The Effect of Corticotrophin-releasing Hormone (CRH) on Esophageal Sensitivity in Healthy Volunteers
Condition: Sensitivity (Hyper); Gastrointestinal
MeSH terms: Hypersensitivity
Study type: Interventional
Phase: Phase 4

Summary: 
      Introduction and aim

      Stress is well known to affect visceral sensitivity in Human. The investigators speculate
      that visceral hypersensitivity plays an important role in symptom perception in
      gastro-esophageal reflux disease (GERD). The role of acute stress mimicked by corticotrophin
      releasing hormone (CRH) administration on esophageal sensitivity has not been studied. The
      investigators hypothesize that stress mediated through CRH-release increases esophageal
      sensitivity. A first step in the investigation of this hypothesis is to study whether
      administration of CRH has an influence on esophageal sensitivity in healthy volunteers (HV).
      Therefore, the aim of this study is to investigate the effect of CRH-administration on
      esophageal sensitivity in a group of HV.

      Methods

      The study will be performed in cross-over on 15 HV with no prior history of digestive
      disease. Esophageal sensitivity will be tested by multimodal stimulation on two sessions
      (placebo and CRH-administration), with an interval at least of one week. The two sessions
      will be scheduled by randomization for every subject. After blinded administration of CRH
      100µg or placebo IV, esophageal sensitivity will be assessed using a multimodal esophageal
      stimulation probe which allows thermal, mechanical, electrical and chemical stimulations of
      the esophagus. Esophageal sensitivity will be assessed using Visual Analogue Scale (VAS), the
      mood with specific questionnaires (Manikin Self assessment SAM, Profile of Mood Schedule
      (POMS, State Trait Anxiety Inventory (STAI)) and the cortisol with salivary samples.

      Statistical analysis

      Esophageal sensitivity for the different stimuli (heat, mechanical, electrical and chemical)
      will be compared between CRH and placebo conditions. To determine the stress-inducing
      capability of CRH-administration, the POMS questionnaire, STAI, Manikin self assessment and
      cortisol levels after the stress-protocol will be compared with the basal measurements.

      Perspectives

      If CRH-administration increases esophageal sensitivity, a stress model could be applied to
      investigate the influence of a real life stressor on esophageal sensitivity in healthy
      subjects. In a third part, a mast-cell stabilizing drug could be tested after administration
      of a stressor in order to investigate its role on esophageal sensitivity. In the future, this
      might be proposed to refractory GERD in a controlled randomized trial.
    

Detailed description: 
      1. INTRODUCTION Gastro-esophageal reflux disease (GERD) is the presence of symptoms
           (heartburn, regurgitation) or lesions that can be attributed to the reflux of gastric
           contents into the esophagus. 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. Typical and
           atypical symptoms may not only arise from acid reflux, but also from reflux with less
           acidic pH (pH 4-7). In GERD patients with persisting symptoms on proton pump inhibitor
           (PPI) therapy, ongoing weakly acidic reflux is well established as an important
           underlying factor. The basis for symptom generation during weakly acidic reflux remains
           to be determined, but acid sensitivity in the pH range 4-7, mechanical distension,
           sensitivity to other chemical factors and esophageal hypersensitivity to physiological
           levels of reflux have been proposed. The investigators speculate 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.
           Also, the investigators previously demonstrated that refractory GERD patients have
           increased visceral hypersensitivity for thermal, chemical and mechanical esophageal
           stimulation compared to HV.

           Stress is well known to affect visceral sensitivity in humans. A majority of patients
           with GERD report stress as an important factor triggering symptom exacerbation. A
           real-life stressor could exacerbate heartburn in GERD patients by enhancing perceptual
           response to esophageal acid exposure. The interaction between psychological state and GI
           function is a complex and developing field. The brain-gut axis, mediating the effects of
           stress on the Gastrointestinal (GI) tract, has been considered a pivotal player in the
           pathogenesis of functional GI disorders like irritable bowel syndrome (IBS) and
           functional dyspepsia (FD). A possible mechanism of stress-induced visceral sensitivity
           could be the barrier dysfunction. A study performed in humans, showed that an acute
           psychological stressor induces hyperpermeability in a mast cell dependent fashion and
           exogenous peripheral CRH recapitulated its effects on barrier function. This increase in
           intestinal permeability is a phenomenon which appears as a prerequisite for visceral
           hypersensitivity. The acute role of CRH on esophageal sensitivity has not been studied.

        2. OBJECTIVE Stress increases permeability via CRH-mediated mast cell activation. The
           investigators hypothesize that stress mediated through CRH-release increases esophageal
           sensitivity. Therefore, the aim of our study is to investigate the effect of
           CRH-administration on esophageal sensitivity in a group of HV.

        3. GENERAL DESCRIPTION Studies will be performed in HV. All participants will receive and
           sign a copy of the informed consent before initiation of the study. Esophageal
           sensitivity will be tested by multimodal stimulation on two sessions (placebo and
           CRH-administration).

        4. MATERIALS AND METHODS Studies will be performed using a multimodal esophageal
           stimulation probe which allows esophageal thermal, mechanical, electrical and chemical
           stimulations.

           During each stimulation, HV will record symptom perception using VAS. First perception
           (VAS=1), pain perception threshold (VAS=5) and pain tolerance threshold (VAS=7) will be
           recorded. All stimulations will be immediately terminated when the VAS 7 is reached. At
           the time of VAS 7, subjects will be asked to draw the referred pain area, to identify
           pain location.

           Thermal stimulation will be performed by re-circulating a saline solution, heated by a
           water bath, through the balloon mounted on the probe. Stimulation temperature will be
           steadily increased by increasing the flow rate from the water bath to the balloon. The
           volume in the balloon will be kept constant (5ml) to avoid mechanical stimulation. A
           temperature sensor in the balloon will continuously monitor the stimulation temperature,
           which is displayed online on a computer throughout the study.

           Mechanical stimulation will be performed by distension of the balloon. The flow of
           saline into the balloon, inducing the distension, is regulated by a computer controlled
           pump. The volume in the balloon is displayed on the computer screen throughout the
           stimulation. Mechanical stimulations will be performed with water of 37 degrees Celsius,
           to avoid thermal stimulation.

           Electrical stimulation will be performed by 2 electrodes mounted on the probe. Single
           burst pulses will be given with duration of 1ms at 200Hz. The amplitude of the pulses
           will increase with steps of 0.5mA. The maximum intensity is limited to 50 mA, as
           previous studies have shown atrial capturing with higher intensities. Electrocardiogram
           (ECG) monitoring will be performed as a safety measure during the electrical
           stimulations.

           Chemical stimulation will be performed by infusing an acidic solution (HCl 0.1N) in the
           distal esophagus, with a flow rate of 2ml/min. The stimulation will last for a maximum
           of 30 min.

           After an overnight fast subjects will come to the endoscopy unit of the Universitary
           Hospital of Leuven,Gasthuisberg, where the study will be performed. Two sessions will be
           scheduled for every subject: one placebo and one CRH session, with one week interval at
           least between each of them. Sessions will run in a single-blind way, as far as the
           placebo or drugs are concerned. The order of placebo and CRH-administration will be
           randomized by drawing cards from a box of cards determining the sequence.

           At the beginning of the session, the multimodal stimulation probe will be positioned
           through the mouth. After the probe is positioned in the esophagus, it will be fixed to
           the chin and the subject will remain in semi-recumbent position for the entire study.
           Before the actual stimulations start, there will be an adaptation period of 15 min, to
           get used to the feeling of the probe and to provide instructions for the correct use of
           the VAS meter. Fifteen minutes after the ingestion of the multimodal esophageal
           stimulation probe, 100µg CRH powder for injection (CRH ferring®, Ferring, Aalst,
           Belgium) and 1mL of NaCl 0.9% will be put together, then the solution will be injected
           intravenously over the course of 1 minute. With this dose, side-effects are limited to
           transient facial flushing that lasts from 5 to 45 min in 75% of patients. During placebo
           sessions, 1mL of NaCl 0.9% will be put in an identical syringe as the one used for CRH
           administration, and then injected intravenously (IV). In this way the HV will be blinded
           for the administration of CRH or placebo. Over time, each HV will receive placebo or CRH
           in the first session in a random sequence. In the second session, the subject will
           receive the other product that he/she didn't receive the first time.

           Salivary samples will be obtained at each session to determine salivary cortisol
           immediately before placebo or CRH-administration, at 30, 60, 90 and 120 min after
           administration. Salivary cortisol will be determined by ELISA. On every session, an
           assessment of general mood will be performed by the POMS and the STAI state
           questionnaires before and after the stimulation tests. The POMS consists of words
           describing different feelings and emotions at the present moment. The STAI state is
           validated, and widely used measuring transitory anxiety states.

        5. DATA ANALYSIS The main objective is to show a difference for thermal stimulation with or
           without injection of CRH. The number of HV to be included is calculated with a medium
           comparison test. For a first species of risk α of 5% and a unilateral formulation, the
           investigators need to include 15 HV in total in order to highlight the expected
           differences and ensure a power of 80%.

           Temperature, volume, cross-section area of the balloon, pressure and electrical current
           will be measured at first perception, pain perception threshold and pain tolerance
           threshold and will be used to determine esophageal sensitivity. Esophageal sensitivity
           for the different stimuli (heat, mechanical, electrical and chemical) will be compared
           between CRH and placebo conditions.

           To determine the stress-inducing capability of CRH-administration, the POMS, STAI and
           cortisol levels after the stress-protocol will be compared with the basal measurements
           of the first study day.

        6. PERSPECTIVES If CRH-administration increases esophageal sensitivity, a stress model
           could be applied to investigate the influence of a real life stressor on esophageal
           sensitivity in HV. In a third part, a mast-cell stabilizing drug could be tested after
           administration of a stressor in order to investigate its role on esophageal sensitivity.
           In the future, this might be proposed to refractory GERD in a controlled randomized
           trial.
    

Intervention name(s): CRH; Placebo
Intervention type(s): Drug; Other
Intervention description(s): 100µg CRH powder for injection (CRH ferring®, Ferring, Aalst, Belgium) and 1 mL of NaCl 0.9% will be put together, then the solution will be injected intravenously over the course of 1 minute; 1 mL of NaCl 0.9% will be injected intravenously over the course of one minute
Other intervention name(s): CRH ferring®, Ferring, Aalst, Belgium; Saline solution
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Keywords: health; age between 18 to 60 years old; no history of gastrointestinal symptoms or complaints