Prucalopride reduces the number of reflux episodes and improves subjective symptoms in gastroesophageal reflux disease: a case series

Gastroesophageal reflux disease (GERD) is a relevant disorder in western countries with increasing frequency and incidence [1]. Most patients with acid reflux episodes do adequately respond to proton pump inhibitor (PPI) therapy [2]. More challenging is treatment of “PPI-persistent” or weakly and/or non-acid reflux episodes, which may also cause relevant reflux symptoms [3]. In persistent symptoms to standard PPI therapy, high-dose PPI therapy or baclofen, a GABA B agonist, are reported to reduce weakly and/or non-acid gastroesophageal reflux episodes in single cases [4]. Whereas double doses of PPIs are an appropriate therapy with significant reduction of liquid and/or mixed reflux events [5], available data related to baclofen therapy are inconclusive and symptom responder rates are poor [6].

In the past, cisapride, a procinetic non-selective serotonin (5-HT₄) receptor agonist, was used with good amelioration of reflux symptoms [7]. Therapeutic effects might be explained by a decrease in transient lower esophageal sphincter relaxation, enhanced lower esophageal motor activity, and enhanced gastric or duodenal emptying [8‐11]. However, due to severe cardiac side-effects (QT-time prolongation), cisapride was removed from the market in the year 2000 [12]. Prucalopride, a new selective high affinity serotonin (5-HT₄) receptor agonist, was introduced on the German market in 2010. It is approved in the therapy of chronic constipation in women and stimulates colonic movement [13]. In addition, possible effects on upper intestinal motility similar to cisapride are conceivable. So far, no reports on the effect of prucalopride in GERD patients are available.

Combined esophageal pH or multichannel impedance (MII) monitoring [14] allows detection of all types of reflux events [15], which enables the characterization of persistent gastroesophageal reflux episodes [16]. This method has been shown to be highly sensitive [14]. Therefore, pH and/or MII is a suitable technique to objectively evaluate pathological reflux episodes in patients with non-acid reflux episodes.

GERD is defined as esophageal acid exposure >5% in 24 hour pH monitoring [17] or the number of total reflux episodes greater than 73 in MII monitoring [18].

In the presented case report, we provide experiences with four patients with PPI-persistent or weakly and/or non-acid reflux episodes treated with prucalopride due to chronic constipation.

Four female Caucasian patients from our outpatient department with chronic constipation and typical reflux symptoms (heartburn), despite standard PPI therapy for at least four weeks, were asked to perform pH and/or MII monitoring before initiation of and during prucalopride therapy. Our patients completed a symptom-based questionnaire before pH and/or MII monitoring in each case. This standardized questionnaire asked the patients about typical and atypical GERD-symptoms, the frequency of these symptoms and the subjective evaluation of the influence of these symptoms on daily life. This previously published questionnaire [5] focuses on subjective parameters instead of another objective scoring system, such as the Frequency Scale for the Symptoms of GERD (FSSG) [19]. To evaluate objective parameters, combined MII and pH monitoring was performed using an ambulatory, multi-channel, intra-luminal impedance system, consisting of a portable data logger and a combined pH impedance catheter (Tecnomatix ZAN S 61C 01 E, Sandhill Scientific, Highlands Ranch, CO, USA). Six impedance electrodes as well as a distal pH-antimony probe were placed at pre-defined spots on this catheter (3.0cm, 5.0cm, 7.0cm, 9.0cm, 15.0cm and 17.0cm; pH probe 5.0cm). The catheter was placed with the pH antimon probe located 5cm above the manometrically-defined lower esophagus sphincter. Data were recorded for 21 hours and 23 hours, respectively.

Gastroesophageal reflux was detected by impedance changes was defined on the basis of previous reports [1, 2, 18]. Reflux episodes were defined as either acidic or non-acidic, and if a retrograde bolus movement was detected by impedance and pH value was below or above 4, respectively. Furthermore, the content of the reflux episode was characterized according to its composition (gas, fluid or mixed). Meals were excluded from analysis.

The characteristics of each patient are summarized in Table 1. Results of pH or MII monitoring before and after prucalopride treatment and associated subjective symptom scores are displayed in Tables 2 and 3.

There were no major adverse events in any patient during therapy with prucalopride.

This case series indicates for the first time that prucalopride, single therapy or in addition to PPI medication, might relevantly reduce the number of “PPI-persistent” reflux episodes in patients with typical reflux symptoms and an increased number of reflux episodes, assessed by combined impedance and pH monitoring. The objective findings were concordant with subjective reports of symptom relief.

In our case series, numbers of all reflux episodes as well as non-acid reflux episodes were reduced in all of our patients. In acid reflux episodes, results are controversial. However, there were only a few episodes of acid reflux during the first measurement, so that the increase of these episodes can possibly be explained by physiologic reflux variability during the different measurements. Our other two patients (with initially pathologic elevated acid reflux episodes) showed a relevant reduction for this kind of reflux during prucalopride medication. Taking all objective and subjective parameters in the four patients together, there was good response to prucalopride therapy.

Prucalopride mainly effects colonic motility and, therefore, is used in the therapy of chronic constipation. Prior experiments in animals indicated that prucalopride also effects contractility of the stomach [20, 21] Moreover, a positive effect on gastric motility was already observed in the chronic constipated patient. In our patients, prucalopride led to an accelerated overall gastric emptying and small bowel transit which we believe to be the main effect of prucalopride on GERD [22]. However, this effect could not be affirmed in healthy, non-constipated subjects [23]. In addition, we hypothesize an influence of prucalopride on upper gastrointestinal motility in analogue to the effect described in cisapride, including enhanced lower esophageal motor activity, a decrease of transient lower esophageal sphincter relaxation and enhanced gastric and/or duodenal emptying [8‐11], at least in the constipated patient. In addition, a stimulation of esophageal body contraction and an elevation of lower esophagus sphincter (LES) resting pressure was also shown for mosapride, another selective 5-HT₄-agonist [24], and is, therefore, used for GERD patients (in combination with PPI) in some Asian countries [25]. Of course, due to the different structures of these 5HT₄ agonists, the characteristic effects of these drugs are not directly comparable, especially since prucalopride is a high affinity 5HT₄ agonist mainly effecting colonic movement. However, there is evidence that prucalopride can have an effect on upper gastrointestinal motility (in the constipated patients) [22], even if this effect possibly is weaker than the effect of cisapride or mosapride. The effect of prucalopride on esophageal motility will need further objective evaluation, with high resolution (HR) manometry testing before and during prucalopride therapy. In fact, HR manometry would have been an excellent diagnostic tool in our case series and should be included in further trials.

As a main limitation to our study, the small number of patients in a single center setting needs to be mentioned. However, all of our patients were analyzed in a standard outpatient setting. Considerable subjective improvement of reflux symptoms after one week was reported in all of our patients. Still, we report a preliminary case series. The primary goal in this case series was to report the effect of prucalopride in GERD patients. For a final conclusion, double-blinded trials are needed.

In conclusion, our case series showed a reduction of “PPI-persistent” and non-acid reflux episodes during prucalopride therapy in four chronically constipated women. Therefore, prucalopride might be a new and promising therapeutic option in the challenging demand for treating constipated patients with GERD who had standard PPI-persistent reflux episodes. Further prospective, placebo-controlled studies involving a larger number of patients and esophageal motility studies are needed to prove these findings and to evaluate if prucalopride could also be an appropriate therapy in the non-constipated GERD patient.

Written informed consent was obtained from our patients for publication of this case series. A copy of the written consents is available for review by the Editor-in-Chief of this journal.