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General discussion 243 10 small-intestinal release peppermint oil did show statistically significant improvements in secondary outcomes of IBS symptoms that indicate clinically meaningful differences, such as IBS symptom severity, abdominal discomfort, and more relief of IBS symptoms ( chapter 7 ). The difference in efficacy rates might therefore not be at odds with prior work, but merely a consequence of reporting the rigorous and stringent outcome measures predefined by the FDA/EMA for the first time in peppermint oil research. Inclusion of our study data and thus a broader array of outcome measures in the meta- analysis subsequently led to widening of the uncertainty around the estimate of efficacy. 23,24 Future research is needed to clarify the role of these different outcome measures on efficacy results. The importance of an appropriate target population Another reason for the general low level of efficacy in IBS trials may be related to the definition of the target population. The Rome criteria recommend to include only the Rome IV-defined IBS population in clinical trials to increase standardization and increase reproducibility of study findings. We did not find any association between baseline abdominal pain and being an abdominal pain responder in our study ( chapter 7 ). Neither do we know whether inclusion of additional Rome-III positive Rome IV-negative patients with ‘milder’ IBS symptoms might have resulted in better efficacy of peppermint oil compared to inclusion of Rome IV-positive patients only. It should be noted that we included patients from both primary and secondary/tertiary care and this may have led to a higher applicability of trial results to the general population. Nevertheless, one could speculate on the outcome of efficacy of peppermint oil when a pragmatic trial in real-world setting would have been conducted. In such a trial, all patients in routine care with IBS-like symptoms and without an organic cause that have IBS according to their doctor’s opinion (without Rome IV criteria confirmation necessarily). To date, only very few pragmatic trials have been performed in IBS, e.g. one investigating the efficacy of acupuncture 25 and one investigating on-demand usage of antispasmodics. 26 Further insight into pathophysiological mechanisms underlying IBS can also aid selection of the best treatment for a specific patient. Subsequently, this may lead to more cost-effective treatment of patients with IBS. Our group previously performed a trial with probiotics selected to affect visceroperception in a subgroup of patients with visceral hypersensitivity. Unfortunately, preselection of patients did not lead to a better outcome. 27 IBS is generally considered a complex multifactorial disorder. For tailored treatment strategies, better insight in single or combined factors contributing to predominant symptoms in subgroups of patients is needed.