This subgroup analysis of randomized controlled trials indicates that Menthacarin is capable to reduce concomitant IBS symptoms of FD patients. Since the IBS subgroup improved to an extent comparable to the ITT analysis dataset with its large percentage of patients suffering from FD alone, we conclude that the symptoms associated with IBS were reduced together with the improvement of FD. Considering the large degree of symptom overlap, this result is not unexpected.
With regard to the primary outcome measure for treatment efficacy, the reduction of disease-related pain, the subgroup analysis of the data reported by May and colleagues  shows that the pain reduction under Menthacarin in the IBS subset was about twice as large as in the placebo group. A similar improvement was shown for the IBS-associated symptoms flatulence, diarrhea, and feelings of pressure, heaviness, or fullness in the Menthacarin group compared to the placebo group. In the data reported by Freise and Köhler  and by Madisch and colleagues , the differences in changes of intensity of pain between Menthacarin on the one hand and the enteric-soluble formulation of the fixed peppermint oil/caraway oil combination and cisapride on the other hand were negligible in patients with IBS as in the complete ITT analysis dataset. Furthermore, for the IBS subgroups, the improvement in intensity of pain was comparable for those treated with Menthacarin in all three trials. At the same time, this improvement was similar to the improvement of the patients with FD treated by Menthacarin. The trials thus are a hint that patients with IBS may benefit from treatment with Menthacarin to the same extent as patients with FD.
Medications based on herbal substances have been used in many countries for the treatment of patients with functional gastrointestinal diseases. Caraway oil exerts cholagogic and choleretic effects , and inhibits the smooth muscle contraction . Peppermint oil as well as one of its major constituents, menthol, possess calcium antagonistic properties comparable to those of potent calcium channel blockers like verapamil, nifedipine, and diltiazem , by virtue of reducing calcium influx [23,24,25]. In addition, peppermint oil influences the transport activity of the enterocytes in the intestinal lumen by inhibiting their glucose uptake . These findings explain the relaxant effect of the drug on gastrointestinal smooth muscles, which was found in both animal and human colon [25, 27], and which may contribute to its beneficial effects in IBS. Recently, several reviews and meta-analyses have been published that support the efficacy of peppermint oil in the symptomatic treatment of IBS [28,29,30,31,32]. Compared to placebo, the largest beneficial effects of the herbal drug were observed for abdominal pain and distension, global improvement, and quality of life. These findings explain the relaxant effect of the drug on gastrointestinal smooth muscle, which was found in both animal and human colon tissue [25, 33] and which may underlie the beneficial effects of peppermint oil in IBS, notably the reduction of abdominal pain and distension, that have been confirmed by several reviews and meta-analyses [28,29,30,31,32].
In functional gastrointestinal disorders, peppermint oil and caraway oil can therefore be expected to show a synergistic effect. Indeed, Micklefield and colleagues  have demonstrated in healthy volunteers that Menthacarin causes smooth muscle relaxation in the gastroduodenal tract by decreasing the number and amplitude of contractions in the migrating motor complex.
In our analysis, the fact that the observer ratings of severity of illness in Trial C were on average less favorable in the IBS subset than in the complete ITT analysis dataset was not reflected in the patients’ self-assessment of the severity of FD-related symptoms, and may thus indicate a certain bias introduced by the small sample size of the IBS subset in this particular trial.
The efficacy of Menthacarin in functional dyspepsia (FD) was investigated in five double-blind, randomized clinical trials: four trials demonstrated that the herbal combination is more effective than placebo or as effective as the prokinetic agent cisapride in reducing FD-associated pain and other cardinal symptoms of the disease [14,15,16,17]; in another trial, enteric-coated capsules of Menthacarin were equivalent in efficacy to an immediate-release formulation of the same essential oils while showing a better tolerability .
The investigators’ diagnosis of IBS in about 30% of the patients included into Trials A through C is consistent with the observations of Talley , who noticed that one third of the patients with FD also suffer from IBS. Considering this large subgroup within FD patients, it is particularly important that the beneficial effect of Menthacarin demonstrated in the primary publications [13,14,15,16,17] applied to the “typical” IBS-associated symptoms as well.
Recent meta-analyses have shown that average placebo response rates around 40% and rates of up to 70% in individual trials have to be expected in IBS [35, 36]. With roughly 45% of the patients improved in the placebo group of May et al.  as well as in the IBS subgroup from the same trial, our findings are consistent with the published literature on therapeutic clinical trials in IBS. The data also indicate that the percentage of patients in whom FD can be expected to improve without specific, pharmacologically active treatment does not differ between patients with or without accompanying IBS. Furthermore, these findings underline the importance of a successful physician–patient relationship that is of particular relevance in diseases that may have a strong psychological or psychophysiological component.
The subgroup analysis did not indicate any treatment-emergent risks that were specific to patients with IBS. The findings of Freise and Köhler  that the enteric-coated formulation leads to fewer side effects is consistent with published literature according to which adverse reactions like heartburn and eructation occur less frequently when the ethereal oil is not released in the stomach but in the bowel [37, 38]. Since the enteric-coated and the enteric-soluble formulations were comparably effective, the enteric-coated formulation may be preferable.
In conclusion, our subgroup analysis indicates that Menthacarin may offer promising perspectives for the treatment of IBS. These encouraging results merit validation in studies specifically investigating the efficacy and tolerability of Menthacarin in IBS.