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Addendum 256 the time to reach the maximum concentration of the menthol metabolite, menthol- glucuronide, was significantly longer for ileocolonic release compared to small-intestinal release peppermint oil, i.e. 360 versus 180 min. The lag time – time to reach a systemic concentration - was also significantly longer, i.e. 225 compared to 37 min, respectively. These results point to the likely release of peppermint oil in the more distal part of the intestine, the ileocolonic region. We then investigated both formulations of peppermint oil in the PERSUADE trial, described in chapter 7 . The primary objective of this multicenter, randomized, placebo-controlled study was to determine the efficacy of small-intestinal release peppermint oil according to FDA and EMA guidelines. Moreover, we aimed to explore efficacy of the novel ileocolonic release peppermint oil. In 189 Rome IV diagnosed IBS patients, both formulations of peppermint oil did not result in statistically significant abdominal pain reduction or global symptom relief, when using stringent FDA and EMA recommended endpoints. The small-intestinal peppermint oil did, however, show greater improvements versus placebo in secondary outcomes, i.e. abdominal discomfort, IBS severity, and moderate relief. Adverse events were mild but more common in both peppermint oil groups as compared to placebo. As our results did not show benefits of ileocolonic release peppermint oil, i.e. upper GI adverse events were indeed reduced but abdominal cramping was increased in some patients, findings did not support the further development of ileocolonic release peppermint oil for IBS. Small-intestinal release peppermint oil, however, can be considered a moderately effective treatment based on the results of our study being the largest RCT with peppermint oil to date. Ideally, treatments should not only be effective, but also cost-effective. It is known that IBS not only has a large negative impact on quality of life, but is also associated with increased direct healthcare costs ( e.g. consultations, emergency room visits) and indirect healthcare related costs ( e.g. sick leave, decreased productivity at work). In chapter 8 , we described a cost-effectiveness study of the small-intestinal release peppermint oil compared to placebo that was performed alongside the clinical RCT (PERSUADE study). The peppermint oil group had a slightly higher increase in utility scores (quality adjusted life years) than placebo during treatment. In addition, the peppermint oil group appeared to incur fewer total costs during treatment. Results of the cost-effectiveness analysis showed that peppermint oil is likely cost-effective with a probability varying between 56% and 89%, depending on the outcome measure and willingness to pay threshold used. Data analyses showed some uncertainty surrounding these results.