Donahue RR, Winter MK, Jutras BL, He Y, Hu X, Wieskopf JS, Mogil JS, Storm DR, Wang ZJ, McCarson KE, Taylor BK. Constitutive mu-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science. 2013 Sep 20;341(6152):1394-9. doi: 10.1126/science.1239403. Erratum In: Science. 2013 Nov 8;342(6159):693.
PMID: 24052307
citation: Pereira MP, Werner MU, Ringsted TK, Rowbotham MC, Taylor BK, Dahl JB. Does naloxone reinstate secondary hyperalgesia in humans after resolution of a burn injury? A placebo-controlled, double-blind, randomized, cross-over study. PLoS One. 2013 May 31;8(5):e64608. doi: 10.1371/journal.pone.0064608. Print 2013.
PMID: 23741350
citation: Pereira MP, Donahue RR, Dahl JB, Werner M, Taylor BK, Werner MU. Endogenous Opioid-Masked Latent Pain Sensitization: Studies from Mouse to Human. PLoS One. 2015 Aug 25;10(8):e0134441. doi: 10.1371/journal.pone.0134441. eCollection 2015.
PMID: 26305798
citation: Edwards RR, Ness TJ, Fillingim RB. Endogenous opioids, blood pressure, and diffuse noxious inhibitory controls: a preliminary study. Percept Mot Skills. 2004 Oct;99(2):679-87. doi: 10.2466/pms.99.2.679-687.
PMID: 15560360
citation: Singla NK, Desjardins PJ, Chang PD. A comparison of the clinical and experimental characteristics of four acute surgical pain models: dental extraction, bunionectomy, joint replacement, and soft tissue surgery. Pain. 2014 Mar;155(3):441-456. doi: 10.1016/j.pain.2013.09.002. Epub 2013 Sep 6.
PMID: 24012952
citation: Glass PS, Jhaveri RM, Smith LR. Comparison of potency and duration of action of nalmefene and naloxone. Anesth Analg. 1994 Mar;78(3):536-41. doi: 10.1213/00000539-199403000-00021.
PMID: 8109774
responsible party type: Sponsor-Investigator
investigator affiliation: University of Copenhagen
investigator full name: mads u werner
investigator title: Associate professor
mesh term: Pulpitis
mesh term: Hyperalgesia
mesh term: Inflammation
mesh term: Acute Pain
mesh term: Naloxone
sharing ipd: Yes
ipd description: Data will be made available as a supplementum to the published scientific article. Anticipated available in Spring 2018.