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Novel ileocolonic release peppermint oil 133 6 As discussed above, there are indications that peppermint oil has a direct local anti- nociceptive effect in the intestine through an interaction with transient receptor potential (TRP) channels. When peppermint oil makes contact with the skin or oral membranes, a general cooling sensation is induced through stimulation of the TRPM8 (transient receptor potential melastain 8) receptor. 42 Interestingly, experimental research in murine models suggests that L-menthol, through stimulation of the TRPM8 receptor, may be able to cross-desensitize the TRPV1 (transient receptor potential vanilloid 1) receptor. TRPV1 is a pro-nociceptive receptor, well-known for its involvement in animal models of visceral hypersensitivity and its up-regulation in the colon-mucosa of IBS patients 13,43 , indicating a role in pain generation in IBS. Together with its role in thermo-sensation, TRPM8 is believed to play a role in protective mechanisms in states of intestinal inflammation. 44 Similar to the stimulation of TRPM8, menthol may also be able to stimulate the TRPA1 (transient receptor potential ankyrin 1) receptor, another TRP channel suggested to contribute to visceral pain. TRPV1, TRPA1, and TRPM8 receptors are probably co-expressed on ileocolonic mucosal afferents 11,45 , suggesting a complex and incomprehensively understood interaction between these receptors that leads to the analgesic effect of peppermint oil. We hypothesize that the ileocolonic release of peppermint oil enhances the therapeutic efficacy as the application specifically results in increased exposure of the ileocolonic mucosal afferents described. Moreover, the anti-spasmodic effect and, thereby, alleviating effect of peppermint oil performs equally well, if not better, when peppermint oil is applied to the colon locally; it has been applied intraluminally in endoscopic practice to decrease pain caused by the procedure and to enhance the field of view during the endoscopy through the suppression of peristalsis. 46-48 This pharmacokinetic study served as proof of concept study and we are currently conducting a randomized, placebo-controlled trial in IBS patients to compare the efficacy of small-intestinal and ileocolonic release peppermint oil in IBS patients (NCT 02716285). This study should confirm whether peppermint oil capsules with an ileocolonic release do indeed attenuate abdominal pain in IBS patients. A potential limitation of this study is that L-menthol was the only ingredient of peppermint oil taken into account; other constituents of peppermint oil include menthone, cineole, menthyl acetate, isomenthone, menthofurane, limonene, pulegone, carvone, and isopulegol. 32,49 These could potentially contribute to clinical effects, but were not measured in the plasma samples. For example, in addition to the anti- spasmodic effect, peppermint oil has been shown to inhibit serotonin type 3 receptors (5HT 3 ) in the human colon. 15 This inhibitory effect could only be partly accounted for by L-menthol in another experimental study 50 , suggesting the involvement of one or more