Zsa Zsa Weerts

Efficacy and safety of peppermint oil in IBS 143 7 Introduction Irritable bowel syndrome (IBS) is a disorder of the gut-brain axis characterized by recurrent chronic abdominal pain and altered bowel habits. 2 IBS is highly prevalent with an estimated prevalence in the general population of 5-6% according to Rome IV criteria. 3,4 IBS has a profound negative impact on quality of life and carries a substantial socioeconomic burden. 5 Although the number of therapeutic options has grown recently 6 , treatment of abdominal pain remains challenging and is often unsatisfactory. One of the pharmacotherapeutic entities currently used is peppermint oil. This agent of herbal origin has menthol as its main constituent and is presumed to have several mechanisms of action including intestinal smooth muscle relaxation 7 , modulation of transient receptor potential (TRP) channel mediated visceral nociception 8-10 , 5-hydroxytryptamine antagonism 11 , antimicrobial and antifungal effects 12-14 , and ĸ-opioid receptor agonism. 15 Enteric-coated capsules that release peppermint oil in the small intestine are currently available as an over-the-counter (OTC) drug in Europe 16 and as a medical food labeled product in the USA and Canada. 17 Guideline recommendations 18 regarding the use of (small-intestinal release) peppermint oil in IBS treatment are currently based on prior studies showing highly favorable results in terms of abdominal pain reduction and global improvement of symptoms. 17,19-23 Most of these studies, however, were hampered by significant methodological shortcomings that impede the ability to draw firm conclusions. Moreover, the Food and Drug Administration (FDA) 24 and the European Medicines Agency (EMA) 25 have defined robust, albeit provisional, endpoints for IBS trials since 2012, and the Rome diagnostic criteria for IBS have been updated in 2016. Taken together, there is a need for a well- designed trial in Rome IV-defined IBS patients that investigates efficacy according to these stringent endpoints to refute or validate earlier findings. The primary objective of this multicenter, randomized, placebo-controlled study was thus to determine the efficacy and safety of small-intestinal release peppermint oil in a Rome IV IBS population according to FDA and EMA guidelines. We hypothesized that, in Rome IV IBS patients, conventional small-intestinal release peppermint oil would be more effective compared to placebo. A secondary aim was to explore the efficacy and safety of a novel soft gel peppermint oil capsule with a predominant distal ileocolonic release. The pharmacokinetic profile of this formulation has been described recently. 1 The rationale for using ileocolonic release was based on experimental findings that peppermint oil has a direct local antinociceptive effect in the colon through an interaction of menthol with TRPM8 and/or TRPA1