Zsa Zsa Weerts

TRP channels as therapeutic targets in IBS 93 4 Multiple small trials have evaluated the efficacy of peppermint oil in IBS. Side effects of this herbal therapy are rather mild, with heartburn being the most common. 91 One meta-analysis reported that 75% of IBS patients experience improvement in abdominal pain compared with only 27% in patients receiving placebo. 91 In a more recent trial, patients received either a sustained release peppermint oil preparation ensuring drug release in the small intestine, or a placebo. Patients receiving peppermint oil reported a significantly greater reduction in abdominal pain or discomfort compared with patients receiving placebo after a treatment duration of 28 days. 93 New preparations have been developed recently ensuring peppermint oil release in the colon, trials are ongoing and data on the efficacy of these new formulations will be reported in the near future. Downstream targets of therapy Drugs that target molecules downstream of TRPV1 provide an attractive pharmacological alternative to direct TRPV1 inhibition. As TRPV1 activation is accompanied by the release of sensory neuropeptides inducing neurogenic inflammation and sensitization of surrounding nociceptors, it makes sense to target mediators (or their respective receptors) of this process. Indeed, antagonists of the tachykinin NK1 and NK2 receptors of substance P and neurokinin A respectively, are being developed for various purposes, among others for symptom relief in IBS. For example, ibodutant, a neurokinin-2 receptor antagonist, has been shown to improve abdominal pain and stool pattern in female IBS-D patients. 94 Moreover, neurokinin-1 receptor antagonists such as aprepitant are currently being used as anti-emetics and have been suggested as analgesics as well. 95,96 Unfortunately, several pre-clinical studies demonstrated that NK1 antagonists lacked analgesic effects. 97 It should be noted that animal models studying the effects of NK1 antagonists simulated somatic pain, whereas the NK1 receptors are more relevant in visceral pain. 96 Moreover, NK1 antagonists are thought to function as anti- hyperalgesic agents rather than analgesics as they do not affect baseline nociception, but attenuate nociceptive responses sensitized through inflammation. 97 Although at first sight this does not appear favourable, inhibiting the sensitized state rather than the normal resting state may actually make NK1 antagonists excellent candidates for treating visceral pain. The most important advantage would be that physiological functions may remain unaltered. In fact, similar mechanisms likely explain the beneficial effects of the HRH1 antagonist ebastine in IBS patients, which has been discussed above. 34 As TRPV1 sensitization after histamine pre-treatment has been shown to be HRH1 mediated, the effects of ebastine on abdominal pain are thought to be related to the inhibition of the sensitized state of TRPV1.