<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/NCT03014843</url>
  </required_header>
  <id_info>
    <org_study_id>S54661</org_study_id>
    <nct_id>NCT03014843</nct_id>
  </id_info>
  <brief_title>The Effect of Naloxone and Methylnaltrexone on Esophageal Sensitivity in Health</brief_title>
  <official_title>The Effect of Naloxone and Mehtylnaltrexone on Esophageal Sensitivity in Healthy Volunteers: a Randomized, Double-blind, Placebo-controlled Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universitaire Ziekenhuizen KU Leuven</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Universitaire Ziekenhuizen KU Leuven</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of this study was to investigate the effect of naloxone (IV or IM administration) and&#xD;
      methylnaltrexone (subcutaneous administration) on esophageal sensitivity, in a group of&#xD;
      healthy volunteers in order to evaluate the role of endogenous opiods in symptom perception&#xD;
      in gastro-esophageal reflux disease. Esophageal sensitivity was assessed by using a&#xD;
      multimodal esophageal stimulation protocol where sensitivity to thermal, mechanical,&#xD;
      electrical and chemical stimulation was tested.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      INTRODUCTION Gastroesophageal reflux disease (GERD), defined as the presence of symptoms or&#xD;
      lesions that can be attributed to the reflux of gastric contents into the esophagus, is an&#xD;
      increasingly prevalent condition in Western societies. The most typical symptoms are&#xD;
      heartburn and regurgitation, but GERD can manifest itself through a variety of esophageal and&#xD;
      extra-esophageal symptoms (e.g. chronic cough).&#xD;
&#xD;
      In humans, pain is a multimodal experience composted of sensory, physiological and&#xD;
      psychological aspects. In order to mimic the clinical situation, experimental models should&#xD;
      be based on multimodal testing regimens in which different receptors and central nervous&#xD;
      system mechanisms are activated.&#xD;
&#xD;
      Advances in esophageal sensory stimulation have established that both typical and atypical&#xD;
      symptoms may not only arise from acid reflux, but also from reflux events with less acidic pH&#xD;
      (pH 4-7). In GERD patients with symptoms that persist in spite of PPIs, ongoing weakly acidic&#xD;
      reflux is now well established as the main underlying factor.&#xD;
&#xD;
      The basis for symptom generation during weakly-acidic reflux events remains to be determined,&#xD;
      but acid sensitivity in the pH range 4-7, mechanical distention (enhanced by air in the&#xD;
      refluxate), sensitivity to other chemical factors (e.g. bile) and esophageal hypersensitivity&#xD;
      to physiological levels of reflux have all been proposed.&#xD;
&#xD;
      HYPOTHESIS The investigators speculated that visceral hypersensitivity plays an important&#xD;
      role in symptom perception. This is suggested by the reflux parameters that are usual within&#xD;
      the physiological number during PPI therapy.&#xD;
&#xD;
      Naloxone is indicated for the complete reversal of opioid depression, including respiratory&#xD;
      depression, induced by natural and synthetic opioids. Naloxone is also indicated for&#xD;
      diagnosis of suspected or known acute opiod overdosage. Off label it is also used for&#xD;
      alcoholic coma, Alzheimer's disease, schizophrenia, opioid addiction and narcotic induced&#xD;
      pruritis. Methylnaltrexone bromide (Relistor) is indicated for the treatment of&#xD;
      opioid-induced constipation in patients with advanced illness who are receiving palliative&#xD;
      care, when response to laxative therapy has not been sufficient.&#xD;
&#xD;
      AIM The aim of the study was to investigate the effect of naloxone (IV or IM administration)&#xD;
      and methylnaltrexone (subcutaneous administration) on esophageal sensitivity, in a group of&#xD;
      healthy volunteers in order to evaluate the role of endogenous opiods in symptom perception&#xD;
      in gastro-esophageal reflux disease..&#xD;
&#xD;
      METHODS Studies were performed in 12 healthy volunteers, to have sufficient data to compare&#xD;
      subjects mutual and to be able to make conclusions. Since this concerns measurements with&#xD;
      drugs that were never tested in this field of work, the investigators did not have&#xD;
      information regarding esophageal sensitivity after administration of these different&#xD;
      substances. Because of previous experience with these types of measurements (i.c. multimodal&#xD;
      stimulation with other substances), the investigators concluded that a number of 12 healthy&#xD;
      volunteers was sufficient to detect a 30% difference with a 5% significance level.&#xD;
&#xD;
      For safety reasons, subjects were prohibited to drive a vehicle or work with heavy machinery&#xD;
      on the day of the study. Each subject that was willing to participate was submitted to a&#xD;
      physical examination. Medical history was taken and the use of medication was inquired.&#xD;
&#xD;
      Studies were performed using a multimodal esophageal stimulation probe which allows chemical,&#xD;
      mechanical, electrical and thermal stimulations of the esophagus in one single protocol.&#xD;
&#xD;
      During each stimulation, subjects were instructed to record perception of symptoms using an&#xD;
      electronic VAS meter. This device allows the subject to scale perception and pain on a scale&#xD;
      from 0 to 10.&#xD;
&#xD;
      First perception (VAS=1), pain perception threshold (VAS=5) and pain tolerance threshold&#xD;
      (VAS=7) were recorded. All types of esophageal stimulations were immediately terminated when&#xD;
      the pain tolerance threshold was reached. At the time when the pain tolerance threshold was&#xD;
      reached (VAS=7), the subjects were asked to draw the referred pain area, to identify where&#xD;
      the pain was located.&#xD;
&#xD;
      Thermal stimulation Thermal stimulation was performed by re-circulating a saline solution&#xD;
      (NaCl 0.09%), heated by a water bath, through the balloon mounted on the probe. Stimulation&#xD;
      temperature was steadily increased by increasing the flow rate from the water bath to the&#xD;
      balloon. Flow rate will be controlled by a computer operated pump. The volume in the balloon&#xD;
      was kept constant at 5ml to avoid mechanical stimulation of the esophagus.&#xD;
&#xD;
      A temperature sensor present in the balloon montinuously monitored the stimulation&#xD;
      temperature, which was displayed on a computer display throughout the study.&#xD;
&#xD;
      Mechanical stimulation Mechanical stimulation was performed by distention of the balloon&#xD;
      mounted on the probe. The flow of saline (NaCl 0.09%) into the balloon, inducing the&#xD;
      distention, was regulated by a computer controlled pump. The volume in the balloon was&#xD;
      displayed on the computer screen throughout the stimulation. Mechanical stimulations were&#xD;
      performed with water of 37°C, to avoid thermal stimulation of the esophagus.&#xD;
&#xD;
      Mechanical stimulation was preceded by a preconditioning period during which the balloon was&#xD;
      distended until the pain perception threshold (VAS=5) was reached. This preconditioning&#xD;
      period was used to precondition the esophageal tissue and to allow the subject to get used to&#xD;
      the feeling of mechanical distention.&#xD;
&#xD;
      Electrical stimulation Electrical stimulation was performed by 2 stimulation electrodes&#xD;
      mounted on proximal to the balloon. Electrical block pulses were given using a standard&#xD;
      electrical stimulator. Single burst pulses were given with duration of 1ms at 200Hz. The&#xD;
      amplitude of the pulses was steadily increased, with steps of 0.5mA and an interval of 15sec.&#xD;
      The maximum intensity is limited to 60 mA, as previous studies have shown atrial capturing&#xD;
      with higher intensities. ECG monitoring was performed as a safety measure during the&#xD;
      electrical stimulations of the esophagus.&#xD;
&#xD;
      Chemical stimulation Chemical stimulation was performed in distal esophagus by infusing an&#xD;
      acidic solution (HCl 0.1N) in the esophagus. Chemical stimulations were controlled by a&#xD;
      peristaltic infusion pump with a flow rate of 2ml/min.&#xD;
&#xD;
      Naloxone/Methylnaltrexone or placebo administration As test solutions, naloxone (bolus of 0.4&#xD;
      mg followed by continuous infusion 20 µg/kg/h) or methylnaltrexone bromide (12 mg s.c.,&#xD;
      Relistor 0.6ml administrated subcutaneously) were administered. During placebo sessions, a&#xD;
      physiological solution (saline 0.9%), was administered IV and SC. Over time, each participant&#xD;
      received placebo or naloxone or methylnaltrexone bromide in the first session in a random&#xD;
      sequence. In the second and third session, the subject received one of the other products&#xD;
      that he/she did not receive the first time.&#xD;
&#xD;
      STUDY OUTLINE After an overnight fast subjects were expected at the endoscopy unit of the UZ&#xD;
      Gasthuisberg, where the study was performed. Three sessions were scheduled for every subject:&#xD;
      one placebo, one naloxone session and one methylnaltrexone session, with at least one week&#xD;
      interval between each of them. Sessions were run in a double blind way, as far as the placebo&#xD;
      or drugs are concerned. The order of placebo and drug administration was randomized by&#xD;
      drawing cards from a box of cards determining the sequence.&#xD;
&#xD;
      The volunteer received placebo, naloxone or methylnaltrexone at the beginning of the session.&#xD;
&#xD;
      The multimodal stimulation probe was positioned through the mouth. After the probe was&#xD;
      positioned in the esophagus, it was fixed to the chin and the subject remained in a bed, in&#xD;
      semi-recumbent position for the entire study period. Esophageal stimulation was performed&#xD;
      immediately after intubation.&#xD;
&#xD;
      Before the actual stimulations started, there was an adaptation period for the subjects, to&#xD;
      get used to the feeling of the probe and to provide instructions for the correct use of the&#xD;
      VAS meter since VAS scores were monitored during each type of stimulation.&#xD;
&#xD;
      All stimulations were immediately stopped at the moment the subject reached the pain&#xD;
      tolerance threshold (VAS=7).&#xD;
&#xD;
      ANALYSIS Temperature, volume, and electrical current will be measured at VAS=1 (first&#xD;
      perception), VAS=5 (pain perception threshold) and VAS=7 (pain tolerance threshold) and were&#xD;
      used to determine esophageal sensitivity. Esophageal sensitivity for the four different&#xD;
      stimuli (temperature, mechanical, electrical and chemical) were compared between the three&#xD;
      conditions.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2013</start_date>
  <completion_date type="Actual">January 2014</completion_date>
  <primary_completion_date type="Actual">January 2014</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Measurement of changes in esophageal sensitivity after IV naloxone or IM methylnaltrexone administration</measure>
    <time_frame>3 sessions per HV with at least one week interval, duration of each session: approximately 2 hours. Temperature stimulation: 30 minutes</time_frame>
    <description>Investigation of the effect of Naloxone and methylnaltrexone-administration on esophageal sensitivity to multimodal stimulation in a group of healthy volunteers. This will be assessed by comparing the Temperature values (°C) of the stimulation tests between the placebo and naloxone and methylnaltrexone condition to see if CRH affects the sensitivity to increasing temperature</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Measurement of changes in esophageal sensitivity after IV naloxone or IM methylnaltrexone administration</measure>
    <time_frame>3 sessions per HV with at least one week interval, duration of each session: approximately 2 hours. Mechanical stimulation: 30 minutes</time_frame>
    <description>Investigation of the effect of Naloxone and methylnaltrexone-administration on esophageal sensitivity to multimodal stimulation in a group of healthy volunteers. This will be assessed by comparing the balloon volumes (volume in ml) of the stimulation tests between the placebo and Naloxone and methylnaltrexone condition to see if Naloxone and methylnaltrexone affect the sensitivity to increasing balloon volume.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Measurement of changes in esophageal sensitivity after IV naloxone or IM methylnaltrexone administration</measure>
    <time_frame>3 sessions per HV with at least one week interval, duration of each session: approximately 2 hours. Electrical stimulation: 30 minutes</time_frame>
    <description>Investigation of the effect of Naloxone and methylnaltrexone-administration on esophageal sensitivity to multimodal stimulation in a group of healthy volunteers. This will be assessed by comparing the tolerated intensity of the electrical pulses (mA) of the stimulation tests between the placebo and Naloxone and methylnaltrexone condition to see if Naloxone and methylnaltrexone affect the sensitivity to increasing electrical pulses.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Measurement of changes in esophageal sensitivity after IV naloxone or IM methylnaltrexone administration</measure>
    <time_frame>3 sessions per HV with at least one week interval, duration of each session: approximately 2 hours. Chemical stimulation: 30 minutes</time_frame>
    <description>Investigation of the effect of Naloxone and methylnaltrexone-administration on esophageal sensitivity to multimodal stimulation in a group of healthy volunteers. This will be assessed by comparing the volume of infused acid (ml) of the stimulation tests between the placebo and Naloxone and methylnaltrexone condition to see if Naloxone and methylnaltrexone affect the sensitivity to acid infusion.</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Endogenous and Esophageal Sensitivity</condition>
  <arm_group>
    <arm_group_label>Naloxone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Administration of a centrally acting µ-opioid receptor antagonist Naloxone (20µg/kg/h intravenous infusion after 0.4mg bolus) to investigate the effect of esophageal sensitivity assessed by multimodal esophageal stimulation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Methylnaltrexone bromide</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Administration of a peripherally acting µ-opioid receptor antagonist Methylnaltrexone (12mg/0.6mL subcutaneous injection) to investigate the effect of esophageal sensitivity assessed by multimodal esophageal stimulation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Administration of placebo injection (1mL 0.9% saline IV or 0.6 IM) as a control condition to compare to the administration of naloxone or methylnaltrexone bromide in the multimodal esophageal stimulation protocol.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Naloxone</intervention_name>
    <description>20µg/kg/h intravenous infusion after 0.4mg bolus of Naloxone and 0.6mL IM NaCl (0.9%) injection (this step is necessary to keep the subject blinded for the condition since nalaxone and methylnaltrexone have different administration routes)</description>
    <arm_group_label>Naloxone</arm_group_label>
    <other_name>Naloxon, B.Braun</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methylnaltrexone Bromide</intervention_name>
    <description>12mg/0.6mL subcutaneous injection and 1mL bolus of NaCl (0.9%) followed by intravenous infusion (this step is necessary to keep the subject blinded for the condition since nalaxone and methylnaltrexone have different administration routes)</description>
    <arm_group_label>Methylnaltrexone bromide</arm_group_label>
    <other_name>Relistor</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>0.6 mL of NaCl 0.9% will be injected IM and 1mL bolus injection of NaCl(0.9%) will be administered IV followed by IV NaCl 0.9% infusion</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Saline solution (0.9% NaCl)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  18 to 60 years old&#xD;
&#xD;
          -  No history of gastrointestinal symptoms or complaints&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A history of allergic reaction to naloxone or methylnaltrexone bromide or multiple&#xD;
             allergies to several foods and drugs.&#xD;
&#xD;
          -  Pregnancy, lactation.&#xD;
&#xD;
          -  Concomitant administration of monomine oxidase inhibitors (MAOI), verapamil or&#xD;
             diltiazem or medications affecting esophageal motility.&#xD;
&#xD;
          -  Significant co-morbidities (neuromuscular, psychiatric, cardiovascular, pulmonary,&#xD;
             endocrine, autoimmune, renal and hepatic).&#xD;
&#xD;
          -  Prior history of esophageal, Ear-Nose-Troat or gastric surgery or endoscopic&#xD;
             anti-reflux procedure.&#xD;
      </textblock>
    </criteria>
    <gender>All</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>Jan Tack, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>KU Leuven</affiliation>
  </overall_official>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>January 5, 2017</study_first_submitted>
  <study_first_submitted_qc>January 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 9, 2017</study_first_posted>
  <last_update_submitted>January 5, 2017</last_update_submitted>
  <last_update_submitted_qc>January 5, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 9, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Esophagal sensitivity, GERD, endogenous opiods</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypersensitivity</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bromides</mesh_term>
    <mesh_term>Naloxone</mesh_term>
    <mesh_term>Methylnaltrexone</mesh_term>
  </intervention_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/NCT03014843
org study id: S54661
nct id: NCT03014843
lead sponsor: 
has dmc: No
The aim of this study was to investigate the effect of naloxone (IV or IM administration) and
      methylnaltrexone (subcutaneous administration) on esophageal sensitivity, in a group of
      healthy volunteers in order to evaluate the role of endogenous opiods in symptom perception
      in gastro-esophageal reflux disease. Esophageal sensitivity was assessed by using a
      multimodal esophageal stimulation protocol where sensitivity to thermal, mechanical,
      electrical and chemical stimulation was tested.
INTRODUCTION Gastroesophageal reflux disease (GERD), defined as the presence of symptoms or
      lesions that can be attributed to the reflux of gastric contents into the esophagus, is an
      increasingly prevalent condition in Western societies. The most typical symptoms are
      heartburn and regurgitation, but GERD can manifest itself through a variety of esophageal and
      extra-esophageal symptoms (e.g. chronic cough).

      In humans, pain is a multimodal experience composted of sensory, physiological and
      psychological aspects. In order to mimic the clinical situation, experimental models should
      be based on multimodal testing regimens in which different receptors and central nervous
      system mechanisms are activated.

      Advances in esophageal sensory stimulation have established that both typical and atypical
      symptoms may not only arise from acid reflux, but also from reflux events with less acidic pH
      (pH 4-7). In GERD patients with symptoms that persist in spite of PPIs, ongoing weakly acidic
      reflux is now well established as the main underlying factor.

      The basis for symptom generation during weakly-acidic reflux events remains to be determined,
      but acid sensitivity in the pH range 4-7, mechanical distention (enhanced by air in the
      refluxate), sensitivity to other chemical factors (e.g. bile) and esophageal hypersensitivity
      to physiological levels of reflux have all been proposed.

      HYPOTHESIS The investigators speculated that visceral hypersensitivity plays an important
      role in symptom perception. This is suggested by the reflux parameters that are usual within
      the physiological number during PPI therapy.

      Naloxone is indicated for the complete reversal of opioid depression, including respiratory
      depression, induced by natural and synthetic opioids. Naloxone is also indicated for
      diagnosis of suspected or known acute opiod overdosage. Off label it is also used for
      alcoholic coma, Alzheimer's disease, schizophrenia, opioid addiction and narcotic induced
      pruritis. Methylnaltrexone bromide (Relistor) is indicated for the treatment of
      opioid-induced constipation in patients with advanced illness who are receiving palliative
      care, when response to laxative therapy has not been sufficient.

      AIM The aim of the study was to investigate the effect of naloxone (IV or IM administration)
      and methylnaltrexone (subcutaneous administration) on esophageal sensitivity, in a group of
      healthy volunteers in order to evaluate the role of endogenous opiods in symptom perception
      in gastro-esophageal reflux disease..

      METHODS Studies were performed in 12 healthy volunteers, to have sufficient data to compare
      subjects mutual and to be able to make conclusions. Since this concerns measurements with
      drugs that were never tested in this field of work, the investigators did not have
      information regarding esophageal sensitivity after administration of these different
      substances. Because of previous experience with these types of measurements (i.c. multimodal
      stimulation with other substances), the investigators concluded that a number of 12 healthy
      volunteers was sufficient to detect a 30% difference with a 5% significance level.

      For safety reasons, subjects were prohibited to drive a vehicle or work with heavy machinery
      on the day of the study. Each subject that was willing to participate was submitted to a
      physical examination. Medical history was taken and the use of medication was inquired.

      Studies were performed using a multimodal esophageal stimulation probe which allows chemical,
      mechanical, electrical and thermal stimulations of the esophagus in one single protocol.

      During each stimulation, subjects were instructed to record perception of symptoms using an
      electronic VAS meter. This device allows the subject to scale perception and pain on a scale
      from 0 to 10.

      First perception (VAS=1), pain perception threshold (VAS=5) and pain tolerance threshold
      (VAS=7) were recorded. All types of esophageal stimulations were immediately terminated when
      the pain tolerance threshold was reached. At the time when the pain tolerance threshold was
      reached (VAS=7), the subjects were asked to draw the referred pain area, to identify where
      the pain was located.

      Thermal stimulation Thermal stimulation was performed by re-circulating a saline solution
      (NaCl 0.09%), heated by a water bath, through the balloon mounted on the probe. Stimulation
      temperature was steadily increased by increasing the flow rate from the water bath to the
      balloon. Flow rate will be controlled by a computer operated pump. The volume in the balloon
      was kept constant at 5ml to avoid mechanical stimulation of the esophagus.

      A temperature sensor present in the balloon montinuously monitored the stimulation
      temperature, which was displayed on a computer display throughout the study.

      Mechanical stimulation Mechanical stimulation was performed by distention of the balloon
      mounted on the probe. The flow of saline (NaCl 0.09%) into the balloon, inducing the
      distention, was regulated by a computer controlled pump. The volume in the balloon was
      displayed on the computer screen throughout the stimulation. Mechanical stimulations were
      performed with water of 37°C, to avoid thermal stimulation of the esophagus.

      Mechanical stimulation was preceded by a preconditioning period during which the balloon was
      distended until the pain perception threshold (VAS=5) was reached. This preconditioning
      period was used to precondition the esophageal tissue and to allow the subject to get used to
      the feeling of mechanical distention.

      Electrical stimulation Electrical stimulation was performed by 2 stimulation electrodes
      mounted on proximal to the balloon. Electrical block pulses were given using a standard
      electrical stimulator. Single burst pulses were given with duration of 1ms at 200Hz. The
      amplitude of the pulses was steadily increased, with steps of 0.5mA and an interval of 15sec.
      The maximum intensity is limited to 60 mA, as previous studies have shown atrial capturing
      with higher intensities. ECG monitoring was performed as a safety measure during the
      electrical stimulations of the esophagus.

      Chemical stimulation Chemical stimulation was performed in distal esophagus by infusing an
      acidic solution (HCl 0.1N) in the esophagus. Chemical stimulations were controlled by a
      peristaltic infusion pump with a flow rate of 2ml/min.

      Naloxone/Methylnaltrexone or placebo administration As test solutions, naloxone (bolus of 0.4
      mg followed by continuous infusion 20 µg/kg/h) or methylnaltrexone bromide (12 mg s.c.,
      Relistor 0.6ml administrated subcutaneously) were administered. During placebo sessions, a
      physiological solution (saline 0.9%), was administered IV and SC. Over time, each participant
      received placebo or naloxone or methylnaltrexone bromide in the first session in a random
      sequence. In the second and third session, the subject received one of the other products
      that he/she did not receive the first time.

      STUDY OUTLINE After an overnight fast subjects were expected at the endoscopy unit of the UZ
      Gasthuisberg, where the study was performed. Three sessions were scheduled for every subject:
      one placebo, one naloxone session and one methylnaltrexone session, with at least one week
      interval between each of them. Sessions were run in a double blind way, as far as the placebo
      or drugs are concerned. The order of placebo and drug administration was randomized by
      drawing cards from a box of cards determining the sequence.

      The volunteer received placebo, naloxone or methylnaltrexone at the beginning of the session.

      The multimodal stimulation probe was positioned through the mouth. After the probe was
      positioned in the esophagus, it was fixed to the chin and the subject remained in a bed, in
      semi-recumbent position for the entire study period. Esophageal stimulation was performed
      immediately after intubation.

      Before the actual stimulations started, there was an adaptation period for the subjects, to
      get used to the feeling of the probe and to provide instructions for the correct use of the
      VAS meter since VAS scores were monitored during each type of stimulation.

      All stimulations were immediately stopped at the moment the subject reached the pain
      tolerance threshold (VAS=7).

      ANALYSIS Temperature, volume, and electrical current will be measured at VAS=1 (first
      perception), VAS=5 (pain perception threshold) and VAS=7 (pain tolerance threshold) and were
      used to determine esophageal sensitivity. Esophageal sensitivity for the four different
      stimuli (temperature, mechanical, electrical and chemical) were compared between the three
      conditions.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Measurement of changes in esophageal sensitivity after IV naloxone or IM methylnaltrexone administration
time frame: 3 sessions per HV with at least one week interval, duration of each session: approximately 2 hours. Temperature stimulation: 30 minutes
description: Investigation of the effect of Naloxone and methylnaltrexone-administration on esophageal sensitivity to multimodal stimulation in a group of healthy volunteers. This will be assessed by comparing the Temperature values (°C) of the stimulation tests between the placebo and naloxone and methylnaltrexone condition to see if CRH affects the sensitivity to increasing temperature
measure: Measurement of changes in esophageal sensitivity after IV naloxone or IM methylnaltrexone administration
time frame: 3 sessions per HV with at least one week interval, duration of each session: approximately 2 hours. Mechanical stimulation: 30 minutes
description: Investigation of the effect of Naloxone and methylnaltrexone-administration on esophageal sensitivity to multimodal stimulation in a group of healthy volunteers. This will be assessed by comparing the balloon volumes (volume in ml) of the stimulation tests between the placebo and Naloxone and methylnaltrexone condition to see if Naloxone and methylnaltrexone affect the sensitivity to increasing balloon volume.
measure: Measurement of changes in esophageal sensitivity after IV naloxone or IM methylnaltrexone administration
time frame: 3 sessions per HV with at least one week interval, duration of each session: approximately 2 hours. Electrical stimulation: 30 minutes
description: Investigation of the effect of Naloxone and methylnaltrexone-administration on esophageal sensitivity to multimodal stimulation in a group of healthy volunteers. This will be assessed by comparing the tolerated intensity of the electrical pulses (mA) of the stimulation tests between the placebo and Naloxone and methylnaltrexone condition to see if Naloxone and methylnaltrexone affect the sensitivity to increasing electrical pulses.
measure: Measurement of changes in esophageal sensitivity after IV naloxone or IM methylnaltrexone administration
time frame: 3 sessions per HV with at least one week interval, duration of each session: approximately 2 hours. Chemical stimulation: 30 minutes
description: Investigation of the effect of Naloxone and methylnaltrexone-administration on esophageal sensitivity to multimodal stimulation in a group of healthy volunteers. This will be assessed by comparing the volume of infused acid (ml) of the stimulation tests between the placebo and Naloxone and methylnaltrexone condition to see if Naloxone and methylnaltrexone affect the sensitivity to acid infusion.
arm group label: Naloxone
arm group type: Active Comparator
description: Administration of a centrally acting µ-opioid receptor antagonist Naloxone (20µg/kg/h intravenous infusion after 0.4mg bolus) to investigate the effect of esophageal sensitivity assessed by multimodal esophageal stimulation.
arm group label: Methylnaltrexone bromide
arm group type: Active Comparator
description: Administration of a peripherally acting µ-opioid receptor antagonist Methylnaltrexone (12mg/0.6mL subcutaneous injection) to investigate the effect of esophageal sensitivity assessed by multimodal esophageal stimulation.
arm group label: Placebo
arm group type: Placebo Comparator
description: Administration of placebo injection (1mL 0.9% saline IV or 0.6 IM) as a control condition to compare to the administration of naloxone or methylnaltrexone bromide in the multimodal esophageal stimulation protocol.
intervention type: Drug
intervention name: Naloxone
description: 20µg/kg/h intravenous infusion after 0.4mg bolus of Naloxone and 0.6mL IM NaCl (0.9%) injection (this step is necessary to keep the subject blinded for the condition since nalaxone and methylnaltrexone have different administration routes)
arm group label: Naloxone
other name: Naloxon, B.Braun
intervention type: Drug
intervention name: Methylnaltrexone Bromide
description: 12mg/0.6mL subcutaneous injection and 1mL bolus of NaCl (0.9%) followed by intravenous infusion (this step is necessary to keep the subject blinded for the condition since nalaxone and methylnaltrexone have different administration routes)
arm group label: Methylnaltrexone bromide
other name: Relistor
intervention type: Other
intervention name: Placebo
description: 0.6 mL of NaCl 0.9% will be injected IM and 1mL bolus injection of NaCl(0.9%) will be administered IV followed by IV NaCl 0.9% infusion
arm group label: Placebo
other name: Saline solution (0.9% NaCl)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jan Tack, MD, PhD
role: Principal Investigator
affiliation: KU Leuven
responsible party type: Sponsor
mesh term: Hypersensitivity
mesh term: Bromides
mesh term: Naloxone
mesh term: Methylnaltrexone
sharing ipd: No