Introduction: This systematic review summarizes published data on Menthacarin, the proprietary combination of peppermint oil and caraway oil, in the treatment of functional gastrointestinal disorders. Efficacy was assessed by meta-analysis of placebo-controlled trials. Methods: We searched PubMed, the Cochrane Library, and the manufacturer’s information system for clinical studies investigating the safety and efficacy of Menthacarin. Efficacy analyses included change from baseline of epigastric pain and general improvement of the patients’ condition. Results: Five randomized trials involving 580 patients were found, demonstrating significant effects of Menthacarin on symptoms of functional dyspepsia (FD) compared to placebo or similar effects compared to a reference drug. Seven other studies reported favorable results on therapeutic application in FD patients with concomitant Helicobacter pylori infection, in irritable bowel syndrome (IBS), and on tolerability in FD patients from 12 years of age. Three trials in FD with 249 patients were eligible for meta-analysis. Results demonstrate a significant reduction in pain intensity (standardized mean difference: 0.80; 95% confidence interval (CI): 0.39–1.21) and in item 2 of the Clinical Global Impression Scale (risk ratio: 2.65; 95% CI: 1.81–3.87) for Menthacarin. Conclusions: Menthacarin was shown to be effective and safe for the treatment of FD and represents a promising option for symptoms of IBS.

Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are neurogastrointestinal disorders also classified as disorders of the gut-brain axis (Rome IV). The “Rome IV diagnostic consensus” defines FD as postprandial distress syndrome (PDS) with postprandial fullness and early satiety as well as epigastric pain syndrome (EPS) with epigastric pain or burning. Related symptoms are nausea, bloating, and belching. IBS is characterized by abdominal pain associated with bowel movements. Subtypes of IBS comprise IBS with predominant constipation, with predominant diarrhea, with mixed bowel habits, and unclassified IBS. Thus, the diagnosis of both FD and IBS is symptom-based and largely depends on the patient’s perception [1].

In both FD and IBS, the pathophysiology comprises visceral hypersensitivity or hyperalgesia, disturbances in gastrointestinal motility or epithelial barrier function, and/or by alteration in the enteric nervous system and the central processing. It is therefore not surprising that many patients with FD have comorbid IBS or vice versa. A systematic review and meta-analysis indicated that the prevalence of IBS in subjects with dyspepsia was 37% [2]. The analysis also showed that individuals with FD had an 8-fold increased risk of having comorbid IBS compared to the population without FD. Evidence is evolving that gastric motility abnormalities and gastric hypersensitivity in FD are caused via the duodenum, possibly by low-grade eosinophilic inflammation and increased mucosal permeability or by an altered duodenal content [3]. In addition, similar to IBS, altered mucosal permeability of the duodenal mucosa in FD could be shown by confocal laser endomicroscopy [4]. The treatment of FD and IBS is largely symptomatic. In FD, eradication therapy should be offered to patients who tested positive for Helicobacter pylori (H. pylori) [5] followed by symptomatic treatment [6] with drugs such as proton pump inhibitors, histamine-2 receptor antagonists, prokinetics, spasmolytics, phytotherapeutics, or central neuromodulators [7]. Proton pump inhibitors are not authorized for long-term treatment [8]. Side effects such as those on the central nervous system hinder long-term intake of prokinetics, and the quality of evidence for their efficacy in treating FD is generally low [9]. Approaches to IBS treatment include lifestyle modification, diet interventions, probiotics, pharmacotherapy with antispasmodic and antimotility agents, laxatives in case of constipation, and psychological interventions [10]. Overall, there is a need for well-tolerated and effective preparations that are also suitable for long-term use, particularly in IBS.

A combination of peppermint oil and caraway oil is of particular interest in FD and IBS because the reported mechanistic studies suggest a synergistic as well as an additive effect of the combination against the sensation of abdominal pain and bloating by a multitarget approach [11‒16]. The German IBS guideline [17] specifically recommends peppermint oil for the treatment of pain and bloating due to its proven efficacy. Several other phytotherapeutic preparations have been shown to be effective for symptom relief and should be individually integrated into the treatment concept. Covers with hot caraway oil are also considered helpful for the global IBS complex.

Menthacarin® is a proprietary combination of peppermint oil (90 mg WS® 1340) and caraway oil (50 mg WS® 1520) with specified quality (active substance of Carmenthin® and Gaspan®, manufactured by Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany). In specimens of surgically resected human intestines, peppermint oil as well as caraway oil inhibited muscle contractility, as indicated by sustained muscle relaxation and decrease in phasic contractility. These effects occurred in small and large intestinal preparations by inhibition of L-type calcium channels [11]. Normalizing motility by reducing spasms contributes to reduced intensity or elimination of epigastric and abdominal pain. Peppermint oil activates cold receptors (TRPM8) and thereby blocks pain-mediated signals [12, 13]. Peppermint oil and caraway oil were tested separately and in combination in a model of post-inflammatory visceral hyperalgesia. The combination had a significant effect on the sensitivity to pain, whereas neither peppermint oil nor caraway oil showed any activity when administered individually [14]. Peppermint oil and caraway oil both reduce foam production in artificial gastric juice [15]. At the same time, Menthacarin exerts a potentially beneficial effect on gut flora [16]. This probably leads to a decrease in microbial gas formation and contributes to the anti-meteoric effect. The main mechanisms of action of Menthacarin are summarized in Figure 1.

Fig. 1.

Illustration of main mechanisms of action of Menthacarin.

Fig. 1.

Illustration of main mechanisms of action of Menthacarin.

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So far, no meta-analysis has been conducted exclusively on the efficacy of Menthacarin. A former meta-analysis included one study with a combination of caraway oil and menthol instead of peppermint oil [18] and another study where the product was not Menthacarin [19]. The aim of our study was to summarize published data from clinical studies on the efficacy and safety of Menthacarin in FD and IBS and to conduct a meta-analysis of randomized placebo-controlled trials in FD regarding improvement of epigastric pain and the clinical global impression of the patient.

Search Strategy and Selection Criteria

A systematic literature search was conducted in the electronic databases PubMed (www.pubmed.ncbi.nlm.nih.gov) and Cochrane library (www.cochranelibrary.com). Search terms were “peppermint oil” and “caraway oil” and publication dates up to June 2022 were covered. The manufacturer of Menthacarin was asked to provide additional references, clinical study reports, and data of eligible studies. The review was not preregistered. Inclusion criteria were all controlled and uncontrolled clinical studies in functional gastrointestinal disorders as well as secondary analyses of such studies related to both efficacy and safety. After duplicates and nonclinical studies had been excluded, the reports were screened for those meeting the inclusion criteria. For meta-analysis, eligible reports were then searched for randomized placebo-controlled trials in functional gastrointestinal disorders.

Outcome Measures

The objective of the systematic review was to quantitatively describe the knowledge base of Menthacarin regarding its therapeutic use and safety. Primary outcome measures for meta-analysis of treatment effects were the improvement of epigastric pain and the global improvement of the patients’ condition. Global improvement of the patients had to be measured by means of item 2 of the Clinical Global Impressions (CGI) Scale. This is a 7-point rating scale (from “very much improved” to “very much worse”) for the investigator to describe how the state of the patient’s illness has changed from baseline. It was shown to be a robust measure in clinical drug trials and is easy and quick to apply even in routine practice [20].

Since epigastric pain is one of the main ailments in most patients, pain intensity was an appropriate outcome criterion. As a subjective parameter, it was assessed by the patient on a visual analog scale (VAS; 0 = absent to 10 = maximum intensity) or on a 6-point scale. Together with the global improvement, these measures are clinically relevant and adequate for treatment success.

Statistics

Meta-analyses performed for continuous variables were based on the mean value difference between the treatment groups and the associated 95% confidence intervals (CI) in their original scale. In case that an outcome was assessed in all included trials, but, e.g., on different scales, the standardized mean difference was used as a summary statistic in meta-analysis. Meta-analyses of outcomes which were dichotomized were based on risk ratios (RR) and their 95% CI. Heterogeneity between the trials was assessed using the I2 statistic. For obtaining the pooled meta-analysis estimates, random effects models were applied. Review Manager (RevMan) Version 5.4 was used for all meta-analyses [21]. Treatment differences were considered descriptively significant if the 95% CI of the point estimate did not include the value of 0 for differences between means or of 1 for RR. The analyses were based on the full analysis sets (FAS; for efficacy) of the original trials. Analyses were performed separately for each indication, provided that sufficient trials could be found to conduct a meta-analysis. Study selection and methods of the analysis were specified in advance and documented accordingly.

Ethics

All trials included in this meta-analysis were reported as planned, conducted, and analyzed according to the principles of Good Clinical Practice and the Declaration of Helsinki. The trial protocols and other required trial documents were approved by the respective independent ethics committees and competent authorities. All trial participants gave their informed consent.

Study Risk of Bias Assessment

One author rated the analyzed randomized controlled trials by means of the Jadad score [22] to assess the risk of bias (Table 1). This instrument addresses bias in the three domains “randomization”, “blinding”, and “withdrawals/dropouts”. Scores can range between 0 (high risk of bias) and 5 (low risk of bias).

Table 1.

Overview of the randomized, controlled studies investigating Menthacarin in patients with FD (FAS populations, LOCF)

 Overview of the randomized, controlled studies investigating Menthacarin in patients with FD (FAS populations, LOCF)
 Overview of the randomized, controlled studies investigating Menthacarin in patients with FD (FAS populations, LOCF)

The literature search retrieved 60 records (Fig. 2). Of these, 18 duplicate records and 5 records for nonclinical trials had to be removed. The remaining 37 records were screened for compliance with the inclusion criteria, resulting in 26 publications for which full-text articles were assessed for eligibility. During full-text screening, a further 12 articles had to be excluded [19, 23‒33]. Five publications on clinical pharmacology or pharmacokinetic studies without a therapeutic approach were not taken into consideration [23‒27]. The title of one study published in Chinese contained one former brand name of Menthacarin (“Enteroplant”) [19]. However, it turned out that this publication dealt with a different preparation. It was therefore excluded from the review. One case report [28], four therapeutic recommendations [29‒32], and one systematic review [33] were excluded as well.

Fig. 2.

PRISMA 2020 flow diagram of study selection.

Fig. 2.

PRISMA 2020 flow diagram of study selection.

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Therefore, 14 eligible records could be included in the qualitative review. Seven of these were publications of randomized controlled clinical trials in FD and their follow-up treatments; seven publications reported on other studies. The flow diagram of the systematic literature search and the study selection process is shown in Figure 2.

Randomized Controlled Trials in FD

Five publications described double-blind randomized controlled clinical trials with Menthacarin including patients with FD (Table 1). The Jadad scores presented in Table 1 revealed a low risk of bias for all 5 trials. Two of them were followed by a follow-up trial phase, which was published separately, resulting in the total number of 7 publications [34‒40].

The most recent prospective, randomized, placebo-controlled multicenter trial, conducted by Rich et al. [34], investigated the effect of Menthacarin on symptom intensity and disease-specific quality of life. 114 adult patients with FD and symptoms lasting for at least 6 months were enrolled. The validated Nepean Dyspepsia Index (NDI) was applied to quantify the symptom intensity. The NDI incorporates 42 items which are each assessed on 5-point Likert scales (ranging from 1 = “not at all” to 5 = “extremely”). Thereby, quality of life can be assessed across 17 key aspects of FD. It also includes a checklist to measure the frequency (0 = “not at all” to 4 = “every day/almost every day”), intensity (0 = “not at all” to 5 = “very severe”), and bothersomeness (0 = “not at all” to 4 = “extremely”) of 15 upper gastrointestinal symptoms. The trial showed that, after 4 weeks of treatment with Menthacarin, the NDI pain score, the NDI discomfort score, and the NDI total score had improved to a significantly greater extent compared to placebo (p < 0.0001). The intensity of pain was assessed by a continuous VAS (0 = absent to 10 = maximum intensity) by the patients.

Additionally, an 8-week follow-up treatment phase of this clinical trial was published, in which the sustainability of the effects was investigated [35]. 54 out of the 114 randomized patients volunteered to participate in this follow-up. From baseline until the end of the follow-up phase, the NDI pain score was reduced by an average of 8.7 ± 4.9 points in the Menthacarin group compared to 5.1 ± 4.9 points in the placebo group (p = 0.005). During the same period, the NDI discomfort score was reduced by a mean of 3.7 ± 2.5 and 1.3 ± 2.6 points for the Menthacarin and placebo groups, respectively (p = 0.0014). In addition, during treatment with Menthacarin, the NDI total score improved considerably in comparison to placebo.

A further double-blind, randomized, placebo-controlled trial was published in 2000 by May et al. [37]. Between pre-treatment and study day 29, the average intensity of pain on a VAS (0 = absent to 10 = maximum intensity) in patients receiving Menthacarin decreased by 2.60 ± 2.44 points (mean ± SD), or 40% of the initial mean level of 6.50 ± 1.40 points for the intention-to-treat analysis. During the same period, the placebo group showed a pain intensity reduction of 1.46 ± 1.77 points, or 22% of the pretreatment level of 6.71 ± 1.13 points. A significant difference (p = 0.0003) was already achieved at the interim analysis.

At the end of treatment, 66.7% of patients in the Menthacarin group had very much or much improved versus 20.8% in the placebo group (p = 0.0001), as determined by CGI item 2 (Table 1). The sensation of pressure, heaviness, or fullness improved significantly more in patients taking Menthacarin compared to placebo (p < 0.0005).

72 of the 96 patients (only FAS analysis) included in this randomized placebo-controlled trial participated in an open-label, 11-month follow-up [38]. During this follow-up phase, all patients took Menthacarin. In both former treatment groups, symptoms improved and aligned with each other over time.

The third double-blind, placebo-controlled multicenter trial in FD was published by May et al. [36] in 1996. After 4 weeks of treatment, the intensity of pain measured on a 6-point scale ranging from 0 = no pain to 5 = extremely severe (p = 0.015) as well as the CGI item 2 (p = 0.008) significantly improved for the group of patients treated with Menthacarin compared to the placebo group (Table 1). Sensation of pressure, heaviness or fullness and flatulence significantly improved during this trial as well.

A reference-controlled trial [39] compared the efficacy of Menthacarin with cisapride in the treatment of FD. The mean reduction in the pain score during the 4-week treatment was 4.62 points with Menthacarin and 4.60 points with cisapride (Table 1). The non-inferiority of Menthacarin was demonstrated in treating pain intensity compared to cisapride (p = 0.021). After 4 weeks, 78.6% of the patients in the Menthacarin group had very much improved or much improved compared to baseline (p = 0.331) versus 70.9% of the patients in the cisapride group. Other gastrointestinal symptoms improved as well, e.g., sensation of pressure, heaviness, or fullness in 72.7% of patients or flatulence in 71.8% of patients.

Another trial [40] compared the gastro-resistant capsule with an immediate-release formulation. It demonstrated clinical equivalence in terms of pain intensity, superiority in pain frequency, as well as the CGI item 2 (Table 1). Other gastrointestinal symptoms improved as well, e.g., bloating in 80.4% of patients, feelings of pressure in 84.3% of patients, and change in stool form or frequency in between 36.3% and 49.5% of patients.

Other Studies

A prospective, pharmacy-based cohort study [41] documented Menthacarin treatment of 50 pharmacy customers (mean age 54 years) with functional gastrointestinal complaints, especially mild gastrointestinal cramps, flatulence, and/or bloating. The mean sum of 13 symptoms and their severity score from baseline and after 3 weeks of use improved from 48.6 ± 17.1 points to 22.8 ± 12.3 points (p < 0.001). The most significant improvements were seen for the symptoms most frequently reported as bothersome: abdominal pain, pressure/feeling of fullness, and flatulence. 83.3% of the study participants rated their health status as improved. The tolerability as well as the effects of taking the product were predominantly rated as very good or good by pharmacy customers and pharmacists [41].

For a pooled analysis [42], data of FD patients with concomitant typical IBS symptoms were selected from randomized clinical trials. Three studies with 376 patients were suitable for analysis [34, 36, 37]. In total, 111 patients suffered from concomitant IBS (30%) in these studies. The reduction in the concomitant IBS symptoms such as feelings of pressure, bloating, or diarrhea was approximately twice as pronounced with Menthacarin than with placebo.

In a randomized, placebo-controlled clinical trial published as a congress abstract, 200 patients with IBS took one capsule of Menthacarin or placebo twice daily for 2 months [43]. This was followed by a 1-month treatment period in which all patients received Menthacarin. Abdominal pain as well as discomfort, cramps, bloating, and fullness had improved after 4 and 8 weeks of treatment. However, due to the high heterogeneity in these patients, statistical significance could not be reached. According to the authors, particularly IBS-patients with the diarrhea subtype seemed to benefit from taking Menthacarin. The treatment over 12 weeks was shown to be safe and tolerable [43].

A 4-week, multicenter, open-label study on Menthacarin in the treatment of 2,148 patients (mean age 48.4 ± 16.1 years) with dyspeptic complaints was conducted in 448 primary care practices [44]. In the study, pain reduction occurred under Menthacarin therapy (baseline vs. week 4: postprandial, present in 53% vs. 7% of patients; recurring, 80% vs. 15%; nightly, 41% vs. 3%). This study confirmed that dyspeptic complaints are often accompanied by typical IBS symptoms such as irregular stool patterns and flatulence. Positive responses were observed for both FD and IBS symptoms (baseline vs. week 4: dyspeptic symptoms, present in 60% vs. 1% of patients; irregular stool pattern, 22% vs. 1%; flatulence, 51% vs. 1.5%). Menthacarin was tolerated very well (1,511 of 2,103 patients) or well (547 of 2,103 patients). Eight adverse events were reported in 6 patients (0.3%); two of them (increase in abdominal pain, eructation) were potentially attributable to Menthacarin [44]. From this observational study, the treatment effect in the group of adolescents (n = 55) was analyzed separately and published as a conference abstract [45]. Patients aged 12–18 years suffering from dyspeptic complaints, especially with mild gastrointestinal cramps, flatulence, and/or bloating, took the herbal drug for 4 weeks. Information was available for 51 patients. The global efficacy assessment by the physician was mostly very good (n = 33) or good (n = 16). The global assessment of tolerability by the physician was very good (n = 42) or good (n = 9).

A review on the safety and tolerability of Menthacarin in patients with functional gastrointestinal complaints included all data from clinical trials up to October 2014 [33]. Two pharmacology studies and 11 clinical trials, as well as two other studies with Menthacarin, were identified, including those in other therapeutic indications than FD. This made it possible to analyze data from a total of 3,144 patients and 58 healthy volunteers. The study population mainly consisted of patients with functional gastrointestinal disorders, and duration of treatment varied between 28 days and 3 months. Overall, Menthacarin proved to be well tolerated in all studies. No serious adverse events in association with the intake of Menthacarin occurred. In the identified 7 double-blind, placebo-controlled trials, the number and type of adverse events were similar between Menthacarin and placebo. The evaluation of clinical data in the patients treated with Menthacarin showed a slightly higher relative risk of eructation and hypersensitivity reactions of the skin in comparison to the placebo group.

About 1 fourth of the patients in the randomized placebo-controlled trial in FD [37] were diagnosed as H. pylori infected. May et al. [46] reported a post hoc subgroup analysis which was performed to investigate if the presence of H. pylori had an influence on the efficacy of Menthacarin. It was shown that the efficacy variables – intensity of gastric pain, sensation of fullness, and persistence of FD-related pain – were not affected by the H. pylori infection, and it was concluded that the H. pylori status of patients does not seem to have any effect on the response to Menthacarin therapy.

Meta-Analyses

Three of the above-described placebo-controlled trials in FD [34, 36, 37] applied homogenous outcome criteria and were thus suitable for performing a meta-analysis. The three trials involved a total of 249 patients in the FAS.

In the three trials, the intensity of pain was either assessed by continuous 6-point scale or by VAS (0 = absent to 10 = maximum intensity). Meta-analysis results showed significantly better pain reduction from baseline to week 4 for Menthacarin compared to placebo (standardized mean difference 0.80 [95% CI: 0.39–1.21]) (Fig. 3).

Fig. 3.

Random effects meta-analysis (standardized mean differences) for change in pain intensity after 4 weeks of treatment with Menthacarin compared to placebo in three randomized placebo-controlled trials [34, 36, 37].

Fig. 3.

Random effects meta-analysis (standardized mean differences) for change in pain intensity after 4 weeks of treatment with Menthacarin compared to placebo in three randomized placebo-controlled trials [34, 36, 37].

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All 3 trials measured general improvement of the patients’ condition by means of CGI item 2. Meta-analysis of the three placebo-controlled trials showed that a significantly higher number of patients had considerably improved (i.e., rated as much or very much improved) at week 4 in the Menthacarin group compared to placebo according to CGI Item 2 (RR 2.65 [95% CI: 1.81–3.87]) (Fig. 4).

Fig. 4.

Random effects meta-analysis for CGI item 2 (global improvement): number of patients rated as much or very much improved after 4 weeks of treatment with Menthacarin compared to placebo in three randomized placebo-controlled trials [34, 36, 37] (primary or secondary endpoint, respectively).

Fig. 4.

Random effects meta-analysis for CGI item 2 (global improvement): number of patients rated as much or very much improved after 4 weeks of treatment with Menthacarin compared to placebo in three randomized placebo-controlled trials [34, 36, 37] (primary or secondary endpoint, respectively).

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In the indication IBS, only one double-blind, randomized clinical trial could be found. A meta-analysis could therefore not be performed.

Our literature analysis showed that the 5 randomized controlled trials evaluating Menthacarin in FD were of satisfactory quality since they reached the maximum Jadad score. The results of the clinical studies in patients with FD deliver proof of Menthacarin’s efficacy in treating gastrointestinal symptoms and discomfort, particularly epigastric and abdominal pain, bloating and distention, flatulence, as well as feeling of fullness. The present meta-analysis is the first to be performed exclusively with placebo-controlled trials investigating Menthacarin. The results demonstrate a statistically significant reduction in pain and a statistically significant improvement of the patient’s global condition compared to placebo. It has further been shown that the combination of peppermint oil and caraway oil significantly improves quality of life in FD patients, according to the NDI [34]. Menthacarin was also shown to be safe and tolerable in FD patients from 12 years of age [33, 44, 45], FD patients with concomitant H. pylori infection [46], and in long-term treatment [38].

Menthacarin appeared to be as potent as cisapride, a gastroprokinetic drug that increases motility in the upper gastrointestinal tract by acting directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic by stimulating the release of acetylcholine in the muscarinic receptors. This reference drug was selected at the time of the study because of its proven efficacy in the treatment of FD. Due to safety concerns, however, cisapride was either withdrawn or its indications were limited in many countries in 2000. The use of other drugs like metoclopramide and domperidone was restricted for similar reasons. Herbal medicinal products, however, have multitarget effects on pathogenetic factors and may fill the resulting therapeutic gap [47].

With the publication of the Rome IV criteria in May 2016 [1], consensus emerged that functional gastrointestinal disorders were to be classified as disorders of gut-brain interactions. Treatment remains a challenge, particularly in primary care, and it focusses on the relief of symptomatic distress (primarily chronic and recurrent abdominal pain) and the improvement of the patients’ quality of life. Symptom-related therapy of FGID belong to the most important indications for phytotherapy, a statement which considers the variety of herbal medicinal products and their widespread use. Due to their favorable safety profile, herbal medicines are marketed as over-the-counter medications in most European countries. Evidence of safety and efficacy is a prerequisite for physicians to recommend or prescribe herbal products. So far, no treatment guideline exists for FD. Administering effective herbal treatments in primary care may subsequently reduce healthcare utilization. It may also help to reduce invasive diagnostic or therapeutic measures which are initiated if there is no improvement of the symptoms. In addition, herbal treatments often satisfy patients’ preferences. Thorough safety and efficacy assessments, quality control, as well as pharmacovigilance procedures are a prerequisite for the application of phytotherapeutic medicines [48]. Peppermint oil and caraway oil have a long tradition in the treatment of gastrointestinal complaints. The combination is provided as gastro-resistant capsules which dissolve in the alkaline medium of the jejunum, where the active substance is released into the bowels. It was shown to develop both local and systemic relaxing effects on the smooth muscle cells [25].

A shortcoming of our meta-analysis may be the rather low number of eligible placebo-controlled trials and patients for meta-analysis. However, the sample size of each clinical trial included had been proven to be sufficient for demonstrating the superiority of Menthacarin over placebo for the predefined primary outcome measure of the respective trials. With respect to heterogeneity, the value of I2 – as a measure for the strength of evidence for heterogeneity – was acceptable. However, due to the low number of trials in our meta-analysis, the uncertainty in the value of I2 was increased and should be interpreted with caution. In addition, looking at the magnitude and direction of effects, there is no considerable variation in the direction of effects, and all trials consistently show a more favorable outcome for the Menthacarin-treated patients.

This literature review and meta-analysis presents an overall summary of clinical data on Menthacarin. The meta-analyses performed with three placebo-controlled clinical trials demonstrate its superiority compared to placebo in terms of pain reduction and global clinical improvement. Clinical trials showed that Menthacarin has clinically relevant treatment effects on abdominal pain, bloating, and/or sensation of fullness. The favorable safety profile in short- and long-term use makes it suitable for the chronic, recurring nature of this health problem. Thus, the combination of peppermint oil and caraway oil is an efficacious, safe, and well-tolerated treatment option for functional gastrointestinal complaints and presents a valuable and well-established therapeutic option in primary care.

Medical writing services for the first manuscript draft were provided by Dr. Birgit Lüttig, Hannover, Germany.

This study is based exclusively on published literature. All trials included in this meta-analysis were reported as planned, conducted, and analyzed according to the principles of Good Clinical Practice and the Declaration of Helsinki. The trial protocols and other required trial documents were approved by the respective independent ethics committees and competent authorities. All trial participants gave their informed consent.

Ahmed Madisch, Thomas Frieling, Margrit Hollenz, Joachim Labenz, and Stephan Miehlke have received honoraria from Dr. Willmar Schwabe GmbH & Co. KG. Berenike Stracke and Andrea Zimmermann are salaried employees of Dr. Willmar Schwabe GmbH & Co. KG.

This research including medical writing services and open access funding was sponsored by Dr. Willmar Schwabe GmbH & Co. KG.

Ahmed Madisch participated in study concept and design, data interpretation, and review/revision of the manuscript for intellectual content and performed the study risk of bias assessment. Thomas Frieling, Margrit Hollenz, Joachim Labenz, and Stephan Miehlke participated in the study concept and design, data interpretation, and review/revision of the manuscript for intellectual content. Andrea Zimmermann analyzed the data and participated in study concept and design, data interpretation, and review/revision of the manuscript for intellectual content. Berenike Stracke initiated the project, participated in the study concept and design, performed the literature search, provided additional data, and participated in interpretation of data and writing of the manuscript. The first draft of the manuscript was written by a professional medical writer paid by the sponsor. All authors read and approved the manuscript to be submitted and retained the final decision on content.

Raw data cannot be shared both due to ethical reasons and to data protection laws. To the extent permitted by law, the trial data required for validation purposes have already been disclosed in result reports on corresponding databases. All relevant data are within the publication. Further inquiries can be directed to the corresponding author.

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