Functional dyspepsia and irritable bowel syndrome (IBS) are the most frequent functional gastrointestinal disorders. In a Western population, their prevalence is estimated at approximately 10–20 % each [1]. Symptoms of both disorders may overlap, showing components of functional dyspepsia and of IBS at one time [2]. Functional gastrointestinal disorders are frequently perceived as psychological or psychosomatic disorders. They are the box to which patients are allocated, if organic disease is absent. In an attempt to find something “real”, patients may undergo unneeded diagnostic approaches [3].

Since 1987, scientists and clinicians have worked on the understanding and classification of functional gastrointestinal disorders and have developed the Rome criteria, which are now applied for diagnosis [4]. The current Rome III diagnostic criteria classify functional gastrointestinal disorders into several categories according to the regional location of symptoms, the predominant symptoms, and the age. Functional gastrointestinal disorders are currently explained by a biopsychological model, which “allows for symptoms to be both physiologically multi-determined and modifiable by sociocultural and psychosocial influences”. In this model, psychosocial factors and physiology are interlinked through the “brain-gut axis”, with the elements influenced by genetic and environmental factors (Fig. 1) [3]. The Rome III diagnostic criteria for functional dyspepsia and IBS are shown in Tables 1 and 2 [5, 6].

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The therapy for functional dyspepsia and IBS is multi-faceted and includes patient education, dietary recommendations, physical exercise, relaxation, and stress management. If such non-pharmacological measures are not successful, pharmacologic interventions like proton pump inhibitors, prokinetic drugs, antibiotics for the eradication of Helicobacter pylori, if positive, antidiarrhoics, dietary fibers, bulking agents, anticholinergic spasmolytics, tricyclic antidepressants, and herbal drugs are recommended [1, 2, 7, 8]. With the exception of herbal combination medicines, pharmacological drugs mostly treat only one symptom at a time and thus cannot address overlapping and variable complaints. In addition, side-effects with chronic treatment can be observed.

Functional gastrointestinal disorders are not life-threatening and in the strict sense of the word also not debilitating diseases. Accordingly, they are not desperate illnesses, which require desperate remedies. However, functional gastrointestinal disorders relevantly reduce the quality of life and often require chronic therapy [9]. Thus it is important not only to supply effective therapy to patients, but also to focus on the long-term tolerability.

The herbal combination preparation STW 5 (Iberogast®, Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany) has been comprehensively studied for the treatment of functional gastrointestinal disorders of the upper and lower abdomen. STW 5 contains alcoholic extracts of Iberis amara totalis recens, Angelicae radix, Cardui mariae fructus, Chelidonii herba, Liquiritiae radix, Matricariae flos, Melissae folium, Carvi fructus and Menthae piperitae folium and has been used for the therapy of functional gastrointestinal disorders for five decades. The extracts exert different proven pharmacological effects on different regions of the gastrointestinal tract and thus address the whole symptom complex of functional dyspepsia syndrome and IBS [10]. The tolerability of STW 5 was favorable both in clinical studies and in post-marketing use.

This review was performed to evaluate the available clinical data on STW 5 with a focus also on its tolerability profile.

We reviewed the following clinical studies and report information on study design, patient characteristics and efficacy and safety outcomes:

Interventional studies had been reviewed by the appropriate ethics committee and were performed in accordance with the ethical standards laid down in the Declaration of Helsinki. All patients gave their informed consent prior to their inclusion in the studies. Eleven older studies with STW 5 performed before 1990, when the first European GCP guideline was adopted, were not taken into account.

The characteristics of the studies are tabulated in Table 3. Overall, 413 patients were treated with STW 5 in randomized controlled studies, about 5,795 patients in prospective non-interventional studies, and more than 40,000 children in retrospective database surveillances.

Comparative clinical studies

Functional dyspepsia

Four clinical studies evaluated STW 5 versus placebo and one study tested the non-inferiority of STW 5 to the prokinetic drug cisapride. A panel of gastroenterological experts participated in planning the studies and developed the primary efficacy criterion, the gastrointestinal symptom score (GIS). This score is a summary score consisting of ten gastrointestinal symptoms, which are evaluated on five-point Likert scales. The GIS was validated and is sensitive, responsive, and specific for functional dyspepsia [26]. All studies had a similar design.

Von Arnim et al. [11, 27] performed a randomized, double-blind, placebo-controlled study, which included 315 patients with functional dyspepsia diagnosed according to the Rome II criteria. After a washout of 7 days, the patients were randomized to an 8 weeks treatment period with either STW 5 3 × 20 drops/day or placebo. Patients were followed up for 6 months. The primary endpoint was the change of the GIS over the treatment period. The GIS improved in both groups (see Fig. 2). After 4 and 8 weeks of treatment, the improvement was significantly higher in the STW 5 group compared to placebo and the difference between the two groups was clinically relevant. Investigators’ and patients’ global assessments confirmed the significant superiority of STW 5. On average, patients treated with STW 5 remained recurrence-free longer than patients who had received placebo. Though in the very good and good categories of tolerability assessments by patients, there was a slight imbalance in favor of placebo, the overall tolerability of STW 5 and placebo were comparable (see Fig. 3). No clinically relevant changes of laboratory or vital parameters and no serious adverse events occurred. The proportion of patients with documented adverse events was practically identical in both treatment groups. Five patients reported seven adverse events, in which a causal relationship to STW 5 could not be excluded (abdominal pain, pruritus, sore throat, alopecia, hypersensitivity, hypertension, gastrointestinal pain).

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The other three studies in patients with functional dyspepsia comparing STW 5 to placebo showed basically similar results, i.e. a statistically significant and clinically relevant superiority of STW 5 versus placebo as determined by the GIS and an almost identical proportion of patients with adverse events in both treatment groups. Adverse events at least possibly related to STW 5 reported in these studies were esophagitis, bronchitis, diarrhea, nausea, stomatitis, and abdominal pain [12, 13, 14].

One of the studies examined gastric emptying as secondary parameter with the help of the ¹³C octanoic acid breath test for the assessment of the gastric half-emptying time [14]. The findings from this study suggested that the clinical effects of STW 5 were not simply mediated by accelerating gastric emptying, but by more complex processes, reflecting the multi-faceted pharmacological profile of the drug.

The studies of STW 5 versus placebo with patients suffering from functional dyspepsia were sufficiently comparable in design to be submitted to several meta-analyses [17, 18, 19]. These meta-analyses detected a significant efficacy of STW 5. The latest and largest included 637 patients and found a standardized mean difference of − 1.1, indicating a large and clinically relevant effect (p = 0.0005), although there was statistically significant heterogeneity between studies [19].

One clinical trial compared STW 5 to the prokinetic drug cisapride 3 × 20 mg/day [15]. To ensure double-blind conditions, this study used a double dummy design. One-hundred eighty-six patients with functional dyspepsia of the dysmotility type were enrolled and received STW 5, cisapride, or a research compound for 4 weeks after a 1-week washout phase. Patients were followed up for 6 months. Like in the placebo-controlled studies, the primary endpoint was the change of the GIS during the treatment period. During treatment, the GIS decreased significantly in both groups: from comparable baseline scores of 14.3–14.5 points, the GIS decreased to 2.3 points in the STW 5 group and to 3.5 in the cisapride group, showing a numerical superiority of STW 5 and a statistically confirmed non-inferiority to cisapride (see Fig. 4). Patients, who were symptom-free after treatment, were evaluated for recurrence during the 6-month follow-up period. There were no significant differences between the groups in this parameter. A further secondary endpoint, the efficacy assessments by investigators and patients, again showed comparable results for STW 5 and cisapride. The tolerability of STW 5 was assessed as being very good or good by more than 93 % of investigators and patients; in the cisapride group, this proportion was between 81 and 91 %. More patients reported adverse events in the cisapride group (33 %) compared to the STW 5 group (21 %). Two adverse events in the STW 5 group were classified as having a probable causal relation relationship to the study medication (abdominal cramps; dizziness and nausea), whereas in the cisapride group one such adverse event was reported (diarrhea).

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IBS

One randomized, double-blind, and placebo-controlled clinical study analyzed the efficacy and safety of STW 5 in IBS [16]. As one primary efficacy endpoint, the study used an abdominal symptom score developed by a gastroenterological expert panel, which included eight IBS-specific symptoms evaluated on four-point Likert scale. Two-hundred and eight patients underwent a 1-week washout phase and were then randomized to STW 5, two research compounds, or placebo for 4 weeks. STW 5 reduced the IBS symptom score by 1.5 points more than placebo, a clinically relevant superiority that was also statistically significant (p < 0.0004). The co-primary endpoint abdominal pain, evaluated on four-point Likert scales for the four abdominal quadrants, showed comparable results and again a statistically significant superiority of STW 5 versus placebo. The tolerability as assessed by investigators was generally ‘very good’ or ‘good’ (STW 5: 98 %; placebo: 89 %), with no essential differences to patients’ assessments. There was one adverse drug reaction in the STW 5 group (constipation). No serious adverse events were reported and blood chemistry before and after treatment showed no clinically relevant variations.

On one hand, there is a widespread perception of herbal remedies as being only mild and moderately effective or not evidence based at all. On the other hand, some of the pharmacologically most active—and toxic—drugs are or have been derived from plants, among them aspirin, digitalis, colchicine, and the taxanes. Accordingly, in Europe herbal drugs have to meet regulatory requirements comparable to chemical or biopharmaceutical drugs. This means that they are required to undergo pre-clinical and clinical studies showing their safety and efficacy, before they are allowed to be sold or to remain on the markets. Under certain conditions, herbal medicines lacking a sufficiently scientific basis and evidence of efficacy may be marketed as traditionally used medicines [29]. It should furthermore be considered that efficacy is not identical to effectiveness. Roughly speaking, effectiveness describes an improvement of symptoms over time, whereas efficacy describes the course of symptoms in comparison to an active control or to a placebo group. Efficacy is thus effectiveness ‘cleaned’ of confounding effects like the natural course of the disease or placebo effects.

Treatment of functional gastrointestinal disorders remains a major challenge as pathomechanisms are complex. Thus, a multi-target approach is likely to be more successful than a drug directed to an individual target [30]. STW 5 as an herbal combination preparation with individually active components [31] has not only shown its effectiveness in improving symptoms over time in non-interventional studies as well as in retrospective database surveillances. It also passed the higher hurdle of proving its efficacy in studies versus placebo and cisapride as an active control. The efficacy observed was clinically relevant, as indicated by the effect size versus placebo as well as by an overall similar and even numerically superior effect when compared to cisapride.

The prokinetic cisapride was a standard for the treatment of functional (upper) gastrointestinal disorders before its withdrawal from most markets for safety reasons, namely, a prolongation of the QT time and resulting cardiac arrhythmia. Two other drugs of this class, domperidone and metoclopramide, have recently undergone labeling changes or are currently under review by the European Medicines Agency due to neurological and/or cardiovascular events [32, 33]. Other drugs for treating functional gastrointestinal disorders currently recommended in guidelines are proton pump inhibitors, antidiarrhoics, anticholinergic spasmolytics, tricyclic antidepressants, and herbal drugs [1, 2, 7, 8]. All possess specific tolerability issues which have to be evaluated and considered when selecting a suitable therapy for patients. Proton pump inhibitors tend to be over utilized. They have been associated with rebound acid hypersecretion, which may aggravate the symptoms of functional dyspepsia [34], whereas the compliance with spasmolytics like mebeverine, and also with tricyclic antidepressants as drugs of the last resort for functional gastrointestinal disorders, may be limited by their characteristic therapeutic profile [1, 2, 7, 8]. In addition to these safety issues, the drugs enumerated are rarely adequate for patients suffering from mixed complaints of the upper and lower gastrointestinal tract, as they address only one symptom at a time. The combination of drugs helpful for symptoms both of the upper and lower abdomen will generally further increase the side-effects the patient has to tolerate.

In several countries, STW 5 is approved as the only product both covering functional dyspepsia as well as IBS. It is furthermore included in the therapy guidelines for both upper and lower functional gastrointestinal disorders [7, 35]. STW 5 has been thoroughly evaluated for tolerability over approximately five decades. Pre-clinical and clinical studies have especially searched for signals of hepatotoxicity and abnormal liver function tests, as herbal drugs may possess hepatotoxic effects. They have shown that STW 5 has no such effects. For celandine herbs, very rare and reversible dose-dependent cases of hepatic side effects had been reported. However, the daily doses for which these hepatic side effects of celandine herbs have been described are approximately 100–200 times higher than those applied with STW 5. Furthermore, interventional and non-interventional clinical studies with STW 5 as well as database surveillances specifically assessed liver function as a safety parameter. These studies under controlled conditions found no hepatotoxicity cases associated temporally or causally with STW 5. The only adverse reactions considered attributable to STW 5 are hypersensitivity reactions as described in the summary of product characteristics. They have been observed very rarely in predisposed patients and may take the form of pruritus, dyspnea, or skin reactions. Thus, STW 5 shows the favorable tolerability profile important for a preparation used for functional gastrointestinal disorders, because the chronic nature of these diseases often requires long-term therapy.