Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03014843 |
| Other study ID # |
S54661 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
January 5, 2017 |
| Last updated |
January 5, 2017 |
| Start date |
October 2013 |
| Est. completion date |
January 2014 |
Study information
| Verified date |
January 2017 |
| Source |
Universitaire Ziekenhuizen Leuven |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Belgium: Federal Agency for Medicinal Products and Health ProductsBelgium: Ethics Committee |
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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.
