J Neurogastroenterol Motil 2024; 30(1): 54-63  https://doi.org/10.5056/jnm23014
The Effect of STW5 (Iberogast) on Reflux Symptoms in Patients With Concurrent Dyspeptic Symptoms: A Double-blind Randomized Placebo-controlled Crossover Trial
Renske A B Oude Nijhuis,* Thijs Kuipers, Jac M Oors, Thomas V K Herregods, Boudewijn F Kessing, Jeroen M Schuitenmaker, Andreas J P M Smout, and Albert J Bredenoord
Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Center, Amsterdam, the Netherlands
Correspondence to: *Renske A B Oude Nijhuis, MD, PhD
Department of Gastroenterology and Hepatology, Amsterdam UMC, PO Box 22660, 1100 DD Amsterdam, the Netherlands
Tel: +31-20-7325052, E-mail: r.a.oudenijhuis@amsterdamumc.nl
Received: January 31, 2023; Revised: April 3, 2023; Accepted: August 7, 2023; Published online: December 2, 2023
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background/Aims
It has been suggested that STW5 (Iberogast) reduces heartburn symptoms in patients with functional dyspepsia, but underlying mechanisms of action are unclear. The aim of this study is to investigate whether STW5 affects esophageal sensitivity or esophageal motility, thereby reducing occurrence and perception of reflux events.
Methods
We performed a double-blind, randomized, placebo-controlled, crossover trial in patients with functional dyspepsia (Rome IV) and reflux symptoms. After 4 weeks of treatment with either placebo or STW5, patients were studied with an esophageal acid perfusion test and ambulatory 24-hour pH-impedance monitoring.
Results
A total of 18 patients (7 men, median age 54, range [19-76]), were included in the study. Although we found no statistical difference in our primary outcome the total Reflux Disease Questionnaire score 2.33 (0.25-4.33) vs 2.67 (1.17-4.00), P = 0.347, “gastroesophageal reflux disease” and “regurgitation” subscale scores were lower after STW5 treatment compared to placebo (P = 0.049 and P = 0.007). There was no statistical difference in number of reflux events, acid exposure time and acid sensitivity scores between STW5 and placebo. In a subgroup analysis of patients with pH-metry confirmed gastroesophageal reflux disease, treatment with STW5 significantly reduced the total number of acidic reflux events (P = 0.028). Moreover, in patients with reflux esophagitis, the median lag time to acid perception increased after STW5 treatment (P = 0.042).
Conclusions
We found some indications pointing towards a beneficial effect of STW5 on reflux symptoms in dyspeptic patients, with reduction of esophageal hypersensitivity as a potential underlying mechanism. Our findings will have to be confirmed in larger studies.
Keywords: Dyspepsia; Esophageal reflux; Gastroesophageal reflux; Heartburn; Reflux esophagitis
Introduction

Dyspeptic symptoms are one of the most prevalent reasons for consultation of a general practitioner and frequently lead to referral to a gastroenterologist.1 Although dyspeptic symptoms can have organic causes such as gastric malignancies or peptic ulcer disease, in most situations, an organic cause cannot be found and the diagnosis of functional dyspepsia (FD) is made. The symptom presentation in FD differs greatly. Most patients describe epigastric pain as the predominant symptom, often associated with other complaints including epigastric fullness, nausea, bloating, or heartburn.2 The pathophysiology of FD is multifactorial; impaired gastric emptying, visceral hypersensitivity and Helicobacter pylori infection all play a role.3 As a result, targeted therapy in these patients is complex and often directed by the type of clinical symptoms. Although acid-suppressive drugs, prokinetics, H. pylori eradication and psychotropic drugs have all been shown to be effective, the effect of these therapies is only modest, and in the majority of patients, the symptoms persist.4 In line with this, FD with heartburn is often treated with a proton pump inhibitor (PPI), although its effect is limited.5 It has been suggested that the explanation for the poor therapeutic response in these patients is that pharmacological therapies only tackle one aspect of FD, whereas it is a multifactorial disorder. A post hoc analysis of a randomized controlled trial showed that STW5 (Iberogast), an herbal preparation that has proven efficiency in placebo controlled trials for functional gastrointestinal disorders such as FD and irritable bowel syndrome, effectively reduced heartburn in patients with FD.6 However, the mechanism of action of STW5 in reduction of reflux symptoms is unknown. It has been demonstrated that STW5 affects gastric motility in healthy controls and in an in vitro model7,8 which could theoretically result in a reduced number of reflux events.9 Another study showed that STW5 can decrease afferent sensitivity in the small intestine, and therefore STW5 could potentially also have an effect on esophageal visceroperception.10 Given that the effect of PPI in FD with reflux symptoms is limited and that there are few alternatives, there is a demand for new multi-target therapies in FD. Therefore, we aim to study the effect of STW5 on patients with FD and heartburn and its underlying working mechanisms, in particular its effect on reflux symptoms, incidence of reflux episodes and esophageal sensitivity.

Materials and Methods

Study Design

We performed a single-center, double-blind, randomized placebo-controlled, crossover trial in dyspeptic patients with reflux symptoms between June 2015 and April 2021 (Fig. 1). Patients were randomly assigned in a double-blind fashion in a 1:1 ratio to either 1 of the 2 treatment blocks. Randomization was conducted by the hospital trial pharmacist. One group of patients received 4 weeks of STW5 (20 drops 3 times daily), followed by a second 4-week period in which patients received placebo. The patients assigned to the other study arm, started with placebo for 4 weeks, followed by STW5 for 4 weeks. On the last day of the 4-week treatment period, patients underwent an esophageal acid perfusion test to assess esophageal sensitivity to acid. Subsequently, patients went home with an ambulatory pH-impedance recording device. Gastroesophageal reflux events and acid exposure time were monitored for 24 hours. Gastric acid suppressants or medication that potentially affected esophageal motility were discontinued 7 days before inclusion. Reflux and dyspeptic symptoms were evaluated at the end of each of the 4-week treatment periods. The study was conducted according to the principles of the Declaration of Helsinki, complied with Good Clinical Practice and the Dutch Act on Medical Research Involving Human Subjects. Written informed consent was obtained from all patients before study participation. The Clinical Research Unit of the University Medical Center monitored the study. The study was prospectively registered in the Dutch trial registry (Trial NL6113, trialregister.nl).

Figure 1. Schematic study outline.

Patient Selection

We included adult patients with a history of dyspepsia, according to the Rome IV criteria,11 who, in addition, had symptoms of heartburn. Patients were excluded if they had undergone esophageal or gastric surgery, a history of other gastroesophageal diseases including Barrett’s esophagus and gastrointestinal malignancies, or used medication with a potential effect on gastrointestinal motility, secretion or sensitivity that could not be stopped. If not previously performed within 1 year before enrolment, an upper endoscopy and abdominal ultrasonography were done to rule out other upper gastrointestinal disorders that could explain the symptoms.

Study Medication

Verum and placebo were provided by Steigerwald Arzneimittel GmbH, Bayer Consumer Health (Leverkusen, North Rhine-Westphalia, Germany) STW5 consists of hydroethanolic herbal extracts from bitter candy tuft, peppermint leaf, chamomile flower, liquorice root, Angelica root, caraway fruit, milk thistle fruit, Melissa leaf, and greater celandine herb. A placebo of similar appearance and taste was used in order to ensure that the patients were not able to discriminate between active treatment and placebo (coloring agents: yellow orange E 110, quinolone yellow E 104, and brilliant black E 151; flavoring substances: herbage aroma Sym 202848 and liquorice aroma Sym 202850). Study medication was packaged in labelled white boxes and these were stored and dispensed on a patient-named basis by the University Medical Center Trial Pharmacy conform Good Clinical Practice guidelines. In all previous clinical studies, STW5 was administered as 20 drops 3 times daily in a small amount of liquid, taken orally before or during meals. For this study, the same dosage and route of administration were applied.

Study Procedures

Esophageal manometry and acid perfusion (Bernstein) test

A water-perfused manometry catheter fitted with 7 side holes at 5-cm intervals and an additional side-hole for the acid perfusion was introduced transnasally and positioned to measure pressures from hypopharynx to stomach. Following a standardized protocol, patients were placed in supine position (20°) and received 10 boluses of 5 mL water at intervals of 20 seconds. Before and after the wet swallows, a period of 30 seconds without swallows was included for baseline measures. After an adaptation period of 15 minutes, saline was infused into the esophagus for 5 minutes, followed by infusion of 0.1 M of hydrochloric acid for a duration of 15 minutes or until the patient reported heartburn that was intense enough to induce discomfort or pain. The perfusion test was terminated before the maximum duration of 15 minutes in those who reported pain. Patients were blinded for the infused solution. Both saline and hydrochloric acid were instilled at a rate of 8 mL/min, as controlled by an automatic pump (IVAC 560 Volumetric Pump; Rhys International Ltd, Bolton, UK). Subjects were asked to report all esophageal or thoracic sensations during the acid perfusion test and to rate them on a visual analogue scale (VAS).

Ambulatory 24-hour pH-impedance monitoring

After the manometry catheter was removed, a 24-hour esophageal pH-impedance study was carried out using a combined pH-impedance catheter assembly (Unisensor AG, Attikon, Switzerland). The catheter contained 6 impedance recording segments which were located at 2-4, 4-6, 6-8, 8-10, 14-16, and 16-18 cm above the upper border of the manometrically localized lower esophageal sphincter (LES) and 1 ion-sensitive field-effect transistor pH electrode which was placed 5 cm above the upper border of the LES. The impedance and pH signals were stored on a digital data logger (Ohmega, MMS, Enschede, the Netherlands), using a sampling frequency of 50 Hz and 1 Hz, respectively. Patients were instructed to press the event marker button on the pH data logger whenever they were experiencing symptoms. During the 24-hour monitoring period, the patients consumed 3 meals and 4 beverages at fixed times and kept a diary of symptoms, meal periods and the period spent in the supine position.

Symptom questionnaires

Prior to inclusion all patients underwent a complete symptom assessment. Recorded data included duration and type of symptoms, demographics, medication use, intoxications, and medical history. Reflux and dyspeptic symptoms were assessed using the Reflux Disease Questionnaire (RDQ) and the Short Form Nepean Dyspepsia Index Questionnaire (SF-NDI)12,13 at the end of each of the 4-week treatment periods. The RDQ is a 12-item questionnaire assessing the current severity and frequency of 3 gastroesophageal reflux disease (GERD)-related symptom domains (heartburn, regurgitation, and epigastric pain). Each domain is assessed by 4 questions, all rated on a 5-point Likert scale. The mean of all 3 dimensions gives a total score ranging from 0 to 5. The specific GERD dimension is determined by the mean of the dimensions heartburn and regurgitation.

Data Analysis

Outcome measures

The predefined primary outcome of the study was the total RDQ score. Secondary outcomes included RDQ subscores, esophageal sensitivity and motility parameters, number of reflux events and acid exposure recorded during the 24-hour pH impedance study and dyspepsia symptom scores.

Manometry and Bernstein test

The time interval between the start of acid infusion to initial perception, discomfort, pain, and the maximum VAS score during acid perfusion were noted. The perfusion sensitivity score was calculated as (total acid perfusion time − lag time to discomfort) × maximum VAS.14 Esophageal motility was evaluated according to the classification of Spechler and Castell15 for conventional manometry.

Ambulatory 24-hour pH-impedance monitoring

Ambulatory 24-hour pH-impedance tracings were analyzed manually by 2 investigators independently. Gastroesophageal reflux events were detected using the impedance tracings and classified into acidic and weakly acidic reflux episodes. Total acid exposure time, defined as the percentage of time with pH < 4, was assessed in the upright and supine positions. The correlation between reflux symptoms and reflux events was analyzed using the symptom index and symptom association probability, in which a positive correlation was defined as occurrence of a symptom episode within 2 minutes from the start of a reflux event.

Statistical Methods

Sample size calculation

The sample size calculation was based on a previous study which made a post hoc analysis of patients of 3 placebo-controlled trials in which the effect of STW5 on FD was investigated using the validated gastrointestinal symptom score.6 A total of 135 patients in that report had moderate reflux symptoms, patients with severe reflux symptoms were not included. This post hoc study found a mean decrease in reflux symptom score of 1.06 in the active treatment group compared to 0.70 in the placebo group with a P < 0.001. The standard deviation calculated from this information is approximately 0.57. Using a paired 2-sided t test with a significance level of 5% and a power of 80%, the sample size required for our study was therefore 22 subjects. However, since patients with more severe reflux symptoms were not included, we estimated that this sample size is slightly overestimated since patients who have more reflux symptoms are more likely to show a larger effect of the treatment. Therefore we decided to use a standard deviation of 0.5 which resulted in a required sample size of 18 subjects.

Endpoint analysis

Descriptive statistics were presented as percentage for categorical data and as mean with standard deviation or median with range for continuous variables. Analysis was performed using the paired Student’s t test for parametric data and the Wilcoxon signed rank test for non-parametric data. The log-rank test was used to compare lag times to perception, discomfort and pain. A P-value of < 0.05 was considered significant. SPSS statistics (version 26; SPSS, Chicago, IL, USA) was used for statistical analysis.

Results

Patient Characteristics

A total of 18 patients (7 men, median age 54 [range 19-76], and body mass index of 26 [19-39]) were included in the study. Nine patients were randomized to receive placebo first, the other 9 patients received STW5 first (Fig. 2). One patient withdrew informed consent before the first day of study tests. All patients described a history of dyspepsia according to the Rome IV criteria and reported symptoms of heartburn with a median duration of 17 (2-192) months. The main patient characteristics and demographics are presented in Table 1. Upper endoscopy was performed in all patients prior to inclusion. A hiatal hernia was seen in 6 (33.3%) patients and 8 (44.4%) patients were diagnosed with reflux esophagitis; 6 patients grade A, 1 patient grade B, and in 1 patient the grade was not specified. The majority (88.9%) of patients used medication prior to inclusion to reduce reflux symptoms, PPIs being the most frequently used. Ten (55.6%) patients were classified as overweight (body mass index > 25).

Figure 2. Participant flow diagram.

Table 1 . Baseline Characteristics of Included Patients (N = 18)

Characteristicsn (%)Median (range)
Demographics
Sex
Male7 (38.9)
Female11 (61.1)
Age at inclusion (yr)54 (19-76)
BMI26 (19-39)
Reflux symptom duration (mo)17 (2-192)
Medication use prior to participation16 (88.9)
Proton pump inhibitors14 (77.8)
Histamine H2 receptor antagonist3 (16.7)
Antacids6 (33.3)
Endoscopic findings
Reflux esophagitis8 (44.4)
Grade A6 (75.0)
Grade B1 (12.5)
Not specified1 (12.5)
Hiatal hernia (not specified)6 (33.3)
Hernia and esophagitis4 (22.2)

BMI, body mass index.



Primary Outcome: Reflux Symptoms

The total RDQ score (median [interquartile range]) after 4 weeks of placebo treatment was 2.67 (1.17-4.00) versus 2.33 (0.25-4.33) after 4 weeks of STW5 treatment. This difference was not statistically significant (P = 0.347). However, there was a significant decrease in the subscales “GERD” (2.75 [0.00-3.88] vs 1.75 [0.00-4.25], P = 0.049) and “regurgitation” (2.50 [0.00-4.25] vs 1.75 [0.00-4.00], P = 0.007) when STW5 was used. The heartburn and dyspepsia subscales did not differ between the 2 treatment periods (P = 0.991 and P = 0.359), as shown in Figure 3.

Figure 3. Reflux Disease Questionnaire (RDQ) score (total and dimensions). *P < 0.05, **P < 0.01.

Secondary Outcomes

Esophageal acid perfusion test

Most patients developed symptoms during esophageal acid perfusion, both after 4 weeks of placebo treatment (88.2%), and after 4 weeks of STW5 treatment (88.2%). Although the median lag times until first perception, discomfort and pain were higher after STW5 treatment than after placebo (3, 8, and 8 minutes vs 1, 6, and 4 minutes), these differences were not statistically significant (Table 2) Maximum VAS pain scores during STW5 and placebo treatment were similar (5.7 [2.8-9.6] vs 5.7 [1.4-8.9], P = 0.201). Perfusion sensitivity scores after treatment with STW5 and after placebo were not significantly different (14.8 [0.0-107.8] vs 17.4 [0-115.2], P = 0.594).

Table 2 . Esophageal Acid Perfusion (Bernstein) Test After 4 Weeks of STW-5 and 4 Weeks of Placebo Treatment (N = 17)

PlaceboSTW5
Median (range)n (%)Median (range)n (%)P-value
Perception occurred15 (88.2)15 (88.2)
Time to perception (min)1 (0-10)3 (0-11)0.257
Discomfort occurred11 (64.7)12 (70.6)
Time to discomfort (min)6 (1-14)8 (0-14)0.398
Pain occurred2 (11.8)2 (11.8)
Time to pain (min)a4 (2-6)8 (1-15)-
Maximum VAS5.7 (1.4-8.9)5.7 (2.8-9.6)0.201
Perfusion sensitivity score14.8 (0.0-107.8)17.4 (0.0-115.2)0.594

aNot enough events to calculate P-value.

VAS, visual analogue scale.



Ambulatory 24-hour pH-impedance monitoring

The total acid exposure time after 4 weeks of STW5 was 4.0% (0.8-13.3) compared to 5.9% (0.2-19.3) after placebo treatment, however this difference was not statistically significant (P = 0.997) (Table 3). Likewise, there were no differences in the incidences of reflux episodes (total, acidic, and weakly acidic) after treatment with STW5 when compared with the incidences after placebo treatment (P-values 0.623, 0.820, and 0.777, respectively).

Table 3 . Esophageal pH-impedance and Manometry Parameters After 4 Weeks of STW5 and 4 Weeks of Placebo Treatment (N = 17)

PlaceboSTW5
Median (range)NMedian (range)NP-value
Ambulatory pH-impedance monitoring
Acid exposure time (%)
Total5.9 (0.2-19.3)4.0 (0.8-13.3)0.977
Upright5.9 (0.3-25.6)3.4 (0.0-23.2)0.638
Supine1.5 (0.0-14.7)0.2 (0.0-27.7)0.280
Total reflux episodes (n)41 (9-120)45 (5-136)0.623
Acidic reflux episodes28 (8-82)31 (4-57)0.820
Weakly acidic reflux episodes11 (0-57)9 (1-79)0.777
Reflux episodes supine2 (0-23)3 (0-37)0.615
Reflux episodes upright38 (5-97)40 (1-99)0.756
Manometry
Lower esophageal sphincter pressures (mmHg)
Basal pressure7 (0-26)9 (0-25)0.462
Relaxation pressure4 (0-10)3 (0-8)0.265
Esophageal motility parameters
Distal peristaltic wave amplitude55 (32-150)69 (19-143)0.959
Gastric pressure6 (0-23)9 (0-16)0.324
Classification of esophageal motilitya
Normal motility1516
Ineffective esophageal motility11
Diffuse esophageal spasm10

aClassification according to Spechler and Castell.15



Manometry

In 1 patient esophageal motility was classified as ineffective based on both manometries. Another patient was diagnosed with diffuse esophageal spasm with more than > 20% simultaneous contractions based on one of the 2 manometries. All other patients had normal esophageal peristalsis. As can be seen in Table 3, there were no statistically significant differences in distal wave amplitude, LES basal, and LES relaxation pressures for the 2 treatment groups.

Dyspeptic symptoms and health-related quality of life

No significant difference in health-related quality of life was seen after treatment with STW5 compared with placebo. Likewise, the SF-NDI was statistically not different after treatment with STW5 versus placebo (18 [0-30] vs 12 [4-29], P = 0.924). In line with this, no significant difference was seen in the weighted dyspepsia score when comparing placebo 1.60 (0.24-2.87) to STW5 1.78 (0.24-2.96) (P = 0.072).

Subgroup Analysis

To evaluate the effect of STW5 on patients with demonstrated reflux disease, 2 subgroup analyses were performed. First, a subgroup analysis was performed in the 8 patients with an acid exposure > 6% during the pH-impedance study after 4 weeks of placebo treatment (Supplementary Table). Secondly, the 7 patients with endoscopic reflux esophagitis were analyzed separately (Table 4). In line with the results of the total study population, no statistically significant improvement in median RDQ scores, acid exposure time, maximum VAS score and perfusion sensitivity score was observed after STW5 treatment for the 2 subgroups. However, in the subgroup of patients with a pathological acid exposure, the number of acidic reflux episodes was significantly lower from 52 (17-82) to 33 (4-57) after STW5 treatment (P = 0.028). Moreover, as displayed in Figure 4, a significant increase in median lag time until perception to acid from 1.5 (0-10) to 3 (0-11) minutes was observed in patients with reflux esophagitis (P = 0.042).

Figure 4. Median lag times until perception to acid in the total study population (N = 17), patients with esophagitis (n = 8), and patients with pathological acid exposure times, > 6% (n = 8). *P < 0.05.

Table 4 . Subgroup Analysis in Patients With Endoscopic Reflux Esophagitis (N = 8)

PlaceboSTW5
Median (range)n (%)Median (range)n (%)P-value
Primary outcome
RDQ2.58 (1.17-3.92)2.42 (0.58-4.08)0.528
pH impedance parameters
Total acid exposure time (%)8.0 (1.0-19.3)7.1 (2.2-12.9)> 0.999
Total reflux episodes (n)45 (18-92)52 (5-91)0.833
Acid reflux episodes (n)33 (17-82)37 (4-52)0.735
Weakly acidic reflux episodes (n)10 (1-13)8 (1-16)0.666
Esophageal sensitivity parameters
Time to perception (min)1 (0-10)7 (87.5)3 (0-11)8 (100.0)0.042
Time to discomfort (min)6 (3-14)6 (75.0)12 (3-13)6 (75.0)0.068
Time to pain (min)6 (6-6)1 (12.5)15 (6-15)1 (12.5)-
Perfusion sensitivity score33.4 (0.0-84.0)15.4 (0.0-115.2)0.398
Manometric parameters
Gastric pressure7 (1-14)12 (0-13)0.340
LES basal pressure (mmHg)16 (3-26)9 (0-16)0.141
LES relaxation pressure (mmHg)4 (0-10)3 (0-8)0.112
LES distal wave amplitude83 (32-150)63 (19-129)0.263

RDQ, Reflux Disease Questionnaire; LES, lower esophageal sphincter.



Adverse Events

No serious adverse events occurred during this trial. Abdominal pain (n = 1) and diarrhea (n = 1) were reported during placebo treatment. One patient reported dysphagia during placebo treatment, and 1 patient during STW5 treatment. However, symptoms resolved after treatment with antacids. During treatment with STW5 1 patient reported loss of appetite and 1 patient reported nausea which were both mild and resolved spontaneously. Transient symptoms of headache were reported by 1 patient during STW5 treatment.

Discussion

Dyspeptic symptoms are very common and patients often display a variety of gastrointestinal symptoms, including reflux symptoms such as heartburn and regurgitation. Due to a multifactorial etiology, patients with FD often respond poorly to pharmacological therapy. This randomized controlled trial studied the effect of STW5, a multi-target herbal preparation, on reflux, and reflux symptoms in dyspeptic patients, specifically focusing on its potential underlying mechanisms of action. Although we did not find a significant effect in the total RDQ score for STW5 compared to placebo, RDQ subscales “GERD” and “regurgitation” were lower after STW5 treatment compared to placebo. In a subgroup analysis of patients with pH-metry confirmed reflux disease, the number of acidic reflux events was lower after treatment with STW5 compared to placebo. Moreover, patients with reflux esophagitis became less sensitive to acid after treatment with STW5. Our findings suggest that STW5 is a safe and potentially effective add-on therapy for reflux symptoms in dyspeptic patients. Nevertheless, the mechanisms underlying these effects remain incompletely understood, as we found no statistically significant differences for acid perfusion sensitivity scores and esophageal motility after 4 weeks of STW5 treatment compared to placebo.

Although our primary endpoint, the total RDQ score, was 2.3 after 4 weeks of STW5, compared to 2.7 after 4 weeks of placebo treatment, we observed no significant difference. In line with this, the difference in total acid exposure after STW5 treatment (from 6% to 4%), was not statistically significant. Although these endpoints all seemed to improve after STW5 treatment, we were not able to objectify a statistically significant effect, which may indicate that either STW5 has no beneficial effect on reflux symptoms, or that our sample size was insufficient to show a significant difference. The finding that the RDQ subscales “GERD” and “regurgitation” were lower after STW5 treatment compared to placebo, suggest that STW5 potentially has a favorable effect on reflux symptoms. The reason for the lack of effect in our primary outcome might lie in our sample size calculation, which was based on a post hoc analysis of dyspeptic patients with heartburn, however by downsizing the standard deviation and using a power of 80%, our sample size calculation possibly was underpowered, leading to a type II error. This might also explain the lack of effect of STW5 on dyspeptic symptoms in this study; after 4 weeks of treatment with STW5 the SF-NDI dyspepsia score decreased from 18 to 12, which was not statistically significant, while several trials have reported superiority of STW5 over placebo for the relief of dyspeptic symptoms.16,17 Another factor that might have contributed was our heterogeneous study population. We included patients with FD accompanied by symptoms of heartburn, and did not use pH-metry to confirm presence of GERD prior to inclusion. Instead, we opted for a pragmatic approach and included a typical primary care population, which constitutes the largest subset of patients referred to the gastroenterologist. Nevertheless, a study population of confirmed GERD cases with a higher initial symptom and reflux burden, would probably have increased the treatment effect.

Although herbal drugs have a long history of use in the treatment of dyspeptic symptoms, their underlying working mechanisms are often incompletely understood. Previous in vitro studies have shown that STW5 has a region-specific effect on gastric motility by relaxing the proximal stomach and increasing antrum contractility.8,18,19 This region-specific effect was also described by Pilichiewicz et al,7 who studied 29 healthy volunteers and found that STW5 increased proximal gastric volume while increasing antral pressure waves. These findings may suggest a mechanistic rationale for STW5. In contrast to these studies, we specifically evaluated the effect of STW5 on esophageal motility. We observed no differences in distal wave amplitude, LES basal, and relaxation pressures, which might suggest that STW5 has no effect on esophageal motility. However, acid exposure time decreased from 6% to 4%, without a change in the total number of reflux events, which potentially suggests that acid clearance time was shorter when patients used STW5. This could implicate that reduced volume of refluxed acid, possibly a result of improved gastric emptying, and thus gastric motility, might underlie the pharmacological effect of STW5. The finding that in patients with pathological acid exposure fewer reflux events were recorded on STW5 than on placebo further supports this hypothesis. Another proposed target of STW5 is esophageal hypersensitivity. Previous experimental animal studies have found that STW5 can decrease afferent sensitivity in the small intestine, which suggests that STW5 may also have an effect on esophageal visceral perception.10 We investigated this concept by studying esophageal sensitivity to acid using the Bernstein test. The median lag times to symptom perception, discomfort, and pain were higher after treatment with STW5 compared to placebo. Although these differences were not statistically significant, it might suggest a favorable effect of STW5 on esophageal hypersensitivity. Interestingly, in the subgroup of patients with reflux esophagitis, we did find a significant decrease in acid perception after treatment with STW5. Several previous studies have shown that esophageal sensitivity to acid is increased in patients with demonstrated GERD as compared to healthy controls, which might also be the explanation for the significant effect in our subgroup analysis.20

The results of this study give some insight in the potential therapeutic targets of STW5. Our study suggests a beneficial effect of STW5 for reflux symptoms in dyspeptic patients. Based on a large body of evidence and over 60 years of experience with STW5 in clinical practice, we know that STW5 has an excellent safety profile. Likewise in our study, STW5 was well-tolerated without any relevant adverse effects. Therefore, STW5 can still be considered as an (accessible and safe) potential therapeutic option for patients with dyspepsia and reflux symptoms.

Some limitations must be acknowledged. As previously mentioned, it is likely that our study was underpowered with a too small study sample, resulting in a non-significant difference in our primary outcome (ie, type II error). Secondly, we specifically focused on esophageal motility, while gastric motility seems to be a more important therapeutic target of STW5. Gastric emptying scintigraphy would have provided more information in this regard. Nevertheless, this is the first study that assessed the effect of STW5 on esophageal motility and hypersensitivity in dyspeptic patients with concomitant reflux symptoms. Although we found some indications pointing towards a beneficial effect of STW5 in this patient group, our findings will have to be confirmed in larger studies.

In conclusion, although we found no statistical difference in our primary outcome (total RDQ score), “GERD” and “regurgitation” subscale scores did decrease after STW5 treatment compared to placebo. Moreover, STW5 was well-tolerated without relevant adverse effects. Our findings point towards a beneficial effect of STW5 on reflux symptoms in dyspeptic patients, with reduction of esophageal hypersensitivity as a potential underlying mechanism. Nevertheless, future studies should confirm our results and clarify the exact underlying mechanisms through which STW5 acts.

Supplementary Material

Note: To access the supplementary table mentioned in this article, visit the online version of Journal of Neurogastroenterology and Motility at http://www.jnmjournal.org/, and at https://doi.org/10.5056/jnm23014.

Financial support

This investigator initiated study was financially supported by Steigerwald Arzneimittelwerk GmbH, Bayer Consumer Health.

Conflicts of interest

Renske A B Oude Nijhuis, Thijs Kuipers, Jac M Oors, Boudewijn F Kessing, Jeroen M Schuitenmaker, and Andreas J P M Smout have no financial or personal competing interests. Albert J Bredenoord received research funding from Nutricia, Norgine, SST, Thelial, and Bayer and received speaker and/or consulting fees from Laborie, EsoCap, Medtronic, Dr. Falk Pharma, Calypso Biotech, Robarts, Reckett Benkiser, Regeneron, and AstraZeneca. Jac M Oors received speaker and consulting fees from Laborie.

Author contributions

Renske A B Oude Nijhuis, Boudewijn F Kessing, Thomas V K Herregods, Albert J Bredenoord, and Andreas J P M Smout played a role in planning of the study; Renske A B Oude Nijhuis, Thijs Kuipers, and Thomas V K Herregods had a role in conducting the study; Renske A B Oude Nijhuis, Thijs Kuipers, and Jac M Oors were involved in the acquisition of data; Renske A B Oude Nijhuis, Thijs Kuipers, and Albert J Bredenoord had a role in collecting and/or interpreting data; Renske A B Oude Nijhuis and Thijs Kuipers played a role in drafting the manuscript; Boudewijn F Kessing, Thomas V K Herregods, Jeroen M Schuitenmaker, Andreas J P M Smout, and Albert J Bredenoord played a role in reviewing and revising the manuscript for important intellectual content. All authors approved the final draft submitted.

References
  1. Castillo EJ, Camilleri M, Locke GR, et al. A community-based, controlled study of the epidemiology and pathophysiology of dyspepsia. Clin Gastroenterol Hepatol 2004;2:985-996.
    Pubmed CrossRef
  2. Moayyedi P, Lacy BE, Andrews CN, Enns RA, Howden CW, Vakil N. ACG and CAG clinical guideline: management of dyspepsia. Am J Gastroenterol 2017;112:988-1013.
    Pubmed CrossRef
  3. Bredenoord AJ, Chial HJ, Camilleri M, Mullan BP, Murray JA. Gastric accommodation and emptying in evaluation of patients with upper gastrointestinal symptoms. Clin Gastroenterol Hepatol 2003;1:264-272.
    Pubmed CrossRef
  4. Ford AC, Moayyedi P, Black CJ, et al. Systematic review and network meta-analysis: efficacy of drugs for functional dyspepsia. Aliment Pharmacol Ther 2021;53:8-21.
    Pubmed CrossRef
  5. Pinto-Sanchez MI, Yuan Y, Hassan A, Bercik P, Moayyedi P. Proton pump inhibitors for functional dyspepsia. Cochrane Database Syst Rev 2017;11:Cd011194.
    Pubmed KoreaMed CrossRef
  6. Madisch A, Mueller MH, Vinson BR, Weiser D. Herbal preparation STW 5 significantly improved concomitant reflux symptoms in patients with functional dyspepsia- a subgroup analysis of placebo-controlled trials. Gastroenterology 2008;134:A-422.
    CrossRef
  7. Pilichiewicz AN, Horowitz M, Russo A, et al. Effects of Iberogast on proximal gastric volume, antropyloroduodenal motility and gastric emptying in healthy men. Am J Gastroenterol 2007;102:1276-1283.
    Pubmed CrossRef
  8. Schemann M, Michel K, Zeller F, Hohenester B, Rühl A. Region-specific effects of STW 5 (Iberogast) and its components in gastric fundus, corpus and antrum. Phytomedicine 2006;13(suppl 5):90-99.
    Pubmed CrossRef
  9. Stacher G, Lenglinger J, Bergmann H, et al. Gastric emptying: a contributory factor in gastro-oesophageal reflux activity?. Gut 2000;47:661-666.
    Pubmed KoreaMed CrossRef
  10. Muller MH, Liu CY, Glatzle J, et al. STW 5 (Iberogast) reduces afferent sensitivity in the rat small intestine. Phytomedicine 2006;13(suppl 5):100-106.
    Pubmed CrossRef
  11. Aziz Q, Fass R, Gyawali CP, Miwa H, Pandolfino JE, Zerbib F. Functional esophageal disorders. Gastroenterology 2016;150:1368-1379.
    Pubmed CrossRef
  12. Shaw MJ, Talley NJ, Beebe TJ, et al. Initial validation of a diagnostic questionnaire for gastroesophageal reflux disease. Am J Gastroenterol 2001;96:52-57.
    Pubmed CrossRef
  13. Talley NJ, Verlinden M, Jones M. Validity of a new quality of life scale for functional dyspepsia: a United States multicenter trial of the Nepean Dyspepsia Index. Am J Gastroenterol 1999;94:2390-2397.
    Pubmed CrossRef
  14. Fass R, Pulliam G, Johnson C, Garewal HS, Sampliner RE. Symptom severity and oesophageal chemosensitivity to acid in older and young patients with gastro-oesophageal reflux. Age Ageing 2000;29:125-130.
    Pubmed CrossRef
  15. Spechler SJ, Castell DO. Classification of oesophageal motility abnormalities. Gut 2001;49:145-151.
    Pubmed KoreaMed CrossRef
  16. von Arnim U, Peitz U, Vinson B, Gundermann KJ, Malfertheiner P. STW 5, a phytopharmacon for patients with functional dyspepsia: results of a multicenter, placebo-controlled double-blind study. Am J Gastroenterol 2007;102:1268-1275.
    Pubmed CrossRef
  17. Melzer J, Rösch W, Reichling J, Brignoli R, Saller R. Meta-analysis: phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast). Aliment Pharmacol Ther 2004;20:1279-1287.
    Pubmed CrossRef
  18. Schemann M, Landmann M, Kelber O, Ammar RM, Krueger D, Michel K. Effects of the herbal preparation STW 5-II on in vitro muscle activity in the guinea pig stomach. Neurogastroenterol Motil 2021;33:e13984.
    Pubmed CrossRef
  19. Hohenester B, Rühl A, Kelber O, Schemann M. The herbal preparation STW5 (lberogast) has potent and region-specific effects on gastric motility. Neurogastroenterol Motil 2004;16:765-773.
    Pubmed CrossRef
  20. Weijenborg PW, Smout A, Krishnadath KK, Bergman J, Verheij J, Bredenoord AJ. Esophageal sensitivity to acid in patients with Barrett's esophagus is not related to preserved esophageal mucosal integrity. Neurogastroenterol Motil 2017;29:e13066.
    Pubmed CrossRef


This Article


Cited By Articles
  • CrossRef (0)

Author ORCID Information

Services

Social Network Service

e-submission

Archives

Aims and Scope